Myocardial protection 2004

Myocardial Protection

This book is dedicated to our wivesMichelle Ricci andHelen Salerno

MyocardialTProtectionEDITED BY

Tomas A. Salerno, MDProfessor and Chief

Division of Cardiothoracic SurgeryUniversity of MiamiJackson Memorial HospitalMiami, Florida

and

Marco Ricci, MDAssistant Professor of Surgery

Division of Cardiothoracic SurgeryStaff Surgeon, Section of Pediatric Cardiac SurgeryUniversity of Miami

Jackson Memorial HospitalMiami, Florida

BlackwellPublishing

Futura, an imprint of Blackwell Publishing

© 2004 by Futura, an imprint of Blackwell Publishing

Blackwell Publishing, Inc./Futura Division, 3 West Main Street, Elmsford, New York 10523, USABlackwell Publishing, Inc., 350 Main Street, Maiden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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0304050654321

ISBN: 1-4051-1643-9

Library of Congress Cataloging-in-Publication Data

Myocardial protection / edited by Tomas A. Salerno and MarcoRicci. — Isted.

p.; cm.Includes bibliographical references and index.ISBN 1-4051-1643-91. Heart—Surgery—Complications—Prevention. 2. Myocardium.

3. Cardiac arrest, Induced. 4. Myocardial reperfusion. 5. Re-perfusioninjury—Prevention. I. Salerno, Tomas A. II. Ricci,

Marco, M.D.[DNLM: 1. Cardiovascular Surgical Procedures—methods.

WG168M99582004]RD598.M9152004617.4'l-dc21

2003009294

A catalogue record for this title is available from the British Library

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Notice: The indications and dosages of all drugs in this book have been recommended in the

medical literature and conform to the practices of the general community. The medicationsdescribed do not necessarily have specific approval by the Food and Drug Administration for

use in the diseases and dosages for which they are recommended. The package insert for eachdrug should be consulted for use and dosage as approved by the FDA. Because standards forusage change, it is advisable to keep abreast of revised recommendations, particularly thoseconcerning new drugs.

Contents

List of Contributors, vii

Foreword, xiW. Gerard Rainer, MD

Preface, xii

1 The History of Myocardial Protection, 1Anthony L Panos, MD, MSc, FRCSC, FACS

2 The Duality of Cardiac Surgery: Mechanical andMetabolic Objective, 13Gerald D. Buckberg, MD

3 Modification of Ischemia-Reperfusion-InducedInjury by Cardioprotective Interventions, 18Ming Zhang, MD, Tamer Sallam, BS, BA, Yan-JunXu, PhD, andNaranjan S. Dhalla, PhD, MD(Hon), DSc (Hon)

4 Anesthetic Preconditioning: A New Horizon inMyocardial Protection, 33Nader D. Nader, MD, PhD, FCCP

5 Myocardial Protection During Acute MyocardialInfarction and Angioplasty, 43Alexandre C. Ferreira, MD, FACC and EduardodeMarchena, MD, FACC

6 Intermittent Aortic Cross-Clamping forMyocardial Protection, 53Fabio Biscegli Jatene, MD, PhD, Paulo M.Pego-Fernandes, MD, PhD, and AlexandreCiappina Hueb, MD

7 Intermittent Warm Blood Cardioplegia: TheBiochemical Background, 59Ganghong Tian, MD, PhD, TomasA. Salerno, MD,and Roxanne Deslauriers, PhD

8 Warm Heart Surgery, 70Hassan Tehrani, MB, BCh, Atiq Rehman, MD,Pierluca Lombardi, MD, Mohan Thanikachalam,MD, and Tomas Salerno, MD

9 Intermittent Antegrade Warm BloodCardioplegia, 75Antonio Maria Calafiore, MD, Giuseppe Vitolla,MD, and Angela laco, MD

10 Antegrade, Retrograde, or Both?, 82Frank G. Scholl, MD and Davis C. Drinkwater, MD

11 Miniplegia: Biological Basis, Surgical Techniques,and Clinical Results, 88Giuseppe D'Ancona, MD, Hratch Karamanoukian,MD, LuigiMartinelli, MD, Michael O. Sigler, MD,and TomasA. Salerno, MD

12 Substrate Enhancement in Cardioplegia, 94Shafie Fazel, MD, Marc P. Pelletier, MD, andBernard S. Goldman, MD

13 Is There a Place for On-Pump, Beating HeartCoronary Artery Bypass Grafting Surgery? ThePros and Cons, 119Simon Fortier, MD, Roland G. Demaria, MD,PhD, FETCS, and Louis P. Perrault, MD, PhD,FRCSC, FACS

14 Myocardial Protection in Beating Heart CoronaryArtery Surgery, 126Vinod H. Thourani, MD and John D. Puskas,MD, MSc

15 Beating Heart Coronary Artery Bypass Grafting:Intraoperative Strategies to Avoid MyocardialIschemia, 134Kushagra Katariya, MD, Michael O. Sigler, MDand Tomas A. Salerno, MD

16 Beating Heart Coronary Artery Bypass in Patientswith Acute Myocardial Infarction: A New Strategyto Protect the Myocardium, 144Jan F. Gummert, MD, PhD, Michael A. Borger,MD, PhD, Ardawan Rastan, MD, and Friedrich W.Mohr, MD, PhD

VI Contents

17 Beating Heart Coronary Artery Bypass withContinuous Perfusion Through the CoronarySinus, 152Harinder Singh Bedi, MCh, FIACS

18 On-Pump Beating Heart Surgery for Dilated

Cardiomyopathy and Myocardial Protection, 160Tadashi Isomura, MD and Hisayoshi Suma, MD

19 Myocardial Protection with Beta-Blockers inValvular Surgery, 167Nawwar Al Attar, FRCS, MSc, FETCS, MarcioScorsin, MD, PhD, andArrigo Lessana, MD, FETCS

20 Myocardial Protection in Minimally InvasiveValvular Surgery, 174Rene Pretre, MD and Marko I. Turina, MD

21 Intermittent Warm Blood Cardioplegia in Aortic

Valve Surgery: An Update, 181M. Saadah Suleiman, PhD, Raimondo Ascione,

MD, and Gianni D. Angelini, MD, FRCS

22 Myocardial Protection in Surgery of theAortic Root, 189Stephen Westaby, PhD, MS, FETCS

23 Myocardial Protection in Major AorticSurgery, 193Marc A. Schepens, MD, PhD and Andrea Nocchi,

MD

24 Recent Advances in Myocardial Protection forCoronary Reoperations, 196Jan T. Christenson, MA, MD, PhD, PD, FETCS and

Afksendiyos Kalangos, MD, PhD, PD, FETCS

25 Myocardial Protection During Minimally InvasiveCardiac Surgery, 203Saqib Masroor, MD, MHS and Kushagra Katariya,

MD

26 Current Concepts in Pediatric MyocardialProtection, 207Bradley S. Allen, MD

27 Myocardial Preconditioning in the ExperimentalModel: A New Strategy to Improve MyocardialProtection, 230Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD,and Hong-Ling Li, MD, MSc

28 New Concepts in Myocardial Protection in

Pediatric Cardiac Surgery, 264Bindu Bittira, MD, MSc, Dominique Shum-Tim,

MD, MSc, and Christo I. Tchervenkov, MD

29 Extracardiac Fontan: The Importance of AvoidingCardioplegic Arrest, 275Carlo F. Marcelletti, MD and Raul F. Abella,

MD

30 Preservative Cardioplegic Solutions in CardiacTransplantation: Recent Advances, 282

Romualdo J. Segurola Jr., MD and Rosemary F.

Kelly, MD

31 Myocardial Preservation in Clinical CardiacTransplantation: An Update, 292Louis B. Louis IV, MD, Xiao-Shi Qi, MD, PhD,

and Si M. Pham, MD, FACS

32 Myocardial Protection During Left VentricularAssist Device Implantation, 301Aftab R. Kherani, MD, Mehmet C. Oz, MD, and

YoshifumiNaka, MD, PhD

33 Gene Therapy for Myocardial Protection, 304Said F. Yassin, MD and Christopher G. McGregor,MD

34 Aortic and Mitral Valve Surgery on the BeatingHeart, 311Marco Ricci, MD, Pierluca Lombardi, MD, Michael

O. Sigler, MD, Giuseppe D'Ancona, MD andTomasA. Salerno, MD

Index, 321

List of Contributors

Raul F. Abel la, MDConsultant in Cardiac Surgery, Division of PediatricCardiovascular Surgery, Ospedale Civico di Palermo,Palermo, Sicily, Italy

Nawwar Al Attar, FRCS,MSc, FETCSCardiac Surgeon, Department of Cardiac Surgery,Centre Cardiologique du Nord, St. Denis, France

Bradley S. Allen, MDChief, Division of Pediatric Cardiac Surgery, University ofTexas, Houston; Memorial Hermann Children's Hospital,Houston Texas, USA

Gianni D. Angelini, MD, FRCSBristol Heart Institute, University of Bristol, Bristol,United Kingdom

Raimondo Ascione, MDBristol Heart Institute, University of Bristol, Bristol,United Kingdom

Harinder Singh Bedi, MCH, FIACSChief Cardiac Surgeon and Chairman, CardiovascularSurgery, Metro Heart Institute, Noida, New Delhi, India

Bindu Bittira, MD, MSCChief Resident, Thoracic Surgery, Division ofCardiothoracic Surgery, The Montreal General Hospital,McGill University, Montreal, Quebec, Canada

Michael A. Borger, MD, PHDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Gerald D. Buckberg, MDDivision of Thoracic and Cardiovascular Surgery,University of California, Los Angeles, Los Angeles,CA, USA

Antonio Maria Calaf iore, MDProfessor and Chief, Department of Cardiac Surgery,"G. D'Annunzio" Chieti University, Chieti, Italy

Jan T. Christenson, MA, MD, PHD,PD, FETCSChief of Clinic, Department of Surgery, Clinic forCardiovascular Surgery, University Hospital of Geneva,Geneva, Switzerland

Giuseppe D'Ancona, MDHospital San Martino Geneva, University of GenevaMedical School, Geneva, Italy

Eduardo deMarchena, MD, FACCProfessor of Medicine and Surgery, Chief, InterventionalCardiology, University of Miami School of Medicine,Miami, FL, USA

Roland G. Demaria, MD, PHD, FETCSDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

Roxanne Deslauriers, PHDDirector of Research, Institute for Biodiagnostics, NationalResearch Council, Winnipeg, Manitoba, Canada

Naranjan S. Dhalla, PHD, MD(Hon),DSc (Hon)Distinguished Professor and Director, Institute ofCardiovascular Sciences, St. Boniface General HospitalResearch Centre, Winnipeg, Manitoba, Canada

Davis C. Drinkwater, MDDepartment of Cardiothoracic Surgery, VanderbiltUniversity Medical Center, Nashville, TN, USA

Shaf ie Fazel, MDResident, Division of Cardiac Surgery, University ofToronto, Toronto, Ontario, Canada

Alexandre C. Ferreira, MD, FACCAssistant Professor of Medicine, Coordinator,Interventional Training Program, University of MiamiSchool of Medicine, Miami, FL

Simon Fortier, MDDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

VII

VIM List of Contributors

Bernard S. Goldman, MDSurgeon, Division of Cardiovascular Surgery, Sunnybrookand Women's College Health Sciences Centre, Toronto;Professor, Department of Surgery, University of Toronto,Toronto, Ontario, Canada; Editor-in-Chief, Journal ofCardiac Surgery

Jan F. Gummert, MD, PHDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Alexandre Ciappina Hueb, MDDepartment of Thoracic and Cardiovascular Surgery,Heart Institute, University of Sao Paulo, Sao Paulo,Brazil

Angela lacd, MDStaff Surgeon, Department of Cardiac Surgery, "G.D'Annunzio" Chieti University, Chieti, Italy

Tadashi Isomura, MDDirector, Cardiovascular Surgery, Hayama Heart Center,Hayama, Kanagawa, Japan

Fabio Biscegli Jatene, MD, PHDDepartment of Thoracic and Cardiovascular Surgery,Heart Institute, University of Sao Paulo, Sao Paulo, Brazil

Af ksendiyos Kalangos, MD, PHD,PD, FETCSChief of Service, Department of Surgery, Clinic forCardiovascular Surgery, University Hospital of Geneva,Geneva, Switzerland

Hratch Karamanoukian, MDCenter for Less Invasive and Robotic Heart Surgery, KaleidaHealth, Buffalo, NY, USA

Kushagra Katariya, MDDivision of Cardiothoracic Surgery, University of Miami,Jackson Memorial Hospital, Miami, FL, USA

Rosemary F. Kelly, MDAssistant Professor of Surgery, University of Minnesota,Cardiovascular and Thoracic Surgery, Minneapolis, MN,USA

Aftab R. Kherani, MDResident in General Surgery, Duke University MedicalCenter, Durham, NC; Research Fellow, Division ofCardiothoracic Surgery, Columbia University, College ofPhysicians and Surgeons, New York, NY, USA

Arrigo Lessana, MD, FETCSChief of Surgery, Department of Cardiac Surgery, CentreCardiologique du Nord, St. Denis, France

Pierluca Lombard!, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Louis B. Louis IV, MDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

Carlo F. Marcel letti, MDCardiovascular Surgeon-in-Chief, Division of PediatricCardiovascular Surgery, Ospedale Civico di Palermo,Palermo, Sicily, Italy

Luigi Martinelli, MDHospital San Martino Genova, University of GenevaMedical School, Genova, Italy

Saqib Masroor, MD, MHSDivision of Thoracic and Cardiovascular Surgery, Universityof Miami, Jackson Memorial Hospital, Miami, FL, USA

Christopher G. McGregor, MDMayo Clinic Foundation, Rochester, MN, USA

Friedrich W. Mohr, MD, PHDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Nader D. Nader, MD, PHD, FCCPAssociate Professor of Anesthesiology, Surgery, Pathology,and Anatomical Sciences, State University of New York atBuffalo; Chief, Perioperative Care and Anesthesia, UpstateVA Healthcare System, Buffalo, NY, USA

Yoshifumi Naka, MD, PHDHerbert Irving Assistant Professor of Surgery, Director,Mechanical Circulatory Support, Columbia University,College of Physicians and Surgeons, New York, NY, USA

Andrea Nocchi, MDCardiothoracic Surgeon, Department of Cardiac Surgery,Ospedale Carlo Poma, Mantova, Italy

Mehmet C. Oz, MDAssociate Professor of Surgery, Director, The CardiovascularInstitute, Columbia University, College of Physicians andSurgeons, New York, NY, USA

Anthony L. Panos, MD, MSC, FRCSC,FACSDivision of Cardiothoracic Surgery, William S. MiddletonVA Medical Center; Associate Professor, University ofWisconsin at Madison, Madison, WI, USA

Paulo M. Pego-Fernandes, MD, PHDDepartment of Thoracic and Cardiovascular Surgery, HeartInstitute, University of Sao Paulo, Sao Paulo, Brazil

List of Contributors IX

Marc P. Pel letter, MDSurgeon, Division of Cardiovascular Surgery, Sunnybrookand Women's College Health Sciences Centre, Toronto;Assistant Professor, Department of Surgery, University ofToronto, Toronto, Ontario, Canada

Louis P. Perrault, MD, PHD, FRCSC, FACSDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

Si M. Pham, MD, FACSDirector, Section of Cardiopulmonary Transplantation,Division of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL

Rene Pretre, MDCardiovascular Surgery, University Hospital Zurich, Zurich,Switzerland

John D. Puskas, MD, MSCAssociate Professor of Surgery, Carlyle Fraser Heart Center,Division of Cardiothoracic Surgery, Department of Surgery,Emory University School of Medicine, Atlanta, GA, USA

Xiao-Shi Qi, MD, PHDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

W. Gerard Rainer, MDDistinguished Clinical Professor of Surgery, University ofColorado Health Sciences Center; Past President andHistorian, Society of Thoracic Surgeons

Ardawan Rastan, MDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Atiq Rehman, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Marco Ricci, MDAssistant Professor of Surgery, Division of CardiothoracicSurgery, University of Miami, Jackson Memorial Hospital,Miami, FL, USA

Eliot R. Rosenkranz, MDDirector, Section of Pediatric Cardiac Surgery, AssociateProfessor of Surgery, University of Miami, JacksonMemorial Hospital, Miami, FL, USA

Tomas A. Salerno, MDProfessor and Chief, Division of Cardiothoracic SurgeryUniversity of Miami, Jackson Memorial Hospital,Miami, FL, USA

Tamer Sal lam, BS, BAResearch Fellow, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

Marc A. Schepens, MD, PHDDepartment of Cardiothoracic Surgery, St. AntoniusHospital, Nieuwegein, The Netherlands

Frank G. Scholl, MDDepartment of Cardiothoracic Surgery, VanderbiltUniversity Medical Center, Nashville, TN, USA

Marcio Scorsin, MD, PHDCardiac Surgeon, Department of Cardiac Surgery, CentreCardiologique du Nord, St. Denis, France

Romualdo J. Segurola Jr., MDCardiovascular and Thoracic Surgery, University ofMinnesota, Minneapolis, MN, USA

Michael O. Sigler, MDDepartment of Surgery, University of Miami, JacksonMemorial Hospital, Miami, FL, USA

Dominique Shum-Tim, MD, MSCStaff Surgeon, The Montreal Children's Hospital; StaffSurgeon, The Montreal General Hospital; AssistantProfessor of Surgery, McGill University, Montreal, Quebec,Canada

M. Saadah Suleiman, PHDBristol Heart Institute, University of Bristol, Bristol, UnitedKingdom

Hisayoshi Suma, MDHonored Director, Cardiovascular Surgery, Hayama HeartCenter, Hayama, Kanagawa, Japan

Christo I. Tchervenkov, MDDirector, Cardiovascular Surgery, The Montreal Children'sHospital, Montreal, Quebec, Canada

Hassan Tehrani, MB, BCHFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Mohan Thanikachalam, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Vinod H. Thourani, MDResident in Cardiothoracic Surgery, Carlyle Fraser HeartCenter, Division of Cardiothoracic Surgery, Department ofSurgery, Emory University School of Medicine, Atlanta, GA,USA

List of Contributors

Ganghong Tian, MD, PHDAssociate Research Officer, Institute for Biodiagnostics,National Research Council, Winnipeg, Manitoba, Canada

Marko I. Turina, MDCardiovascular Surgery, University Hospital Zurich, Zurich,Switzerland

Giuseppe Vitolla, MDStaff Surgeon, Department of Cardiac Surgery,"G. D'Annunzio" Chieti University, Chieti, Italy

Stephen Westaby, PHD, MS, FETCSOxford Heart Centre, John Radcliffe Hospital, Oxford,United Kingdom

Yan-Jun Xu, PHDResearch Scientist, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

Said F. Yassin, MDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

Ming Zhang, MDResearch Fellow, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

Foreword

When open heart surgery became a possibility one-half century ago, it seems that considerable atten-tion was directed toward protection of the body as awhole (perhaps it was assumed that this would takecare of the needs of the heart as well). Hypothermia,

partial perfusion, intermittent aortic cross-clampingand a variety of other techniques were thought tosuffice until careful observers noted occurrence ofsuch events as "stone heart," subendocardial ischemia,and other manifestations of inadequate myocardialprotection. This dramatically demonstrated that theheart could not be treated as just any other organ orpart of the body. Its function is so different because ofits intricate neuromuscular structure that investiga-tions were begun (and continue until the present) todefine the cellular metabolic needs of the heart and todevelop ways to meet those needs so that, hopefully,minimal cardiac function will be lost following correc-tion of the underlying abnormality.

Salerno and Ricci have admirably filled a neededniche by pulling together various approaches andmodalities for myocardial protection applicable tomany different scenarios—the chapter titles speak forthemselves in exhibiting the array of situations dis-cussed in detail along with au courant data regardingvarious methods of protection based upon pioneer-ing investigations by contributors such as Kirklin,Buckberg, and others.

This volume is an absolute necessity for cardiac sur-geons in training and in practice and is so designed tobe an invaluable teaching tool and reference into the

foreseeable future.

W. Gerard Rainer, MD

Distinguished Clinical Professor of Surgery

University of Colorado Health Sciences CenterPast President and Historian, Society

of Thoracic Surgeons

XI

Preface

Cardiac surgery has undergone major changes in therecent past. With changes came new knowledge, tech-nology and progress, all aimed at providing bettercare to our patients. Fundamentally, however, cardiacsurgery "is myocardial protection," the realizationthat no matter how perfect the reparative surgery,myocardial function has to be preserved for a shortand long-term successful outcome. The pace of tech-nological advancements has accelerated over the lastfive years, allowing surgeons to perform cardiac surgerydifferently and more comfortably. For each proced-ure, there is the need for different technology, such asdevices, valves, suture materials, stabilizers, shunts,blowers, and others. One factor, however, has remainedconstant, i.e. the need for individualization for aspecific method of myocardial protection tailored toeach operation.

It is in this spirit that the editors of this book felt the

need to put together a collection of manuscripts writ-ten by experts in the different fields of myocardial pro-tection. The idea is to give the reader an up-to-dateview of how myocardial protective strategies are beingutilized by surgeons performing different procedures.Although it was recognized that the past plays a majorrole in current methods of myocardial protection, thebook was intentionally aimed at the present and thefuture.

The editors are grateful to all the authors andco-authors who wrote this modern book. Their taskswere time consuming, aside from their daily work asclinicians and scientists. It is a tribute to them that thepublishers were able to print a textbook that is up todate with current knowledge regarding myocardialprotection.

TomasA. Salerno, MDMarco Ricci, MD

XII

CHAPTER 1

The history of myocardialprotection

Anthony L Panos, MD, MSC, FRCSC, FAGS

Introduction

The history of myocardial protection is a rich andvaried story that encompasses the work of basic scient-ists and clinicians working in different countries overmany years. It is an excellent example of clinical prob-lems stimulating basic research and then translatingthat knowledge back "from the bench to the bedside."Many surgeons are aware of the famous quotation bythe great 19th century surgeon Theodore Billroth, that"any surgeon who operates upon the heart, shouldlose the respect of his colleagues." At the time thatBillroth made that statement, cardiac surgery wasindeed very hazardous because knowledge and tech-niques were not available to make it safe. The ensuingyears saw a growth in knowledge and new technologythat led to the development of modern cardiac surgeryas we currently practice it.

Myocardial protection was a key part of thesedevelopments that allowed safe cardiac surgery tobe performed. The term myocardial protection en-compasses more than just cardioplegia, and can besaid to include things such as the perioperative man-agement of patients with medical treatment (suchas beta-blockers, etc.), or support devices (such asintraaortic balloon pumps), better anesthetic agents,and better hemodynamic management. All of thesetreatments contribute to making cardiac surgerysafer, and to get a sick patient through a major opera-tion. However, for the purposes of our discussion wewill focus more on the development of cardioplegia.This is a very large field of research and has beenreviewed in several books [1-5] and review articles[6]. In one chapter we will only be able to go oversome of the important highlights, and give a general

outline of the work that has brought us to where weare today.

Early cardiac physiology

The whole of biologic and medical sciences floweredat the end of the 19th century, as exemplified by themicrobiologic discoveries of Pasteur, Koch's postul-ates, and Claude Bernard's emphasis on homeostasisas a principle, to maintain the "internal milieu" [7].There were also great advances in physiology, espe-cially cardiac physiology and the understanding ofmuscle mechanics by Otto Frank [8-10], and Starling[11].

The pioneering work of Sydney Ringer on theeffects of electrolytes on the regulation of the heartbeat [12-15] is summarized by Toledo-Pereyra [16].Physiologists in the late 19th century thought aboutcontrol of cardiac function in terms of myogenic ver-sus neurogenic theories. It was in this atmosphere thatRinger conducted his elegant experiments and showedthe effects of various ions on the heartbeat. Ringer'swork was initally not appreciated in Europe, but wasfollowed by American physiologists, who extended it[17-21]. As early as 1935, Zwikster and Boyd hadshown that the heart could be reversibly arrested usingpotassium [22]. However, surgeons did not appreciatethis physiological research, and the clinical applica-tion of this knowledge would occur 20 years later.

Cardiovascular physiology continued to expandthrough the early years of the 20th century, but wascarried on largely by zoologists, and physiologistsworking on problems of basic science. For example,there were studies of the thebesian vein system thatwould later become especially important to the

CHAPTER 1

technique of retrograde cardioplegia [23-31]. Othersstudied the electrophysiology [21,32] of the heart,the physiology of coronary blood flow [33-38], myo-cardial energetics [31,39-41], and the relationshipsbetween coronary blood flow and cardiac mechanics[42-44]. All of this important basic science work wascrucial to later clinical applications.

Early operations—closed

Surgeons returned from the second world war afterexposure to military surgery, and had developed aninterest in the treatment of traumatic chest wounds[45]. This renewed interest in cardiac surgery led to agreat expansion of the specialty in the 1950s. Cardiacsurgery developed later than other surgical specialties,largely due to the technical difficulties of operating onthe heart. The surgeon could not support the circula-tion while working on the heart, and this limited thekinds of surgery that could be done upon the heart. Asa result, the early operations for cardiac disease con-sisted mostly of extracardiac procedures, such as theligation of a patent ductus arteriosus by Gross andHubbard [46], and the revolutionary work of Blalockand Taussig to create palliative shunts for the treat-ment of cyanotic congenital heart disease [47].

There were other early attempts to operate onthe surface of the heart. These operations includedmethods to treat ischemic heart disease by increas-ing the blood flow to the myocardium by creatingnoncoronary collateral blood supply to the heart.Pericardial adhesions were created, for example, bymeans of pericardial irritation, or by covering theheart with omentum after epicardial and pericardialabrasion [48-50]. Some investigators studied theeffects of coronary sinus ligation in animal modelsin an effort to impede venous outflow and therebyimprove coronary artery perfusion of myocardium[27-29,51]. Dr Claude Beck developed an operationto "revascularize" the heart using the cardiac venoussystem [48-50]. The Beck operation created a venousbypass to the epicardial veins of the heart and sub-sequent ligation of the coronary sinus [52-56]. It isremarkable how much Beck achieved with the limitedtechnology available to him, and how prescient hiswork was, predicting that surgery would becomeimportant in the treatment of angina pectoris.

There were also some closed operations performed,such as mitral commissurotomy for the treatment

of mitral valve stenosis [57-59] or pulmonary valvestenosis [60]. There were a variety of ingenious opera-tions done through artificial "wells," for example, toallow closure of an atrial septal defect "underwater"[61].

All of these operations reflected the limits of thetechnology of their time. Most were very ingenious,and in many ways ahead of their time. However, in thefinal analysis they all required the ability to supportthe circulation to make the breakthroughs that theywere seeking.

Early operations—open

Experimental work using inflow occlusion to allowwork within the heart (i.e. "open" operations) foundthat brain injury occurred when the cerebral bloodflow was interrupted. The irreversible brain injuryoccurred with interruptions of about 4 min duration.Bigelow first proposed the use of hypothermia dur-ing cardiac surgery in 1950 [62]. This led Bigelow,Swan, Boerema, and others to investigate the useof hypothermia in cardiac surgery [39,62-71]. Thislaboratory work was then taken into the clinical worldand the first intracardiac repairs using systemichypothermia were reported [67,69,70,72]. However,it is important to note that in these early papers theoriginal intention for the use of hypothermia was toprotect primarily the brain, and not the heart.

In 1950 Bigelow found that in experimental modelsthe total body oxygen consumption decreased withtemperature, and this included myocardial metabol-ism [62,63]. This data was later expanded and becamethe rationale for the use of hypothermia as a techniqueto protect the heart.

The crucial technology of artificial circulatory sup-port was developed, principally by the perseverance ofDr John Gibbon [73-75]. The "heart-lung machine"of Gibbon could support the circulation, and thisdevelopment really allowed cardiac surgery to be done[76]. Surgeons could at last safely support the patient'scirculation while working within the heart. However,in order to provide the body's oxygen requirements,high flow rates were needed. This was initially a dif-ficult problem, and stressed the available technologyof early oxygenators. Investigators reassessed Bigelow'searlier findings for total body oxygen consumptionand temperature dependence. They found that byadding hypothermia, the total body requirements for

History of myocardial protection

oxygen were greatly decreased in patients. Therefore,the total flow rates needed to provide the body'soxygen requirements could also be decreased greatly.

Cardioplegia

The first use of "elective cardiac arrest" was by Melrosein 1955, who also coined the term "cardioplegia" forthe technique [77]. Melrose used a solution con-taining potassium to remove the transmembraneelectrical potential and hence to stop the cardiac im-pulse and arrest the heart in diastole. However, onceagain, the paper by Melrose makes it clear that hisinitial impetus to devise the technique was to reducethe foaming that occurred with the cardiopulmonarymachines he was using, in order to reduce air emboli,and not to protect the heart.

Also, during the 1950s there was the first use ofalternate routes of cardioplegia administration andvarious temperatures [78-80]. Gott et al. used retro-grade perfusion of the heart via the coronary sinususing warm blood with Melrose solution, both experi-mentally and clinically [78,79]. Lillehei's group alsoused retrograde perfusion of the coronary sinus withblood during aortic valve surgery [80].

Gradually as experience with the technique increased[81], the long-term effects of Melrose solution becameknown. Surgeons found that there was late vascularand myocardial injury in these patients [82-88]. As aresult, surgeons abandoned the technique.

Some surgeons used direct ostial cannulation of thecoronary ostia in order to perfuse the heart duringsurgery. However, reports of ostial stenoses discour-aged most surgeons from using this technique [89,90].

In the late 1950s and early 1960s Shumwayand Lower reported their work using hypothermicmethods to protect the heart [91]. The use ofhypothermia became widespread, and combined withintermittent ischemia became the dominant methodof myocardial management during cardiac surgery inthe USA during the 1960s. Despite the problems withMelrose solution, some surgeons in Europe continuedto use and develop cardioplegia [92]. Bretschneiderand others continued to develop the methods of car-dioplegia based on an "intracellular" electrolyte solu-tion, which reduced transmembrane gradients, andarrested the heart [93-95]. Others, such as Hoelscher,studied the effects of magnesium-procainamideas compared to potassium citrate cardioplegia, and

found that there was no ultrastructural damagewith the magnesium-procainamide method [96,97].Bretschneider also developed the idea of buffering ofthe cardioplegic solution as an important principle ofmyocardial protection [92,94]. This continuing workon cardioplegia in Europe was important to the even-tual resurgence of interest in America in the 1970s.

Reassessment of myocardialdamage

In the 1960s surgeons reviewing the complicationsof cardiac surgery did not consider that the complica-tions were due to the surgery itself. Slowly data accu-mulated that questioned this prevailing concept. In1967, Taber's group reported that there was myocar-dial necrosis following cardiac surgery [98]. He foundthat patchy necrosis affected as much as 30% of themyocardium. In a paper by Najafi's group, the authorsfound that there was subendocardial necrosis seen inpatients who underwent valve surgery, with normalcoronary arteries [99]. In the setting of double valveoperations Cooley et al. first described the conditionof "stone heart" [100]. This was seen when theischemic time was prolonged, and the hearts wentinto a state of ischemic contracture.

Other investigators also found that patients under-going valve surgery, who had otherwise normal coron-ary arteries, had perioperative myocardial infarction[101,102]. Storstein et al. studied the mechanismsof these infarctions [103]. In other studies, patientsundergoing atrial septal defect repair had enzymeevidence of myocardial infarction [104]. This gradu-ally led surgeons to once again question whether theintraoperative myocardial protection was effectivelyprotecting the heart, and whether they could improvetheir techniques.

Reintroduction of cardioplegiaSome investigators, such as Tyers, identified theproblems with Melrose solution as toxicity due toinappropriately high ionic concentrations, rather thandue to the idea of electromechanical arrest in andof itself [105,106]. In 1973 Gay and Ebert pioneeredthe reintroduction of cardioplegia using crystalloidsolutions with much lower concentrations of KC1,which were just sufficient to give electromechanicalarrest [107]. In 1974 Hearse's group reported theirexperimental work with a potassium chloride solution

CHAPTER 1

[108]. In 1976 another paper extended this work[109]. These experimental papers led to the develop-ment of cardioplegic solutions for clinical use, such asthe St Thomas' solution [108-112], which was firstused clinically in 1976 [ 110].

A great deal of work ensued on the various com-ponents of cardioplegia solutions, on what should beincluded in the solutions, and in what concentrations.Many papers were written on the proper use and con-centrations of buffers, Mg2+, Ca2+, acid-base balance,local anesthetics, and even oxygen.

Some investigators wanted to deliver oxygen duringthe arrest period and introduced oxygen into the car-dioplegia solutions to "oxygenate" them [113,114].There was even interest in the use of artificial solutionssuch as fluorocarbons for cardioplegia because of theiroxygen-carrying capacity [115-118].

Blood cardioplegia

The interest in delivering oxygen and buffering thecardioplegia solution led investigators to questionwhether the best buffer and oxygen-carrying could beachieved by blood itself. Dr Gerald Buckberg's groupworking at UCLA did a large amount of experimentalwork that led to the development of blood cardio-plegia in the late 1970s [119]. Other surgeons werealso interested in the technique [120-122], its usespread, and it became widely adopted as a cardioplegicmethod during the 1980s.

Nevertheless, there are many proponents ofcrystalloid cardioplegia [113,114,123], and othermethods of myocardial protection such as fibrillatoryarrest [124,125], who continue to use their methodswith good results.

Dr Buckberg's group continued to work onmyocardial protection and developed several veryimportant techniques. Their work asked whether wecould use cardioplegia not merely to prevent damage,but also to act as a form of treatment, and to reverseinjury to the myocardium.

They reported the use of warm blood cardioplegiagiven to induce cardiac arrest and replenish high-energy phosphates in energy-depleted hearts beforegiving cold cardioplegia [126]. This is important inchronically ill patients, and also those suffering fromacute ischemia [127].

This led to investigations altering the conditionsof reperfusion (pressure, temperature, etc.) at theend of the arrest period. The use of terminal warm

cardioplegia, the so-called terminal "hot-shot," wasconfirmed experimentally [128] and clinically [129] tobe advantageous to myocardial metabolism.

Buckberg's group also investigated the use of aminoacids in the cardioplegia to provide substrates forKreb's cycle [ 130]. This method of substrate enhance-ment has been shown to be beneficial clinically, reduc-ing the need for inotropic support or the use of theintraaortic balloon pump [131-133]. This work alsoled to the development of "secondary" blood cardio-plegia to resuscitate poorly functioning injured heartsat the end of the operation with a further period ofwarm cardioplegic arrest [ 134,135].

Continuous cardioplegia

Salerno's group at the University of Toronto wasinterested in myocardial protection, both experiment-ally and clinically. They questioned whether surgeonscould avoid ischemia altogether [136]. Several investi-gators had used continuous cold blood cardioplegia,in patients undergoing valve surgery [137], in acutepostinfarction mitral regurgitation [138], and inpatients with ventricular hypertrophy [139].

The use of continuous blood cardioplegia was donein an effort to provide oxygen and substrate through-out the operation. This eventually led to questionsabout the ability to deliver oxygen at lower tempera-tures. It was well known that the oxygen-hemoglobindissociation curve was shifted to the right by hypo-thermia, and interfered with unloading of oxygen atthe cellular level. The question was "Did we needhypothermia"? If we used a warm induction dose ofcardioplegia, cold in the middle, and a "hot-shot" atthe end, did we really need the cold in the middle? Alihas summarized the theoretical background andrationale of the technique [ 140,141 ].

After Salerno reintroduced the use of continu-ous normothermic blood cardioplegia [142], initialexperimental [143] and clinical [144-146] work led torenewed interest in the technique. It led to the devel-opment of new technology in order to use the tech-nique to advantage. Visualization could be difficult, soa variety of "blowers" were developed to aid the sur-geon [147,148]. Some investigators developed the useof equipment to monitor the adequacy of perfusionduring the operation. Other groups explored thephysiological limits of the technique. Could the flowbe interrupted, and if so, for how long? This was stud-ied experimentally [149,150] and clinically [151-154].


There was initially some concern about the issueof neurologic protection [155]. However, other in-vestigators found that the neurologic threat was notseen in their studies [156-160]. A great deal of workensued concerning the use of normothermic tech-niques. This was summarized in a monograph [5].After the initial flush of enthusiasm, the technique hasfound its niche, and shown that myocardial protectioncan be achieved with methods other than hypother-mia, which had become so deeply entrenched.

Retrograde cardioplegia

There was a resurgence of interest in coronary sinusretroperfusion of the heart in the early 1980s, led byGundry, Chitwood, Menasche, Fabiani, Carpentier,Fuentes, and Chiu, among others. Coronary sinus per-fusion was used initially with crystalloid cardioplegia,and then with blood cardioplegia, and both were used"cold." However, the need to deliver cardioplegia ina near continuous fashion for the normothermictechniques of warm heart surgery led some surgeonsto reexamine the retrograde route of administration[161,162]. It had been used by surgeons sporadic-ally over the years [163—169], but became much morewide-spread after the upsurge in interest in normo-thermic techniques.

Thebesius first described the anatomy of the coro-nary veins in 1708 [170], and this was studied furtherby Abernathy in 1798 and Langer in 1880. This led tothe work by Pratt in 1898, in which the feline heartwas supported with retrograde perfusion alone forup to 1 h [23]. In 1928 Wearn showed that coronaryveins communicate with thebesian veins [24-26], andin 1929 Grant found that effluent drained into bothventricles. Katz showed great variability in venousanatomy in 1938 [38]. In the same year, Gregg showedthat there was increased backflow through the coron-ary arteries when the coronary sinus was ligated [27].In 1943 Roberts performed dye injection of the coron-ary sinus, and found filling of the coronary arteries[171,172]. This suggested that the heart could benourished via retrograde perfusion, and maybe usefulin the treatment of myocardial ischemia.

Dr Claude Beck tested these hypotheses in 1945.Beck was an early proponent of coronary sinus inter-vention [48,52-55,173-175]. He found a decreasein the size of an experimental myocardial infarctionwith ligation of the coronary veins to that area. Thisled to the "Beck operation," in which a bypass was

performed from the aorta to the coronary sinus. Thiswas modified by the ligation of the coronary sinusto facilitate retroperfusion of the myocardium (theBeck II operation). By 1954 Beck had performed theoperation on 43 patients and symptoms of anginawere improved in 88% [176]. However, it was adifficult operation to perform using the technologythen available. The difficulty of the operation, earlysurgical failures, and deaths led to the abandonmentof the procedure.

In 1956 the pioneering work in cardiac surgeryfrom the University of Minnesota extended to theinvestigation of cardiac perfusion and cardioplegia.Gott and Lillehei first used retrograde continuousnormothermic blood cardioplegia in a dog model[78] using potassium citrate blood cardioplegia asdescribed by Melrose. They also went on to use thetechnique clinically in valve surgery [79,80]. However,as outlined above, other technical developmentssuperceded this technique.

Work continued on retroperfusion in experimentalmodels. In 1967 Hammond et al. found that retro-perfusion provided some myocardial protection dur-ing coronary artery ligation in dogs [177]. In 1973Lolley et al. found that retroperfusion with substrateenhancement gave better protection during nor-mothermic ischemic arrest [178]. The technique ofretroperfusion of the heart was picked up again clinic-ally in the following decade.

There were several studies done to assess theadequacy of retrograde coronary sinus perfusion forprotection of the heart, and it was especially importantwith the normothermic blood cardioplegia techniquebecause of the question of right ventricle protection[163,179-182]. Most surgeons today have had someexperience with the retrograde route of cardioplegiaadministration, and many would advocate its usein redo surgery or valvular surgery. Some surgeons,such as Buckberg and Salerno, have also advocated theuse of simultaneous antegrade and retrograde deliveryof cardioplegia to better perfuse all capillary beds[181,183-185].

Other subgroups of patients

The growth of cardiac surgery led investigators to tryto improve myocardial protection in various sub-groups of patients. In particular, some subgroupshave a higher mortality rate, such as patients at theextremes of age, both the very young and the very old.

CHAPTER 1

There has been research in optimizing the methods ofmyocardial protection in these more extreme groups.

Patients undergoing the repair of congenital heartdefects often have multiple abnormalities, not justcardiac ones. In addition, there is some evidence thatthe myocardium of these patients may be differentfrom normal on a cellular level. Pediatric heart sur-geons have carried out work to improve the protectionof the heart during repair of congenital lesions inimmature and newborn children [186-196].

The population in western countries is increas-ingly aging. Cardiac surgeons are operating on olderpatients, with more comorbidities. This group ofpatients also poses special challenges for myocardialprotection. Several investigators have studied thechanges associated with aging, and the effects onmyocardial protection [197-201]. The "senescent"myocardium changes as it ages, and several studiessuggest we may get better myocardial protection inthis age group by altering the cardioplegia ingredients,or by changing our strategy.

There was also an enthusiasm for alternativemethods of achieving cardiac arrest that use potassiumchannel "openers" to remove the transmembranepotential [202-206]. Further work needs to be donebefore we better understand the role of this technique.

Summary

One could consider that the whole field of myocardialprotection has gone almost full circle as the emphasishas returned to the avoidance of ischemia. The otherchapters in this book will address each topic morefully, but one might view the return of beating heartsurgery as the best way to avoid ischemia altogether.This is certainly a promising area for research, bothwith regards to myocardial protection and neurolog-ical functioning. We may see a change in emphasis aswe adopt the new paradigm of "off-pump" surgery,but we will still need the basic concepts of myocardialprotection, even in that setting. We will also need touse methods of circulatory support and myocardialprotection for "open" procedures, such as valvesurgery or intracardiac repairs of congenital defects,for the foreseeable future. There will still be a need formyocardial protection.

The topic of myocardial protection is very large. Inthis chapter we have given only an overview. It is astory that continues to evolve, and is not yet com-

pleted. The history of this topic was written, and con-tinues to be written, by the contributors to this book.

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118 Stefaniszyn HJ, Wynands JE, Salerno TA. InitialCanadian experience with artificial blood (Fluosol-DA-20%) in severely anemic patients. / Cardiovasc Surg1985; 26: 337-42.

119 Follette DM, Mulder DG, Maloney JV, Jr, Buckberg GD.Advantages of blood cardioplegia over continuouscoronary perfusion and intermittent ischemia. / ThoracCardiovasc Surg 1978; 76:604-19.

120 Earner HB, Laks H, Codd JE et al. Cold blood as thevehicle for potassium cardioplegia. Ann Thorac Surg1979; 28: 509-16.

121 Earner HB, Kaiser GC, Tyras DH et al. Cold blood as thevehicle for hypothermic potassium cardioplegia. AnnThorac Surg 1980; 29: 224-30.

122 Engelman RM, Rousou JH, Dobbs W, Pals MA, LongoF. The superiority of blood cardioplegia in myocardialpreservation. Circulation 1980; 62 (SupplI): 62-6.

123 Hendry PJ, Masters RG, Haspect A. Is there a place forcold crystalloid cardioplegia in the 1990s? Ann ThoracSurg 1994; 58:1690-4.

124 Akins CW. Noncardioplegic myocardial preservationfor coronary revascularization. / Thorac Cardiovasc Surg1984; 88:174-81.

125 Akins CW. Hypothermic fibrillatory arrest for coronaryartery bypass grafting. / Cardiac Surg 1992; 7: 342—7.

126 Rosenkranz ER, Vinten-Johansen J, Buckberg GD et al.Benefits of normothermic induction of cardioplegia inenergy-depleted hearts, with maintenance of arrest bymultidose cold blood cardioplegic infusions. / ThoracCardiovasc Surg 1982; 84:667-77.

127 Rosenkranz ER, Buckberg GD, Mulder DG, Laks H.Warm-glutamate blood cardioplegia induction ininotropic, intra-aortic balloon dependent coronarypatients in cardiogenic shock. Initial experience andoperative strategy. / Thorac Cardiovasc Surg 1983; 86:507-18.

128 Follette D, Steed D, Foglia R, Fey K, Buckberg GD.Reduction of post ischemic myocardial damage bymaintaining arrest during initial reperfusion. Surgforwm!977;28:281-3.

129 Teoh KH, Christakis GT, Weisel RD et al. Acceleratedmyocardial metabolic recovery with warm blood car-dioplegia. / Thorac Cardiovasc Surg 1986; 91: 888-95.

130 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safetyof prolonged aortic clamping with blood cardioplegia.Aspartate enrichment of glutamate blood cardioplegiain energy depleted hearts after ischemic and reperfusioninjury. / Thorac Cardiovasc Surg 1986; 91:428-35.

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131 Allen BS, Buckberg GD, Schwaiger M et al. Studiesof controlled reperfusion after ischemia. XVI. Earlyrecovery of regional wall motion in patients followingsurgical revascularization after eight hours of acutecoronary occlusion. / Thome Cardiovasc Surg 1986; 92:636-48.

132 Laks H, Rosenkranz ER, Buckberg GD. Surgical treat-ment of cardiogenic shock after myocardial infarction.Circulation 1986; 74 (Suppl 3): 16-22.

133 Rosenkranz ER, Buckberg GD, Laks H, Mulder DG.Warm induction of cardioplegia with glutamate-enriched blood in coronary patients with cardiogenicshock who are dependent on inotropic drugs and intra-aortic balloon support. / Thorac Cardiovasc Surg 1983;86:507-18.

134 Lazar HL, Buckberg GD, Manganaro AM, Becker H.Myocardial energy replenishment and reversal ofischemic damage by substrate enhancement of sec-ondary blood cardioplegia with amino acids duringreperfusion. / Thorac Cardiovasc Surg 1980; 80: 350-9.

135 Lazar HL, Buckberg GD, Manganaro AM, Becker H,Maloney JV, Jr Reversal of ischemic damage with aminoacid substrate enhancement during reperfusion. Surgery1980; 88: 702-9.

136 Cusimano RJ, Ashe KA, Salerno PR, Lichtenstein SV,Salerno TA. Oxygenated solutions in myocardial pre-servation. Cardiac Surg 1988; 2:167-80.

137 Bomfim V, Kaijser L, Bendz R, Sylven C, Olen C.Myocardial protection during aortic valve replacement.Cardiac metabolism and enzyme release following con-tinuous blood cardioplegia. Scand J Thorac CardiovascSurg 1981; 15:141-7.

138 Panos A, Christakis GT, Lichtenstein SV et al. Operationfor acute postinfarction mitral insufficiency using con-tinuous oxygenated blood cardioplegia. Ann ThoracSurg 1989; 48: 816-19.

139 Khuri SF, Warner KG, Josa M et al. The superiority ofcontinuous cold blood cardioplegia in the metabolicprotection of the hypertrophied human heart. / ThoracCardiovasc Surg 1988; 95:442-54.

140 Ali IS, Al-Nowaiser O, Deslauriers R et al. Continu-ous normothermic blood cardioplegia. Sem ThoracCardiovasc Surg 1993; 5:141-50.

141 Ali IS, Panos AL. Origins and conceptual framework ofwarm heart surgery. In: Salerno TA, ed. Warm HeartSurgery. London: Arnold, 1995:16-25.

142 Salerno TA. Continuous blood cardioplegia. option forthe future or return to the past? / Mo/ Cell Cardiol 1990;22 (Suppl V):S49.

143 Panos A, Kingsley SJ, Hong AP, Salerno TA,Lichtenstein SV. Continuous warm blood cardioplegia.Surg Forum 1990; 41:233-5.

144 Panos A, Ashe K, El-Dalati H et al. Heart surgery withlong cross-clamp times. Clin Invest Med 1989; 12 (5Suppl): C55.

145 Panos A, Ashe K, El-Dalati H et al. Clinical comparisonof continuous warm (37°C) versus continuous cold(10°C) blood cardioplegia in CABG surgery. Clin InvestMed 1989; 12(5 Suppl): C55.

146 Panos A, Abel J, Slutsky AS, Salerno TA, LichtensteinSV. Warm aerobic arrest: a new approach to myocardialprotection. /Mo/ Cell Cardiol 1990; 22 (Suppl V): S31.

147 Maddaus M, Ali IS, Birnbaum PL, Panos AL, SalernoTA. Coronary artery surgery without cardiopulmonarybypass. Usefulness of the surgical blower-humidifier.J Cardiac Surg 1992; 7: 348-50.

148 Teoh KHT, Panos AL, Harmantas AA, Lichtenstein SV,Salerno TA. Optimal visualization of coronary arteryanastomoses by gas jet. Ann Thorac Surg 1991; 52:564.

149 Tian G, Xiang B, Butler KW et al. A 31-P nuclear mag-netic resonance study of intermittent warm blood car-dioplegia. J Thorac Cardiovasc Surg 1995; 108:1155-63.

150 Misare BD, Krukenkamp IB, Caldarone CA, Levitsky S.Can continuous warm blood cardioplegia be safelyinterrupted. SurgForum 1992; 43:208-10.

151 Ali IM, Kinley CE. The safety of intermittent warmblood cardioplegia. Eur J Cardiothorac Surg 1994; 8:554-6.

152 Doyle D, Dagenais F, Poirier N, Normandin D, CartierP. La cardioplegie sanguine «chaude» intermittente.Ann Chir 1992; 46: 800-4.

153 Calafiore AM, Teodori G, Mezzetti A et al. Intermittentantegrade warm blood cardioplegia. Ann Thorac Surg1995; 59:398-402.

154 Calafiore AM, Mezzetti A. Intermittent antegradenormothermic blood cardioplegia. In: Salerno TA, ed.Warm Heart Surgery. London: Arnold, 1995: 77-89.

155 Martin TD, Graver JM, Gott JP et al. Prospective, ran-domized trial of retrograde warm blood cardioplegia:myocardial benefit and neurologic threat. Ann ThoracSurg 1994; 57:298-304.

156 Warm Heart Investigators. Randomised trial of nor-mothermic versus hypothermic coronary bypasssurgery. Lancet 1994; 343 (8897): 559-63.

157 Wong BI, McLean RF, Naylor CD et al. Central-nervous-system dysfunction after warm or hypothermiccardiopulmonary bypass. Lancet 1992; 339 (8806):1383-4.

158 Singh AK, Bert AA, Feng WC. Neurological complica-tions during myocardial revascularization using warm-body, cold-heart surgery. Eur J Cardiothorac Surg 1994;8:259-64.

159 Singh AK, Feng WC, Bert AA, Rotenberg FA. Warmbody, cold heart surgery: clinical experience in 2817patients. Eur J Cardiothorac Surg 1994; 7:225—30.

160 Laursen H, Waaben J, Gefke K et al. Brain histology,blood—brain barrier and brain water after normother-mic and hypothermic cardiopulmonary bypass in pigs.Eur] Cardiothorac Surg 1989; 3:539-43.

161 Rashid A, Fabri BM, Jackson M et al. A prospective ran-domised study of continuous warm versus intermittentcold blood cardioplegia for coronary artery surgery:preliminary report. Eur J Cardiothorac Surg 1994; 8:265-9.

162 Salerno TA, Houck JP, Barrozo CAM et al. Retrogradecontinuous warm blood cardioplegia: a new conceptin myocardial protection. Ann Thorac Surg 1991; 51:245-7.

History of myocardial protection 11

163 Menasche P, Kural S, Fauchet M et al. Retrogradecoronary sinus perfusion: a safe alternative for ensuringcardioplegic delivery in aortic valve surgery. Ann ThomeSurg 1982; 34:647-58.

164 Fabiani JN, Romano M, Chapelon C et al. La car-dioplegie retrograde: etude experimentale et clinique.[Retrograde cardioplegia. experimental and clinicalstudy.] Ann Chir 1984; 38: 513-16.

165 Gundry SR, Kirsh MM. A comparison of retrograde car-dioplegia versus antegrade cardioplegia in the presenceof coronary artery obstruction. Ann Thome Surg 1984;38:124-7.

166 Gundry SR, Sequiera A, Razzouk AM, McLaughlin JS,Bailey LL. Facile retrograde cardioplegia. transatrialcannulation of the coronary sinus. Ann Thome Surg1990; 50: 882-6.

167 Fabiani JN, Deloche A, Swanson J, Carpentier A.Retrograde cardioplegia through the right atrium. AnnThome Surg 1986; 41:101-2.

168 Guiraudon GM, Campbell CS, McLellan DG et al.Retrograde coronary sinus versus aortic root perfusionwith cold cardioplegia. Randomized study of levels ofcardiac enzymes in 40 patients. Circulation 1986; 74(Suppl III): 105-15.

169 Chitwood WR, Jr. Myocardial protection by retrogradecardioplegia: coronary sinus and right atrial methods.Cardiac Surg 1988; 2:197-218.

170 Langer L. Die foramina Thebesii im herzen desmenschen. Sitzungsb D KAkad Wissensch Math-Naturw1880; 82 (3 Abth): 25-39.

171 Roberts JT. Experimental studies on the nourishment ofthe left ventricle by the luminal (Thebesial) vessels. FedProd 943; 2:90.

172 Roberts JT, Browne RS, Roberts G. Nourishment of themyocardium by way of the coronary sinus. Fed Proc1943; 2:90.

173 Beck CS. The development of a new blood supply to theheart by operation. Ann Surg 1935; 102:801-13.

174 Beck CS. A new blood supply to the heart by operation[editorial]. Surg Gynecol Obstet 1935; 61:407-10.

175 Beck CS. Further data on the establishment of a newblood supply to the heart by operation. / Thome Surg1936;5:604-11.

176 Beck CS, Leighninger DS. Operations for coronaryartery disease. JAMA 1954; 156:1226-33.

177 Hammond GL, Davies AL, Austen WG. Retrogradecoronary sinus perfusion. A method of myocardial pro-tection in the dog during left coronary artery occlusion.Ann Surg 1967; 166: 39-47.

178 Lolley DM, Hewitt RL, Drapanas T. Retroperfusionof the heart with a solution of glucose, insulin, andpotassium during anoxic arrest. / Thome CardiovascSurg 1974; 67: 364-70.

179 Gundry SR, Wang N, Bannon D et al. Retrogradecontinuous warm blood cardioplegia: maintenance ofmyocardial homeostasis in humans. Ann Thome Surg1993;55:358-61.

180 Menasche P, Fleury JP, Droc L etal. Metabolic and func-tional evidence that retrograde warm blood cardioplegia

does not injure the right ventricle in human beings.Circulation 1994; 90:11310-15.

181 Partington MT, Acar C, Buckberg GD, Julia PL. Studiesof retrograde cardioplegia. II. Advantages of antegrade/retrograde cardioplegia to optimize distribution injeopardized myocardium. / Thome Cardiovasc Surg1989;97:613-22.

182 Stirling MC, McClanahan TB, Schott RJ et al. Dis-tribution of cardioplegic solution infused antegradelyand retrogradely in normal canine hearts. / ThomeCardiovasc Surg 1989; 98:1066-76.

183 Ihnken K, Morita K, Buckberg GD et al. The safety ofsimultaneous arterial and coronary sinus perfusion:experimental background and initial clinical results.J Cardiac Surg 1994; 9:15-25.

184 Hoffenberg EF, YeJ, Sun J, Ghomeshi HR, Salerno TA,Deslauriers R. Antegrade and retrograde continuouswarm blood cardioplegia: a 31P magnetic resonancestudy. Ann ThoracSurg 1995; 60:1203-9.

185 Tian G, Shen J, Sun J et al. Does simultaneousantegrade/retrograde cardioplegia improve myocardialperfusion in the areas at risk? A magnetic resonance per-fusion imaging study in isolated pig hearts. / ThomeCardiovasc Surg 1998; 115:913-24.

186 del Nido PJ. Myocardial protection and cardiopulmonary bypass in neonates and infants. Ann ThoracSurg 1997; 64:878-9.

187 Takeuchi K, Nagashima M, Itoh K et al. Improvingglucose metabolism and/or sarcoplasmic reticulumCa2+-ATPase function is warranted for immature pres-sure overload hypertrophied myocardium. Jpn Circ J2001;65:1064-70.

188 Gundry SR. Retrograde cardioplegia in infants and chil-dren. In: Mohl, W, ed. Coronary Sinus Interventionsin Cardiac Surgery. Austin TX: RG Landes, 1994: 67-70.

189 Hammon JW, Jr. Myocardial protection in the imma-ture heart. Ann Thorac Surg 1995; 60:839-42.

190 McMahon WS, Gillette PC, Hinton RB et al. Devel-opmental differences in myocyte contractile responseafter cardioplegic arrest. / Thorac Cardiovasc Surg 1996;111:1257-66.

191 Rebeyka IM, Hanan SA, Borges MR et al. Rapid coolingcontracture of the myocardium. The adverse effect ofprearrest cardiac hypothermia. / Thorac Cardiovasc Surg1990; 100:240-9.

192 Williams WG, Rebeyka IM, Tibshirani RJ et al. Warminduction blood cardioplegia in the infant. A techniqueto avoid rapid cooling myocardial contracture. / ThoracCardiovasc Surg 1990; 100: 896-901.

193 Jessen ME, Abd-Elfattah AS, Wechsler AS. Neonatalmyocardial oxygen consumption during ventricularfibrillation, hypothermia, and potassium arrest. AnnThorac Surg 1996; 61:82-7.

194 Abd-Elfattah AS, Ding M, Wechsler AS. Myocardialstunning and preconditioning: age, species, and modelrelated differences: role of AMP-5'-nucleotidase inmyocardial injury and protection. / Card Surg 1993;8 (2 Suppl): 257-61.

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195 Rebeyka IM, Yeh T, Jr, Hanan SA et al Alteredcontractile response in neonatal myocardium to citrate-phosphate-dextrose infusion. Circulation 1990; 82 (5Suppl): IV367-IV370.

196 Mask WK, Abd-Elfattah AS, Jessen M et al. Embryonicversus adult myocardium: adenine nucleotide degrada-tion during ischemia. Ann Thome Surg 1989; 48:109-12.

197 Blanche C, Khan SS, Chaux A et al. Cardiac reoperationsin octogenarians, analysis of outcomes. Ann Thorac Surg1999; 67:93-8.

198 Burns PG, Krukenkamp IB, Caldarone CA et al. Isthe preconditioning response conserved in senescentmyocardium? Ann Thorac Surg 1996; 61:925—9.

199 Caldarone CA, Krukenkamp IB, Burns PG et al. Bloodcardioplegia in the senescent heart. / Thorac CardiovascSurg 1995; 109:269-74.

200 Panos AL, Khan SI, Del Rizzo DF et al. Results of cardiacsurgery in the elderly using normothermic techniques.Cardiol Elderly 1995; 3:189-92.

201 Amrani M, Chester AH, layakumar J, Yacoub MH.Aging reduces postischemic recovery of coronary

endothelial function. / Thorac Cardiovasc Surg 1996;111:238-45.

202 Cason BA, Gordon HI, Avery IVEG, Hickey RF. Therole of ATP sensitive potassium channels in myocardialprotection. / Card Surg 1995; 10 (4 Suppl): 441-4.

203 Cohen NM, Wise RM, Wechsler AS, Damiano RJ,Ir Elective cardiac arrest with a hyperpolarizingadenosine triphosphate-sensitive, potassium channelopener. A novel form of myocardial protection?) Thorac Cardiovasc Surg 1993; 106:317-28.

204 Cohen NM, Damiano RJ, Jr, Wechsler AS. Is there analternative to potassium arrest? Ann Thorac Surg 1995;60:858-63.

205 Maskal SL, Cohen NM, Hsia PW, Wechsler AS,Damiano RJ, Jr. Hyperpolarized cardiac arrest witha potassium-channel opener, aprikalim. / ThoracCardiovasc Surg 1995; 110 (4 Part 1): 1083-95.

206 Menasche P, Mouas C, Grousset C. Is potassiumchannel opening an effective form of precondition-ing before cardioplegia? Ann Thorac Surg 1996; 61:1764-8.

CHAPTER 2

The duality of cardiac surgery:mechanical and metabolic objective

Gerald D. Buckberg, MD

There are dual objectives at operation, and the twofundamental components are technical success andabsence of iatrogenic injury due to inadequate myo-cardial protection. We have entered a new millen-nium, and the spectrum of surgical procedures used tocorrect abnormal structure is expanding. Intervals ofaortic clamping need to be longer, so that we make thecorrect diagnosis and implement a more natural cor-rection (i.e. mitral valve repair, Ross procedure, aorticreconstruction with stentless valves, homografts).

In addition, our patients' vulnerability to injuryhas increased, so we need to improve our methods ofprotection as well as learn new operative techniques.This chapter deals both with the evolution of currentmethods and the recognition of newer methods ofprotection, so that the dual relationship between pro-tection and procedures is not separated.

Technical success and the avoidance of intra-operative damage are our dual surgical objectives. Theearly and late success of a cardiac surgical procedureis related to how well the operation corrected themechanical problem, and how carefully myocardialprotection avoided the secondary dysfunctional effectsof aortic clamping for technical repair. There is noseparation between these two central events. Themechanically perfect heart cannot undergo early orlate survival if operative damage from protection issevere. An example is the development of "stone"heart after 30 min of normothermic aortic clampingfor aortic stenosis, or late dilatation from evolving scarfrom intraoperative ischemic damage. Conversely,the normal myocardium on bypass, with preservedstructural and biochemical integrity, cannot maintaincardiac output if there is a technical operative error,

such as a closed coronary anastomosis or iatrogenicvalvar insufficiency.

The need for these vital elements to be in harmonyis well known, yet there are important differences inthe cardiac surgical approaches to these two funda-mental determinants of outcome. On one level, themeticulous pursuit of mechanical perfection is unend-ing; for example, through cardiac vision (i.e. eyeglasses, 2-5-3-5 loops, 4-5 loops, 6-0 loops, the micro-scope, and finally robotic magnification away from thedirect operative field). Surgical suture techniques,starting at 5-0 prolene, progress to 10-0 to secure aperfect anastomosis or repair. Major interventionalchanges in mitral valve repair are developed to avoidreplacement, and novel mechanical methods areintroduced to return the ventricle in a normal ellipt-ical cardiac position. This structural goal is the tech-nical belief of cardiac surgery and the pursuit ofexcellent technology will never end.

Focal examples of this drive come from the ongoingsearch for perfection, through learning the Ross pro-cedure for aortic valve replacement and repeated visitsto valvuloplasty clinics to enlarge our concepts ofvalve repair to avoid mechanical replacement. Theundercurrent theme is that sufficient time must bespent during aortic clamping, in an unhurried wayto: (i) inspect the functional anatomy; and then(ii) accomplish a novel technical repair. There is anenlarging body of surgeons wanting to utilize thesecreative technical approaches, but the numbers ofclinical centers dealing with these more difficultvalvular problems is limited. The surgical restriction,despite an available cadre of patients, is underlyingconcern about producing extended intraoperative

13

14 CHAPTER 2

damage during the prolonged aortic clamping timesrequired for novel technical success.

On a second level, these more extensive proceduresare often withheld from patients with underlyingimpairment of ventricular function due to: (i) recog-nized increased vulnerability to damage in hearts withhypertrophy and/or coronary disease; (ii) limitedfunctional reserve if protection is marginal; and/or(iii) use of a shorter procedure (i.e. using an artificialvalve) to avoid the prolonged intra-aortic clampingneeded to be used for correcting the lesion in a morenatural way.

The performance of evolving operative techniquesis halted in many centers by the conceptual barrierthat "prolonged aortic clamping will cause progressivetissue damage" when the new task is undertaken,because of the knowledge that repair "burns extraminutes" into our efforts to achieve mechanicalsuccess. The barrier is the uncertainty of the value ofcurrent techniques of myocardial protection duringprolonged aortic clamping in patients with advancedcardiac disease when there is diminished preoperativefunction. Unfortunately, unbridled progress to learnnew techniques is unaccompanied, in many centers,with a similarly more intensive understanding, look-ing for reasons why more damage is invoked if theinterval of clamping is prolonged. A fundamental rea-son is that techniques of improved protection havemade slower educational progress during our ongoingpursuit of the evolution of improved technique.

I will cite several examples of evolving methods ofprotection, to bring into focus this disparity betweenmechanical and metabolic excellence. So that allsurgeons can have the freedom to use their technicalskills to the full, this disparity should be dissolved.

The first method of protection is hypothermia,provided by cold perfusate and surface cooling basedupon findings by Shumway in 1959 to limit damagefrom normothermia. To some, this became the his-toric "end stop" of myocardial protective strategies.This may reflect the "iceberg age," and restricted focusupon this method alone has arrested progress towarda full understanding of the mechanics of ischemicdamage, and how to reverse these changes. Ourprogress becomes cushioned by the classic statement"we have good results, why change"? The reason tochange methods of protection is obvious, unlesscurrent protective methods provide complete avoid-ance of massive inotropic support, assist devices, or

transplantation, following technically successful repair.Hopefully, a "rigid" concept that cold is everything"will not veil" any further development of our know-ledge in cardiac protection.

Our capacity to stop metabolic demands quickly,and simultaneously limit progressive extension ofdamage over time, has been enhanced by cardioplegictechniques that retard metabolism, and are now usedalmost universally. Hypothermia is a vital component,but reflects an addition, rather the unifying forcethat becomes the only solution. Further progress hasdeveloped by general agreement that blood containsnatural benefits over conceptual crystalloid tech-niques, red blood cells are a fundamental componentof most cardioplegic solutions. Those who externallycreate a crystalloid component and exclude bloodmust now address the well-proven benefits of restor-ing the blood vehicle that normally nourishes thenonbypassed heart that must function when bypassis discontinued. In addition, strategic methods todistribute solution, both antegrade, retrograde, andsimultaneously antegrade/retrograde, have beendeveloped, and are used commonly throughout theworld. More importantly, new methods to preventischemic damage (i.e. buffering, hypocalcemia, oxy-gen radical scavengers, reducing complement) undermore favorable conditions have been added. How-ever, few centers are now involved with the surgicaladoption of these new protective techniques. Manyuse methods that were developed 20 years ago. Theinjury could be limited if we addressed the newermetabolic and delivery changes that have been initi-ated. Consequently, there has been a mechanicalleap in technical skills, but only "microsteps" takenin advancing and using efforts for protection.

The recognition that temperature and cardiologicvehicle do not insure adequate distribution hasallowed the evolution of retrograde delivery. Thesemethods of retroperfusion are used in greater than60% of patients in the United States and somewhatless worldwide. However, this is not a universal vehiclefor cardioplegic delivery, despite evidence that differ-ent areas of diseased hearts are perfused by antegradeand retrograde techniques. This is very importantbecause of the limited capacity of retrograde methodsto consistently protect the right ventricle, and is espe-cially important in reoperative coronary procedures.

The ready clinical demonstration that differentregions are perfused by retrograde perfusion (i.e.

Duality of cardiac surgery 15

coronary sinus effluent during antegrade perfusionsstarting blue and becoming red, then with retrogradeperfusion, aortic effluent starting blue and thenbecoming red), indicates that different areas are per-fused during the period of aortic clamping. This showsthat some regions were imperfectly perfused usingone technique only. Clinical evidence has graduallyattained general acceptance that these antegrade andretrograde delivery methodologies should be com-bined. These changes are further limited by those whohave not yet "made this step of transatrial cannula-tion." To many, a slight prolongation of operationto open the right atrium and directly cannulate thecoronary sinus provides a sufficient reason to limitpursuing retrograde methodology. Little attention isgiven to the prolonged inotropic and metabolicsupport that is needed when this potential 5-min sup-plement is excluded. Some accept the prolongedintensive care unit and increased hospital stay, andmortality is due to the nature of the disease ratherthan the potential consequence of not using thismethodology. The value in morbidity of consecutivehospital cases and reduced cost was shown nicely in astudy by Loop several years ago at the Cleveland Clinic

[1].The aforementioned applications of cold blood

cardioplegia and retrograde perfusion are simply thestart of the advanced techniques of myocardial protec-tion, as many centers have made physiologic variancesin the cardioplegic temperature while using bloodcardioplegic protection. Evidence is clear that thejeopardized heart has increased vulnerability to dam-age, and that this injury can be modified, both experi-mentally, and clinically, by a warm controlled bloodcardioplegic reperfusion, especially if there is aminoacid enrichment [2-4]. Despite this knowledge,there is much slower adaptation to using proven con-cepts of controlled reperfusion before releasing theaortic clamp. Warm reperfusion is used in less than50% of centers, with fewer participants in Europe.Furthermore, it should be recognized that ongoingischemia during aortic clamping is not needed whenthe procedure is ongoing and direct heart visualiza-tion is unimpaired (i.e. doing proximal anastomosis,placing sutures from the valve ring to the valve, andclosing the aorta or atrium) as the procedure pro-gresses. During these times, continuous cold bloodperfusion is available, yet is not commonly used. Theresult is that ischemia is prolonged unnecessarily. The

potential injury could be limited if there was under-standing of the availability of reperfusion, especiallyretrograde, when operative vision does not becomeimpaired by ongoing perfusion while the aorta isclamped.

The "blending" of methods of protection can beused to avoid the arbitrary "alternative positionstance," where there is an unnecessary introduction ofa surgically imposed contrast between "warm versuscold, antegrade versus retrograde, intermittent versuscontinuous," which now becomes an "integratedmethod." This integrated approach takes advantageof the benefits of each method, rather than pittingone method against the other. The result is thateach patient receives warm induction, cold bloodcardioplegia, and a warm reperfusate, with deliveryantegrade, retrograde, and sometimes simultane-ously antegrade and retrograde, in either an inter-mittent delivery, and in a continuous way if vision isnot impaired by perfusion. The cold arrested heartremains stopped by hypothermia, so that the blooddelivery can be with either a cardioplegia solution,or with cold regular blood, or a nonpotassium-containing solution with the cardioplegic constituents[5,6]. The benefits of this combined approach wereshown, recently, in more than 1500 patients withadvanced heart disease, and even more extensivelyin an alternate subset of patients with valve complexmitral valve disease [5] or Ross procedures with dam-aged ventricles, where ischemic times were greaterthan 180-250 min without inotropic support [7].

Further supplemental steps like white blood cellfiltration, oxygen radical scavenger addition, magne-sium supplementation, low Po2 to limit reoxygenationdamage, short-acting calcium antagonists to reduceand prevent calcium-related injury, adding sodiumhydrogen ion exchangers, and other evolving regionsare at the frontier of better techniques to protect theheart. These concepts have been developed, yet thereis a slower pathway among surgeons towards incor-porating these procedures into the operation. Somethink change is "living with the university." That issimply the wrong idea. We must advance in our learn-ing of myocardial protection modalities, in the sameway as we progress with mechanical matters to pro-vide our patients with many of the benefits of eachaspect that should be in the armamentarium of thecardiac surgeon, just as in the natural evolution ofmechanical methods of repair.

16 CHAPTER 2

The concepts of myocardial protection developedin adults are directly applicable to the pediatricpopulation, where vulnerability to damage is highestbecause of preoperative ischemia and cyanosis. Theseapproaches are similar to adult methods, but arerarely employed. The increasing tendency to avoidcardiopulmonary bypass to reduce the inflammatoryreaction to extracorporeal circulation has led to cor-onary artery bypass graft (CABG) without bypass. It isclear that the precursor to regional stunning (that weknow globally as the low-output syndrome) is briefocclusion for 10-15 min with normal blood reperfu-sion. This established technique of damage is appliedto patients with coronary artery disease, but there isless damage in them because of collateral flow fromstenotic lesions. Methods to protect the regional seg-ment in patients undergoing CABG without bypassmust be addressed and included, to avoid stunning ofboth the endothelium and the myocyte.

The method of surgery on the beating heart, whichis useful without bypass, is also applicable in patientson extracorporeal circulation. The beating heart withregional ischemia has been used in CABG procedures,since bypass reduces global oxygen demand, and thenonischemic areas remain perfused which potentiallylimits their injury. A marked advantage of surgery onthe beating heart has been achieved during ventricularrestoration, where the beating heart is opened andcontinually perfused as its volume is reduced. Thismethod has been useful both experimentally, and clin-ically [8-10]. The principle of using the beating heartis not new, as this method has been used during surg-ical treatment of ventricular arrythmias [ 11 ]. It is alsowell known, from Kirklin's studies of aortic stenosis,that continuous perfusion of the beating vented heartcan cause marked subendocardial ischemia if thereis left ventricular hypertrophy [ 12]. The goal in select-ing a method of protection is to make the choiceafter learning how and why the method has beendeveloped, and understanding how to benefit from itsadvantages, and avoid inappropriate use by recogniz-ing the disadvantages. The choice for protection isprecisely similar to the selection of a structural tech-nique for surgical repair of an underlying cardiaclesion.

The underlying principle in this dual bilateral pro-gram is for each of us to recognize that each effort(mechanical and metabolic) is of equal importance.Failure in either modality is not a surgical problem,

but rather a problem for the patients and the existingcost of caring for those who have delayed recoverydespite a technically successful procedure.

Improved myocardial protection is not a phaseof surgical development, but rather is intrinsic toimproved surgical care. The virtual absence of papersat surgical meetings about myocardial protection mayindicate that the problem of myocardial protectionhas not been solved. Despite this, there are reportsof patients needing intra-aortic balloons and mech-anical assist devices when protection has been inad-equate. The search for technical improvement mustbe accompanied by ongoing learning about cardio-protective methods that avoid completely the needto use machines to correct cardiac performance afterthe heart has been mechanically restored to its morenormal architecture. We should strive to increaseour knowledge about protection, as it must becomean essential component of the surgical correction ofcardiac defects. Protection and technical adequacycannot be separated, as our deep understanding ofhow to correct the cardiac lesion must be matched by arecognition of how to avoid damage as we satisfy ourdual goals.

References1 Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG.

Myocardial protection during cardiac operations.7 Thome Cardiovasc Surg 1992; 104:608-18.

2 Allen BS, Buckberg GD, Fontan F et al. Superiorityof controlled surgical reperfusion vs. PTCA in acutecoronary occlusion. / Thorac Cardiovasc Surg 1993;105:864-84.

3 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety ofprolonged aortic clamping with blood cardioplegia. III.Aspartate enrichment of glutamate-blood cardioplegia inenergy-depleted hearts after ischemic and reperfusioninjury. / Thorac Cardiovasc Surg 1986; 91:428-35.

4 Allen BS, Rosenkranz ER, Buckberg GD et al. Studies onprolonged regional ischemia. VI. Myocardial infarctionwith LV power failure: a medical/surgical emergencyrequiring urgent revascularization with maximal protec-tion of remote muscle. / Thorac Cardiovasc Surg 1989; 98:691-703.

5 Buckberg GD, Beyersdorf F, Allen B, Robertson JM.Collective review: Integrated myocardial management.Background and initial application. / Card Surg 1995; 10:68-89.

6 Kronon MT, Allen BS, Halldorsson A et al. Delivery of anonpotassium modified maintenance solution to enhancemyocardial protection in stressed neonatal hearts: a newapproach. / Thorac Cardiovasc Surg 2002; 123:119-129.

Duality of cardiac surgery 17

7 Allen BS, Murcia-Evans D, Hartz RS. Integrated cardio-plegia allows complex valve repairs in all patients. AnnThoracSurg 1996:62: 23-9.

8 Athanasuleas CL, Stanley AWH, Jr, Buckberg GD.Restoration of contractile function in the enlarged leftventricle by exclusion of remodeled akinetic anteriorsegment: surgical strategy, myocardial protection, andangiographic results. / Card Surg 1998; 13:418-28.

9 Athanasuleas CL, Stanley AWH, Jr, Buckberg GD et al.and the Restore Group. Surgical anterior ventricularendocardial restoration (SAVER) in the dilated remod-eled ventricle following anterior myocardial infarction.] Am Coll Cardiol 2000: 37:1199-209.

10 Sakamoto Y, Mizuno A, Buckberg GD et al. Restoring theremodeled enlarged left ventricle: experimental benefitsof in vivo porcine cardioreduction in the beating openheart. / Cardiac Surg 1998; 13:429-39.

11 Mickleborough LL, Carson S, Ivanov J. Repair ofdyskinetic or akinetic left ventricular aneurysm: resultsobtained with a modified linear closure. / ThoracCardiovasc Surg 2001; 121:675-682.

12 Sapsford RN, Blackstone EH, Kirklin JW. Coronary per-fusion versus cold ischemic arrest during aortic valvesurgery. Circulation 1974; 49:1190.

CHAPTER 3

Modification of ischemia-reperfusion-induced injury bycardioprotective interventions

Ming Zhang, MD, Tamer Sallam, BS,BA, Yan-JunXu, PHD,Naranjan S. Dhalla, PHD, MD (HON), DSC (HON)

Introduction

Myocardial ischemia-reperfusion is a phenomenoncaused by various clinical procedures such as angio-plasty, coronary bypass, and thrombolytic therapy.It is a lethal medical problem and a major eco-nomic healthcare concern due to high mortality andmorbidity. Multiple factors are involved in ischemia-reperfusion injury; occurrence of Ca2+ overload,excessive formation of oxygen-derived free radical,and alterations of enzyme activity are considered tobe the major causes of myocardial cell damage andcardiac dysfunction. Ischemia-reperfusion may causecontractile failure, arrhythmias and cell death leadingto heart failure or sudden death in patients. Accord-ingly, it has become vital to develop effective thera-peutic strategies to combat the deleterious effects ofischemia-induced myocardial injury. At present, manystudies have been conducted to determine the pos-sibility of amplifying the beneficial effects of reperfu-sion and diminishing the harmful effects of ischemiathrough pharmacological intervention. This chapterreviews the mechanisms of some of the therapies whichare useful in attenuating the ischemia-reperfusion-induced injury in the heart.

Ischemia means little or no blood flow to the tissues[ 1 ], resulting in not only a decrease in the supply ofoxygen and nutrients to the heart, but also a build upof metabolic wastes locally and thus debilitating themaintenance of an adequate rate of energy productionand cellular integrity [2]. Myocardial ischemia can be

characterized by rapid accumulation of protons, ces-sation of oxidative metabolism, cessation of electrontransport, and the initiation of the inefficient pro-cesses of anaerobic metabolism. Reperfusion injuryis a major complication characterized by restora-tion of flow to a previously ischemic heart [3]. Manyfactors have been shown to cause ischemic heartdisease; major ones include atherosclerosis of thecoronary arteries, thrombosis, and coronary arteryspasm [4]. Ischemia-reperfusion injury is one of themost common cardiovascular diseases; this injurydamages vascular cells and cardiomyocytes [5].

In spite of the variable incidence of ischemic heartdisease, it has become one of the most significant med-ical problems and a major economic healthcare con-cern for the lethal damage of ischemia-reperfusioninjury. It has been reported that almost 45% of alldeaths in northern European countries during thepast decade were due to cardiovascular disease [6]. Inaddition, 200 000 Americans under 65 die each yearfrom ischemic heart disease and 25 times that numbersuffer from symptoms related to the disease [4]. Asimilar situation exists in Canada, where cardiovascu-lar disease causes more deaths than any other disease,with more than 58% of these deaths attributed toischemic lesions in 1990 [7]. In economic terms, thedirect and indirect cost of heart attack and stroke peryear was about $259 billion in the USA [8]. In Canada,cardiovascular disease contributed to 21% of the totalhealthcare expenditure in 1986, and has became themost expensive disease with direct costs of $5.2 billion

18

Treatment of ischemia-reperfusion injury 19

and indirect costs of $11.6 billion [4]. Consequently itis crucial to find ways to attenuate the events associ-ated with the irreversible ischemic injury.

At present, many studies have been designed todetermine the possibility of amplifying the beneficialeffects of reperfusion and diminishing the harmfuleffects of ischemia through pharmacological interven-tion [9]. Those include: preconditioning, antioxidants,Ca2+ channel blockers, phospholipase A2 inhibitors,Na-H+ exchange inhibitors, P38 MAP (mitogen-activated protein) kinase inhibitors, phosphataseinhibitors, pentoxifylline, 5-HT receptor antagonists,and so on. The aim of this article is to review thepathophysiology of ischemia-reperfusion injury andthe mechanisms of pharmacological interventions forthis disease.

Preconditioning

Myocardial ischemic preconditioning is a phenome-non produced by brief episodes of cardiac ischemiaand reperfusion leading to a decrease in the rate ofprogression of ischemia-induced myocardial injuryand the development of resistance to subsequentischemic episodes [10-12]. The potential therapeuticbenefits of this adaptive mechanism have gener-ated much attention in the scientific community,and have revolutionized our understanding ofsignal transduction and subsequent intracellularevents mediating ischemia-reperfusion [13]. Severalintracellular signaling pathways which have beenimplicated in the protective mechanism of ischemicpreconditioning include the activation of G protein-linked phospholipase C-coupled receptors, adenosinereceptor, bradykinin receptor, opioid receptor, tyro-sine kinase pathways, and protein kinase C (PKC)[12,14-16].

Different mechanisms explain the role ofpreconditioning in ischemia-reperfusion. Ischemicpreconditioning might render protection againstischemia-reperfusion-induced damage to the myocar-dium by improving sarcoplasmic reticulum function.This is attributed to decreased ryanodine-sensitivesarcoplasmic reticulum Ca2+ release and the regulationof sarcoplasmic reticulum phosphorylation by endo-genous Ca2+/calmodulin-dependent protein kinase(CaMK) [17,18]. Some studies have reported thatischemic preconditioning triggers phospholipase Dsignaling in ischemic myocardium, which appears to

be beneficial for the heart because of the production ofphosphatidic acid and diacylglycerol as well as subse-quent activation of PKC [ 19].

In addition, the adenosine triphosphate (ATP)-sensitive potassium channel is a strong candidate formediation of preconditioning protection. Pharma-cological and electrophysiological evidence favorablyimplicate the involvement of mitoKATp rather thansurfaceKATp as the relevant mediator of precondi-tioning [14]. Opening of mitoKATP has been shownto block apoptosis in cardiac myocytes via PKC-eactivation [20]. Preconditioning additionally protectsagainst cell necrosis and possibly against stunning[21]. The mechanism of such protection is stillunclear, yet it has been demonstrated that the ATPcontent of the myocardium is reduced followingischemic preconditioning. However, during pro-longed coronary occlusion, the rate of decline in ATPis initially slower in a preconditioned myocardium ascompared to a nonpreconditioned one [11]. Thus analteration in the energy supply-demand relationshipmay be involved [22]. Preconditioning might furtherprotect against necrosis through its action on tumornecrosis factor alpha (TNF-ct) because it has beenshown to reduce myocardial TNF-a production andTNF-a-induced myocardial injury [23].

Preconditioning may also induce protection againstother aspects of ischemia/reperfusion injury such ascoronary endothelial damage or arrhythmias [13,24].It has been reported that the incidence of ventricularfibrillation decreases from 90% in control hearts to20% in preconditioned hearts; also, it has been shownthat ischemic preconditioning exerted its protectiveeffect primarily by maintaining the function of theforward mode of the Na-Ca2+ exchanger and limit-ing the development of intracellular acidosis. Thisreduces the occurrence of intracellular Ca2+ overload,thus protecting the heart against arrhythmias [25,26].Other evidence suggests that the antiarrhythmic effectsof ischemic preconditioning are mediated through theactivation of endothelium bradykinin receptor-1 [16].It has also been reported that ischemic precondition-ing preserved endothelium-dependent coronary dila-tion significantly [24]. Therefore, the preservation ofendothelial function may be one of the mechanismsby which preconditioning reduces the amount oftissue necrosis during reperfusion.

In conclusion, the mechanisms modulating ischemicpreconditioning include alterations in antioxidant

20 CHAPTER 3

defence [27], stimulation of adenosine Aj receptors,activation of PKC, activation of phospholipase D,induction of heat shock proteins, reduction in TNF-a production, attenuation of the development ofintracellular acidosis, and prevention of the intracellu-lar Ca2+ overload [18,19,23]. The existing evidencestrongly favors preconditioning as an effective inter-vention of ischemia-reperfusion injury.

Antioxidants

Reactive oxygen species, including the superoxideanion (O2~), hydrogen peroxide (H2O2), and thehydroxyl radical (OH), are derivatives of many bio-logic systems, and in high concentrations are associatedwith oxidative stress and subsequent cardiovasculartissue injury [11]. The superoxide anion is a keyentity in the production of the hydroxyl radical. Ithas been demonstrated that superoxide radicals andhydrogen peroxide exert their deletions effect on cellsthrough the generation of the highly reactive hydroxylradicals, and are therefore not directly toxic [9]. Onemajor site of oxygen free radical production andcell injury is endothelial cells. In fact, endothelialcells have been shown to possess a free radical systemcapable of generating oxygen radicals [28]. Normallyoxygen-derived free radicals interact with cellularconstituents, including lipids, proteins and nucleicacids. In turn, they can disrupt membrane integrity,ion channels, and enzymatic activities. Such adverseeffects of toxic oxygen metabolites were additionallyassociated with dysfunction of sarcoplasmic reticulum,mitochondria and creatine kinase upon reperfusion ofthe ischemic myocardium [15].

The view that reactive oxygen species are implicatedin ischemia-reperfusion is further substantiated whenconsidering the effects of antioxidants on hearts sub-jected to ischemia-reperfusion. The antioxidant abil-ity of the cell can be divided into two categories. Thefirst line of cellular defence against oxidative injuryis free radical scavenging enzymes including super-oxide dismutase, catalase, glutathione peroxidase,and glutathione. The second line antioxidant is thenonenzymatic scavengers such as alpha-tocopherol(vitamin E), beta-carotene, vitamin A, ascorbate, andsulfhydryl-containing compounds [28]. The endo-genous antioxidants are depleted by ischemia, predis-posing the myocardium to oxidant injury [ 15]. In fact,a direct correlation between the myocardial dysfunc-

tion induced by ischemia-reperfusion and the magni-tude of free radical generation by exogenously admin-istered oxidants has been previously demonstrated[17]. This further indicates the major role of anti-oxidant treatment for ischemia-reperfusion injury. Ithas been shown that SOD (superoxide dismutase)plus CAT (catalase) treatment prevents changes insarcoplasmic reticulum protein phosphorylation in theischemic reperfused heart [17]. Other agents shownto have beneficial effects acting as antioxidants are:N-2 mercaptopropionyl glycine and N-acetylcysteine;melatonin [29]; as well as allopurinol, oxypurinol, anddesferrioxamine [15,29-31].

New antioxidant interventions are currently beingdeveloped. Recently certain amino acids, such as tau-rine, have been used for the purpose of maintainingmembrane stabilization. In vitro and in vivo studiesindicate that taurine has the ability to scavenge HOC1and thereby prevent ischemia-reperfusion-inducedmembrane damage as induced by lipid peroxidation[32]. Clearly, anti-free-radical interventions mayreduce the severity of reperfusion injury as shown bynumerous studies. However, some reports discussingthe failure of some antioxidant treatments [33,34]indicate that reperfusion injury is a complex phe-nomenon and further research is needed to betterelucidate this dynamic process.

Ca2+ channel blockers

It is well accepted that Ca2+ ions are major regulatorsof cardiac excitation-contraction coupling. Some ofthe roles of Ca2+ in cardiac myocyte function includemediating systolic contraction and diastolic relaxationas well as affecting enzymatic activities and mito-chondria function. Additionally, Ca2+ is importantfor maintaining cellular integrity, cell proliferation,cell growth, and the regulation of metabolism. TheL-type Ca2+channel is considered the most significantCa2+channel in the human heart. The small amount ofCa2+ entering the cytosol through this channel triggersthe release of additional Ca2+ from the sarcoplasmicreticulum [35]. Reperfusion-induced Ca2+ overloadwas described three decades ago [36]. Recent studiesdemonstrate that Ca2+ overload is a major cause ofmyocardial cell damage and cardiac dysfunction inischemic heart diseases. The Ca2+ overload evoked bypostischemic reperfusion is associated with irrever-sible injury such as ultrastructure damage, enzyme


leakage, membrane damage, reduced capacity of themitochondria to regenerate ATP, and increasedinfarct size [36]. The role of Ca2+ in cardiac dysfunc-tion may be further extended to ischemia-inducedarrhythmias, especially ventricular tachycardia andventricular fibrillation which are the major causes ofsudden cardiac death.

Calcium channel blockers are used in the treatmentof ischemic heart disease and these function throughreducing the contractility of the myocardium, decreas-ing the contraction of smooth muscle in the vascula-ture, and altering the conducting system of the heart[37]. Generally Ca2+ channel blockers can be class-ified as dihydropyridines and nondihydropyridines.The dihydropyridines act primarily by relaxation ofvascular smooth muscle with less effect on cardiaccontractility and conduction; nifedipine is the mostcommonly used representative of dihydropyridines.Nondihydropyridines such as verapamil and diltiazemact primarily on myocardium and cardiac conductingtissue with less effect on vascular smooth muscle. Atpresent, nifedipine, diltiazem and verapamil are thethree most clinically used calcium channel blockers[38]. Other Ca2+ channel blockers were also appliedin experimental research, such as felodipine, S-2150,lacidipine, anipamil, and benidipine [39-43]. Sev-eral mechanisms describe the protective effect ofCa2+ antagonists on the myocardium with ischemia-reperfusion injury including: coronary vasodilatation[43-45], an energy-sparing effect which results in alower rate of ATP depletion, slower loss of adenosineprecursors [39,40,46], decreased release of degrad-ative lysosomal proteases [47,48], protection of thesarcolemma [49,50], attenuation of the ischemia-reperfusion-induced mobilization of norepinephrine[51], lower endothelial permeability [52], protec-tion of mitochondrial function [53], attenuationof ischemia-induced acidosis [54,55], retardation ofthe early rise in cytosolic Ca2+ [56], protection oflipid-containing membranes against lipid peroxida-tion caused by free radicals [41], and antiarrhythmiceffects believed to be related to their inhibitoryaction on the phosphatidylethanolamine (PE) N-methylation activity [57]. It appears that calciumchannel blockers are an effective treatment of ischemia-reperfusion injury as indicated by different approachessuch as cellular pharmacology, molecular biology,in vitro and in vivo animal pharmacology, clinicalpharmacology, and clinical efficacy studies [58].

Phospholipase A2 inhibitors

The membranes of living cells consist of phospho-lipids, cholesterol, and proteins. The integrity of themembrane is important for proper cell functioning.Phospholipids, the major constituents of the cellularmembrane, provide the principal structural frame-work of the membrane and therefore undergo acontinued turnover process; hence, enabling the cellto synthesize required phospholipids and to regulatethe fatty acid composition of the phospholipids. Anintegral enzyme involved in the hydrolytic part ofphospholipid regulation is phospholipase A (PLA),with its two isoforms, namely, phospholipase At

(PLAj) and phospholipase A2 (PLA2) [35]. Of at leastthree different types of phospholipase A2 (PLA2) in thehuman heart, the group II PLA2 has been cloned andwell studied [59,60]. The regulation of the group IIPLA2 activity occurs through multiple entities, such ascytokines (TNF-oc, IL-1, IL-6) and Ca2+ concentration.

Phospholipid metabolism is disturbed duringmyocardial ischemia. Several studies indicate that thedegradation of membrane phospholipid is associatedwith enhanced PLA2 activity stimulated by the Ca2+

overload and increase in cytokines [35]. This activa-tion leads to increased phospholipid catabolismand subsequently the liberation of lysophosphatidyl-choline (LPC). LPC has been reported to induce majorchanges in membrane function. It has been shownto increase the intracellular Na+ concentration byinhibiting myocardial Na-K+ ATPase and increasingthe burst of the Na+ influx, in turn producingCa2+ overload via the Na+-Ca2+ exchanger. It has beenadditionally reported that LPC might directly increasesarcolemmal permeability to Ca2+ and increase non-selective cation currents for Na+, K+, and Ca2+. All ofthese effects demonstrate that LPC is an arrhythmo-genic agent. In addition, LPC accumulation in cardiacmyocytes augments the activity of PLA2 via a positivefeedback mechanism [61-64].

In light of the above mentioned results a pharma-ceutical agent possessing antiphospholipase activitywould render protection against ischemia-reperfusiondamage. Manoalide, a phospholipase A2 inhibitor, hasbeen shown to protect the heart from the injuryby ischemia-reperfusion and by partially inhibitingthe degree of LPC-induced increase in Ca2+ [61].Mepacrine, another phospholipase inhibitor, whiledecreasing the level of phospholipid degradation,

22 CHAPTER 3

displayed a negative inotropic effect and appeared tointerfere with calcium currents across the sarcolemma[65]. Chlorpromazine and MR-256 (an oligomerof prostaglandin Ej) are two unrelated drugs, bothof which were shown to have a protective effect onischemia-reperfused heart due to their ability toinhibit PLA2 [66]. It has been further reported thatcoenzyme Q10 could inhibit the effect of PLA2 on innermembranes of myocardial mitochondria or dipalmi-toyl phosphatidylcholine, and in turn prevents thedevelopment of mitochondrial dysfunction and mito-chondria phospholipid hydrolysis by phospholipase[67]. Despite the encouraging results shown byphospholipase inhibitors, their mechanisms of actionare still unknown and specific agents need to bedeveloped.

Na+-H+ exchanger inhibitors

The sarcolemma Na+/H+ exchanger (NHE) is an elec-troneutral exchanger that extrudes one proton inexchange for one Na+ under normal conditions [68].At least five different isoforms of NHE are known toexist. NHE1, the most widely distributed type, is pre-dominant in cardiac tissue. It is thought to mediate anumber of physiological functions in various cell typesincluding maintenance of intracellular pH and cellvolume. Additionally, it controls cell growth and pro-liferation by mediating the action of a number ofmitogens and growth factors [69,70]. The acidosisinduced by a shift to anerobic metabolism duringischemia-reperfusion can activate the NHE. In fact,NHE activity was found to correlate with internal pH;the exchanger is maximally active at low intracellularpH (pH < 6.5) [70]. The intracellular Na+ level is elev-ated by the activation of NHE and this change leadsto Ca2+ overload via the Na-Ca2+ exchanger [71] andsubsequent cell injury via necrosis and/or apoptosisand ventricular arrhythmias. In chronic situations,ischemia-reperfusion injury stimulates NHE expres-sion and improves NHE synthesis; finally it inducesventricular remodeling and heart failure [69]. Al-though not fully understood, the above mechanismsindicate that an inhibitor of NHE may play a key rolein protection against ischemia-reperfusion injury.

A great deal of research is focused on studying theinhibitor of NHE as a potential treatment of ischemia-reperfusion injury [72,73]. Presently, NHE inhibitorsare investigated by the use of Na+ nuclear magneticresonance (NMR). Many inhibitors of NHE have been

used in clinical settings including amiloride and itsderivatives (EIPA, DMA, MIBA, HMA), or non-amiloride structure inhibitors, cariporide and HOE642 [72,74]. These are commonly known as selectiveNHE1 inhibitors. Since the early 1990s, it has beendemonstrated that amiloride and its derivativesreduced Na+ overload in cardiac ischemia-reperfusioninjury and consequently influenced Ca2+ accumula-tion [75-77]. Similarly, cariporide had no effect on thedecline in cytosolic pH while preventing the accu-mulation of intracellular sodium due to ischemia-reperfusion. A reduction in infarct size, enzymerelease, edema formation, arrhythmias and inductionof apoptosis in the ischemic reperfused myocardiumwere additionally observed [78]. Some NHE inhibitorssuch as SM-20550 were reported to reduce the Ca2+

and Na+ levels at the end stage of ischemia in guineapig Langendoff heart. These protective effects mightbe modulated at the mitochondrial level because HOE694, another inhibitor of NHE, prevented clumpingof Ca2+ aggregates in mitochondria. Clearly, themitochondria may play a major role in the regulationof both physiological and pathological cell deaths inmyocytes [79]. Currently, clinical studies are beingcarried out which may reveal that NHE inhibitorsare an effective intervention for the treatment ofischemia-reperfusion myocardial injury.

P38 MAP kinase inhibitors

MAP (mitogen-activated protein) kinases are re-cognized as regulators of cell growth and prolifera-tion. The MAP kinases are activated upon bindingof peptide growth factors to their tyrosine kinasereceptors. Three pathways are currently describedwhich ultimately lead to MAP kinase activation. Theseare adhesion molecules, G protein-coupled receptors,and stress-activated MAP kinase pathways. The stress-activated MAP kinase pathway plays an important rolein the response to ischemia-reperfusion in the heartsince this phenomenon presents a real pathologicalstress [80]. The MAP kinases involved in this pathwayinclude c-jun amino-terminal kinase, which phos-phorylates the transcription factor c-jun, and P38 MAPkinase. The increase in H2O2 concentration in theheart during ischemia and/or reperfusion couldactivate P38 MAP kinase [81,82]. Normally mitogenicMAP kinases stimulate protein synthesis and cellproliferation but inhibit apoptosis; however, stress-activated pathways promote apoptosis and cytokine


production. P38 MAP kinase appears to be a keyfactor in the signal transduction cascade of myocardialapoptosis proceeding ischemia and reperfusion [83-89]. In addition, P38 MAP kinase has been implied tophosphorylate 72-kDa heat shock protein and 27-kDaheat shock protein, which provide cytoprotection bystabilizing the actin cytoskeleton [90,91 ].

More research is being directed towards the inhibi-tion of the P38 MAP kinase pathway as an interventionin ischemia-reperfusion injury [92,93]. Currently, SB203580 is the most effective inhibitor of P38 MAPkinase. An important finding from current animalmodels is that myocardial treatment with SB 203580significantly decreases the level of cellular apoptosis,and equally significant is the improvement in cardiacfunction recovery after reperfusion [94,95]. SB203580 selective blocking of P38 MAP kinase activa-tion and inhibition of the critical component in thesignal transduction pathway leading to apoptotic celldeath explain these findings. Thus, SB 203580 hasthe capability to attenuate postischemic myocardialinjury and improve heart function recovery. It hasbeen reported that administration of SB 203580significantly attenuated postischemic myocardialnecrotic injury, since the protective effect of SB203580 against necrotic injury was related to its abilityto reduce early apoptosis in the ischemia reperfusedheart [93]. Although numerous studies support thenotion that P38 MAP kinase inhibition is protective[93,96,97], the benefits of inhibiting this kinase con-tinue to be a subject of controversy [98]. Furthermore,few effective agents have been found that are capableof inhibiting it.

Protein phosphatase inhibitors

Protein kinases have been studied for many yearsbecause of their important role in the regulation ofheart function; however, it has also been demon-strated that protein phosphatases play an equallyimportant role [99]. Protein phosphatases are cur-rently classified into two groups: type 1 (PP1) and2 phosphatase (PP2); type 2 is further subdividedinto PP2A, PP2B, and PP2C. Three major proteinphosphatases control cell function and these are PP1,PP2A, and PP2B. They comprise more than 90% ofthe phosphatase activity in mammalian cells. Thesephosphatases provide the cell with the ability torapidly change proteins from their phosphorylated todephosphorylated form in order to meet different

physiological needs such as cell cycle regulation, genetranscription, carbohydrate and lipid metabolism,organization of cytoskeleton, cholesterol and proteinbiosynthesis [ 100]. It has been postulated that proteindephosphorylation during ischemia could result indamage to the cytoskeletal integrity that leads to celldeath. It was believed that the heart can be protectedby inhibiting the dephosphorylation rate or by stimu-lating kinase activity to maintain protein phosphory-lation, which could be preserved by ATP utilizationunder physiological conditions[101,102].

Many phosphatase inhibitors have been widelyapplied in experimental research and clinical settings.Fostriecin is a highly selective inhibitor for PP2A andis used as an antitumor agent [103]. Although thereis no evidence to demonstrate the effectiveness offostriecin when applied to ischemic heart patients,several studies have suggested the beneficial effects offostriecin on ischemic heart disease in experimentalmodels [102,104,105]. In animal models this drug hasbeen reported to protect the heart from infarctionbefore or after the onset of ischemia. Weinbrenneret al. [101] have suggested that fostriecin may inhibitdephosphorylation of PKC-specific substrates andthus protect the heart during ischemia. In anotherstudy it was reported that fostriecin had similar car-dioprotective effects as preconditioning in both rabbitand pig models. This protection might occur via thesame effector's mechanism that preserves cytoskeletalphosphorylation and integrity of cell plasma [ 102,106].Vanadate is another protein phosphate inhibitor. Ithas been identified to inhibit the dephosphorylationof the aB-crystallin which is translocated to interca-lated disks and Z line to stabilize the myofibrils duringischemia in rat [107]. It was also demonstrated thatthis agent presents some other beneficial effects suchas attenuating acidosis and changing glucose utiliza-tion in isolated perfused rat heart [ 108]. Other proteinphosphatase inhibitors, such as okadaic acid, calyculinA, and cantharidin, have facilitated the study of pro-tein phosphatase function [109,110] and have beenshown to protect ischemic rat and rabbit cardiomy-ocytes [105,111].

Phosphodiesteraseinhibitor—pentoxifylline

Pentoxifylline, a derivative of theobromine, is asynthetic methylxanthine with a long side chain dis-placing the methyl group on the carbon position 1 of

24 CHAPTER 3

caffeine. Many experimental and pharmacodynamicstudies demonstrate the beneficial effect of pentox-ifylline in myocardial vascular disorder [112-118]. Inone study, 40 ischemic heart disease patients treatedwith pentoxifylline 600 mg per day for 25-30 daysshowed a reduction in glyceryl trinitrate consump-tion, improved exercise tolerance, improved EGGrecording, and reduced tachycardia [119]. The prim-ary pharmacodynamic effects of pentoxifylline aredue to increased red blood cell deformability anddecreased blood viscosity [119]. Dauber et al. [116]demonstrated that pentoxifylline attenuated the cor-onary microvascular protein leak and decrement inendothelium-dependent relaxation in the coronaryepicedial arteries after ischemia and reperfusion. Theincrease in neutrophil cyclic AMP induced by pentox-ifylline also diminishes superoxide production andadherence of neutrophils to vascular endothelium, aswell as a reduction in the response of neutrophil toplatelet-activating factor and cytokines such as TNF,interleukin 1 (IL-1) [120-122].

Cytokines are important mediators of cardio-vascular diseases. Myocardial ischemia-reperfusionprompts a release of cytokines and other inflam-matory mediators that cause coronary vascular injury.The specific target of such mediators appears to bethe endothelium and neutrophils. Inflammatorycytokines, such as TNF-a and IL-1, act on neutrophilsand adhere to the vascular endothelium inducing theobstruction of the capillary bed and the "no-reflow"phenomenon during reperfusion. Moreover, accu-mulation of TNF-a and IL-1 within ischemic tissuedirectly injures the tissue and releases proteolyticenzymes as well as oxygen free radicals, which inducefurther damage to the endothelium [ 123]. Other stud-ies have demonstrated that TNF-a directly decreasescontractile function in isolated hamster trabeculae,dogs, and human subjects [124,125]. This acutenegative inotropic effect of TNF-a interferes withCa2+ homeostasis, consequently disrupting excitation-contraction coupling and desensitizing the p-receptor[126]. In addition, TNF-a induces the production ofnitric oxide (NO), hence, desensitizing the myofila-ment sensitivity to Ca2+, which in turn mediates thelate contractile dysfunction [127]. The early con-tractile depression induced by TNF-a is mediated bysphingosine, an endogenous second messenger [128].Another mechanism of cardiac depression provokedby TNF-a is the induction of apoptosis in cardiomy-

ocytes, a process that appears to be mediated bysphingosine and nitric oxide [129-131]. The studiesindicate that anti-TNF-a therapy may be useful inischemia-reperfusion injury.

Reduction in TNF-a production has been shown tobe an important mechanism by which pentoxifyllineprotects against ischemia-reperfusion heart injury.This has been shown to occur in vitro and/or in vivo.Pentoxifylline decreases TNF-a synthesis via twomechanisms:1 One of its metabolites can inhibit the lysophospha-tidic acid acyltransferase that converts lysophospha-tidic acid to phosphatidic acid. This induces a rise inCa2+ concentration and an increase in the synthesis ofTNF-a [132].2 As an inhibitor of phosphodiesterase, pentoxifyllineinduces prolonged cyclic AMP activity resulting inactivation of protein kinase A, which serves to blocknuclear factor KB inhibition of TNF-a mRNA tran-scription [133]. This indicates that the phosphodi-esterase inhibitor blocks TNF-a gene transcriptionand consequently protein production [ 134].

Pentoxifylline was also reported to decreasemyeloperoxidase (MPO), an index of tissue leukocyteaccumulation in ischemic myocardium. This demon-strates that pentoxifylline modification significantlyreduced leukocyte adhesion [112,135]. In addition,pentoxifylline is an effective hydroxyl radical scav-enger, preventing endothelial injury by reactiveoxygen species [114]. Presently, pentoxifylline, withlimited side effects and favorable activity in hemorhe-ologic properties, has received attention for itsbeneficial effect in the ischemic heart disease. Someinvestigators postulate that it aided the effectivenessby reducing Ca2+ overload, but this mechanism stillneeds to be developed through future research.Pentoxifylline has gained widespread interest and iswidely considered as an effective intervention forischemia-reperfusion although the dosage and timeof treatment remains a subject of debate.

5-HT receptor antagonists

Serotonin (5-HT) is stored in platelets and releasedduring platelet aggregation. It is present in large quan-tities within the heart and is able to stimulate it directlyvia specific receptors. The receptors are classified as5-HTj, 5-HT2, 5-HT3, and 5-HT4 [136]. It has beenreported that 5-HT plays a role as a mediator of

Treatment of ischemia- reperfusion injury 25

inflammation, since neutrophil uptake of 5-HTresults in release of a vasoconstrictive substance. 5-HTsimilarly affects the function of other leukocytes suchas macrophages. The effects of 5-HT suggest a poten-tial therapeutic value on the process of reperfusioninjury after experimental ischemia [137]. In addition,5-HT has been found to provoke contraction ofisolated coronary arteries in various species; it maybe a major component in eliciting artery vasospasmand thus contribute to arrhythmias indirectly. Thefindings suggest that 5-HT may play a pathologic rolein a variety of low blood flow conditions.

It was believed that 5-HT is released during cer-tain types of myocardial ischemia, particularly whenthrombosis persists. The role of 5-HT is to amplify theocclusive event via activation of the 5-HT2 receptor.5-HT is also implicated in platelet-vessel wall interac-tions inducing vascular smooth muscle cell prolifera-tion, vasospasms, and arterial thrombosis. Therefore,5-HT receptor antagonists may offer possible treat-ments for ischemic heart disease [ 138]. Previous stud-ies were able to show the contractile effect of serotoninor 5-HT2 receptor agonists on isolated rat intramy-ocardial coronary artery, while 5-HT1A or 5-HT3

receptor agonists showed no contraction [139]. Thissuggests that the 5-HTj receptor mediates vasodilata-tion [140], while the 5-HT2 receptor mediates vaso-constriction. In the ischemic reperfused heart thereis marked impairment of endothelium-dependentrelaxation of the coronary arteries [141]. Thevascoconstriction of 5-HT2 occurs due to a defect inthe counterregulation of vasorelaxation by normalendothelial cells.

Since 5-HT2 receptors play a functional role inplatelet aggregation, thrombus formation, and theimpairment of endothelin-dependent relaxation ofarteries [142], many 5-HT2 receptor antagonists havebeen studied as intervention for ischemia-reperfusioninjury; these agents include MDL28, 133 A, LY53857,DV-7028, ICS 205-930, cinanserin, mianserin,ketanserin, and yohimbine [143-146]. Undoubtedly,in vivo studies of 5-HT2 receptor antagonists exhibitinhibition of 5-HT-induced platelet aggregation,decreased lysis time, and delayed reocclusion. In vitrostudies report that 5-HT2 receptor antagonistsincreased the time to contracture in isolated globallyischemic rat heart [147]. It was further suggested that5-HT might be implicated in the genesis and determi-nation of severity of ventricular arrhythmias induced

by acute myocardial ischemia, especially via 5-HT2

receptors. Hence, 5-HT2 receptor antagonists may beuseful therapeutic agents for these arrhythmias. Themechanism of 5-HT2-mediated effects may occurthrough activation of phospholipase C (PLC) andaccumulation of inositol phosphates causing therelease of Ca2+ from intracellular pools [148], yet theexact mechanism of 5-HT2 receptor antagonists thatattenuate ischemic injury is still unknown.

Conclusions

Ischemic heart disease is one of the most significantproblems facing clinicians now and in recent years.Therefore the need to understand the mechanismsunderlying ischemia-reperfusion injury and the devel-opment of effective treatments against it has grown tobe equally important. As summarized in Figures 3.1and 3.2, the causes of ischemia-reperfusion injuryinclude: Ca2+ overload for inducing contractilefailure and arrhythmias; production of cytokines(TNF-a, IL-1) for inducing apoptosis and myocytedysfunction; formation of oxygen-derived free rad-icals for disturbing membrane integrity, ion channeland enzyme function; and for inducing inflam-mation due to neutrophil accumulation. In this re-view we have discussed some of the interventions inischemia-reperfusion heart injury, focusing on gen-eral aspects (see Tables 3.1 and 3.2 for a summary).Pharmacological approaches to protect the heart fromischemia-reperfusion injury are currently present, butthey still need to be well established from futureresearch.

The multiple deleterious effects of ischemia-reperfusion injury remain a major challenge in pre-venting this type of dysfunction. Therefore at presentresearchers have devoted their efforts towards findinga high-quality agent to protect the heart, or test theeffect of a combination of drugs that have provenbeneficial for ischemia-reperfusion injury.

Acknowledgments

The work reported in this article was supported by agrant from the Canadian Institutes of Health Research(CIHR Group in Experimental Cardiology). N.S.D.held the CIHR/Pharmaceutical Research and Devel-opment Chair in Cardiovascular Research supportedby Merck Frosst Canada.

Figure 3.2 Causes of ischemia-reperfusion injury.


Table 3.1 Effects of antioxidants, Ca2+ channel blockers, Na+-H+ exchanger inhibitors, and phospholipase A2 inhibitors on

ischemia-reperfusion induced heart injury.

Class Drugs Target Effect Reference

Antioxidants

Ca2+channel blockers

Na+-H+ exchanger inhibitors

Phospholipase A2 inhibitors

Superoxide dismutase

Catalase

Glutathione

Vitamin E

Vitamin A

N-acetylcysteine

Verapamil

Nifidipine

Diltiazem

Amiloride

Cariporide

SM-20550

Mepacrine

Manoalide

Free radicals Decrease oxidative

metabolism

L-type Ca2+ channel Block Ca2+ influx,

protect energy-rich

phosphate reserve

Na+-H+ exchanger Reduce Na+ overload

[15,28,29]

[36]

[72, 74, 79]

Phospholipase A2 Reduce phospholipid [61,65]

degradation, maintain

membrane stabilization

Table 3.2 Effects of MAP kinase inhibitor, phosphodiesterase inhibitor, 5-HT2 receptor antagonists, and protein

phosphatase inhibitors on ischemia-reperfusion induced heart injury.

Class Drugs Target Effect Reference

MAP kinase inhibitor

Phosphodiesterase

inhibitor

5-HT2 receptor antagonists

Protein phosphatase

inhibitors

SB-203580

MDL28

133A

LY53857

DV-7028

ICS 205-930

Cinanserin

Miancerin

Ketanserin

Yohimbine

Fostriecin

Vanadate

P38 MAP kinase

Pentoxifylline TNF-a

5-HT2 receptor

Protein phosphatase

Reduce myocardial apoptosis, [94, 95]

improve cardiac function

Decrease the production [114, 120, 122]

of TNF-a, reduce the

endothelium-neutrophil

adhesion

Inhibit platelet aggregation [143-146]

Maintain the phosphorylated

state of some cytoskeletal

protein or protein kinase

[101,107]

28 CHAPTER 3

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32 CHAPTER 3

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129 Krown KA, Page MT, Nguyen C et al. Tumor necrosisfactor alpha-induced apoptosis in cardiac myocytes.Involvement of the sphingolipid signaling cascade incardiac cell death. / Clin Invest 1996; 98:2854-65.

130 Bergman MR, Holycross BJ. Pharmacological modula-tion of myocardial tumor necrosis factor alpha produc-tion by phosphodiesterase inhibitors. / Pharmacol ExpTher 1996; 279:247-54.

131 Vandenabeele P, Declercq W, Vanhaesebroeck B,Grooten J, Fiers W. Both TNF receptors are required forTNF-mediated induction of apoptosis in PC60 cells.JImmunol 1995; 154:2904-13.

132 Abraham E, Bursten S, Shenkar R et al. Phosphatidicacid signaling mediates lung cytokine expression andlung inflammatory injury after hemorrhage in mice.JExpMed 1995; 181:569-75.

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139 Deptuch TW, Kurenko-Deptuch M, Witanowska Aetal. Influence of selective 5-HT agonists and myocard-ial preconditioning on ischaemia/reperfusion inducedchanges in isolated heart of the rat. Inflamm Res 1999; 48(Suppll):S96-S97.

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CHAPTER 4

Anesthetic preconditioning: a newhorizon in myocardial protection

Nader D. Nader, MD, PHD, FCCP

Introduction

Ischemic heart disease and myocardial infarction aremajor causes of morbidity and mortality in developedcountries. According to statistics released by theAmerican Heart Association at least one in every fivedeaths is caused by heart attacks while an estimated12.6 million people are currently living with someform of coronary disease. In recent years, early reper-fusion of the ischemic myocardium has becomethe mainstay of optimal therapeutic management tolimit ventricular injury and infarct expansion, therebyimproving patient survival. It has become clear thatreperfusion promotes effective tissue repair anddecreases ventricular remodeling even under circum-stances where reperfusion is effected at too late a timeto limit myocardial necrosis. One of the strikingdifferences between reperfused and nonreperfusedmyocardial infarctions is that the early intense inflam-matory reaction, which ensues immediately uponreperfusion, has been demonstrated to potentiallyextend myocardial injury.

Reperfusion itself poses a threat to the ischemicmyocardium by increasing the generation of oxidantsthat trigger signal transduction pathways eventuallyleading to apoptosis, otherwise known as ischemia-reperfusion injury (IRI) [ 1 ]. IRI, which is a significantsource of morbidity, is potentially preventable withthe use of antioxidants or calcium antagonists [2]. IRIis generally characterized by a series of events startingwith reperfusion arrhythmias, microvascular damage,decreased myocardial systolic and diastolic function,and eventually ending with cell death [ 3 ].

Brief periods of myocardial ischemia and sub-sequent reperfusions are almost inevitable during

cardiac surgery. The incidence of ischemic insult andreperfusion is more common in coronary revascul-arization procedures; however, it is also seen in valvu-lar and even congenital cardiac surgery. The terms"stunned" and "hibernating myocardium" refer toabnormalities in the systolic and diastolic function ofthe heart following reperfusion. In both situationsmyocardial contractility and relaxation are deterior-ated while the cardiac myocytes are still viable. Inhibernating myocardium, however, a programmedcell death (apoptosis) pattern has been described.Myocardial ischemia results in utilization of adeno-sine triphosphate (ATP) stores secondary to theparalysis of aerobic metabolism and oxidative phos-phorylation. Immediate effects of this change includereduced lactate uptake and the loss of sarcoplasmicreticulum and mitochondrial membrane integrity.

Myocardial ischemia results in clinical symptomsranging from angina during exertion to acute massivemyocardial infarction leading to cardiogenic shockand/or lethal arrhythmias. Hypotheses have beenevolving around the pathophysiology of myocardialischemia-reperfusion injury. This chapter aims toreview the current theories describing the mechan-isms of myocardial injury associated with ischemia-reperfusion of the heart. It will also review novelfindings in the role of various anesthetic agents thatdemonstrate potential in being utilized for myocardialprotection. Although the use of these agents formyocardial protection is in its infancy, the widespreadutilization of anesthetics during cardiac surgerymakes them potential candidates for cardioprotectivepurposes in the future. The term "anesthetic precon-ditioning" is commonly used to note the similarityof anesthetic action to the mechanism of ischemic

33

34 CHAPTER 4

Figure 4.1 Alteration of ion exchangeduring myocardial ischemia-reperfusion.

preconditioning (IPC). Laboratory and clinical stud-ies have shown that single or multiple brief episodesof ischemia are not only nondeleterious but alsoappear to protect the myocardium against subsequ-ent ischemic episodes (e.g. stunning, infarction, andmalignant ventricular dysrhythmias). The timeframeof myocardial protection following IPC is bimodalwith an early peak within 1-2 h and a late peak appear-ing in 24 h and lasting 3 days. Although this phe-nomenon is first described in the heart, IPC is notorgan-specific and is a fundamental endogenousprotective mechanism against ischemic injury in avariety of tissues.

Cell biology of cardiac myocyteduring ischemia-reperfusion injury

The pathophysiology of IRI has been extensivelystudied over the past few years. A simplified diagramdepicting the cascade of the events during myocardialischemia-reperfusion is shown in Figure 4.1. In brief,following utilization of cellular stores of ATP, trans-location of calcium ions is greatly disturbed. Inabilityof cardiac myocytes to internalize and reuptake excesscytoplasmic Ca2+ leads to deposition of this ion intothe mitochondria. The sarcoplasmic reticulum isthe major organelle to eliminate the excess of Ca2+

from the sarcolemma. Although the influx of this ionis necessary for the contractile function of the cardiacmyocyte, an active reuptake and decline of cytoplas-mic Ca2+ is required for effective relaxation of cardiacmyocyte and its subsequent contraction.

Central to myocytic calcium homeostasis is the roleof mitochondrial adenosine triphosphate-sensitivepotassium channels (KATP). Opening of these chan-nels is crucial for the protective effects of IPC. As isshown in Figure 4.1, adenosine is the main ligand thatcontrols the opening and closure of these channels.KATp channels act as metabolic sensors, and its activa-tion leads to shortening of the action potential in thecardiac myocyte by limiting the rate of Ca2+ influx [4,5 ].Oral hypoglycemic agents, especially glybenclamide,are the specific antagonists of these channels andneutralize the protective effects of IPC. This may beconsidered of clinical importance for diabetic patientsreceiving oral hypoglycemic drugs. These drugs needto be investigated for their potential detrimental effectin patients undergoing coronary revascularizationprocedures. Volatile anesthetics have been shown toprotect the ischemic rabbit myocardium from infarc-tion [6]. Despite several potential targets of volatileanesthetics, KATp channels have been hypothesized tobe one of the major target proteins involved in cardio-protective effects of volatile anesthetics. Their effects

Anesthetic preconditioning 35

on the myocardium mimic the mechanism describedfor IPC, which is otherwise known as "anesthetic pre-conditioning". However, whether volatile anestheticsare able to open the KATP channel independently orthey just potentiate the effects of other agonists is stillcontroversial. A recent study on isolated guinea pigcardiac myocyte by Kwok et al. has demonstrated thatthe effects of isoflurane are additive to a specific ago-nist of the KATP channel, 2,4-dinitrophenol (DNP),and are reversed after the volatile agent is washed outof the perfusate [7]. These investigators also demon-strated that halothane either inhibits or has no specificeffects on the 2,4-DNP on KATP channels.

We have performed a series of experiments onisolated myocytes from the rat heart. The isolated cellswere loaded with fura-2 and paced at a frequency of1 or 2 Hz in a pacing chamber. The rate of changesin the light absorbency A340 (intracellular calcium)to A380 (extracellular calcium) ratio were measuredand graphed as a function of time (Figure 4.2, lowerpanel). We concurrently measured changes in thevoltage (index of length) over time (6V/8T) (Figure

4.2, upper panel). Our results indicate that there is atight coupling between myocyte shortening and cal-cium transients. During reperfusion subsequent to a30-min period of ischemia, there is a hypercontractile

state in the myocyte. Additionally, there is 20%increase in amplitude of calcium influx during reper-fusion. The addition of halothane to the perfusateuncouples calcium transients from the myocyte short-ening. Exposure of the myocyte to halothane alsodiminishes the extent of calcium transients, indicatingan inherent inhibitory effect of halothane on voltage-dependent calcium channels.

Inflammatory response tomyocardial ischemia

An inflammatory response is an important compon-

ent of the acute coronary syndromes. However, itsorigin and mechanism remain unclear. Inflammationplays an important role in mediating cardiac remodel-ing following an ischemic event. The intracellularexcess of Ca2+ results in activation of protein kinase C,mitogen-activated protein kinases (MIP kinases), andprotein tyrosine kinases, and subsequent activation ofdownstream inflammatory cascade following ischemia-reperfusion. It is evident that myocardial stunningand infarction following an ischemic event involvesan inflammatory component along with an electricalimbalance across the cell membrane. The inflam-matory component of this process will be discussed in

Figure 4.2 Rat cardiac myocytes were isolated and loaded with fura-2. Changes in voltage and A340/380 were plotted overtime while the cells were paced in a pacing chamber perfused with media culture solution vaporized with halothane.

36 CHAPTER 4

detail below. Chronic inflammation is also implicatedin the pathogensis of atheromatous plaque and devel-opment of atherosclerosis and resultant ischemicheart diseases. However, the focus of this review is toidentify local and systemic responses following anacute ischemic event and how they contribute to thepathophysiology of myocardial function.

Cytokine responseCytokines modulate immunologic processes, inflam-mation, proliferative responses, and apoptosis. Recentstudies have focused on the role of proinflammatorycytokines in cardiovascular diseases. Proinflammat-ory cytokines, such as interleukin 6 (IL-6), IL-lp andtumor necrosis factor alpha (TNF-a) play import-ant roles in acute coronary syndrome by regulatinginflammation, cellular adhesion, and the productionof growth factors and various vasoactive substances.Reperfusion after myocardial infarction and transientmyocardial ischemia induces the generation of pro-inflammatory cytokines, which in part play a rolein producing myocardial injury during IRI [8-11].Expression of proinflammatory cytokines in the iso-lated heart model of myocardial ischemia is furtherevidence for the myocardial source of these inflam-matory mediators [12]; however, a role for cardiacresident mast cells cannot be ruled out [13,14]. It hasalso been suggested that the IRI-induced release ofproinflammatory cytokines is involved in neutrophilchemotaxis to the site of inflammation [15,16]. TNF-oc and IL-6 are major stimulating factors for CXCchemokine (IL-8) production from macrophages [ 15].

IL-6 is an acute reactant cytokine with very earlyexpression following reperfusion of the infracted myo-cardium [17]. Serum levels of IL-6 are elevated aftermyocardial infarction (MI), and the myocardium isthe major site of IL-6 production during myocardialischemia [18]. IL-6 delays the apoptosis processin neutrophils, resulting in a larger population ofneutrophils with greater capacity for oxidant produc-tion [19]. IL-6 is also the primary stimulus for inter-cellular adhesion molecule 1 (ICAM-1) induction, andenhances neutrophil-endothelium and neutrophil-monocyte adhesion and interactions [15]. IL-6 alsohas a regulatory role in the generation of othercytokines such as IL-8. The effects of IL-6 on neu-trophils are postulated to play a role in the mech-anisms whereby IL-6 contributes to multiple organdysfunction [20].

Both mRNA and protein levels of TNF-a andIL-6 are increased within 15-30 min of left anteriordescending artery (LAD) occlusion in the hearthomogenates, and these elevated levels are generallysustained for 3 h [ 17]. These studies indicate that dur-ing early reperfusion, mRNA levels for IL-6 and trans-forming growth factor betaj (TGF-pj) are significantlyreduced compared with permanent LAD occlusion. Inboth groups, cytokine mRNA levels all returned tobaseline levels at 24 h, while IL-lp, TNF-a and TGF-Pj mRNA levels again rose significantly at 7 days onlyin animals with permanent LAD occlusion. However,the exact role of these cytokines in mediation of theinjury is not clear [21]. Neutralization of local TNF-a release from cardiac myocytes after ischemia byspecific antibody improves myocardial recovery dur-ing reperfusion [22,23], although we have not beenable to reproduce these results in isolated rabbithearts. By contrast, our data indicate that administra-tion of recombinant TNF-a to the isolated heart dur-ing reperfusion following 15 and 50 min of ischemiaimproves both contractile function and myocardialrelaxation. This functional improvement, however, isnot associated with decreases in myocytic damageas examined by the release of myoglobin and troponinI into the perfusate solutions. This finding indic-ates that postischemic autocrine and paracrine TNF-a activity plays an important role in myocardialfunction.

In a murine model of myocardial IRI, the extent ofreperfusion-induced apoptosis is modulated by theinflammatory process, during which locally producedTNF-a plays a significant role in the developmentof tissue injury. Subsequently, this proinflammatoryreaction is followed by endogenous production of theanti-inflammatory cytokine IL-10, which serves as aphysiological counterbalance to the effects of TNF-a[24]. There is also evidence that exogenous adminis-tration of IL-10 reduces cellular injury following IRIin the myocardium, as evident by increases in tissueinhibitor of metalloproteinases (TIMP)-l mRNAexpression [24,25]. This protective effect is also dueto an inhibitory effect of IL-10 on generation ofTNF-a. We postulate that the duration of ischemia is amajor determinant of the pattern of cytokine expres-sion that may lead to activation of protective versusinjurious cytokines. Exposure of isolated humanperipheral mononuclear cells to halothane, enflurane,or sevoflurane demonstrates suppressive effects of


Figure 4.3 Blood samples wereobtained from both a coronary sinuscatheter and an indwelling arterialcatheter for patients undergoingCABG surgery. IL-6 was measured inplasma samples using an ELISAtechnique.

IL-1 (3 and TNF-a release [26]. The anti-inflammatoryeffect of these volatile anesthetics may also be bene-ficial in limiting the extent of IRI after percutaneoustransluminal coronary angioplasty (PTCA) and/orcoronary artery bypass. Ultimately, by identifyingthe exact mechanisms of signaling that lead to theactivation of proinflammatory cytokines, we will be

able to modify these responses to maximize the levelof cardiac protection.

Several anesthetic agents decrease the extent ofinflammatory cytokine response to myocardial IRI.We have previously assessed the effects of sevofiurane-

vaporized cardioplegia solution on the local genera-tion and release of TNF-a and IL-6 into the coronarysinus blood during aortic cross-clamping in patientsundergoing coronary artery bypass surgery. Ourresults indicate that the concentrations of both IL-6and IL-8 significantly increase following the release ofaortic cross-clamp when compared to their baselinelevels in the coronary sinus blood. The concentra-

tions of these cytokines partly declined by the fourthhour after termination of cardiopulmonary bypass.Vaporizing cardioplegia solutions with sevofluraneblunts the initial IL-6 and IL-8 response locally(Figure 4.3). TNF-a levels were not detectable ineither group of patients. Using a rabbit model ofmyocardial IRI we have demonstrated that the con-centration of TNF-a increases after 4 h in the tissuehomogenates obtained from the heart following15 min occlusion of the LAD. Exposure of theseanimals to isoflurane attenuates the TNF-a band onthe Western blotting, while propofol (an intravenousanesthetic) accentuates the tissue concentration ofthis cytokine (Figure 4.4). Interestingly, blockingTNF-a does not improve the myocardial contrac-tion or relaxation following ischemia-reperfusionof global anoxia-reoxygenation in isolated hearts.Troponin T and myoglobin release from the isolatedhearts are also not affected by blocking TNF-a duringreperfusion.

Figure 4.4 Western blotting performedon heart homogenates prepared afteran in vivo ischemia (10 min) andsubsequent reperfusion for 4 h. Thisdemonstrates an increase in localexpression of this cytokine 4 h afterIRI that is blunted by isoflurane.Recombinant rabbit TNF-a was usedfor the positive control (lane 1).

I

38 CHAPTER 4

Propofol is an intravenous anesthetic that is oftenused in cardiac surgery due to its favorable pharma-cokinetic effects of rapid awakening, low incidence ofnausea, and ease of titration control [27]. Further-more, propofol may prove beneficial in reducing IRIdue to its structure, similar to vitamin E, which gives itfree radical scavenging properties [28,29], and alsocalcium channel blocking properties [30,31]. Despitethis, conflicting studies on its ability to reduce IRI hasmade propofol a well-studied but controversial topicover the past few years. Some clinical and experi-mental studies find that in normal hearts, propofol hascardiodepressive effects such as decreasing myocardialcontractility and relaxation, whereas other studies,involving ischemic hearts, report a cardioprotectivefunction, or no effect of reducing IRI. For example,studies involving ischemic rat hearts, which under-went global ischemia for 25 min or 1 h with immedi-ate reperfusion of 30 min or 1 h, respectively, suggestthat propofol, in high doses, facilitates the recoveryof myocardial contractility, decreases the release oflactate dehydrogenase (LDH) and histological injury,and attenuates the increase of left ventricular end-diastolic pressure during ischemia and reperfusion[28,32]. On the other hand, a recent study by De Hertetal. found a load-dependent decrease in dP/dT(max)which was preserved in patients anesthetized withsevoflurane [33].

Ketamine, another intravenous anesthetic in clin-ical use, has been reported to inhibit the productionof TNF-a following endotoxin stimulation in a dose-dependent manner [34]. Ketamine also significantlyimproved arterial oxygen tension (Pao2), metabolicacidosis and hypoglycemia, and attenuated endotoxin-induced hepatic injury in a dose-dependent fash-ion. In addition, ketamine treatment significantlyimproved lipopolysaccharide-induced lethality incarrageenan-sensitized mice [35]. The majority ofanti-inflammatory effects of ketamine are mediatedvia its action on neutrophils.

Neutrophilic inflammatory response tomyocardial ischemiaInflammatory cells are recruited to the area of theinjury if the ischemic event leads to necrosis of cardiactissue. This recruitment is part of a physiologic repairmechanism in action to promote ventricular remodel-ing and adaptation of the injured myocardium tothe altered geometry of the heart. Since the cardiac

myocyte is a well-differentiated omnipotent cell, itsrepair mechanism involves fibrosis and replacementof cardiac tissue with fibroblasts and scar forma-tion. Neutrophils are the predominant phagocytes inthe early stages of myocardial ischemia-reperfusionresponse and are also implicated in the developmentof tissue damage. Neutrophils are quickly recruitedto the site of myocardial infarction following experi-mental occlusion of coronary arteries in animalmodels [16]. This neutrophilic infiltration is evidentby increases in myeloperoxidase activity measured inthe heart homogenates of these animals. Mechanismsby which neutrophils are attracted to the myocard-ium in ischemia/reperfusion are not fully defined.Lipopolysaccharide-induced CXC chemokine (LIX),cytokine-induced neutrophil chemoattractant (KG),and macrophage inflammatory protein-2 (MIP-2)are rodent chemokines with potent neutrophil-chemotactic activity. In humans, IL-8, which is ananalog of the rodent MIP-2, seems to be a majorchemotactic factor that promotes neutrophil recruit-ment. IL-8 is produced by various other types of cellsfollowing inflammatory stimuli and exerts a variety offunctions on leukocytes [36]. Furthermore, comple-ment activation and release of C5a play some rolein neutrophil activation and migration to the siteof myocardial injury. LIX is highly regulated in thecardiac myocytes following an ischemic event and itsregulation is mediated through a redox stress andactivation of nuclear factor kappa B (NFKB) [37].

Upon reperfusion, neutrophils accumulate and pro-duce an inflammatory response in the myocardiumthat is responsible in part for the extension of tissueinjury associated with reperfusion [24,38]. Neutrophilactivation occurs in two phases following IRI [39].The early phase is a result of complement activation(release of C5a), and it is abolished in a C6-deficientanimal model [40]. Activation of neutrophils at thisphase results in further generation of IL-8. Myocardialischemia and reperfusion result in release of chemoat-tractants in response to locally produced endothelin1 proteins [41]. Local generation of complement-related chemotactic factors is presumed to mediate thesequence of events leading to the infiltration of neu-trophils at inflammatory sites. It has been shown thatpatients with acute myocardial infarction have a tran-sient but significant rise in serum IL-8 concentrationwithin 24 h after the onset of symptoms, whereas IL-8is not detected in any of the samples from patients


Figure 4.5 Flow cytometry of peripheral blood cells performed on samples obtained from the coronary sinus (pre and post

CPB) and a peripheral artery (4th post CPB) from left to right. The blood cells were stained with antiCDI 3-cy5, antiCD11 b-

PE, and antiCD18-FITC. CD13+ cells were gated and counted to a total number of 5000 cells.

with angina pectoris or normal controls [42]. Thetransient nature of the plasma IL-8 elevation is prob-ably due to a high affinity of this cytokine for the redblood cells [43]. Similar findings have been reportedin a canine model of myocardial ischemia with mRNAupregulation of IL-8 and evidence for its presence inthe inflammatory infiltrate near the border betweennecrotic and viable myocardium [44]. IL-8 initiatesneutrophil recruitment by increasing the expressionof (3-integrins. The effect of TNF-oc on adherenceis significantly inhibited by monoclonal antibodyagainst ICAM-1, indicating a regulatory role for thiscytokine in expression of ICAM-1 following myocar-dial ischemia [45].

The leukocyte-adhesion molecule family GDI I/CD 18 ((32 integrins) is critical to the function of neu-trophils and monocytes in inflammation and injury[46]. These interactions are exaggerated during IRI bytriggering the expression of E-selectin mRNA in the

reperfused organ [47]. Our clinical studies indicatethat the CD lib/CD 18 ratio dramatically increasesfollowing cardiopulmonary bypass, suggesting activa-tion of neutrophils during cardiopulmonary bypass(Figure 4.5). In vivo activation of neutrophils is initi-ated by the adherence of these cells to the proteinsexpressed on the surface of vascular endothelium."Tethering" of these adhesion molecules to theendothelium stimulates neutrophilic oxygen "burst"and generation of reactive oxygen species [48]. Activa-tion of neutrophils occurs in response to complementactivation secondary to cardiopulmonary bypass (CPB)and release of IL-8 from the myocardial origin due to

ischemia and reperfusion. In our laboratory measure-ment of IL-8 in the blood draining from the coronarysinus has demonstrated significant rises of thischemokine. The CD lib/CD 18 ratios parallel the risesof IL-8 concentrations, implying the importance ofischemia-reperfusion in initiating the inflammatorycascade leading to neutrophilic activation. However,the use of CPB also results in upregulation of (3-integrins on the surface of neutrophils through theactivation of complement (alternate pathway). Whilesevoflurane-vaporized cardioplegia does not affect thealternate pathway—activation of complement due toCPB—it significantly decreases IL-8 generation andthe classic pathway of complement as quantified bymeasurement of C4b component of the complementsystem. Therefore, we hypothesize that the main anti-inflammatory effects of sevoflurane are mediatedthrough its inhibitory role in myocardial IRI.

Furthermore, concurrent perfusion of isolatedhearts with neutrophils and platelet activating factor(PAF), a phospholipid mediator of inflammation,results in detrimental mechanical function andconduction blocks. Specific antagonists of PAF andeicosanoids such as leuktrienes can effectively blockthe negative inotropic and arrhythmogenic effects ofneutrophils [49]. Regardless of the source of stimula-tion, activated leukocytes are attracted to the ischemicmyocardium secondary to upregulation of ICAM-1in the ischemic tissue and will result in neutrophil-induced injury to the myocardium at risk. Neutrophilsactivated in this manner generate PAF, and the effectsof their activation are prevented by blockade of

40 CHAPTER 4

PAF receptors. Thus, during reperfusion of ischemicmyocardium, PAF generated by activated neutrophilsis most likely a cause of arrhythmias [50]. In sum-mary, damage to the heart due to IRI is a source ofmorbidity and mortality during revascularizationprocedures. Volatile anesthetics reduce postischemicadhesion of neutrophil in the coronary system, anddecrease adhesion to cultured human endothelial cells

[51].

The role of oxidants as neutrophilicmediators of ischemia-reperfusioninjuryOxidative metabolism and generation of reactiveoxygen species (ROS) are also increased in the pres-ence of oxygen excess during the reperfusion phase.In myocardial IRI, neutrophils and the ischemicmyocytes are "primed" for free radical production[52]. With reperfusion and reintroduction of mole-cular oxygen there is a burst of oxygen radical pro-duction resulting in extensive tissue destruction.Limitation of infarct size in anesthetized dogs follow-ing occlusion and reperfusion of the left circumflexcoronary artery by ibuprofen has been associatedwith marked suppression of leukocyte accumulationwithin the ischemic myocardium [53]. The poten-tial sources of ROS during myocardial IRI includethe mitochondrial electron transport system [54],prostaglandinbiosynthesis [55], activated neutrophilsthat infiltrate ischemic and reperfused myocardium,and the enzymatic pathway involving xanthine oxi-dase which is localized within the vascular endothe-liuni in many animal species [56]. The oxidase formof this enzyme is generated upon activation of Ca2+-proteases [57]. CI-959, a cell-activation inhibitorthat prevents the formation of ROS by inflammatorycells, significantly reduces the myocardial infarct sizewithout causing thinning of the resultant scar [58].A protective effect of superoxide dismutase againstmyocardial IRI further signifies the role of neutrophil -mediated myocardial damage [59]. A recent study byZilberstein et al. has demonstrated that administra-tion of ketamine inhibits superoxide generation byperipheral neutrophils following cardiopulmonarybypass. Furthermore, inclusion of ketamine in theanesthesia induction results in inhibition of super-oxide generation by neutrophils following chemicaland bacterial stimulation. This inhibition lasts up to7 days following cardiopulmonary bypass [60].

Although there is a general agreement about theinjurious nature of oxidant excess in tissues, mito-chondrial generation of these reactive species is neces-sary for full protection of IPC and volatile anesthetics.A recent study has demonstrated that the beneficialeffects of isoflurane are eliminated by antioxidant pre-treatment. These antioxidants do not have any directeffect on myocardial function during IRI. Oxidat-ive metabolism is also regulated by KATP channelslocated on the surface of mitochondria. Opening ofthese channels enhances the oxidative metabolismand subsequent changes of the redox state of themitochondria. On the other hand, cytoplasmic con-centrations of ROS adversely affect the enzymaticfunction and membrane integrity through carbonyla-tion and peroxidation of protein and lipid molecules.Furthermore, ROS alter gene expression and deterio-ration of transcription machinery through their effectson DNA molecules.

Conclusions

Anesthetic agents are a hydrophobic class of chemicalswith high affinity to the lipid membrane of living cells.This particular characteristic of anesthetics makesthem potentially active on cellular ion exchange andseveral membrane-related functions of mammaliancells. Myocardial ischemia and reperfusion involvesmultiple steps in the process of cellular injury, rang-ing from reversible electrical imbalance to activationof the inflammatory cascade leading to cell death.Various anesthetic agents offer protective effects atboth electrical and inflammatory stages of IRI. Inclu-sion of these agents in myocardial protection strate-gies will potentially provide a novel venue to preservethe myocardial function and minimize cellular dam-age to the heart during cardiac surgery.

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18 Guillen I, Blanes M, Gomez-Lechon MJ, CastellJV. Cytokine signaling during myocardial infarction:sequential appearance of IL-1 beta and IL-6. AmfPhysiol1995; 269: 229-35.

19 Biffl WL, Moore EE, Moore FA et al. Interleukin-6 delaysneutrophil apoptosis. Arch Surg 1996; 131: 24-9.

20 Biffl WL, Moore EE. Splanchnic ischaemia/reperfusionand multiple organ failure. BrJAnesth 1996; 77: 59-70.

21 Eddy LJ, Goeddel DV, Wong GH. Tumor necrosisfactor-alpha pretreatment is protective in a rat model of

myocardial ischemia-reperfusion injury. Biochem BiophysResCommun 1992; 184:1056-9.

22 Gurevitch J, Frolkis I, Yuhas Y et al. Tumor necrosisfactor-alpha is released from the isolated heart undergo-ing ischemia and reperfusion. JAm Coll Cardiol 1996; 28:247-52.

23 Gurevitch J, Frolkis I, Yuhas Y et al. Anti-tumor necrosisfactor-alpha improves myocardial recovery after ischemiaand reperfusion. JAm Coll Cardiol 1997; 30:1554-61.

24 Daemen MA, van de Ven MW, Heineman E,Buurman WA. Involvement of endogenous interleukin-10 and tumor necrosis factor-alpha in renal ischemia-reperfusion injury. Transplantation 1999; 67: 792—800.

25 Frangogiannis NG, Mendoza LH, Lindsey ML et al.IL-10 is induced in the reperfused myocardium and maymodulate the reaction to injury. / Immunol 2000; 165:2798-808.

26 Frohlich D, Wittmann S, Rothe G, Schmitz G, Taeger K.Thiopental impairs neutrophil oxidative response byinhibition of intracellular signalling. Eur ] Anaesthesiol2002; 19: 474-482.

27 Schuttler J, Stoeckel H, Schwilden H. Pharmacokineticand pharmacodynamic modelling of propofol ('Diprivan')in volunteers and surgical patients. Postgrad Med J 1985;61(Suppl.3):53-54.

28 Ko SH, YuCW, Lee SK et al. Propofol attenuatesischemia-reperfusion injury in the isolated rat heart.AnesthAnalg 1997; 85: 719-24.

29 Kokita N, Hara A. Propofol attenuates hydrogenperoxide-induced mechanical and metabolic derange-ments in the isolated rat heart. Anesthesiology 1996; 84:117-27.

30 Cain BS, Meldrum DR, Harken AH. Protein kinase C innormal and pathologic myocardial states. J Surg Res 1999;81:249-59.

31 Ebel D, Schlack W, Comfere T, Preckel B, Thamer V.Effect of propofol on reperfusion injury after regionalischaemia in the isolated rat heart. Br J Anesth 1999; 83:903-8.

32 Mathur S, Farhangkhgoee P, Karmazyn M. Cardiopro-tective effects of propofol and sevofiurane in ischemicand reperfused rat hearts: role of K (ATP) channels andinteraction with the sodium-hydrogen exchange inhibitorHOE 642 (cariporide). Anesthesiology 1999; 91: 1349-60.

33 De Hert SG, ten Broecke PW, Mertens E et al. Sevofiuranebut not propofol preserves myocardial function in cor-onary surgery patients. Anesthesiology 2002; 97:42-9.

34 Takenaka I, Ogata M, Koga K, Matsumoto T, ShigematsuA. Ketamine suppresses endotoxin-induced tumornecrosis factor alpha production in mice. Anesthesiology1994; 80: 402-8.

35 Koga K, Ogata M, Takenaka I, Matsumoto T, ShigematsuA. Ketamine suppresses tumor necrosis factor-alphaactivity and mortality in carrageenan-sensitized endo-toxin shock model. Circ Shock 1994; 44:160-8.

36 Harada A, Sekido N, Akahoshi T et al. Essential involve-ment of interleukin-8 (IL-8) in acute inflammation.JLeukocBiol 1994; 56:559-64.

42 CHAPTER 4

37 Chandrasekar B, Smith JB, Freeman GL. Ischemia-reperfusion of rat myocardium activates nuclearfactor-kappa B and induces neutrophil infiltration vialipopolysaccharide-induced CXC chemokine. Circula-tion 2001; 103:2296 -302.

38 Bohle RM, Pich S, Klein HH. Modulation of theinflammatory response in experimental myocardialinfarction. EurHeart J1991; 12 (Suppl. D): 28-31.

39 Ivey CL, Williams FM, Collins PD, Jose PJ, Williams TJ.Neutrophil chemoattractants generated in two phasesduring reperfusion of ischemic myocardium in therabbit. Evidence for a role for C5a and interleukin-8[comment]./C/mInvest 1995; 95: 2720-8.

40 Kilgore KS, Park JL, Tanhehco EJ et al. Attenuation ofinterleukin-8 expression in C6-deficient rabbits aftermyocardial ischemia/reperfusion. / Mol Cell Cardiol1998; 30: 75-85.

41 Hofman FM, Chen P, Jeyaseelan R et al. Endothelin-1induces production of the neutrophil chemotactic factorinterleukin-8 by human brain-derived endothelial cells.Blood 1998; 92:3064-72.

42 Abe Y, Kawakami M, Kuroki M et al. Transient rise inserum interleukin-8 concentration during acute myocar-dial infarction. BrHeartJ1993; 70:132^4.

43 de Winter RJ, Manten A, de Jong YP et al. Interleukin 8released after acute myocardial infarction is mainlybound to erythrocytes. Heart 1997; 78:598-602.

44 Kukielka GL, Hawkins HK, Michael L et al. Regulation ofintercellular adhesion molecule-1 (ICAM-1) in ischemicand reperfused canine myocardium. / Clin Invest 1993;92:1504-16.

45 Ikeda U, Ikeda M, Kano S, Shimada K. Neutrophiladherence to rat cardiac myocyte by proinflammatorycytokines. / CardiovascPharmacol 1994; 23: 647-52.

46 Dana N, Fathallah DM, Arnaout MA. Expression of asoluble and functional form of the human beta 2 integrinGDI Ib/CDlS.ProcNatlAcadSciUSA 1991; 88:3106-10.

47 Billups KL, Palladino MA, Hinton BT, Sherley JL. Expres-sion of E-selectin mRNA during ischemia/reperfusioninjury. ]Lab Clin Med 1995; 125:626-33.

48 Walzog B, Jeblonski F, Zakrzewicz A, Gaehtgens P. Beta2integrins (GDII/CD 18) promote apoptosis of humanneutrophils.FASEB/1997; 11:1177-86.

49 Alloatti G, Montrucchio G, Emanuelli G, Camussi G.Platelet-activating factor (PAF) induces platelet/neu-trophil cooperation during myocardial reperfusion. JMolCell Cardiol 1992; 24:163-71.

50 Hoffman BF, Feinmark SJ, Guo SD. Electrophysiologiceffects of interactions between activated canine neu-trophils and cardiac myocytes. / Cardiovasc Electrophysiol1997; 8:679-87.

51 Kowalski C, Zahler S, Becker BF et al. Halothane,isoflurane, and sevoflurane reduce postischemic adhe-sion of neutrophils in the coronary system. Anesthesiology1997; 86:188-95.

52 Hammond B, Kontos HA, Hess ML. Oxygen radicals inthe adult respiratory distress syndrome, in myocardialischemia and reperfusion injury, and in cerebral vasculardamage. Can JPhysiol Pharmacol 1985; 63:173-87.

53 Werns SW, Shea MJ, Lucchesi BR. Free radicals inischemic myocardial injury. / Free Radic Biol Medl985;1:103-10.

54 Otani H, Tanaka H, Inone T et al. In vitro study on con-tribution of oxidative metabolism of isolated rabbit heartmitochondria to myocardial reperfusion injury. Circ Res1984;55:168-75.

55 Egan RW, Gale PH, Kuehl FA Jr. Reduction of hydroper-oxides in the prostaglandin biosynthetic pathway by amicrosomal peroxidase. / Biol Chem 1979; 254: 3295-302.

56 Jarasch E, Bruder G, Heid H. Significance of xanthineoxidase in capillary endothelial cells. Acta Physiol Scand1986; 548: 39-46.

57 Parks D, Granger D. Xanthine oxidase: biochemistry,distribution and physiology. Acta Physiol Scand 1986;548:87-99.

58 Burke SE, Wright CD, Potoczak RE et al Reduction ofcanine myocardial infarct size by CI-959, an inhibitor ofinflammatory cell activation. / Cardiovasc Pharmacol1992; 20:619-29.

59 Alloatti G, Montrucchio G, Camussi G. Role of platelet-activating factor (PAF) in oxygen radical-induced cardiacdysfunction. J Pharmacol Exp Ther 1994; 269: 766-71.

60 Zilberstein G, Levy R, Rachinsky M et al. Ketamineattenuates neutrophil activation after cardiopulmonarybypass. Anesth Analg 2002; 95:531-6.

CHAPTER 5

Myocardial protection duringacute myocardial infarctionand angioplasty

Alexandre C. Ferreira, MD, FACC &Eduardo deMarchena, MD, FACC

Survival of ischemic myocardium requires timelyreperfusion. It has been demonstrated that reperfu-sion has a harmful and injurious component, whichin experimental models appears to be mediated byreperfusion-induced augmentation of the inflammat-ory response and generation of reactive oxygen freeradicals [ 1 ].

Myocardial protection, during myocardial infarctor percutaneous coronary intervention, is achievedby strategies which attempt to either decrease oxygenrequirements by the ischemic myocardium, makemyocytes more resistant to ischemia, and/or decreasereperfusion injury.

The timing and mechanism ofreperfusion

Critically well-timed coronary reperfusion as treat-ment for acute myocardial infarction (AMI) reducesmyocardial infarct size, enhances recovery of left ven-tricular function, and improves short and long-termsurvival. There is still concern that at the time of reper-fusion a further injury occurs to the myocardium. Atleast in theory, if reperfusion injury could be pre-vented or eliminated, the outcome for patients withmyocardial infarction may improve. The generalnotion of reperfusion injury is closely connected to theconcept that oxygen radicals generated at the time ofreperfusion cause cell death and necrosis [2]. At leastfour expressions of myocardial reperfusion injuryhave been defined:

1 Reperfusion arrhythmias.2 Postischemic contractile dysfunction or myocardialstunning.3 Coronary vascular and microvascular reperfusioninjury.4 Precipitation of necrosis in reversibly injured cells.

The speed and completeness of reperfusion dependson the type of strategy used for reperfusion, primaryangioplasty, or thrombolytic therapy. At least in theelderly, patients with extensive infarct and heartfailure, there is superiority of a mechanical reperfu-sion over thrombolitic agents. There may be severalexplanations for the smaller myocardial infarct sizeafter primary angioplasty. First, a higher rate of openinfarct-related vessels after angioplasty may resultin more effective myocardial salvage. Thrombolyticagents will achieve reperfusion at best in 60% ofpatients. Clinical trials of angioplasty in AMI havebeen found to achieve reperfusion in over 90% ofpatients. A second explanation of the better resultsafter angioplasty is that reperfusion is faster or morecomplete with angioplasty. Further, aggressive anti-coagulation can lead to hemorrhagic conversion ofinfarct, a phenomenon that reflects severe micro-vascular injury with extravasation of erythrocytes [3].

Thrombolytic agents may also have a proinflam-matory effect. An extensive neutrophil aggregationcaused by thrombolytic therapy may promote myo-cardial injury. A higher reocclusion rate due to aprocoagulant activity and a depletion of the reservoirof plasminogen in serum reduces clot lysability and

43

44 CHAPTER 5

therefore the efficacy of these agents. Left ventriculardysfunction, which has also been described after treat-ment of AMI, varies with the reperfusion strategy. Inone animal model, the induction of a systemic lyticstate resulted in immediate echocardiographic andearly histologic alterations characteristic of reperfu-sion injury and was associated with impaired func-tional recovery of the myocardium. Such effects arenot observed with direct recanalization of thromboticocclusions by mechanical interventions [4].

Regardless of the mechanism of reperfusion, fur-ther improvement is feasible if myocardial cells aremade more resistant to ischemia, oxygen requirementis reduced and reperfusion injury is avoided.

Making myocytes more resistant toischemic injury

Ischemic preconditioningExperimental studies indicate that brief, transientepisodes of ischemia render the heart very resistantto infarction from a subsequent sustained ischemicinsult, an effect termed "ischemic preconditioning."Transient and repetitive occlusion of a coronary arteryin the catheterization laboratory is associated withprogressively less intense chest discomfort and a lesserdegree of electrocardiographic abnormalities. It hasbeen demonstrated that preconditioning myocard-ium before prolonged occlusion with brief ischemicepisodes affords substantial protection to the cellsby delaying lethal injury, thereby limiting infarct size[5]. The mechanism of ischemic preconditioningis not totally understood. Some oral hypoglycemicagents appear to block the ischemic preconditioningresponse in diabetics. This effect may be due to block-ade of potassium channels. Adenosine receptors andadrenoreceptors may also play a pivotal role in thisprocess.

Animal studies have suggested that stimulation ofadenosine receptors can be a critical event in ischemicpreconditioning. Human studies have shown thatexogenous adenosine administration can limit signsof ischemia with repetitive coronary occlusion, andpretreatment with agents that block adenosine re-ceptors, either selectively or nonselectively, can alsolimit ST-segment depression with repetitive coronaryocclusion.

Adrenoreceptors are ubiquitous to all mammalianspecies. There are clinical and animal data to suggest

that they play an important role in mediating ischemicpreconditioning. During cycles of myocardial ischemia,cardiomyocytes have to depend exclusively onanerobic glycolysis for energy production. Stimulationof alphaj-adrenoreceptors increases glucose transportinside the cardiomyocytes and enhances glycogenolysisby activating phosphorylase kinase. It also causesan increase in the rate of glycolysis by activating theenzyme phosphofructokinase. Stimulation of alphaj-receptors also inhibits apoptosis by increasing thelevels of the antiapoptotic protein Bcl-2.

Interestingly, myocardial ischemia produces anincrease in the expression of alphaj-adrenoreceptorsin cardiomyocytes. The levels of the alphaj-agonist,norepinephrine also increases several fold. Duringischemic states, upregulation of alphaj-adreno-receptors and an increase in norepinephrine releasecould be a powerful adaptive mechanism that drivesischemic preconditioning [6].

One human model of ischemic preconditioningis repetitive occlusion of a coronary artery duringangioplasty, in which pain and ST-segment depres-sion are lower after the initial balloon occlusion ofthe artery [7].

Clinical data, although limited, suggest that episodesof angina within 24 h of an infarct, improve clinicaloutcome and decrease infarct size. This effect is pre-sent even in the absence of collaterals, indicating thepresence of a cellular protective mechanism [8].

Glucose insulin potassiumSeveral metabolic mechanisms have been implicatedfor the beneficial effects of glucose insulin potassium(GIK) in AMI. GIK decreases both circulating levelsof free fatty acids (FFA) and myocardial FFAuptake. Increased FFA levels are toxic to ischemicmyocardium and are associated with increased mem-brane damage, arrhythmias, and decreased cardiacfunction. Another possible beneficial effect of GIK isthe stimulation of myocardial K+ reuptake by insulin'sstimulation of Na+,K+-ATPase and the provision ofglucose for glycolytic ATP production. The signific-ance of the relatively small increase in ischemic gly-colytic ATP production that results from increasedprovision of glycolytic substrate has been questioned.Experimental data also show that a high glucose sub-strate increases myocyte resistance to the toxic effectsof the increase in cell calcium concentration thatoccurs during hypoxia [9].

Myocardial protection during AMI and angioplasty 45

Since first introduced by Sodi-Pallares et al. [10],the usage of GIK in AMI is controversial and clinicaltrials have yielded mixed results. A recent meta-analysis of all randomized clinical trials where GIKwas initiated relatively early, discarding those in whichGIK was started too late to be useful or in inadequatedoses, suggested that GIK was highly likely to reduceAMI mortality [11].

The ECLA (Estudios Cardiologicos Latinoamerica)trials demonstrated AMI mortality reduction by GIKin the thrombolytic era. The ECLA CollaborativeGroup were able to show a dramatic reduction indeath rate from AMI, from 11.5% in the control groupto 6.7% in patients treated with GIK. This is thelargest reduction of mortality by any intervention thathas been tried [12]. Other clinical trials have notconfirmed those findings, and the use of GIK in AMIremains controversial.

Adenosine tri phosphate-potassiumchannel agonistThe concept of ischemic preconditioning appearsto be closely linked to the ATP-K channel. The adeno-sine triphosphate-dependent potassium channel wasshown to be vital to this cardioprotective mechanismin numerous animal models. As we previously indic-ated in this chapter, sulfonylurea drugs block thispotassium channel and may therefore attenuate thispotentially beneficial mechanism of cardioprotection,which could contribute to the adverse clinical out-comes of diabetic patients treated with sulfonylureasafter acute coronary syndromes. Both the adaptationto balloon inflations during angioplasty, which wasalso previously discussed, and the contractile recoveryafter ischemia can be blocked by glyburide [13].

Patients with noninsulin-dependent diabetesmellitus experience a higher cardiovascular mortalityrate than patients with insulin-dependent diabetesmellitus. It appears that K(ATP) channel inhibitionwith oral sulfonylureas prevents myocardial precondi-tioning and may explain the increased cardiovasculardeath in patients with noninsulin-dependent dia-betes mellitus. The relationship between the K(ATP)channels and human myocardial preconditioning isan interesting one. In experimental models treatmentwith a selective mitochondrial K(ATP) channel openerfor 5 min, followed by a 10-min washout, protectsboth viability and function of human myocardiumagainst ischemia/reperfusion [ 14,15].

Nicorandil, a drug with both nitrate-like and ATP-sensitive potassium-channel (K + ATP) activatingproperties, has been available in Europe for the treat-ment of refractory angina and may have a myocardialprotective effect.

Nicorandil, as an antianginal drug, significantlyimproved the results of exercise tolerance tests inpatients with stable effort angina pectoris. Thedrug also improved the results of exercise toler-ance tests relative to placebo in early randomized,double-blind, placebo-controlled trials. In random-ized, double-blind comparative studies in patientswith angina pectoris, nicorandil has demonstratedequivalent efficacy, as measured by exercise tolerancetesting, to isosorbide di- and mononitrate, beta-blockers and calcium blockers [16]. The IONA studywas conducted to see whether these antianginal effectswould translate into reductions in clinical eventsin stable angina patients. The trial involved 5126patients with stable angina and one or more of thefollowing risk factors: decreased left ventricular (LV)systolic function, LV hypertrophy, diabetes mellitus,and hypertension. The patients were randomized tonicorandil 20 mg twice daily or placebo in additionto standard antianginal therapy. Mean follow-up was1.6 years. The primary composite endpoint of cor-onary heart disease (CHD) death, nonfatal MI, orunplanned hospital admission for cardiac chest painwas significantly reduced by 17% in the nicorandilgroup. The secondary endpoint of CHD death ornonfatal MI was not significantly different betweenthe groups [17].

Studies in patients undergoing percutaneous trans-luminal coronary angioplasty (PTCA) have shownthat the administration of nicorandil reduces ST-segment elevation during ischemia, thus demon-strating its cardioprotective effects. The effects ofnicorandil on various aspects of myocardial recoveryfrom ischemic damage caused by AMI have beeninvestigated in the short term. Regional LV wallmotion, a marker of myocardial function, was signi-ficantly improved in nicorandil recipients relativeto control.

In summary, nicorandil has demonstrated poten-tial cardioprotective effects when used as part of anintervention strategy directly after AMI in high-riskpatients. Further large-scale longer-term studies ofnicorandil in this latter indication are awaited withinterest.

46 CHAPTER 5

HypothermiaHypothermia may render the myocardium less sus-ceptible to ischemia. A large amount of experimentaland clinical data suggests that moderate hypothermiasuppresses the generation of oxygen free radicals andthe inflammatory response that compounds injuryafter ischemia. There is also some indication thatit may reduce reperfusion injury after successfulrecanalization, both in the brain and in the heart.

Surface cooling, with cold air blankets and alcoholrub down, while effective in reducing core tempera-ture, is usually imprecise and followed by unstabletemperatures over the course of maintenance. Surfacecooling also causes naturally uncontrolled shivering.Patients need to receive paralytic drugs and sedationto hamper the shivering. Ventilatory support is alsofrequently necessary to address the suppression ofrespiration from paralytic drugs.

A new internal cooling device is now undergoingclinical trials for myocardial protection in patientsundergoing AMI. The COOL MI trial will randomize40 MI patients presenting less than 6 h from symptomonset. The trial will incorporate a new technology toachieve and maintain hypothermia, called the SetPoint(Radiant trademark) Endovascular Temperature Man-agement System. The new system uses a catheterinserted into the inferior vena cava to achieve andmaintain temperatures in the range of 32-33°C. Withthe new device, core temperatures can be reducedas surface warmth is maintained, so that the patientcan be both awake and comfortable during cooling.Results are not yet available [ 18].

Fatty acid oxidation inhibitorsNormally the heart obtains its major source of energyfrom the oxidation of fatty acids. This process requireslarge amounts of oxygen, and during ischemia thesupply of oxygen is diminished. Under these circum-stances, glucose provides a more efficient source ofenergy. During myocardial ischemia, at a time ofdecreased oxygen supply, there is a significant increasein fatty acid levels.

Agents belonging to a new class, the fatty acidoxidase inhibitor drugs, called fatty acid oxidationinhibitors (pFOX), are under clinical investigation.The pFOX inhibitors increase the efficiency of oxygenuse during ischemic stress by shifting the metabolismto a more efficient fuel source, glucose, instead of fattyacids. This metabolic change allows for an increase in

ATP production per mole of oxygen consumed. At thesame time it reduces the rise in lactic acid and acidosis,and maintains myocardial function under conditionsof reduced myocardial oxygen supply.

Ranolazine, a pFOX inhibitor, reduces cellularacetyl-CoA content via inhibition of fatty acid beta-oxidation and activates pyruvate dehydrogenase. Thepossible benefit of ranolazine was evaluated in theCARISA trial. This was a phase III, multinational, ran-domized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacyof ranolazine for the treatment of chronic angina.CARISA randomized 823 patients with stable anginato either a 12-week course of two different doses ofranolazine (570 mg/bid or 1000 mg/bid) or placebo.Ranolazine produced a modest increase in exercisetime in patients with chronic angina. Unlike beta-blockers, the drug has no effect on heart rate or con-tractility. There was a small dose-related prolongationof the QT interval [19].

Ranolazine may be effective in reducing myocardialinfarct size. In the rat model of left anterior descend-ing coronary artery occlusion and reperfusion, ratssubjected to ranolazine bolus injection plus infusionprior to left anterior descending coronary arteryocclusion had a significant reduction in myocardialinfarct size of approximately 33% compared to salinecontrol (P< 0.05). In addition, infusion of ranolazinesignificantly attenuated the release of cardiac troponinT into the plasma [20]. It is still unclear whetherranolazine causes a reduction of infarct size andcardiac troponin T release in humans.

Reducing oxygen requirements

A reduction in oxygen requirement by the heart maybe achieved by drugs such as ACE inhibitors or beta-blockers, or by mechanical devices. Several mechan-ical approaches have been developed as adjuncts tohigh-risk coronary angioplasty to improve patienttolerance of coronary balloon occlusion and maintainhemodynamic stability in the event of complications.These percutaneous techniques include intra-aorticballoon counterpulsation, coronary sinus retroper-fusion, and cardiopulmonary bypass.

Angiotensin blockersInfarct size maybe reduced by the use of AT(1) recep-tor blockers. Patients under treatment with AT(1)


receptor blockers for indications such as hypertensiontreatment or prevention of ventricular remodelingafter myocardial infarction may have improved prog-nosis after suffering a second AMI. Pretreatment withAT( 1) receptor blockers may protect the myocardiumagainst ischemic injury during elective interventionswith the risk of regional ischemia, such as percuta-neous transluminal coronary angioplasty or coronaryartery bypass grafting [21].

The renin-angiotensin system is activated duringmyocardial ischemia, and local angiotensin II forma-tion occurs in ischemic hearts. Although at least twoangiotensin II receptor subtypes, the AT(1) and theAT(2) receptor, have been identified, the cardiovas-cular effects of angiotensin II have been attributedlargely to activation of AT( 1) receptors. In the animalmodel, the density of AT( 1) receptors is higher thanthat of AT(2) receptors, whereas data on the AT recep-tor subtype density and its distribution in humanhearts remain controversial. In animal studies, AT(1)receptor blockade increases coronary blood flow dur-ing ischemia and during reperfusion, reduces the incid-ence of ischemia-related arrhythmias, limits infarctsize, improves functional and metabolic recoveryafter myocardial ischemia, and attenuates ventricularremodeling postmyocardial infarction.

The potential mechanisms responsible for thecardioprotection by AT(1) receptor blockade remainto be elucidated in detail, but appear to involve AT(2)receptor activation and the subsequent action ofbradykinin, prostaglandins, and/or nitric oxide.

Experimental evidence for the beneficial effects onheart failure of chronic treatment with ACE inhibitorsaccumulated from early 1980 in experimental modelsof LV dysfunction secondary to AMI. These studiesdemonstrated an improvement in hemodynamics, LVremodeling, and mortality with ACE inhibitor treat-ment. The effect of ACE inhibitors during the acutephase of AMI was less clear, although there was evid-ence of protection from ischemic damage, possiblymediated by an increase in collateral coronary bloodflow [22]. Likewise, patients under treatment withAT( 1) receptor blockers for indications such as hyper-tension and ventricular dilatation after myocardialinfarction are likely to have improved prognosis whensuffering an AMI [23].

Beta-adrenergic blockersBeta-blockers appear to be beneficial in reducing

mortality after myocardial infarction. This benefitmay be due to their negative chronotropic andinotropic effects, leading to reduction of arterial bloodpressure, reduction of myocardial oxygen demand,and arrhythmogenesis. Further, beta-blockers alsoimprove epicardial to endocardial flow ratios andmyocardial energy efficiency.

Early treatment with an intravenous beta-blocker isrecommended for most patients with an acute infarct,as it appears to reduce infarct size. This recommenda-tion is based on several randomized clinical trials con-ducted in the 1970s and early 1980s. The benefits ofearly beta-blocker treatment are greater in older thanin younger patients and in patients with larger infarcts.Although most of the clinic data derived from stud-ies conducted in the prereperfusion era, the resultsremain applicable today. Overall, mortality rates werereduced by 25-30% within the first year in these trials.

Although beta-blocker use reduces infarct size inspontaneously occurring nonreperfused infarcts, itmay not affect infarct size in patients treated withreperfusion therapy. The role of beta-blockers innon-Q wave infarction is less clear. More recently,the second Thrombolysis in Myocardial Infarction(TIMI) trial indicated that beta-blockers reducerecurrent ischemic events even in patients receivinga thrombolytic agent [24].

A recent observational study also suggested thatbeta-blocker use concurrent with percutaneous coron-ary intervention (PCI) decreased the risk of creatinekinase (CK)-MB elevation [25].

Treatment with a beta-blocker should be startedwithin 24 h of a myocardial infarction. The size of theinfarct can be reduced by intravenous metoprolol oratenolol followed by oral beta-blockers. This regimenalso reduces the incidence of reinfarction, ventricularfibrillation, cardiac rupture, and intracranial hemor-rhage in hospital. Treatment should be continued forat least 2 or 3 years and for longer if well tolerated[26,27]. The beneficial effects of beta-blockers seem tobe a class effect. However those with partial agonistactivity do not show a beneficial effect on mortality,and their use cannot be recommended.

Intra-aortic balloon pumpThe concept of the intra-aortic balloon pump (IABP)is an interesting one. The inflation during diastoleimproves coronary blood flow and during systoleallows ventricular emptying at lower resistance.

48 CHAPTER 5

IABP is usually indicated in cardiogenic shock, butit is also frequently placed during myocardial infarc-tion, refractory unstable angina, and prophylactic forhigh-risk angioplasty [28]. For patients who remainhemodynamically unstable, IABP offers the angio-plasty operator the chance to have a less complicatedangioplasty procedure with a higher technical success[29].

Cardiogenic shock mortality in the setting of AMIin the absence of IABP and aggressive revasculariza-tion is over 85%. Nonrandomized clinical trials inwhich aggressive hemodynamic support and revascu-larization were performed revealed improved out-come. In the SHOCK trial, the beneficial effect of earlyrevascularization on 6- and 12-month survival wasobserved in the context of most patients receivingIABP.

IABP may be used to prevent reocclusion after suc-cessful angioplasty. Patients with an acute anteriorinfarct who had successful angioplasty of their infarct-related artery were randomized to either 24 h of coun-terpulsation after angioplasty or conventional therapy.The reocclusion rate was 2.4% compared to 17.7% inthe conventional group [30].

It is difficult to establish the benefit of IABP forprophylatic use for high-risk angioplasty. IABP is usu-ally used when a critical amount of myocardium isabout to be made ischemic during angioplasty. Theuse of perfusion balloons and stents has decreased thenecessity for mechanical support during angioplasty[31].

Cardiopulmonary bypass supportCardiopulmonary bypass support (CPS) is frequentlyused in the catheterization laboratory during ahemodynamic collapse complicating an angioplastyprocedure or providing stand-by circulatory supportfor high-risk procedures.

The use of large femoral cannulas which can be per-cutaneously placed make this technique safe and easyto apply by most interventionists. This techniqueallows hemodynamic stability to be maintained dur-ing high-risk interventional procedures regardless ofintrinsic cardiac function. This form of support alsopermits transport of the patient to the operating roomin a stable condition after an unsuccessful angioplasty.

A National Registry of 14 centers performing elect-ive CPS-supported angioplasty was created. Sug-gested indications were ejection fraction less than

25% or a target vessel supplying more than half themyocardium, or both. The data from 105 patientsundergoing supported angioplasty were entered intothe Registry. Twenty patients were considered notto be bypass surgery candidates, and 30 patientshad dilatation of their only patent coronary vessel.Seventeen patients had stenosis of the left main coro-nary artery and 15 underwent dilatation of that vessel.Chest pain and electrocardiographic changes occurreduncommonly despite prolonged balloon inflations.The angioplasty success rate was 95% for the 105patients. Morbidity was frequent (41 patients), in mostcases due to arterial, venous or nerve injury associatedwith cannula insertion or removal, or both [32].

Because of many drawbacks associated with pro-phylactic CPS, standby CPS is now the preferredmethod. The patient's outcome is significantly im-proved when CPS is initiated within 10 min of cardiacarrest. Improvement in angioplasty technique andavailability of stents have greatly decreased the needfor CPS.

Coronary retroperf usionSynchronized coronary sinus retroperfusion producespulsatile blood flow via the cardiac veins to the coron-ary bed distal to a stenosis. This perfusion techniquelimits the development of ischemic chest pain andmyocardial dysfunction in patients undergoing pro-longed balloon inflations.

This technique was inspired in the abandoned BeckII surgical procedure for coronary disease (performedin the 1950s), which entailed arterial grafting to thecoronary sinus to perfuse the myocardium from thevenous end of its circulation. In 1984, Mohl etal. [33]first reported intermittent catheter occlusion of thecoronary sinus to protect myocardium during experi-mental coronary occlusion. In 1976, coronary sinusretroperfusion was used in animals and since then thetechnique has been applied in humans.

Weiner et al. [34] treated patients with unstableangina, and several workers reported use duringangioplasty in 1990. During angioplasty, it appears toreduce wall motion abnormalities during ballooninflation. In one study of 28 patients undergoing leftanterior descending artery (LAD) angioplasty assistedby retrograde coronary venous perfusion, the incid-ence of angina was reduced by 50% [35].

Coronary retroperfusion provides regional myo-cardial support mainly during LAD angioplasty.


The major disadvantage of this technique is that itdoes not provide systemic support. Transient atrialfibrillation and coronary sinus staining have beenreported.

Reducing reperfusion injury

Antiplatelet llb-llla inhibitorsThe glycoprotein Ilb-IIIa receptor inhibitors effect-ively block the final common pathway of plateletaggregation. Clinical trials have demonstrated mortal-ity benefit in patients with unstable angina under-going angioplasty, decrease in enzymes elevationduring elective angioplasty, and improved myocardialperfusion during acute infarct.

The EPIC trial was the first large-scale study to testthe hypothesis that glycoprotein receptor inhibitors,in this case abciximab, could reduce angioplasty pro-cedural complications in a high-risk population. EPICconclusively demonstrated that glycoprotein Ilb-IIIareceptor inhibitors can prevent acute ischemic eventsin the highest risk subset of patients with unstableangina (UA) under-going PTCA [36]. Since then,many clinical trials have confirmed the benefit of Ilb-IIIa inhibitors in angioplasty of patients with stableand unstable angina, and for the medical treatment ofacute coronary syndromes.

In the 1990s, Gibson and colleagues [37] intro-duced the concept of myocardial perfusion blushscore, which takes into consideration both epicardialand microvascular flow.

The usage of Ilb-IIIa inhibitors became very attract-ive as it improves myocardial and microvascular per-fusion during acute myocardial infarction angioplastyand lytic therapy.

Combining fibrinolytic therapy and angioplastywith antiplatelet therapy appears to improve tissueperfusion and therefore decrease myocardial infarctsize. This approach is presently undergoing clinicalinvestigation.

The sodium-hydrogen exchangerThe sodium-hydrogen exchanger (NHE) acts toextrude hydrogen from cells, protecting them fromacidosis. There are six known isoforms of theexchanger. Cardiac myocytes mostly express NHE-1.The activity of NHE is determined by intracellularpH, but it also responds to extracellular stimuli suchas thrombin and angiotensin II.

During ischemia, the NHE mechanism removeshydrogen from within the cell, and exchanges it forsodium. Because the NHE mechanism becomes inact-ive in the setting of ischemia, intracellular sodiumbuilds. An increase in intracellular sodium stimulatescalcium influx through the NHE mechanism, leadingto lethal calcium overload. The mechanism is activebetween ischemia and reperfusion and may con-tribute to reperfusion injury [38].

The use of NHE inhibitors is presently beinginvestigated with two agents, cariporide and eni-poride. The NHE inhibitors appeared, in preclinicalstudies, to limit the extent of myocardial infarctionwhen administered prior to coronary occlusion. Itis not yet clear if these agents are beneficial if givenafter coronary occlusion but before reperfusion.

Two clinical trials to date, ESCAMI andGUARDIAN, using eniporide and cariporide, respect-ively, failed to demonstrate a significant benefit ofNHE inhibitors in AMI patients undergoing reper-fusion therapy. It is possible the ineffectiveness ofthese agents in the clinical trials could have beendue to the inability of the drug to achieve the site ofaction due to the presence of an occluded vessel. Theideal setting for NHE inhibitors would be priorto ischemia. The drug may be of benefit in certain cir-cumstances where one can give it before ischemiaonset, such as prior to coronary artery bypass grafting(CABG) or in patients with unstable angina, prior tomyocardial infarction. In the GUARDIAN trial, asubgroup of patients receiving the highest dose of cari-poride prior to CABG appeared to derive ischemicinjury protection [39].

In summary, further carefully designed clinicaltrials are required, in which the dose and timing ofdrug treatment are rationally chosen, to prove if NHEinhibitors are beneficial as cardioprotective agents.

MagnesiumMagnesium may protect ischemic myocardium fromreperfusion injury. Studies in different animal modelsof coronary occlusion and reperfusion have demon-strated that magnesium administration before or atthe time of restoration of perfusion reduces infarctsize; the benefit is markedly reduced or lost if mag-nesium administration is delayed after reperfusion.

The mechanism of the beneficial effect of mag-nesium has not yet been elucidated. It has beenhypothesized that supplemental magnesium would

50 CHAPTER 5

have an antiarrhythmic effect, reducing peri-infarctarrhythmias. It may also decrease peri-infarct heartfailure and mortality independent of the decrease inarrhythmia. Magnesium also has an antiplatelet effect,which may help to prevent arterial reocclusion, andvasodilatory effect, which may decrease afterload andprevent spasm. Magnesium is also functional as aninorganic calcium channel blocker and it can inhibitefflux of calcium from the cardiac sarcoplasmicreticulum [40].

In humans, a direct myocardial protective effectof magnesium at the time of reperfusion has beenadvocated to explain the beneficial effect of intra-venous magnesium. Two meta-analyses, includingseven small randomized trials, and the second LeicesterIntravenous Magnesium Intervention Trial (LIMIT-2) demonstrated a protective effect of magnesium.

The benefit of magnesium remains controversial,as in the fourth International Study of Infarct Sur-vival (ISIS-4) there was no benefit of intravenousmagnesium. Some workers have attributed this lackof benefit to the fact that magnesium therapy wasstarted relatively late and this would have hamperedthe high magnesium serum concentration to beachieved at the onset of reperfusion in most patientsrandomized to magnesium infusion. Therefore thecontroversy about the role of magnesium in AMI isfar from being settled. According to experimentaldata, magnesium might protect the myocardium fromreperfusion injury and reduce infarct size only if it isadministered at the initiation of or before reperfusion[41-43].

AdenosineAdenosine has well-known vascular smooth-musclerelaxing effects and has antiadrenergic and negativechronotropic and dromotropic properties.

Adenosine is a cardioprotective agent, which hasbeen used during cardiac surgery. Adenosine exhibitsa broad spectrum of effects against neutrophil-mediated events and can therefore intervene in theischemia and reperfusion response, a capacity that mayoffer therapeutic benefits. Adenosine may also triggera hibernation effect that may be cardioprotective.

The cardioprotective effect of adenosine wasinvestigated in the setting of AMI and reperfusion.Adenosine is a promising agent for reduction ofinfarct in patients undergoing reperfusion therapy.It may limit infarct size, replenish phosphate stores,

reduce platelet aggregation, mediate preconditioning,and inhibit free radical formation [44].

In the AMISTAD I trial, 236 patients treated withadenosine had a 33% reduction in infarct size, but thiswas only apparent in patients with anterior MI [45].No benefit was seen in patients with inferior MI andthis group also showed an increase in bradycardia andhypotension with adenosine treatment.

The AMISTAD II trial enrolled only patientswith anterior ML The study randomized 2118 suchpatients within 6 h of symptom onset to two dosesof adenosine. The primary endpoint of death/newheart failure/rehospitalization for heart failure at6 months showed a trend towards benefit with thepooled adenosine groups, but this was not statisticallysignificant. The higher dose showed better results thanthe lower dose, but this still did not reach statisticalsignificance. The secondary endpoint of infarct sizealso showed a trend towards benefit with adenosine,which was statistically significant in the high-dosegroup.

Leukocyte receptor monoclonalantibodyReperfusion injury is usually associated with inflam-mation and migration of macrophages into theinfarcted area. The integrin receptor CD 11/CD 18plays a key role in the migration of macrophagesthrough the endothelium into the infarcted area.Monoclonal antibodies against GDI 1/CD18 have beendeveloped and clinical trials are under way to assesstheir benefit in reducing infarct size [46].

The HALT-MI trial was designed to assess theeffect of the monoclonal antibody to CD 11/CD 18(Hu23F26, Leukarrest) on infarct size in AMI patientsundergoing primary angioplasty [47]. Hu23F26 is ahumanized monoclonal antibody that binds to andblocks an integrin receptor necessary for the migra-tion of macrophages across endothelium. It was feltthat the treatment with Hu23F26 at the time ofangioplasty would limit reperfusion injury-associatedinflammation and thus reduce infarct size. This smalltrial failed to demonstrate any significant reduction ininfarct size as measured by SPECT imaging. There wasa trend toward a beneficial effect on both mortalityrate and congestive heart failure, but the trial was notpowered to detect an effect on clinical end points.Other trials with other CD 11/CD 18 inhibitors areneeded and are ongoing.


Complement inhibitorsThe complement system has been implicated in reper-

fusion injury during AMI. Animal data suggested that

a monoclonal antibody (MAb) to the complement

component C5a reduces reperfusion injury. In vitro

the MAb reduces C5a-stimulated neutrophil aggre-

gation, chemotaxis, degranulation, and superoxide

generation. At least in the pig model, inhibition

of C5a limits neutrophil-mediated impairment of

endothelium-dependent relaxation after cardiopul-

monary bypass and cardioplegic reperfusion. It has

no effect on short-term myocardial functional preser-

vation [48].

In one animal study of occlusion/reperfusion using

13 control pigs and nine pigs pretreated with this MAb,

infarct area was significantly reduced. The authors

concluded that myocardial infarction-reperfusion

is associated with activation of the alternative com-

plement pathway. Furthermore, a MAb to C5a that

inhibits neutrophil cytotoxic activity, decreases infarct

size in pigs [49]. This data suggests an important role

of the alternative complement pathway and C5a in the

propagation of ischemic cardiac damage during reper-

fusion. It appears that adhesion of the white cell to

vascular endothelium maybe an important element of

the pathogenesis of myocardial infarction.

Because C5a induces tissue injury by activating

polymorphonuclear leukocytes, it is possible that

inhibition of C5a activity would also reduce infarct

size and reperfusion injury in humans.

Summary

Myocardial protection during acute myocardial

infarction and angioplasty can be achieved with

pharmacotherapy and mechanical devices. Rapid

catheter-based reperfusion, the use of beta-blockers

to decrease oxygen requirements, ACE-inhibitors to

promote better healing, and antiplatelet Ilb-IIIa

inhibitors for better tissue perfusion, remain the most

appropriate strategy, as many other approaches con-

tinue to be developed to resolve this complex problem.

References

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2 Kloner RA. Does reperfusion injury exist in humans?JAm Coll Cardiol 1993; 21:537-45.

3 Nash IS. Improving outcomes of percutaneous interven-tion. Am Heart 11999; 137:979-982.

4 Beranek ST. Why primary angioplasty is less offensive tothe myocardium compared with thrombolysis for acutemyocardial infarction. Am Heart J 2000; 140: 5-6.

5 Nakagawa Y. Effect of angina pectoris on myocardialprotection in patients with reperfused anterior wallmyocardial infarction: retrospective clinical evidence of"preconditioning". / Am Coll Cardiol 1995; 25: 1076-83.

6 Sawi S. Protecting the myocardium from ischemic injury.A critical role for alphaj-adrenoreceptors? Chest 2001;119:1242-1249.

7 Heidland VE. Preconditioning during PTCA. Am Heart}2000; 140: 813-20.

8 Ottani F. Prodromal angina limits infarct size. A role forischemic preconditioning. Circulation 1995; 91:291—7.

9 Apstein CS, Taegtmeyer H. Glucose-insulin-potassiumin acute myocardial infarction: the time has come for alarge, prospective trial. Circulation 1997; 96:1074-7.

10 Sodi-Pallares D, Testelli MR, Fishleder BL et al Effects ofan intravenous infusion of a potassium-glucose-insulinsolution on the electrocardiographic signs of myocardialinfarction: a preliminary clinical report. Am J Cardiol1962; 9:166-81.

11 Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassiumtherapy for treatment of acute myocardial infarction:an overview of randomized placebo-controlled trials.Circulation 1997; 96:1152-6.

12 Diaz R, Paolasso EC, Piegas LS et al. on behalf of theECLA (Estudios Cardiologicos Latinoamerica) Collab-orative Group. Metabolic modulation of acute myocar-dial infarction: the ECLA Glucose-Insulin-PotassiumPilot Trial. Circulation 1998; 98:2227-34.

13 McGuire DK. Diabetes and ischemic heart disease. AmHeart J1999; 138 (5 Part 1): S366-75.

14 Pomerantz BJ. Selective mitochondrial KATp channelopening controls human myocardial preconditioning,too much of a good thing? Surgery 2000; 128: 368-73.

15 Spedding M. Medicines interacting with mitochondria:anti-ischemic effects of trimetazidine. Therapie 1999; 54:627-3.

16 Markham A. Nicorandil: an updated review of its use inischemic heart disease with emphasis on its cardiopro-tective effects. Drugs 2000; 60:955-74.

17 Lesnefsky EJ. The IONA study: preparing the myocar-dium for ischemia? Lancet 2002; 359 (9314): 1262-3.

18 COOL AID. Pilot Study suggests hypothermia may limitischemic damage. Heart Wire News 2001; February 20.

19 Pepine CJ. A. controlled trial with a novel anti-ischemicagent, ranolazine, in chronic stable angina pectoris that isresponsive to conventional antianginal agents. RanolazineStudy Group. Am J Cardiol 1999; 84:46-50.

20 Zacharowski K. Ranolazine, a partial fatty acid oxidationinhibitor, reduces myocardial infarct size and cardiactroponin T release in the rat. Eur J Pharmacol 2001; 418:105-10.

21 Zuanetti G, Latini R, Maggioni AP et al. Effect of the ACEinhibitor lisinopril on mortality in diabetic patients with

52 CHAPTER 5

acute myocardial infarction: data from the GISSI-3 Study.Circulation 1997; 96:4239-4245.

22 Roberts R, Rogers WJ, Mueller HS et al. Immediate vs.deferred |3-blockade following thrombolytic therapy inpatients with acute myocardial infarction. Results ofThrombolysis Myocardial Infarction (TIMI) II-B study.Circulation 1991; 83:422-37.

23 Mehta R, Eagle KA. Secondary prevention in acutemyocardial infarct. BrMedJ 1998; 316: 838-42.

24 ISIS-1 (First International Study of Infarct Survival)Collaborative Group. Randomised trial of intravenousatenolol among 16 027 cases of suspected acute myocar-dial infarction. Lancet 1986; ii (8498): 57-66.

25 Ellis SG, Brener SJ, Lincoff AL et al. p-Blockers beforepercutaneous coronary intervention do not attenuatepostprocedural creatine kinase isoenzyme rise. Circula-tion 2001; 104:2685.

26 The MIAMI Trial Research Group. Metoprolol in acutemyocardial infarction (MIAMI): a randomised placebo-controlled international trial. Eur Heart } 1985; 6:199-226.

27 Hjalmarson A, Elmfeldt D, Herlitz J et al. Effect on mor-tality of metoprolol in acute myocardial infarction. Adouble-blind randomised trial. Lancet 1981; ii (8251):823-7.

28 Flaherty JT, Becker LC, Weiss JL et al. Results of arandomized prospective trial of intra-aortic ballooncounterpulsation and intravenous nitroglycerin inpatients with acute myocardial infarction. / Am CollCardiol 1985; 6:434-46.

29 Hochman JS. The SHOCK Trial Study Group: Shouldwe Emergently Revascularize Occluded Coronaries forCardiogenic Shocfc. An international randomized trial ofemergency PTCA/CABG—trial design. Am Heart] 1999;137:313-21.

30 Field JM. The reperfusion era strategies for establishingor maintaining coronary patency. Cardiol Clin 2002; 20:137-157.

31 O'Rourke MF, Norris RM, Campbell TJ et alRandomized controlled trial of intra-aortic ballooncounterpulsation in early myocardial infarction withacute heart failure. Am ] Cardiol 1981; 47:815-20.

32 Vogel RA. Initial report of the National Registry ofElective Cardiopulmonary Bypass Supported CoronaryAngioplasty. ] Am Coll Cardiol 1990; 15:23-9.

33 Mohl W, Glogar DH, Mayr H et al. Reduction ofinfarct size induced by pressure-controlled intermittentcoronary sinus occlusion. Am J Cardiol 1984; 53:923—8.

34 Weiner BH, Gore JM, Benotti JR et al. Preliminaryexperience with synchronized coronary sinus retroperfu-sion in humans. Circulation 1986; 74: 381-8.

35 Kar S. Reduction of PTCA induced ischemia with retro-perfusion. J Am Coll Cardiol 1990; 15:250.

36 EPIC Investigators. Use of a monoclonal antibodydirected against the platelet glycoprotein Ilb/IIIa receptorin high-risk coronary angioplasty. N Engl J Med 1994;330:956-66.

37 Gibson CM, Cannon CP, Daley WL et al. TIMI framecount: a quantitative method of assessing coronary arteryflow. Circulation 1996; 93:879-88.

38 Yellon DM, Baxter GF. Sodium-hydrogen exchange inmyocardial reperfusion injury. Lancet 2000; 356: 522-3.

39 Avkiran M, Marber MS. Na(+)/H(+) exchange inhibitorsfor cardioprotective therapy. J Am Coll Cardiol 2002; 39:747-753.

40 Christensen CW, Rieder MA, Silverstein EL, GencheffNE. Magnesium sulfate reduces myocardial infarctsize when administered before but not after coronaryreperfusion: a canine model. Circulation 1995; 92:2617-21.

41 ISIS-4. A randomised factorial trial assessing early oralcaptopril, oral mononitrate, and intravenous magnesiumsulfate in 58,050 patients with suspected acute myocar-dial infarction. Lancet 1995; 345: 669-85.

42 Woods KL, Fletcher S, Roffe C, Haider Y. Intraven-ous magnesium sulfate in suspected acute myocardialinfarction: results of the second Leicester IntravenousMagnesium Intervention Trial (LIMIT-2). Lancet 1992;339:1553-8.

43 The MAGIC Steering Committee. Rationale and designof the magnesium in coronaries (MAGIC) study: a clin-ical trial to reevaluate the efficacy of early administrationof magnesium in acute myocardial infarction. Am Heart J2000; 139(1 Parti): 10-14.

44 Mahaffey KW, Puma JA, Barbagelata NA et al. Adenosineas an adjunct to thrombolytic therapy for acute myocar-dial infarct. JAm Coll Cardiol 1999; 34:1711-20.

45 Mentzer RM Jr. Adenosine myocardial protection: pre-liminary results of a phase II clinical trial. Ann Surg 1999;229:643-9.

46 Curtis WE, Gillinov AM, Wilson 1C et al. Inhibition ofneutrophil adhesion reduces myocardial infarct size.Ann Thorac Surg 1993; 56: 1069-72; discussion 1072-3.

47 Faxon DP. The effect of blockade of the CD 11 /CD 18 inte-grin receptor on infarct size: the results of the HALT-MIstudy. JAm Coll Cardiol 2002; 40:1199-1204.

48 Amsterdam EA, Stahl GL, Pan HL et al. Limitation ofreperfusion injury by a monoclonal antibody to C5a dur-ing myocardial infarction in pigs. Am J Physiol 1995; 268(!Part2):H448-57.

49 Tofukuji M, Stahl G, Agah A et al. Anti C5a monoclonalantibody reduces cardiopulmonary bypass and cardiople-gia-induced coronary endothelial dysfunction. / ThoracCardiovasc Surg 1998; 116:1060-8.

CHAPTER 6

Intermittent aortic cross-clampingfor myocardial protection

Fabio Biscegli Jatene, MD,PHD, Paulo M. Pego-Fernandes, MD,PHD, &Alexandre Ciappina Hueb, MD

Introduction

One of the main causes of morbidity and mortalityin heart surgery is inadequate myocardial protection,leading to intraoperative myocardial damage.

There are a number of myocardial protective tech-niques that have been used throughout the evolutionof heart surgery. Bigelow and Shumway made the firstreferences to myocardial protection in the early 1950s,based on the evidence that hypothermia reducedsignificantly myocardial metabolism [ 1,2].

In the early days of heart surgery, the most fre-quently employed technique was to have the heartperfused and beating empty while normothermicdespite technical disadvantages. Up to 1975, this tech-nique was considered to provide the best myocardialprotection and gathered many advocates [3], Tech-nical difficulties during surgery and studies showedthat myocardial protection was not ideal [4,5]. Thetechnique was therefore almost completely abandoned.

Despite theoretical criticisms of intermittent aorticcross-clamping at core temperatures of 32°C, thesimplicity of the technique and positive clinical out-comes led a number of surgeons to use this technique.To perform the anastomosis, the aorta is intermittentlycross-clamped when the core temperature reaches31-32°C, with opening of the clamp and subsequentreperfusion of one anastomosis after the other.

This technique is based on the concept thatmyocardial oxygen consumption reduces duringhypothermia and that the effects of ischemia that lastsless than 20 min are quickly reversed with blood reper-fusion. For each 3-4 min of clamping, reperfusion is

allowed for 1 min. As reported by Flameng [6], despitethe fact that clinical outcomes are an imprecise indexto assess myocardial protection, good clinical out-comes are the most important criteria to assesswhether protection was adequate.

One of the issues concerning the technique of inter-mittent aortic cross-clamping is that repetition ofischemic episodes, which are individually reversible,could lead to cumulative damage and consequentnecrosis [7]. Reimer et al. [8] showed experimentallythat intermittent reperfusion prevents cumulativemetabolic deficits and myocardial ischemia with celldeath. The first episode of ischemia reduces theconsumption of high-energy phosphates during thefollowing episodes.

A number of other studies [9-11] showed that briefepisodes of ischemia do not cause irreversible celldamage and do not lead to build up of metabolic,structural, and functional deficits. Conversely, it wasdocumented that brief periods of ischemia increasethe heart tolerance, instead of making it morevulnerable to consecutive episodes of ischemia. Thisischemia-tolerance induction was named ischemicpreconditioning [12].

Ischemic preconditioning was described by Murryet al. [12], who demonstrated in animal experimentsthat the heart, subjected to intermittent reversibleischemia with periods of reperfusion, demonstratesmyocardial resistance to infarction after a prolongedischemic period, which would otherwise lead toirreversible damage. In addition to protection againstinfarction, ischemic preconditioning can preventreperfusion arrhythmia, contractile dysfunction, and

53

54 CHAPTER 6

ischemic contracture [13-15]. Moreover, it canimprove the metabolic status of myocytes throughlimitation of acidosis [13] and preservation of myo-cardial high-energy phosphates [16]. This mechanismof endogenous protection was demonstrated in allstudied animal species [17], and some authors alsosuggested its existence in humans [ 18-24].

Pathophysiology of intermittentaortic cross-clamping

During the initial episode of intermittent aortic-clamping, endogenous substances are formed orsecreted, starting the mechanisms of myocardial pro-tection; the same substances, or others, may sub-sequently maintain protection during the followingepisode of ischemia. Adenosine, acetylcholine, cate-cholamines, angiotensin II, bradykinin, and opioidsare involved in intermittent cross-clamping, but theirquantitative contribution and effective participationat the beginning or as a mediator varies from speciesto species [25].

Adenosine is released during the process of ischemia-reperfusion from the receptor of Al adenosine, whichis coupled to G-protein, through secondary messen-gers leading to translocation of cytosol proteinkinaseC to the membrane and causing phosphorylation of anonidentified protein that mediates protection [26].Such protein may be the adenosine triphosphate-dependent potassium channel (KATp) that is activ-ated during the intermittent aortic-clamping process,leading to reduction of action potential duration andcalcium influx, and consequent loss of contractilefunction and energy-saving effect. There is evidencethat adenosine may protect the heart against ischemia -reperfusion injury [17,27].

Yao and Gross [27] suggested that endogenousadenosine released during the ischemic episode wasan important trigger or mediator of intermittentclamping. They also suggested that multiple complexmechanisms should be involved in the production ofthis kind of endogenous heart protective phenomenon.

Operative technique

Once extracorporeal circulation (ECC) is establishedwith aortic and single bicaval cannulation, systemiccooling to 32°C is induced after which intermittentaortic cross-clamping is applied. In order to avoid

excessive manipulation of the aorta, the Departmentof Bioengineering of Institute do Cora9ao constructedan aortic clamp with longer serrated tips so it could beplaced at one point on the aorta, promoting openingand closing of the clamp without having to repositionit for each procedure.

During each period of aortic clamping, an anasto-mosis was constructed between the graft and thecoronary artery to be revascularized. For each 3-4 minof clamping, 1 min of reperfusion was allowed. Theprocedure was used both for the distal and proximalanastomoses. If the anastomosis could not be per-formed within 10 min, the procedure was interrupted;the aortic clamp was opened with a reperfusion periodof 3-4 min. Then the aorta was reclamped to con-clude the anastomosis. During the performance of thelast anastomosis, the patient was rewarmed. By theend of the last anastomosis, the aorta was declamped,normal temperature and hemodynamics becamestable, and disconnection of the ECC followed.

One of the advantages of the use of intermittentaortic cross-clamping is the moment-by-momentfunctional assessment of the myocardium. In addi-tion, it is easier to position and accommodate thegrafts and to manage the surgery. The disadvantagesare frequent aortic manipulation because of thevarious clamping procedures and the limited timefor performance of the anastomosis.

The aortic clamp with longer serrated tips allowsthe clamp to remain in place and partially occluded,avoiding excessive manipulation (Figure 6.1).

Comments

There are few randomized studies comparing theefficacy of intermittent aortic cross-clamping with theuse of cardioplegic solutions [28-32] and none ofthem concluded which method was the best. Jateneet al. [33-35] have used intermittent clamping since1969 with excellent clinical outcomes. Data collectedfrom myocardial revascularization with intermittentaortic-clamping in populations from 500 to 5880 sub-jects showed that mortality ranged from 0.2 to 2.1%[31,36]. The use of an intra-aortic balloon pump inthe studies varied from 0.2 to 1% [33,35]. The incid-ence of perioperative myocardial infarction rangedfrom 2 to 4.1%. Flameng [6] who used this tech-nique reported his experience with 3529 patients pre-treated with lidoflazine. The results showed an overall

Intermittent aortic cross-clamping for myocardial protection 55

Figure 6.1 Use of aortic clamp with longer serrated tips.

mortality of 1.2% from cardiac problems, but whenanalyzing the elective cases, mortality from myo-cardial causes was 0.4%. The use of an intra-aorticballoon was present in 0.6% and left ventricular assist-ance devices were used in 0.2%.

Kirklin et al. [36] analyzed 5880 patients operatedon with intermittent aortic-clamping and found anexpected 10-year survival rate of 80%, the same sur-vival expected for the general population with similardemographic characteristics; mortality by the end ofthe first year was 1.6%. Other data, such as the correla-tion with the use of the internal thoracic artery, for

example, were similar to those of other studies ofpatients subjected to myocardial revascularization,regardless of the technique used.

In a prospective randomized study we com-pared the intermittent clamping technique with theSt Thomas cardioplegic solution and analyzed 163patients subjected to elective myocardial revascul-arization with preserved ventricular function andsubjected to no other procedures. Patients wererandomized in two groups: (i) the intermittent aorticcross-clamping (IACC) group, 93 patients, 86%males, mean age 57.7 years; and (ii) the crystalloid car-dioplegia (CC) group, 70 patients, 80% male, meanage 56.7. The period analyzed comprised the surgeryundertaken up to the 61st postoperative month.

The surgical technique employed was similar inboth groups. After sternotomy, extracorporeal cir-culation was established. Patients were then subjectedto moderate hypothermia at 32°C. In the IACC groupwhen the temperature was reached, the aorta wascross-clamped and maintained until the end of the

anastomosis. Intracavity air was then aspirated andthe aortic clamp was released. In the CC group, car-dioplegia was started at the aortic root after aorticclamping. Cardioplegia was then repeated every 20min until the anastomoses were constructed.

The clinical variables analyzed were: (i) electro-cardiographic findings; (ii) enzyme abnormalities(CK-MB); (iii) postoperative low cardiac output; (iv)length of stay in the ICU; and (v) late clinical evolution

(Table 6.1).In the IACC group, 82.8% of the patients were

asymptomatic in the period between 30 and 61months (±37.1 months). There were five deaths, onefrom cardiac disease, during the 22nd month. In the

CC group, 77.1% of the patients were asymptomaticbetween 31 and 61 months (±38.9 months). Therewas one sudden death probably caused by coronaryfailure. Statistical analysis did not show statistically

Table 6.1 Clinical variables in groups

IACC and CC.

Ischemic abnormality in the ECG*

CK-MB increase*

Abnormal ECG and CK-MB*

Low cardiac output*

Length of stay in the ICU (days)

Group IACC

7 (7.5)

14(15)

2(2.1)

2(2.1)

2-5 (±2.3)

Group CC

9(12.8)

5(7.1)

1(1.4)

6 (8.5)

2-5 (±2.3)

Results given show frequency with percentage in parentheses.

56 CHAPTER 6

significant differences between the studied variables inthe groups.

In a study conducted by Gerola et al. [29], com-paring blood normothermic cardioplegic solutionenriched with aspartate and intermittent aortic-clamping in a group of 60 randomized patients under-going myocardial revascularization, it was observedthat both groups behaved in the same way whenhemodynamic variables and intrahospital mortalitywere examined.

Advances in diagnostic methods have allowed thedetection of minor myocardial episodes, which havelittle or no hemodynamic repercussion. The develop-ment of radioisotopes and the dosage of myocardial-specific enzymes have enabled a better comparisonof the various methods used to provide myocardialprotection during surgery in humans. Among themarkers of myocardial damage, troponin I, CK-MB,intramyocardial ATP content, and lactate arehighlighted.

A recent study was carried out with myocardialdamage markers in patients subjected to intermittentaortic cross-clamping by Pego-Fernandes et al. [37].The authors evaluated 18 patients subjected tomyocardial revascularization with intermittent aorticcross-clamping. The criteria for inclusion were: (i)preoperative ejection fraction higher than 30%; (ii) noreoperation; (iii) at least two coronary arteries dam-aged; (iv) extracorporeal circulation (ECC) provided;(v) no operative unstable angina present; (vi) patientnot to be in an acute myocardial infarction; and (7) noother corrections of valvulopathies or left ventricularaneurysms. After the establishment of ECC, a catheterwas introduced into the coronary sinus for collectionof blood samples. Following systemic cooling to 32°C,aortic-clamping was initiated. Between each aortic-clamping, one anastomosis was connected betweenthe graft and the coronary artery to be revascularized.For each 3-4 min of clamping, there was 1 min ofreperfusion. The same procedure was followed forboth distal and proximal anastomoses.

The blood samples were collected directly from thecoronary sinus. The samples were collected at threestages: at the beginning of ECC under normothermicconditions (moment 1); immediately after the firstanastomosis was made at 32°C (moment 2); and at theend of ECC, again under normothermic conditions(moment 3). The blood samples were used for dosagesof troponin I, lactate, CK-MB, and adenosine. No

Figure 6.2 Graphic representation of the mean evolutionof values for lactate, troponin, CK-MB, and adenosine, atthe three moments of dosage.

patient presented signs of intraoperative myocardialinfarction.

The mean values of troponin I at moment 3 were152.55% higher than those for moment 2. Upon com-paring the medians of troponin I at moments 2 and 3,the authors concluded that there was a significantincrease (P< 0.001) (Figure 6.2). For lactate, there wasa statistically significant increase at moment 2 com-pared to moment 1 (P< 0.001). Moment 2 was similarto moment 3 (P = 0.098). Moment 3 had a statisticallysignificant difference from moment 1 (P = 0.002),despite the tendency to restore to initial values.

For CK-MB, there was a progressive increase indosage values at the three moments: moment 2 wasgreater than moment 1 (P < 0.001), and moment 3 wasgreater than moment 2 (P < 0.001). There was an in-crease in adenosine at moment 2 compared to moment1, which was statistically significant (P < 0.001). Atmoment 3, there was a decrease in adenosine, butnot enough to restore moment 1 levels [38,39].

Researchers [17,24,37,39] studied the differencebetween the dosage in the artery and the coronarysinus of lactate, inorganic phosphate, and potassiumlevels, after the opening of aortic-clamping in a groupof 72 randomized patients who underwent myocardialrevascularization surgery. Three techniques of myo-cardial protection were used: (i) intermittent aorticcross-clamping at 34°C; (ii) intermittent aortic cross-clamping at 25°C; or (iii) continuous aortic-clampingassociated with the use of St Thomas cardioplegicsolution.

Cumulative enzymatic release was small andthere were no marked structural changes in the mito-chondria, presenting no difference among the threetechniques. The study's purpose was to compare

Intermittent aortic cross-clamping for myocardial protection 57

techniques. There was a larger difference between the

arterial and coronary sinus dosages in the first reper-

fusion period than in the following periods. These

findings were observed for the dosage of lactate,

inorganic phosphate, and potassium, and reflected the

action of the ischemic preconditioning mechanism.

One author, upon reviewing data years after, pointed

out a decrease in the clearing of inorganic phosphates

after subsequent intervals of ischemia, as a result of the

increase of ischemia tolerance [32].

Pego-Fernandes et al. [37] demonstrated a similar

behavior for the release of CK-MB, troponin I and

lactate in the coronary sinus of the control group, and

the group submitted to preconditioning, leading us to

the conclusion that intermittent aortic cross-clamping

as employed by us and most surgeons may be con-

sidered an effective preconditioning modality.

In conclusion, the intraoperative damage from

inadequate myocardial protection has decreased pro-

gressively. Intermittent cross-clamping is a simple,

safe, and efficient operative technique that provides

excellent clinical results.

References1 Reissman KR, Van Citters RL. Oxygen consumption and

mechanical efficiency of the hypothermic heart. / ApplPhyszoZ 1956; 9:427-32.

2 Lee 1C. Effect of hypothermia on myocardial metabolism.AmJPhysiol 1965; 208:1253-8.

3 Buckberg GD, Olinger GN, Mulder DG, Maloney JV Jr.Depressed postoperative cardiac performance: preven-tion by adequate myocardial protection during car-diopulmonary bypass. / Thorac Cardiovasc Surg 1975; 70:974-94.

4 Follette D, Fey K, Mulder D, Maloney JV Jr, BuckbergGD. Prolonged safe aortic clamping by combining mem-brane stabilization, multidose cardioplegia and appropri-ate pH reperfusion. / Thorac Cardiovasc Surg 1977; 74:682-94.

5 Miyamoto ATM, Robinson L, Matloff JM, Norman JR.Perioperative infarction: effects of cardiopulmonarybypass on collateral circulation in an acute canine model.Circulation 1978; 58 (Suppl 1): 1147-55.

6 Flameng W. Intermittent ischemia. Semin ThoracCardiovasc Surg 1993; 5:107-13.

7 Whalen DA Jr, Hamilton DG, Ganote CE, Jennings RB.Effect of a transient period of ischemia on myocardialcells: I—effects on cell volume regulation. Am } Pathol1974;74:381-97.

8 Reimer KA, Murry CE, Yamasawa I, Hill ML, JenningsRB. Four brief periods of myocardial ischemia cause nocumulative ATP loss or necrosis. Am ] Physiol 1986; 251(6Part2):H1306-15.

9 Heyndrickx GR, Millard RW, McRitchie RJ, MarokoPR, Vatner SF. Regional myocardial functional and elec-trophysiological alterations after brief coronary arteryocclusion in conscious dogs. / Clin Invest 1975; 56:978-85.

10 Henrichs KJ, Matsuoka H, Schaper J. Influence ofrepetitive coronary occlusions on myocardial adeninenucleosides, high energy phosphates and ultrastructure.BasicRes Cardiol 1987; 82:557-65.

11 Lange R, Ware J, Kloner RA. Absence of a cumulativedeterioration of regional function during three repeated 5of 15 minute coronary occlusions. Circulation 1984; 69:400-8.

12 Murry CE, Jennings RB, Reimer KA. Preconditioningwith ischemia: a delay of lethal cell injury in ischemicmyocardium. Circulation 1986; 74:1124-36.

13 Asimakis GK, Inners-McBride K, Medellin G, Conti VR.Ischemic preconditioning attenuates acidosis and postis-chemic dysfunction in isolated rat heart. Am J Physiol1992; 263 (3 Part 2): H887-94.

14 Shiki K, Hearse DJ. Preconditioning of ischemicmyocardium: reperfusion-induced arrhythmias. Am JPhysiol 1987; 253 (6 Part 2): H1470-6.

15 Cohen MV, Liu GS, Downey JM. Preconditioning causesimproved wall motion as well as smaller infarcts aftertransient coronary occlusion in rabbits. Circulation 1991;84:341-9.

16 Murry CE, Richard VJ, Reimer KA, Jennings RB.Ischemic preconditioning slows energy metabolism anddelays ultrastructural damage during a sustained ischemicepisode. CircRes 1990; 66:913-31.

17 Downey JM, Liu GS, Thornton JD. Adenosine and theanti-infarct effects of preconditioning. Cardiovasc Res1993; 27: 3-8.

18 Tomai F, Crea F, Gaspardone A et al. Ischemic pre-conditioning during coronary angioplasty is preventedby glibenclamide, a selective ATP-sensitive K+ channelblocker. Circulation 1994; 90: 700-5.

19 Patel DJ, Purcell HJ, Fox KM. Cardioprotection by open-ing of the KATP channel in unstable angina: is this aclinical manifestation of myocardial preconditioning?Results of a randomized study with nicorandil. Eur Heart} 1999; 20: 51-7.

20 Ikonomidis JS, Tumiati LC, Weisel RD, Mickle DAG, LiRK. Preconditioning human ventricular cardiomyocyteswith brief periods of simulated ischaemia. Cardiovasc Res1994; 28:1285-91.

21 Alkhulaifi AM. Preconditioning the human heart. Ann RColl Surg Engl 1997; 79:49-54.

22 Szmagala P, Morawski W, Krejca M, Gburek T, BochenekA. Evaluation of perioperative myocardial tissue dam-age in ischemically preconditioned human heart duringaorto coronary bypass surgery. / Cardiovasc Surg 1998;39: 791-5.

23 Alkhulaifi AM, Yellon DM, Pugsley WB. Preconditioningthe human heart during aorto-coronary bypass surgery.Eur JCardiothorac Surg 1994; 8:270-6.

24 Jenkins DP, Pugsley WB, Alkhulaifi AM et al. Ischaemicpreconditioning reduces troponin T release in patients

58 CHAPTER 6

undergoing coronary artery bypass surgery. Heart 1997;77:314-18.

25 Downey JM, Cohen MV. Signal transduction in ischemicpreconditioning. ZKardiol 1995; 84 (Suppl4): 77-86.

26 Chagas ACP, Galvao TFG, Ferreiro CR, Luz PL. Pre-condicionamento isquemico: um mecanismo protetoreficaz do coracao em risco de necrose. Rev Soc CardiolEstado Sao Paulo 1998; 8: 314-28.

27 Yao Z, Gross GJ. A comparison of adenosine-inducedcardioprotection and ischemic preconditioning in dogs:efficacy, time course, and role of KATP channels. Circula-tion 1994; 89:1229-36.

28 Jatene FB, Ferreira HP, Ramires JA et al. Estudo compar-ative da cardioplegia e do clampeamento intermitenteda aorta em cirurgia de revascularizacao do miocardio.ArqBras Cardiol 1990; 54:105-9.

29 Gerola LR, Oliveira SA, Moreira LF et al. Blood cardiople-gia with warm reperfusion versus intermittent aorticcrossclamping in myocardial revascularization: random-ized controlled trial. / Thorac Cardiovasc Surg 1993; 106:491-6.

30 Pepper JR, Lockey E, Cankovic-Darracott S, BraimbridgeMV. Cardioplegia versus intermittent ischaemic arrestin coronary bypass surgery. Thorax 1982; 37:887-92.

31 Flameng W, Van der Vusse GJ, De Meyere R et al.Intermittent aortic cross-clamping versus St Thomas'Hospital cardioplegia in extensive aorta-coronary bypassgrafting: a randomized clinical study. / Thorac CardiovascSurg 1984; 88:164-73.

32 Anderson JR, Hossein-Nia M, Kallis P et al. Comparisonof two strategies of myocardial management during coron-ary artery operations. Ann Thorac Surg 1994; 58: 768-73.

33 Jatene AD, Paulista PP, Souza LC. Tratamento cinirgicoda insuficiencia coronariana com ponte de safena:aspectos tecnicos. Arq Bras Cardiol 1970; 23:85-90.

34 Jatene AD, Sousa JEMR, Paulista PP et al Le pontageaorto-coronarie de viene saphene: a propos de 671 cas.Cower 1972; 3:607-18.

35 Jatene AD. Late results of aorto coronary saphenous veinby-pass grafts. / Cardiovasc Surg (Torino) 1975; (specialissue): 91-4.

36 Kirklin JW, Naftel CD, Blackstone EH, Pohost GM.Summary of a consensus concerning death and ischemicevents after coronary artery bypass grafting. Circulation1989; 79 (6 Part 2): 181-91.

37 Pego-Fernades PM, Jatene F, Kwasnicka K etal Ischemicpreconditioning in myocardial revascularization withintermittent aortic cross-clamping. / Card Surg 2000; 15:333-8.

38 Pego-Fernades PM, Jatene F, Coelho FF et al. Evolucaohemodinamica da revasculariza9ao do miocardio comdois metodos de protecao miocardica. Rev Bras CirCardiovasc 2000; 15:212-18.

39 Pego-Fernades, Jatene F, Gentil AF et al. Influence ofischemic preconditioning in myocardial protection inpatients undergoing myocardial revascularization withintermittent crossclamping of the aorta. Analysis of ionsand blood gases. Arq Bras Cardiol 2001; 77:318-23.

CHAPTER 7

Intermittent warm bloodcardioplegia: the biochemicalbackground

Ganghong Tian, MD, PHD, TomasA. Salerno, MD,& Roxanne Deslauriers, PHD

Introduction

Cardioplegia has been used to protect the heart duringcardiac surgery for several decades [ 1,2]. Its protectiveeffects result mainly from the inhibition of myocardialelectromechanical activity by the induction of rapiddiastolic arrest and lowering of heart temperature,leading to a significant decrease in myocardial oxygenconsumption [1,2]. Even when arrested, the oxygenconsumption of the heart is not zero [3]. Ischemicinjury will occur if infusion of cardioplegic solution isinterrupted. However, a quiescent bloodless field issometimes essential for surgeons to perform delicatesurgical procedures. Thus, repetitive short periods ofinterruption of cardioplegic infusion are inevitableduring certain types of cardiac surgery. This chapterfocuses on the effects of intermittent warm blood car-dioplegia (IWBC) on myocardial energy metabolism.

Use of magnetic resonancespectroscopy and imaging forstudies of cardioplegia

It is well known that myocardial energy metabolismas manifest in the levels of ATP, phosphocreatine(PCr), and intracellular pH (pHi) is closely related tocellular homeostasis [4-8]. Hearse et al. showed thatmyocardial contracture occurred when the level ofmyocardial ATP dropped below 12 (j,mol/g dry wt[9,10]. Moreover, according to Gebhard and others,reversible myocardial ischemic injury can be defined

in terms of myocardial energy metabolism as < 40%decrease in ATP and < 80% decreases in PCr [10-13].It has also been demonstrated that the decrease in pHiis almost linearly related to the severity of myocardialinjury. In mild ischemic injury, a small decrease in pHiaccelerates glycolysis, whereas in a severe ischemicinjury a large drop in pHi inhibits glycolysis [14,15].Conceivably, tissue pH is also an important and reli-able metabolic indicator of ischemic injury.

The high-energy phosphates and pHi of theheart can be monitored using phosphorus-31 (31P)magnetic resonance (MR) spectroscopy. Because theenergy used in MR spectroscopy and imaging is verylow and many MR-sensitive nuclei, such as 1H, 31P and23Na, are ubiquitous, MR spectroscopy and imagingare noninvasive and nondestructive [16,17]. Con-sequently, 31P MR spectroscopy and *H imaging areideal techniques for serial studies on a single heartbecause the heart can serve as its own control. Thechanges in myocardial high-energy phosphates,enzyme kinetics, ionic gradients, and pHi can be fol-lowed quantitatively and repetitively using 31P MRspectroscopy throughout an experiment without anyneed to take tissue samples, while physiological para-meters, such as cardiac contractile function, myocar-dial oxygen consumption, and coronary flow, can becontinuously monitored [18,19]. With the advent ofnew techniques in 31P MR spectroscopy, myocardialhigh-energy phosphates and pHi can be measured atdifferent depths across the left ventricular wall. Usinglocalized 31P MR spectroscopy, it was found that the

59

60 CHAPTER 7

PCr content and the PCr/ATP ratio are lower in thesubendocardium than in the subepicardium whereasthe ATP content is constant throughout the ventri-cular wall [20,21]. Localized 31P spectroscopy alsoshowed that ischemic changes induced by occlusion ofthe left anterior descending artery (LAD) in a beatingheart are different across the ventricular wall [20-24].The application of 31P MR spectroscopy to studies ofcardioplegia has led to fundamental new informationon myocardial energy metabolism, force generation,ischemia, and reperfusion injury.

Contrast-enhanced MR perfusion imaging hasrecently been developed for noninvasive assessmentof myocardial perfusion [25-27]. It uses fast gradient-echo imaging sequences to follow the changes in signalintensity after a bolus injection of a contrast agent.The degree of signal change is related to blood flowand can be used to calculate regional myocardial per-fusion. Contrast-enhanced MR imaging offers highspatial resolution and is excellent for detecting smallregions of perfusion deficit. For example, the field ofview of a heart image obtained from an isolated heartusually covers an area of 150 x 150 mm2 with a resolu-tion of 128x128, resulting in a pixel size of 1.17x1.17mm2. This pixel size is much smaller than that achiev-able using conventional techniques. The pixel sizefor radioactive microspheres, for example, may rangefrom 5 x 5 mm2 to 10 x 10 mm2. In addition, MRperfusion imaging can follow dynamic changes ofcontrast agent during its first pass, which providesinformation about the hemodynamics of the coronarycirculation. This cannot be obtained using radioactivemicrospheres. Using an intravascular contrast agent(gadolinium diethylenetriamine pentaacetic acid-Polylysine, Gd-DTPA-Polylysine) in the isolated pigheart, we showed that when Gd-DTPA-Polylysine isinjected during antegrade cardioplegia, changes in MRsignal intensity peaked within seconds and returned tothe baseline level at a similar rate [28]. However, withGd-DTPA-Polylysine administered into the coron-ary sinus during retrograde cardioplegia at the same"coronary flow" as antegrade cardioplegia, it tookmuch longer for the MR signal intensity to reach amaximum. The mean transit time of the contrastagent measured during retrograde cardioplegia wassignificantly longer than that obtained during ante-grade cardioplegia [28]. This suggests that the actualmyocardial blood flow of retrograde cardioplegia issignificantly lower than that of antegrade cardioplegia,

even though the delivery rate of cardioplegia is similarfor both cardioplegic techniques.

Both Tl- and T2*-weighted MR imaging methodshave been used for the assessment of myocardial per-fusion in vivo and ex vivo. We found that Tl- and T2*-weighted imaging techniques emphasize differentaspects of tissue perfusion, which maybe related to thedifferences in their mechanisms of image genera-tion [29,30]. Tl-weighted images may reflect mainlyexchange/diffusion processes while T2*-weightedimages may be more dependent on vascular flushing[29,30]. The combination of MR contrast agentswith MR imaging has provided a unique method forthe evaluation of myocardial perfusion and injury.Information obtained using MR contrast agents hassignificantly helped in the understanding of myo-cardial physiology and pathology. Based on their dis-tribution, MR contrast agents can be divided intothree types: intravascular (confined exclusively withinvascular compartment), extracellular (moving freelyout of the vascular compartment into the interstitialspace), and all compartment types (diffuse freely toall compartments and have the largest distributionvolume) [31]. Because each type of contrast agent hasits own confined distribution space, use of varioustypes of agents consecutively in one subject may helpdistinguish nutritional flow from total vascular flow.Finally, when MR perfusion imaging and MR spec-troscopy are used together, heart metabolism, pHi andionic gradients across the cell membrane as well astissue perfusion can be assessed simultaneously.

Effect of intermittent cardioplegiaon myocardial energy metabolism

Continuous normothermic antegrade blood car-dioplegia (CNABC) has emerged as an alternativemethod of myocardial protection. In theory, thismethod may be optimal for myocardial protectionduring cardiac surgery because it aims to avoidmyocardial ischemia and subsequent reperfusioninjury [32]. Practically, continuous infusion of warmblood cardioplegia may result in inadequate visual-ization of the operative field and make intracardiacmanipulations difficult in some circumstances [33].Surgical precision may require the interruption ofdelivery of cardioplegia for short intervals. As a result,IWBC may be more feasible clinically than CNABC.One consideration with this technique, however, is

Intermittent warm blood cardioplegia 61

Figure 7.1 Time course of myocardial ATP,phosphocreatine (PCr), and inorganic phosphate (Pi) frompig hearts during control perfusion, intermittent warmblood cardioplegia, and reperfusion. Data are presentedas means ± standard errors of means. Reprinted fromDeslauriers R, Tian G, Kupriyanov V, Lareau S & Salerno TA.Basic research on myocardial protection: a magneticresonance approach. In: Salerno TA (ed.) Warm HeartSurgery. © 1995, by permission of Hodder Arnold.

that interruption of cardioplegia, particularly undernormothermic conditions, may cause cumulativeischemic damage, leading to impaired recovery ofheart function following cardiac surgery.

To determine the effect on myocardial energymetabolism of IWBC and to determine whetherischemic changes induced by IWBC are cumulative,we subjected isolated pig hearts to six 5-min periodsof warm blood cardioplegia, which were interruptedby six 10-min ischemic episodes. It was found that a10-min ischemic interval resulted in a decrease ofapproximately 50% in the level of PCr with a cor-responding increase in inorganic phosphate (Pi)(Figure 7.1) [34]. There were no significant differ-ences between PCr values measured at the end of thesix ischemic intervals (Table 7.1). Moreover, althoughPi levels increased significantly during each ischemic

interval, the differences in Pi at the end of the skischemic intervals were not statistically significant(Table 7.1). Our results suggest that IWBC with thepattern of cardioplegia infusion and interruptiondescribed above does not result in cumulative loss ofPCr or increase in Pi. The intracellular pH of the heartwas obtained indirectly by measuring the difference inchemical shifts of the Pi and PCr peaks. During con-trol perfusion and reperfusion, pHi was 7.22 ± 0.02and 7.20 ± 0.03 pH units, respectively (Table 7.1).A 10-min interruption of warm blood cardioplegiaresulted in an average decrease in pHi by 0.12 pH units(Table 7.1). Subsequent interruptions of cardioplegiadid not cause any further decrease in pHi. Thisalso suggests that IWBC does not cause cumulativemyocardial injury. Moreover, we found that the re-covery of contractile function of the hearts subjectedto IWBC was similar to that of hearts subjected toCNABC. The results of our study demonstrate thatIWBC with 10 min of ischemic interruption resultsin mild ischemic changes, which are not cumulative.This suggests that warm blood cardioplegia can besafely interrupted for surgical precision providedinterruption is not longer than 10 min. Other inves-tigators have also reported longer safe ischemicintervals.

According to the levels of myocardial high-energyphosphates, reversible myocardial injury can be arbi-trarily divided into three phases: latency, survivaltime, and revival time [1]. During the first period ofischemia, there are essentially no changes in the levelsof ATP, PCr, or Pi. Oxidative phosphorylation isstill the major energy source for maintenance of func-tion and structure of the myocytes by using oxygenremaining in the myocardium in the form of oxy-myoglobin, oxyhemoglobin, and physically dissolvedoxygen. Myocardial oxygen consumption in a normal

Table 7.1 Effect of intermittent warm blood cardioplegia on intracellular pH, PCr, and Pi.

End of each interruption

pHi

PCr*

Pi*

Precardioplegia

7.22

230

70

1

7.10

128

131

2

7.13

122

136

3

7.12

115

144

4

7.10

118

141

5

7.10

119

143

6

7.10

119

147

Reperfusion

7.20

265

80

pHi, intracellular pH; PCr, phosphocreatine; Pi, inorganic phosphate.

* Intensity relative to ATP levels measured precardioplegia.

Image Not Available

62 CHAPTER 7

beating heart is approximately 10 ml/min/100 gtissue. The total oxygen reserve in the myocardium atthe beginning of ischemia is about 1-2 ml/100 gtissue. The latency period initiated by stopping cor-onary flow in a beating heart therefore lasts only5-20 s. This period will be significantly prolonged inan arrested heart because oxygen consumption issignificantly reduced. As a result, the latency period ina heart subjected to IWBC may be as long as 1-2 min.During this period, myocardial energy metabolism,structure, and function remain essentially unchanged.

During the second phase of ischemia (survivaltime), PCr is used to replenish ATP stores in thecytoplasm, which leads to a decrease in the PCr level,accompanied by a rise in Pi. This period ends when thePCr level decreases to 40% of its normal value andlasts about 1-3 min in a beating heart. In arrestedhearts, it lasts more than 10 min due to cessation ofenergy consumption for electromechanical activity.As found in our study, it took 10 min for PCr todecrease to 50% of its normal level. This suggests thatischemic injury resulting from a 10-min interruptionof warm blood cardioplegia still falls within the sur-vival phase of reversible injury. As a result, we believethat IWBC with 10 min of ischemic intervals is safe forsurgical precision as well as myocardial protection.

One important consequence of myocardial ischemiais generation of protons derived from anaerobicglycolysis and from other metabolic cycles, leading toa decrease in tissue pH [16]. As discussed above, theseverity of ischemic injury is related to the extent ofdecrease in pHi [15]. Accumulation of protons causesinflux of sodium and calcium via Na+-H+ andNa+'Ca^ exchange [35-37]. Moreover, a fall in pHiinhibits the activity of phosphofructokinase, whichin turn decreases energy production during ischemia[16]. It is generally accepted that pHi below 6.2 rep-resents severe ischemia [38]. In our study, a 10-mininterruption of warm blood cardioplegia resulted in adecrease in pHi only by 0.12 unit (from its controlvalue of 7.22-7.10) and subsequent interruption didnot cause any further decrease in pHi (Table 7.1). ThepHi at the end of each ischemic interval remainedwithin the normal physiological range. This furthersuggests that interruption of warm blood cardioplegiafor 10 min results in mild alteration in myocardialenergy homeostasis.

It is well known that reperfusion is not always fullybeneficial although it is an absolute prerequisite for

survival of the ischemic myocardium [39,40]. Theseverity of reperfusion injury is closely related tothe degree of sodium and calcium overload. Dysfunc-tion of the Na+-K+ pump is one of the importantmechanisms responsible for overload of these cations.Under physiological conditions, the free energy ofATP hydrolysis (AGATP) is normally about 15-20kilojoules per mole greater than the energy required todrive the Na+-K+pump [41]. The decreases in ATPand pHi observed during a 10-min interruption ofwarm blood cardioplegia were not significant (Fig-ure 7.1 & Table 7.1). Therefore, the pump kinetics arenot expected to be limited during IWBC. As a result,intracellular sodium and calcium would not increasesignificantly during IWBC with a similar ischemicinterval. This suggests that IWBC should not resultin significant reperfusion injury. This was supportedby comparable recovery of contractile function inthe hearts preserved with either IWBC or CNABC(Figure 7.2).

Heterogeneous ischemic changesduring intermittent warm bloodcardioplegiaAs mentioned above, the decreases in PCr, ATP, andpHi observed during 10 min of interruption of warmcardioplegia are within the survival phase of reversibleischemic injury. In the above study, however, myo-cardial ATP, PCr, Pi, and pHi were measured from thewhole hearts and were averages of these parametersover different regions of the heart and various layersof the ventricular wall. It has been shown thatmyocardial ischemic injury induced by occlusion ofa coronary artery, lowering of perfusion pressure, oran increase in heart work in a beating heart may bemore severe in the subendocardium than in the sub-epicardium [20-22]. The heterogeneity of ischemicinjury is attributed to a decrease in blood flow to theinner layer of the ventricular wall and higher workloador muscle tension in this region relative to those in theouter layer of the heart [20-22]. Under arrest condi-tions, the variations in mechanical work and muscletension between different layers of the myocardiummay be abolished or minimized. The transmuralheterogeneity of ischemic changes in an arrestedheart may therefore differ from that observed underbeating conditions. To determine whether ischemicchanges induced by interruption of warm blood


Figure 7.2 Comparison of rate-pressureproduct (RPP) and +dp/dt measuredduring reperfusion in pig heartssubjected to either continuous or

intermittent warm blood cardioplegia.Reprinted from Deslauriers R, Tian G,Kupriyanov V, Lareau S & Salerno TA.Basic research on myocardial protection:a magnetic resonance approach. In:Salerno TA (ed.) Warm Heart Surgery. ©1995, by permission of Hodder Arnold.

cardioplegia are homogenous across the ventricular

wall, we repeated the above study using localized 31PMR spectroscopy. A surface coil was positioned overthe anterior wall of the left ventricular wall and signalswere recorded from four separate layers across theventricular wall.

Representative localized 31P MR spectra obtainedacross the left ventricular wall during warm blood car-dioplegia and interruption of cardioplegia are shownin the top and bottom panels of Figure 7.3, respect-ively. The spectra in the top panel were obtained dur-ing infusion of cardioplegia and show prominentpeaks from ATP and PCr without evident elevation ofPi peak in all layers of the heart wall. The spectra in the

bottom panel of Figure 7.4 were acquired at the end of

the ischemic interval and show a more prominentdecrease in PCr and increase in Pi in the outer layersthan in the inner layers of the myocardium. Becausethe signal intensity of phosphorus spectra is highlydependent on the distance from the MR coil tothe region of myocardium where MR signals areacquired, it is difficult to compare the absolute levels

of compounds between various layers of the ventri-cular wall. For this reason, the ratio of Pi/PCr was used

as measurement of ischemic injury. This ratio wassignificantly higher in the subepicardium (Pi/PCr =1.27) than in the subendocardium (0.45), suggestingthat the ischemic changes induced by the interruption

Image Not Available

64 CHAPTER 7

Figure 7.3 Transmural 31P MR spectra acquired from theanterior wall of the left ventricle during warm bloodcardioplegia (a) and at the end of ischemic interval (b).Reprinted from Journal of Thoracic and CardiovascularSurgery, Vol. 109, Tian G, Xiang B, Butler KW eta/. A31Pnuclear magnetic resonance study of intermittent warmblood cardioplegia, pp. 1155-1163. © 1995, withpermission from Elsevier.

of warm blood cardioplegia were more severe in theSubepicardium than in the subendocardium. Becausethe localized 31P MR spectroscopy used in this studymay cause unidirectional signal overlap between theadjacent layers of myocardium, the spectra supposedto be from the inner layer of the ventricular wall mayactually contain some MR signals from the outer layerof the ventricular wall. Therefore, it is possible thatthe real difference in the ratio of Pi/PCr between thesubendocardium and the Subepicardium may belarger than that shown in Figure 7.3. Nevertheless, theratio returned to normal level rapidly in all layers ofthe ventricular wall upon infusion of warm bloodcardioplegia.

The severity of ischemic injury is dependent on thebalance between the energy requirement (determinedby basal metabolism and mechanical work) and bloodsupply. When the heart is arrested, electromechanicalactivity ceases and basal metabolism and blood supplythen become the main factors in influencing myocar-dial survival. Studies from various laboratories haveshown that blood supply between the inner and outerlayers of the ventricular wall is highly dependent onheart rate [42,43]. Blood flow to all layers of themyocardium is almost uniform when heart rate isaround 100 bpm [42]. As heart rate increases, theratio of blood flow to the subendo/subepicardiumdecreases and reaches 0.5 when the heart rate is about200 bpm, indicating that the subendocardium receivesapproximately half of the blood flow delivered to theSubepicardium under strenuous working conditions.When the heart is arrested, the ratio of blood flow tothe subendo/subepicardium is about 1.5, suggestingthat the subendocardium receives as much as 50%more blood flow relative to the Subepicardium whenheart muscle is completely relaxed [42]. This heartrate-dependent property of blood flow is related to thecompression force upon the subendocardium gen-erated by myocardial contraction. By measuring thetransmural distribution of blood flow and energymetabolites (ATP, PCr, and Pi), Bache and associatesfound that an increase in heart rate from 200 to 240bpm resulted in a significant decrease in blood flow tothe subendocardium with the depletion of PCr andappearance of Pi in this region [44]. These results indi-cate that blood distribution across the ventricular wallis highly dependent on the heart rate or mechanicalwork of the heart. When the heart is arrested, bloodflow favors the subendocardium. We believe that thisis the reason for more prominent ischemic changesobserved in the Subepicardium than in the subendo-cardium when blood cardioplegia is interrupted.

The above studies indicate that cardioplegia pro-vides preferential protection to the subendocardiumrelative to the Subepicardium due to higher blood flowdelivered to the region. Ischemic injury induced by theinterruption of warm blood cardioplegia is thereforeunlikely to be more prominent in the subendo-cardium than in the Subepicardium in the normalheart. It has been shown that the coronary blood dis-tribution is also affected by perfusion pressure [21 ]. Astudy from Ugurbil's laboratory suggested that lower-ing the perfusion pressure decreased the ratio of blood


Figure 7.4 Time courses of phosphocreatine (PCr) and inorganic phosphate (Pi) measured during warm blood cardioplegiaat different perfusion pressures.

flow to the subendocardium relative to the subepi-cardium [21]. In hearts with severe coronary disease,myocardial blood flow to the inner layer of theventricular wall may already be impaired. Under theseconditions, warm blood cardioplegia may compro-

mise myocardial protection in the subendocardialregion if perfusion pressure is not sufficiently high.Therefore, the minimum perfusion pressure or flowrate of warm blood cardioplegia necessary to avoidregional ischemic injury remains to be defined.

66 CHAPTER 7

Figure 7.5 Representative contrast-enhanced MR images obtained from a pig heart during antegrade warm bloodcardioplegia at perfusion pressures of 24, 17, and 7 mmHg. Perfusion deficits became apparent only when the heart wasperfused at 7 mmHg perfusion pressure.

Minimum perfusion pressure ofwarm blood cardioplegia to sustainnormal myocardial energymetabolism

To determine the minimum perfusion pressure ofwarm blood cardioplegia required to maintain normalmyocardial energy levels, we monitored ATP, PCr,and Pi in the region normally served by the LAD usinga 1.0-cm-diameter MR surface coil positioned overthe anterior wall of the left ventricle in isolated pighearts. The hearts were perfused using a mixture ofblood and K-H solution in 1 : 1 ratio. Perfusion pres-sure was gradually decreased until the appearance ofapparent ischemic changes. Each perfusion pressurewas used for 20 min to ensure that its ability to sustainmyocardial energy metabolism was properly assessed.As shown in Figure 7.4, no decrease in PCr or increasein Pi was observed during 20 min of IWBC at either24 or 17 mmHg perfusion pressure. This suggests thatthe blood flow at 17 mmHg perfusion pressure issufficiently high to sustain normal myocardial energymetabolism. Ischemic changes (decrease in PCr withincrease in Pi) were observed only when the perfusionpressure was lowered to 7 mmHg, which is consider-ably lower than that used during cardiac surgery(70-90 mmHg) (Figure 7.4). The results indicate thatIWBC is very effective in terms of oxygen delivery to

the myocytes. The perfusion pressure of IWBC doesnot need to be in the range of physiological arterialpressure to ensure adequate myocardial protection.

To determine whether antegrade warm blood car-dioplegia at a relatively low perfusion pressure pro-vides homogenous perfusion, MR contrast agent wasinjected into the aorta during the period of cardiople-gia. Its distribution was assessed using MR imaging.As shown in Figure 7.5, warm blood cardioplegia atperfusion pressures of 25 mmHg and 15 mmHg pro-vided homogenous perfusion across the myocardium.When perfusion pressure decreased to 7 mmHg, per-fusion deficits were observed in the subendocardialregions (Figure 7.5). The results demonstrate thatwarm blood cardioplegia at physiological pressureshould not result in regional ischemic injury. It shouldbe mentioned that this study was performed in younghealthy pigs with normal coronary systems. The rela-tion between cardioplegia pressure and myocardialperfusion in the hearts with severe coronary diseasemay differ from that observed in our studies.

Significant coronary stenosis and occlusion com-promise the delivery of cardioplegia to the jeopardizedmyocardium. Under these conditions, the use ofIWBC may result in regional ischemic injury if adja-cent normal arteries cannot deliver sufficient blood tothe jeopardized myocardium. To determine whetherthe coronary artery system in the pig had significant


Figure 7.6 Representative MR images obtained during antegrade warm blood cardioplegia with contrast agent deliveredinto the left circumflex artery (LCX, left panel), the left anterior descending artery (LAD, middle panel), and the rightcoronary artery (RCA, right panel).

Figure 7.7 Outflow rates measured at the venting arteriesduring antegrade warm blood cardioplegia. LAD, leftanterior descending artery; RCA, right coronary artery; LCX,left circumflex artery.

collateral circulation, areas of the myocardium sup-ported by each of three major coronary arteries weredefined using contrast-enhanced MR imaging. Wefound no significant overlap among the regions servedby the three coronary arteries (Figure 7.6). This sug-gests there was no significant arterial collateral circula-tion between the coronary arteries. We also found thateffluents collected from the two nonused coronaryarteries were insignificant when warm blood cardio-plegia was conducted through a single coronary artery(Figure 7.7). This also demonstrates that normalhearts have no significant arterial collateral circula-tion. As a result, regional ischemic injury may occur inthe heart with severe coronary stenosis if IWBC isthe only technique used for myocardial protection. Inthis situation, retrograde cardioplegia or simultane-ous antegrade/retrograde cardioplegia (SARC) mayhave to be instituted periodically to prevent regionalischemic injury. Using localized 31P MR spectroscopyand MR imaging, we have recently found that SARC

provides sufficient blood flow to sustain normalmyocardial energy metabolism in myocardium distalto a coronary occlusion [45].

Summary

Intermittent antegrade warm blood cardioplegia is auseful technique for myocardial protection duringcardiac surgery. The ischemic interval should beshorter than 10 min to prevent severe and cumulativeischemic injury. In contrast to the changes that occurin the beating heart, the ischemic changes resultingfrom repetitive interruption of warm blood cardio-plegia are more prominent in the subepicardiumthan in the subendocardium. A perfusion pressuresignificantly lower than physiological arterial perfu-sion pressure is able to sustain normal myocardialenergy metabolism.

References1 Gabhard MM, Bretschneider HJ, Schnabel PA.

Cardioplegia principles and problems. In: Sperelakis N,eds. Physiology and Pathophysiology of the Heart, 2nd edn.Boston: Kluwer Academic, 1989:655-69.

2 Takahashi A, Chambers DJ, Braimbridge MV et al.Cardioplegia: relation of myocardial protection to infu-sion volume and duration. Eur J Cardiothorac Surg 1989;3:130-4.

3 Preusse CH, Winter J, Schulte HD et al. Energy demandof cardioplegically perfused human hearts. / CardiovascSurg 1985; 26:558-63.

4 Allen D, Orchard C. The role of intracellular calcium,pH and ATP in myocardial failure during hypoxia. In:Yamada K, Katz AM, Toyama I, eds. Cardiac Function

68 CHAPTER 7

Under Ischemia and Hypoxia. Nagoya: University ofNagoya Press, 1986:303-16.

5 Kammermeier H, Schmidt P, Jungling E. Free energychange of ATP hydroxlysis: a causal factor of earlyhypoxic failure of the myocardium? / Mol Cell Cardiol1982; 14:267-77.

6 Opie LH. ATP synthesis and breakdown: adenosine andresponse to ischemia. In: Opie LH, ed. The Heart: phy-siology and metabolism. New York: Raven Press, 1991:247-74.

7 Kentish JC, Allen DG. Is force production in themyocardium directly dependent upon the free energychange of ATP hydrolysis. / Mol Cell Cardiol 1986; 18:879-82.

8 Veech RL, Lawson JWR, Cornell NM et al. Cytosolicphosphorylation potential. / Biol Chem 1979; 254:6538-47.

9 Hearse DJ, Braimbridge MV, Jynge P, eds. Protection ofthe Ischemic Myocardium. Cardioplegia. New York: RavenPress, 1981.

10 Hearse DJ. Ischemia, reperfusion, and the determinantsof tissue injury. Cardiovasc Drugs Ther 1990; 4:767-76.

11 Kubler W, Spieckermann PG. Regulation of glycolysisin the ischemic and the anoxic myocardium. / Mol CellCardiol 1970; 1:352-77.

12 Kubler W, Katz A. Mechanism of early pump failure ofthe ischemic heart: possible role of adenosine triphos-phate depletion and inorganic phosphate accumulation.Am J Cardiol 1977; 40:467-71.

13 Bretschneider HJ, Gebhard MM, Preusse CJ. Reviewingthe pros and cons of myocardial preservation withincardiac surgery. In: Longmore DB, ed. Towards SaferCardiac Surgery. Boston: GK Hall Medical Publishers,1981:21-53.

14 Tantillo MB, Khuri SF. Myocardial tissue pH in theassessment of the extent of myocardial ischemia and ade-quacy of myocardial protection. In: Piper HM, PreusseCJ, eds. Ischemia-Reperfusion in Cardiac Surgery. London:Kluwer Academic, 1993: 335-52.

15 Dennis SC, Gevers W, Opie LH. Proton in ischemia:where do they come from; where do they go to? JMol CellCardiol 1991; 23:1077-86.

16 Ingwall JS. Phosphorus nuclear magnetic resonance spec-troscopy of cardiac and skeletal muscle. Am J Physiol1982; 242: H729-44.

17 Gillies RJ. Nuclear magnetic resonance and its applica-tions to physiological problems. Ann Rev Physiol 1992;54: 733-48.

18 Brunotte F, Peiffert B, Escanye JM et al. Nuclear magneticresonance spectroscopy of excised human hearts. BrHeart} 1992; 68:272-5.

19 Koretsky AP. Application of localized in vivo NMR towhole organ physiology in the animal. Annu Rev Physiol1992; 54: 799-826.

20 Path G, Robitaille PM, Merkle H et al. Correlationbetween transmural high energy phosphate levels andmyocardial blood flow in the presence of graded coronarystenosis. CircRes 1990; 67:660-73.

21 Fukunamki M, Yellon DM, Kudoh Y et al. Spatial andtemporal characteristics of the transmural distribution ofcollateral flow and energy metabolism during regionalmyocardial ischemia in the dog. Can J Cardiol 1987;3:94-103.

22 Bache RJ, McHale PA, Greenfield JC. Transmuralmyocardial perfusion during restricted coronary inflowin the awake dog. Am J Physiol 1977; 232: H645-51.

23 Gelpi RJ, Cingolani HH, Mosca SHAM et al. Myocardialblood flow distribution across the left ventricular wall.III. Mechanical factors. Arch Int Physiol Biochim 1982;70:377-83.

24 Bottomley PA, Weiss RG. Noninvasive localized MRquantification of creatine kinase metabolites in normaland infarcted canine myocardium. Radiology 2001; 219:411-18.

25 Saeed M, Wendland MF, Higgins CB. The developingrole of magnetic resonance contrast media in the detec-tion of ischemic heart disease. Proc Soc Exp Biol Med1995; 208:238-54.

26 Wilke N, Kroll K, Merkle H et al. Regional myocardialblood volume and flow: first-pass MR imaging withpolylysine-Gd-DTPA. Magn Reson Med 1995; 5:227-37.

27 Simor T, Chu WJ, Johnson L et al. In vivo MRI visualiza-tion of acute myocardial ischemia and reperfusion inferrets by the persistent action of the contrast agent Gd(BME-DTPA). Circulation 1995; 92:3549-59.

28 Tian G, Shen J, Su S et al. How effective is retrograde car-dioplegia? A perfusion imaging perspective. In: Proceed-ings of the International Society for Magnetic Resonance inMedicine, vol 2, p 678, abstract.

29 Su S, Shen J, Tian G et al A re-evaluation of Tl - and T2*-weighted imaging methods for myocardial perfusion.Proceedings of the International Society for MagneticResonance in Medicine, vol 2, p 684, abstract.

30 Tian G, Shen J, Dai G et al. An interleaved Tl—T2* imag-ing sequence for assessing myocardial injury. / CardiovascMagn Reson 1999; 1:145-51.

31 Nelson KL, Runge VM. Principles of MR contrast. In:Runge VM, ed. Contrast-enhanced Clinical MagneticResonance Imaging. Lexington: The University Press ofKentucky, 1997:1-13.

32 Matsuura H, Lazar HL, Yang X et al. Warm versus coldblood cardioplegia: is there a difference? / ThoracCardiovasc Surg 1993; 105:45-51.

33 Buckberg GD. Myocardial protection: an overview.Semin Thorac Cardiovasc Surg 1993; 5:98-106.

34 Tian G, Xiang B, Butler KW et al. A 31P nuclear magneticresonance study of intermittent warm blood cardiople-gia. JThorac Cardiovasc Surg 1995; 109:1155-63.

35 Philipson KD. Cardiac sodium-calcium exchange research,new directions. Trends Cardiovasc Med 1992; 2:12-14.

36 Haigney MCP, Miyata H, Lakatta EG et al. Dependence ofhypoxic cellular calcium loading on Na+-Ca2+ exchange.CircRes 1992; 71:547-57.

37 Fliegel L, Wang H. Regulation of the Na+/H+ exchangerin the mammalian myocardium. JMol Cell Cardiol 1997;29:1991-9.


38 Garlick PB, Radda GK, Leeley PJ. Studies of acidosisin the ischemic heart by phosphorus nuclear magneticresonance. BiochemJ 1979; 184:547-54.

39 Hearse DJ, Bolli R. Reperfusion-induced injury, mani-festations, mechanisms, and clinical relevance. TrendsCardiovascMed 1991; 1:233-40.

40 Hearse DJ. Reperfusion injury, progress and problems.Cardiovasc Drugs Ther 1991; 5:313-16.

41 Chapman JB. Thermodynamics and kinetics of electro-genie pumps. In: Blaustein MP, Leiberman M, eds. Elec-trogenic Transport. New York: Raven Press, 1984:17-32.

42 Spaan JAE, ed. Coronary Blood Flow. London: KluwerAcademic, 1991:1-36.

43 Rouleau J, Boerboom LE, Surjadhana A et al. The roleof autoregulation and tissue diastolic pressures in thetransmural distribution of left ventricular blood flow inanesthetized dogs. CircRes 1979; 45: 804-15.

44 Bache RJ, Zhang J, Path G et al. High energy phosphateresponses to tachycardia and inotropic stimulation inleft ventricular hypertrophy. Am J Physiol 1994; 266:H1959-70.

45 Tian G, Xiang Dai G et al. Simultaneous antegrade/retrograde cardioplegia protects myocardium distal to acoronary occlusion: a study in isolated pig hearts. MagnResonMed200l; 46: 773-80.

CHAPTER 8

Warm heart surgery

Hassan Tehrani, MB, BCH, Atiq Rehman, MD,Pierluca Lombardi, MD, Mohan Thanikachalam, MD,& Tomas Salerno, MD

Introduction

The historical background of warm heart surgery fol-lows the typical cyclical nature of medical progress.Although originally proposed by Gott in 1957 [ 1 ], theconcept of warm heart surgery came as a natural stepin the evolution of myocardial protection.

The combination of hypothermia introduced byBigelow et al. [2] and potassium cardioplegic arrestintroduced by Melrose et al. [3] became the mostcommon method of myocardial protection duringthe 1960s and 1970s. Later, blood was added to car-dioplegia solution to supply the myocardium withoxygen, nutrients, and buffers.

Studies by Buckberg et al. [4] clarified the patho-physiology of myocardial ischemia and reperfusioninjury. As a consequence of these findings, Rosenkranzand colleagues [5] introduced the concept of sub-strate-enhanced warm cardioplegia induction. Teohand colleagues [6] in Toronto followed this with theproposal of the so-called terminal "hot shot" beforeremoving the aortic cross-clamp. In 1989, Salerno'sgroup [7] introduced normothermic blood cardio-plegia, considering the addition of hypothermia nolonger necessary. A new era in myocardial preserva-tion had begun.

Anatomic and physiologic basis

The guiding rule for myocardial protection duringcardiac surgery should be the maintenance of a balancein the myocardial energy supply/demand equation.

The arrested, normothermic heart requires 90%less oxygen than does the normal working heart due

to the elimination of electromechanical activity. Theaddition of hypothermia decreases oxygen require-ments by over 50%, but this has to be regarded in thecontext of an overall decrease in oxygen requirementsfrom only 10% to 5% of normal by adding hypothermiato cardioplegia-induced electromechanical arrest. Dur-ing the administration of continuous normothermiccardioplegia, oxygen and substrate delivery for meta-bolism is at approximately 30-50% of normal levels.This allows for a considerable safety margin, with anabundance of oxygen and substrate to accommodatethe metabolic needs of the myocardium [8].

The rationale for continuous as opposed to inter-mittent warm cardioplegia administration is to avoidperiods of normothermic ischemia. Despite continu-ous cardioplegia perfusion, near perfect visualizationcan still be achieved for construction of anastomoses,thereby preventing a period of normothermic ischemia.However, animal and clinical studies demonstratethat warm blood cardioplegia infusion can be safelyinterrupted for periods of less than 10-12 min with-out clinical or metabolic sequelae [9].

Hypothermia appears to have several detrimentalcellular and subcellular effects, such as impairedmitochondrial and cell volume control, membranestability, and sarcoplasmic reticulum calcium han-dling. These effects lead to a depletion of myocardialenergy supplies and a delay in the metabolic andfunctional recovery of the heart [ 10].

Conversely, continuous normothermic cardioplegiahas several potential disadvantages including systemichyperkalemia, hyperglycemia, and hemodilutiondue to the increased volume of cardioplegia delivery.Altering the blood-crystalloid ratio (2 : 1 and 4 : 1 )

70

Warm heart surgery 71

and using modified cardioplegia delivery systemshave been observed to reduce the cardioplegic loadand hemodilution. Furthermore, normothermia andhemodilution lead to systemic vasodilatation neces-sitating vasoconstrictor agents to maintain adequateperfusion pressures, with an increased risk of vaso-spasm of native arteries and bypass grafts.

Results of clinical trials

Since the introduction of warm continuous blood car-dioplegia as a means of myocardial protection, there

have been multiple trials published on this subject inthe literature. These studies have compared warm ortepid blood cardioplegia with cold blood or crystalloidcardioplegia delivered either continuously or inter-mittently, and either in antegrade or retrograde fash-ion. The largest trials (each involving more than 1000patients) have been the Warm Heart InvestigatorsTrial and the Emory Study. The results of these twotrials and other trials are summarized in Table 8.1.

The Warm Heart Investigators [12] enrolled over1700 patients at three centers. This was a prospectiverandomized trial of 37°C cardioplegia with systemic

Table 8.1 Review of trials on warm continuous blood cardioplegia in myocardial protection. Adapted from Caputo eta/. [11].

Study

Warm Heart

Investigators

[13]

Martin eta/.

[14]

Pelletiereta/.

[15]

Rousou eta/.

[16]

Fremeseta/.

[18]

Bouchart eta/.

[19]

Subject

CAWBC/IAWBCvs.

IACBC

CRWBC vs. IACCC

IAWBC vs. IACBC.

Clinical and myocardial

metabolic evaluation

Clinical and metabolic

changes for CRWBC

with varying periods of

ischemic interruptions

CAWBC/IAWBC vs.

IACBC

CAWBC vs. IACCC vs.

IACCC with terminal

Methodology

Three-center prospective

randomized study.

Morbidity and mortality

comparison

Prospective randomized

study. Morbidity and

mortality comparison


study. CK-MB and

troponin-T release

comparison

Clinical and metabolic

comparison

Late follow-up from one

of centers in Warm

Heart Investigators trial


study. Functional and

Finding

No difference in

morbidity or mortality.

T Low cardiac output in

IACBC group

No difference in

infarction or mortality

rate. Higher stroke rate

in warm group (3.1 %

vs. 1 .0%)

Similar morbidity and

mortality. CK-MB and

troponin-T lower in

IAWBC

No differences

Nonfatal perioperative

cardiac events are

associated with reduced

late survival

CK-MB lowest in

CAWBC

Conclusion

Better myocardial

protection in warm group

Equivalent myocardial

protection. Higher stroke

rate in warm group

Better myocardial

protection in warm group

Brief periods of warm

cardioplegia interruption

are well tolerated

No difference between

warm and cold groups

Warm cardioplegia

provides best myocardial

Jacqueteta/.

[20]

'hotshot' in

hypertrophied hearts

IAWBC vs. IACCC/IRCCC


following isolated aortic

valve surgery


study. Functional and


No difference in

myocardial infarction,

morbidity or mortality

rate

protection in

hypertrophied hearts

Better myocardial

protection in warm group,

but no difference in clinical

outcomes

CAWBC, continuous antegrade warm blood cardioplegia; CK-MB, isoenzyme of creatine kinase; CRWBC, continuous

retrograde warm blood cardioplegia; IAWBC, intermittent antegrade warm blood cardioplegia; IACBC, intermittent

antegrade cold blood cardioplegia; IACCC, intermittent antegrade cold crystalloid cardioplegia; IRCCC, intermittent

retrograde cold crystalloid cardioplegia.

72 CHAPTER 8

normothermia versus hypothermic coronary bypasssurgery. Blood cardioplegia was administered eitheras antegrade continuous or intermittent (CAWBC orIAWBC) in the warm group and intermittent ante-grade in the cold group (IACBC). The results showeda nonsignificant decrease in mortality rates (1.4% vs.2.5%, P < 0.12) in favor of warm cardioplegia. Therewas no difference in the nonfatal Q-wave myocardialinfarction (MI) rate, but enzymatic infarction rates byserial creatine kinase-myoglobin (CK-MB) fractionmeasurements were lower in the warm group (12.3%vs. 17.3%, P < 0.001). The incidence of postoperativelow cardiac output syndrome was lower in the warmgroup (6.1% vs. 9.3%; P<0.01).

In a follow-up study, Fremes et al. [18] examinedlate outcomes of patients previously enrolled at oneof the centers in the Warm Heart Investigators trial.They hypothesized that: (i) nonfatal perioperativecardiac events are associated with reduced survival;and (ii) because nonfatal perioperative cardiac eventsand mortality rates were decreased in the warm car-dioplegia arm (though not significant statistically),this would reach significance at late follow-up. Theyconfirmed that late survival was significantly reducedin those patients who suffered perioperative nonfatalMI, but that there was no difference in late survivalbetween the warm and cold cardioplegia groups.

Martin et al. [14] enrolled 1000 patients in a pro-spective randomized trial of continuous retrogradewarm blood cardioplegia (CRWBC) versus intermit-tent antegrade cold crystalloid cardioplegia (IACCC).There was no difference in MI or mortality ratesbetween the groups. Strikingly there was a higherincidence of total neurologic events (4.5% vs. 1.4%;P< 0.005) and strokes (3.1% vs. 1.0%; P< 0.02) in thewarm group.

Pelletier et al. [15] randomized 200 patients under-going coronary artery surgery to either receiveIAWBC or IACBC. Mortality and myocardial infarc-tion rates were similar in the two groups. Release ofthe isoenzyme of creatine kinase (CK-MB) and tro-ponin T were significantly lower in the IAWBC group.

In a study examining the effects of varying lengthsof interrupting warm retrograde cardioplegia ad-ministration, Rousous et al. [16] compared clinicaloutcomes, MI, use of intra-aortic balloon pump,mortality, and length of stay. They concluded thattemporarily interrupting cardioplegia administra-tion was not deleterious with respect to outcomes.

Concerns regarding interrupting warm cardioplegiaadministration have been echoed by Menasche [17],who cautions that "it is virtually impossible to pre-dict in a given patient, the time point beyond whichmyocardial metabolism is going to shift toward ana-erobic patterns."

Bouchart et al. [19] studied patients undergoingsurgery for isolated aortic stenosis. They comparedthree strategies of myocardial protection in thisgroup of patients with hypertrophied myocardium.Patients were randomized to receive CAWBC,IACCC, or IACCC with a terminal "hotshot." Therewas no difference found among the groups in termsof morbidity, mortality, or length of stay in hospital.Postoperative CK-MB release was lower in thosepatients receiving CAWBC, though this did not trans-late into a lower rate of MI.

Conclusion

The ability of cardiac muscle to tolerate ischemia isfinite. Kirklin et al. have shown that the severity ofischemia is directly proportional to the cross-clamptime. Using hypothermia in addition to cardioplegiaadministration was seen as yet another way of increas-ing the level of myocardial protection during this crit-ical period. The addition of blood to cardioplegia wasseen as a way of providing oxygen, nutrients, andbuffering capacity. However, there exists a delicatebalance between the beneficial and deleterious effectsof hypothermia on jeopardized myocardium. Theuse of hypothermia has been shown to be counter-productive at temperatures lower than 15°C due tothe leftward shift of the oxyhemoglobin curve,leading to a decrease in oxygen unloading and toimpaired utilization of oxygen by the myocardium.Thus, hypothermic blood cardioplegia leads to cold,ischemic and anaerobic arrest. To prepare the heartfor this insult, Buckberg and colleagues supplementedcold arrest with warm induction and the terminal hotshot. This method of sandwiched cold cardioplegiaproved to be a better strategy for myocardial protec-tion, especially in ischemic injured hearts [5].

In the light of Buckberg's findings that warm bloodcardioplegia added a measure of protection whenplaced at the beginning and the end of cross-clampduration so as to protect the heart from the inter-vening cold-ischemic-anaerobic arrest, the questionremained as to why not eliminate ischemia altogether

Warm heart surgery 73

by giving continuous warm blood cardioplegia? Giventhe deleterious effect of hypothermia and the veryminimal additive benefit to myocardial protection,why cool the heart so aggressively?

Since its introduction in the late 1980s, the use ofwarm blood cardioplegia as a means of myocardialprotection has stimulated much debate in the car-diac surgery community. As in the aforementionedstudies, the safety record of warm heart surgery iscomparable to that of cold cardioplegia, and froma metabolic standpoint it clearly provides superiormyocardial protection, and is of greater benefit tohigh-risk patients who may have metabolically com-promised hearts. The latter benefit is attained byavoiding the further ischemic insult that occurs withtraditional hypothermic arrest.

One concern initially raised with the introduc-tion of warm heart surgery was the apparent increasedincidence of stroke. The findings from the 1994 warmheart trial at Emory University, showing an increasedrate of perioperative strokes in patients undergoingwarm heart surgery, received much attention, and ledto a backlash against the use of this form of myocardialprotection. Although the exact etiology of the signific-antly higher neurological event and stroke rate in thatstudy still remains unknown, the proposed theoriesfor this have included maintenance of systemicperfusion above 37°C and hyperglycemic crystalloidcardioplegia exacerbating intraoperative neurologicinjury. Since then, multiple other studies have coun-tered this finding. It is generally accepted that allow-ing the systemic temperature to drift to 32-34°Cduring warm heart surgery allows for cerebral protec-tion and avoids the need to use significant quantitiesof vasoconstrictors due to normothermic-inducedvasodilatation. Thus warm blood cardioplegia notonly protects but also more likely prevents ischemiato the heart while additionally protecting the brain.In addition, there are concerns regarding possiblefailure of the pump oxygenator during warm heartsurgery as the heart is not as protected due to thelack of hypothermia. However, pump failure is cur-rently extremely rare and, as mentioned before,temporary interruptions of warm cardioplegia arenot deleterious.

Warm heart surgery has proven in the last decade tobe a safe method of myocardial protection. As thepractice of cardiac surgery includes a greater numberof high-risk patients, alternative techniques such as

warm heart surgery should continue to remain in thearmamentarium of cardiac surgeons.

References1 GottVL,GonzalezJL,PanethMetal. Cardiacretroperru-

sion with induced asystole systole for open surgery uponthe aortic valve or coronary arteries. Proc Soc Exp BiolMed 1957; 94:689-92.

2 Bigelow WG, Lind WK, Greenwood WF. Hypothermia:its possible role in cardiac surgery. An investigation offactors governing survival hi dogs at low body tempera-tures. Ann Surg 1950; 132: 849-66.

3 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Electivecardiac arrest. Lancet 1955; ii: 21-2.

4 Buckberg GD, Brazier JR, Nelson RL et al. Studies ofthe effects of hypothermia on regional myocardialblood flow and metabolism during cardiopulmonarybypass. I. The adequately perfused beating, fibrillating,and arrested heart. / Thorac Cardiovasc Surg 1977; 73:87-94.

5 Rosenkranz ER, Vinten-Johansen J, Buckberg GD et alBenefits of normothermic induction of blood cardiople-gia in energy-depleted hearts with maintenance of arrestwith multidose blood cardioplegia infusions. / ThoracCardiovasc Surg 1982; 84:667-77.

6 Teoh KH, Christakis GT, Weisel RD. Acceleratedmyocardial metabolic recovery with terminal warmblood cardioplegia (hot shot). / Thorac Cardiovasc Surg1986;91:888-95.

7 Lichtenstein SVEL, Dalati H, Panos A, Slutsky AS. Longcross clamp time with warm heart surgery [letter]. Lancet1989; i: 1443.

8 Bernhard WF, Schwarz HF, Malick NP. Selectivehypothermia cardiac arrest in normothermic animals.Ann Surg 1961; 153:43-51.

9 Deslauriers R, Butler KW, Haas N et al. The effect ofintermittent cold and continuous warm blood cardiople-gia on isolated pig hearts: P NMR and functional studies.In: Proceedings of the llth Annual Meeting of the Society ofMagnetic Resonance in Medicine, Berlin, August 8—14,1992.

10 Panos A, Ashe K, El-Dalati H etal. Clinical comparison ofcontinuous warm (37°C) versus continuous cold (10°C)blood cardioplegia in CABG surgery. Clin Invest Med1989;12(5Suppl):C55.

11 Caputo M, Bryan AJ, Calafiore AM et al. Intermittentantegrade hyperkalaemic warm blood cardioplegiasupplemented with magnesium prevents myocardialsubstrate derangement in patients undergoing coronaryartery bypass surgery. Eur } Cardiothorac Surg 1998; 14:596-601.

12 Salerno TA, Houck IP, Barozzo CA et al. Retrogradecontinuous warm blood cardioplegia: a new concept inmyocardial protection. Ann Thorac Surg 1991; 51:245-7.

13 The Warm Heart Investigator. Randomised trial of nor-mothermic versus hypothermic coronary bypass surgery.Lancet 1994; 343:559-63.

74 CHAPTER 8

14 Martin TD, Graver JM, Gott JP et al. Prospective, ran-domized trial of warm blood cardioplegia: myocardialbenefit and neurologic threat. Ann Thorac Surg 1994; 57:298-304.

15 Pelletier LC, Carrier M, Leclerc Y et al. Intermittentanterograde warm versus cold blood cardioplegia: aprospective, randomized study. Ann Thorac Surg, 1994;58:41-8.

16 Rousous JA, Engelman RM, Flack JE et al. Does inter-ruption of normothermic cardioplegia have adverseeffect on myocardium? A retrospective and prospectiveclinical evaluation. Cardiovasc Surg 1995; 3: 587-93.

17 Menache P. Blood cardioplegia: do we still need to dilute?Ann Thorac Surg 1996; 62:957-60.

18 Fremes SE, Tamariz MG, Abramov D et al. Late results ofthe warm heart trial: the influence of nonfatal cardiacevents on late survival. Circulation 2000: 102 (sill):339-45.

19 Bouchart F, Bessou JP, Tabley A et al. How to protecthypertrophied myocardium? A prospective clinical trialof three preservation techniques. IntJArtif Organs 1997;20:440-6.

20 Jacquet LM, Noirhomme PH, Van Dyck MJ et al.Randomized trial of intermittent antegrade warm bloodversus cold crystalloid cardioplegia. Ann Thorac Surg1999; 67:471-7.

CHAPTER 9

Intermittent antegradewarm blood cardioplegia

Antonio Maria Calafiore, MD, Giuseppe Vitolla, MD,& Angela lacd, MD

During the last decade warm heart surgery, reportedby Salerno et al. [1,2], was accepted as a feasible andsafe technique for myocardial protection. This con-cept has had a striking impact on modern cardiacsurgery. It was possible to maintain the heart indiastolic arrest without cooling. The basic concept hadalready been known for many years. The oxygen con-sumption of a heart arrested by potassium-enrichednormothermic blood is 90% less than baseline value[3] and only a slight reduction in oxygen consumptionis achieved by lowering the temperature to 11°C.Salerno et al. [1] underlined that continuous perfu-sion of warm blood was needed by the retrograderoute, by means of coronary sinus cannulation, ensur-ing continuous normothermic perfusion during theaortic cross-clamping period. In our institution a dif-ferent approach to warm blood cardioplegia with twocharacteristics was standardized: the delivery routeis exclusively antegrade, and cardioplegic flow is dis-continued for 85-90% of the aortic cross-clampingperiod, and only KC1 is added to blood.

The antegrade method ofcardioplegia delivery

In 1898 Pratt [4] theorized the retrograde coronaryroute to deliver oxygenated blood to myocardium;later Lillehi et al. [5] reported the first clinical use andMenasche [6] reproposed this route of cardioplegiadelivery. However, the fundamental question remains,"can retroperfusion of the coronary sinus provideenough flow for the whole heart?"

Many studies on the anatomy of coronary veins

clarify that there are two venous systems in the heart:the greater and the lesser systems. The lesser cardiacsystem is composed of the small thebesian veins,which are venous or sinusoidal connections to the car-diac chambers. These drain primarily the septum, theconus of the right ventricle, and the lateral walls of theatria. Seventy percent of venous return is drained bythe coronary sinus; the remainder is drained throughthe lesser system. Therefore, if more thebesian veinsand an arteriovenous shunt exist there is less nutrientflow to the capillaries. Real nutritional flow maybe reduced further in hearts with coronary artery dis-ease. Possible detrimental effects of retrograde per-fusion may be enhanced by continuous warm bloodcardioplegia. The potential benefits of the retrograderoute exist in acute coronary occlusion when even alow amount of nutrient flow may be useful in main-taining cellular viability. However, many other tech-niques are effective in this situation (cold, warm,noncardioplegia).

Warm blood cardioplegia

Bigelow et al. [7] demonstrated the essential role ofhypothermia in preserving the heart and whole bodyduring open-heart procedures. This is still valid even ifhypothermia has some detrimental effects [8]. Thereis metabolic evidence that the sodium-potassium,ATPase and calcium ATPase enzyme systems of thesarcoplasmic reticulum are inactivated by hypother-mia. All ATPase-dependent reactions are impaired,with a negative influence on membrane stability,energy production, enzyme function, aerobic glucose

75

76 CHAPTER 9

utilization, ATP generation and utilization, cyclicadenosine monophosphate production, and osmotichomeostasis. Moreover, cold blood fails to delivernormal amounts of oxygen to the tissues; with hypoxia,lactate acidosis accumulates from glucose utilizationvia the Embden-Meyerhoff pathway. Intracellularand extracellular pH falls further impairing a varietyof pH-dependent enzymatic processes.

The availability of warm blood cardioplegia repres-ents a radical change in arrested heart management,and surgical teams have adopted the warm techniquesroutine for their clinical use whereas other teams aremore cautious. We began our experience with thewarm technique in 1991, and demonstrated the super-iority of warm over cold protection, which we hadused previously, as shown by lower morbidity andmortality rates [9,10].

Intermittent delivery of warmcardioplegia

The fundamental principle of warm heart surgery(90% reduction of O2 consumption at 37°C if the heartis arrested) has led us to change only the temperatureof the blood cardioplegic solution. The maximumischemic interval allowed during surgery was notknown on a scientific basis, but we think that 15 minof normothermic ischemia allows construction ofthe distal anastomoses without reinfusion of car-dioplegia. In our experience, "intermittent" meansthat the ischemic time is 85-90% of total aortic cross-clamping time. Continuous antegrade delivery of

warm cardioplegia is difficult to manage during sur-gery, mainly in mitral valve operations. The physiologicantegrade route ensures homogenous distribution ofcardioplegic flow and reinfusion over 15 min, allowscomplete reperfusion of the heart, replenishes theenergy stores, and prepares the heart for anotherperiod of ischemia. During ischemic periods, notanoxic intervals, the surgical field is without bloodand the operation becomes easier and quicker. Clin-ical experience shows that repeated short periods ofcontrolled ischemia, even for aortic cross-clampingtime exceeding 2 h, allows excellent cardiac recoverybecause the ischemic periods are not cumulative.

Surgical technique and deliveryprotocol

Cannulation of the heart is via the ascending aorta anda single double stage right atrial cannula (two separatecannulas in mitral valve surgery). An aortic needle isused for cardioplegic infusion and/or venting whennecessary. Blood is taken directly from the oxygenatorby means of quarter-inch tubing and a roller pump,then is infused into the aortic root. The tubing is con-nected to a syringe pump that delivers potassium ata concentration of 2 mEq/mL. The circuit is shownin Figure 9.1 and the delivery protocol is shown inTable 9.1. After the first infusion of cardioplegia(600 mL in 2 min), reinfusions are administered afterconstruction of each distal anastomosis or after 15min of ischemia. The duration of each reperfusionmay be prolonged, if necessary for contingent reasons

Figure 9.1 The circuit for theadministration of intermittentantegrade warm blood cardioplegia(see text).

Intermittent antegrade warm blood cardioplegia 77

Table 9.1 Delivery protocol. From

Calafiore eta/. [9], with permission from

Society of Thoracic Surgeons.

1st dose

2nd dose

3rd dose

4th dose

5th dose

6th dose

Flow rate

Roller pump

(mllmin)

300

200

200

200

200200

Syringe pump

(1 ml/2 mEq)

push 2 ml then 150

60

60

40

40

40

Duration

(min)

2

2

2

2

2

2

[K+](mEqIL)

18-20

10

10

6.7

6.7

6.7

by reducing the syringe pump flow rate. The bodytemperature is actively maintained at 37°C, which isthe same temperature as the cardioplegic solution.

Metabolic studies

Preservation of myocardial function during globalischemia for aortic cross-clamping represents a majorconcern during open-heart surgery. In fact, termina-tion of ischemia by the resumption of coronary flow,while necessary for myocardial recovery, can resultin paradoxical extension of the ischemic damage, theso-called ischemia-reperfusion injury. Biochemical

evidence suggests that this injury is partly mediated bythe oxygen-derived free radicals which are maximallyproduced at the onset of myocardial reperfusion [11].A salient biochemical feature of free radical injury isrepresented by oxidation of biomembranes at cellularand subcellular levels. This reaction exists in a self-expanding chain, ultimately resulting in loss of mem-brane integrity and cellular necrosis. The level of thisoxidative stress is strictly dependent on the precedingischemic period.

Free radical production duringopen-heart surgeryCavarocchi et al. [12] first reported evidence of freeradicals production during cardiopulmonary bypassin humans. Marked and sustained coronary sinusrelease of reduced and oxidized glutathione (expres-sion of increased oxidative stress) has recently beenreported during reperfusion in patients subjected tolong-lasting hypothermic cardiac arrest during coron-ary surgery. Several studies in animal models haveshown that adding free radical enzymatic and non-enzymatic scavengers to the cardioplegic solution

could reduce myocardial oxidative damage. More-over, an increased level of lipid peroxides has recentlybeen demonstrated at the end of prolonged ischemicperiods in the human myocardium protected bycold crystalloid cardioplegia [13,14]. This increasedoxidative stress is associated with the depletion ofglutathione and activation of cellular antioxidantenzymes. There is a significant positive correlationbetween tissue lipid peroxide levels and the durationof the ischemic period, confirming the existence of acrucial relationship between severity of ischemia andfree radical production during reperfusion.

Effect of warm blood cardioplegia onfree radical generationThe essential role of myocardial protection consists oflowering the tissue energy requirements during car-dioplegic arrest. In other words, the marked reductionof coronary perfusion due to aortic cross-clampingmust not be followed by myocardial damage. Formany years hypothermia was considered to be oneof the most important means to obtain this result

[15,16]. Hypothermia slows myocardial metabolism,thereby reducing ischemia-reperfusion free radicalgeneration. Various authors have shown myocardialfree radical production after prolonged hypothermiccardioplegic arrest [14-17]. However, normothermiccardioplegia has been shown to offer good metabolicand clinical results [1]. We compared the effects ofintermittent antegrade warm blood cardioplegia andintermittent antegrade cold blood cardioplegia on themyocardial metabolism, and free radicals generatedduring reperfusion after cardioplegic arrest, in 30patients undergoing mitral valve replacement [10](Table 9.2). The levels of fluorescent lipoperoxida-tion products, reduced and oxidized glutathione, and

78 CHAPTER 9

Patients (n)

Age (yr)

Sex (M/F)

NYHA class (II/III/IV)

CPBtime(min)

Aortic clamping time (min)

IAWBC

15

63 ±2.8

8/7

8/6/1

76.4 ±9.656.5 ±8.7

IACBC

15

69 ±4.7

9/6

8/5/2

83 ±18.6

62.5±16

P

0.27

0.23

0.21

Data shown are mean ± standard deviation of the mean.

IAWBC, intermittent antegrade warm blood cardioplegia; IACBC, intermittent

antegrade cold blood cardioplegia; NYHA, New York Heart Association; CPB,

cardiopulmonary bypass.

GSH sinus concentration

Throughout reperfusion (nmol/dl)

GSSG sinus concentration


After cross-clamp off (URF/ml)

Ascorbic acid

After cross-clamp off (nmol/dl)

Cross-clamp off (U/L)

Lactate


Elastase cross-clamp off (ng/dl)

IAWBC

(nmol/dl)

-24.8 ±4.5

-3.2 + 1.3

-1.9 ±0.4

-0.41 ±0.3

-12.2±1.8

+0.4 ±0.1

427 + 35

IACBC

(nmol/dl)

-161 + 19

-23.9 ±3.3

-16.3 ±2.8

-4.35 ±0.5

-41.5 + 4.3

-0.9 ±0.2

521 ±34

P

<0.0001

<0.0001 FPL

<0.0001

<0.0001 CPK

<0.0001

<0.0001

<0.0001

Table 9.2 Clinical data of patients

included in the metabolic study. From



Table 9.3 Metabolic data:

arterial-coronary sinus differences in

plasma levels.

CPK, creatinine phosphokinase; FLP, fluorescent lipoperoxidation products.

ascorbic acid were used as an index of myocardialoxidative stress. The values of these parameters weremeasured with lactate, creatinine phosphokinase, andin blood samples withdrawn from radial artery andcoronary sinus before and after aortic cross-clamping.It is evident (Table 9.3) that the oxidative stress wascompletely prevented in the hearts protected by inter-mittent antegrade warm cardioplegia; in fact there areno significant differences in these values in compar-ison with baseline. However, in hearts protected withintermittent antegrade cold blood cardioplegia, thereinfusion of oxygenated blood seems to shift theoxidation-reduction state of cells toward oxidationwith free radical generation and finally myocardialdamage. In conclusion, metabolic studies seem todemonstrate that hypothermia is not a necessarycomponent of the cardioplegic solution. It appearsthat normothermia in an arrested heart is the most

favorable condition for myocardial protection duringopen-heart surgery.

Clinical results

Coronary artery bypass graftingSince 1991 over 4000 myocardial revascularizationprocedures have been performed using intermittentantegrade warm blood cardioplegia. This method ofmyocardial protection has become routine in ourinstitution. In 1995 we published our results inpatients who had undergone coronary revasculariza-tion with warm blood cardioplegia in comparisonwith cold cardioplegia [9]. The preoperative and post-operative data are reported in Tables 9.4 and 9.5,respectively. In this study we found that the warmgroup had less mortality and morbidity in comparisonwith the cold group. The incidence of perioperative


Table 9.4 Preoperative demographic

data of patients who underwent

coronary artery bypass graft. From



Table 9.5 Clinical data of patients who

underwent CABG. From Calafiore eta/.

[9], with permission from Society of

Thoracic Surgeons.

Age (yr)

Sex F (no.)

Body surface area (m2)

Unstable angina (no.)

Urgent/elective (no.)

One-vessel disease (no.)

Two-vessel disease (no.)

Three-vessel disease (no.)

Main left stenosis (no.)

Redo rate (no.)

LVEF (%) mean

LVEF < 35% (no.)

Group A

IAWBC

59.4 ±10.0

28

1.79±0.16

115

86/164

23

94

133

16

16

51 ±20

53

Group B

IACBC

59.9 ±7.8

23

1.79 + 0.16

103

71/179

20

109

121

10

10

54112

28

P

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

<0.0025

<0.005

LVEF, left ventricle ejection fraction; NS, not significant.

CPB time (min)

Ao. cl.time (min)

Ischemictime (% Ao. cl. time)

Grafts/patients (no.)

Spontaneous rhythm

Circulatory assistance

IABP

Low output syndrome

Lidocaine infusion

Deaths

Poor LV

PMI

CK-MB peaks

Absolute value

% total CK

CVA

Awaking time (h)

ICU stay (h)

Postoperative inhospital stay (d)

IAWBC

67.2121.3

45.2116.3

87.8129.8

2.910.5

248

-

-

1

5

2

0/53

3

38138

6.112.9

4

2.711.5

2817

8.2 + 5.0

IACBC

76.3127.5

44.8115.2

87.6130.7

3.010.5

103

5

4

20

18

9

2/28

7

51130

8.214.1

7

3.912.8

43110

9.819.5

P

<0.0005

NS

NS

NS

<0.0005

<0.025

<0.05

<0.0005

<0.01

<0.05

<0.05

NS

<0.0005

<0.0005

NS

<0.0005

<0.0005

<0.0005

Ao. cl. time, aortic clamping time; CVA, cerebrovascular accident; IABP, intra

aortic balloon pump; ICU, intensive care unit; PMI, post myocardial infarction.

Poor LV (EF < 30%).

myocardial infarction was also lower in the warmgroup.

Valve surgeryIn valve surgery the technique of cardioplegia deliveryis slightly different. In fact, even if the first dose isdelivered in the same way via the aortic root, it maybe necessary to inject the cardioplegia directly in to

the coronary ostia. In any case, the second dose ofcardioplegia has to be infused in the left coronaryostium while sutures are being placed on the ring.

We published our results in patients who under-went aortic and mitral valve surgery with intermittentwarm cardioplegia in comparison with a cold cardio-

plegia in 1996 [18]. The characteristics and results ofthese patients are reported in Tables 9.6 and 9.7. In

80 CHAPTER 9

Patients (no.)

Age (yr)

M/F

LVEF (%)

LVEF < 35%

CPBtime(min)

Ao. cl.time(min)


IABP

Low output syndrome

Lidocaine infusion

CVA

Ventricular arrythmia

Deaths

ICU stay (h)


IAWBC

50

63.9 ±10.9

34/16

57.4 ±17.6

10

63.2+15.6

47.9+12.9

0

0

0

2

2

1

0

24±10

9.0 + 3.4

IACBC

50

60.2+11.9

37/13

59.9+14.4

4

82.8 + 21.1

56.5115.9

5

0

8

8

2

1

4

41±15

11.2±4.9

P

NS

NS

NS

NS

<0.0005

<0.0025

<0.025

-

<0.005

<0.05

-

<0.05

<0.05

<0.0005

<0.01

Table 9.6 Demographic and clinical data

of patients who underwent aortic valve

surgery. From Calafiore eta/. [9].

Patients (no.)

Age (yr)

M/F

LVEF (%)

LVEF < 35%

CPBtime(min)

Ao. cl.time(min)


IABP

Low output syndrome

Lidocaine infusion

CVA

Ventricular arrhythmia

Deaths

ICU stay (h)


IAWBC

50

57.1 + 11.0

21/29

58.1 ±7.8

6

76.1+27.0

59.7 ±20.1

0

0

1

3

1

1

2

28 + 9

9.3 ±2.8

IACBC

50

57.1 ±10.4

24/26

63.1 ±8.7

3

87.0 + 21.0

59.0 ±16.5

6

0

8

5

0

2

2

40±13

10.9±3.3

P

NS

NS

<0.0025

NS

<0.05

NS

<0.025

-

<0.025

NS

NS

NS

NS

<0.0005

<0.01

Table 9.7 Demographic and clinical data

of patients who underwent mitral valve

surgery. From Calafiore eta/. [9].

both types of surgery there was significantly lowermortality, postoperative morbidity, ICU and inhos-pital stay in the warm group. Since 1991 over 600aortic valve replacements and 500 mitral repairs andreplacements were performed using this method ofmyocardial protection.

Comment

Intermittent antegrade warm blood cardioplegia(IAWBC) is not only recognized as an alternative, but

also as a safe technique for myocardial protectioncurrently available. This method is similar to othercardioplegic techniques except for the temperature ofthe solution delivered. Surgeons using this techniquedo not need to change their strategy for the opera-tion because IAWBC allows us to have a bloodlessoperative field.

Despite previous studies demonstrating theinfluence of temperature on cerebral perfusion andmetabolism [19], Engelman et al. recently reportedthat hypothermia might be detrimental to cerebral


function [20]. Gaudino et al. found that the pre-

valence of neurologic events was similar in patients

undergoing hypothermic or normothermic cardio-

pulmonary bypass, and could not document any effect

of the temperature at cardiopulmonary bypass on the

prevalence of perioperative stroke [21]. However,

Jacquet et al. [22] demonstrated the evidence that

IAWBC results in less myocardial cell damage in a ran-

domized trial. The same authors demonstrated that

impaired right ventricular filling is always associated

with cold cardioplegia, which seemed better preserved

by IAWBC [23].

Finally, experimental, metabolic and clinical stud-

ies have shown that IAWBC is a safe and effective

technique providing superior results in comparison

to intermittent antegrade cold blood cardioplegia.

Therefore, the technique of IAWBC has found a place

as a myocardial protective strategy in surgery.

References1 Salerno TA, Houck JP, Barrozo CA et al. Retrograde

continuous warm blood cardioplegia: a new concept inmyocardial protection. Awn ThoracSurg 1991; 51:245-74.

2 Lichtenstein SV, Ashe KA, El Dalati H et al. Warm heartsurgery. / Thorac Cardiovasc Surg 1991; 101:269-74.

3 Buckberg GD, Brazier JR, Nelson RL et al. Studies on theeffect of hypothermia on regional myocardial blood flowand metabolism during cardiopulmonary bypass. / ThoracCardiovasc Surg 1977; 73:87-94.

4 Pratt FH. The nutrition of the heart through the vessels ofThebesius and the coronary veins. Am J Physiol 1898; 1:86-103.

5 Lillehi CW, Dewall RA, Gott VL et al. The direct visioncorrelation of calcine aortic stenosis by means of pumpoxygenator and retrograde coronary sinus perfusion.Dis Chest 1956; 30:123-32.

6 Menasche P, Kural S, Fauchet M et al. Retrograde coron-ary sinus perfusion: a safe alternative for ensuringcardioplegic delivery in aortic valve surgery. Ann ThoracSurg 1982; 34:647-58.

7 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia:its possible role in cardiac surgery. Ann Surg 1950; 132:849-66.

8 Kaijser L, Hansson E, Schmidt W et al. Myocardial energydepletion during profound hypothermic cardioplegia forcardiac operation. / Thorac Cardiovasc Surg 1985; 90:900-86.

9 Calafiore AM, Teodori G, Mezzetti A et al. Intermittentantegrade warm blood cardioplegia. Ann Thorac Surg1995; 59: 398-402.

10 Mezzetti A, Calafiore AM, Lapenna D et al. Intermittentantegrade warm blood cardioplegia reduces oxidativestress and improves metabolism in the ischemic reper-fused human myocardium. / Thorac Cardiovasc Surg1995,1995:109: 787-95.

11 McCord IM. Oxygen-derived free radicals in postis-chemic tissue injury. NEngJMed 1985; 312:159-63.

12 Cavarocchi NC, England MD, Schaff HV et al. Oxygenfree radical generation during cardiopulmonary bypass:correlation with complement activation. Circulation1986; 74:130-3.

13 Mezzetti A, Lapenna D, Pierdomenico SD et al.Myocardial antioxidant defenses during cardiopul-monary bypass. / Card Surg 1993; 8:167-71.

14 Lapenna D, Mezzetti A, De Gioia S et al. Blood cardiople-gia reduces oxidant burden in the ischemic reperfusedhuman myocardium. Ann ThoracSurg, 1994; 57:1522-5.

15 Roe BB, Hotchinson JC, Fishman NH, Ullyot DJ, SmithD. Myocardial protection with cold ischemic cardiople-gia. J Thorac Cardiovasc Surg 1977; 73:366-70.

16 Earner HB, Laks H, Codd JE et al. Cold blood as thevehicle for hypothermic potassium cardioplegia. AnnThoracSurg 1979; 28: 509-21.

17 Ferrari R, Alfieri O, Curello S et al. Occurrence of oxid-ative stress during reperfusion of the human heart.Circulation 1990; 81:201-11.

18 Calafiore AM, Teodori G, Bosco G et al. Intermittentantegrade warm blood cardioplegia in aortic valvereplacement. / Card Surg 1996; 11: 348-54.

19 O'Dwyer C, Prough DS, lonston WE. Determinantsof cerebral perfusion during cardiopulmonary bypass./ Cardiothorac VascAnesth 1996; 10:54-65.

20 Engelman RM, Fleet AB, Rousou IA et al. Influence ofcardiopulmonary bypass perfusion temperature on neu-rologic and hematologic function after coronary arterybypass grafting. Ann ThoracSurg 1999; 67:1547-56.

21 Gaudino M, Martinelli L, Di Leila G et al. Superior exten-sion of intraoperative brain damage in case of normoth-ermic systemic perfusion during coronary artery bypassoperations. / Thorac Cardiovasc Surg 1999; 118:432-7.

22 lacquet LM, Noirhomme PH, Van Dick MJ et al.Randomized trial of intermittent antegrade warm bloodversus cold crystalloid cardioplegia. Ann Thorac Surg1999;67:471-7.

23 lacquet LM, Honore P, Beale R. et al. Cardiac functionafter intermittent antegrade warm blood cardioplegia:contribution of the double indicator dilution technique.Intensive Care Med 2000; 26:686-92.

CHAPTER 10

Antegrade, retrograde, or both?

Frank G. Scholl, MD & Davis C. Drinkwater, MD

Introduction

The achievement of a technically perfect operationperformed under bloodless conditions in a still operat-ive field resulting in minimal myocardial injury anddysfunction while yielding the best long-term bene-fit is the goal of any myocardial protective strategy.The techniques used should be integrated into theconduct of the operation, allowing the smooth seam-less performance of the technical aspects of the casewhile achieving optimal preservation of myocardialfunction. In addition, myocardial protective strat-egies must be aimed toward minimizing reperfusioninjury upon resolution of the coronary occlusion andrelease of the aortic cross-clamp. Operative strategiesmust also allow for resuscitation of acutely ischemicmyocardium should the need arise. The attributesof an ideal cardioprotective strategy are outlined inTable 10.1.

While the ideas for cardiac surgery and myocardialprotection utilizing cardiac arrest and hypothermiadate back to the 1950s [1,2], current techniques util-izing warm and cold blood cardioplegia given via theantegrade and retrograde routes have evolved as aresult of experimental work and the clinical applica-tion of it over the past 30 years. As evidenced by the

Table 10.1 Attributes of an ideal myocardial protection

strategy.

Still, dry operative field

Homogenous delivery of cardioplegia

Reduction of the utilization of high energy phosphates

Decreased anerobic metabolism

Buffering of acidosis

Replenishment of energy stores

myriad of articles in the current literature regardingtechniques and types of cardioplegia and its delivery, itis likely that in the majority of patients with adequatemyocardial reserve the type of cardioplegia solution,its temperature, and its delivery route may have a min-imal impact on patient survival. However, the high-risk patient with proximal coronary artery stenosesand poor left ventricular function may suffer shouldthe cardioplegia and delivery techniques used proveineffective in providing adequate metabolite andenergy supply to prevent myocardial damage duringand following aortic cross-clamping. Analyzing thebenefits and limitations of the various cardioplegiadelivery techniques has allowed us to develop a com-bined approach to the problem of myocardial protec-tion in these high-risk patients.

Antegrade delivery

The ability to deliver cardioplegia in antegrade fashionvia the aortic root or with direct coronary cannulationprovides a route of delivery which mimics the naturalpath of blood flow through the coronary circulation.The technique is simple in its use, requiring only asuitable cannula and a way to secure it in the aorticwall. In the case of direct coronary cannulation this iseven simpler, only requiring a traumatic right-angledcannula held firmly against the coronary ostium.Antegrade delivery of cardioplegia ensures that thecardioplegia reaches all of the myocardium the nat-ive coronary circulation can supply. Herein lie boththe strengths and weaknesses of the technique. It isobviously beneficial to provide the myocardium withoxygenated blood which parallels the nonarrestedstate as closely as possible to help maintain cellularmetabolism and carry away waste products. However,in patients with significant coronary artery obstructive

82

Antegrade, retrograde, or both? 83

disease there maybe a nonuniform distribution of car-dioplegia. Coronary obstruction and stenoses, whichcause myocardial ischemia in the perfused workingnormal state, also prevent cardioplegia from reachingthese areas when it is provided in an antegrade fash-ion. Thus the administration of antegrade cardioplegiavia the aortic root, or even via the coronary ostia bydirect cannulation with an open root, may not provideadequate perfusion of arrested myocardium [3]. Thisis of particular concern in patients with high-grade leftmain and/or right coronary artery lesions in whichlarge areas of myocardium may be left unprotected.

An additional concern with the administration ofantegrade cardioplegia is noted in patients with aorticregurgitation. In these patients even mild amounts ofaortic valve insufficiency may lead to poor antegradecoronary perfusion and ventricular distention. Thiscombination of factors can result in severe myocar-dial dysfunction upon weaning from cardiopulmon-ary bypass. Inadequate delivery of cardioplegia tothe coronaries may produce ischemic areas of myo-cardium and myocardial necrosis, while distention ofthe left ventricle causes overstretching of myocardialfibers (increased wall tension and decreased coronaryperfusion) and later inefficient contractility.

Direct coronary perfusion is a potential way aroundthe problem of aortic insufficiency. The coronary ostiaare cannulated usually with a soft tip right-angledcannula and the tip is held firmly against the ostiawhile cardioplegia is administered. While this allowsaccurate and reliable delivery to the coronary circula-tion, the technique has significant shortcomings. Itrequires cessation of the technical aspects of the oper-ation to manually give cardioplegia, thus interruptingthe smooth flow of the procedure. The technique alsorequires "downtime" to give the dose of cardioplegiaand thus increases aortic cross-clamp time and theoverall length of the operation. Additionally, thereexists potential for injury to the coronary ostia fromthe cannula tip, leading to acute coronary artery dis-section or embolization of debris down the artery,and late ostial stenoses [4]. In patients with an ostialleft main or ostial right coronary lesion, injury maybe more likely to occur and the technique shouldprobably be avoided in these patients or certainlylimited to the use of a cannula with a flat-tipped softcontact surface.

Several strategies of antegrade delivery have beenproposed in attempts to circumvent the nonhomoge-

nous distribution of cardioplegia. The aorta itself,vein grafts, and distal native coronaries at the site ofplanned anastomosis have all been used as routes ofdelivery for antegrade cardioplegia. However, thesetechniques still run the risk of delayed protectionin areas served by a stenotic coronary artery that isrevascularized late in the cross-clamp period, suchas by internal mammary artery grafting [5,6].

Patients undergoing aortic valve replacement foraortic stenosis should be able to tolerate induction ofarrest with antegrade cardioplegia down the aortic rootprovided the degree of associated aortic insufficiencyis mild. However, patients with a large amount of aorticinsufficiency associated with aortic stenosis or patientsundergoing aortic valve replacement for primaryaortic regurgitation are unlikely to benefit from solelyantegrade delivery via the aortic root as previouslymentioned. Thus, in these patients the aortic root maybe opened immediately after aortic cross-clampingand cardioplegia infused directly down the coronaryostia, or alternative methods of delivery can be used.

An additional concern with the use of antegradecardioplegia delivery via the aortic root arises inpatients requiring mitral valve procedures. Placementof retractors for adequate visualization of the mitralapparatus required to carry out the procedure will dis-tort the aortic valve and render it incompetent. Thisleads to the inability to give additional antegrade dosesof cardioplegia via the aortic root due to low pressurein the root. It also will lead to filling of the left ventricleand obstruction of the operative field. The aortic rootmay be opened to give direct ostial antegrade cardio-plegia; however, this will disrupt the smooth flow ofthe operation and has the additional dangers of ostialcannulation.

Retrograde delivery

The delivery of cardioplegia via the coronary sinus wasdescribed as early as 1957 [7]. The advantages of a ret-rograde delivery route include the potential for a morehomogenous delivery of cardioplegia in the presenceof proximal coronary artery stenosis or occlusion [8],thus avoiding the problem of "islands" of poorly pro-tected myocardium, which can be seen with antegradedelivery. This method of delivery in conjunction withinitial doses of antegrade cardioplegia has been shownto be as safe and effective as antegrade cardioplegiaalone in a prospective randomized trial [9].

84 CHAPTER 10

The mechanism of myocardial protection due toretrograde cardioplegia is similar to that of antegradecardioplegia, in that both techniques can providenutritive (i.e. capillary bed) flow and myocardialcooling. However, the two routes differ in their distri-bution. Retrograde flow via the coronary sinus dis-tributes to subendocardial muscle whether coronaryarterial stenoses are present or not, and has prefer-ential distribution in the left ventricle, with decreasedflow to the right ventricle and septum. Despite thisdecreased flow to the right side of the heart, retrogradedelivery does provide effective cooling of the rightventricle and septum [ 10].

The use of retrograde cardioplegia during coronaryrevascularization allows arterial grafts to be de-airedin a retrograde fashion after completion of the distalanastomosis. The retrograde technique is also usefulin reoperative surgery to help flush out old vein graftsand prevent distal migration of atheroemboli.

An additional advantage of retrograde cardioplegiais the ability to give cardioplegia while performingkey technical components of an operation. Aortic[11] and mitral valve operations are ideally suited tothe use of retrograde cardioplegia. The placementof a suction catheter near the coronary ostia allowsdelivery of cardioplegia while debridement of theaortic valve is carried out, valve sutures are placed, orthe valve is being sized, it can also be given while theaorta is being closed to help de-air the aortic root.During mitral valve operations retrograde cardioplegiamay be given without the need to reposition theretractors, as the myocardial protection is no longerdependent on a competent aortic valve as it wouldbe in the case of antegrade delivery, thus allowing anuninterrupted progression of the operation.

The use of a left internal mammary artery is thestandard of care in modern coronary revasculariza-tion and it is often anastomosed to the left anteriordescending coronary artery. Additionally, the use ofthe right and/or both internal mammary arteries isbecoming more frequent as the goal of all arterialrevascularization is realized. Myocardium distal to thesite of internal mammary artery anastomosis cannotbe adequately protected in the presence of proximalnative coronary disease when antegrade cardioplegictechniques are used alone. The delivery of retrogradecardioplegia can protect what is usually a significantarea of myocardium.

The benefits of a warm dose of low potassiumcardioplegia at the end of the aortic cross-clamp

period have been shown in experimental studies [12],although clinical results are controversial [13,14].We routinely use a warm dose of low potassiumretrograde cardioplegia prior to the removal of theaortic cross-clamp.

Various techniques have been described to achieveadequate delivery, including right atrial delivery withclamping of the pulmonary artery and passive flowinto the coronary sinus [15] which has been largelyabandoned, direct cannulation of the coronary sinusostia with or without a pursestring, and trans-atrial"blind" cannulation via a stab wound in the right atrialfree wall [16].

When used by itself the retrograde technique has aprolonged time to arrest when compared to antegradedelivery [17]. Other disadvantages include possibledirect injury of the coronary sinus by the catheter,stylet, or balloon. Myocardial injury with subsequenthemorrhage and edema if cardioplegia is delivered atpressures higher than 45-50 mmHg has been shown[18]. Retrograde delivery can be a technically morecumbersome technique depending on how it is insti-tuted. In the case of right atrial delivery, the largevolumes required and ineffectiveness of the techniquein the presence of an atrial septal defect are disadvant-ages. We have described a simplified method of directtransatrial coronary sinus cannulation for retrogradedelivery, which can eliminate these disadvantageswhen used correctly [ 16]. We have used this techniquesince 1988.

A further disadvantage of retrograde delivery aloneis the possibility of inadequate protection of the rightventricle. This may be exacerbated if the tip of thedelivery catheter is placed deep into the coronary sinusproximal to the ostium of the posterior interventri-cular vein. It has been proposed that the technique ofright atrial isolation and delivery can avoid this prob-lem; however, this technique depends on distention ofthe right ventricle, which may produce postoperativedysfunction [19]. Placing a pursestring within theostium of the coronary sinus and directly cannulatingthe ostium may avoid the problem. This techniquehas the disadvantage of requiring bicaval cannulationand isolation of the right atrium, but we feel it likelyaffords better distribution of retrograde cardioplegiato the right ventricle, and we use this technique forprocedures with potentially long cross-clamp timeswhere it may be imprudent or inconvenient to giverepeated doses of antegrade cardioplegia as in theRoss operation. It is important that the pursestring be


placed within the coronary sinus ostium and notaround it if atrioventricular (AV) conduction prob-lems are to be avoided.

Combined use of antegrade andretrograde cardioplegia

The benefits of both antegrade and retrograde deliverycan be maximized and the risks minimized when thetechniques are combined in an integrated system ofmyocardial protection. Since 1988 we have used thistechnique exclusively for our myocardial protectionstrategy in both acquired and selective congenitallesions of the adult and pediatric age groups [16,20].Our strategy affords us the advantages of rapid arrestand myocardial cooling with antegrade cardioplegiavia the aortic root, with the improvement in homo-genous delivery of the retrograde technique. The twomethods are usually used sequentially, to avoid myo-cardial hemorrhage and edema when given simultane-ously. This may be a theoretical concern, as a recentrandomized study has shown improvement in func-tional recovery and oxygen utilization with simultane-ous antegrade and retrograde delivery when comparedto continuous retrograde alone [21]. Although thistechnique may eventually prove safe and gain wide

acceptance, we currently limit it to patients with high-grade proximal left main and right coronary lesionswhose right-sided grafts have been completed. Wecan then use retrograde delivery supplemented bysimultaneous antegrade delivery down the right graftsdirectly or via the aortic root to enhance right-sidedprotection.

Our current technique consists of standard aorticand single venous cannulation for cardiopulmonarybypass (except in patients undergoing intracardiacprocedures). The aortic cannula includes a side portfor passive root venting. A coronary sinus cannulawith a passively inflating balloon is placed via a mat-tress suture in the lateral wall of the right atrium afterplacement of the venous cannula, except in patients inwhom the right heart is opened where a catheter with amanually inflating balloon is placed via the coronarysinus and a pursestring is placed within the ostiumof the sinus itself (this technique will avoid injuryto the AV node). Figure 10.1 shows the setup of ourintegrated cardioplegia delivery and cardiopulmonarybypass system. We use the identical setup for adultand pediatric patients including transplantation; thedelivery cannula and tubing are changed accordingto patient size. For standard coronary revasculariza-tion patients are systemically cooled to 29°C, for more

Figure 10.1 Intraoperative diagramof integrated cardioplegia/cardiopulmonary bypass system.Cardioplegia delivery, antegrade orretrograde, can be selected with simpleinline switches. Continuous deliverypressures are measured. The passiveaortic root vent is integrated into thesystem and selected with switches.Arrows indicate the direction ofblood flow.

86 CHAPTER 10

complex procedures a goal of 26°C or lower maybe used. In adult patients the initial dose of coldantegrade blood cardioplegia solution diluted at aratio of 4 : 1 (blood : cardioplegia) is given at rates of300 ml/min or at a maximum pressure of 70 mmHgfor 2 min, followed by a dose of retrograde cardio-plegia at 200 ml/min or a maximum pressure of35 mmHg for 2 min. It is essential that pressure bemonitored continuously in both the antegrade andretrograde cannulas to assure proper administrationof cardioplegia. A low retrograde pressure identifies animproperly positioned cannula, and a low antegradepressure may indicate aortic valve incompetence.The maintenance doses are then given approximatelyevery 15-20 min via the retrograde cannula. We haveadapted a goal of all arterial grafting for our coron-ary revascularizations whenever possible. Due to theabsence of valves in the radial artery conduits thepatency of distal anastomoses can be assessed by dir-ect visualization of the effluent exiting the proximalaspect of these grafts during retrograde cardioplegiaadministration. Patients are individually selected forstandard revascularization using cardioplegic arrestor for off pump coronary artery bypass (OPCAB) ona case-by-case basis. Our policy is to perform theproximal anastomosis of a graft immediately follow-ing the distal anastomosis. In the event a patient hasan occluded right coronary artery and high-gradeproximal left-sided lesions we will graft the right-sidedvessels first and give antegrade cardioplegia via theaortic root down newly completed radial artery graftsto augment right heart protection.

After completing the last anastomosis just priorto unclamping the aorta we give a dose of 300 ml ofwarm retrograde cardioplegia; this is followed bywarm whole blood until the cross-clamp is removed.In certain higher risk patients the final dose of warmcardioplegia will be enhanced with the hydrophilicbasic amino acids glutamate and aspartate. We useeither 37°C antegrade or retrograde delivery and give300 ml as a final dose prior to switching to wholeblood. Patients who have suffered an acute myocardialinfarction undergoing emergent revascularization,and patients undergoing procedures with relativelylong cross-clamp periods such as a Ross procedureor a double switch for congenitally corrected trans-position of the great vessels, are most likely to receiveenhanced cardioplegia. Glutamate- and aspartate-enhanced leukocyte-depleted controlled reperfusion

Table 10.2 Components of enhanced reperfusate.

Normal saline

Tromethamine

CPD

KCI

Monosodium glutamate/aspartate

500ml

200 ml 0.3 mol/l

50ml

30 mmol/l

250 ml 0.46 mol/l

is also given in an antegrade fashion to all of our hearttransplant recipients prior to removal of the aorticcross-clamp. Table 10.2 shows the components of theenhanced cardioplegia. This solution is mixed withoxygenated whole blood at a 4 : 1 ratio prior toinfusion and is delivered in a controlled fashion at apressure of 50 mmHg or less antegrade or 30 mmHgor less retrograde.

Conclusions

We have used the described integrated approach tomyocardial protection since 1988, albeit with modi-fication of the technique to suit the development ofnewer operations, such as all arterial coronary graftingand the Ross procedure. The results of our experi-ence from 1997 to the present in consecutive patientsundergoing coronary artery bypass grafting usingcardiopulmonary bypass, alone or in combinationwith valvular procedures, along with our consecutiveseries of patients undergoing Ross and Ross/Konnoprocedures are summarized in Table 10.3. These

Table 10.3 Results with antegrade and retrograde

integrated cardioplegia strategy: 1997-2001.

Patients Early mortality

(no.) (%)

CABG alone

Combined CABG/valve

CABG/AVR

CABG/MVR

CABG/AVR/MVR

Combined CABG/MVR

Ross and Ross/Konno procedure

(adult and pediatric)

843

147

83

22

5

37

72

2.5

5.4

4.1

Total patients* 1062 3.0

* Deaths due to low cardiac output: 2.4%.

CABG, coronary artery bypass graft; AVR, aortic valve

replacement; MVR, mitral valve replacement.


techniques have led themselves to a broad varietyof both adult and congenital cardiac operations withsatisfying results. Our clinical results are contingentupon homogenous distribution of cardioplegia to thepotentially ischemic myocardium and this integratedapproach with its basis in careful experimental andclinical evaluation appears to have achieved this goalin most patients.

References1 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Elective

cardiac arrest. Lancet 1955; ii: 21.2 Bigelow W, Lindsay W, Greenwood W. Hypothermia: its

possible role in cardiac surgery. Ann Surg 1950; 132:849.3 Hilton CJ, Teubl W, Acker M et al. Inadequate cardio-

plegic protection with obstructed coronary arteries. AnnThome Surg 1979; 28:323-34.

4 Midell AI, DeBoer A, Bermudez G. Postperfusion coron-ary ostial stenosis: incidence and significance. / ThoracCardiovasc Surg 1976; 72:80-5.

5 Menasche P, Piwnica A. Cardioplegia by way of thecoronary sinus for valvular and coronary surgery. / AmColl Cardiol 1991; 18:628-36.

6 Buckberg GD, Beyersdorf F, Kato NS. Technical con-siderations and logic of antegrade and retrograde bloodcardioplegic delivery. Semin Thorac Cardiovasc Surg1993;5:125-33.

7 Gott V, Gonzalez J, Paneth M et al. Retrograde perfusionof the coronary sinus for direct vision aortic surgery. SurgGynecol Obstet 1957; 104:319-28.

8 Gundry SR, Kirsh MM. A comparison of retrograde car-dioplegia versus antegrade cardioplegia in the presence ofcoronary artery obstruction. Ann Thorac Surg 1984; 38:124-7.

9 Diehl JT, Eichhorn EJ, Konstam MA et al. Efficacy ofretrograde coronary sinus cardioplegia in patients under-going myocardial revascularization: a prospective ran-domized trial. Ann Thorac Surg 1988; 45: 595-602.

10 Partington MT, Acar C, Buckberg GD, lulia PL. Studiesof retrograde cardioplegia. II. Advantages of antegrade/retrograde cardioplegia to optimize distribution in

jeopardized myocardium. / Thorac Cardiovasc Surg 1989;97:613-22.

11 Menasche P, Kural S, Fauchet M et al. Retrogradecoronary sinus perfusion: a safe alternative for ensuringcardioplegic delivery in aortic valve surgery. Ann ThoracSurg 1982; 34:647-58.

12 Lazar HL, Buckberg GD, Manganaro AJ et al. Reversal ofischemic damage with amino acid substrate enhance-ment during reperfusion. Surgery 1980; 88: 702—9.

13 Teoh KH, Christakis GT, Weisel RD et al. Acceleratedmyocardial metabolic recovery with terminal warmblood cardioplegia. / Thorac Cardiovasc Surg 1986; 91:888-95.

14 Edwards R, Treasure T, Hossein-Nia M et al. A controlledtrial of substrate-enhanced, warm reperfusion ("hotshot") versus simple reperfusion. Ann Thorac Surg 2000;69:551-5.

15 Fabiani IN, Deloche A, Swanson J, Carpentier A.Retrograde cardioplegia through the right atrium. AnnThorac Surg 1986; 41:101-2.

16 Drinkwater DC, Laks H, Buckberg GD. A new simplifiedmethod of optimizing cardioplegic delivery without rightheart isolation. Antegrade/retrograde blood cardioplegia./ Thorac Cardiovasc Surg 1990; 100: 56-63; discussion63-4.

17 Fiore AC, Naunheim KS, Kaiser GC et al. Coronary sinusversus aortic root perfusion with blood cardioplegia inelective myocardial revascularization. Ann Thorac Surg1989; 47:684-8.

18 Hammond GL, Davies AL, Austen WG. Retrogradecoronary sinus perfusion: a method of myocardial pro-tection in the dog during left coronary artery occlusion.Ann Surg 1967; 166: 39-47.

19 Salter DR, Goldstein IP, Abd-Elfattah A et al. Ventricularfunction after atrial cardioplegia. Circulation 1987; 76(5Part2):V129-40.

20 Drinkwater DC Jr, Cushen CK, Laks H, Buckberg GD.The use of combined antegrade-retrograde infusion ofblood cardioplegic solution in pediatric patients under-going heart operations. / Thorac Cardiovasc Surg 1992;104:1349-55.

21 Jasinski M, Wos S, Kadziola Z et al. Comparison ofretrograde vs simultaneous ante/retrograde cold bloodcardioplegia. / Cardiovasc Surg (Torino) 2000; 41 (1): 11-6.

CHAPTER 11

Miniplegia: biological basis,surgical techniques, andclinical results

Giuseppe D'Ancona, MD, Hratch Karamanoukian, MD,Luigi Martinelli, MD, Michael O. Sigler, MD,d- TomasA. Salerno, MD

Introduction

Different researchers have substantiated the superior-ity of blood versus crystalloid cardioplegia in the late1970s and early 1980s. Feindel et al. [1] first showedthe superiority of blood cardioplegia in reducing irre-versible myocardial injury in a canine model of globalmyocardial ischemia. In a later prospective random-ized study, Fremes et al. [2] demonstrated that bloodcardioplegia enhanced aerobic metabolism duringaortic cross-clamping, increased myocardial oxygenconsumption, reduced anaerobic lactate production,and preserved high-energy phosphate stores. Bloodcardioplegia also improved both diastolic and systolicfunction following surgery [2]. Studies by Follete et al.also suggested that blood constituted the best vehiclefor cardioplegia delivery after myocardial ischemicinjury [ 3 ]. The advantages offered by blood cardioplegiawere attributed to its oxygen- and nutrients-carrying,osmotic and buffering natural capacities. The originalformula of blood cardioplegia included 4 parts ofblood and 1 part of crystalloid solution. This dilutionwas necessary in part to prevent hyperviscosity andred cells' rouleau formation at low perfusion tem-peratures. Secondly, hemodilution and the additionof biochemical substrates in the crystalloid solutioncould actively ease the protective and restorative capa-city of the final cardioplegic formulation. Finally, mod-erate hemodilution would decrease the concentrationof inflammatory chemical and cellular mediators that

are inevitably stimulated by cardiopulmonary bypassand result in myocardial ischemic insult. In the early1990s Menasche et al. suggested that undiluted bloodcardioplegia could retain the same functions of bloodcardioplegia, avoiding the possible disadvantages ofhemodilution [4,5]. Menasche simplified the bloodcardioplegia formula by using a minimal amount ofcrystalloid additives including potassium and mag-nesium. This new miniplegia formulation would, intheory, maximize the endogenous protective andnutritious properties of blood, eliminating the neces-sity for added buffers, calcium-chelating agents, andmetabolic substrates.

In this chapter we will summarize the biochemicalbasis of miniplegia and will focus on its clinicalapplication, as originally described by Menascheet al. We will then summarize the limited existingresearch studies that compare diluted cardioplegiaversus miniplegia, attempting to define the pros andcons of these two techniques.

Miniplegia: rheologic and biologicissues

Blood hyperviscosity and red blood cell aggregationhave been demonstrated when the blood temperatureis lowered [6]. As a result, the risk of capillary occlu-sion and consequent tissue underperfusion triplicatesfrom 37°C to 10°C [7j. For this reason, cardioplegiadilution should be advocated when maintaining a

88

Miniplegia 89

perfusate temperature around 4-10°C. However, theintroduction and popularization of warm heart sur-gery [8] has led to the concept of miniplegia andminimal cardioplegia dilution. As demonstrated bothin vitro [9] and in vivo [10], if blood cardioplegia isperfused in the 30-37°C range (tepid and warm car-dioplegia) increased blood viscosity is improbable[9] and coronary vascular resistance is unchanged[10]. For temperatures below 27°C viscosity sharplyincreases for increasing hematocrit levels [9]. Froma rheologic standpoint it seems to be unnecessary tolower the perfusate hematocrit level when warm car-dioplegia is used, at least in the absence of pathologicprothrombotic states, such as polycythemia. As a con-sequence, in the clinical setting, warm cardioplegiacan be safely used by maintaining the perfusate hema-tocrit level at a value of 25%.

Apart from the above-mentioned rheologic issues,the addition of crystalloid solution to the bloodcardioplegia formulation was viewed as a vehicleto provide the myocardium with arresting (potas-sium), calcium-chelating (citrate-phosphate-dextrose,CPD), buffering (tris-hydroxymethyl aminomethane,THAM), and nutritious (aspartate, glutamate, glucose)agents. The usefulness of providing most of theseadditives has been re-evaluated with the introductionof miniplegia.

The addition of arresting agents such as potassiumis mandatory to achieve adequate mechanical myo-cardial arrest. In the original miniplegia formulationof Menasche, potassium was added to the cardioplegicblood to reach a concentration of 16 mEq/L. Further-more, to enhance cardiac arrest and antagonize cal-cium ions at the sarcolemmal and intracellular level,an adjunct of 3 mmol/L of magnesium was recom-mended. The desired quantity of potassium andmagnesium is easily mixed in a 20-ml ampoule andis injected to achieve cardiac arrest within 1 min ofaortic cross-clamping.

CPD is added in order to reduce the concentrationof ionized calcium in the cardioplegic solution and, asa consequence, to decrease the chances of myocardialcalcium overload at the time of arrest and duringreperfusion. However, animal studies have demon-strated that warm perfusates may prevent postischemicintracellular calcium overload [11]. Continuous warmblood cardioplegia may maintain adequate myocardialaerobic metabolism and support energy for normalfunctioning of the calcium pumps. Furthermore, the

dilutional effect of the crystalloid pump prime, whichper se reduces cardioplegia ionized calcium concentra-tion, and the supplementation with magnesium, whichantagonizes the remaining calcium ions, has beenshown to ease postischemic myocardial recovery andreduce enzyme leakage [ 12]. On the basis of these con-siderations, the calcium paradox may be prevented byadding magnesium to the warm blood perfusate with-out including pharmacologic chelating agents (CPD).

As with chelating agents, pharmacologic buffers(THAM) are omitted in the original miniplegia for-mulation. Continuous warm cardioplegia maintainsaerobic metabolism and prevents the accumulationof intramyocardial lactates. In this condition, anyexternal buffering agent is unnecessary and actuallymay result in the creation of a deleterious alkaloticstatus that indirectly will cause intracellular calciumoverload. Furthermore, as demonstrated in animalstudies, both THAM and bicarbonate do not seemto improve the natural buffering capacity of bloodcardioplegia [13,14].

Aspartate and glutamate seem to ease the produc-tion of ATP in anaerobic conditions and, for thisreason, they should be added in cardioplegic vehicleswith low oxygen tension (i.e. crystalloid cardioplegia).In the setting of continuous/intermittent warm bloodperfusion, where aerobic conditions are maintained,free fatty acids and glucose are the main nutrients formyocardial metabolism. Although some benefits fromaspartate and glutamate utilization have been shownin experimental studies [15,16] with cold blood car-dioplegia, the use of amino acids in the clinical settingremains controversial [ 17,18]. However, adoption of aminiplegia formula does not preclude the utilizationof amino acids that can be concentrated in a smallvolume of fluid.

Miniplegia: perfusion technique

Menasche et al. [4] described a simplified method forminiplegia delivery. Blood for cardioplegia is with-drawn directly from the oxygenator via a standardperfusion tubing (2.5 inches (7.5 cm)) that passesthrough a separate roller pump allowing delivery ofcardioplegia at a controlled flow rate (Figure 11.1).The limb of the tubing distal to the roller pump goes tothe aortic root and incorporates a three-way stopcockused for the delivery of the miniplegia solution into theoxygenated blood. The cardioplegia solution consists

90 CHAPTER 11

Figure 11.1 The miniplegia circuit.Reprinted from [20], with permissionfrom Society of Thoracic Surgeons.

of 20 ml ampoules containing potassium chloride(16 mEq per ampoule) and magnesium chloride(6 mEq per ampoule) in distilled water. After aorticcross-clamping, normothermic blood perfusion isbegun into the aortic root at a rate of 300 ml/min.Meantime, a 20-ml ampoule of cardioplegia is manu-ally injected over a 30-s period via the stopcock. Oncethe heart is arrested, blood is perfused in a retrogradefashion via the coronary sinus at a rate of 150-200 mL/min. An electrically driven syringe is con-nected to the stopcock, allowing for the continuousdelivery of retrograde cardioplegia during the remain-ing cross-clamp time. The syringe is filled with 3ampoules (60 ml) of cardioplegia and the infusion rateis empirically set at 45 ml/h (36 mEq KCl/h). Whenrecurrence of electromechanical activity is noticed,the flow rate is temporarily increased (up to 60 ml/h).If stable asystole has been achieved, the syringe infu-sion rate is transiently dropped (down to 30 ml/h).So, for a 1-h period of aortic occlusion, the averagevolume of infused crystalloid solution will be 65 ml(20 ml for induction and 45 ml for replenishment) fora total KC1 load of 52 mEq (16 mEq for induction and

36 mEq for replenishment). To maintain the desiredcomposition of the blood cardioplegic solution(25 mmol/L KC1 concentration for induction and9 mmol/L for maintenance), Le Houerou et al. [19]

calculated normograms for the infusion rate of theKCL syringe. At any given cardioplegia roller pumpoutput, the KC1 syringe infusion rate can be calculatedusing the following formula:

q = 60[Q(p-k)]/K-p

where q is the estimated infusion rate of the KC1syringe expressed in ml/h, 60 the conversion factorfrom ml/min to ml/h, Q the oxygenated blood outputfrom the cardioplegia pump in ml/min, p the desiredconcentration of KC1 in the blood cardioplegia(high = 25 mmol/L, low = 9 mmol/L), k the patient'sserum potassium level expressed in mmol/L, and K

the concentration of potassium in the syringe KC1solution.

Furthermore, the same authors [19] proposed theuse of two separate syringes, one containing KC1and the other magnesium sulfate (12 mmol at 10%)and CPD (30 ml). The magnesium syringe infusionrate is obtained with the following formula:

<j = 0.48xQ

where Q represents the oxygenated blood output fromthe cardioplegia pump and 0.48 represents the factorthat allowed the authors to achieve a magnesium con-centration of 3.5 mmol/L in the blood cardioplegiaand to deliver a CPD concentration equivalent to theFremes' solution [19].

More recently, Calafiore et al. [20] proposed analternative miniplegia delivery protocol with exclusiveuse of intermittent (every 15 min) antegrade warm

blood cardioplegia. As summarized in Table 11.1,the total amount of delivered potassium is around37mEq/h[20].

Miniplegia 91

Miniplegia: clinical andexperimental studies

Although the theoretical bases of miniplegia are clear,its advantages in the clinical setting remain poorlyinvestigated and the number of prospective random-ized studies comparing standard versus minimallydiluted cardioplegic solutions are limited. In a pro-spective study including 50 patients, Menasche et al.[5] demonstrated that the use of miniplegia reducesthe incidence of perioperative systemic vasodilatationand the need for vasopressors infusion and volumeloading. However, no differences in terms of perioper-ative myocardial injury, recovery, and function andno differences in terms of mortality and morbidityrates were reported between the highly and minimallydiluted cardioplegia groups [5]. The authors con-cluded that routine use of the miniplegia techniqueshould be advocated to prevent peripheral vasodilata-tion occurring with warm heart operations, to simplifythe formulation of cardioplegia, to enhance control onpotassium perfusion rate, and to reduce operative eco-nomic burdens. In a more recent retrospective study,Calafiore et al. [20] analyzed perioperative results in acohort of 500 patients operated upon using eitherintermittent antegrade warm blood miniplegic solu-tion or intermittent antegrade cold (10°C) blooddiluted solution (half blood and half crystalloid solu-tion). As summarized in Table 11.1, the cardioplegiainfusion protocol in the miniplegia group slightly dif-fered from that proposed by Menasche. Perioperativemortality rate was significantly lower in the warmblood miniplegia group (0.8% vs. 3.6%, P < 0.05).Furthermore, the occurrence of perioperative low-output syndrome, use of the intra aortic balloon pump(IABP) or ventricular assistance, CK-MB release, ICUand postoperative inhospital length of stay, were all

significantly lower in the warm blood miniplegiagroup [20]. Although these findings are encouraging,it remains difficult to determine whether the differ-ences in the two groups' outcomes were the result ofeither the cardioplegic perfusion temperature (warmvs. cold) or the cardioplegic dilution level (miniplegiavs. diluted).

In an animal study, Velez et al. tested the differencesbetween miniplegia and highly diluted cardioplegiadelivered in a continuous retrograde tepid (30°C)modality during surgical reperfusion of evolving myo-cardial infarction [21]. No differences between thetwo groups were noticed in terms of CK-MB activity,myocardial infarction size, and systolic shortening.Although a trend for a greater tissue (heart, lung,liver, skeletal muscle) edema was reported in thediluted cardioplegia group, significant differenceswere noticed only at the duodenal and renal level. Atthe coronary endothelial level, the minicardioplegiagroup had greater adherence of unstimulated neu-trophils in both the ischemic and nonischemic areas,suggesting damage to the coronary artery endothe-lium [21]. Furthermore, coronary artery maximumrelaxation responses to acetylcholine and sodiumnitroprusside were impaired in the minicardioplegiagroup. The greater endothelial dysfunction in theminiplegia group may be related to the higher con-centration of neutrophils present in the solution.The interaction between neutrophils and ischemiawill determine endothelial injury, which manifestsas abnormal response to vasodilating agents andincreased adherence of unstimulated neutrophils.Although there were no large-scale acute differencesbetween the two cardioplegia groups, the long-termeffects of the endothelial dysfunction present in theminicardioplegia group were not investigated in thatstudy. In reality, this condition could predispose to

Table 11.1 Intermittent antegrade

warm blood minicardioplegia protocolas proposed by Calafiore eta/. [20].

Image Not Available

92 CHAPTER 11

coronary thrombosis and enhance extension of myo-cardial infarcted areas.

Yeatman et al. [22] investigated the effects ofmagnesium supplementation during intermittentantegrade warm minicardioplegia delivery. In this pro-spective randomized study, 400 elective and emergentCABG patients were treated with either magnesiumenriched or magnesium depleted cardioplegia. Per-fusion protocols and dilution levels of the miniplegiasolution followed the above-mentioned Calafiore'sindications [20] (Table 11.1). Analysis of 178 patientsundergoing urgent CABG for unstable symptomsdemonstrated significantly lower requirement forinternal defibrillation and temporary epicardial pac-ing in the magnesium enriched cardioplegia group.Furthermore, there was a nearly two-fold lowerincidence of new postoperative atrial fibrillation inthe same group. Moreover, postoperative plasmaMg2+ levels were consistently lower in patients whodeveloped new postoperative atrial fibrillation com-pared with those who did not [22].

Conclusion

In summary, in the context of warm or tepid bloodcardioplegia, the minicardioplegia technique maypresent some advantages over the 4 : 1 cardioplegiaformulation, including limitation of fluid overloadand systemic vasodilatation [5], enhanced controlof potassium infusion, improved practicality, andimproved cost-effectiveness. Furthermore, improvedperioperative outcomes seem to result with intermit-tent antegrade warm blood miniplegia compared tointermittent antegrade cold diluted blood solutions[20]. Moreover, the addition of magnesium in thecardioplegia formulation reduces the rate of perio-perative cardiac arrhythmias [22]. However, recentexperimental studies suggest that miniplegia usemay cause endothelial injury, which manifests as anabnormal response to vasodilating agents and increasedadherence of unstimulated neutrophils.

Although initial clinical results with miniplegia areencouraging, further prospective randomized studieson larger cohorts of patients are needed in order tobetter define the pros and cons of this technique.

References1 Feindel CM, Tait GA, Wilson G. Multidose blood versus

crystalloid cardioplegia. Comparison by quantitativeassessment of irreversible myocardial injury. / ThoracCardiovasc Surg 1984; 87:585-95.

2 Fremes SE, Christakis GT, Weisel RD et al. A clinical trialof blood and crystalloid cardioplegia. / Thorac CardiovascSurg 1984; 88: 726-41.

3 Follette DM, Fey K, Buckberg GD et al. Reducingpostischemic damage by temporary modification ofreperfusate calcium, potassium, pH, and osmolarity./ Thorac Cardiovasc Surg 1981; 82:221-38.

4 Menasche P, Touchot B, Pradier F et al. Simplifiedmethod for delivering normothermic blood cardioplegia.Ann Thorac Surg 1993; 55:177-8.

5 Menasche P, Fleury JP, Veyssie L et al. Limitation ofvasodilation associated with warm heart operation by amini-cardioplegia delivery technique. Ann Thorac Surg1993; 56:1148-53.

6 O'Neill MJ, Francalancia N, Wolf PD et al. Resistancedifferences between blood and crystalloid cardioplegicsolutions with myocardial cooling. / Surg Res 1981; 30:354-60.

7 Sakai A, Miya J, Sohara Y et al. Role of red blood cellsin the coronary microcirculation during cold bloodcardioplegia. Cardiovasc Res 1988; 22:62-6.

8 Salerno TA, Houck JP, Barrozo CA et al. Retrogradecontinuous warm blood cardioplegia: a new concept inmyocardial protection. Ann Thorac Surg 1991; 51:245-7.

9 Rand PW, Lacombe E, Hunt HE et al. Viscosity of normalhuman blood under normothermic and hypothermicconditions. / ApplPhysiol 1964; 19:117-22.

10 Hayashida N, Weisel RD, Shirai T et al. Tepid antegradeand retrograde cardioplegia. Ann Thorac Surg 1995; 59:723-9.

11 Liu X, Engelman RM, Rousou JA et al. Normothermiccardioplegia prevents intracellular calcium accumulationduring cardioplegic arrest and reperfusion. Circulation1994; 57:177-82.

12 Takemoto N, Kuroda H, Hamasaki T et al. Effect ofmagnesium and calcium on myocardial protection bycardioplegic solutions. Ann Thorac Surg 1994; 57: 177-82.

13 Neethling WML, van de Heever JJ, Cooper S et al. Inter-stitial pH during myocardial preservation: assessment offive methods of myocardial preservation. Ann ThoracSurg 1993; 55:420-6.

14 Warner KG, Josa M, Butler MD. Regional changes inmyocardial acid production during ischemic arrest: acomparison of sanguineous and asanguineous cardiople-gia. Ann Thorac Surg 1988; 45: 75-81.

15 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safetyof prolonged aortic clamping with blood cardioplegia.II. Glutamate enrichment in energy-depleted hearts./ Thorac Cardiovasc Surg 1984; 88:402-10.

16 Lazar HL, Buckberg GD, Mangarano AM et al. Myo-cardial energy replenishment and reversal of ischemic

Miniplegia 93

damage by substrate enhancement of secondary bloodcardioplegia with amino acids during reperfusion./ Thome Cardiovasc Surg 1980; 80: 350-9.

17 Wallace AW, Ratcliffe MB, Nose PS et al Effect of induc-tion and reperfusion with warm substrate-enriched car-dioplegia on ventricular function. Ann Thorac Surg 2000October; 70:1301-7.

18 Edwards R, Treasure T, Hossein-Nia M et al. A controlledtrial of substrate-enhanced, warm reperfusion ("hotshot") versus simple reperfusion. Ann Thorac Surg 2000;69:551-5.

19 Le Houerou D, Singh Al, Romano M et al. Minimalhemodilution and optimal potassium use during

normothermic aerobic arrest. Ann Thorac Surg 1992; 54:815-16.

20 Calafiore AM, Teodori G, Mezzetti A et al. Intermittentantegrade warm blood cardioplegia. Ann Thorac Surg1995; 59:398-402.

21 Velez DA, Morris CD, Budde JM et al All-blood (mini-plegia) versus dilute cardioplegia in experimental surgicalrevascularization of evolving infarction. Circulation 2001;104:1296-302.

22 Yeatman M, Caputo M, Naravan P et al. Magnesium-supplemented warm blood cardioplegia in patientsundergoing coronary artery revascularization. AnnThorac Surg 2002; 73:112-18.

CHAPTER 12

Substrate enhancement incardioplegia

ShafieFazel, MD, Marc P. Pelletier, MD,d* Bernard S. Goldman, MD

Introduction

Cardioplegic arrest is the most common method forintraoperative myocardial protection. Traditionally,arrest has been achieved with high potassium solu-tions. Optimal protection entails delivering cardiople-gia in the right vehicle, at the right temperature, andvia the most effective route. The University of Torontohas a rich history in investigating cardioplegic deliv-ery. Years of investigation, mostly in Dr R.D. Weisel'slaboratory, have revealed that the best cardioplegicvehicle is blood, that the optimal temperature for car-dioplegia is tepid, and that the most effective deliveryroute is a combination of antegrade and retrograderoutes. The next step in myocardial protection, nowthat it can be delivered to all cardiomyocytes, is tomodify the solution to target various intracellularevents that are triggered by the ischemia-reperfusioncardioplegic arrest event. Ischemia-reperfusion causesmetabolic derangement, triggers ischemic precondi-tioning, predisposes to myocardial stunning, inducesan inflammatory reaction, precipitates endothelialdysfunction, and enhances reactive oxygen species-mediated myocardial damage (Figure 12.1) [1]. Ourdiscussion of cardioplegia additive solutions there-fore will address the aforementioned six end pro-ducts of ischemia-reperfusion injury. In the domain ofischemia-reperfusion, cardioplegic arrest, postinfarc-tion reperfusion, and coronary angioplasty representdifferent perspectives on the same injurious pathway.In the following chapter, therefore, we have made aneffort to bring the cardiologist's perspective to bear

on a purely surgical problem. We have much to learnfrom the cardiology data, and the cardiologists havemuch to extract from the data uncovered by varioussurgical research groups.

Each section begins by introductory remarks tohelp with understanding of the various investigationsreported therein. Each cardioplegia additive subsec-tion begins by highlighting the evidence from animalexperiments before discussing limited human trials,and concludes, if applicable, with presenting the resultsof randomized clinical trials.

While we have made every effort to make the fol-lowing an exhaustive discussion of cardioplegic addit-ives, it is inevitable that the important work of manyinvestigators has gone unmentioned. We apologize tothose investigators in advance.

Figure 12.1 The effects of an ischemia-reperfusion eventsuch as cardioplegic arrest.

94

Substrate enhancement in cardioplegia 95

Figure 12.2 Myocardial metabolism.Under aerobic conditions, thecardiomyocyte is able to use fattyacids, lactate, glucose, and aminoacids to run the electron transportchain, and generate ATP by oxidativephosphorylation. Under anaerobicconditions, however, pyruvatedehydrogenase (PDH) is inactive, andthe Kreb's cycle is shut down. Energyrequirements of the cell are derivedfrom glycolysis, which leads to theconversion of pyruvate to lactate. Undersuch conditions, the cellular ATP andhigh-energy phosphates are depleted.

Myocardial metabolism

A synopsis of the key points of myocardial metabolismis presented below to serve as background to the vari-ous cardioplegia-enhancement techniques aimed atalleviating the metabolic derangements induced bythe ischemia-reperfusion insult of cardioplegic arrest.

Glucose enters the cardiomyocyte where it under-goes glycolysis to pyruvic acid. Pyruvate dehydroge-nase (PDH) then converts pyruvic acid to acetyl-CoAunder aerobic conditions. Acetyl-CoA, in turn, istransported into the mitochondria, with the help ofL-carnitine, where acetyl-CoA enters the Kreb's cycle.The Kreb's cycle, or the citric acid cycle, oxidizesacetyl-CoA to yield NADH, FADH2, GTP, water,and carbon dioxide. This oxidization process yieldselectrons to the electron transport chain, where thetransfer of the electron allows the activation of hy-drogen ion pumps. The increasing H+ concentrationwithin the inner mitochondrial membrane drives theATPase to produce ATP. Key intermediates in theKreb's cycle include cc-ketoglutarate and oxaloacet-ate. These two intermediates allow the entry of amino

acids glutamate and aspartate into the Kreb's cycle.Fatty acids may also participate in oxidative phos-

phorylation by being converted to acetyl-CoA (Fig-ure 12.2). Under anaerobic condtions, pyruvate isconverted to lactic acid by lactate dehydrogenase andback to glucose through the Cori cycle, which involvesthe liver.

Principles of substrate enhancement of cardioplegicsolutions center around restoring aerobic metabolismefficiently after the onset of reperfusion, and restoringdrained supplies of various intermediates that allowresumption of oxidative metabolism.

InsulinInfusion of a glucose-insulin-potassium (GIK) solu-tion was first shown to limit infarct size and increasesurvival in 1965 by Sodi-Pollares [2]. Results from atrial by the British Medical Research Council, how-

ever, dampened initial enthusiasm for GIK therapyby showing that GIK infusion after a myocardialinfarction did not affect patient outcome [3]. Morerecently a significant amount of laboratory data atteststo the benefit of GIK in ameliorating the ischemia-reperfusion injury caused by cardioplegic arrest, espe-cially in the era of warm heart surgery. The concernwith cold cardiopulmonary bypass and cardioplegia wasthat during hypothermia, the enzymatic machinery

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activated by GIK infusion would be inactive becauseof the low temperature [4].

The benefits of providing GIK to ischemic myo-cardium has been well worked out in several animalmodels. The results of these investigations are detailedbelow. During ischemia the principal cellular fuel isglucose. By providing GIK, ATP levels derived fromglycolysis are maintained. Insulin also activates pyruv-ate dehydrogenase, and promotes the cardiomyocyteto switch back to aerobic metabolism upon reperfu-sion. In addition, the presence of insulin ensuresrepletion of the Kreb cycle intermediates. GIK solu-tion also helps to reverse insulin resistance after car-diopulmonary bypass. In addition, there is evidenceto suggest that insulin helps nitric oxide productionby the endothelium, and thus prevents endothelialdysfunction associated with reperfusion injury [5,6].

Following the positive laboratory results, Lazar andcolleagues undertook investigations [7,8] to study thepossible benefits of GIK infusion in cardiac surgery.GIK was started in a randomized fashion upon anes-thetic induction and continued for 12 h postoperat-ively in 30 patients. The authors reported that theGIK patients had higher cardiac indices, a decreasedneed for inotropic support, faster extubation, andshorter intensive care and hospital stays [7,8]. Theseresults were also seen in diabetic patients undergoingcoronary artery bypass grafting (CABG) who receivedGIK solution [9]. The results from the University ofToronto [ 10] in a large trial, enrolling a total of 1127patients, did not support Lazar's findings. In thisInsulin Cardioplegia Trial, patients who received 10IU/L of insulin cardioplegia were shown, in a random-ized double blind prospective manner, to have thesame clinical outcome as those patients who were notrandomized to the insulin arm. Specifically, mortality,myocardial infarction, and postoperative low-outputsyndrome were similar between the two groups [10].The major difference between these two studies wasthat Lazar's group began insulin administration atinduction and continued the infusion up to 12 h post-operatively, whereas we only supplied insulin in thecardioplegia line. It may be that prolonged GIK infu-sion is required to duplicate the promising results thatwere obtained in the laboratory.

Glutamate-aspartateEarly work by Sanborn and associates [11] in rabbits

suggested that the amino acids glutamate and aspart-ate might be used by the anoxic cardiomyocyte inthe Kreb's cycle to generate ATP. Interestingly, in aporcine model of myocardial infarction followed byreperfusion, Engelman etal. [12] were able to demon-strate a significant reduction in infarct size if a solu-tion of aspartate and glutamate was administeredimmediately before reperfusion. In a canine model,Rosenkranz et al. [13] demonstrated that follow-ing global ischemia, hearts that were arrested withaspartate-enriched glutamate cardioplegia demon-strated more complete functional recovery than thecontrol group. The work of Svedjeholm [14] and col-leagues in CABG patients demonstrated that glutamateis lost during ischemia, and that upon replenishmentit is incorporated into the myocardium. Glutamateadministration also increased myocardial lactateuptake and led to better myocardial performance inthis study. Teoh et al. [15] from the University ofToronto, reported on a randomized trial of CABGpatients in which a terminal "hot-shot" enriched withglutamate and aspartate was used. In the studypatients, terminal warm blood cardioplegia acceler-ated myocardial metabolic recovery, preserved high-energy phosphates, improved the metabolic responseto postoperative hemodynamic stresses, and reducedleft atrial pressures. A study by Edwards et al. [16],however, did not support these earlier findings. Assuch, the role of glutamate-aspartate enrichment ofcardioplegia solution remains unproven.

L-carnitineFatty acids are activated on the outer mitochondrialmembrane and oxidized in the matrix. Long-chainacyl CoA molecules do not readily traverse the innermitochondrial membrane, and require a special trans-port mechanism. Carnitine [17], a lysine derivative,carries activated long-chain fatty acids across the innermitochondrial membrane, where (3-oxidation takesplace. It has also been shown to stimulate the oxidationof fatty acids, and suppress the development of dam-age caused by reactive oxygen species [18]. Kobayashietal. [ 19] in a canine model of left anterior descending(LAD) ligation followed by reperfusion, showed thatcarnitine levels fell in ischemic myocardium and long-chain acyl CoA accumulated in the cytosol. If the dogswere treated with exogenous carnitine, however, thesechanges were reversed. Furthermore, ATP levels were


increased and postischemic ventricular fibrillationwas decreased in the carnitine group. Paulson and col-leagues [20] also demonstrated significantly improvedrecovery of cardiac output following global ischemiaand reperfusion with L-propionylcarnitine. In isolatedrat heart model of ischemia-reperfusion, L-propionyl-carnitine protected against washout of high-energyphosphates [21]. Nakagawa et al. [22] demonstratedthat exogenous carnitine is incorporated into thecellular energy metabolism pathway and preservesmyocardial ATP levels. In 18 patients with coronaryartery disease, administration of L-carnitine inducedlactate and free fatty acid extraction [23]. In a modelof cardioplegic arrest of isolated rat hearts, finally,Tatlican et al. [24] demonstrated improved myocar-dial function after arrest with L-carnitine-enhancedcardioplegia. At our current state of knowledge, thesefindings are not robust enough to mandate a humanclinical trial.

Histidine-tryptophan-ketoglutarateBretschneider popularized histidine-tryptophan-ketoglutarate (HTK) crystalloid cardioplegia in the1970s [25]. Histidine acts as a buffer, ketoglutarateimproves high-energy production during reperfusion,and tryptophan stabilizes cell membranes. With theadoption of blood cardioplegia, the HTK solutionis becoming more or less abandoned. The evidenceregarding the HTK cardioplegia solution is there-fore only examined briefly. Kober et al. [26,27]compared the HTK cardioplegia with the Universityof Wisconsin, St Thomas' Hospital, and NationalInstitute of Health cardioplegia solution. The HTKsolution in these investigations demonstrated bettermyocardial protection with improved postcardio-plegic arrest ventricular function in a working ratheart model. In a human trial Sakata and associates[28] demonstrated that in 46 patients undergoingmitral valve surgery, HTK cardioplegia resulted inincreased spontaneous defibrillation and decreasedrequirement for pacing when compared to cold bloodcardioplegia. It is of note, however, that in this studycreatine kinase (CK) leakage tended to be less in thecold blood cardioplegia group. The study by Careagaet al. [29] also demonstrated the decreased incid-ence of postoperative arrhythmias and low-outputsyndrome. The crystalloid HTK solution, however, isnot in routine use.

Coenzyme Q10Coenzyme Q10 (CoQIO), also known as ubiquinone,is part of the oxidative machinery of the mitochon-dria. Electrons in the iron-sulfur clusters of NADH-Q reductase are shuttled to CoQIO, reducing it toubiquinol. The electrons then flow from ubiquinol tocytochrome c, a proton pump in the respiratory chain.CoQIO is therefore directly involved in energy trans-duction and aerobic ATP production, and couples therespiratory chain to oxidative phosphorylation [30]. Itis also a powerful antioxidant [31]. As such, CoQIOmay serve as a therapeutic agent to reduce myocardialischemia-reperfusion injury [32].

Sugawara et al. [33] demonstrated that ischemialeads to decreased CoQIO levels. Subsequent studiesshowed that high-energy phosphate stores were betterpreserved [34], ATP content was higher [35], andaortic flow was improved when dog hearts wereprotected with CoQIO supplementation. Atar andassociates [36] further demonstrated that myocardialstunning was attenuated by CoQIO administration.Hano and colleagues [37] found that CoQIO improvedfunctional recovery during reperfusion by enhancingrecovery of high-energy phosphates and prevent-ing calcium overload. The work of Yokoyama et al.[38] on isolated perfused rat hearts documented thedirect antioxidant effects of CoQIO, which lead inturn to better preservation of endothelium-dependentvasorelaxation when compared with the control group.Investigations by Crestanello etal. have confirmed theabove findings as well [39,40].

Sunamori et al. [41] in a clinical trial demonstratedthat patients who were administered CoQIO 2 h priorto CABG surgery had lower creatine kinase-myoglobin(CK-MB) levels and higher stroke work indices post-operatively. Patients receiving CoQIO supplementa-tion also had a lesser incidence of low cardiac output[42]. Chello et al. [43] documented decreased inci-dence of ventricular arrhythmia in patients treatedwith CoQIO 7 days before elective CABG. Interestingly,as later confirmed by Zhou and associates [44], thedegree of lipid peroxidation seemed also to be reducedin the CoQIO-treated patients. Results reported byTaggart et al. [45], however, stand in contrast withthe above results. In a randomized trial of CoQIOadministration 12 h preoperatively versus placebo,they found higher troponin T leakage in the treatmentgroup, and no evidence for myocardial protection.

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Figure 12.3 Ischemic preconditioning.Ischemia or binding of thetransmembrane receptor for adenosineleads to the activation of phospholipaseC (PLC) through interaction with a Gprotein (G). This, in turn, leads toproduction of diacyl glycerol (DAG)that activates protein kinase C (PKC).Activation of PKC allows the openingof mitochondriol K-ATPase andresults in the classic, or immediatepreconditioning of the cardiomyocyte.PKC activation also results, throughactivation of transcription factors, innew gene transcription and proteinsynthesis. The new gene expressionenhances ischemic tolerance in delayedpreconditioning.

Ischemic preconditioning

Murry and colleagues first described the phenomenonof preconditioning [46]. In a canine model of 40 minof ischemia, the dogs that had been subjected to serial5-min episodes of ischemia followed by reperfusionfor 5 minutes, had a substantially smaller infarct size.Much work has ensued ever since to elucidate themechanism of ischemic preconditioning. The follow-ing discussion will only address classic or immediatepreconditioning, and not delayed preconditioningthat becomes evident after 24—96 h [47].

Although the triggers and mediators of precondi-tioning are unclear, the three players identified thusfar are adenosine, KATP channels, and the epsilon iso-form of protein kinase C (PKC) kinase (Figure 12.3)[48-50]. Adenosine is released into the extracellularfluid very early during ischemia. In a rabbit model, Liuet al. [51] showed that adenosine, which is released,acted through the Al receptor to induce precondi-tioning. In a canine model, Grover and associatesshowed that stimulation of the Al adenosine receptorled to the activation of KATP channels, and that byinhibition of the KATP channels using glyburide, theycould block preconditioning. Furthermore, adenosinestimulation of Al receptor also leads to PKC activa-tion [52], which most likely mediates the late responseafter a brief episode of ischemia. Ultimately, thesechanges lead to slower energy metabolism, thus allow-ing longer periods of ischemia before irreversiblemyocardial injury [53].

The results of a study published by Juggi et al. [54]are interesting. This group showed that precondition-ing, when combined with hypothermia or hypothermiccardioplegia, offered no significant additional protec-tion for global ischemia of isolated rat hearts [54].

KATP channel openersDiazoxide has been shown to be a relatively spe-cific opener of mitochondrial KATP channels, andto induce preconditioning [55-57]. However, morerecently diazoxide has also been shown to opensarcolemmal KATP channels [58]. In an ischemia-reperfusion injury model of human atrial trabeculae,KATP channel opening by diazoxide protected viabil-ity and function of the myocytes [59]. In an isolatedrabbit heart model of myocardial infarction, pre-ischemic diazoxide treatment reduced the area ofmyocardial infarction significantly. The KATP channelblocker 5-hydroxydecanoate blocked this effect [60].Wang and associates [61] extended these observationsby noting that PKC translocated to the mitochondriaof Langendorff-perfused rat hearts upon treatmentwith diazoxide. Furthermore, treatment of rats withphorbol 12-myristate 13-acetate, which downregulatesPKC activation, abolished the noted cardioprotec-tion in the presence of diazoxide. Diazoxide treat-ment before ischemia-reperfusion injury stabilizedmitochondrial membrane potential and decreasedapoptosis by preventing mitochondrial damage andcytochrome closs [62]. Finally, in a porcine modelof LAD ligation, followed by global ischemia under


cardioplegic arrest, followed by reperfusion, Wakiyamaet al. [63] demonstrated smaller infarct area indiazoxide-treated hearts. Apoptosis, as estimatedby TUNEL staining, was also significantly decreasedin the border-zone of the diazoxide hearts.

In spite of these encouraging laboratory results,diazoxide enhancement of cardioplegic solutions hasnot been investigated in humans. Because the safetyprofile of diazoxide is well established, such trialswould be relatively easy to conduct. Perhaps diazoxidetherapy should first be investigated in diabetic patientswho are on sulfonylurea drugs because these drugshave been shown to block the mitochondrial KATPchannels and preclude preconditioning.

NicorandilNicorandil is another KTP channel opener. Sugimotoand associates first used it as a pretreatment of guineapig papillary muscle preparation in a cardioplegicischemia model [64]. The investigators reported sig-nificant negative inotropic phenomenon associatedwith nicorandil use. Mechanical function, however,was better preserved in this cohort. Isolated rat heartsdemonstrated an improvement in myocardial pro-tection in a cardioplegic global ischemia model whenpretreated with nicorandil. This effect was abolishedby pretreatment with the sulfonylurea glibenclamide[65]. As with diazoxide, it also limits the area of infarc-tion in a rabbit model of LAD ligation [66-68]. In ahuman trial with a total of 40 patients, nicorandilenhancement of the cardioplegic solution resulted insignificantly lower serum CK levels. Troponin T levelstended to also be lower, and the cardiac output tendedto be higher in this cohort [69]. Hayashi et al. con-firmed these results by showing lower CK-MB levelsand decreased exogenous catecholamine require-ments in 35 patients who received nicorandil therapywhen compared with the 35 patients who did not [70].Thus, although randomized clinical trials are lacking,the initial experience with nicorandil is positive. Itsnegative inotropic effects, however, may be both alimiting and a confounding factor in the applicationof this substrate to cardioplegic arrest.

Recent evidence suggests that KATP opening leadsto inhibition of the Na-H exchange channel [71],which in turn may aid cardioprotection. The evid-ence for myocardial protection with Na-H exchangeinhibition will be covered in the section "Myocardialstunning" below.

AdenosineConsiderable evidence indicates that adenosine is acardioprotective agent. In numerous species, adeno-sine has been shown to decrease myocardial stunning[72-74]. It enhances the myocardial phosphorylationpotential and thereby improves myocardial energeticsin the stunned heart [75]. It has also been shown todecrease oxygen-derived free radical production byneutrophils [76]. In 1995, Lee and associates reportedthe first trial of adenosine in cardiac surgery [77].A total of 14 patients with ejection fractions of about30% and triple-vessel disease were assigned to eitherreceive adenosine prior to the institution of cardiopul-monary bypass or not. The patients who receivedadenosine had a better cardiac index immediately and40 h postoperatively. They also had lower CK levels,indicating better myocardial protection. In a phase 1dose-ranging trial, Fremes et al. [78] from our centerat the University of Toronto reported that adenosinein doses greater than or equal to 50 |J,inol/L resulted inhypotension and increased phenylephrine use, butthat it was otherwise safe. In a phase 2 trial, this samegroup concluded that there was no evidence of anyconsistent treatment benefit with adenosine cardio-plegia dosages of up to 100 |iimol/L [79]. In a parallelseries of studies, Mentzer and colleagues [80,81] stud-ied higher doses of adenosine up to 2 mmol/L withoutadverse hypotensive episodes. Presumably, usingwarm blood cardioplegia in Fremes' study resulted inhigher predisposition to hypotension. In the higheradenosine groups, Mentzer reported less incidenceof the composite outcome of high-dose dopamineuse, epinephrine use, intra-aortic balloon counter-pulsation, myocardial infarction, or death. Warm car-dioplegia, however, has been associated with a lowerincidence of postoperative low-output syndrome[82]. It remains unclear therefore whether cold andhigh-dose adenosine-enhanced cardioplegia wouldprovide better myocardial protection when comparedwith warm cardioplegia alone.

Excitation-contraction couplingThe depolarization of the sarcolemmal membraneleads to an inward calcium current at the sarcolemmalcisternae, T tubular network, and the sarcoplasmicreticulum. The bulk of the cytosolic calcium is derivedfrom the passage through the L (long-lasting) calciumchannel. The L-type calcium channels open at a mem-brane potential of -30 to -20 mV and remain open

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Figure 12.4 Calcium channels andnormal cytosolic calcium homeostasis.Modified from Guyton eta/. [83].

through much of the action potential. The troponin-calcium complex then uncovers tropomyosin-coveredactive actin sites. The energized myosin heads cannow engage actin and sweep the actin filament along.The myosin heads, following de-energization in thisprocess, "recock" and are ready for another cycle ofinteraction with actin. Myosin-ATPase mediates thisaction. The cytosolic calcium is then pumped acrossthe sarcolemmal and sarcoplasmic membranes by theaction of the calcium-ATPase channels. Thus, diastolicextrusion of cytosolic calcium is an energy-dependentprocess. Catecholamine stimulation of the cardiomy-ocyte activates a stimulatory G protein, which inturn increases the intracellular c-AMP concentrationthrough the activation of adenyl cyclase. Increasedc-AMP levels lead to calcium channel activation,induced by phosphorylation-related conformationchange, and to increased activity of c-AMP-dependentprotein kinase, which leads to phosphorylation ofphospholamban. Calcium channel activation leads toa positive chronotropic effect at the SA node, positivedromotropic effect at the AV node, positive inotropic

effect by increasing myosin-actin interaction, andpostive lusitropic effect by enhancing sarcoplasmicreticulum calcium uptake at the end of the actionpotential (Figure 12.4) [83].

Myocardial stunningHeyndrickx and colleagues [84] demonstrated ina canine model in 1975 that coronary occlusion of5-15 min, which does not induce myocardial celldeath, resulted in decreased contractile function ofthe affected area for up to 24 h after reperfusion.Braunwald and Kloner [85] termed this phenomenon"myocardial stunning" in 1982. The essential attributeof the dysfunctional myocardium is the decouplingof the excitation-contraction process [49,50]. Muchinvestigational work has been performed to elucidatethe exact mechanism of myocardial stunning. Thusfar oxygen-derived free radicals and disruption incalcium homeostasis have been implicated in thepathogenesis of myocardial stunning (Figure 12.5)[86]. The role of oxygen free radicals will be discussedin the section "Reactive oxygen species."

Image Not Available


Figure 12.5 Myocardial stunning.Increased reactive oxygen species andcytosolic calcium decrease the sensitivityof the contractile proteins tointracellular calcium perhaps throughdegradation of myofibrils and troponin Iby the activated calpain I.

Disruption of calcium homeostasis inmyocardial stunningMarban and colleagues [87] demonstrated an increasein cytosolic calcium levels in ferret hearts during15 min of ischemia. The calcium levels returned tonormal levels upon reperfusion. Przyklenk and Kloner[88] studied the effect of verapamil treatment onstunning in a canine model of transient myocardial

ischemia. They found that pretreatment with vera-pamil essentially ablated the phenomenon of postis-chemic stunning as segment shortening was restoredto 115 + 8% of normal after 3 h of reflow, thus arguingfor a pivotal role of L-type calcium channels in mediat-

ing stunning. Krause and associates also documentedthe decreased activity of the sarcoplasmic reticulumCa-ATPase [89]. More recently, Valdivia and associ-ates [90], studying the effect of transient ischemia of10 min in a pig model, showed that both the rate ofsarcoplasmic reticulum calcium uptake and releasevia the ryanodine receptor calcium-release channelswas decreased in stunned myocardium. Additionally,the intracellular acidosis caused by ischemia activatesthe Na+-H+ exchanger, which promotes transport ofa hydrogen ion in exchange for a sodium ion. In turn,the rising intracellular Na+ concentration leads toincreased levels of intracellular calcium by activat-ing the Na+-Ca2+ exchanger [91,92]. The increased

cytosolic calcium (Figure 12.6) levels in turn havebeen shown to decrease the responsiveness of the car-diac myofilaments to intracellular calcium [93-95]. It

appears that activation of the calcium-dependent pro-tease Calpain I leads to the proteolysis of the myofibrilsand troponin I [96,97]. Interestingly, troponin Idegradation and stunning could be prevented by alow calcium reperfusion buffer in the intact heart [97].

L-type calcium channel blockade incardioplegiaSeveral laboratories were involved in investigatingthe effects of various L-type calcium channel blockers(CCBs) in providing superior myocardial protectionin the early 1980s. These investigations were spurredby the previous findings that necrotic myocytes hadexceptionally high cytosolic calcium levels. The role ofcalcium in myocardial stunning was not well describedat the time. These early animal studies demonstrated aconsistent superiority of CCBs in the return of leftventricular function postcardioplegic arrest with noevidence of decreased myocardial necrosis on micro-scopic examination of pathologic slides [98-104].Interestingly, metabolic studies did not reveal betterpreservation of high-energy phosphates in these ex-periments. In retrospect, these findings are consistentwith decreased levels of myocardial stunning.

The success of the initial laboratory findings pro-vided an impetus to various clinical investigators to

take CCBs to human trials. Clark and associates [99]first reported a decrease in the use of intra-aortic bal-loon pump counterpulsation in high-risk patients withpoor ventricular function who underwent cardioplegic

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Figure 12.6 The role of various ionchannels in ischemic injury. Intracellularacidosis leads to an increase inintracellular sodium by activating theNa+-H+ antiport and inhibiting theNa+-K+ ATPase. The Na+-Ca2+ channel,in turn, leads to the exchange ofextracellular calcium for intracellularsodium. Ischemia also inhibits thesarcoplasmic reticulum Ca2+-ATPase,which is responsible for the uptake ofcytosolic calcium into the sarcoplasmicreticulum during diastole.

arrest at the time of operation with nifidepine-enhanced cardioplegic solution when compared withsimilar patients who did not receive nifedipine. Inlater studies the authors documented better cardiacindices, stroke volume, and left ventricular work indexin nifedipine cardioplegic patients. More importantly,low cardiac output death declined from 11% in theregular cardioplegic group to 4% in the nifedipinecardioplegic group [105,106]. Flameng and colleagues[107], in a randomized study of 48 patients under-going bypass or valve operations, documented adecrease in left ventricular stroke work index in thenifedipine group immediately after bypass. Afteradmission of the patients to the intensive care unit,however, the incidence of low cardiac output tendedto be lower in the nifedipine group. Presumably thenegative inotropic effects of CCB, followed by anattenuating effect of CCB on myocardial stunning,cause the particular sequence of events. These resultshave been confirmed in a double-blind, placebo-controlled, randomized clinical study conducted byTrubel and associates [108]. Diltiazem cardioplegiawas studied at the University of Toronto by Christakisand colleagues [109] in a prospective, randomizedtrial. Whereas diltiazem cardioplegic patients hadhigher postoperative cardiac indices and lower CK-MB levels, placebo patients had higher left ventricularstroke work indices and shorter periods of electrome-chanical arrest. The authors concluded that diltiazemcardioplegia should be used with caution in patients

with ventricular dysfunction because of its negativeinotropic effects. In a single blind randomized study,Earner and associates [110] showed higher cardiacindices, higher stroke work indices, and lower CK-MB peak levels in diltiazem cardioplegia patients incomparison with placebo patients. These effects wereshown to be dose dependent. Lastly, verapamil cardio-plegia has also been shown to decrease release ofCK-MBisoenzyme[lll].

The totality of this experience indicates a similaraction of the three major classes of L-type CCBs. Whilethe decreased release of CK-MB in some of the studiesin the patients treated with CCBs indicates a lowermyocyte necrosis rate induced by cardioplegic arrest,the improved postcardioplegia systolic function ofthe left ventricle in the CCB-treated patients wouldargue for a lesser degree of myocardial stunning. Ashighlighted in some of the above studies, importantconfounding and clinically significant variables are thenegative chronotropic, dromotropic, and inotropiceffects of the CCB. Currently, CCB-enhanced cardio-plegia is not used at our center. The dose of thismedication may also be of paramount importancein balancing the risks and benefits of calcium channelblockade. Alternatively, should a CCB with an ex-tremely short half-life become available, the use of thisparticular CCB only during cardioplegiac arrest, andits clearance immediately after removal of the aorticcross-clamp, could allow for myocardial stunningblockade without the negative inotropic effects.


Na+-H+ exchanger inhibitorsAs described above, intracellular acidosis ultimatelyresults in the activation of the Na+-H+ exchanger(NHEI), which in turn results in increased concentra-tions of cytosolic calcium (Figure 12.6). This effect isparticularly pronounced upon reperfusion of ischemic

cardiomyocytes when extracellular lactic acid is washedout [112]. Inhibitors of the NHEI have therefore beenstudied in various settings as cardiomyocyte protect -ants [113]. Studies of isolated rat hearts subjected toregional ischemia and reperfusion in the presence orabsence of amiloride, amiloride derivate, or cariporide(HOE694) delineated several benefits in inhibitionof the NHEI [113-115]. Specifically, the investigatorsdemonstrated decreased incidence of reperfusionarrythmias, decreased release of lactate dehydrogenase(LDH) and CK, and increased levels of glycogen and

high-energy phosphates [113-115]. Mochizuki et al.[116] further demonstrated that NHEI administrationwas best done during ischemia. Moffat and colleagues[117] confirmed that NHEI-treated isolated rat heartsregained more contractile function than the controlgroup when treated prior to reperfusion. Hendrikxet al. [118] extended these observations to a rabbitmodel. In a porcine model of ischemia-reperfusion,Sack and colleagues [119] demonstrated decreasedultrastructural changes and necrosis in the heart of thepigs treated with NHEI prior to the onset of ischemia.In addition, NHEI also seemed to protect againstneutrophil-induced reperfusion injury [120]. Interest-ingly, the work of Gumina and associates [121,122]demonstrated that not only is NHEI administra-tion efficacious just before revascularization of anoccluded LAD, but that the protection afforded byNHEI administration was greater than that afforded

by ischemic preconditioning in a canine model ofmyocardial infarction.

Experience with NHEI-enhanced cardioplegia,however, is surprisingly small and limited to isolatedrodent heart models. Myers et al. [123] first demon-strated better systolic and diastolic functional recov-ery after cardiplegic arrest and profound hypothermic(4°C) storage for 12 h if the cardioplegia solutioncontained cariporide. Other investigators have alsoshown, under different cardioplegic arrest protocols

and temperatures, improved recovery of ventricularfunction [124-126].

The positive results from various animal modelsserved as impetus to a major, multicentred, ran-

domized, double-blind, placebo-controlled trial bythe GUARD during Ischemia Against Necrosis(GUARDIAN) investigators [127,128]. More than11 000 patients with unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), or under-going percutaneous or surgical revascularization wererandomized to receive cariporide or placebo. Drug

therapy was initiated as soon as possible after admis-sion in patients with UA/NSTEMI and between 15 minand 2 h before revascularization. No significant sur-vival benefit of cariporide could be demonstratedacross a wide range of clinical situations. In the high-dose cariporide CABG group, however, there was asignificant relative risk reduction of c. 25% (P = 0.03)in the incidence of nonfatal myocardial infarctions.

Two years after the publication of this trial, cari-

poride is still not used as a cardioplegic additive. With

the c. 25% relative and c. 5% absolute risk reduction innonfatal MI rate in the CABG group, the numberneeded to treat to prevent one nonfatal MI would be25. We postulate that cariporide would have an evengreater impact on the incidence of postoperative low

output syndrome. Perhaps its use should be adoptedand its role as a pure cardioplegia additive should be

evalutated.

The inflammatory reaction

Cardioplegic arrest of the heart, akin to ischemia-reperfusion, stimulates a cascade of inflammatoryreactions [129]. These involve complement activa-tion, neutrophil interaction with selectins and inter-cellular adhesion molecules (ICAMs), leading to theiractivation in the inflammatory milieu of a reperfusedheart. There is subsequent plugging of capillaries,release of oxygen free radicals, and vasospasm ofthe myocardial beds correlated with elevated levelsof endothelin. This leads to myocardial damage byapoptosis, decreased blood flow, "no reflow" phe-nomenon, and myocardial stunning. Thus intenseinvestigation has ensued in search of a method toabrogate this inflammatory cascade of events duringcardioplegic arrest of the heart. The systemic inflam-matory response to cardiopulmonary bypass will not

be discussed in this chapter.

Complement cascade

In the setting of ischemia-reperfusion injury and

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Figure 12.7 Neutrophil-endotheliuminteraction. Expression of selectins bythe endothelial cells after ischemic injuryleads to the rolling of the neutrophils(PMN) over endothelial cells by selectinligand-selectin interaction. Expressionof integrins by damaged endotheliumallows firm adhesion of PMN to theendothelium through their intercellularadhesion molecule (ICAM)-integrininteraction. Chemoattractants such ascomplement fragments C3a and C5a,and interleukin 8 (IL-8) promote thediapedesis of the PMN into the tissue.

cardiopulmonary bypass, the complement cascade isactivated, leading to the generation of complementfragments. While membrane attack complexes inducedirect cell injury, C3a and C5a fragments act aschemoattractants and inflammatory mediators. Therole of complement activation in myocardial infarc-tion has been well established [ 130-132]. Therapeuticalternatives have involved use of the cobra venomfactor complement depletion [133], specific anti-bodies against complement fragments [134], or useof a soluable complement receptor [135,136]. Inthe arena of cardiac surgery, Tofukuji et al. [137]reported on the use of anti-C5a antibodies in reducingcardioplegia-related injury. Following cardioplegicarrest of pig hearts for 1 h, the investigators foundthat pretreatment with anti-C5a antibody improvedendothelium-dependent relaxation, decreased neu-trophilic infiltration, and decreased myeloperoxidaseactivity (a surrogate marker for neutrophilic activa-tion). However, there was no difference in postarrestleft ventricular function. In a porcine infarct followedby cardioplegic arrest, revascularization, and reperfu-sion model, Riley and associates [138] investigatedthe role of a recombinant C5a antagonist. Theyreported a significant reduction of the infarcted areaand improved postbypass ventricular function withthe use of the C5a antagonist. Although these resultssuggest a modest benefit to complement inactivationin the setting of cardioplegic arrest, our knowledgeis too limited at this point to allow for the design ofhuman clinical trials.

Neutrophil activationThe initial event in neutrophil activation is the inter-action between the neutrophil and the endotheliumthrough P- and E-selectins on the endothelium that

interact with membrane oligosaccharides on theneutrophil surface. As indicated in a previous section,this leads to rolling of the neutrophil along theendothelium until integrin-ICAM interactions allowsticking of neutrophils followed by transmigration(Figure 12.7). Therefore, the initial investigations ininterfering with the mechanism have been focusedon blocking selectin-mediated rolling of neutrophils.Using fucoidin, a nontoxic sulfated fucose oligosac-charide that blocks selectins, Miura et al. [139]concluded that selectin blockade resulted in betterrecovery of left ventricular function, coronary bloodflow, and myocardial energy consumption after coldischemia in an isolated, blood-perfused neonatallamb heart model. Using a similar model, Nagashimaand colleagues [140] demonstrated the efficacy of P-selectin specific monoclonal antibody-enriched car-dioplegia solution. Schermerhorn et al. [141] extendedthese observations, using a synthetic oligosaccharideanalog of sialyl-Lewis (x)—natural ligand for selectins—to show that endothelial function was better pre-served with selectin blockade. In a canine model, how-ever, selectin blockade made no difference in preloadrecruitable stroke work or neutrophilic myeloper-oxidase activity [ 142]. Therefore, in spite of the soundtheoretical basis arguing for a beneficial effect of selectinblockade in cardioplegic arrest, this therapy remainsmostly unproven, even in the laboratory setting.

Steroid therapyAlthough initial laboratory results suggested possiblebeneficial effects of methylprednisolone on recoveryfrom cardioplegic arrest [143], subsequent studiesfailed to show a benefit [144-147]. Systemic steroidtherapy received a significant amount of attention withregards to fast tracking of cardiac surgery patients. As


a pure cardioplegic additive, however, steroids havenot shown any benefit. This is likely because of thetimeline of steroid activity. Steroids exert their effectsby entering cells and binding to cytosolic steroidreceptors, then migrating to the nucleus and enhanc-ing the transcription of certain genes. As such, steroidtherapy results in biologic responses hours aftersteroid administration. The finding that cardioplegiaenhancement with steroids does not attenuate myo-cardial recovery is therefore not surprising.

Endothelial dysfunctionEndothelium supports cardiovascular function bypromoting vasodilatation, and inhibiting plateletaggregation, white blood cell adhesion, and smoothmuscle cell proliferation. Chronic dysfunction of theendothelium has been documented in patients withcoronary artery disease risk factors. In the acutesetting of global ischemia followed by reperfusion,there is strong evidence of acute endothelial dysfunc-tion as well [148]. Under these circumstances, activa-tion of the endothelium by the hypoxic arrest andreperfusion-induced oxygen free radical burst leads toincreased vasomotor tone and capillary plugging bywhite blood cells. Ischemia-reperfusion reduces bothbasal and stimulated nitric oxide (NO) release, alsoreferred to as the endothelium-derived relaxing factor.This decrease in NO also aids neutrophil adherenceto the endothelium. Hypoxia induces endothelialWeibel-Palade bodies to release P-selectin and,through activation of the NF-KB pathway, promotestranscription of E-selectins, ICAMs, IL-8, and IL-1genes. Neutrophils begin rolling along the endothelium

through their interaction with the selectins. TheICAM-integrin interaction leads to firm adherence ofthe neutrophils and their transmigration. Ischemia-reperfusion injury also promotes release of endothe-lin, which is a highly potent vasoconstrictor. Alongwith platelet aggregation and leukocyte degranula-tion, endothelin-induced vasoconstriction may leadto significant impairement of microcirculatory flow.This has been termed the no-reflow phenomenon.Attenuating endothelial activation is therefore im-portant in improving intraoperative myocardialprotection and postoperative myocardial function.

Nitric oxide pathwayNO is becoming increasingly recognized as an import-ant mediator of endothelial function. It is producedby nitric oxide synthetase (NOS). The three isoformsof NOS include neuronal (nNOS), inducible (iNOS),and endothelial (eNOS). Under normal circumstances,L-arginine is oxidized in the presence of tetrahydro-biopterin (BH4) to L-citrulline and NO with the con-comitant consumption of NADPH. Although theexact redox mechanism by which BH4 participatesin the biosynthesis of NO is still not understood,accumulated evidence indicates that an optimal con-centration of this compound is of critical import-ance for normal functioning of eNOS. Suboptimalconcentrations of BH4 lead to "uncoupling ofNOS" with a resultant decrease in NO synthesis andincreased formation of superoxide anions such as per-oxynitrite and hydrogen peroxide (Figure 12.8) [149].Attempts at increasing NO tissue levels have includedthe use of nitroglycerine, HMG-CoA inhibitors,

Figure 12.8 Nitric oxide production. Inthe presence of tetrahydrobiopterin(BH4), endothelial nitric oxide synthase(eNOS) converts L-arginine to L-citrullineand nitric oxide (NO). Uncoupling ofeNOS in the presence of low tissue BH4

levels, leads to the production of thesuperoxide anion and peroxynitrite(OONO-).

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angiotensin-converting enzyme inhibitors, and anti-oxidants. Several strategies have also been developedto increase cardiac NO production at the time ofcardioplegic arrest as detailed below.

Nitric oxide donorsAs indicated above, the innate endothelial mecha-nisms to synthesize NO may be disrupted in situationsof ischemia and reperfusion. For instance, productionof NO from L-arginine under conditions where BH4 isnot in abundance may be suppressed in favor of theproduction of oxygen free radicals. For this reason,some investigators have turned to direct NO donorsfor myocardial protection. Johnson and associates[150,151], for instance, showed that administrationof authentic NO gas or NaNO2 at the onset of reper-fusion in a feline model of ischemia-reperfusiondecreased infarct size by nearly 75%. This effect wasevident at subvasodilatory concentrations of NO.Nakanishi and colleagues [152] used SPM-5185, acysteine-containing compound that readily releasesNO [153], in a canine model of cardioplegia duringcardiopulmonary bypass. One hour of cardioplegicarrest was followed by 1 h of reperfusion, after whichtime the left ventricular systolic performance wasmeasured. This revealed that hearts arrested withSPM-5185-enhanced blood cardioplegia showed com-plete recovery of systolic performance in comparisonwith only c. 50% recovery of function in the controlgroup. In other models of ischemia-reperfusion,however, studies have shown deleterious effects ofthe NO breakdown product, peroxynitrite, on boththe endothelium and myocardium [154,155]. This isin contrast to other similar studies [156]. It appearsthat peroxynitrite's effect on the heart is milieu-dependent. For instance, peroxynitrite appears to bedeleterious in crystalloid cardioplegia while beingbeneficial in blood cardioplegia [157]. The role ofNO donors in cardioplegia therefore requires moreelucidation.

L-arginineEngelman and associates [158,159] first reported onthe use of L-arginine as a cardioplegic additive in aporcine model. They showed that enhancement withL-arginine led to higher myocardial NO levels, alongwith a reduction in lipid peroxidation, plasma levelsof soluble adhesion molecules, myocardial stun-ning, and arrhythmias. Furthermore, the investigators

demonstrated better-developed aortic pressures inthe L-arginine group following ischemia-reperfusion.Sato et al. [160], in a parallel series of experiments in acanine model of LAD occlusion for 30 min followedby revascularization, concluded that cardioplegic solu-tion supplemented with L-arginine reduced infarctsize, preserved postischemic systolic and diastolicregional function, and prevented endothelial dysfunc-tion. L-arginine supplementation also allowed for anincrease in coronary blood flow and a faster recoveryof myocardial tissue pH [ 161 ]. In a phase I pilot study,Carrier and colleagues documented the safety ofL-arginine cardioplegia in 50 patients. Subsequently,Wallace and associates [162] demonstrated thatsystemic L-arginine infusion reduced postcardiopul-monary bypass coronary vasoconstriction. Finally, ina prospective randomized, double-blind clinical trialinvolving 200 patients undergoing aortocoronarybypass operations, Carrier and associates recentlydemonstrated that L-arginine cardioplegia decreasedlevels of troponin I release (P = 0.03), increased car-diac indices (P = 0.09), and decreased ICU and hospi-tal stays (P = 0.09). It appears therefore that L-argininesupplementation may provide better myocardialprotection.

TetrahydrobiopterinAs indicated above, tetrahydrobiopterin (BH4) has amajor role in the synthesis of NO (Figure 12.8), andinhibiting the production of oxygen free radicalssuch as peroxynitrite and hydrogen peroxide. It mayalso play a role in the biosynthesis of catecholamines[163]. There is mounting evidence that in acuteischemia-reperfusion models and chronic endothelialdysfunction models, increased oxidative stress leadsto a decline in tissue BH4, thus leading to decreasedendothelial NO output as eNOS is "uncoupled." In avariety of rat and pig models of chronic endothelialdysfunction, supplementation of BH4 has been shownto have beneficial effects on endothelial function[164-169]. In humans, the evidence is quite strong aswell. Higman et al. [170] showed that saphenous veinrings from smoking patients had increased vasorelax-ation when incubated with the calcium ionophoreA23187 and BH4 when compared with vein ringsthat were only treated with A23187. Enhancement ofsaphenous vein endothelium-dependent relaxation,when incubated with BH4, has been also observedin patients with coronary artery disease [171]. Ueda


and associates [172], demonstrated that BH4 supple-mentation improved the bioactivity of endothelium-derived NO in smokers. The work of Stroes et al. [173]extended these observations to hypercholesterolemicpatients. In patients with coronary artery disease, BH4

prevented acetylcholine-induced vasoconstriction ofangiographically normal vessels by the use of coronaryflow velocity measurements [ 174].

Despite the heterogeneity of animal models andpatient populations studied, BH4 appears to have con-sistently improved endothelium-dependent vasore-laxation. Although the role of BH4 in intraoperativemyocardial protection has not been addressed yet,studies are underway to evaluate its effectiveness inthe coronary bypass operation. BH4 may prove to bean important adjunct to bypass operations, especiallywith the increasing use of arterial conduits.

EndothelinEndothelin 1 (ET-1) is the most widely distributedand studied of the three isoforms of endothelin.ET-1 exerts its effects through ETA and ETB receptors.ET-1 is a potent vasoconstrictor and an importantchemoattractant and mitogen when acting throughETA on endothelium, vascular smooth muscle cells,and fibroblasts (Figure 12.9). It is also an inflammatorymediator by activating monocytes, and a vasodilatorwhen acting through ETB receptors on monocytesand endothelial cells, respectively [175,176].

Endothelin has been increasingly implicated incardiovascular disease processes [177]. Specifically,

endothelin appears to play a major deleterious rolein both acute and chronic models of myocardialinjury. In a study of endothelin levels in 142 patients 3days after a myocardial infarction, Omland and col-leagues [178] reported a strong correlation betweenET-1 levels and 1 -year mortality. In a canine ischemia -reperfusion model, endothelin levels increased duringischemia and correlated with decreased blood flowon reperfusion [ 179]. Endothelin levels also correlateddirectly with pulmonary hypertension and vascularresistance, and inversely with cardiac indices in24 patients with chronic heart failure [180]. In a ratmodel of chronic heart failure, ETA receptor antago-nism greatly improved survival and was associatedwith improvement of left ventricular function andprevention of ventricular remodeling. In a random-ized controlled trial, bosentan inhibition of ETAand ETB receptors led to a decrease in mean bloodpressure of essential hypertension patients [181], andan increase coronary artery blood flows [182].

In the setting of cardioplegic arrest and cardiopul-monary bypass, there is increasing evidence that ET-1levels increase during cardiopulmonary bypass (CPB)and that ET-1 levels are associated with depressedmyocardial function and increased vasoconstrictionpost CPB [183]. Increased ET-1 levels are caused bysystemic and cardiomyocyte ET-1 production [184,185]. In an isolated porcine myocyte system, Dormanet al. demonstrated reduced myocyte-shorteningvelocity when exposed to ET-1 and associated higherintracellular calcium levels when compared to control

Figure 12.9 Role of endothelin 1.Production of endothelin 1 (ET-1) by theendothelial cell results in potentvasoconstriction, and smooth muscle cellgrowth and division by acting throughendothelin receptor A (ETA). ET-1 alsoacts on the endothelin receptor B (ETB)on endothelial cells to promoteproduction of nitric oxide (NO) andenable vasodilatation. The specific effectof endothelin therefore depends on therelative density of ETA and ETBreceptors.

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myocytes. Goldberg and associates, however, recentlydemonstrated increased contractility when exposingmyocardial biopsies of CABG patients to endothelin[ 186]. In isolated blood-perfused neonatal lamb heartsbefore and after 2 h of 10°C cardioplegic ischemia,Hiramatsu and colleagues examined the effects ofthe ETA receptor antagonist BE-18257B [187]. At30 min of reperfusion, the ETA antagonist heartshad significantly greater recovery of LV systolic anddiastolic function, coronary blood flow, and Mvo2

when compared with controls. In isolated rat hearts,coronary blood flow was improved with the endo-thelin converting enzyme inhibitor bosentan follow-ing prolonged hypothermic arrest [188]. Also, therewas preservation of ATP pool and high-energy phos-phates levels [189]. Finally, Maxwell and colleagues[190] showed increased microvascular competenceand diminished necrosis with ischemia-reperfusionof isolated rat hearts when treated with endothelinantagonists.

Thus, there is ample evidence to suggest thatmyocardial protection may be enhanced at severallevels, from contractility to energy metabolism, inthe ischemia-reperfusion that occurs at cardioplegicarrest if the actions of endothelin are counteracted.It is unclear from the literature which endothelinreceptor should be blocked or whether dual-receptorantagonism should be employed. It appears thatendothelin is cleared in the lungs via binding to theETB receptor [191,192], and that by blocking bothreceptors the half-life of endothelin in the systemiccirculation maybe prolonged.

Reactive oxygen speciesReactive oxygen species (ROS) are molecules withunpaired electrons in their outer orbit. They havethe potential to directly injure cardiac myocytes andendothelium, and to trigger an inflammatory cascadeby inducing the production of cytokines and com-plement. In addition, a body of evidence is gather-ing that supports a major role for ROS in inducingmyocardial stunning by interfering with calciumhomeostasis.

Intracellular sources of ROS include the electrontransport chain in the mitochondria, amino acidoxidation in microsomes, the cytochrome P450 activ-ity in the endoplasmic reticulum, and the arachidonicacid cascade in the sarcolemma. An importantsource of extracellular ROS is the oxidative burst

by the myeloperoxidase machinery of the activatedneutrophil.

Multiple defence mechanisms exist in the mam-malian cells to scavenge or inhibit the activity of ROS.Superoxide dismutase (SOD) catalyzes O2 dismuta-tion to H2O2. Subsequently, H2O2 is reduced to H2Oand O2 by peroxidases such as glutathione peroxidaseor catalase. Glutathione peroxidase catalyzes the per-oxidation of H2O2 in the presence of glutathione toform H2O and oxidized glutathione, which in turnrequires NADPH from the hexose monophosphateshunt to be reduced by glutathione reductase backto glutathione (Figure 12.10). It is important to noteat this point that SOD activity is therefore the mostproximal arm of the antioxidant apparatus. Otherendogenous antioxidants include vitamin E, vitaminC, and vitamin A.

Considering that each bolus of cardioplegia is areperfusion event after an ischemic period, adminis-tration of antioxidants at the time of cardioplegiadelivery would be ideal. It is based on this theory thatmuch experimental work has been done to assessthe efficacy of various antioxidant additives to thecardioplegic solution.

By way of an example and a word of caution, therole of SOD and catalase, in the setting of myocardialinfarction, is reviewed here. Jolly and associates [193]demonstrated that a combination of SOD and catalasereduced infarct size in a canine model of ischemiaand reperfusion. This observation combined with theworks of Woo etal. [194] and Chen etal. [195] led totwo clinical trials using human recombinant SOD.The recombinant SOD was used in the setting ofmyocardial infarction in patients undergoing eitherthrombolysis [196] or balloon angioplasty [197].There was no significant improvement in left ven-tricular function in the two trials. These trials arereminders of the difficulty in extrapolating data froma controlled laboratory setting to an uncontrolledclinical setting. As a result, only human studies withantioxidant-enhanced cardioplegia will be presentedbelow.

DeferoxamineSuperoxide anion and hydrogen peroxide may giverise, through the Haber-Weiss reaction and in thepresence of iron or copper, to the cytotoxic hydroxylradical. Chelation of iron or copper, theoretically,would quench this mechanism of ROS-derived


Figure 12.10 Reactive oxygen species(ROS). The injurious superoxide anion(O»2> is converted by superoxidedismutase (SOD) to hydrogen peroxide.In the presence of iron, the Haber-Weissreaction results in the production of thehighly cytotoxic hydroxyl radical («OH).Catalase and glutathione peroxidase(GPX) allow hydrogen peroxide to beconverted to water. GPX requires thepresence of glutathione (GSH). ROSscavengers, such as vitamin E, scavengehydroxyl radicals and thereby protectthe cells against lipid peroxidation.

cytotoxicity. Myers and associates [198] first testedthis hypothesis in 1986. In an isolated rabbit heartmodel of cardioplegic arrest for 2 h followed by reper-fusion for 1 h, the investigators found that deferoxam-ine supplementation prevented ischemia-inducedincrease in coronary vascular resistance. It failed,however, to provide any benefit to the function of thereperfused left ventricle. In a separate study, however,Menache et al. [199,200] were able to demonstratesignificantly improved ventricular systolic function inan isolated rat heart model when deferoxamine wasadded to the cardioplegic mix. There is evidence tosuggest that deferoxamine enhancement also aidspostcardioplegia diastolic dysfunction [201]. DeBoerand colleagues demonstrated improved survival in rat

hearts subjected to 25 min of normothermic globalischemia followed by deferoxamine-enhanced cardio-plegia and reperfusion [202]. Further experimentalwork has now shown that deferoxamine also decreasesmyocardial stunning after regional ischemia causedby LAD ligation followed by surgical revasculariza-tion [203]. It also decreases endothelial dysfunction

after cardioplegia-reperfusion [204]. Interestingly,the addition of zinc or gallium to the deferoxaminecardioplegia increased the benefits of iron chelation,presumably by causing displacement of iron by theredox-inactive zinc or gallium metal molecules [205].

In a human trial, Ferreira et al. [206] were unableto confirm decreased ROS activity by chemilumines-cence technique, but they did detect fewer damagedmitochondria on electron microscopy of biopsiestaken from human hearts arrested using deferoxam-ine cardioplegia. In the only other human study,however, Drossos and associates also documenteddecreased levels of superoxide anion production invalve patients who underwent supplementation oftheir cardioplegia with deferoxamine. In spite of the

positive experimental and human investigations car-ried out so far, no prospective, randomized trial hasbeen initiated to examine the role of deferoxamine-enhanced cardioplegia. Considering the weight of theevidence outlined above, such a trial should be forth-coming, especially in light of our knowledge of the sideeffect profile of deferoxamine.

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AllopurinolThe evidence for allopurinol enhancement of cardio-plegia solution is not as strong as the evidence fordeferoxamine enhancement. Allopurinol inhibits theenzyme xanthine oxidase, which catalyzes the conver-sion of hypoxanthine (derived from adenosine—the breakdown product of ATP) to uric acid. Thebyproduct of this reaction is ROS production. It ispostulated that a significant amount of intracellularROS activity, especially after ischemia-reperfusioninjury, is derived from the action of this enzyme. Theinhibition of xanthine oxidase should therefore con-fer superior myocardial protection. The initial workby Chambers and associates [207] suggested thatin an isolated rat heart model allopurinol enhance-ment of cardioplegia solution conferred benefit onlywith normothermic ischemic arrest and not underhypothermic conditions. Vinten-Johansen's [208]work confirmed in a canine model that allopurinoladdition to cardioplegia enhanced postischemic per-formance of the left ventricle. During a 12-h preserva-tion study of rabbit hearts, Nishida also concludedthat the added combination of allopurinol and cata-lase to the cardioplegia solution enhanced left ven-tricular developed pressures and decreased diastolicpressures [209]. The result of two human trials ofpretreatment with allopurinol also demonstrated lessinotropic usage, better cardiac indices, fewer periop-erative myocardial infarctions, and decreased lipidperoxidation [210,211]. The trial conducted by Bicaletal. [212] is the only human trial in which allopurinolhas been used as a cardioplegic additive. In this trial theauthors reported no difference among patients under-going cold blood cardioplegia with blood reperfusion,crystalloid cardioplegia with crystalloid reperfusion,and crystalloid cardioplegia with allopurinol-enrichedblood reperfusion with respect to adenine nucleotidesand malondialdehyde (surrogate marker for ROS-induced lipid peroxidation) levels. Improvements ofleft ventricular function, however, were not docu-mented. It may be that adequate inhibition of xan-thine oxidase by allopurinol may require more timethan the cardioplegic period.

GlutathioneGlutathione is an endogenous intracellular antioxid-ant that is involved in the peroxidation of the H2O2

molecule. The addition of exogenous glutathioneto the cardioplegia solution may aid in extracellular

scavenging of ROS. This concept has been tested asdetailed below with some indication that it may bebeneficial.

The initial dog experiments performed byStandeven et al. [213] suggested that exogenousglutathione was not beneficial. Evidence from a hearttransplant preservation solution, however, indicatedthat addition of glutathione would provide bettergraft preservation in buffer-perfused rat hearts andheterotopic rabbit heart transplantation [214,215].Recent evidence from Nakamura and colleagues [216]in a canine model of global normothermic ischemiafollowed by 60 min of intermittent cold crystalloidcaridoplegia showed that glutathione enhancementpreserved systolic and diastolic function, preservedendothelial function, and decreased neutrophil adher-ence. Evidence from glutathione transgenic (overex-pressing glutathione) and knockout mice (with noglutathione expression) myocardial infarction modelsclearly documented the importance of glutathionein preserving ischemic myocardium [217,218]. Inthe only human trial, glutathione enhancement ofcrystalloid cardioplegia significantly reduced CK-MBrelease after cardiac surgery [219]. No other benefitwas demonstrated in this limited study. The evidencetherefore for the use of glutathione in cardioplegicsolution is scant at present.

NitecaponeNitecapone is a catechol-O-methyl transferase inhib-itor, and was first used to extend the action of levodopain Parkinson's patients [220]. It has also been shownto have significant antioxidant activity [221]. In aLangendorff rat heart model of ischemia-reperfusion,it was shown to have some beneficial effects indecreasing myocardial enzyme leakage [222]. Ventoand associates [223,224], in a rat heart transplantmodel, showed decreased levels of lipid peroxidationand myeloperoxidase activity. These observationswere extended to a small human trial in which patientsundergoing CABG had cardioplegic arrest in the pres-ence of nitecapone [225,226]. The authors noticeda decrease in cardiac neutrophilic accumulation andactivation in the nitecapone-enhanced cardioplegiapatient group. Although the incidence of ventriculararrythmias was significantly reduced in the nitecaponegroup, no other clinical benefit was found.

In summarizing the work with reactive oxygenspecies, there is a trend towards preservation of


cardiac function in multiple animal models. In thefew human trials, there appears to be limited clinicalbenefit. Thus, pending data from larger clinical trials,routine use of ROS cannot be advocated for routineuse in cardiac surgery.

Conclusion

It is becoming increasingly difficult to demonstratemortality differences between two methods ofcardio-plegic arrest. At the University of Toronto we havebegun emphasizing the importance of other endpoints such as postoperative low-output syndromeas an indicator for the degree of protection affordedby one cardioplegia method versus another in clinicaltrials. The fact, however, remains that our currentmethods of myocardial protection are very effective,and improving on a good thing is a difficult task. Thedata presented above highlights several very import-ant points with regards to myocardial protection. First,it is imperative that we understand the exact mole-cular signaling and pathways that lead to ischemia-reperfusion injury to be able to, with surgicalaccuracy, attenuate it. The surgeon therefore shouldbecome a more sophisticated operator. Second, it isbecoming increasingly clear that many injurious path-ways interact synergistically. For instance, myocardialstunning is caused by reactive oxygen species and dis-ruption of calcium homeostasis. It should follow,then, that effective inhibition of myocardial stunningshould combine attenuating reactive oxygen species-mediated damage and preventing cytosolic calciumoverload. By corollary, stimulating ischemic precon-ditioning and abrogating myocardial stunning maylead to exponential increase in benefits. Third, weshould begin shifting our myocardial protectionparadigm: it is possible to prepare the myocardiumfor a limited ischemia-reperfusion injury prior toopening the chest. The experiences with cariporideand allopurinol clearly illustrate this point. Fourth,myocardial reserve far exceeds the body's demands inthe same manner as the renal and pulmonary reservesclearly exceed the body's requirements. However,myocardial loss no matter how clinically silent todaywill translate, as is the case with glomerular or alveolarloss, to significant impediment years later. Thereforeeven in the absence of 30-day mortality benefits weshould continue to refine our myocardial protec-tion methodologies. Molecular biology is an exciting

domain, and as surgeons it is imperative that wekeep up to date with advances that will enable us toperform increasingly better procedures. We hope thatthis chapter has been successful in shedding light ona few molecular pathways that mediate ischemia-reperfusion injury, and on how to effect a change inthose pathways.

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118 CHAPTER 12

recovery of ventricular function in patients undergoingcoronary angioplasty for acute myocardial infarction.Circulation 1994; 89:1982-91.

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216 Nakamura M, Thourani VH, Ronson RS et al.Glutathione reverses endothelial damage from peroxy-nitrite, the byproduct of nitric oxide degradation, incrystalloid cardioplegia. Circulation 2000:102: III332-8.

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218 Yoshida T, Maulik N, Engelman RM et al. Glutathioneperoxidase knockout mice are susceptible to myocardialischemia reperfusion injury. Circulation 1997; 96:11216-20.

219 Amano J, Sunamori M, Okamura T, Suzuki A. Effectof glutathione pretreatment on hypothermic ischemiccardioplegia. Jpn ]Surg 1982; 12: 87-92.

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224 Vento AE, Ramo OJ, Nemlander AT et al. Nitecaponeinhibits myeloperoxidase in vitro and enhances func-tional performance after 8 h of ischemia in experimentalheart transplantation. Res Exp Med (Berl) 1999; 198:299-306.

225 Vento AE, Aittomaki J, Verkkala KA et al. Nitecapone asan additive to crystalloid cardioplegia in patients whohad coronary artery bypass grafting. Ann Thorac Surg1999; 68:413-20.

226 Pesonen EJ, Vento AE, Ramo J et al. Nitecapone reducescardiac neutrophil accumulation in clinical open heartsurgery. Anesthesiology 1999; 91: 355-61.

CHAPTER 13

Is there a place for on-pump,beating heart coronary arterybypass grafting surgery?The pros and cons

Simon Fortier, MD, Roland G. Demaria, MD, PHD, FETCS, e^ LouisR Perrault, MD, PHD, FRCSC, FAGS

Background

Coronary artery bypass grafting was first conceivedof and experimented on by Alexis Carrel at the begin-ning of the previous century [1]. Sabiston in 1962performed the first aortocoronary venous bypass graftin humans [2] and Kolesov the first left internal mam-mary artery (IMA) to left anterior descending (LAD)graft in 1966 [3]. All these operations were performedon the beating heart. At the end of the 1960s, Favaloroand the Cleveland Clinic team opened the era ofmodern coronary artery bypass surgery [4]. All thesepioneers were confronted with the issue of bloodintrusion at the anastomotic site. Different techniquessuch as compression, irrigation of the area, or externalclampage with poor stabilization were used. Rapidly,cardiopulmonary bypass (CPB) without and eventu-ally with cardioplegic arrest was used almost univer-sally in coronary artery bypass surgery to obtain anoptimal bloodless and motionless operative field. Themajority of coronary operations were soon performedwith this technique, and beating heart coronaryrevascularization was abandoned except in selectedsituations. Because CPB entails a risk of systemicinflammatory response and various complications insome patients, and probably because of economicalreasons, some surgical teams were involved in therevival of beating heart coronary surgery.

Recently, minimally invasive coronary artery bypass

grafting has been the subject of several studies, withemphasis usually put on the switch from conven-tional median sternotomy to minithoracotomy [5,6]or to the port-access approach [7]. The invasivenessof coronary artery operations is determined moreby myocardial ischemia incurred during the cross-clamping period and the inflammatory response toCPB than by the site and type of incision. Ideally, thesetwo issues are addressed by off-pump surgery, but thisstrategy, which is far from new [8], raises the very con-cerns that led to the development of CPB. An interme-diary option is to continue to use CPB but to eliminatethe ischemic component of invasiveness by avoidingaortic cross-clamping and keeping the heart beatingthroughout the operation.

Principles of myocardial protection

In the new millennium, despite new minimally invasivetechniques, the basic principles of myocardial pro-tection have remained the same. Maintenance ofthe balance between myocardial oxygen demand andsupply, modification and control of reperfusion, andimprovement of endogenous bioprotection are thethree basic concepts that need to be respected [9].

Ischemia and reperfusionThe heart represents only 0.5% of total body weightbut has an oxygen consumption (MVo2) of 7% [10].

119

120 CHAPTER 13

The three determinants of MVb2 are the heart rate,the stroke work, and the inotropic state. The lowestMVo2 during open heart surgery is obtained duringtotal electromechanical quiescence and the maximumMVo2 occurs during weaning of cardiopulmonarybypass run, when the heart recovers from the oxygendebt contracted during the aortic cross-clampingperiod [11,12]. In an experimental study, the heart'stotal oxygen requirements were reduced by approx-imately 70% when the external work of the heartwas eliminated by emptying the heart with CPB andventricular decompression and controlling the heartrate to 100 beats per minute [13]. Myocytes havelittle glycolytic reserve and poorly adapt to anerobia.Ischemia can be global as with cardioplegic arrest orregional with temporary vessel occlusion. Ionic shiftsand intracellular calcium accumulation follow. Aorticcross-clamping during CPB and the resulting myocar-dial ischemia has the potential to cause severe damageto the myocytes and endothelium of coronary arteries,which is compounded with restoration of blood flow,the so-called reperfusion injury [ 10]. During coronaryreperfusion, blood-borne cells (such as neutrophils)and the endothelium are activated, with generationand release of oxygen radicals. The ionic shifts areexaggerated and interstitial and intracellular wateraccumulate, resulting in swelling and disruption ofmembrane integrity. Hypercontracture of myofibrilsis probably one of the major causes of cell deathfollowing reperfusion [14]. Evidence of reperfusioninjury is present at autopsy in 25% of cases succumb-ing to heart surgery and is associated with long periodsof aortic cross-clamping [15].

Cardiac arrest and cardioplegiaThe first description of induction of cardiac arrestgoes back to 1955 by Melrose who used a hyper-kalemic blood cardioplegia solution. Unfortunately itwas abandoned because of cardiac injury secondaryto the excessively high potassium concentration [16].In the following years, improvements in cardioplegictechniques were introduced to reduce cardiac energyrequirements. Intermittent aortic cross-clamping withventricular fibrillation was nearly abandoned becauseof the greatly increased cardiac energy requirementsduring fibrillation. However, some groups still use thistechnique with good results [17,18]. Repeated briefepisodes of ischemia induced by intermittent aorticcross-clamping may be a form of preconditioning.This may protect the heart from a longer period of

ischemia by mechanisms that are still incompletelydetermined [19].

Numerous randomized studies have demonstratedthe superiority of sanguineous cardioplegia solutionsover crystalloid cardioplegia in reducing morbidity[20-25] and mortality [26]. However, continuousnormothermia blood cardioplegia, which is expectedto keep the heart in an aerobic and normothermic en-vironment, may not completely prevent some degreeof postoperative stunning or myocardial dysfunction[27,28]. This can be explained by myocardial edemaformation which decreases left ventricular function.Organized myocardial contraction, lost with cardiacarrest, appears to be the major factor for optimalmyocardial lymphatic drainage [29]. Occurrence ofmyocardial edema can also be explained by the pro-longed time available for myocardial microvascularfluid filtration associated with the diastolic state[28,30]. Beating heart surgery, avoiding this diastolicand arrested state, can prevent myocardial edema for-mation. Even with reduced contractility such as underbeta-blockade, keeping the heart beating is associatedwith less myocardial edema and a better postoperativefunction [31].

The optimal composition of cardioplegia solutionsand temperature are still a matter of debate. Dataare confusing due to lack of clear definitions aboutprimary end points and the different techniques [32].However, by avoiding cold cardioplegia, which leadsto myocardial hypothermia, recovery is faster [33].Delivery of cardioplegia through the antegrade routemay be reduced with severe coronary stenosis andretrograde cardioplegia may underprotect the rightventricle and septum, increasing the risk of myo-cardial injury during surgery. Combination of thetwo delivery techniques may be optimal but does notcompletely eliminate the risk of myocardial injury.

Effects of beating heart surgeryperformed with cardiopulmonarybypass

The detrimental effects of aortic cross-clamping areprobably inconsequential in the vast majority ofpatients with sufficient cardiac reserve but may pre-cipitate hemodynamic failure in patients with mar-ginal left ventricular function. Theoretically, the idealsolution to this problem is myocardial revasculariza-tion without extracorporeal circulation. However, thisapproach raises some concerns. Clinical outcomes for

On-pump beating CABG surgery 121

low-risk patients are excellent [34-37], but controver-sial in high-risk groups [38]. In fact, no significantchange in mortality and morbidity has been observed.Neurologic events are not eliminated with off-pumpcoronary bypass. Good patency rates at dischargeare documented [39], although the long-term graftpatency and clinical results of this approach are stillunknown [40]. One study, with a mean follow-upof 3 months, demonstrated a poor patency for graftsanastomosed to vessels other than the left anteriordescending artery [41]. Currently available data do notconclusively establish the superiority of the beatingheart technique over any other method of myocardialprotection; in fact, excellent clinical results have beenreported in high-risk patients with the use of differentstrategies of cardioplegic arrest [42,43].

Nevertheless, low ejection fraction, evolving myo-cardial ischemia, and advanced age are all factors foran increased morbidity and mortality after coronaryartery bypass grafting [44], and this alone provides asound rationale for the investigation of alternativesurgical approaches in high-risk patients. For this rea-son, on-pump, beating-heart bypass may constitute,in selected patients, an interesting trade-off.

In an attempt to find an alternative surgicalapproach, a nonrandomized prospective study wasconducted with 43 consecutive patients with poorleft ventricular function (median ejection fraction of26%), evolving myocardial ischemia or acute myo-cardial infarction, old age (mean of 79.5 years), andcomorbid conditions [45,46]. These patients wereoperated for myocardial revascularization with CPBon the beating heart. Clinical outcomes (morbidityand mortality), markers of myocardial ischemia (tro-ponin Ic), systemic inflammation (interleukins 6, 10and elastase) and the adaptation to stress (heat shockprotein (HSP) 70 mRNA from the right atrium) wereanalyzed. This group was compared to a control groupoperated with conventional CPB and normothermicblood cardioplegia. In the on-pump beating heartgroup, there was one cardiac-related death (2.3%)and one myocardial infarction (2.3%). There wasno stroke or differences in inotrope or intra-aorticballoon pump requirements, time to extubation, andalveolar-arterial gradients. Myocardial injury wasminimal with a twofold decrease in postoperativetroponin Ic levels compared to controls. There wasno significant difference in the peak levels of inflam-matory mediators. Finally, a threefold increase inbeating heart group of HSP 70 levels suggested better

adaptation to stress than controls, as a rise in HSP 70has been associated with an increased tolerance toischemia [19,47].

Other groups have reported similar results.Sweeney et al. [48] using biventricular assist devicesduring coronary revascularization in a similar patientpopulation reported one cardiac-related death (2.3%),with improvement in cardiac function in all survivorsat follow-up (averaging 8.9 months). Krejca and histeam studied cardiac troponin T release during myo-cardial revascularization in three randomized groups:CPB and intermittent cross-clamping, CPB withbeating heart, and beating heart without CPB [49].However, this was in a low-risk population. Never-theless, troponin T levels were significantly higherin the group with intermittent cross-clamping whencompared to the other groups. Troponin T levelswere significantly higher in the beating heart groupwith CPB compared to the beating heart group with-out CPB at 48 h and 72 h, suggesting low myocardialinjury when aortic cross-clamping is avoided.

Maintenance of the heart in a beating state through-out the operation seems to cause less damage thanaortic cross-clamping, even when blood cardioplegiais used in a continuous fashion. This conclusion isbased on two specific findings: a lower release of tro-ponin I, a highly cardiac specific marker of tissue dam-age [50], and a threefold increase in the postoperativemyocardial content of mRNA coding for HSP 70 com-pared with the preoperative value (Table 13.1).

Not surprisingly, troponin I levels were lower with-out the use of aortic cross-clamping. In fact, althoughoxygen demand is minimal with sanguineous cardio-plegia, sustained aerobiosis is deficient. Distribution isnot always uniform and continuous, leading to anero-bic metabolism in some parts of the myocardium. InCPB without aortic cross-clamping, global ischemicdamage to myocytes is avoided, explaining these results.

Increases in the postoperative myocardial contentof mRNA coding for HSP 70 reflect the preservedability of the beating heart to display an appropriateadaptive response to ischemic stress. The arrestedheart may lose this capacity, as demonstrated by thefact that levels of HSP 70 mRNA at the end of cross-clamping were unchanged from baseline in patientsundergoing conventional warm cardioplegic arrest inour study. This observation is consistent with that ofMcGrath and coworkers [51], who failed to documentany change in myocardial levels of HSP 72 in patientsprotected with cardioplegia when undergoing various

122 CHAPTER 13

Table 13.1 Comparison of markers of inflammation and ischemia for three different techniques of surgical myocardial

revascularization.

Markers

Inflammation

Technique

1-CPB: cardioplegic arrest

2-CPB: beating heart

3-OPCAB

P value

References

IL-6

TTT1-2 NS

1-3 NS

[45,68]

IL-10

TT<->1-2 NS

1-3<0.05

[45,68]

Elastase

TT<-»

1-2 NS

1-3<0.05

[45,74]

Ischemia

Troponin Ic

TTTT1-2<0.05

1-3<0.05

[45,68]

Troponin T

TTTT1-3<0.05

2-3 NS

[49,73]

HSP-70

o

TX

1-2<0.05

[45]

CPB, cardiopulmonary bypass; OPCAB, off-pump coronary artery bypass; HSP, heat shock protein; NS, not significant.

T, increase; <->, no change; x, not applicable.

open heart operations. Several experimental studieshave documented a close relationship between in-creased myocardial levels of HSPs and attenuationof stunning. Plumier and coauthors [52] and Marberand colleagues [53] have shown improved recoveryafter ischemia in mice overexpressing the gene forHSP. As ischemia seems to prevent the expression ofHSPs [54], our study documents, at the molecularlevel, the effectiveness of the beating heart techniquein ensuring adequate prevention against myocardialinjury, thereby making this technique a major com-ponent of any minimally invasive procedure.

The benefits of ventricular decompression shouldnot be overlooked. Indeed, with reduction of the ven-tricular wall tension, the resistance to flow throughstenotic coronary arteries may be decreased. Bloodflow can therefore increase in ischemic regions [55].The size of acute infarct can actually be decreasedexperimentally with ventricular decompression [56].Especially in impaired ventricles, left ventricular walltension reduction with augmented coronary flow isprobably beneficial.

On-pump beating heart coronary artery bypasssurgery may also be used as a learning step for traineesin beating heart revascularization. With the hemody-namic stability afforded by CPB, the anastomosis on abeating heart can be easily performed [57].

Adverse effects

A systemic inflammatory syndrome is triggered byCPB. Excellent reviews have been published about this

subject [58,59]. This inflammatory response resultsfrom the contact of cellular and humoral blood com-ponents with the extracorporeal circuit, even whenheparin-coated. Leukocyte and endothelial activationsecondary to ischemia and reperfusion and endotox-emia are also implicated.

At the cellular and molecular level, numerouspathways and mediators have been identified in thisinflammatory response. Activation of the comple-ment, of the intrinsic (material contact) and extrinsic(surgical wound and trauma and tissue factor) coagu-lation pathways, and of fibrinolysis, as well as platelets,endothelial cells, and neutrophils, are all involved inproducing organ failure and postoperative complica-tions following CPB.

Clinically, this is manifested by bleeding and coagu-lopathy, pulmonary dysfunction and prolonged intu-bation times, stroke and neurologic/neuropsychologicdeficiencies, renal failure, and gastrointestinal compli-cations. Neurologic injury, initially thought to resultfrom pump-generated embolism, now appears to berelated mostly to atheroembolism from manipula-tion of the aorta [60]. This can explain in part whystrokes still happen with off-pump beating heartsurgery [38,60].

Of the inflammatory mediators released duringCPB, elastase, interleukin (IL) 6, and IL-10 wereselected as sensitive markers of neutrophil activa-tion, proinflammatory cytokine production, and anti-inflammatory cytokine production, respectively [61,62]. Measurements of markers for systemic inflamma-tion are not significantly different between the beating


heart technique and the warm blood cardioplegicapproach (Table 13.1) [47]. The ischemic and reper-fused heart is a major source of inflammatory media-tors, in particular of neutrophil chemotactic factorsand cytokines [63,64]. Perhaps the specific productionof cytokines by the myocardium was not capturedin our study because of the timing and site of bloodsamples, since release of inflammatory mediatorsby myocardium occurs early after aortic declamping[65,66], while our samples were taken 4 h after bypassfrom the peripheral blood. However, regardless oftheir source, inflammatory mediators are released inresponse to CPB, but there is no conclusive evidencethat this translates into clinically relevant postoperat-ive adverse events. Whether the magnitude of theresponse may be mitigated by the use of heparin-coated circuits, as suggested by some studies [67],cannot be determined from these data.

Another concern about beating heart surgeryis the risk of temporary occlusion of target vesselsand associated regional ischemia. Some studies havedemonstrated regional wall contractility abnorm-alities [68], although this was not associated withthe elevation of biochemical markers of myocardialinjury. Snaring of coronary arteries seems to cause lessmyocardial injury than global ischemia induced bycardioplegia [69]. However, endothelial denudationand vascular injury may occur due to the hemostaticdevices used in off-pump coronary artery bypass(OPCAB), especially shunts and intravascular coron-ary occludens [ 70 -72 ].

Conclusions

In selected high-risk patients who may poorly toleratecardioplegic arrest and in situations where an OPCABintervention is not technically feasible, myocardialrevascularization on the pump-supported, decom-pressed, noncross-clamped heart maybe an acceptablealternative. The conjunction of the two techniques,in addition to the better understanding of the con-sequences of coronary artery manipulation at the levelof the vascular wall, associated with the surgeon's train-ing and experience, will lead to continued improve-ment in the long-term results of this revived aspectof cardiac surgical revascularization. Studies of lategraft patency and randomized studies are needed toestablish the proper place of OPCAB in the field ofmodern myocardial revascularization.

In conclusion, we do not believe that the on-pump,beating heart technique is a panacea, but it may be atransitional step to "off-pump" coronary artery bypassgrafting and a useful tool in the surgical armament-arium in contemporary myocardial revascularization.

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35 Pfister AJ, Zaki MS, Garcia JM et al Coronary arterybypass without cardiopulmonary bypass. Ann ThoracSurg 1992; 54:1085 -92.

36 Moshkowitz Y, Lucky A, Mohr R. Coronary artery bypasswithout cardiopulmonary bypass. Analysis of short-term and mid-term outcome in 220 patients. / ThoracCardiovasc Surg 1995; 110:979-87.

37 Buffolo E, de Andrade JCS, Branco JNR et al Coronaryartery bypass grafting without cardiopulmonary bypass.Ann Thorac Surg 1996; 61:63-6.

38 Yokoyama T, Baumgartner FJ, Gheissari A et al Off-pump versus on-pump coronary bypass in high-risksubgroups. Ann Thorac Surg 2000; 70:1546-50.

39 Puskas JD, Thourani VH, Marshall JJ et al Clinicaloutcomes, angiographic patency, and resource utilizationin 200 consecutive off-pump coronary bypass patients.Ann Thorac Surg 2001; 71:1477-83.

40 Gundry SR, Razzouk Al Bailey LL. Coronary arterybypass with and without the heart—lung machine: a case-matched 6 year follow-up [abstract]. Circulation 1996; 94(Suppl 1): 52.

41 Omeroglu SN, Kirali K, Guler M et al. Midterm angio-graphic assessment of coronary artery bypass graftingwithout cardiopulmonary bypass. Ann Thorac Surg 2000;70: 844-9.

42 Diet! CA, Berkheimer MD, Woods EL et al Efficacy andcost-effectiveness of preoperative IABP in patients withejection fraction of 0.25 or less. Ann Thorac Surg 1996; 62:401-9.

43 Chan RKM, Raman J, Lee KJ et al Prediction of outcomeafter revascularization in patients with poor left ventricu-lar function. Awn Thorac Surg 1996; 61:1428-34.

44 Rao V, Ivanov J, Weisel RD et al Predictors of low cardiacoutput syndrome after coronary artery bypass. / ThoracCardiovasc Surg 1996; 112: 38-51.

45 Perrault LP, Menasche P, Peynet J et al. On-pump, beating-heart coronary artery operations in high-risk patients: anacceptable trade-off? Ann Thorac Surg 1997; 64: 1368-73.

46 Bel A, Menasche P, Paris B et al La chirurgie coronaire acoeur battant sous circulation extracorporelle chez lespatients ii haut risque. Un compromis acceptable? ArchMai Cceur 1998; 91:849-53.

47 Williams RS. Heat shock proteins and ischemic injury tothe myocardium. Circulation 1997; 96:4138-40.

48 Sweeney MS, Frazier OH. Device-supported myocardialrevascularization: safe help for sick hearts. Ann ThoracSurg 1992; 54:1065-70.

49 Krejca M, Skiba J, Szmagala P et al. Cardiac troponinT release during coronary surgery using intermittentcross-clamp with fibrillation, on-pump and off-pumpbeating heart. Eur } Cardiothorac Surg 1999; 16: 337-41.


50 Adams JE, Abendschein DR, Jaffe AS. Biochemicalmarkers of myocardial injury. Is MB creatine kinasethe choice for the 1990s? Circulation 1993; 88: 750-63.

51 McGrath LB, Locke M, Cane M et al. Heat shock protein(HSP 72) expression in patients undergoing cardiac oper-ations. / Thome Cardiovasc Surg 1995; 109: 370-6.

52 Plumier JCL, Ross BM, Currie RW et al. Transgenic miceexpressing the human heat shock protein 70 haveimproved postischemic myocardial recovery. / Clin Invest1995;95:1854-60.

53 Marber MS, Mestril R, Chi SH et al. Overexpression ofthe rat inducible 70-kD heat stress protein in a transgenicmouse increases the resistance of the heart to ischemicinjury. / Clin Invest 1995; 95:1446-56.

54 Plumier JCL, Robertson HA, Currie RW. Differentialaccumulation of mRNA for immediate early genes andheat shock genes in heart after ischaemic injury. JMol CellCardiol 1996; 28:1251-60.

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56 Lachterman BS, Felli P, Smalling RW. Improved infarctsalvage by left ventricular unloading with the hemopumpimmediately prior to and during reperfusion after a 2-hour coronary occlusion [abstract]. J Am Coll Cardiol1991;17(Suppl2A):134.

57 Ricci M, Karamanoukian HL, D'Ancona G et al. Survey ofresident training in beating heart operations. Ann ThoracSurg 2000; 70:479-82.

58 Wan S, LeClerc JL, Vincent JL. Inflammatory responseto cardiopulmonary bypass: mechanisms involved andpossible therapeutic strategies. Chest 1997; 112:676-92.

59 Asimakopoulos G. Mechanisms of the systemic inflam-matory response. Perfusion 1999; 14:269-77.

60 Blauth CI. Macroemboli and microemboli during car-diopulmonary bypass. Ann Thorac Surg 1995; 59:1300-3.

61 Faymonville ME, Pincemail J, Duchateau J et al.Myeloperoxidase and elastase as markers of leukocyteactivation during cardiopulmonary bypass in humans./ Thorac Cardiovasc Surg 1991; 102: 309-17.

62 Steinberg JB, Kapelanski DP, Olson JD et al Cytokineand complement levels in patients undergoing cardiopulmonary bypass. / Thorac Cardiovasc Surg 1993; 106:1008-16.

63 Elgebaly SA, Hashmi ES, Houser SL et al. Cardiac-derivedneutrophil chemotactic factors. Detection in coronarysinus effluents of patients undergoing myocardial revas-cularization. / Thorac Cardiovasc Surg 1992; 103:952-9.

64 Wan S, DeSmet JM, Barvais L et al. Myocardium is amajor source of proinflammatory cytokines in patientsundergoing cardiopulmonary bypass. / Thorac CardiovascSurg 1996; 112:806-11.

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66 Weerwind PW, Maessen JG, van Tits LJH et al. Influenceof Duraflo II heparin-treated extracorporeal circuits onthe systemic inflammatory response in patients havingcoronary bypass. / Thorac Cardiovasc Surg 1995; 110:1633-41.

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70 Perrault LP, Menasche P, Wassef M et al. Endothelialeffects of hemostatic devices for continuous cardioplegiaor minimally invasive operations. Ann Thorac Surg 1996;62:1158-63.

71 Demaria RG, Fortier S, Carrier M et al. Early multifocalstenosis after coronary artery snaring during off pumpcoronary artery bypass in a patient with diabetes. / ThorCardiovasc Surg 2001; 122:1044-45.

72 Menasche P, Haydar S, Peynet J et al. A potential mech-anism of vasodilation after warm heart surgery. Thetemperature-dependent release of cytokines. / ThoracCardiovasc Surg 1994; 107: 293-9.

CHAPTER 14

Myocardial protection in beatingheart coronary artery surgery

VinodH. Thourani, MD 6^ John D. Puskas, MD,MSC

Introduction

Although coronary artery bypass graft surgery (CABG)was first performed without the use of extracorporealcirculation in the late 1960s [1,2], this technique waslargely abandoned after the use of cardiopulmonarybypass (CPB) and cardioplegic arrest became routine.However, increased awareness that blood contact withthe CPB circuit produces a well-documented diffuseinflammatory response affecting multiple organ sys-tems has led to the resurgence of off-pump coronaryartery bypass grafting (OPCAB). Specific deleteriouseffects of the inflammatory response following CPBhave been documented in the heart, lungs, centralnervous system, kidneys, and gastrointestinal tract,and increase with increased duration of CPB [3,4].With presently available instrumentation, off-pumpCABG via sternotomy can now be performed forlesions in virtually any coronary artery with a highdegree of patient safety and surgeon comfort. Recentreports have documented improved outcomes, excel-lent short-term angiographic patency, and lower costswith OPCAB [5,6]. Techniques of myocardial pro-tection specific to OPCAB are essential to optimizeoutcomes with this procedure.

The goals of myocardial protection during off-pump coronary surgery are not only to avoid iatro-genic surgical injury induced by manipulation of theheart, but also to prevent reperfusion injury uponresolution of the coronary occlusion. Furthermore,basic tenets of myocardial protection including main-taining a balance in myocardial oxygen delivery/consumption, reducing ventricular distention, and pre-venting postoperative ventricular arrhythmias shouldbe maintained. Well-orchestrated and methodical

protection of the heart should remain the cornerstoneof coronary artery surgery, whether performed on-or off-pump. The resurgence of off-pump coronaryartery surgery has led cardiac surgeons to re-evaluatethe role of myocardial protection for these patients.This chapter outlines the current strategy and prac-tice of myocardial protection for cardiac surgeonsperforming off-pump coronary artery bypass grafting.

Myocardial injury in off-pumpcoronary artery bypass grafting

Concern for myocardial protection during OPCABstems from the knowledge that the brief periods ofischemia necessary to visualize the target vessels dur-ing construction of distal anastomoses produce somedegree of myocardial injury that may not only affectthe individual target areas, but also cause cumulativeglobal dysfunction after sequential occlusions imposedduring multivessel bypass grafting. Even brief periodsof ischemia during simulated OPCAB in animals areassociated with measurable contractile dysfunction,endothelial injury in the target coronary artery, myo-cardial edema, and the genesis of apoptosis that maycontribute to postrevascularization pathology [7-11].Reperfusion of ischemic myocardium in the absenceof cardioprotective strategies applied during eitherischemia or reperfusion results in additional vascularendothelial dysfunction, contractile dysfunction, andmyocardial infarction over and above that observedduring the ischemic period [7-11]. Furthermore,myocardial stunning, even after a transient period ofischemia, may render the ventricle more susceptibleto arrhythmias [12]. In humans, Bonatti et al. [10]have shown that subclinical myocardial injury is a

126

OPCAB myocardial protection 127

common event in OPCAB when measured by the sen-sitive myocardial marker protein cTnl. In addition,Imasakaeffl/. [13] and others [14] have demonstratedcontractile dysfunction in regional wall motioninduced by intraoperative myocardial ischemia utiliz-ing sophisticated transesophageal echocardiography(TEE) technology.

Although the period of target vessel occlusionimposed during OPCAB may be confined to approx-imately 5-15 min, the notion that multiple grafts mayimpose cumulative ischemic injury on sequential tar-get areas raises concern. The knowledge that the targetvessel(s) is not reperfused adequately until the prox-imal anastomoses are completed for all vessels height-ens concern about extended myocardial ischemicintervals during OPCAB. Strategies to protect themyocardium from ischemic and reperfusion injuriesmay improve both acute and longer-term outcomesafter OPCAB procedures.

Overview of myocardial protection

The most important contributors to myocardialprotection during OPCAB are gentle cardiac mani-pulation, which maintains stable hemodynamics, andappropriate graft sequencing, which limits cumulativeischemia. In addition, the OPCAB cardioprotect-ive armamentarium includes systemic intravenouspharmacologic agents, ischemic preconditioning, cor-onary shunting, preload and afterload reduction usingaxial pumps, intra-aortic balloon counterpulsation,and perfusion-assisted direct coronary artery bypass(PADCAB) with or without intracoronary pharmaco-logic agents.

Systemic intravenous pharmacologicagentsMyocardial protection during OPCAB has takenmany forms during the evolution and refinement oftechniques for OPCAB. Early on, prior to the develop-ment of sophisticated mechanical stabilizing devices,intermittent, pharmacologic arrest with bolus dosesof adenosine, or profound bradycardia induced byshort-acting beta-blockers, enjoyed a brief period ofclinical interest. Other pharmacologic agents tried asmyocardial protectants included nucleoside transportinhibitors, selective Na+-H+ exchange inhibitors,ATP-dependent potassium-channel opening agents,and adenosine derivatives including acadesine. Among

the various benefits touted for these pharmacologicinterventions was myocardial protection due toreduced myocardial oxygen consumption with sub-sequent reduction in the metabolic substrates re-sponsible for myocardial ischemia-reperfusion injury[15]. Due to the limited effectiveness and significantnegative hemodynamic effects of these agents, they arenot routinely used as clinical myocardial protectiveagents and have largely been abandoned with theadvent of third generation mechanical stabilizers.

Ischemic preconditioningIschemic preconditioning also enjoyed a brief popu-larity as a cardioprotective strategy during off-pumpcoronary grafting. The theoretical benefit of briefocclusion and reperfusion preceding the longer occlu-sion necessary to construct a coronary anastomosiswas supported by abundant laboratory evidencedemonstrating improved protection in the subtendedmyocardium [7-9,16,17]. In the human heart under-going cardiopulmonary bypass, ischemic precondi-tioning has been shown to be associated withbeneficial metabolic effects including a reduced rate ofhigh-energy phosphate catabolism and deleteriousmetabolite accumulation during prolonged periods ofischemia, the additive result of which enhances postis-chemic myocardial function [18]. Since in humans,ischemic preconditioning has not been universallyshown to attenuate myocardial contractile dysfunc-tion or "stunning" [19], the clinical utility of thistechnique in OPCAB has been questioned. It is plaus-ible that patients with severe coronary stenoses haveundergone endogenous ischemic preconditioningduring their disease process. Although ischemic pre-conditioning seemed appropriate and acceptable forsingle-vessel bypass via small thoracotomy, as thenumber of bypass grafts performed during OPCABincreased, the enthusiasm of surgeons to performrepeated episodes of ischemic preconditioning foreach coronary artery has diminished.

While presently a small minority of OPCAB sur-geons perform surgical ischemic preconditioning, achemical preconditioning mimetic agent is conceiv-able. Pharmacologically, ischemic preconditioninghas been mimicked with adenosine, norepinephrine,bradykinin, nitric oxide, and endothelin receptoragonists [20-24]. Furthermore, protein kinase C andATP-sensitive potassium channel-mediated mechan-isms have been suggested as likely end effectors which

128 CHAPTER 14

lead to myocardial protection [25,26]. Although theexact mechanisms, dosing, timing, and duration ofthese mimetics remains unclear, these agents maybecome important clinical adjuncts for myocardialprotection during off-pump coronary artery bypassgrafting in the future.

Intracoronary shuntsMyocardial ischemia during OPCAB may be reducedby the use of intracoronary or aortocoronary shunts[27-30]. Intracoronary shunts have been demon-strated to cause loss of vascular endothelial cells in andaround the anastomotic site, and for this reason areused sparingly by the authors. However, particularlyin the case of a large right coronary artery where risk ofbradyarrhythmias and heart failure during coronaryocclusion is quite real, an intracoronary shunt may beuseful. Also, if an important collateralizing artery mustbe occluded prior to restoration of alternative flowduring OPCAB, an intracoronary shunt may prev-ent sudden cardiac collapse due to critical ischemia.Intracoronary shunts rely on passive flow through afixed lumen and do not bridge the native coronarystenosis for which bypass is necessary. Although flowthrough an intracoronary shunt must be considered tobe significantly less than optimal coronary flow, eventhis small amount of flow may help maintain hemody-namic stability function during the time required toconstruct a distal anastomosis. Similarly, aortocoro-nary shunts may provide direct flow into the coronaryartery distal to the anastomotic site during construc-tion of distal anastomoses. Aortocoronary shunts,like intracoronary shunts, constitute an obstacle atthe anastomotic site around which the surgeon mustmaneuver in order to construct the sutured anasto-mosis. While aortocoronary shunts provide flow dir-ectly distal to the anastomosis, bypassing the proximalnative coronary stenosis, they include a fixed stenosiswithin the length of the shunt itself and are dependenton systemic arterial pressure for passive flow.

Hemodynamic changes duringheart manipulation

During off-pump coronary artery bypass, optimizingcoronary perfusion pressure throughout the proced-ure is vitally important. Ensuring an adequate coron-ary perfusion pressure begins with maintenance ofadequate stable systemic hemodynamics. During the

performance of distal anastomoses, hemodynamicinstability may be caused by two categories of events,namely, regional myocardial ischemia and its sequelaand mechanical disturbances of cardiac functiondue to cardiac displacement/stabilization. Of these,mechanical disturbances are more common andmore often problematic. While regional ischemia maycause regional myocardial dysfunction, bradycardiaor other arrhythmias, compression of the right or leftventricle by stabilizing devices, or manipulations ofthe heart leading to partial obstruction of the superiorand inferior vena cava or pulmonary artery or veinsare common.

The techniques for manipulating the heart andexposing posterior and lateral vessels have evolvedand improved dramatically over the last 3-5 years.Previous studies have reported that vertical displace-ment of the heart is associated with hemodynamicinstability hallmarked by reduced cardiac output andhypotension [31-33]. Although not used in our prac-tice, right heart circulatory support has been reportedin off-pump coronary artery patients to alleviate acutehemodynamic compromise during distal anastomosis[33,34]. While the need for inotrope administration tomaintain blood pressure was common in our earlyexperience, the requirement for pharmacologic sup-port has been markedly reduced by refinements insurgical techniques. It is now very infrequent that theauthors encounter significant hemodynamic instabil-ity during multivessel OPCAB.

Simple, inexpensive techniques have been devel-oped and implemented to facilitate the performanceof multivessel off-pump coronary artery bypass graft-ing. It is important to open the pericardium widelyand to divide the pericardium from the diaphragmbilaterally down towards (but not into) the phrenicnerves on both sides. The right pleural cavity is openedwidely whenever an obtuse marginal coronary arterygraft is anticipated. The diaphragmatic muscle slips,which insert on the right side of the xiphoid, arescrupulously divided and the right sternal border iselevated, creating space for the apex of the heart torotate under the right sternal border and into the rightpleural cavity. Simply placing two folded towels underthe right limb of the sternal retractor can facilitate this.Traction sutures are used liberally. The most usefultraction suture is a deep pericardial suture placedapproximately two-thirds of the way between theinferior vena cava and the left inferior pulmonary


vein at the point where the pericardium reflects overthe posterior aspect of the left atrium. This suture,retracted toward the patient's feet, elevates thebase of the heart toward the ceiling and tilts the apexvertically. This is especially useful when approachingthe posterior descending coronary artery (PDA) andposterior left ventricular (PLV) branches of the rightcoronary artery. It may also be useful when approach-ing the posterolateral obtuse marginal (PLOM) coro-nary arteries. However, when approaching the leftanterior descending (LAD), diagonal coronary arter-ies, ramus intermedius, or anterior marginals, thistraction suture must be retracted toward the patient'shead, thereby rotating the heart into the right pleuralcavity and avoiding compression of the right ventricleand inflow/outflow tracts. With careful application ofthese techniques, the majority of hearts can be rotatedso that the apex passes under the right sternal borderand the lateral wall is well visualized. A variety ofcotton slings has been described and may aid in gentlydisplacing the heart into the right pleural cavity, espe-cially when cardiomegaly is present. In addition toeffective cardiac manipulation, rotation and tilting ofthe operating table are vital adjuncts to proper cardiacpositioning during OPCAB. Vigorous tilting of thebed toward the patient's right will aid in displacementof the heart into the right pleural cavity. Similarly,impaired inflow to the right side of the heart, whichmay accompany vigorous rotation, can be amelioratedby steep Trendelenburg position. It is vital to recognizethat excellent hemodynarnics may be maintained ifthe heart is slowly and gently manipulated, rotated, ordisplaced. The heart may not, however, be compressedagainst the right sternal border or right pericardium.Thus, no traction is placed on the right pericardiumduring maneuvers to expose the left-sided vessels. Aclear understanding and gentle application of theseprinciples will allow the careful surgeon to maintainremarkably stable hemodynamics while perform-ing multivessel OPCAB. Several manufacturers haverecently introduced suction-based devices to providegentle traction on the apex of the heart to assist withcardiac repositioning/displacement during OPCAB.These devices do, indeed, provide exposure of the lat-eral and inferior/posterior walls of the heart withoutcardiac compression and will have a role in facilitatingbroader adoption of multivessel OPCAB.

Preoperative insertion of an intra-aortic balloonpump in initially unstable patients may provide an

additional measure of hemodynamic stability, allow-ing OPCAB to be performed in very high-risk patients[35].

Off-pump coronary artery bypassgraft sequence and distalanastomosis construction

With the advent of more sophisticated mechanicalstabilization devices, surgeons are more able to per-form complex multivessel OPCAB cases. We believethat certain practical considerations during the cre-ation of proximal and distal anastomoses are essentialto effective myocardial protection during OPCAB.Perhaps the simplest and most important is thechoice of graft sequence or order during multivesselOPCAB. As a general rule, it is important to graft thecollateralized vessel(s) first, reperfuse these by per-forming proximal anastomoses or releasing clamps onthe internal mammary artery pedicles, and then tograft the collateralizing vessels. By this approach, vitalcoronary flow provided by collateralizing vessels is notinterrupted prior to restoration of flow to the collater-alized vessels via the newly constructed coronary grafts.Though the tendency among many OPCAB surgeonsto perform left internal mammary artery grafting(LIMA) to the LAD first is based on the principle ofrestoring flow to the anterior wall and septum of theleft ventricle, this approach is clearly ill advised ifthe LAD is the collateralizing vessel for the majorityof the rest of the heart.

The right coronary artery, particularly whenlarge and dominant, can pose significant risks for theOPCAB surgeon. If its degree of stenosis is relativelyminor (60-80%), residual flow within the right cor-onary artery may be high; therefore acute occlusionof the vessel for construction of a distal OPCABanastomosis may be poorly tolerated and may leadto bradyarrhythmias. This situation may be bestavoided by the use of epicardial pacer wires to elimin-ate bradycardia and by the use of an intracoronaryshunt if a prolonged period of target vessel occlusionis expected.

Construction of proximal anastomoses first allowsthe surgeon to immediately reperfuse each coronaryartery upon completion of the distal anastomosis.However, this approach makes estimation of optimalgraft length somewhat more difficult. Similarly, per-formance of the LIMA-LAD anastomosis first may

130 CHAPTER 14

require that the IMA pedicle be left somewhat longerthan it otherwise might be, perhaps increasing the riskof kinking or redundant folding of the IMA pedicle.Thus, the preferred sequence is outlined in the follow-ing six rules:1 Graft completely occluded, collateralized vesselsfirst. There will be little decrement in myocardial per-fusion during construction of this distal anastomosis.Once this graft has been constructed and reperfused,the collateralizing vessel may be more safely occludedand grafted.2 Be flexible with the timing of the LIMA-LADanastomosis. It should be done first when the LADis collateralized and in most cases of tight left mainstenosis. However, LIMA-LAD grafting should beperformed last if the LAD is the least diseased, collater-alizing vessel. To occlude the lightly diseased, collater-alizing LAD first is to critically limit total myocardialblood flow during construction of the LAD-LIMAanastomosis, since the collateralized vessel(s) will beeffectively occluded simultaneously.3 Be flexible with the timing of proximal anasto-moses. Aorto-saphenous or aorto-radial anastomosesmay be done first or early in the case after the distalanastomosis of critical collateralized target(s). The col-lateralized vessels are then reperfused via the graftsbefore the collateralizing coronary artery is occludedand grafted. This limits global ischemia and dysfunc-tion. In most routine cases, however, the proximalaorto-saphenous anastomoses may be constructedafter all distals have been completed, allowing graftlength to be most easily estimated.4 Be aware that occlusion of the large right coronaryartery (RCA) may result in bradycardia. Epicardialpacing should be immediately available, as well asa selection of appropriately sized intracoronary oraortocoronary shunts. Reperfusion of an adjacent orcollateralizing coronary graft(s) either by completionof the proximal anastomosis or via perfusion-assistedtechniques (see below) prior to occlusion of the RCAmay reduce the likelihood of untoward events.5 Hearts with ischemic mitral regurgitation may bestabilized by early grafting and reperfusion of theculprit vessel(s) causing papillary muscle dysfunction.6 Above all, customize the graft sequence for eachindividual case, considering coronary anatomy,patterns of collateralization, myocardial contractility,atherosclerosis of the ascending aorta, conduit avail-ability, and graft geometry.

Myocardial protection during OPCAB can be dra-matically improved by expeditious construction ofdistal anastomoses and rapid perfusion of grafts. Toprevent iatrogenic coronary artery injury during distalanastomosis, the authors prefer to occlude each cor-onary artery only proximal to the chosen anastomoticsite with a soft Silastic vessel loop (Quest Medical,Allen, TX) and apply the minimum tension necessaryto occlude antegrade flow. Coronary artery retrogradeback bleeding into the anastomotic site is dispersedusing a sterile, humidified, carbon dioxide blower(DLP, Medtronic, Minneapolis, MN). The blowershould be directed toward the intima only during theactual moments of suturing to minimize endothelialinjury. The solution used for humidification should bepH neutral crystalloid. Although the authors currentlyuse the Medtronic Octopus III device (Medtronic,Minneapolis, MN) as a stabilizer, other stabilizingdevices provide adequate immobilization of targetvessels to facilitate surgical precision.

Perfusion-assisted direct coronaryartery bypass

While gentle manipulation of the heart and strictadherence to the basic principles of coronary exposureduring OPCAB will allow the experienced OPCABsurgeon to complete the large majority of multivesselOPCAB cases with good hemodynamic stability, adownward spiral of hemodynamic instability canoccasionally develop. The cumulative global effect ofsequential periods of regional ischemia can lead todeclining systemic arterial pressure. This may producea decrease in coronary perfusion pressure, resultingin myocardial dysfunction, causing further decline insystemic arterial pressure. This feedback loop maybecome a vicious downward spiral. Perfusion-assisteddirect coronary artery bypass (PADCAB) provides adisconnection between coronary perfusion pressureand systemic arterial pressure, and therefore inter-rupts or aborts this downward spiral [36-38]. DuringPADCAB, distal anastomoses are constructed as usualin OPCAB, and graft(s) are immediately connected tothe outflow of a small pump circuit (Figure 14.1).Inflow to this circuit is provided by placement of asmall cardioplegia-type catheter in the ascending aortaor femoral artery. The Quest Medical MPS (QuestMedical, Allen, TX) system constitutes the principalcomponent of this circuit and allows exact control of


Figure 14.1 Perf usion-assisted direct coronary artery bypasssystem.

coronary perfusion pressure. Temperature is also con-trolled and chemical additives may be included in theoutflow circuit at precisely controlled concentrations.Thus, distal anastomoses may be constructed withvenous or radial arterial grafts and perfused at any pre-determined pressure, irrespective of systemic arterialpressure. Flows can be measured precisely to confirmand document graft patency. Grafted, collateralizedcoronary arteries may then be used to drive coronaryperfusion retrograde through the collaterals to the col-lateralizing native coronary artery during grafting ofthat target. This multilimbed device distributes flowto the various coronary grafts and allows each to beperfused during construction of the LIMA-LAD anas-tomosis. Thus, the cumulative effect of sequentialepisodes of regional ischemia is reduced or eliminated.Similarly, perfusion via collaterals of adjacent myo-

cardial regions may also contribute to improvedmyocardial protection. The addition of nitroglycerin,adenosine, or other coronary vasodilators may furtherimprove regional and collateral myocardial perfusion.

Muraki et al. [39] in our laboratory investigatedthe adequacy of oxygen supply versus demand with

intracoronary shunts (passive perfusion) compared toactive perfusion using the PADCAB technique. Inanesthetized canines, a 2.23-mm (90% of the nativeLAD diameter) intravascular shunt was placed in the

LAD. Transmural myocardial blood flow was reducedby more than 60%. When hypotension was simul-ated by elevating the heart, subendocardial flow andregional oxygen consumption decreased further, witha decrease in oxygen supply/consumption ratio anda net production of lactate, indicating the presenceof ischemia in the target myocardium. However,PADCAB perfusion of the target myocardium wasassociated with blood flow rates and subendocardialdistributions equivalent to baseline, and hypotensiondid not alter the regional distribution or adequacy ofoxygen supply relative to demand from either baselineor the nonhypotensive state. Therefore, an active per-fusion mechanism may overcome the limitations ofthe intracoronary or aortocoronary shunt, especiallyduring hypotension. Furthermore, the PADCAB tech-nique allows intracoronary administration of cardio-protective agents to the revascularized segment tominimize reperfusion injury [39].

Summary

In summary, the techniques utilized in performingmultivessel OPCAB remain diverse and multifactorial[15,40,41]. Careful maintenance of stable systemichemodynamics and individualized choice of graftsequence are of central importance. Recently refinedtechniques for atraumatic rotation of the heart andvisualization of coronary anastomoses allow precise

and controlled grafting of all coronary territorieswithout cardiopulmonary bypass in the large major-ity of cases. Perfusion-assisted direct coronary arterybypass techniques, in which coronary perfusion pres-sure is independent of systemic arterial pressure, canavoid or abort a downward hemodynamic spiral,which may occasionally occur during complex, multi-

vessel OPCAB.

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15 Chitwood WR Jr, Wixon CL, Elbeery JR et al. Minimallyinvasive cardiac operation: adapting cardioprotectivestrategies. Ann Thorac Surg 1999; 68:1974-7.

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17 Richard V, Kaeffer N, Tron C et al. Myocardialischemia/reperfusion/PTCA. Ischemic preconditioningprotects against coronary endothelial dysfunction inducedby ischemia and reperfusion. Basic Sci Rep Circ 1994; 89:1254-61.

18 Alkuhlaifi AM, Yellon DM, Pugsley WB. Preconditioningthe human heart during aortocoronary bypass surgery.Eur] Cardiothorac Surg 1994; 8:270-5.

19 Ovize M, Przyklenk K, Hale SL et al. Preconditioningdoes not attenuate myocardial stunning. Circulation1992; 85:2247-54.

20 Downey JM, Cohen MV, Ytrehus K, Liu Y. Cellularmechanisms in ischemic preconditioning: the role ofadenosine and protein kinase C. Ann NYAcad Sci 1994;723:82-98.

21 Bankwala Z, Hale SL, Kloner RA. Alpha-adrenoceptorstimulation with exogenous norepinephrine or release ofendogenous catecholamines mimics ischemic precondi-tioning. Circulation 1994; 90:1023-8.

22 Wall TM, Sheehy R, Hartman JC. Role of bradykinin inmyocardial preconditioning. / Pharmacol Exp Ther 1994;270:681-9.

23 Bilinska M, Maczewski M, Beresewicz A. Donors of nitricoxide mimic effects of ischaemic preconditioning onreperfusion induced arrhythmias in isolated rat heart.MolCellBiochem 1996; 160-61:265-71.

24 Wang P, Gallagher KP, Downey JM, Cohen MV.Pretreatment with endothelin-1 mimics ischemic pre-conditioning against infarction in isolated rabbit heart.JMol Cell Cardiol 1996; 28: 579-88.

25 Cleveland JC, Meldrum DR, Rowland RT, Banerjee A,Harken AH. Adenosine preconditioning of humanmyocardium is dependent upon the ATP-sensitive K+

channel. JMol Cell Cardiol 1997; 29:175-82.26 Auchampach JA, Gross GJ. Adenosine Aj receptors, KATP

channels, and ischemic preconditioning in dogs. AmJPhysiol 1993; 264: H1327-36.

27 Rivetti LA, Gandra SMA. Initial experience using anintraluminal shunt during revascularization of the beat-ing heart. Ann TnoracS«rgl997;63:1742-7.

28 Lucchetti V, Capasso F, Caputo M et al. Intracoronaryshunt prevents left ventricular function impairmentduring beating heart coronary revascularization. Eur] Cardiothorac Surg 1999; 15:255-9.

29 Van Aarnhem EE, Nierich AP, Jansen EW. When andhow to shunt the coronary circulation in off-pump coro-nary artery bypass grafting. Eur} Cardiothorac Surg 1999;16(Suppl2):S2-6.

30 Dapunt OE, Raji MR, Jeschkeit S et al. Intracoronaryshunt insertion prevents myocardial stunning in a juve-nile porcine MIDCAB model absent of coronary arterydisease. Eur J Cardiothorac Surg 1999; 15:173-8.

31 Griindeman PF, Borst C, van Herwaarden JA, Beck HJM,Jansen EWL. Hemodynamic changes during displace-ment of the beating heart by the Utrecht Octopusmethod. Ann Thorac Surg 1997; 63: S88-S92.

32 Griindeman PF, Borst C, Verlaan CWJ et al. Verticaldisplacement of the beating heart by the Octopus tissuestabilizer: influence on coronary flow. Ann Thorac Surg1998;65:1348-52.

33 Griindeman PF, Borst C, Verlaan CWJ et al. Exposureof circumflex branches in the tilted, beating porcineheart: echocardiographic evidence of right ventriculardeformation and the effect of right or left heart bypass.J Thorac Cardiovasc Surg 1999; 118:316-23.

34 Mathison M, Buffolo E, Jatene AD et al. Right heart circu-latory support facilitates coronary artery bypass without


cardiopulmonary bypass. Ann Thome Surg 2000; 70:1083-5.

35 Graver JM, Murrah CP. Elective intra-aortic ballooncounterpulsation for high-risk off-pump coronary arterybypass operations. Ann Thome Surg 2000; 71:1220-3.

36 Guyton RA, Thourani VH, Puskas JD et al. Perfusion-assisted direct coronary artery bypass: selective graft per-fusion in off-pump cases. Ann Thome Surg 2000; 69:171-5.

37 Puskas JD, Thourani VH, Vinten-Johansen J et al. Activeperfusion of coronary grafts facilitates complex off-pumpcoronary artery bypass surgery. Heart Surg Forum 2001;4(1): 64-8.

38 Steele M, Palmer-Steele C. Perfusion technique forperfusion-assisted direct coronary artery bypass(PADC AB)JExtra Corpor Technol2000; 32:158-61.

39 Muraki S, Morris CD, Budde JM et al. Experimental off-pump coronary artery revascularization with adenosine-enhanced reperfusion. / Thome Cardiovasc Surg 2001;121:570-9.

40 Flameng W. Role of myocardial protection for coronaryartery bypass grafting on the beating heart. Ann ThoracSurg 1997; 63:518-22.

41 Puskas JP, Vinten-Johansen J, Muraki S, Guyton RA.Myocardial protection for off-pump coronary artery bypasssurgery. Sem Thorac Cardiovasc Surg 2001; 13:82-8.

CHAPTER 15

Beating heart coronary arterybypass grafting: intraoperativestrategies to avoid myocardialischemia

Kushagra Katariya, MD, Michael O. Sigler, MD, & TomasA.Salerno, MD

Coronary artery bypass grafting (CABG) is one of themost common surgical operations performed in theUnited States today. In 1962, Sabiston performed thefirst human aorto-coronary artery graft using a pieceof saphenous vein as conduit to bypass a lesion inthe right coronary artery (RCA), and in 1964 Garrettbypassed a lesion in the left anterior descendingcoronary artery (LAD) [ 1 ]. Kolessov, in the same year,anastomosed the left internal mammary artery (LIMA)to a marginal branch of the circumflex coronary artery[2]. All these early coronary artery bypass operationswere done on the beating heart despite the availabilityof the heart-lung machine. After 1968, when coron-ary artery surgery became routine, the use of theheart-lung machine became more commonplace andwas widely adopted to allow surgeons to work in abloodless and still field to accurately perform vascularanastomoses onto coronary arteries. Since then, agreat amount of effort has been expanded to refinetechniques of extracorporeal circulation and identifynew strategies of myocardial preservation to improvethe safety of this technique. During this time period,when the volume of coronary artery bypass grafting(CABG) operations performed increased exponen-tially, myocardial revascularization on the beatingheart was not abandoned completely. Buffolo fromBrazil and Benetti from Argentina, separately, but atthe same time continued to perform CABG surgery onthe beating heart through the last two decades [3,4]. In

the United States, Salerno, Subramanian and Pfisterrekindled the technique in the early 1990s and overthe last 5 years it has become more widely acceptedand practiced.

Several approaches have been proposed for the off-pump technique of CABG surgery. In 1995, Benettiproposed [5] a minimally invasive operation via asmall left anterior thoracotomy in the fourth inter-costals' space to graft the LIMA to the LAD, a tech-nique referred to as the MIDCAB (minimally invasivedirect coronary artery bypass operation) or the LAST(left anterior small thoracotomy) approach. The ini-tial results from various institutions were conflictingwith respect to patency rates of the LIMA to LAD graft[6]. The motion of the heart prevented an accurateanastomosis through this small incision and this led tothe development of devices to stabilize the specificarea of the heart being worked on. These stabilizers,as they were called, created an area of relative still-ness allowing accurate placement of sutures for theanastomosis.

The technical limitations of the MIDCAB and LASToperations were soon realized, since these approachescould only be used for coronary arteries on the anter-ior and anterolateral surfaces of the heart, namely theLAD and its diagonal branches. Thus, only patientswith single-vessel disease localized to these arteries arecandidates for this procedure. Approaching the heartvia a median sternotomy allows visualization of the

134

Beating heart CABG 135

entire heart and allows the surgeon to bypass all themajor coronary arteries. Using innovative techniquesto manipulate and stabilize the heart and achievemyocardial protection, it is possible to achieve totalrevascularization for a patient with multivessel cor-onary artery disease. This technique, also popularlyknown as OPCAB (off-pump coronary artery bypass),has the most versatility for surgeons wanting toavoid extracorporeal circulation for coronary bypassoperations. OPCAB via a median sternotomy hasthus become the most commonly used technique forperforming off-pump coronary artery surgery.

The feasibility of performing total myocardial re-vascularization on the beating heart is largely depend-ent on the ability to expose all coronary targets andminimize myocardial ischemia and hemodynamicinstability during the operation. As such, myocardialprotection during the operation is extremely import-ant to avoid ischemia-related complications intra-operatively as well as postoperatively. Manipulation ofthe heart is necessary during beating heart coronaryartery bypass grafting, and this makes the myocar-dium more susceptible to ischemia. After comple-tion of the coronary grafting, reperfusion injury inthe revascularized myocardium also needs to beavoided. Intraoperative ischemia in the unprotectedmyocardium can lead to perioperative myocardialinfarction with all its attendant complications, intra-operative arrhythmias and hemodynamic alterations,all of which may lead to inability to complete revascu-larization and thus an incomplete operation. It mayalso lead to intraoperative hemodynamic collapsenecessitating the use of extracorporeal circulation forassistance.

Intraoperative myocardial ischemia is commonlyproduced when the target coronary artery is occludedto allow precise placement of anastomotic sutures orplacement of an intracoronary shunt. This ischemiamay produce localized dysfunction, but over a periodof multiple sequential occlusions, global dysfunc-tion may result. This may be seen postoperatively asregional wall motion abnormalities on echocardio-gram [7,8] or a state of global contractile dysfunc-tion [9-13]. Ventricular tachyarrhythmias may resultas a consequence of intraoperative ischemia due tomyocardial stunning complicating the conduct ofthe operation. Subclinical myocardial injury duringOPCAB by using cardiac troponin I protein as amarker has been documented in the literature [ 12].

It is thus as, if not more, important to avoidmyocardial ischemia during OPCAB as it is in coron-ary bypass grafting using the heart-lung machine.Various strategic maneuvers, drugs, and devices enablethe surgeon to perform complete revascularizationwhile still protecting the myocardium during theperformance of OPCAB.

The role of the anethesiologist during this opera-tion cannot be overemphasized. The anesthesiologistis a critical member of the operating team and must beclosely involved throughout the procedure. Routinemonitoring of the patient's hemodynamic status, theEGG, and the intraoperative transesophageal echocar-diogram (TEE) are just some of the important roles ofthe anesthesiologist. He/she must be aware of everystep of the operation to be able to cooperate with thesurgeon during the procedure. Maintenance of stablehemodynamic indices using mechanical or pharma-cologic means of support at appropriate times duringthe operation is critical to the success of the procedure.Mechanical support may mean as little as positioningthe operating table to allow easier manipulation ofthe heart and improved exposure of the target vessel.Throughout the OPCAB operation the heart is manip-ulated out of the pericardium and does not remainin the anatomic position. This leads to changes in thepattern of the EGG and TEE images. Despite this,constant attention needs to be paid to these monitor-ing techniques to determine the onset of myocardialischemia as rapidly as possible. The routine use of apulmonary artery (PA) catheter has declined tremen-dously since the advent of OPCAB, but whenever a PAcatheter is in place, it supplies valuable informationabout the status of myocardial function. Any suddenor slow increase in the PA pressure with or without adrop in systemic blood pressure may signify myocar-dial ischemia and appropriate corrective action mayneed to be undertaken rapidly. It is equally importantfor the anesthesiologist to be proficient in the use ofinotropic agents since these may help or hurt myo-cardial perfusion. It is rare at the present time to needmuch inotropic support during the performanceof OPCAB surgery and the need to do so may alsobe a sign of impending or ongoing localized/globalmyocardial ischemia.

Pharmacologic support during OPCAB may takemany different forms. Preoperative administration ofbeta-blockers has been shown to conclusively reducethe incidence of perioperative myocardial infarction

136 CHAPTER 15

in patients with coronary artery disease undergoingany kind of cardiac or noncardiac surgery [14]. Mostpatients undergoing coronary artery bypass graftingsurgery would already be on beta-blocker therapy, butif they are not, it should be started. Beta-blocker drugsare thought to have a cardioprotective effect, thusreducing the overall incidence of perioperative myo-cardial infarctions. Ultra-short-acting beta-blockerswere used commonly to induce bradycardia duringthe early stages of development of stabilizing devicesto help achieve a less mobile target during perform-ance of the distal anastomosis. Intravenous adenosinewas also used for the same purpose. Multiple otheragents have been tried as myocardial protectingagents such as selective Na+-H+ exchange inhibitors(Cariporide, Aventis Pharmaceuticals), ATP-dependentpotassium channel-modifying agents [15]. Most ofthese agents are not used any more since the develop-ment of the new mechanical stabilizers. If anything,bradycardia maybe treated by the application of tran-sient epicardial atrial or ventricular pacing to improvethe cardiac index and hemodynamic status of thepatient. In addition to these pharmacologic agents,intravenous nitroglycerine can be used judiciously dur-ing the operation to improve coronary perfusion viacoronary vasodilatation. This needs to be monitoredcarefully by the anesthesiologist to avoid hypotensionfrom excessive venodilatation. Some surgical teamshave used a technique known as hypotensive anesthesiausing small doses of arteriodilators to reduce the sys-tolic blood pressure and the systemic vascular resist-ance and thus reduce the left ventricular stroke workindex to reduce myocardial oxygen demand [16].Continuous monitoring of the cerebral oximetry isperformed during this period of relative hypotensionto ensure adequate oxygen supply to the brain.

The patient's temperature also needs to bemonitored closely. During OPCAB surgery, it is notuncommon for the patient's body temperature todrift down over a period of time, which may lead to allthe attendant complications of hypothermia. Thereis a sizeable amount of heat lost with the chest beingopen for a long time, and the intravenous fluidsbeing administered should be heated to normother-mic levels. In our practice, we keep the operatingroom significantly warmer than we would otherwisedo and pay meticulous attention to maintaining nor-mothermia throughout and after the operation. A BairHugger maybe used around the lower part of the body

after closure of the saphenous vein excision site, orfrom the very beginning if no lower extremity conduitis being used.

Operative strategy and technique

The operative strategy and technique employed bythe cardiac surgeon has a tremendous impact on pro-tecting the myocardium against ischemia. As men-tioned previously, complete revascularization is thegoal and is certainly achievable when OPCAB surgeryis performed carefully keeping the basic tents ofmyocardial protection and stable hemodynamics inmind. Maintenance of stable hemodynamics ensuresadequate coronary as well as cerebral and systemicperfusion. In the presence of diseased coronary arter-ies, it is especially important to keep the coronary per-fusion as normal as possible due to the limited reservefor oxidative metabolism within the myocardium.Hemodynamic changes and instability may be seen atvarious stages during the operation. Cardiac manipu-lation to expose the various coronary targets causesmechanical disturbance leading to altered hemo-dynamics. It is very important that proper techniquesare utilized to achieve the needed exposure. Most ofthese have focused on combinations of deep pericar-dial suture placement and cardiac displacement orherniation [ 16]. We use a single suture (LIMA suture)technique [17] to elevate the heart and allow easymanipulation and complete exposure of all coronaryarteries. This technique entails placement of a singleheavy suture (#1 Ethibond or silk) in the oblique sinusof the posterior pericardium (Figure 15.1). The sutureis then passed through a long gauze packing, which issecured with a snare placed over the suture. Applica-tion of tension on the packing and snare in differentdirections allows elevation and lateral displacement ofthe heart. The exposure may be further enhanced, ifneeded, by rotation of the operating room table orraising or lowering the head of the table.

To achieve adequate exposure of the lateral,posterior or inferior wall vessels, the gauze packing ispulled gently in a more lateral or inferolateral direc-tion, thus allowing the apex to elevate and rotate asnecessary. The operating table may be placed in theTrendelenburg position to allow the heart to fall awayfrom the diaphragmatic surface of the pericardium,thus allowing for easier exposure of the branches ofthe right coronary artery. Likewise, the table may be


Figure 15.1 (a) Schematic representation of position for the LIMA suture. (Continued overleaf.)

rotated towards the patient's right side to improveexposure of the lateral wall of the heart including thehigh diagonal and obtuse marginal coronary arteries.

While the heart is thus elevated and pericardium isbeing retracted, there may be some constriction of thevena cavae and thus it is important to remember notto pull up on the right side of the pericardium or torelax the right-sided pericardial sutures if these wereplaced before. This will allow unimpeded venousreturn to the right side of the heart and also preventthe heart from hitting the undersurface of the righthemisternum. The scope of this chapter does notallow complete description of the techniques usedfor these maneuvers but the accompanying figures

(Figures 15.2-15.5) allow the reader to understand

the technique. A more complete description may beobtained from reference [17]. It has been reportedpreviously that vertical displacement of the heart isassociated with hemodynamic instability along with

reduced cardiac index and blood pressure [18-20].The use of the single suture technique minimizes car-diac displacement and abolishes the need for adjunct-ive exposure techniques such as cardiac herniation orplacement of multiple deep pericardial sutures.

Various different types of stabilizers are availableto stabilize the area around the target vessel to allowperformance of an accurate anastomosis. These maybe broadly classified into those that use suction tech-nique or those that use a compression technique toachieve this stabilization. Multiple other adjunctive

138 CHAPTER 15

Figure 15.1 (continued) (b) LIMA sutureplacement.

Figure 15.2 Position of the heart fordistal anastomosis to the LAD.

devices are available that ostensibly improve exposure the lateral wall. The use of these devices may make itby aiding in the positioning of the heart by the use of easier to expose the target vessels and thus reduce thesuction applied to the apex of the left ventricle, which amount of cardiac manipulation. Other devices arein turn can be used to verticalize the heart and expose also available that allow for right heart circulatory sup-


Figure 15.3 Position of the heart fordistal anastomosis to the diagonalbranch of the LAD.

Figure 15.4 Position of the heart fordistal anastomosis to the obtusemarginal branch of the circumflexcoronary artery.

port while performing OPCAB [20,21]. We do notbelieve that these devices are necessary for the per-formance of OPCAB to achieve complete myocardial

revascularization safely and we do not use them in our

practice.The use of an intra-aortic balloon pump (IABP) in

patients who are unstable or have poor ventricularfunction may provide an additional degree of hemo-

dynamic assistance and stability with improvement incoronary perfusion, and may allow performance ofOPCAB in such a group of high-risk patients [22].

In the presence of multivessel coronary artery dis-

ease with involvement of LAD, we usually elect tobypass this vessel first. Due to the anterior location ofthe LAD, minimal manipulation and elevation of theheart is required to achieve adequate exposure. Thus,

140 CHAPTER 15

Figure 15.5 Position of the heart fordistal anastomosis to the posteriordescending branch of the rightcoronary artery.

there is minimal hemodynamic instability while per-forming the graft. If the left internal mammary artery(LIMA) is being used to bypass the disease in the LAD,as is usually the case, it also allows for reperfusion ofthe most critical area of the myocardium right away,making it easier for the conduct of the remainder ofthe operation. As long as the pedicled LIMA graft hasbeen harvested to an appropriate length, there is neverany undue tension on the LIMA-LAD anastomosis,no matter how the heart is manipulated to allow theother distal anastomoses to be completed. Many otherauthors have commented on the strategies of graftsequencing and have proposed grafting of the collater-alized vessels first [16,18,23], or to perform proximalanastomoses of the nonpedicled grafts prior to thedistal anastomoses. In our experience, we have notedthat performance of the LIMA-LAD anastomosisfirst reduces hemodynamic problems through the restof the operation and thus allows for greater patientstability. Perhaps since the LAD and its branchestogether supply the largest area of myocardium, allevi-ating ischemia to these areas at an early stage duringthe operation makes for a more stable hemodynamiccourse while manipulating the heart to graft the othertargets.

The availability of the new anastomotic devicessuch as the Symmetry device (St Jude, Minneapolis,MN) allows for the performance of sutureless prox-imal anastomosis but makes it necessary to performthe proximal anastomosis before the distal. This

may be advantageous, since as soon as the distal anas-tomosis is performed that area of the myocardium isrevascularized and ischemia is alleviated. In addition,the aorta does not need to be clamped and OPCABsurgery may be performed without ever clamping theascending aorta.

Performance of the distal anastomoses is the time atwhich maximal cardiac manipulation is undertakenand proper planning is necessary to try and keep anymyocardial ischemia to its minimum. Once the targetcoronary artery has been identified and the area hasbeen stabilized, the distal anastomosis needs to be per-formed with accuracy, which requires a near bloodlessfield. Various techniques are available to achieve thiswhile protecting the myocardium. Most surgeonsprior to coronary arteriotomy use proximal and distalsnares around the target coronary artery to preventflooding of the operative field. This produces somedegree of ischemia distal to the arteriotomy site, espe-cially if there are few or no collateral branches. There isalso a certain amount of coronary artery injury if thesnare is circumferential. Some people have resortedto using Silastic (Quest Medical, Allen, TX) loopsaround the artery to prevent injury. To prevent distalischemia, intracoronary or aortocoronary shunts areavailable that allow some blood flow to pass throughto the artery distal to the site of anastomosis. Intracor-onary shunts allow some passage of blood while keep-ing the anastomotic site relatively bloodless and alsoallow temporary stenting of the coronary artery to


help with accurate suture placement. There has beensome discussion in the literature about shunts caus-ing intimal injury at the anastomotic site [24-27] andthus these should be used only when necessary. If themyocardium distal to the anastomotic site has a goodcollateral supply and there is brisk back bleeding fromthe distal end of the arteriotomy, a shunt may not benecessary to maintain adequate myocardial protec-tion. In the case of a diseased large dominant rightcoronary artery that needs a graft either to the mainright or one of its large branches, however, a shuntshould be used whenever possible since occlusion ofthis vessel for any length of time to facilitate per-formance of an anastomosis may create atrial tachy/bradyarrhythmias. In our practice, it is routine not touse any snares proximally or distally around the targetvessel and to use a blower-mister to keep the bloodaway from the field of work. The blower-mister util-izes a fine spray of CO2 along with normal saline solu-tion to prevent any danger of air embolism. As soon asthe coronary artery is opened, the appropriate sizedintracoronary shunt is slipped into place and with thehelp of the blower-mister to keep the blood out of thefield, the anastomosis can be performed while protect-ing the distal myocardium. It is important to correctlychoose the size of the intracoronary shunt. Too smalla shunt may not help with perfusion and blood willleak around it obliterating vision at the anastomoticsite, while trying to insert too large a shunt may causeintimal injury or dissection of the coronary artery.

On-pump beating heart surgery

OPCAB can be performed for the large majorityof patients with coronary artery disease to achievecomplete revascularization using the basic tenets ofexposure and myocardial protection as outlined above.However, persistent hemodynamic instability mayoccasionally not allow progression of the procedure inan off-pump fashion. This may be due to several fac-tors. Global ventricular dysfunction may occur fromsequential periods of regional ischemia or the heartmay not do well with even minimal manipulation,necessitating abandonment of the off-pump proced-ure. If the patient arrives at the operating room in arelatively unstable condition, further manipulation ofa sick, ischemic heart may injure the myocardium andset the stage for the development of malignant ventric-ular arrhythmias, cardiogenic shock, or intraoperative

cardiac arrest. A vicious cycle is set up in this circum-stance due to the decrease in cardiac output, leadingto further deterioration of coronary perfusion super-imposed on already ischemic myocardium. Variousadjunctive techniques can be utilized to break thisvicious cycle and rest the heart with adequate myo-cardial protection and still maintain normal systemicperfusion. Placing the patient on the heart-lungmachine will achieve this. The operation can still becarried out on the beating heart using the previouslymentioned techniques to achieve complete revascu-larization of all intended target coronary arteries. Theheart can be emptied, the myocardium can be rested,and systemic perfusion is maintained. No cross-clamping of the aorta is necessary and it is not neces-sary to give cardioplegia. Stabilizing devices can beused in the same fashion as in OPCAB to performaccurate anastomosis. Since the heart is kept beatingand perfusion is being maintained by extracorporealcirculation, the demands of the myocardium will bemet till such time that adequate revascularization canbe completed. Another way to perform OPCAB withsome adjunctive help is using perfusion assisted directcoronary artery bypass (PADCAB) [28-30]. With thistechnique distal anastomoses are constructed first, asis done in OPCAB, after which the grafts are prox-imally connected to the outflow of a small pump cir-cuit. The inflow to this circuit is provided by a smallcannula placed in the ascending aorta or the femoralartery. The circuit comprises a pump system called theQuest Medical MPS (Quest Medical, Allen, TX) whichallows accurate control of coronary artery perfusionpressure as well as allowing the addition of variouschemical additives in exact concentration at specifiedtemperature. This enables maintenance of the coro-nary circulation despite changes in systemic pressure,but only after the construction of distal anastomoses.The system does allow delivery of cardioprotectiveagents such as nitroglycerine, adenosine, or elec-trolytes directly into the coronary circulation. In ourpractice, if the patient does not tolerate the OPCABdue to severe hemodynamic alterations, we prefer touse cardiopulmonary bypass to protect the heart butallow it to keep beating and the operation is completedwithout cross-clamping the aorta or ever having tostop the heart with cardioplegia.

Once the proximal and distal anastomoses havebeen completed, it is extremely important to knowthat these anastomoses are patent and allow the grafts

142 CHAPTER 15

to function as they are supposed to. We routinely

measure flows in all grafts prior to closure of the chest

to document patency of the anastomoses. In our prac-

tice we use the (Medistim) transit-time flowmeter,

which is very simple to use in the operating room

and allows correlation of flow to systole or diastole.

Previously published studies have shown that routine

measurement of graft flows allows detection of anas-

tomotic problems and/or conduit problems in 5-7%

of all cases, thus enabling the surgeon to correct the

problem before the patient leaves the operating room

[23].In summary, the avoidance of myocardial ischemia

is an extremely important concept in beating heart

coronary surgery. Central to this concept is the maint-

enance of stable hemodynamics during the operation

for which multiple techniques are available. The above

mentioned techniques allowing easy manipulation

of the heart and affording good exposure of the tar-

get coronary arteries along with the use of atraumatic

stabilizing devices, enables accurate construction of

anastomoses. Careful application of these techniques

achieves excellent results for almost any patient with

multivessel coronary artery disease.

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24 Rivetti LA, Gandra SMA. Initial experience using anintraluminal shunt during revascularization of the beat-ing heart. Ann Thorac Surg 1997; 63:1742-7.

25 Lucchetti V, Capasso F, Caputo M et al. Intracoronaryshunt prevents left ventricular function impairmentduring beating heart coronary revascularization. EurI Cardiothorac Surg 1999; 15:255-9.

26 Van Aarnhem EE, Nierich AP, Jansen EW. When andhow to shunt the coronary circulation in off-pumpcoronary artery bypass grafting. Eur J Cardiothorac Surg1999;16(Suppl2):S2-6.

27 Dapunt OE, Raji MR, Jeschkeit S et al. Intracoronaryshunt insertion prevents myocardial stunning in a juve-

nile porcine MIDCAB model absent of coronary arterydisease. Eur] Cardiothorac Surg 1999; 15:173-8.

28 Guyton RA, Thourani VH, Puskas JD et al. Perfusion-assisted direct coronary artery bypass: selective graftperfusion in off-pump cases. Ann Thorac Surg 2000;69:171-5.

29 Puskas JD, Thourani VH, Vinten-Johansen J et al. Activeperfusion of coronary grafts facilitate complex off-pumpcoronary artery bypass surgery. Heart Surg Forum 2001;4:64-8.

30 Steele M, Palmer-Steele C. Perfusion technique forperfusion-assisted direct coronary arter bypass (PAD-CAB ).JExtracorp Techno/2000; 32:158-61.

CHAPTER 16

Beating heart coronary arterybypass in patients with acutemyocardial infarction: a newstrategy to protect the myocardium

Jan F. Gummert, MD, PhD, Michael A. Borger, MD, PhD, ArdawanRastan, MD, & Friedrich W. Mohr, MD, PhD

Introduction

Acute myocardial infarction (MI) is an extremelycommon clinical entity, with more than 1 millionpeople suffering an acute MI each year in the UnitedStates alone [1]. Despite advances in medical andinterventional management, acute MI continues tocarry a high risk of mortality with approximately 30%of such patients dying pre or posthospitalization.

Therapeutic options for patients presenting withacute MI include medical management (includingthrombolytics and antiplatelet agents), percutaneoustransluminal coronary angioplasty (PTCA), and cor-onary artery bypass grafting (CABG). The vast majorityof acute MI patients are currently treated with medicaltherapy alone, predominantly because of the speedand relative ease with which thrombolytic agents canbe administered. The indications for PTCA follow-ing acute MI are controversial and beyond the scopeof the current chapter. However, large series havedemonstrated that approximately 10% of patients whoundergo PTCA for acute MI subsequently requirecoronary bypass surgery [2]. Surgical revasculariza-tion is currently used in only a small minority ofpatients who present with acute MI.

The purpose of this chapter is to describe a recentlydeveloped surgical option for patients presenting withacute MI—beating heart coronary bypass. Beatingheart surgery represents a paradigm shift in myocar-

dial protection during coronary bypass since coron-ary perfusion is maintained at near physiologic levels[3]. Patients with acute infarction may particularlybenefit from such physiologic perfusion. In addition,avoidance of cardiopulmonary bypass (CPB) maylimit the development of postinfarction microcir-culatory dysfunction (the "no-reflow" phenomenon),since CPB is known to be a potent stimulator of theinflammatory response [4]. Furthermore, temporaryvessel occlusion during the construction of coronaryanastomoses, a common concern during beating heartcoronary bypass, is not as worrisome in acute infarc-tion patients since the target artery is usually alreadyoccluded. Therefore beating heart CABG may be anoptimal therapeutic option for patients with acuteMI. The major issues to be addressed during beatingheart CABG for acute MI are whether or not to per-form complete revascularization (in patients with cir-cumflex disease) and whether or not to employ CPBsupport, i.e. CABG with CPB support but withoutcardioplegic arrest (for patients with severe hemody-namic compromise). These issues and others will bediscussed in more detail later in the chapter.

This chapter is divided into several subsections.First, we will describe the current indications forCABG after acute MI and discuss the optimal timingfor surgical intervention. Second, we will discussthe theoretical benefits of beating heart surgery foracute MI and present a summary of the most recent

144

Beating heart surgery for acute MI 145

literature on this subject. Finally, we will describe ourown surgical methods for beating heart revasculariza-tion after acute MI and present our perioperative andintermediate-term results for these challenging patients.

Indications for coronary arterybypass grafting in acutemyocardial infarction

The current indications for coronary bypass follow-ing acute MI are not well denned. Several studies fromthe early 1980s reported very good results for CABGfollowing acute MI, but the patient populations fromthese studies were significantly different from con-temporary post-Mi patients (see below). In addition,these studies were performed before the adventof thrombolytics and coronary stents, developments

that have significantly altered the management ofsuch patients.

DeWood and colleagues reported one of the largestcohorts of coronary bypass patients following acuteMI in 1983 [5]. These investigators performed CABGin 701 postinfarction patients from 1971 to 1981. Theoverall inhospital mortality was 3.1% for patients pre-senting with nontransmural MI and 5.2% for patientswith transmural infarction. Approximately two-thirdsof transmural infarction patients were operated on

within 6 h of symptoms, and their subsequent mortal-ity was 3.8%. The mortality for patients operated onafter 6 h was 8.0%. The 10-year survival for all patientswas excellent at 90%. However, the average patient agefor the entire cohort was only 55 years and nearlythree-quarters of patients were in clinical class I or IIpreoperatively.

More recent studies of CABG following acute MIhave produced results that are not nearly so favorable.Sergeant et al. examined 269 patients who underwentcoronary bypass for evolving MI (i.e. surgical revascu-larization between 1 and 15 h postinfarction) [6].The inhospital mortality was 15.6% and 10-year sur-vival was 66%. However, the patient population wassignificantly higher risk than the one reported on byDeWood et al. The mean patient age was 60 years andover one-half of patients were in cardiogenic shock orundergoing cardiopulmonary resuscitation prior tothe operation. Similarly, Lee and colleagues recently

performed a retrospective review of patients under-going post-Mi CABG in 32 New York State hospitalsbetween 1993 and 1996 [7]. Hospital mortality for

patients operated on within 1 day of their infarct(n = 1441) was 10.9%. Once again, this patient popu-lation was at significantly higher risk than the onereported by DeWood et al., with an average age of65 years and an 8% prevalence of reoperative coronary

bypass (vs. 0% in DeWood's study).Another controversial issue for post-Mi coronary

bypass is the optimal timing of the procedure. Earlysurgical reperfusion may limit infarct extension, reduceventricular dysfunction and subsequent remodeling,and decrease mortality [8]. Delayed surgery has beenadvocated by several investigators, however, becauseof the increased risk associated with early surgicaltherapy. In addition, delayed surgery may avoid thepotential risk of reperfusion injury and hemorrhagicinfarction. Furthermore, several randomized trials ofearly interventional therapy (predominantly PTCA)versus conservative therapy for acute coronary syn-

dromes have failed to reveal a beneficial effect for earlyaggressive treatment [9],

Many retrospective studies have examined the issueof optimal timing for post-Mi CABG. Creswell et al.

reviewed 1273 patients who were operated on within6 weeks of an MI and found a significantly increasedrisk of mortality for patients receiving early surgicaltherapy [10]. Likewise, Lee et al. studied 44 365 post-Mi CABG patients and found a mortality rate of

11.8% for those operated on within 6 h, 9.5% for 6 hto 1 day, and 2.8% for greater than 1 day postinfarct[7]. However, the increased risk associated with earlysurgery may simply reflect the increased risk factors,in particular cardiogenic shock, present in this pati-ent population. The most common current opinionregarding timing of post-Mi surgery is that it shouldbe delayed unless cardiogenic shock or mechanical

complications (see below) are present [7].Despite controversies regarding the optimal patient

population and optimal timing of CABG after acuteMI, results seem to be better than for patients treatedwith medical management alone. Every and colleaguesin 1996 reviewed 1299 CABG patients who wereadmitted to 19 Seattle hospitals with acute MI over a4-year period, and compared them to patients whowere treated with medical therapy alone (n = 7541)[11]. CABG patients had lower hospital mortality thanmedically treated patients (7.2% vs. 11.4%, P < 0.001).

In addition, CABG patients were less likely to undergoangiography or PTCA during 3 years follow up, andless likely to require rehospitalization when compared

146 CHAPTER 16

to medical patients. CABG may also possess advant-ages over PTCA post-Mi since a more complete revas-cularization is possible.

Coronary bypass remains an uncommon entity inpost-Mi patients, despite its apparent efficacy. Themain reason for this infrequent usage is probablyrelated to technical aspects of cardiac surgery, ratherthan problems with surgical results. Such technicalproblems include the fact that cardiac surgery is notavailable in the majority of centers that admit pati-ents with MI, it requires a well-organized and readilyavailable team, and it may result in unacceptabledelays in treatment when compared to thrombolytictherapy.

Although CABG is uncommon in post-Mi patients,there are some generally agreed upon indications forsurgical intervention postinfarction. These are:1 cardiogenic shock;2 evolving infarction despite thrombolytic and/orPTCA therapy;3 contraindications to thrombolytic and/or PTCAtherapy (e.g. bleeding diathesis, left main stenosis,etc.);4 postinfarction angina with coronary anatomyunsuitable for PTCA;5 acute coronary occlusion during PTCA;6 early post-CABG MI secondary to acute graft occlu-sion;7 acute mitral regurgitation;8 ventricular septal defect;9 myocardial free wall rupture.

The last three indications are the mechanicalcomplications of acute MI and are well recognizedas definite indications for surgery. However, each ofthese complications requires reparative surgery undercardioplegic arrest and therefore will not be discussedany further in this chapter. Post-Mi CABG for theother six indications can be accomplished with beat-ing heart surgical techniques. Of these six indications,postinfarction angina is the most common clinicalentity. However, such patients are relatively stable andtheir surgery can often be performed under a delayed,semielective fashion. Surgical revascularization for theother five indications is usually performed underurgent or emergent conditions and the patients are atmarkedly increased risk. It is these patients who wewill focus on during the discussion of our institutionalresults for beating heart CABG post-Mi (see "Ourexperience" below).

A special note should be made about CABG forpost-Mi cardiogenic shock. Cardiogenic shock isknown to occur in 7-10% of patients hospitalized withacute MI. The SHOCK trial is the largest and mostmethodologically sound study of interventional ther-apy for post-Mi cardiogenic shock. A total of 302 suchpatients were randomized to receive initial medicalstabilization or emergency revascularization within6 h of presentation [12]. Of the 152 patients random-ized to emergency revascularization, 36% underwentcoronary bypass surgery and 64% PTCA. Six-monthmortality was significantly lower in patients assignedto early revascularization (50% vs. 63%, P = 0.03),with further improvements realized for patients under75 years of age.

The SHOCK trial also produced the largest nonran-domized registry of patients with post-Mi cardiogenicshock (n = 1190) [ 13]. In this registry hospital mortal-ity for the 136 patients who underwent CABG was28%, a significant improvement over the 46% mortal-ity for those patients treated with PTCA (n = 268). Inaddition, mortality rates for patients receiving revas-cularization (CABG or PTCA) were much lower thanfor those receiving medical therapy alone (89%,n = 334; P = 0.01). Some of this difference, however,may have been attributable to the higher risk profileof medically treated patients. It should also be notedthat the improved mortality rates for CABG for car-diogenic shock obtained from the SHOCK registry areremarkably similar to pooled estimates obtained from25 different studies [14]. We can therefore concludethat early revascularization, and CABG in particular,should be strongly considered in patients with post-Mi cardiogenic shock.

Beating heart surgery for acutemyocardial infarction

As stated in the Introduction, beating heart coronarybypass is a new treatment strategy for patients withacute MI. As such, there are relatively few studies inthe literature on this topic. In this section we willreview the techniques and results from the availableliterature.

One of the earliest reports of off-pump CABG inpost-Mi patients was reported by Benetti et al. fromArgentina [15]. These investigators performed beat-ing heart surgery within 10 h of acute MI in 32 patientsover an 11-year period. Four patients (13%) were in


preoperative cardiogenic shock. The results achievedwere exceptional. No inhospital deaths occurred andnone of the patients suffered from low cardiac outputsyndrome. Follow up revealed that one patient haddied, one was in congestive heart failure (CHF), andone required redo CABG for angina. The authors con-cluded that beating heart CABG was an acceptablealternative for patients presenting with acute MI.

Mohr et al. from Tel Aviv University published oneof the most important papers on post-Mi beatingheart CABG in 1999 [16]. Of the 1245 patients whowere admitted to their institution with acute MI overa 3-year period, only 67 were referred for coronarybypass surgery. The authors reviewed their experiencewith the 57 surgical patients (mean age 58 years) whounderwent CABG without CPB. All of the patientswere operated on less than 1 week post-Mi, including32 who underwent surgery within 48 h of their infarc-tion and seven who were in cardiogenic shock. Theinvestigators avoided beating heart CABG in patientswith disease in the circumflex territory or with targetcoronary vessels of less than 1.5 mm in diameter (suchpatients underwent conventional CABG with CPB).They attempted to keep the patient's systemic bloodpressure above 100 mmHg intraoperatively in order tomaintain adequate coronary perfusion. Four patientsrequired insertion of an intra-aortic balloon pump(IABP) because of hemodynamic instability. Themean number of coronary bypass grafts was 1.8, with12% of patients receiving a graft to the circumflex ter-ritory. The left internal thoracic artery was used in82% of patients. Approximately one-third of patientsended up with an incomplete revascularization, i.e.without revascularization of the circumflex territory.

The postoperative results achieved by Mohr et al.were excellent. One patient (2%) died perioperativelyand there were no strokes or fatal Mis. The mean hos-pital stay was 7 days. Late follow up (mean 46 monthspostoperation) revealed that eight patients (14%)had died, including five from cardiac causes. Anginareturned in seven patients (12%), two of whomrequired PTCA and one who required redo CABG.Actuarial 5-year survival was 82%. Of the 54 hospitalsurvivors who were available for follow-up, 79% had acompletely uneventful perioperative and long-termoutcome.

These same investigators published another articlein 2000 that focused on patients who underwentCABG within 48 h of acute MI [17]. A total of

77 patients underwent urgent or emergent post-Mirevascularization over a 6-year period, 40 of whichwere performed without CPB. The mean number ofgrafts was 3.0 for the on-pump group versus 1.9 for thebeating heart group (P< 0.001). Perioperative mortal-ity was lower for patients undergoing beating heartCABG (5%) than for those undergoing conventionalCABG (24%, P = 0.01), even after controlling forother risk factors. Furthermore, beating heart CABGpatients had significantly less requirements for post-operative inotropic or IABP support. Long-term fol-low up, however, revealed fewer deaths and fewercardiac reinterventions in the conventional CABGgroup. The authors concluded that although beatingheart CABG results in superior perioperative out-comes post-Mi, long-term outcomes appear to bebetter for patients who undergo conventional CABG.They hypothesized that the increased cardiac eventsin the beating heart group may be related to theincreased incidence of incomplete revascularization.It is possible that so-called "hybrid procedures",i.e. beating heart revascularization of left anteriordescending (LAD) and right coronary artery (RCA)lesions, combined with PTCA of the circumflex ter-ritory, could result in optimal outcomes for thesehigh-risk patients [18].

Two other articles have been recently published onthis topic. Vlassov et al. from Moscow reviewed 26consecutive patients who underwent beating heartCABG within 96 h of acute MI [19]. The authors per-formed conventional off-pump coronary artery bypass(OPCAB) through a median sternotomy in 16 patientsand minimally invasive direct coronary artery bypass(MIDCAB) through a left anterior thoracotomy in10 patients. Four patients (15%) had preoperativecardiogenic shock. The mean number of coronarybypasses was 1.8, with 15% of patients receiving anincomplete revascularization. Two MIDCAB patientsunderwent a hybrid procedure with PTCA of the cir-cumflex territory 10 days postoperatively. The periop-erative mortality rate was 8%. Inotropic support wasnecessary in 35% of patients and 19% of patientsrequired an IABP. Early postoperative angiographyrevealed patency of all studied grafts.

In another recent study, D'Ancona et al. fromBuffalo reviewed their experience with patientsundergoing CABG less than 21 days post-Mi [20].All post-Mi patients undergoing OPCAB (n = 97)were compared to those undergoing conventional

148 CHAPTER 16

on-pump CABG (n = 421) over a 4-year period. Theincidence of preoperative cardiogenic shock was lowat less than 1%. The OPCAB group had a significantlyhigher prevalence of many risk factors including renalfailure, CHF, and redo CABG, but the conventionalgroup had more circumflex disease. ConventionalCABG patients received significantly more coronarybypasses (3.5 vs. 1.8, P< 0.001). The authors failed tofind any statistically significant differences in post-operative outcomes. However, there was a trendtowards higher mortality in the OPCAB group (6% vs.3%, P = NS). The authors for both of these recentstudies concluded that beating heart CABG is a safeand viable treatment alternative for patients present-ing with acute MI.

Our experience

At the Leipzig Heart Center we have performed 1842beating heart coronary bypass procedures between1996 and 2000. These operations include those per-formed through a left anterior minithoracotomy(MIDCAB, n = 1077) as well as those performedthrough a median sternotomy (OPCAB, n = 765).Over this same time period, we have performed 1904isolated coronary bypass procedures in patients withunstable angina and other acute coronary syndromes(Figure 16.1). A comparison of patients with andwithout a history of preoperative MI (i.e. acute andnonacute MI) revealed that perioperative mortal-ity was significantly higher in those with previousinfarction (8.0% vs. 4.1%, P < 0.001). As can be seen

in Figure 16.1, however, mortality was significantlyreduced if revascularization was performed undera beating heart technique. Perioperative mortalitywas 8.5% for post-Mi patients undergoing conven-tional CABG versus 4.3% for beating heart patients(P< 0.001).

It is because of these encouraging results that weenacted an institutional policy of performing beat-ing heart revascularization for patients requiringsurgery after acute MI. We believe that maintainingnear physiologic coronary perfusion in these difficultpatients is an important advantage of this technique.Over the last 2 years, we have performed a total of101 beating heart revascularizations in patients withacute MI. Approximately one-half (n = 49) of thesepatients had ST elevation upon presentation, whilethe remainder had non-ST elevation infarctions. Allpatients underwent surgery within 6 h of presentationto our hospital. The following methods and resultswill focus on these 101 patients.

MethodsOur procedure of choice for post-Mi CABG is viaa median sternotomy (i.e. OPCAB) approach. Ourgoal was to maintain a systemic blood pressure ofgreater than 100 mmHg during the procedure in orderto maximize coronary perfusion. If the patient'shemodynamic status became unstable intraoperat-ively, we inserted an IABP and/or placed the patienton CPB support. Patients who were supported withCPB, however, did not undergo aortic cross-clampingor cardioplegic arrest. That is, we used a beating

Figure 16.1 Perioperative mortalityrates for patients with unstable anginaand other acute coronary syndromes(n = 1904) operated on between 1996and 2000 at the Leipzig Heart Center.Mortality was significantly higher forconventional coronary bypass withcardioplegic arrest when compared tobeating heart surgery, particularly inpatients with a history of preoperativemyocardial infarction. CABG, coronaryartery bypass grafting; Ml, myocardialinfarction.


heart technique with CPB support in these high-riskpatients.

Our surgical technique was otherwise similar tothat used for routine OPCAB surgery. Two retractionsutures were placed in the posterior pericardium. Weused CTS retractors and stabilizers (CardioThoracicSystems Inc.; Cupertino, CA) for target vessel expo-sure and stabilization. A 4-0 polypropylene, pledgetedsuture was placed around the target vessel proximal tothe anastomotic site and was gently tightened with atourniquet in order to achieve hemostasis. The coron-ary arteriotomy was performed 1 min thereafter, ifno significant EGG or hemodynamic disturbancesoccurred. Intracoronary shunts were used if the targetvessel had a subcritical stenosis, if there were signsof hemodynamic or electrocardiographic instabilityduring vessel occlusion, or if coronary blood flow wasexcessive and obscuring the field of vision.

We used the left internal mammary artery (LIMA)to bypass the LAD coronary artery whenever possible.Multiple arterial grafts were used in hemodynamicallystable patients less than 70 years of age. All patientsunderwent intraoperative assessment of graft patencyusing transit time flow measurement (Cardio-MedFlowmeter CM 4000, Medi-Stim; Oslo, Norway).Those patients with a transit time flow of less than 15ml/min underwent intraoperative monoplane angio-graphy and/or surgical revision of the correspondinganastomosis.

ResultsAs previously stated, we performed beating heartCABG within 6 h of hospitalization for acute MI in101 patients. The average patient age was 66 ± 11 years(mean ± SD) and 74% were male. The indications forsurgery were post-Mi cardiogenic shock (26% ofpatients), evolving MI unresponsive to or unsuitablefor lysis or PTCA (48%), early post-Mi angina (14%),or complications of PTCA (12%). In general, the riskprofile for this group of patients was higher than forthe populations in the studies previously discussed.An IABP was inserted preoperatively in 17% ofpatients, 19% were intubated and ventilated, and 18%underwent preoperative cardiopulmonary resuscita-tion (CPR). Table 16.1 displays other preoperativecharacteristics for this group of patients.

The average number of coronary bypass grafts per-formed was 2.8 ± 0.9. We used the LIMA to bypass theLAD in 89% of patients, a vein graft in 6%, and the

Table 16.1 Preoperative characteristics of patients

undergoing early post-Mi beating heart CABG (n = 101) at

the Leipzig Heart Center.

Variable

Diabetes

Hypertension

Renal failure

Previous Ml

LVEF (%)

Previous CABG

Thrombolysis

Glycoprotein llb/llla inhibitors

CK(IU)

CK-MB (IU)

Prevalence (%) *

35

84

13

40

46±16

4

18

19

735 + 1134

1081131

*Continuous variables are expressed as mean ± SD.

Ml, myocardial infarction; LVEF, left ventricular ejection

fraction, CABG, coronary artery bypass grafting; CK,

creatine kinase, CK-MB, creatine kinase MB fraction.

LAD was not bypassed in 5%. Multiple arterial graftswere used in 22% of patients. The right coronaryartery received one or more grafts in 66% of patientsand 78% received one or more grafts to the circumflexterritory. A total of 30 patients (30%) were placed onCPB intraoperatively because of hemodynamic insta-bility (i.e. beating heart CABG with CPB support).CPB support was instituted immediately after arrivalin the operating room in 10 patients and during expo-sure of the circumflex territory in 20 patients. The leftventricle was further unloaded in these patients withhemodynamic instability by inserting a suction vent inthe pulmonary artery.

As expected, the morbidity and mortality for thishigh-risk group of patients was higher than electivecoronary surgery. An IABP was required postoper-atively in 41% of patients, including the 17% whorequired preoperative IABP support. Stroke occur-red in three patients, of which two were fatal. Theaverage intensive care stay (including intensive andintermediate care unit stay) was 7.8 ± 9.8 days. A totalof nine patients required resternotomies for bleed-ing and three patients required revision of one ormore coronary bypass grafts. Inhospital mortalitywas 17%. However, mortality was significantly lowerfor patients without preoperative cardiogenic shockthan for those with preoperative shock (9% vs. 38%,P = 0.001).

150 CHAPTER 16

A special note should be made about postacute MIpatients with circumflex disease. It has been our expe-rience, as with other investigators, that such patientspoorly tolerate surgical exposure of this territory. Theoptions for these patients are to therefore: (i) place thepatient on CPB support; (ii) perform an incompleterevascularization; or (iii) perform a hybrid procedurewith subsequent PTCA of the circumflex lesion. It isour current practice to place such patients on CPBsupport with subsequent revascularization of the cir-cumflex territory whenever possible.

We have concluded from our experience withbeating heart CABG post-Mi that it is a feasible andrelatively safe procedure, and may result in a lowermortality than conventional coronary revasculariza-tion. However, a large proportion of patients mayrequire intraoperative CPB support for hemodynamicinstability, particularly if they had preoperative car-diogenic shock. Further studies are required to deter-mine the optimal population and timing for post-Mibeating heart CABG, as well as to determine what thelong-term outcome is for such patients.

Conclusions

In conclusion, beating heart surgery after acute MIrepresents a paradigm shift in myocardial protectionduring coronary revascularization. It has been hypo-thesized that beating heart CABG may be the optimalsurgical approach post-Mi because of maintenanceof near physiologic coronary perfusion and avoidanceof the deleterious inflammatory effects of CPB. How-ever, relatively few studies exist in the literature tosupport or refute this hypothesis. The small numberof publications is undoubtedly related to the recentdevelopment of this surgical technique and the smallnumber of MI patients that present for surgicalrevascularization.

A critical review of the available literature, as wellas our own institutional results, reveals that beatingheart CABG is feasible and safe in these technicallychallenging patients. Furthermore, preliminary evid-ence suggests that beating heart surgery post-Mi mayresult in lower perioperative mortality than conven-tional CABG. Beating heart CABG after infarctionmay be associated with a higher rate of incompleterevascularization and may result in more long-termcardiac events and reinterventions. Our own institu-tional results, however, suggest that more complete

revascularization is possible with the assistance of CPBsupport. Mortality remains significant for these high-risk patients, however, particularly if cardiogenicshock is the indication for surgery.

Further studies are required before definitive con-clusions can be made about beating heart CABG post-Mi. In addition, future studies should examine theresults of hybrid beating heart CABG and PTCA pro-cedures. It remains to be seen whether the theoreticalbenefits of beating heart revascularization result inimprovements in patient outcomes postmyocardialinfarction.

References1 American Heart Association, http://americanheart.org/

statistics.2 Stone GW, Brodie BR, Griffin JJ et al. Role of cardiac

surgery in the hospital phase management of patientstreated with primary angioplasty for acute myocardialinfarction. Am J Cardiol 2000; 85:1292-6.

3 Flameng WJ. Role of myocardial protection for coronaryartery bypass grafting on the beating heart. Ann ThomeSurg 1997; 63:518-22.

4 Cohn WE, Ruel M. Invited commentary on acutemyocardial infarction: OPCAB is an alternative approachfor treatment. Heart Surg Forum 2001; 4:150-1.

5 DeWood MA, Spores J, Berg R Jr et al. Acute myocardialinfarction: a decade of experience with surgical reperfu-sion in 701 patients. Circulation 1983; 68: II8-II16.

6 Sergeant P, Blackstone E, Meyns B. Early and late out-come after CABG in patients with evolving myocardialinfarction. Eur J Cardiothorac Surg 1997; 11: 848-56.

7 Lee DC, Oz MC, Weinberg AD et al. Optimal timingof revascularization: transmural versus nontransmuralacute myocardial infarction. Ann Thome Surg 2001; 71:1198-204.

8 Kaul TK, Fields BL, Riggins SL et al. Coronary arterybypass grafting within 30 days of an acute myocardialinfarction. Ann Thome Surg 1995; 59:1169-76.

9 Holmes DR. Acute coronary syndromes: extendingmedical intervention for five days before proceedingto revascularization. Am J Cardiol 2000; 86 (Suppl):36M-41M.

10 Creswell LL, Moulton M}, Cox JL et al. Revascularizationafter acute myocardial infarction. Ann Thome Surg 1995;60:19-26.

11 Every NR, Maynard C, Cochran RP et al. Characteristics,management, and outcome of patients with acute myo-cardial infarction treated with surgery. Circulation 1996 ;94:1181-6.

12 Hochman JS, Sleeper LA, Webb JG et al. Early revascular-ization in acute myocardial infarction complicated bycardiogenic shock. NEnglJMed 1999; 341:625-34.

13 Hochman IS, Buller CE, Sleeper LA et al. Cardiogenicshock complicating acute myocardial infarction—


etiologies, management and outcome: a report from theSHOCK trial registry. / Am Coll Cardiol 2000; 36:1063-70.

14 Hochman JS, Gersh BJ. Acute myocardial infarc-tion: complications. In: Topol, EJ, ed. Textbook ofCardiovascular Medicine. Philadelphia: Lippincott-Raven,1998: pp. 437-80.

15 Benetti FJ, Mariani MA, Ballester C. Direct coronarysurgery without cardiopulmonary bypass in acute myo-cardial infarction. / Cardiovasc Surg (Torino) 1996; 37:391-5.

16 Mohr R, Moshkovitch Y, Shapira I et al. Coronary arterybypass without cardiopulmonary bypass for patients withacute myocardial infarction. / Thorac Cardiovasc Surg1999; 118: 50-6.

17 Locker C, Shapira I, Paz Y et al. Emergency myocardialrevascularization for acute myocardial infarction: sur-vival benefits of avoiding cardiopulmonary bypass. Eur JCardiothorac Surg 2000; 17:234-8.

18 Zenati M, Cohen HA, Griffith BP. Alternative approachto multivessel coronary disease with integrated coronaryrevascularization. / Thorac Cardiovasc Surg 1999; 117:439-46.

19 Vlassov GP, Deyneka CS, Travine NO et al. Acutemyocardial infarction: OPCAB is an alternative approachfor treatment. Heart Surg Forum 2001; 4:147-50.

20 D'Ancona G, Karamanoukian H, Ricci M et al.Myocardial revascularization on the beating heart afterrecent onset of myocardial infarction. Heart Surg Forum2001; 4: 74-9.

CHAPTER 17

Beating heart coronary arterybypass with continuous perfusionthrough the coronary sinus

Harinder Singh Bedi, MCH, FIACS

Introduction

In recent times there has been resurgence in interestin the performance of coronary artery bypass surgery(CABG) without the use of cardiopulmonary bypass(CPB). While previously it was being used only incases where cannulation, CPB, or hypothermia werenot possible [1], it is now being used electively.Smoother postoperative recoveries, reduction inhomologous blood transfusion requirement, a shorterICU and hospital stay with quicker return to normallife are also expected. In developing countries, animportant factor that has prompted the interest inbeating heart procedures is the major cost savingwith the avoidance of CPB. However with off-pumpprocedures there has been a compromise in the com-pleteness of revascularization with most authorsreporting ungrafted circumflex coronary artery dis-ease [2,3]. Even with the beating heart technique usingthe octopus suction stabilizer for multivessel diseasevia median sternotomy, all three territories were notgrafted [4]. This is one of the major causes of morbid-ity and mortality.

The excellent long-term patency rates associatedwith conventional CABG must not be compromisedfor the sake of initial patient comfort or cost. Absoluteprerequisites for beating heart surgery are a quietbloodless field and avoidance of ischemia during thetime the coronary artery is snared.

During off-pump CABG (OPCABG) the targetartery has to be snared in order to perform thearteriotomy and subsequent construction of the anas-tomosis without having continuous flow of blood in

the field. Snaring of the artery invariably producesischemia, which may not be tolerated especially whenthe heart is lifted and rotated to reach the lateral wall.The onset of ischemia leading to EGG changes andhemodynamic compromise leads to either conversionto CPB or to hasty completion of the anastomosis,which may have adverse effects on the accuracy of thesuturing. To overcome the period of ischemia and forregional myocardial preservation we have devised atechnique of perfusing the area of myocardium atrisk via retrograde perfusion with oxygenated bloodfrom the ascending aorta allowing performance of anunhurried and precise anastomosis.

Technique

Preoperative preparationThe salient features of preoperative preparation,anesthesia, method of access, and stabilization havebeen previously described [5]. These are describedbelow in brief.

Maintenance of normothermiaOne of the problems with off-pump surgery is that thetemperature of the patient tends to drift, decreasing byas much as 3-4°C if precautions are not taken. In allcases, the operating room (OR) is preheated to 25°C.The sedated patient is placed on a warm water blanketconnected to a Sarns TCM II (Sarns, 3M HealthCare,Ann Arbor, MI). Before draping, an air blanket con-nected to a Bair Hugger (Augustine Medical Inc, EdenPrairie, MN, USA) is used to cover the patient. Allscrub solutions and intravenous fluids are preheated

152

Continuous myocardial perfusion during OPCABG 153

to body temperature. After draping, the nozzle ofthe Bair Hugger is placed under the drapes (makingsure that there is no direct contact with skin). Withthese measures the temperature drift is restricted to

Operative techniqueSurgical access in all cases is via median sternotomy.The skin incision is kept limited both superiorly and

inferiorly by dissecting small skin flaps. We feel that astandard mid-sternotomy is the approach of choicefor precise harvesting of both the internal mammaryarteries, for retrograde cannulation of the coronarysinus (described below in "Technique for avoidance ofischemia and regional myocardial preservation") toaccess all areas of the heart for performance of theproximal anastomoses, and for ease of conversion toCPB should the need arise.

Initial assessmentThe pericardium is opened after sternotomy. Thecoronary artery anatomy is assessed for suitability foran off-pump procedure. All patients coming for elect-ive CABG are candidates for OPCABG. The area thatis the most difficult to approach off pump is the lateraland posterior wall. To expose these areas a very gentletrial lifting of the heart is preformed. Any grosschanges in arterial pressure, pulmonary artery pres-sure, cardiac output, 12 lead ECG, and ST segment arecarefully monitored. If the heart does not toleratehandling, further attempts at OPCABG are abandonedand conventional CPB is used. In all cases, pumpstandby is available with a perfusionist in the OR.

Distal anastomosisAfter heparinization (1.5 mg/kg heparin intraven-ously) the target area is immobilized and snared with asilicone vascular loop (Retract-O-Tape Air Cushion,Deknatel/DSP, Lubeck, Germany) and a blunt needle.Loops are passed deep under and around the coronaryartery. An effort is made to isolate as little as possibleof the coronary artery to minimize ischemia. TheRetract-O-Tape is either snared with a thin siliconetube over a buttress of a piece of pericardium, vein orthymic tissue. The suture may be taken one more timearound the artery and pulled up around the buttress.The anastomosis is constructed with a running 8-0

prolene (Ethicon, Somerville, NJ) (for arterial grafts)or 7-0 prolene (for vein grafts) suture with magnifying

loupes (x3.5). Usually a single running suture is used,or infrequently two sutures beginning at the heel andtoe of the anastomosis. An attempt is made to createtwo anastomoses with one suture by keeping one endextra long and using it for the second graft (using onlyone needle). The goal is to further reduce cost. Thefield is kept bloodless by use of a Visuflow blower(Research Medical, Inc, Midvale, UT), which pro-duces a clear field without drying the tissues. Heparin

is fully neutralized with protamine sulfate at the end of

the procedure.

Maintenance of hemodynamic stabilityDuring construction of the anastomoses the heartrate is brought down to 50-70 beats/min by the useof intravenous beta-blockers with or without intra-venous diltiazem infusion. The need to reduce heartrate has generally decreased with the use of cardiacstabilizers.

Cardiac wall stabilizationStabilization of the target area is achieved by a com-bination of methods. We started with the use of localpericardial stay sutures (exclusively in the first 100cases of multivessel OPCABG) [5], then we went onto use various devices including the Diamond GripRib Spreader/Cardiac Stabilizer (Genzyme Corpora-tion; Cambridge, MA), the Origin Cardiac Stabilizerand Stabilizer Foot (Origin, Menlo Park, CA), the

Mechanical Stabilizer (CTS Inc, Cupertino, CA), andthe Octopus 3-0 Tissue Stabilizer System (Octopus,Medtronic Inc., Minneapolis, MN), and recently theStarfish Heart Positioner (Medtronic Inc, Minneapolis,MN).

Technique for avoidance ofischemia and regional myocardialpreservation

We have employed a new technique for perfusion ofthe myocardium while the coronary artery is snared[5-7]. We do not recommend the use of intraluminalshunts due to their inherent risk of damage to theintima, dislodgement of atheroma, creation of a dis-section, and hindrance with suturing. We use perfu-sion of arterial blood through a retrograde coronary

sinus cannula. The retrograde cardioplegia catheterwith a self-inflating balloon (Gundry RSCP catheter,(Medtronic DLP, Grand Rapids, MI) or a 3M Sarns

154 CHAPTER 17

catheter (3M, Ann Arbor, MI)) is eased transitorilyinto the coronary sinus through a pursestring sutureplaced in the low right atrium by a standard technique[8] after systemic heparinization (1.5 mg/kg heparinintravenously). Insertion of the catheter is easy in abeating off-pump heart (vs. an empty on-pump heart)as the coronary sinus is full and distended. Also thereis no venous drainage cannula in the right atrium. Itsposition is confirmed by palpation and by checkingthe pressure via the integral pressure line (20 mmHgor less). An antegrade cardioplegia cannula (Baxter(Research Medical Inc., Midvale, UT) or Jostra (JostraMedizintechnik, Hirrlingen, Germany)) is positionedinto the ascending aorta and is secured with a purses-tring in a standard way. It is connected via a multipleperfusion set (Baxter, Research Medical Inc, Midvale,UT) to the coronary sinus cannula. After de-airing,oxygenated arterial blood at aortic pressure is allowedto perfuse the coronary sinus. The setup of the can-nulas used is shown in Figure 17.1. The coronary sinuscatheter pressure is carefully monitored. In mostcases it is not allowed to go over 40 mmHg (mean),possibly due to the dimension and length of theconnecting tubings. In four cases flow was reducedby turning the three-way stopcock until the pressuredecreased to 40 mmHg (mean). The change in thepressure curve with perfusion on and off can be appre-ciated (Figure 17.2). Perfusion is allowed to continuethroughout the procedure carefully monitoring pres-sure. The perfusion is turned off after the snares arereleased and antegrade flow (via in situ graft or freegraft connected to a side arm of the multiport) is

Figure 17.1 The setup consisting of the antegrade andretrograde cannula and multiple perfusion cannula. A,antegrade cannula; M, multiperfusion cannula; R,retrograde cannula; B, self-inflating balloon of retrogradecannula; P, integral pressure line of retrograde cannula.

established. We have determined that perfusionoccurs in the blocked areas (mentioned in the results).The fact that there is a two-way flow of blood (down-stream via the normal way, and upstream via thecoronary sinus to capillaries) is possible because ofthe inherent "leak" in the balloon of the catheter(S. Gundry, personal communication). In all cases,

Figure 17.2 Freeze frame of the monitorshowing the coronary sinus pressure(labeled RV) with perfusion off (whitestar) and on (white arrow). Even at asystemic pressure of 153 mmHg systolicthe mean coronary sinus pressure is 30mmHg. Reprinted from [7], withpermission from Society of ThoracicSurgeons.

Image Not Available


as soon as the distal anastomosis is performed, thefree graft-saphenous vein graft (SVG) or radial artery(RA) is connected to a line of the multiport and isallowed to perfuse with oxygenated blood.

Sequence of graftingAfter trying different sequences, we have now de-veloped a set routine [5]. The easiest grafts are donefirst and are allowed to perfuse. This generally trans-lates to a left internal mammary artery (LIMA) or SVGto left anterior descending (LAD), followed by theright internal mammary artery (RIMA)/radial artery(RA)/SVG to right coronary artery (RCA)/posteriordescending artery (PDA). When free grafts are usedthe conduit is connected to a side arm of the multiportcardioplegia set and is perfused by arterial blood fromthe ascending aorta. For the in situ LIMA and RIMA

grafts perfusion starts as soon as the distal anastomosisis completed by opening of the bulldog clamp on theconduit. All proximal anastomoses are performed inthe end—SVG with 6-0 prolene and RA with 7-0 pro-lene. The free RA is anastomosed directly to the aorta(mostly) or on to a SVG as a piggyback graft or to theLIMA as a Y graft (this is done before starting the firstdistal anastomosis). The choice for the proximal siteof the RA depends on the position of the target arter-ies, the length of conduit available, the space availableon the ascending aorta, and the size and flow of theLIMA.

Revascularization assessment criteriaElectrocardiograms are recorded at admission, im-mediate postoperatively, and then daily for 3 days andpredischarge. Serial myocardial fractions of creatinekinase (CK-MB) are determined immediately postop-eratively and for 2 days postoperatively.

Perioperative myocardial infarction was diagnosedin the presence of one or both of the following criteria:(i) CK-MB > 50IU and (ii) the development of new Qwaves. Angiography was performed in 35 patientsafter informed consent on the day before discharge.Graft patency was shown at 97.8% [5].

Follow upMean follow-up time was 38 months (range 1-60months), collected through direct patient contact in

all cases. All patients had serial EGG, two-dimensionalechocardiograms, and exercise testing 3 months post-operatively.

ResultsThe technique of retrograde perfusion has been usedin 545 cases of multivessel OPCABG and in 124 casesof single and double-vessel OPCABG.

There was no episode of ischemia documented byEGG changes or wall motion abnormalities, exceptin three patients in whom a large main RCA wasbeing grafted. In these patients there was a 1-2 mmST-segment elevation during the last stages of thesuturing. This was managed while the anastomosiswas hurriedly completed and the graft subsequentlyperfused. In view of the above problem with ana-stomosis to a large RCA and the fact that retro-grade perfusion may not adequately perfuse the rightventricle [9], we now prefer, wherever possible, tograft a PDA rather than a large RCA. In all the restof the anastomoses there was no period of EGGchanges or gross hemodynamic instability. In factnow we are able to perform the anastomoses verymeticulously (anastomosis time is now longer than inthe earlier stages), so "racing against the clock" doesnot take place.

Retrograde perfusion is quite safe since, in themajority of cases, the pressure in the coronary sinusdoes not increase above the arbitrary level of a mean of40 mmHg [10] (Figure 17.2), even when the systemic

pressure is high.We have confirmed adequacy of perfusion by the

following facts:1 EGG changes on snaring an artery, which revertto normal on starting retrograde perfusion.2 Vigorous backbleeding of dark blood on temporaryrelease of distal snare after arteriotomy (Figure 17.3),as seen during retrograde blood cardioplegia infusionindicating that the myocardium is being perfused andis utilizing the oxygen from the arterial blood perfusedvia the coronary sinus. This visual proof of perfusion

was observed in 10 out of 10 cases in the LAD, 7 out of10 cases in the circumflex area, and 5 out of 10 cases inthe main RCA.3 A good oxygen extraction ratio (across the LADand circumflex area) of 46 ± 4% was noted in 10patients by taking blood from the arteriotomy and

analyzing it:

Oxygen extraction O2 content (arterial) -ratio across _ O2 content (arteriotomy)

myocardium O2 Content (arterial)xlOO

156 CHAPTER 17

Figure 17.3 Intraoperative photograph showing vigorousbackbleeding (black arrow) of dark blood from the site ofarteriotomy with the distal snare not snugged down. Ante,antegrade cannula; R, retrograde cannula; A, site ofarteriotomy. Reprinted from [7], with permission fromSociety of Thoracic Surgeons.

Oxygen content = 1.36 ml O2/g x Hb x O2 saturation +(0.003 x Po2) [9]. This high extraction is suggestive ofthe fact that the myocardium is using up the oxygenbeing delivered via the retrograde route.

In 12 patients endarterectomy of the RCA wasrequired [11]. This is surprisingly easy on the beatingheart, which provides excellent traction-countertrac-tion to get the atheroma out. Distally a completeendarterectomy was possible while proximally theatheroma was cut clean. The arteriotomy was allowedto bleed freely to avoid distal embolization. So far wehave had no patient requiring endarterectomy of theleft system.

Intraoperative complicationsIn one patient with unstable angina while snaringdown on the LAD it was realized that the right ven-tricular (RV) wall adjoining the LAD was edematousand unhealthy. There was excessive bleeding from theRV wall where the retract-O-tape needle had gonethrough. This did not respond to the usual methods oflocal pressure and reversal of heparin and neededpledgetted sutures for control.

In no patient was there any evidence of myocardialedema, excessive distention from coronary veins, or

hemorrhage during and after the period of retrogradeperfusion.

Conversion to cardiopulmonary bypassThis was required in one patient, who had ST changesduring a main RCA-RA grafting. The ST changesrecurred after sternal closure. On reopening it wasseen that the radial artery was in spasm. Althoughthere was a response to topical papaverine/diltiazemand increasing the doses of intravenous diltiazem, itwas decided to supplement the radial artery with a veingraft distal to the radial artery anastomosis site. Thiswas performed on CPB without aortic cross-clamping.On probing the anastomoses it was found that a stitchhad taken both walls of the radial artery graft. This wasalso corrected. The patient did well subsequently.

Discussion

One of the main factors in off-pump CABG that willaffect graft patency and the onset of any major adversecardiac event is precision of the coronary anastomosis.If there is a "race against the clock" while performingthe anastomoses on a beating heart then it can defin-itely jeopardize the accuracy of the suturing.

Our technique is based on the fact that, in coronaryartery disease, parts of the myocardium are underper-fused and this is further exaggerated when the coron-ary artery is snared. Regional myocardial ischemiaoccurs when a coronary artery is snared during con-struction of an anastomosis. An intracoronary shuntmay minimize ischemia during grafting. However,there is the concern that damage to endothelium[12], risk of dissection, dislodgement of an atheroma,risk of an air or particulate embolism, hindrancewith suturing, and at times, difficulty in insertion canoccur. One study showed that intravascular catheterscaused significant endothelial dysfunction in normalporcine coronary arteries of the same magnitudeas the intentional removal of endothelium by endolu-minal rubbing of the intimal surface [12]. Insertionand removal of an intravascular device may causecoronary vasospasm in the acute period after surgerybecause of loss of endothelial coverage. The denudedsite may become a referential site for platelet aggre-gation and activation of the coagulation pathways,which can lead to premature graft failure.

Previous elegant work on pressure controlledintermittent coronary sinus occlusion (PICSO) (which

Image Not Available


redistributes blood to inhomogeneously perfusedischemic zones) and arterial retroperfusion of thecoronary sinus [13,14] (which delivers oxygenatedblood) shows that retrograde perfusion reducesischemia and salvages jeopardized myocardium inpatients with coronary artery disease. Our method is acombination of both these principles. The basic facton which these techniques work is that the coronaryveins are valveless and form a dense network, thevolume of which exceeds the arterial vasculature. Alsoin coronary artery disease this access route remainsspared from the disease process. Probably a superiormethod physiologically may well be a combinationof synchronized retroperfusion (SRP) (in which dur-ing systole balloon occlusion is released and normalvenous drainage occurs—the delivery of retroper-fusate being synchronized to diastole) and PICSO.SRP has been shown to relieve the severity of myocar-dial ischemia in patients with unstable angina [ 15].

Pratt formulated the concept of retroperfusion witharterial blood through coronary veins as early as thelate 1890s [16]. In fact, the Beck II operation (ligationof the coronary sinus orifice and the placement of asaphenous vein graft from the descending aorta to thegreat cardiac vein) was being used as recently as themid-1970s [17]. SRP has shown beneficial effects inpatients undergoing angioplasties [18]. PICSO hasbeen tried during early reperfusion after global cardio-plegic arrest for CABG [ 19].

Svedjeholm et al. [20] reported a case of severeleft main stenosis with thrombus that developedpronounced ST-segment depression and ventriculardilatation in spite of the institution of CPB. Retrogradeperfusion on a beating heart using extension tubingfrom the aorta connected to the retroplegia cannulashowed regression of EGG changes of ischemia andreturn of ventricular contractility. This report demon-strates the efficacy of arterial retroperfusion.

Martin etal. have shown that LV-powered coronarysinus retroperfusion reduces infarct size in acutelyischemic pigs [21]. They used a shunt from the leftventricular apex to the coronary sinus along with par-tial coronary sinus occlusion (PICSO) to deliver oxy-genated blood retrogradely after inducing ischemia bysnaring the two largest diagonal branches of the LAD.There was significant reduction (53% with retrogradeperfusion and 73% when PICSO was added) in thearea of necrosis in the retroperfusion group versus thecontrol areas. Our technique combines retroperfusion

with PICSO (due to the self-inflating balloon of theretroplegia catheter).

Sajja et al. [22] reported a small series where theyused a similar technique of perfusion of the coronarysinus to improve hemodynamics in 15 cases of severeleft main stenosis. They used the driving pressurefrom a 7F femoral artery sheath (instead of the ascend-ing aorta in our technique) and showed an increase inmean arterial pressure, decrease in pulmonary arterydiastolic pressure, and an improvement in left ventric-ular ejection fraction. The principle of their techniqueis the same as ours using the venous system to deliveroxygenated blood beyond areas of coronary arterialstenosis—due to disease (left main stenosis) or iatro-genic (due to snaring of the target artery). Their aimin using this technique was to "buy time" to harvestarterial conduits before the institution of CPB.

It is a fact that manipulation of the heart by what-ever technique causes unfavorable hemodynamicconsequences. When these are coupled with theregional ischemia that is invariably produced when acoronary artery is snared, the combination can bedangerous. A combination of "little" effects (a "little"hemodynamic compromise, a "little" ischemia, a"little" aortic regurgitation due to lifting and tiltingof the heart, a "little" drop in temperature, etc.) cancombine to produce a "major" problem. We stronglybelieve that the ability to successfully and preciselyperform an off-pump CABG lies in attention todetails. Every little extra keeps us on the right side ofthe safety line, giving a safety net in what is essentiallya "new" procedure.

Reversion of EGG changes, as observed with ourtechnique, has also been reported with perfusion-assisted direct coronary artery bypass [23] where apump is used for pressure-controlled blood deliveryfor selective graft perfusion, allowing immediaterestoration of arterial blood to distal coronarybeds after distal coronary anastomosis in OPCABG."Active" perfusion using a pump is logically an excel-lent way of avoiding ischemia—but it is possible onlyafter the distal anastomosis is constructed—whichitself is a period of ischemia. Thus our concern withthis technique is that it does not avoid ischemia duringthe construction of the first graft (which in the seriesreported is not the LIMA to LAD), and the flow to thearea being grafted is dependent on the degree of collat-eralization between the perfused vessel and the vesselbeing grafted. Also, we are not sure that suprasystemic

158 CHAPTER 17

Figure 17.4 Intraoperative photograph showing simplicityof the technique and perfusion of grafts and coronarysinus. A, antegrade cannula; R, retrograde cannula; Ra,radial artery to posterior descending artery being perfusedby a multiport from the ascending aorta; RA, right atrium;RIMA, right internal mammary artery to right coronaryartery graft. Reprinted from [7], with permission fromSociety of Thoracic Surgeons.

perfusion of the grafts, as performed by Guyton et al.

[23], is a good idea because of the inherent risk to the

integrity and function of the endothelium of the vein

or radial artery. We use a similar principle with the use

of aortic pressure to deliver oxygenated blood via each

free graft—by connecting the proximal end of the free

graft to a limb of the multiport from the ascending

aortic antegrade cannula as soon as the distal anasto-

mosis is constructed. Another variation would be to

perform all the proximal anastomoses first so that

perfusion starts as soon as each distal is completed.

With retrograde perfusion we have noted that the

anastomotic time has actually increased, as we have

been able to perform unhurried anastomoses taking

each stitch under vision. The effect of this on graft

patency should logically favorable.

We still have to learn more about the dynamics of

the coronary venous circulation. Possibly a good way

for selective relief of ischemia would be to advance

the coronary sinus catheter upstream as close as pos-

sible in the epicardial veins to the area of ischemia

(snared coronary artery) to selectively oxygenate the

microcirculation in that area. This would require

special catheters and special techniques for optimal

positioning.

The beauty of the technique of coronary sinus

and graft perfusion lies in its efficacy, simplicity (Fig-

ure 17.4), cost effectiveness, and ease of execution and

control [7].

References

1 Bedi HS, Arsiwala S, Sharma V et al. Coronary arterybypass grafting in patients with calcine aortitis. / ThoracicCardiovascular Surg 1991; 102:163-4.

2 Tasdemir O, Vural KM, Karagoz H, Bayazit K. Coronaryartery bypass grafting on the beating heart without theuse of extracorporeal circulation: review of 2052 cases./ Thome Cardiovasc Surg 1998; 116:68-73.

3 Gundry SR, Romano MA, Shattuck OH, Razzouk AJ,Bailey LL. Seven year follow up of coronary arterybypasses performed with and without cardiopulmonarybypass.} Thorac Cardiovasc Surg 1998; 115:1273-8.

4 Reichenspurner H, Boehm DH, Welz A et al. Minimallyinvasive coronary artery bypass grafting: port-accessapproach versus off-pump techniques. Ann Thorac Surg1998; 66:1036-40.

5 Bedi HS, Suri A, Kalkat MS et al. Multivessel globalmyocardial revascularization without cardiopulmonarybypass using innovative new techniques for myocardialstabilization and perfusion. Ann Thorac Surg 2000; 69:156-64.

6 Bedi HS, Kalkat MS. Retrograde perfusion of oxygen-ated blood during off pump revascularization to avoidischemia. Eur J Cardiothorac Surg 2000; 17:193—4.

7 Bedi HS. Selective graft and coronary sinus perfusion inoff-pump CABG: is it necessary? [reply]. Ann ThoracSurg 2001; 71:1070-2.

8 Buckberg BD. Antegrade/retrograde blood cardioplegiato ensure cardioplegia distribution: operative techniquesand objectives. / Card Surg 1989; 4:216-38.

9 Allen BS, Winkelmann JW, Hanafy H. Retrograde car-dioplegia does not adequately perfuse the right ventricle./ Thorac Cardiovasc Surg 1995; 109:1116-26.

10 Eke CC, Gundry SR, Fukushima N, Bailey LL. Is there asafe limit to coronary sinus pressure during retrogradecardioplegia? Am Surg 1997; 63:417-20.

11 Bedi HS, Kalkat MS. Endarterectomy on a beating heart.Ann Thorac Surg 2000; 70:338-40.

12 Chavanon O, Perrault LP, Menasche P, Carrier M,Vanhoutte PM. Endothelial effects of hemostatic devicesfor continuous cardioplegia or minimally invasive opera-tions. Ann Thorac Surg 1999; 68:1118-20.

13 Mohl W, Menasche P, Snyder HE, Roberts AJ. Currentstatus of coronary sinus interventions. In: Karp RB, LaksH, Wechesler AS, eds. Advances in Cardiac Surgery, Vol 2.St Louis: Mosby Year Book, 1990: 31-62.

Image Not Available


14 Gundry SR. Modification of myocardial ischemia in nor-mal and hypertrophied hearts utilizing diastolic retroper-fusion of the coronary sinus. / Thorac Cardiovasc Surg1982; 83:659-69.

15 Gore J, Weiner BH, Benotti JR. Preliminary experiencewith synchronized coronary sinus retroperfusion inhumans. Circulation 1986; 74:381-8.

16 Pratt FH. Nutrition of the heart through vessels of theThebesian and coronary veins. Am J Physiol 1898; 1:86-103.

17 Moll DW, Dziarkowiak A, Edelman M. Arterialization ofthe coronary veins in diffuse coronary arteriosclerosis.] Cardiovasc Surg 1975; 5: 520-5.

18 Hajduczki I, Kar S, Areeda J et al. Reversal ofchronic regional myocardial dysfunction (hibernatingmyocardium) by synchronized diastolic coronary venousretroperfusion during coronary angioplasty. / Am CollCardiol 1990; 15:238-42.

19 Mohl W, Simon P, Neumann F. Clinical evaluation ofpressure-controlled intermittent coronary sinus occlu-sion: randomized trial during coronary artery surgery.Ann Thorac Surg 1988; 46:192-201.

20 Svedjeholm R, Hakanson E, Forsman M. Treatment ofacute myocardial ischemia during early stages of surgeryby an easily applicable method for emergency retroperfu-sion. Eur J Cardiothorac Surg 1999; 15:551-2.

21 Martin JS, Byrne MD, Ghez OY et al. LV powered coro-nary sinus retroperfusion reduces infarct size in acutelyischemic pigs. Ann Thorac Surg 2000; 69:90-5.

22 Sajja LR, Farooqi A, Yarlagadda RB, Mastan SS,Pothineni RB. Retrograde coronary sinus perfusion forsevere left main stenosis. Asian Cardiovasc Thorac Ann2000;8:290-1.

23 Guyton RA, Thourani VH, Puskas JD et al. Perfusionassisted direct coronary artery bypass: selective graft per-fusion in off-pump cases. Ann Thorac Surg 2000; 69:171-5.

CHAPTER 18

On-pump beating heart surgeryfor dilated cardiomyopathyand myocardial protection

Tadashi Isomura, MD & Hisayoshi Suma, MD

Introduction

Myocardial protection for left ventricular (LV) restor-ation in severely dilated cardiomyopathy (DCM) isvery important to prevent myocardial damage duringan operation. It has been considered that cardioplegiadoes not distribute uniformly in the dilated akineticmuscle and that beating heart surgery may minimizemyocardial damage during the operation. This chap-ter compares the operative results with cardioplegicheart arrest to those on beating heart and discussesthe effectiveness of on-pump beating heart surgeryfor DCM.

Patients and methodsFrom December 1996 to July 2001, LV restorationfor DCM was performed in 160 patients. The meanage was 55 years and the preoperative NYHA gradingwas class IV in 78 patients and class III in 84 patients.The etiology was nonischemic DCM in 85 patientsand ischemic DCM in 75 patients. Operations wereperformed electively for 129 patients and emergentlyin 31 patients. Based on the preoperative LV examina-tion and intraoperative echocardiography, LV restora-tion was determined by either partial left ventriculec-tomy (PLV) in 73 patients, endoventricular circularpatch plasty (EVCPP) in 62 patients, or the septalanterior ventricular exclusion (SAVE) operation in 25patients. LV restoration was performed under cardio-plegic arrest in 29 patients and on beating heart in131 patients. The uses of postoperative mechanicalsupport and hospital mortality were compared andstudied.

ResultsIn the nonischemic group, total pump time was 154 minunder cardioplegic arrest, while it was 127 min in theon-pump beating surgery group. Postoperative intra-aortic balloon pump (IABP) was used in 25% of thepatients who received cardioplegic arrest, and in 8.7%of those on beating heart. The hospital mortality inelective operation was 18.2% with cardioplegic arrestsand 7.4% with beating heart. In the ischemic group,total pump time was 149 min under cardioplegicarrest, while it was 137 min in the on-pump beatingsurgery group. Postoperative IABP was used in 15% ofpatients with cardioplegic arrest and in 12% of thoseon beating heart. The hospital mortality in electiveoperation was 11.1% with cardioplegia and 5.5% onbeating heart. The overall survival rate at 4 years was60.2% in the nonischemic group and 74.5% in theischemic group.

ConclusionLV restoration for dilated cardiomyopathy was per-formed with less myocardial damage on the beatingheart than under cardioplegic arrest. Beating heartsurgery improved early and late postoperative results.

History

Since Batista et al. reported partial left ventricul-ectomy (PLV) for DCM in 1996 [1], several reportshave been published with varying mortality andmorbidity. PLV is an effective procedure for DCM insome patients but not in all cases. Operative mortalityin patients with congestive heart failure (CHF) was

160

Beating heart surgery for DCM 161

higher than in other established cardiac procedures.In 2000 Franco-Cereceda et al [2] reported thatmidterm postoperative results with PLV were notsimilar to those after cardiac transplantation. In 1998,Dor et al. [3] reported a new cardiac restoration tech-nique, namely, endoventricular circular patch plasty(EVCPP) for ischemic cardiomyopathy. Conclusionswere made that EVCPP was an alternative procedureto heart transplantation for dilated cardiomyopathy(DCM) after myocardial infarction. We have beenperforming LV restoration for nonischemic andischemic DCM since 1996 [4]. In this article, we com-pare operative results of the procedures performedwith cardioplegic cardiac arrest to that of on-pumpbeating heart surgery and discuss the myocardialprotection strategies during LV restoration surgeryfor DCM.

Patients and methodsFrom December 1996 to July 2001, LV restorationfor DCM was performed in 160 patients. The agesranged from 14 to 80 years, with a mean of 55 years.There were 138 men and 22 women; all patients hadsigns of NYHA class III or IV heart failure (Table 18.1).The etiology was nonischemic in 85 patients andischemic in 75 patients. In the nonischemic group,idiopathic DCM was most common. In ischemic DCMidiopathic cardiomyopathy (ICM), patients with LVaneurysm were excluded. Patients involved were thosewith a left ventricular ejection fraction (LVEF) lessthan 30% and a left ventricular end systolic volumeindex (LVESVI) greater than 100 ml/m2. There wassingle-vessel disease in nine patients and multivesseldisease in 66 patients (Table 18.2). Except in 31 emerg-ent patients, examinations for LV function, includ-ing echocardiography with color kinesis, quantitative

Table 18.1 Clinical characteristics of LV restoration.

N

Age

Years

Range

Female (no.)

NYHA (no.)

Class IV

(Inotrope)

Class III

Nonischemic DCM

85

50+13

14-76

13

49

(37)

36

Ischemic DCM

75

61 ±8

39-80

9

29

(19)

46

gated scintiscan, cine-MRI angiogram, and left ven-triculogram, were performed in all patients before theoperation. Based on the kinesis of the LV wall, operat-ive procedures for LV restoration were selected.

Operative proceduresIn nonischemic DCM, the initial 16 patients receivedcardiac procedures. These included valve surgery andLV restoration under cardiac arrest with 34°C bloodcardioplegia, with a mean aortic cross-clamping timeof 79 + 33 min and a cardiopulmonary bypass (CPB)time of 154 + 57 min. In ischemic DCM, the initial 13patients were operated under cardioplegic arrest witha mean aortic clamping time of 95 + 38 min and a CPBtime of 149 + 65 min. Concluding our initial experi-ence, the cardiac procedures except for mitral valvulo-plasty via right-sided left atrium and multiple CABGwere performed on beating heart and on CPB. Themitral valve replacement was performed via the leftventricle after left ventriculectomy, followed by LVrestoration with the heart beating without aorticcross-clamping.

Table 18.2 Etiology and coronary lesion

in DCM with LV restoration. Etiology in nonischemic DCM*

Idiopathic: 59

Valvular: 9

Dilated HCM: 7

Sarcoidosis: 4

Myocarditis: 2

Others: 4

Coronary lesion in ischemic DC/Wt

Single: 9

Double: 20

Triple: 43

Left main: 3

A/ = 85.

162 CHAPTER 18

Figure 18.1 Diagram showing partial left ventriculectomy (PLV). The LV incision is incised on beating heart from the seconddiagonal branch to the apex of the LV along the LAD. The LV muscle is then palpated to identify the kinetic or akinetic partunder unloaded beating condition and the LV muscle of the posterior lateral wall is excised between two papillary musclesor including one papillary muscle and the LV is closed in two layers with large monofilament sutures. During the beatingheart procedure, air is vented from both the ascending aorta and right side of the upper pulmonary vein in addition to thedeairing from the upper suture line of the left ventriculotomy just before completion of the LV closure.

Beating heart left ventricular surgery: partial leftventriculectomy (Figure 18.1)After the institution of CPB with ascending aorta andbicaval cannulation, mitral valvuloplasty was pre-formed via the left atrium (LA) under cardiac arrest.As the aortic-cross-clamp was removed the heartspontaneously began to beat. An LV incision was madeclose to the second diagonal branch down to the apexof the left ventricle along the left anterior descendingcoronary artery (LAD). The muscle of the left ventriclewas palpated to identify the kinetic or akinetic areasunder unloaded beating conditions. The muscle nearthe posterior lateral wall was excised between the twopapillary muscles. The left ventricle was then closed intwo layers with large monofilament sutures. Duringbeating heart procedures while weaning from CPB, airwas vented from both the ascending aorta and theright side of the upper pulmonary vein. Deairing fromthe upper suture line of the left ventriculotomy justprior to LV closure was also performed.

Endoventricular circular patch plasty(Figure 18.2)After completion of coronary artery bypass grafting(CABG) under cardioplegic arrest, the clamp wasremoved, reperfusion was initiated, and the heartbegan to beat. LV surgery was performed according toDor's techniques. Under beating heart conditionswhile on CPB the left side of the LAD was incised andthe anteroseptal wall palpated to determine placementof the pursestring stitch. After excluding the akineticsite of the anteroseptal wall a 2 x 3 cm oval-shapedHemashield patch was placed to cover the defect. Theincised wall was then closed with running suturesand air was evacuated in the same manner as the PLVprocedures.

Septal anterior ventricular exclusion(Figure 18.3)In case of a preoperative LVESVI greater than150 ml/m2 and akinesis in the septal anterior wall, the


Figure 18.2 Endoventricular circular patch plasty (EVCPP). Under the beating heart, the LV along the LAD is incised and theanteroseptal wall is palpated to decide the site of pursestring stitch. After exclusion of the akinetic site of the anteroseptalwall, an approximately 2 x 3 cm oval-shaped Hemashield patch is placed to cover the defect, and the incised wall is closedwith running sutures. The air is evacuated in a similar way to the PLV procedure.

Figure 18.3 Septal anterior ventricularexclusion (SAVE). In the case of apreoperative LVESVI greater than 150ml/m2 and akinesis in the septal anteriorwall, this technique is used. The incisionis made along to the left side of the LADfrom the apex to the base of the LVbeyond the second diagonal branch.The akinetic septal wall is palpated onbeating heart and it is excluded bymattress stitches with 2-0 Ticrone and alongitudinal oval-shaped Hemashieldpatch is sutured between the septal andanterior wall and then the incised wallis closed with mattress and runningsutures in double layers. The procedureis performed under the beating heartand deairing is similar to the otherprocedures.

164 CHAPTER 18

N

Elective/emergent (no.)

PLV (Batista's op.) (no.)

EVCPP (Dor's op.) (no.)

SAVE op. (no.)

MVR/MVP (no.)

TAP/TVR (no.)

AVR (no.)

Nonischemic DCM*

85

65/20

70

-

15

49/27

50/4

5

Ischemic DC/Wt

75

64/11

3

62

10

11/19

19/0

2

Table 18.3 Operative procedures.

* Previous MVR 5.

t CABG# 3.0 ± 1.2/patient.

PLV, partial left ventriculectomy; EVCPP, endoventricular circular patch plasty;

SAVE, septal anterior ventricular exclusion; MVR, mitral valve replacement;

MVP, mitral valve replacement; TAP, tricuspid annuloplasty; TVR, tricuspid

valve replacement; AVR, aortic valve replacement.

akinetic wall was not resolved with EVCPP, thus wedeveloped large exclusion of the akinetic segment withthe SAVE procedure. An incision was made along theleft side of the LAD from the apex to the base of the leftventricle beyond the diagonal number 2. The septalwall was sutured with a mattress suture with 2-0Ticrone. A longitudinal oval-shaped Hemashield patchwas sutured between the septal and anterior walls.The incised wall was then closed with mattress andrunning sutures in double layers. The procedure wasperformed under beating heart conditions. Deairingmaneuvers were similar to the other procedures previ-ously mentioned.

ResultsThe operation was performed electively in 129 patientsand emergently for 31 patients. LV restoration PLVwas selected in 73 patients, EVCPP in 62 patients,and SAVE operation in 25 patients. Concomitantmitral surgery was performed in 77 patients (91%)for nonischemic DCM, excluding previous mitralvalve replacement (MVR) in five patients, and wasperformed in 30 patients (40%) for ischemic DCM(Table 18.3).

In the nonischemic cardiomyopathy group, proce-dures including LV surgery were performed undercardioplegic arrest in the initial 16 patients and underbeating heart conditions in 69 patients. Among these69 patients, procedures including mitral or tricuspidoperations in addition to LV surgery were performedunder beating heart in 38 of those patients. Thesurgical procedures in those three subgroups are

summarized in Table 18.4. Weaning for CPB waseasiest in the beating heart group. IABP was usedbefore weaning CPB or in the ICU in groups of four,three, or six patients in these three subgroups, respect-ively. Left ventricular assist device (LVAD) was used intwo patients out of 15 patients with emergent surgery(Table 18.4).

In the ischemic cardiomyopathy group, proceduresincluding LV surgery were performed under cardio-plegic heart arrest in the initial 13 patients and underbeating heart conditions in 62 patients. The surgicalprocedures in the two subgroups are summarized inTable 18.5. IABP was used before weaning CPB orin the ICU in two patients in the cardioplegic arrestgroup and in eight patients in the beating heartsurgery group (Table 18.5).

Thirty-day mortality occurred in seven patients andthe total hospital mortality was 28 patients, includ-ing 18 patients who underwent emergent operation.The cause of hospital death was CHF in 15 patients,fetal arrhythmia in three patients, and multiorgan fail-ure in 10 patients. There was no incidence of strokeafter the operation. Follow-up visits showed that outof the 132 patients discharged from hospital therewere 22 late deaths. The cause of death was CHFin 11 patients, sudden arrhythmia in four patients,and other causes in seven patients. Fourteen patientsamong the 22 late deaths (63%) died within 1 yearafter the operation due to cardiac causes. The survivalrate at 4 years was 60.2% in the nonischemic groupand 74.5% in the ischemic group including emergentoperations.


Table 18.4 Operative results in 85 patients with nonischemic DCM.

Number

Cross-clamp time (min)

Total ECCT (min)

IABP (no. (%))

LVAD (no.)


Hospital death (no.)Mortality (no. (%))

Emergent

Elective

Cardioplegic arrest

16

79 ±33

154157

4(25)

—

11/5

6 (37.5% mortality)

4/5 (80)2/11 (18)

LV restoration on beating

mitral plasty under

cardioplegic arrest

31

53 ±24

138±44

3 (9.6)

-

27/4

3 (9.6% mortality)

2/4 (50)1/27 (3.7)

Beating heart

38

-

118±353 (7.9) excluding

preoperative use in 3

2

27/11

9 (23.6% mortality)

6/1 1 (543/27(11)

ECCT, extra corporeal circulation; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device.

Table 18.5 Operative results in 75

patients with ischemic DCM.LV restoration under

cardioplegic arrest

LV restoration

on beating heart

NumberCross-clamp time (min)

Total ECCT (min)

IABP (no. (%))

LVAD


CABG no./patient

Hospital death (no.)

Mortality (no. (%))

62

95 ±38

149 ±65

2(15%)

9/4

3.2±1.24 (30.7% mortality)

Emergent 3/4 (75%)

Elective 1/9 (11%)

63 + 26

137 + 44

8(12%)

55/7

2.9+1.2

6 (9.7% mortality)

3/7(42%)

3/55 (5.4%)

LVAD, left ventricular assist device.

Discussion

LV restoration was used to surgically treat patientswith dilated cardiomyopathy. Procedures were per-formed in several institutions with various operative

morbidities and mortalities [5-11].The major operative mortality was reported to

be prolonged or persistent heart failure, ventriculararrhythmia, or multiorgan failure due to persistentheart failure. In our recent report for LV restoration in74 patients [12], we describe the risk factors for theoperation. Emergent situations and larger ventricularvolume are the risk factors. There was no significancein LV ejection fraction. In our series, after the intro-

duction of on-pump beating heart surgery withoutcardiac arrest the CPB time became shorter. Itappeared that cardiac functional recovery was fasterand the requirements for IABP to wean from CPBdecreased. Beating heart surgery for DCM seemed tobe effective in view of myocardial preservation duringthe procedures. We also found that palpation foridentification of kinetic and akinetic parts of the heartmuscle and selection for the type of surgery for exclu-sion of the akinetic site were important factors. For LVrestoration, we tried to decrease the volume of the leftventricle to less than 100 ml/m2 of the LVESVI byexclusion of the akinetic segment. In our series, thehospital mortality in elective patients was 7.4% in the

166 CHAPTER 18

nonischemic group and 5.4% in the ischemic group.

In the late follow up, the 4-year cumulative survival

rate was 60.2% in the nonischemic DCM and 74.5%

in the ischemic DCM. In several patients the cardiac

function was near complete recovery 1 year post-

surgery. The effectiveness of the LV restoration

seemed to be observed late after surgery, as was seen in

the patients weaned from LVAD. Our early and mid-

term results regarding LV restoration for severely

deteriorated DCM were acceptable. LV restoration

under beating heart surgery conditions was found

to be effective for improving ventricular function,

resulting in favorable early and late surgical results.

References1 Batista RJV, Santos JLV, Takeshita N. Partial left

ventriculectomy to improve left ventricular function inend-stage heart disease. JCard Surg 1996; 1:96-7.

2 Franco-Cereceda A, McCarthy PM, Blackstone EH et al.Partial left ventriculectomy for dilated cardiomyopathy:is this an alternative to transplantation? / ThomeCardiovasc Surg 2001; 121: 879-93.

3 Dor V, Sabatier M, DiDinato M et al. Efficacy of endoven-tricular patch plasty in large postinfarction akinetic scarand severe left ventricular dysfunction: comparison witha series of large dyskinetic scars. / Thorac Cardiovasc Surg1998; 116: 50-9.

4 Suma H, Isomura T, Horii T et al. Nontransplant cardiacsurgery for end-stage cardiomyopathy. / Thorac CardiovascSurg 2000; 119:1233-45.

5 McCarthy PM, Starling RC, Wong J et al. Early resultswith partial left ventriculectomy. / Thorac CardiovascSurg 1997; 114: 755-65.

6 Stolf NAG, Moreira LFP, Bocchi EA etal. Determinants ofmid-term outcome of partial left ventriculectomy in dilatedcardiomyopathy. Ann Thorac Surg 1998; 66:1585-91.

7 Grandinac S, Miric M, Popovic Z et al. Partial left ven-triculectomy for idiopathic dilated cardiomyopathy: earlyresults and six-month follow-up. Ann Thorac Surg 1998;66:1963-8.

8 Batista RJV, Verde J, Nery P et al. Partial left ventri-culectomy to treat end-stage heart disease. Ann ThoracSurg 1997; 64:634-8.

9 Angelini GD, Pryn S, Mehta D et al. Left-ventricular-volume reduction for end-stage heart failure. Lancet1997;350:489.

10 Suma H, Isomura T, Horii T et al. Two-year experience ofthe Batista operation for nonischemic cardiomyopathy.} Cardiol 1998; 32:269-76.

11 Popovic Z, Miric M, Neskovic AN et al. Functional capa-city late after partial ventriculectomy: relation to ventric-ular geometry and performance. Eur J Cardiothorac Surg2001; 19:61-7.

12 Isomura T, Suma H, Horii T et al. Left ventricle restora-tion in patients with nonischemic dilated cardiomyopathy:risk factors and predictors of outcome and change ofmid-term ventricular function. Eur J Cardiothorac Surg2001;19:684-9.

CHAPTER 19

Myocardial protection withbeta-blockers in valvular surgery

Nawwar Al Attar, FRCS, MSC, FETCS, Mar do Scorsin, MD,phD,&Arrigo Lessana, MD, FETCS

Introduction

Advances and new notions in myocardial protec-tion have been developed over the years. Traditionalcardioplegia has been challenged in its concepts, thusevolving from intermittent into continuous, cold intonormothermic, and crystalloid into blood cardioplegia.The goal is avoidance of the deleterious effects ofhypothermia and ischemia-reperfusion injury [1].While the physical properties and delivery systemsof cardioplegia have witnessed significant advances,despite the improvement of the chemical constitutionof cardioplegia solutions with the use of various sub-strates, antioxidants, drugs (e.g. steroids, captopril)[2-4] alone or associated, most infusates continueto induce a hyperkalemic cardiac arrest. However,hyperkalemic solutions have been shown to have adetrimental effect on coronary endothelial cells inaddition to the complications of consequent systemichyperkalemia.

For the above reasons, the search for alternativeagents in warm cardioplegia is ongoing to avoid thecomplications of potassium solutions while provid-ing adequate cardioprotection [5]. Beta-blockade hasbeen shown experimentally to offer cardioprotection[6] conceivably through preconditioning, inhibitionof adenosine triphosphate catabolism, the manage-ment of myocardial edema, reduced endothelial cellinjury, modifying the interaction between activatedleukocytes and the vascular endothelium, and prob-ably other mechanisms [7]. Furthermore, in an ex-perimental study, an ultra-short acting beta-blocker"landiolol" has been shown to have the potential to

enhance the postischemic cardiac function and re-covery after warm cardioplegic arrest [8]. Clinically,beta-blockade limits the release of creatinine kinase-MB after coronary intervention, a sign of less myo-cardial damage [9].

Pathophysiology of valvulardiseases and implications onmyocardial protection

Aortic valve disease

Aortic stenosisThis disease is characterized by a pressure-overloadedventricle that develops concentric left ventricular (LV)hypertrophy and marked thickness of the interven-tricular septum. This leads to an increased vulnerabil-ity from ischemia and reperfusion. There is an increasein the time required for isovolumic relaxation, whichmay contribute to a relative decrease in endocardialcoronary blood flow due to a delay in pressure decay.Coronary artery disease, myocardial bridging, septalperforator compression, coronary vasospasm, andsmall-vessel disease [10] are causes of angina or acutemyocardial infarction with LV hypertrophy. There is adecrease in the endocardial-epicardial flow ratio from1.2 to 0.9 and an increase in oxygen extraction that ishighest in the endocardium [11,12].

Technically, in the presence of significant myo-cardial hypertrophy and fear of inadequate retrogradeperfusion, cannulation of the left coronary ostium tomeasure oxygen saturation from the reflux may helpin guiding the flow rate and pressure of cardioplegia

167

168 CHAPTER 19

so as to keep oxygen saturation in the reflux above35%.

Aortic insufficiencyThis leads to a mixture of pressure and volume over-load. Volume overload is the most important com-ponent and is responsible for the eccentric ventricularhypertrophy. There is early diastolic dysfunction andimpaired LV relaxation. Owing to changes in diastolicperfusion pressure, coronary artery flow may bereduced. Furthermore myocardial oxygen consump-tion (Mvo2) is markedly increased due to the increasedstroke volume and ejection pressure. It has beenshown that diastolic aortic pressures of 40 mmHg orless dramatically reduce coronary artery blood flowand increase myocardial lactate production [13]. Asin aortic stenosis, endocardial and epicardial bloodflow ratios may decrease to as low as 0.76. Theendocardium becomes increasingly ischemic withsubsequent fibrosis and myofibrillar slippage.

Technically, the instauration of antegrade cardio-plegia through the aortic root is not feasible. Thereforeeither primary use of retrograde cardioplegia or directcannulation of the coronary ostia maybe necessary.

Mitral valve disease

Mitral stenosisThere is a diastolic gradient between the left atriumand ventricle. In pure mitral stenosis with LV inflowobstruction, the end-diastolic volume is normal ordecreased, and LV end-diastolic pressure is usuallylow [14-16]. LV peak filling rate is reduced, as isstroke volume, and LV mass is normal or slightlybelow normal [15]. Inflow obstruction is more likelyto be responsible for the decreased cardiac outputthan LV pump failure [17]; however, approximately25-50% of patients with severe mitral stenosis haveLV systolic dysfunction due to associated diseases (e.g.mitral regurgitation, aortic valve disease, ischemicheart disease, etc.) [14,16,18].

Right ventricular function may be disturbed fol-lowing the development of pulmonary hypertension[14,19]. Clinically, increased right ventricular after-load as a result of mitral stenosis is frequently associ-ated with normal right ventricular contractility [ 14].

Atrial-related complications subsequent to high leftatrial pressure include left atrial hypertrophy, atrialfibrillation, and mural thrombi formation [16,20,21 ].

Mitral regurgitationWe are concerned with chronic mitral regurgitationand the adaptive changes that occur over time. Mitralregurgitation increases left atrial pressure and reducesforward systemic flow. LV impedance is reduced,allowing a greater proportion of contractile energy tobe expended in myocardial fiber shortening than intension development [22,23]. Since increased short-ening is less important as a determinant of myocardialoxygen consumption than other components (i.e. ten-sion development and heart rate), mitral regurgitationcauses only small increases in myocardial oxygenconsumption [23,24].

LV mass increases; but unlike the conditions of LVpressure overload, the amount of hypertrophy cor-relates with the amount of ventricular dilatation sothat the ratio of LV mass to end-diastolic volume stayswithin normal range [25-28].

Other valvular pathologiesOther valvular pathologies are uncommon as present-ing lesions and are usually secondary to the above. Fortricuspid valve repair, the open right atrium allows fordirect cannulation of the coronary sinus under visionin retrograde cardioplegia.

Esmolol as an innovative agentin warm blood cardioplegia

To elucidate the performance of beta-blockers as car-dioplegic and cardioprotective agents in warm heartsurgery, we initially conducted a feasibility study thatdemonstrated the safety of the ultra-short-acting beta-blocker "esmolol" in small and large animals [29]. Wethen compared esmolol to potassium in 38 consecut-ive patients with isolated aortic valve stenosis. Thispathology is particularly interesting, as it induces as apart of its natural history considerable concentricmyocardial hypertrophy and thus a myocardium atincreased risk. Technically, replacement of the aorticvalve provides access to the coronary ostia, allowingsampling of the coronary blood reflux and providinganother advantage in choosing this model.

Technical considerations of esmololcardioplegia

PharmacologyEsmolol HC1 (Brevibloc) is a betat-selective (cardio-

Myocardial protection with beta-blockers 169

selective) adrenergic receptor blocking agent with avery short duration of action (elimination half-lifeis approximately 9 min). It is supplied as 2500 mgin 10 ml ampoules. Each milliliter contains 250 mgesmolol HC1 in 25% Propylene Glycol, USP, 25%Alcohol, USP and Water for Injection, USP, bufferedwith 17.0 mg Sodium Acetate, USP, and 0.00715 mlGlacial Acetic Acid, USP. Sodium hydroxide and/orhydrochloric acid are added, as necessary, to adjustthe pH to 3.5-5.5.

Peroperative considerationsAll patients were operated upon through midlinethoracic incision and medial sternotomy. Hepariniza-tion at a dose of 3 mg/kg body weight was administeredbefore cannulation and controlled by activated clot-ting time (ACT) measurements. The ascending aortaand right atrium were cannulated in a conventionalway. For induction of cardioplegia, an aortic needlewas inserted proximal to the aortic perfusion cannula.It also permitted deairing at the end of the procedure.The coronary sinus was cannulated through theright atrium with a self-inflating triple-lumen ballooncannula (DLP, Grand Rapids, Michigan) fixed by asnare of 4-0 prolene to prevent displacement of thecatheter [30] throughout the maintenance phase ofcardioplegia. Left ventricular venting was achieved bya trans-septal needle or a cannula inserted throughthe right superior pulmonary vein.

Study designWe compared the effects of potassium and esmololon myocardial oxygen consumption (Mvo2) andcoronary-released nitric oxide (NO) in 38 patientswith isolated aortic valve stenosis undergoing valvereplacement with retrograde warm blood cardioplegia.The patients were randomly assigned to a continu-ous coronary infusion of either potassium (n = 18)or esmolol (n = 20). Patients on preoperative beta-blocker treatment, severe asthmatics, and those withother contraindications of beta-blocker therapy wereexcluded from the study. Myocardial oxygen con-sumption and coronary lactate release were analyzed bysimultaneous blood samplings from the cardioplegiaperfusion line and left coronary ostium (through a4- or 6-mm angled balloon-tipped coronary cannula,Polystan, Denmark) 10 and 30 min after aortic cross-clamping. Coronary NO release was also quantifiedby simultaneous measurements of NO2/NO3 (Griess

method) in the cardioplegia perfusion line and leftcoronary ostium, 30 min after aortic cross-clamping,and expressed as micromoles per minute. Hemo-dynamic parameters intra- and postoperatively wererecorded by a Swan-Ganz catheter standardized with0.5 Fio2. Pre- and postoperative echocardiographicmeasurements and plasma troponin I (Tnl) levelswere obtained. Statistical analysis was tested by thepaired Student t-test and ANOVA for repeated meas-ures. The results are presented as means plus or minusthe standard deviation (SD).

Cardioplegia protocol

The general setup for retrograde cardioplegia followsthe modified Toronto technique [31].

The protocol for potassium cardioplegia injectionis determined by normograms relating coronary flowand patient's serum potassium concentration. Theconcentration of KCI solutions for induction of car-diac arrest is 25 mmol/L and the maintenance dose is12 mmol/L [32]. A second syringe contains 50 ml of10% magnesium chloride (0.49 mmol/L). The outputis correlated to the injection rate from the cardioplegiapump at a factor of 0.5.

The injection rate is adjusted to blood flow in thecardioplegia line through a Y tubing that allows thesimultaneous injection through two electric syringeinfusion pumps.

Similarly, when employing esmolol cardioplegia,the two electric syringe infusion pumps and Y tubingallow injection of the following cardioplegic solutions:1 Esmolol syringe: the solution of 2.5 g/10 ml is pre-pared by diluting 5 ml in 20 ml of sterile water.2 Magnesium syringe: 10% magnesium chloride(0.49 mmol/L) containing 50 ml of undiluted prod-uct. The perfusion rate is as described above in thepotassium group.

In both groups, cardioplegia is started throughantegrade perfusion by injection in the aortic root.After cardiac arrest, maintenance of cardioplegia iscarried out by retrograde perfusion through the cor-onary sinus.

Induction of cardioplegiaEsmolol is injected at a rate of 2 ml/min equivalent to adose of 100 mg/min.

Magnesium injection is at a rate of 2.5 ml/min giv-ing a dose of 250 mg/min. This perfusion is continued

170 CHAPTER 19

until achieving extreme bradycardia and abolition ofmyocardial contraction. This is often accomplishedwith doses of esmolol between 200 and 500 mg andfollows after 30-50 s in the esmolol group (and 10-15 s in the potassium group). Concomitantly, 150 ml/hof magnesium is injected in the cardioplegia line.

Maintenance of cardioplegiaPerfusion in the retrograde cardioplegia line ofoxygenated blood is at a rate of 250 ml/min in order toachieve a pressure of 30-60 mmHg in the coronarysinus.

In the maintenance phase, the injection rate ofesmolol is reduced to 0.2 ml/min (=10 mg/min) tomaintain an arrested heart or extreme bradycardiaand hypocontractility. Likewise, the rate of magne-sium perfusion is reduced progressively to around100 ml/h (2-1 ml/min). Whenever necessary, cardio-plegia injection was interrupted for short periods.

Results

Although the cardioplegia flow rate and pressure weresimilar in both groups, after aortic cross-clamping,esmolol markedly reduced Mvo2 as compared topotassium, 9.6 ± 1 versus 19 ± 2 ml O2/min (P <0.0001) at 10 min and 10.3 ± 2 versus 22 ± 6 mlO2/min (P< 0.0001) at 30 min, respectively. Coronarylactate production was similar in both groups at10 and 30 min (all inferior to 0.22 mmol/min), indic-ating adequate myocardial perfusion in all patients.Furthermore, esmolol reduced coronary NO release(esmolol, 1.4 ± 0.2 }lmol/min) versus the potassiumgroup (10.7 + 2.4 umol/min, P = 0.04) (Table 19.1).Cardiac index, ejection fraction, and Tnl remainedunchanged postoperatively with either form ofcardioplegia.

Discussion

Potassium remains the principal component ofalmost all cardioplegic solutions. Heart arrest results

from the high extracellular potassium concentrationwhich reduces transmembrane potassium gradientsand membrane resting potential to approximately-50 mV, thus inhibiting the subsequent opening ofsodium channels [33]. Despite the widespread andlongstanding use of potassium, hyperkalemia hasalways been a major drawback. Its consequences maynecessitate the use of insulin, staying for longerperiods on cardiopulmonary bypass or other meas-ures to eliminate the excess potassium and its numer-ous adverse effects [34].

Beta-blockers act by inhibiting the binding ofcatecholamines to adrenergic receptors on the cellmembrane, reducing cellular metabolism and the num-ber of activated calcium channels with consequentbradycardia and hypocontractility [35]. Esmolol has ashort period of action, which facilitates monitoring,and control of its effect on the heart. Very high dosesof esmolol cause severe bradycardia, and temporarypacing of the heart or brief inotropic support cancounteract hypotension and its residual effects duringweaning from cardiopulmonary bypass.

A number of experimental studies have shown amarked increase in catecholamines in ischemic myo-cardial tissue [36] associated with deranged beta-adrenergic mechanisms which correlates with andcontributes to the increased incidence of arrhythmiasand myocardial damage following acute myocardialischemia and reperfusion [37]. This supports the ideathat beta-blockers offer an additional mechanism ofprotection from postcardioplegic contractile dysfunc-tion [38] and in compromised hearts. Intermittentischemic episodes can thus be better tolerated, addingto the comfort of the surgeon during valve replace-ment or repair surgery.

Improved outcome with continuous coronaryperfusion of warm esmolol-enriched blood has beendemonstrated when compared to crystalloid cardio-plegia in coronary artery bypass surgery and moresignificantly in compromised hearts after failed per-cutaneous transluminal coronary angioplasty (PTCA)[39].

Mvo2 (ml O2/min) at 10 min

Mvo2 (ml O2/min) at 30 min

Coronary NO release ̂ mol/min

Esmolol

9.6 ±1

10.3 ±22

1.4 ±0.2

Potassium

19±2

2±6

10.7 ±2.4

P value

<0.0001

<0.0001

0.04

Table 19.1 Myocardial oxygen

consumption (Mi/o2) and coronary nitric

oxide (NO) release in esmolol and

potassium groups.


Continuous cardioplegia perfusion is not withoutits pitfalls [40] and has been criticized for flooding theoperative field and inadequate visualization. Inter-mittent cardioplegia with interruptions of 10-20 minhas been shown to be well tolerated in myocardialrevascularization procedures and is generally con-sidered to be "safe" [41,42]. However, the same can-not be said for its use in valvular or congenital heartsurgery, as these interruptions may prove to be in-adequate. There has been no major study of the safeinterval of interruption of the cardioplegia injection.Additionally, the risk for valve surgery is probablygreater than that for coronary artery bypass grafting.This is due to a number of factors, those related to thevalvular pathology itself with its consequences on theimplementation of adequate myocardial protectionas in aortic insufficiency, and those related to thesecondary changes in the myocardium such as hyper-trophy and/or dilatation. The use of esmolol in warmretrograde cardioplegia seems to offer a superiorlevel of protection, as demonstrated by the significantreduction in myocardial oxygen consumption andprobably other factors. This may consequently extendthe safety limits of interruption of cardioplegia.

Reduction of Mvo2 was historically believed to beachieved by hypothermia. Bernhard [43] andBuckberg[44], who showed that electromechanical arrest of theheart in normothermia reduced oxygen consumptionfrom 80 to 90%, then rectified this. It is interestingto note that despite minimal myocardial contractionin the esmolol group, Mvo2 was lower than in thepotassium group. It is believed that these minor con-tractions may in fact be beneficial by supportingmyocardial fluid balance and preventing myocardialedema formation [45,46]. Nevertheless, the impact interms of patient mortality has not been demonstratedclinically in patients undergoing coronary arterybypass grafting [47].

It has been observed that mammalian myocardiumproduces nitric oxide and that this seems to beregulated mainly by myocardial contractions [48] inaddition to a number of other factors.

Regarding cardiopulmonary bypass and myocardialprotection, little data have been gathered about nitricoxide synthase (cNOS) and its importance. It hasrecently been shown that cardiopulmonary bypassitself increases the production of cNOS, which leadsto an inflammatory reaction and organ injury [49],consequently playing a major role in post-cardiopul-

monary bypass heart dysfunction. However, it is notclear whether this increase is due to cardiopulmonarybypass itself or heart ischemia during cardiac arrest.

In our study, cNOS in the potassium group wasconsistently higher than in the esmolol group, sug-gesting either potassium-induced endothelial injury orimproved myocardial protection with beta-blockers.

Conclusions

Myocardial protection in valvular heart surgery car-ries a supplementary risk due to a number of factors,particularly heart chamber dilatation and hypertrophy.With continuous warm blood cardioplegia, the com-promised myocardium is kept at near normal physio-logical conditions. Ultra-short-acting beta-blockershave shown superior cardioprotective effects in coro-nary bypass grafting and in an aortic stenosis model.Esmolol seems to be an interesting alternative cardio-plegic agent compared to potassium, since it providespotentially superior myocardial protective effects byreducing myocardial oxygen consumption and pre-venting coronary endothelial activation.

Acknowledgments

We would like to thank the staff of the Department ofCardiac Surgery at the Center Cardiologique du Nord.

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2 Salerno TA, Wasan SM, Charrette EJ. Glucose substratein myocardial protection. / Thome Cardiovasc Surg 1980;79: 59-62.

3 Menasche P, Piwnica A. Free radicals and myocardialprotection: a surgical viewpoint. Ann Thorac Surg 1989;47:939-45.

4 Gurevitch J, Pevni D, Frolkis I et al. Captopril in cardio-plegia and reperfusion: protective effects on the ischemicheart. Ann Thorac Surg 1997; 63:627-33.

5 Noera G. When and why CPD in continuous warm bloodcardioplegia?Ann ThoracSurg 1993; 56:1217-18.

6 Katayama O, Ledingham SIM, Amrani M et al.Functional and metabolic effect of adenosine in cardio-plegia and reperfusion: protective effects on the ischemicheart. Ann Thorac Surg 1997; 63:449-55.

7 Wechsler AS, Abd-Elfattah A. Future cardioprotectiveconsiderations./Card Surg 1993; 8:492-502.

8 Yasuda T, Kamiya H, Tanaka Y et al. Ultra-short-acting beta-blockade attenuates postischemic cardiac

172 CHAPTER 19

dysfunction in the isolated rat heart. Eur J CardiothoracSurg 2001; 19:647-52.

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10 Griggs DM, Chen CC, Tchokoev W. Subendocardialanaerobic metabolism in experimental aortic stenosis.AmJPhysiol 1973; 224:607-12.

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25 Ross J Jr. Adaptations of the left ventricle to chronicvolume overload. CircRes 1974; 34/35 (Suppl II:): 64-70.

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28 Yun KL, Rayhill SC, Niczyporuk MA et al. Mitral valvereplacement in dilated canine hearts with chronic mitralregurgitation. Circulation 1991; 84 (Suppl III): 112-24.

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34 Handy JR, Spinale FG, Mukherjee R et al. Hypothermicpotassium cardioplegia impairs myocyte recovery of con-tractility and inotropy. / Thorac Cardiovasc Surg 1994;107:1050-8.

35 Sum CY, Yacobi A, Kartzinel R et al. Kinetics of esmolol,an ultra-short acting beta blocker, and of its majormetabolites. Clin Pharmacol Ther 1983; 34:427-34.

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38 Tevaearai HT, Walton GB, Eckhart AD, Keys JR, KochWJ. Donor heart contractile dysfunction following pro-longed ex vivo preservation can be prevented by gene-mediated beta-adrenergic signaling modulation. Eur }Cardiothorac Surg 2002; 22: 733-7.

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41 Chocron S, Kaili D, Yan Y et al. Intermediate lukewarm(20°C) antegrade intermittent blood cardioplegia com-pared with cold and warm blood cardioplegia. / ThoracCardiovasc Surg 2000; 119:610-16.

42 Yasuda T, Kawasuji M, Sakakibara N etal. Ultrastructuralassessment of the myocardium receiving intermittentantegrade warm blood cardioplegia. Cardiovasc Surg1998; 6:282-7.


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49 Mayers I, Hurst T, Puttagunta L et al. Cardiac surgeryincreases the activity of matrix metalloproteinases andnitric oxide synthase in human hearts. / Thorac CardiovascSurg2001; 122: 746-52.

CHAPTER 20

Myocardial protection in minimallyinvasive valvular surgery

RenePretre, MD &Marko I. Turina, MD

General considerations

Muscular mass and metabolismMost chronic left-sided heart valve diseases producean important increase in the muscular mass of the leftventricle with a relatively small increase in the size andcapacitance of the coronary arteries [1]. The discrep-ancy results in a reduced reserve of the coronary per-fusion and jeopardy of the vulnerable subendocardiallayer [2]. Aortic valve stenosis with the accompanyinghypertrophy of the left ventricle creates circumstancesfor an inadequate perfusion of the thick subendocar-dial layer. In this setting, many clinical studies demon-strated that the method of cardioplegic delivery was arelevant factor of outcome. Retrograde cardioplegiareaches with particular efficiency the subendocardiallayers. The use of retrograde cardioplegia in conjunc-tion with antegrade cardioplegic induction led to animproved recovery of the myocardium after ischemiaand to improved clinical results [3-5]. This combinedmethod of myocardial protection appears as theindispensable way to correctly protect a heart with anincreased muscle mass when a prolonged period ofischemia is anticipated.

Ventricular work is the most important determin-ant of energetic need of the myocardium. The need isreduced by more than 80% with the abolishment ofthe mechanical activity of the myocardium [6,7]. Thefurther reduction of myocardial energetic needs thatcan be obtained by lowering temperature is marginal.Therefore, the main concern of any surgeon workingunder ischemic conditions is the attainment of com-plete electromechanical inactivity of the myocardium.Hypothermia, if it only slightly reduces metabolicneeds, helps maintain electromechanical quietness. In

many situations, it is also helpful to lower myocardialtemperature in order to prolong the duration ofmyocardial stillness.

Cardioplegic deliveryThe majority of cardiac units (especially in teachinghospitals) combine two routes of cardioplegic deliv-ery, and work with differential hypothermia of theheart and body (Table 20.1). Many units start myocar-dial protection with a warm antegrade cardioplegia,especially in risky situations (strained myocardium,reduced ventricular function, associated coronaryartery disease). This warm induction could help car-diomyocytes under stress regenerate their stores ofhigh-energy molecules before ischemia is induced.It could also help to maintain the microcirculationopen for a harmonious subsequent distribution ofcardioplegia within the myocardium. The choice ofthe subsequent temperature of cardioplegia largely

Table 20.1 Most common methods of myocardial

protection.

• Warm or cold induction of cardioplegia, first by

antegrade, then by retrograde delivery

• Maintenance of cardioplegia by continuous retrograde

administration of cold (16-18°C) oxygenated blood in

the coronary sinus at a pressure of 20-25 mmHg

(corresponding to a flow rate of 150-200 ml/min)

• Moderate body hypothermia (28-30°C) to prevent

rewarming of the posterior wall of the left ventricle byadjacent tissue

• Warm cardioplegic reperfusion prior to removal of aortic

cross-clamp

174

Myocardial protection in valvular surgery 175

depends on the surgeon's preference, and the magni-tude or difficulty of the procedure. Many surgeonsprefer normothermic cardioplegia when a straight-forward operation is anticipated [8,9]. Some will alsoselect this cardioplegia when the left ventricle isalready severely damaged [10]. The majority of car-diac surgeons, however, employ a hypothermic car-dioplegia combined with mild systemic hypothermia(Table 20.1). The method is particularly convenientand suitable for long procedures, typically thoseinvolving complicated annular reconstructions orreoperations.

The egress of blood through the coronary ostiaduring retrograde perfusion of the myocardium doesnot disturb most of the steps of an aortic or a mitralvalve repair or replacement. Therefore, a continuousretrograde perfusion of the heart with cold oxygenatedblood results in an effective reduction of the ischemicstress on the myocardium [7]. At the end of the valvu-lar procedure, a dose of normothermic, substrate-enriched cardioplegia is often delivered shortly beforerelease of the aortic cross-clamp. Most procedures onthe tricuspid valve can be performed with a normalperfusion of the aortic root and coronary arteries.Most surgeons perform these operations on a beatingand perfused heart.

ReperfusionThe period during which attention should bedevoted to myocardial protection goes well beyondthe duration of aortic cross-clamping (commonlyconsidered as the period of myocardial ischemia), andextends to the time when the heart starts to resumeactivity and function. Adequate perfusion of the myo-cardium and progressive loading of the heart mayrequire extremely fine tuning for successful wean-ing from cardiopulmonary bypass when ventricularfunction is severely depressed. In the minutes follow-ing removal of the aortic cross-clamp, i.e. duringthe time the heart remains in a plegic state after thehotshot cardioplegia, it is crucial to maintain theleft ventricle adequately decompressed to ensure un-restricted myocardial perfusion. Decompression ofthe left ventricle is best obtained by a vent inserted inthe left ventricle (usually via the right superior pul-monary vein or the roof of the left atrium). Ventingthe main pulmonary artery is another useful yet lesseffective method for decompressing the left side ofthe heart.

Embolism of air bubbles is more frequent inminimally invasive than in conventional surgery. Theimpossibility to puncture the heart apex results in aless efficient de-airing of the left heart cavities. Theappearance of EGG changes during the reperfusiontime (especially ST-segment elevation) should leadto prolonged circulatory support, ideally up to EGGnormalization. Insufflation of CO2 in the operatingfield during the time when the left cardiac cavities areopened results in a swift subsequent dissolution ofair bubbles in the blood. Finally, an active vent inthe ascending aorta should be kept under moderatesuction until air signals have disappeared in trans-esophageal echocardiography. Moderate filling ofthe left ventricle (by increase of venous return) andstimulation with small doses of inotropic agents resultin a controlled expulsion of air bubbles into thevented ascending aorta.

Chest incisionsThe choice of chest incision in minimally invasivesurgery is dictated by the position and orientationof the operated valve (Figure 20.1). Because mobiliza-tion of the heart is restricted, the incision of the chestwall should lie in the direct line of vision of thesurgeon. A partial upper sternotomy (Figure 20.2) or

Figure 20.1 Anatomic position and orientation of the heartvalves in relation to the chest wall.

176 CHAPTER 20

Figure 20.3 Spatial relationship of the mitral valve with chest incisions. The valve lies in the line of the surgeon's eye after a right thoracotomy (left arrow). Traction on the heart is necessary to set it into direct vision after a sternotomy (superior arrow).

an anterior thoracotomy in the second or third intercostal space provides direct visual access to the aortic valve and aortic root. The exact position of the aortic annulus varies from patient to patient. Cohn and coworkers recommend that a chest CT or echocardiography should be carried out to precisely situate the

Figure 20.2 Partial sternotomies. Partial upper sternotomy for the aortic valve (A), J- or inverted C-sternotomy for the mitral valve (B), and partial lower sternotomy for the tricuspid valve (C).

aortic valve in cases of redo surgery (a situation where mobilization of the heart is impossible) [ 111. The partial inverted T-sternotomy is lengthened to the fourth intercostal space when the aortic valve appears deeply seated. The mitral valve after a J- or an inverted C- sternotomy (Figures 20.2 & 20.3) does not come into direct vision unless the heart (mainly the posterior wall) is mobilized. An anterolateral thoracotomy sets the valve into direct vision without further mobilization of the heart and appears appropriate in redo operations (Figure 20.3) (121. The tricuspid valve is frequently operated on in conjunction with mitral valve surgery and is readily accessed with the specific incisions of the mitral valve. A partial inferior sternotomy is also suitable for the rare cases of a procedure confined to the tricuspid valve.

Aortic valve surgery Cardioplegic delivery The use of a partial upper sternotomy (Figures 20.2 & 20.4) or a short anterior thoracotomy does not alter the way antegrade cardioplegia can be delivered but creates more difficult conditions to insert a retrograde cannula into the coronary sinus [ 13-16]. The cannula, which cannot be guided by the hand, should be inserted blindly or semiblindly. Most isolated aortic valve replacement-even when a stentless valve is


Figure 20.4 Operative view of the aorticroot through a partial superiorsternotomy.

used—can be performed in less than three-quarters ofan hour. A heart with a normal or slightly reducedventricular function will recover satisfactorily withintermittent doses of antegrade cardioplegia and doesnot necessarily need further protection via a retro-grade cannula. Some surgeons use continuous ante-grade perfusion of the coronary ostia. A soft, pliablecannula is directly inserted into the coronary ostia,curved at right angles to conform to the inside con-figuration of the aortic root and fixed on the aorticwall with a 4-0 monofilament stitch. The pitfalls of this

technique include obstruction of the narrow operativefield, regurgitation of blood around the cannula, andpossible malperfusion of a large myocardial territorywhen the left main coronary artery is short. Finally,ostial injuries or late stenosis due to intimal hyper-plasia can occur after direct cannulation.

Complex procedures on the aortic valve (aortic rootreplacement, annular enlargement or reconstruction,or redo operation) or a severely damaged ventriclerequire enhanced myocardial protection. In thesesettings, it is also convenient for a surgeon not to beobligated to often interrupt a demanding procedurefor regular delivery of cardioplegia, and to have anoperative field relatively free of instruments. Use ofa retrograde perfusion of the myocardium, usuallycontinuously with cold blood, and mild systemichypothermia create an excellent environment for thesmooth performance of these complex procedures [7].

Insertion of the retrograde cardiocannulaThe use of multiple stay sutures on the pericardiumbrings the ascending aorta and the right atrium into

view. If it appears that the venous cannula will notleave room to subsequently access the right atrium,then the retrograde cannula should be inserted(blindly or under transesophageal echocardiographicguidance) prior to the venous cannula. The return ofsemipulsatile dark blood testifies the correct positionof the retrograde cannula. The use of a vacuum or acentrifugal pump on the venous cannula improvesvenous return and allows insertion of smaller cannu-las. Placement of the retrograde cannula after CPB hasbeen instituted is possible in these situations. Venousreturn should be temporarily reduced to enlarge theright atrium and open the coronary sinus. The tipof the retrograde cannula can be spotted under theatrial wall and guided towards the atrioventriculargroove near the inferior vena cava. Another elegantway to access the coronary ostium is the insertion of aHeartport transjugular coronary sinus catheter prior

to sternotomy. The incremental cost and time entailedwith this cannula and technique of insertion are

definitely offset in reoperations (mainly by the avoid-ance of dissecting the right atrium) and certainlyjustified in many other difficult operations.

Redo operations on the aortic valveReoperative procedures on the aortic valve are parti-cularly suitable for a minimal incision because of thereduction of necessary pericardial dissection [11]. Fullsternotomy and pericardial dissection are associatedwith increased blood loss and increased risk of heart

and graft injury, mediastinal infection, and sternuminstability. The insertion of a retrograde cannula isparticularly helpful to complete antegrade cardiople-gia, especially when previously inserted bypass grafts

178 CHAPTER 20

are patent. Resorting to peripheral cannulation forcardiopulmonary bypass and inserting a Heartporttransjugular retrograde cannula limit subsequent dis-section to the sole ascending aorta (Figure 20.4). Thepresence of a patent internal mammary artery graft,which increases the difficulties in obtaining electro-mechanical stillness, is no contraindication to thetechnique. Systemic cooling to 20-22°C associatedwith cold retrograde perfusion of the heart induceselectromechanical quietness and provides satisfactorymyocardial protection [11]. Short periods of reducedsystemic perfusion may be necessary if retrogradeflow of blood in the left coronary ostium obscuresthe operative field; a situation well tolerated underthese temperatures. The morbidity from increasedCPB time for systemic cooling and rewarming is wellcompensated by the avoidance of a difficult andpotentially hazardous dissection of a patent internalmammary graft. Venting of the left ventricle is moredifficult with limited pericardial dissection. Althoughan access to the left cardiac cavities is possible throughthe roof of the left atrium (between aortic root andright atrium), many surgeons may choose not to ventthe heart in a straightforward reoperation. Once theprosthesis has been implanted and the aortotomyclosed, it is appropriate to perfuse the heart withwarm blood through the retrograde cannula, vent theascending aorta, and wait until mechanical activity hasresumed (sometimes with atrioventricular pacing)before removing the aortic cross-clamp [17]. Theleft ventricle should then be closely scrutinized bytransesophageal echocardiography. Should it get dis-tended with unsatisfactory contractions, the aorticcross-clamp should be reapplied, the ascending aortakept vented, and warm blood delivered through theretrograde cannula until resumption of better func-tion of the heart.

Mitral valve surgery

In the framework of conventional surgical instru-mentation, the mitral valve can be accessed with tworeduced incisions: a partial sternotomy (J- or in-verted C-incision) and an anterior right thoracotomy(Figures 20.2 & 20.3). Both incisions result in a cos-metically superior chest deformation compared tothat after a full sternotomy. The incisions, however,have limitations. The exposure and the handling ofthe mitral valve—especially the anterior annulus and

Figure 20.5 Operative view of the mitral valve through apartial sternotomy, and using a trans-septal approachextended in the roof of the left atrium.

the subvalvular apparatus—are difficult. Therefore,a partial sternotomy is not indicated for all types ofvalvular repair.

Limited sternotomyA J- or inverted C-sternal incision provides an accessto the mitral valve by using a trans-septal approach[13,14]. The trans-septal incision sometimes needs tobe extended in the roof of the left atrium (Figure 20.5)[ 18]. Since the ascending aorta and the coronary sinuslie under direct vision, the placement of cannulasand delivery of antegrade and retrograde cardioplegiaraise no particular problems and can be performedin a conventional way. Many surgeons start with anantegrade cardioplegia to induce electromechanicalquietness and pursue myocardial protection with acontinuous retrograde perfusion of the myocardium,usually with cold blood (Table 20.1).

Right anterior thoracotomyA right anterior thoracotomy is used mainly in redooperations for cosmetic reasons and the avoidance oftight substernal adhesions and patent grafts. Previousimplantation of an aortic stented prosthesis is anotherargument for using this approach [12,19,20]. Theprosthesis renders the anterior annulus of the mitralvalve unbendable. A right thoracotomy sets the mitralvalve in the direct line of vision of the surgeon (Figure20.3), while mobilization of the heart is necessary


with a sternotomy, and may be particularly trouble-some in limited sternal incisions.

Opening the left atria along the interatrial grooveaccesses the valve. The access to the ascending aorta islimited; especially if a cosmetic small thoracotomy hasbeen selected. Peripheral cannulation and percuta-neous insertion of a Heartport retrograde cardioplegiccannula and an endoluminal aortic clamp can providecomplete equipment for CPB and myocardial pro-tection without obstructing the operative field. TheHeartport endoluminal aortic clamp allows selectiveperfusion of the aortic root and, after delivery ofcar-dioplegia, can operate as a left ventricular vent anddeairing aspirator during the reperfusion phase [17].The catheters, however, are not available in mostcardiovascular units. The aorta must then be instru-mented in the usual fashion. With minimal dissection,it can be cross-clamped using a regular clamp insertedthrough the incision or a specially designed clampinserted through a small counterincision in the secondintercostal space [21]. A small cannula in the aorticroot permits antegrade delivery of cardioplegia andsubsequent deairing. Cannulation of the coronarysinus through the right atrium is possible blindly orunder vision after opening of the right atrium. Thelatter approach is preferred when the tricuspid valveneeds concomitant repair.

Redo operations on the mitral valveThe advantage of an approach through an anteriorthoracotomy with reduced dissection must beweighted against the increased difficulty of workingon the subvalvular apparatus. The advantage is cer-tainly decisive in redo operations for a paravalvularleak of a mitral prosthesis or for a mitral valvereplacement when patent coronary grafts lie underthe sternum. The stress on the myocardium can bereduced to a minimum in the case of paravalvular leak.Because the repair can be performed in a very shorttime, it is possible to avoid cross-clamping the aortaand, therefore, myocardial ischemia [12]. The pre-requisite for this simplified approach is the presenceof a competent aortic valve. Peripheral cannula-tion is preferred for cardiopulmonary bypass. Thediaphragmatic surface of the heart is dissected (thispart is usually not tightly adherent) for insertion of afibrillator. The left atrium is opened during inducedventricular fibrillation, the paravalvular leak iden-tified and closed with pledgeted stitches. Although

rarely necessary, one may still need to cross-clamp theaorta for very short periods of time (1 or 2 min) ifdistortion of the aortic annulus during insertion ofthe needle induces aortic regurgitation. At the endof the repair, a vent is inserted through the prosth-esis for correct deairing and blood filling of the leftventricle, and is removed shortly after resumptionof mechanical activity. The aortic root is vented untildisappearance of air signals in transesophagealechocardiography.

Tricuspid valve surgery

Secondary valvular dysfunctionIsolated acquired diseases of the tricuspid valverequiring surgical repair are rare. The most commonsituation leading to repair of the tricuspid valve is adysfunction secondary to chronic mitral valve diseaseand pulmonary hypertension. The ensuing tricuspidvalve regurgitation is due to annular dilatation. Thechoice of chest incision in these cases is dictated bythe mitral pathology and planned repair. Tricuspidvalve repair, which usually merely consists of annularreduction plasty, can be performed with intact coron-ary perfusion, classically during the period of myocar-dial reperfusion. Both vena cava must be cannulatedand isolated. The right atrium is opened and bloodcoming from the coronary sinus is aspirated withcardiotomy sucker.

Primary valvular dysfunctionBacterial endocarditis, Ebstein's anomaly, and prim-ary dilatation of the right atrium are the most com-mon pathologies leading to surgical repair confinedto the tricuspid valve. A limited inferior sternotomy(Figure 20.2) is most appropriate for this approach,although a repair not involving the subvalvularapparatus can also be approached by a right anteriorthoracotomy (an approach considered cosmeticallysuperior in some patients) [15]. Here too peripheralcannulation for CPB may be advantageous, althoughthe ascending aorta and both vena cava can also be dir-ectly cannulated. Lifting up the upper intact sternumgives satisfactory access to the ascending aorta.Temporary cannulation of the right atrial appendageallows complete collapse of the heart and opens theway to both vena cavae.

Simple repair can be performed without aorticcross-clamping. A short period of induced ventricular

180 CHAPTER 20

fibrillation maybe necessary upon opening of the right

atrium to close a patent foramen ovale or another

atrial septum defect. Once an airtight septation of

both atria has been secured, the heart can be allowed

to beat again without risk of sucking air into the left

ventricle. It may be advantageous to have a com-

pletely bloodless field and a motionless heart when

complex repair on the subvalvular apparatus is neces-

sary (transposition of papillary muscles in Ebstein

anomaly's or valvular replacement with a homograft).

By lifting the upper sternum with an army navy re-

tractor, the aorta can be cross-clamped and antegrade

cardioplegia delivered in the usual way [22]. Access to

the coronary sinus is straightforward after opening of

the right atrium. The left ventricle can be vented via

the right superior pulmonary vein or across the atrial

septum. Myocardial protection is then performed in a

standard way.

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CHAPTER 21

Intermittent warm bloodcardioplegia in aortic valvesurgery: an update

M. Saadah Suleiman, PHD, Raimondo Ascione, MD,& Gianni D. Angelini, MD, FRCS

Introduction

Major advances have been made in the preservation ofmyocardial function during open-heart surgery sincethe introduction of cardioplegic arrest [ 1 ]. However,despite variation in the composition of cardioplegia,myocardial protection has been based primarily onhyperkalemic solutions [2]. This decreases electro-mechanical activity and therefore significantly reducesoxygen demand [3]. Hypothermia has also been usedas it can further reduce oxygen demand by decreas-ing basal metabolic rate. However, hypothermia mayhave adverse effects like inhibiting the Na pump [4] tocause edema and shifting of the oxygen-hemoglobindissociation curve leftward [5]. It is not surprisingtherefore that the optimal temperature of cardioplegiaremains controversial [3]. Continuous warm bloodcardioplegia has been widely advocated as a morephysiological approach, but perfusion is often inter-rupted to allow adequate visualization of the operat-ive site [3]. Therefore, intermittent delivery has beenproposed as an equally effective and more practicaltechnique [6].

Myocardial protection techniques have been lar-gely investigated in the clinical setting of coronaryrevascularization; little work has been carried out onmyocardial protection in patients with left ventricularhypertrophy where the choice of optimal cardioplegiaremains controversial [6-10].

Here we provide evidence that intermittent warm

is superior to intermittent cold blood cardioplegia incoronary artery bypass graft surgery but not duringaortic valve surgery. The reason for this may lie inmetabolic differences between the two pathologies.These observations add weight to the suggestion thatresults obtained with cardioplegic techniques in patientsundergoing coronary surgery cannot be uncriticallyextended to patients requiring valve surgery.

Cardiac hypertrophy

Anatomic studies have demonstrated that the upperlimit of a normal heart is 450 g in men and 400 gin women [11]. These values have to be corrected forepicardial fat, body mass, and age. The left ventricularmyocardial weight to body height ratio should norm-ally not exceed 36 g/m [2] in both genders [ 12]. Basedon these values the agreed cut-off limit to separatenormal from hypertrophied hearts by echocardio-graphyis50g/m[2,12].

Generally, cardiac hypertrophy occurs in responseto an overload. Myocyte lengthening with the addi-tion of new sarcomeres in series is the prevailingmechanism following volume overloads, i.e. eccentrichypertrophy, in which ventricular chamber dilata-tion is accompanied by a proportional increase inwall thickness. Lateral expansion of myocytes with theaddition of new sarcomeres in parallel representsthe typical pattern of myocyte growth after pressureoverload, i.e. concentric hypertrophy [11].

181

182 CHAPTER 21

Myocardial metabolic state in cardiachypertrophyHeart muscle can adapt to environmental changesby altering the synthesis and degradation rates ofspecific proteins or, in the short term, by changingflux through metabolic pathways to maintain its stateof equilibrium [13]. When the heart is subjected to achronic overload, it enlarges and major restructuringof organelles and cellular function occurs. Howeverlittle is known about alterations in the energy status ofthe hypertrophied myocyte [ 14].

Aortic insufficiency is associated with periods ofadaptation that include changes in function, meta-bolism, and structure of the left ventricle culminatingin heart failure [15]. Left ventricular hypertrophy isconsidered to be an independent risk factor givingrise to ischemia, arrhythmia, and left ventricular dys-function [16]. Heart failure caused by aortic stenosis,aortic insufficiency, or both, is characterized by adecline in the phosphocreatine/ATP ratio [17]. How-ever most studies suggest normal ATP and total adeninenucleotides in human heart failure [18]. This is con-sistent with most animal experimental models whichalso show that aerobic myocardial glycogen metabol-ism in hypertrophied heart is similar to normal heart[19,20]. Other studies suggest that overload hyper-trophy (volume or pressure) may induce changes inthe metabolism of the myocardium which may in turnlead to persistent modifications in mitochondrialfunction [21].

Susceptibility of hypertrophied heartsto ischemia-reperfusion injuryBecause of the controversy regarding the metabolic stateof the hypertrophied myocardium, it is not surprisingthat the assessment of its susceptibility to ischemicinsults is far from being completed. In severely hyper-trophied myocardium, capillary density is reduced; thediffusion distance for oxygen and nutrients is increasedand the ratio of energy production to energy con-sumption sites is decreased [ 16]. This is likely to makethe heart more vulnerable to ischemic insults. Workon animal models has provided conflicting reports asto the effect of ischemia on hypertrophied heart. Forexample our work on pressure overload hypertrophichearts isolated from spontaneously hypertensive rat(SHR) demonstrates that these are more susceptible to40 min of global ischemia and 60 min reperfusion com-pared to control hearts isolated from normotensive

Figure 21.1 The susceptibility of hypertrophic hearts toischemia-reperfusion injury. Rate pressure product ofhypertrophic and normal Langendorff rat hearts followingexposure to 40 min normothermic global ischemia and 60min reperfusion. Pressure overload hypertrophic heartswere isolated from spontaneously hypertensive (SHR) ratscompared to control hearts isolated from normotensiveWistar Kyoto (WKY) rats. * P< 0.05 versus correspondingpreischemic value. ** P< 0.05 versus WKY preischemicvalue. Open bars, WKY; closed bars, SHR.

Wistar Kyoto (WKY) rats (Figure 21.1). In agreementwith our work, most reports have shown that myo-cardial hypertrophy has increased susceptibility toischemia with accelerated loss of high-energy nucleo-tides, greater accumulation of lactate, and earlier onsetof contracture [20,22-25]. However reports continueto appear suggesting that hypertrophied heart may bemore resistant to ischemia with no significant changein nucleotide metabolism [26].

Myocardial protection during aorticvalve surgeryIsolated stenosis of the aortic valve leads to left ven-tricular hypertrophy which makes myocardial pro-tection difficult during cardiac surgery and the choiceof optimal cardioplegia remains controversial [21]. Beland associates [8], in a study on patients with heavilyhypertrophied hearts, suggested that retrograde warmcardioplegia could effectively maintain myocardialaerobic patterns in patients operated on for aorticvalve stenosis complicated with left ventricular hyper-trophy, provided that oxygen supply was optimized byuninterrupted perfusion, high flow rates (200 ml/min),and high hemoglobin content (which was made pos-

Cardioplegia in aortic valve surgery 183

sible by a low dilution cardioplegia delivery technique).In a randomized study Jin and coworkers [10] assessedthe efficacy of antegrade crystalloid cardioplegia(21 patients), antegrade/retrograde cold blood car-dioplegia (23 patients), and continuous retrogradewarm (37°C) blood cardioplegia (20 patients) onhypertrophic hearts. Perioperative left ventricular (LV)function was assessed using transesophageal M-modeechocardiography, combined with high-fidelity LVpressure recording and thermodilution cardiac out-put, before bypass and 0.5, 1, 3, 6, 12, and 20 h aftercross-clamp removal. They concluded that in thehypertrophied left ventricle, antegrade/retrogradecold blood cardioplegia offers the best preservation ofmyocardial physiologic response and ventricular func-tion with less inotropic support. On the other hand,Calafiore and associates [6] in a retrospective studyon 271 patients with hypertrophic hearts undergoingaortic valve surgery (operated on with intermittentantegrade warm (171 patients) or cold (100 patients)blood cardioplegia) demonstrated that warm cardio-plegia provides lower cardiac-related mortality andmorbidity in comparison with cold blood cardio-plegia. Others have shown no difference in protectionbetween continuous normothermic and intermittenthypothermic cardioplegia [7].

During the last few years our group has had a par-ticular interest in myocardial protection in patientsundergoing coronary artery bypass surgery [27-31].Recently, we have been able to demonstrate thatthe protective effect of cardioplegic techniques usedin patients with ischemic disease are not necessarilyapplicable to patients with aortic valve disease.

Cardioprotection with intermittentwarm or cold blood cardioplegia

Warm is superior to cold in coronaryartery bypass surgeryThe efficacy of intermittent antegrade warm versuscold blood cardioplegia (both with added Mg2+) wasinvestigated in patients undergoing coronary arterysurgery [32,33]. Ischemic stress was assessed by monitor-ing changes in cellular metabolites whereas reperfusioninjury was determined by measuring the postoperat-ive release of myocardial troponin I [32].

Metabolic changes were monitored during ischemiaand after reperfusion in LV biopsies. Full wall thick-

ness transmural biopsies of the left ventricular apicalor anterolateral free wall (4-12 mg wet weight) weretaken using a Trucut needle. The first biopsy was taken5 min after institution of cardiopulmonary bypass(control), the second after 20 min of reperfusion fol-lowing removal of the aortic cross-clamp. In additionto the two biopsies, a third biopsy (ischemic) wasalso collected, 30 min after cross-clamping the aorta.Each specimen was immediately frozen in liquidnitrogen until processing analysis of cellular meta-bolites. Figure 21.2 shows that intermittent antegrade

c changes i n ischemically diseasedhearts during ischemia and upon reperfusion. Myocardialchanges in ATP (a) and lactate (b) in biopsies collected 30min after cross-clamping the aorta (ischemia) and 20 minafter reperfusion in hearts of patients undergoing coronaryartery bypass surgery using intermittent cold or warmblood cardioplegia. Data are shown as mean ±SE. P<0.05ischemia versus control biopsy. Control (open); 30 min afterischemia (hatched); 20 min after reperfusion (solid).Reproduced with permission from Suleiman etal.AmJPhys/o/41: H1063-H1069,1997.

Image Not Available

184 CHAPTER 21

Figure 21.3 Reperfusion injury. Myocardial troponin I totalrelease following coronary (a) or aortic valve surgery (b)using intermittent cold or warm blood cardioplegia. Dataare presented as mean + SE and expressed as ng/ml.* P< 0.05 versus cold blood group.

warm blood cardioplegia is associated with bettermetabolic preservation during ischemia compared tocold blood cardioplegia.

Reperfusion injury was determined by monitor-ing the concentration of myocardial troponin I (asensitive marker of myocardial damage) [32] in bloodsamples collected prior to surgery, and 1,4,12,24, and48 h postoperatively. Consistent with improved meta-bolic preservation using warm blood cardioplegia(Figure 21.2), these patients had also less reperfusiondamage as shown by a reduced postoperative releaseof troponin I (Figure 21.3a).

Cold is superior to warm in aorticvalve surgeryRather than uncritically apply the findings presentedabove, we decided to compare the two techniquesof myocardial protection in the setting of aortic valvesurgery. A significant accumulation of lactate during

Figure 21.4 Metabolic changes in hypertrophic heartsduring ischemia and upon reperfusion. Myocardialchanges in ATP (a) and lactate (b) in biopsies collected30 min after cross-clamping the aorta (ischemia) and20 min after reperfusion in hearts of patients undergoingaortic valve surgery using intermittent cold or warm bloodcardioplegia. Data are shown as mean ± SE (see patients'characteristics in Table 21.1). * P < 0.05 versus controlbiopsy in the same group. ** P< 0.05 versus reperfusionbiopsy in cold blood group. Control (open); 30 min afterischemia (hatched); 20 min after reperfusion (solid).

ischemia was only evident in the warm blood group(Figure 21.4), consistent with significant anerobicmetabolism. However, the warm ischemic electro-mechanical arrest did not significantly influenceATP concentration, although a trend was evident(Figure 21.4). It is likely that the period of ischemia(biopsies were collected after 30 min cross-clamping)interrupted by one reperfusion episode may notbe sufficient to offset the balance between ATPsupply (glycolysis) and demand (basal metabolism).However, as time progresses there will be an increase


Table 21.1 Preoperative data.

Variable

N

Male/female

Age (yr)

Body surface area (m2)

History of hypertension

History of hypercholesterolemia

History of smoking

Ejection fraction

Good (>49%)

Fair (30-49%)

Ventricular mass index (g/m2)

Transvalvular peak gradient (mmHg)

NYHA class

I

II

III

IV

Parsonnet score

CoW blood

16

7/9

64.5 ±11. 9

1.8410.25

10

6

11

14

2

186134

84.5123.8

8

5

2

1

13.4119.15

Warm blood

19

10/9

67.217.6

1.85 + 0.17

12

8

11

15

4

178129

83.6122.2

10

5

3

1

12.3516.75

Data are presented as mean ± standard deviation or number.

Myocardial protection was achieved by using antegrade cold (6-8°C) or warm blood (34°C) cardioplegia, both with added

K+and Mg2+to give a final concentration of approximately 20 mmol K+and 5 mmol Mg2+. The cold blood cardioplegia

solution was a mixture of the patient's blood and St Thomas' I cardioplegia solution (4 blood : 1 St Thomas' I). The warm

blood cardioplegia was the patient's blood with added K+and Mg2+. Following cross-clamping and opening of the

ascending aorta, the cardioplegia solution was administered directly into the coronary ostia as a 1-litre bolus (700 ml in

the left followed by 300 ml in the right) at a pressure of 150 mmHg. Infusions of 200 ml for each ostium were repeated

at 15-min intervals.

Exclusion criteria included: coronary artery disease, concomitant aortic regurgitation, left ventricular ejection fraction of

less than 30%, history of congestive heart failure, diabetes mellitus, and reoperation. Eligibility for surgery was based on

the medical history, echocardiography, and the most recent angiogram. The end points of the study were myocardial

metabolic changes and myocardial injury.

in energy demand particularly as myocardial wall ten-

sion begins to increase and as energy supply decreases,as acidosis associated with lactate accumulation slowsdown glycolysis [34]. The reduced myocardial meta-bolic stress observed with the cold blood cardioplegiamight be, in part, due to the effects of hypothermiaitself, which might have reduced the oxygen demandof the hypertrophic heart. It has been shown that whilethe oxygen consumption of a normal normothermic,nonworking vented heart (6-8 ml O2/100 g/min) isreduced to 0.6-1.5 ml O2/100 g/min by potassiumcardioplegia, cardioplegia itself at normothermia isnot effective in reducing the basal energy requirement

the myocyte, as it has been shown that the potassium-arrested heart has a myocardial consumption of0.31 ml O2/100 g/min at 22°C and of 0.135 ml O2/

100g/minatlO-12°C[35].The increased metabolic stress in the warm blood

group was also associated with a significantly greaterreperfusion injury (release of troponin I) compared tothe cold blood group (Figure 21.3b).

The results of this study suggest that the myocardialprotection of hypertrophic hearts with intermittentantegrade warm blood cardioplegia is not as effectiveas in hearts with ischemic disease [32]. This mightbe explained by the fact that the two pathologies have

of the myocyte [35,36]. However, hypothermia may different metabolic demands [37]. For example as the

contribute to decrease this basal energy requirement of underlying disease is aortic stenosis, the hypertrophy

186 CHAPTER 21

of the left ventricle leads to increases in both leftventricular end-diastolic volume and left ventricularend-diastolic pressure [38], which increase myocardialwork and oxygen demand. In this situation, two of theprimary determinants of myocardial oxygen demand(tension developed by the myocardium and durationof systole) are increased. At the same time, myocardialoxygen supply is impeded owing to an elevated end-diastolic pressure, causing a decrease in coronary per-fusion pressure. Finally, the Venturi effect of the jet ofblood flowing through the aortic valve and past thecoronary arteries may reduce pressure in the coronaryostia enough to reverse systolic coronary blood flow.These factors make the heart more susceptible toischemia, even in the absence of concurrent athero-sclerotic coronary disease [38].

Although the results of this study show thatthe myocardial protection of hypertrophic hearts issuperior when using cold blood cardioplegia, they alsodemonstrate a significant degree of myocardial injuryassociated with this method of cardioplegia. Potentialimprovements of this technique in patients with LVhypertrophy might be achieved by a final dose of warmblood cardioplegia "hot shot" prior to removal of theaortic cross-clamp, or by continuous delivery, whichhas been demonstrated to be beneficial in ischemichearts [39-41].

Metabolic differences betweenhypertrophic and ischemicallydiseased heartsHypertrophic hearts, unlike hearts with coronary dis-ease, have a high myocardial concentration of ATPand lower concentration of lactate (Figure 21.5). Thisis consistent with known consequences of ischemia.In addition to lactate and ATP, there are significantdifferences in the concentrations of alanine and thebranched chain amino acids leucine and valine [37].Measurements of metabolites in hypertrophic heartssuggest that these hearts would be relatively moreresistant to ischemia when compared to hearts withcoronary disease. Our work using intermittent ante-grade warm blood cardioplegia suggests that hyper-trophic hearts are in fact more susceptible to ischemiaand reperfusion injury compared to ischemically dis-eased hearts (Figures 21.2-21.4). It is plausible toassume that ischemically diseased hearts are precondi-tioned and therefore more resistant to ischemia andreperfusion damage compared to hypertrophic hearts.

Figure 21.5 ATP and lactate in hypertrophic andischemically diseased hearts. A scattergram for themyocardial concentration (nmol/mg protein) of ATPand lactate for hypertrophic and ischemic hearts beforeopen heart surgery. For each patient individual values(open squares) in each pathology are shown as well as themean ± SEM. Reproduced from J Mol Cell Cardiol 30(11):2519-2523, Suleiman eta/. 1998, by permission of thepublisher Academic Press London.

However it is worth noting that the ischemic time(cross-clamp time) was relatively longer for valve sur-gery (approx. 45 min) compared to coronary surgery(approx. 35 min). Therefore a firm conclusion cannotbe made from these studies. The use of hypothermiaas an adjunct to cardioplegia conferred better protec-tion on hypertrophic hearts compared to ischemicallydiseased hearts (Figures 21.2-21.4). Hypothermia isknown to neutralize ischemic preconditioning duringcoronary artery bypass surgery [40].

Conclusions

Evidence of metabolic derangement and reperfusioninjury, indicating suboptimal myocardial protection,is seen in patients undergoing aortic valve surgery usingeither cold or warm blood cardioplegia. However,

Image Not Available


cold blood cardioplegia is associated with a relat-

ively reduced metabolic derangement and myocardial

reperfusion injury.

Potential improvements of this technique in patients

with LV hypertrophy might be achieved by a final

dose of warm blood cardioplegia "hot shot" prior to

removal of the aortic cross-clamp. Continuous delivery

of warm blood cardioplegia solutions, demonstrated

to be beneficial in ischemic hearts [39-41 ], might also

improve myocardial protection of the hypertrophic

heart and prevent the deleterious effects associated

with the intermittent delivery [36,42].

Acknowledgments

This work was supported by the British Heart Founda-

tion and the Garfield Weston Trust. We would like

to acknowledge the help and support of staff in the

Department of Cardiac Surgery and the Myocardial

Protection Group.

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17 Conway MA, Allis J, Ouwerker R et al. Lowphosphocreatine/ATP ratio detected in vivo in the failinghypertrophied human myocardium using 31P magneticresonance spectroscopy. Lancet 1991; 338:973-6.

18 Regitz V, Fleck E. Adenine nucleotide metabolism andcontractile dysfunction in heart failure—biochemicalaspects, animal experiments and human studies. BasicRes Cardiol 1992; 87:321-9.

19 Allard MF, Henning SL, Wambolt RB et al. Glycogenmetabolism in the aerobic hypertrophied rat heart.Circulation 1997; 96:676-82.

20 Do E, Baudet S, Verdys M et al. Energy metabolism innormal and hypertrophied right ventricle of the ferretheart. /Mo/ Cell Cardiol 1997; 29:1903-13.

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23 Schonekess BO, Allard MF, Lopaschuk GD. Recovery ofglycolysis and oxidative metabolism during postischemicreperfusion of hypertrophied rat heart. AmJPhysiol 1996;40: H798-805.

24 Takeuchi K, Buenaventura P, Caodanh H et al. Improvedprotection of the hypertrophied left-ventricle by histidine-containing cardioplegia. Circulation 1995; 92:395-9.

25 Zhang YD, Xu SC. Increased vulnerability of hypertrophiedmyocardium to ischemia and reperfusion injury: relationto cardiac renin-angiotensin system. Chin Med J 1995;108:28-32.

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27 Caputo M, Dihmis W, Birdi I et al. Cardiac troponin Tand troponin I release during coronary artery surgery

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using cold crystalloid and blood cardioplegia. Eur JCardiothorac Surg 1997; 12:254-60.

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32 Caputo M, Bryan AJ, Calafiore AM et al. Intermittentantegrade hyperkalemic warm blood cardioplegia sup-plemented with magnesium prevents myocardial sub-strate derangements in patients undergoing coronaryartery bypass surgery. Eur J Cardiothorac Surg 1998; 14:596-601.

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34 Halestrap AP, Wang X, Poole RC et al. Lactate transportin heart in relation to myocardial ischemia. Am J Cardiol1997;80:17-25.

35 Buckberg GD, Brazier JR, Nelson RL et al. Studies ofthe effects of hypothermia on regional myocardial bloodflow and metabolism during cardiopulmonary bypass.] Thorac Cardiovasc Surg 1997; 73:87-94.

36 Landymore RW, Marble AE, MacAulay MA et al.Myocardial oxygen consumption and lactate produc-tion during antegrade warm blood cardioplegia. Eur JCardiothorac Surg 1992; 6:372-6.

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CHAPTER 22

Myocardial protection insurgery of the aortic root

Stephen Westaby, PHD, MS, FETCS

Introduction

A wide variety of pathologic problems present foraortic root surgery [ 1 ]. These range from congenitalaortic stenosis with severe left ventricular hypertro-phy to annulo aortic ectasia with aortic regurgitationand advanced left ventricular dysfunction. These con-ditions may be complicated by coronary anomalies(Figure 22.1) or diffuse coronary artery disease. Inthose with primary aortic pathology, aneurysmaldilatation may extend into or around the aortic arch.

Aortic root surgery has changed considerably overthe past 20 years. Coronary button mobilization andreimplantation has replaced the classic Bentall pro-cedure and the Cabrol operation is virtually obsolete.Valve conservation techniques now account for asignificant proportion of root operations [2]. In turn,

30-40% of patients will need concomitant coronarybypass surgery or aortic arch replacement which maygreatly extend myocardial ischemic time. By contrast,improvements in vascular graft technology and theuse of antifibrinolytic agents have reduced the risk ofabnormal bleeding and shortened the duration of car-diopulmonary bypass (CPB) and operating time [3].

In the 1980s, multivariant analysis showed pro-longed myocardial ischemic time to be a risk factor forhospital death after aortic root replacement [4,5].With improvements in myocardial protection, this isno longer the case. Problematic right ventricular dys-function was often blamed on inadequate myocardialprotection but usually followed coronary air embol-ism or tension and kinking of a reimplanted rightcoronary ostium (Figure 22.2). Again, improvementsin surgical technique have lessened the risk of this

Figure 22.1 Patient undergoing aorticroot replacement whose right coronaryartery originates posteriorly above theleft coronary sinus. Cardioplegia deliverydirectly into the anomalous coronaryostium is shown.

189

190 CHAPTER 22

Figure 22.2 Traction on the right coronary button(a, arrowed) is avoided by performing the distal graftanastomosis before right coronary implantation (b).

complication. In experienced hands, hospital mortal-ity for primary elective aortic root replacement orrepair is now less than for coronary bypass surgery[ 1 ]. The Ross procedure and complex root repair taketime and need not be hurried with the use of modernmyocardial protective methods.

The surgical plan

Operations on the aortic root require a clear surgicalstrategy based on comprehensive preoperative investi-gations. The importance of this plan increases with theneed for additional procedures, including myocardialrevascularization, mitral valve surgery, or extendedaortic resection with hypothermic circulatory arrest.The method of cardioplegia delivery will be deter-

mined by the presence of aortic regurgitation, coron-ary artery disease, or coronary anomalies. In patientswith renal failure, the volume of cardioplegia solu-tion may assume importance and for anuric patientsperioperative hemofiltration is necessary.

Preoperative assessment requires detailed imagingof root and arch anatomy (by CT or nuclear mag-netic resonance imaging) and definition of coronaryanatomy by angiography. Left ventricular functionincluding the degree of left ventricular hypertrophyor dilatation is assessed by two-dimensional echocar-diography. Those with a carotid bruit, a past historyof stroke, or peripheral vascular disease may warrantangiography or Doppler ultrasound imaging of thecarotid arteries. When the full requirement for sur-gical correction is defined, the surgical plan can bedefined in detail. The author's preference is to con-nect coronary bypass grafts first then repair or replacethe aortic root. If arch replacement is necessary, cool-ing to between 16°C and 18°C is undertaken duringthe root repair. The arch is then replaced and anyadditional hemostasis achieved during rewarming.This is the sequence of events in root replacementfor acute type A dissection [6]. Others may prefer toperform arch replacement first then clamp and can-nulate the graft and repair the root during rewarming[7]. This approach may reduce the risk of atheroem-bolism from aortic cross-clamping or pressurizingthe false lumen in type A dissection repair. Irrespect-ive of the strategy chosen, it is important that a clearsequence of events is defined and that the myocardialprotective measures are carefully integrated in theplan. These include systemic and myocardial coolingbefore cross-clamp application, the method of car-dioplegic delivery, and the use of topical myocardialcooling.

The author's technique

For aortic root operations that do not requirehypothermic circulatory arrest, we employ systemiccooling to 28°C, topical cooling with iced saline (4°C),and antegrade cold crystalloid cardioplegia (1000 mlSt Thomas' Solution). A second dose of 200 ml isapplied to each coronary artery prior to implantationof the coronary buttons into the graft.

The degree of aortic regurgitation is determinedpreoperatively. At the onset of CPB an aortic cross-clamp is applied just proximal to the anominate artery

Myocardial protection in aortic root surgery 191

and a vent inserted into the left ventricle. For pati-ents with a competent aortic valve (usually congenitalor complex aortic stenosis), cardioplegia is delivered

directly into the aortic root. In the majority ofpatients, the aorta is transected between one and twocentimeters above the sinotubular junction and car-dioplegia delivered directly into the coronary ostiawith a hand-held cannula. Usually 600 ml is deliveredinto the left main coronary and 400 ml into theright coronary arteries. Cold saline, but not ice, isapplied to the pericardium. Ice may cause temporaryphrenic nerve paralysis. The coronary buttons arethen mobilized from the aortic wall and the nativevalve replaced or repaired. Approximately 30 mininto the procedure a second dose of between 200 and300 ml cardioplegia is delivered into each coronarybefore reimplantation into the Dacron conduit. Therepair is usually complete in less than 60 min ischemictime, after which reperfusion and deairing are under-taken with a perfusion pressure between 40 and50 mmHg.

We consider the sequence of coronary button reim-plantation to be important. The left coronary buttonis implanted first, followed by the distal anastomosisbetween the Dacron graft and native aorta. Only thenis the site of right coronary button reimplantationdetermined. If the right coronary button is reim-planted before the distal anastomosis the change inalignment of the graft may cause tension and kinkingof the right coronary (Figure 22.2). We believe this tobe an important cause of right ventricular dysfunctionin aortic root surgery. The second cause is rightcoronary air embolism irrespective of the deairingprotocol. Intracoronary air is usually displaced by anincrease in systemic perfusion pressure.

For those who require additional procedures orthe Ross operation, ischemic time is between 60 and120 min. For coronary bypass patients, additionaldoses of cold cardioplegia solution can be deliveredthrough the bypass conduits. During arch replace-ment with deep hypothermic circulatory arrest, thelow systemic temperature (16°C) is protective andprevents myocardial rewarming.

This relatively simple approach of myocardialprotection has provided a hospital mortality of lessthan 2% for elective aortic root operations and anoverall mortality of less than 5% when emergency pro-cedures for acute type A dissection and endocarditisare included [ 1 ].

Myocardial protection inother centers

Other myocardial protective strategies have been des-

cribed from specialized aortic surgery centers. Davidin Toronto maintains the systemic temperature at32°C and directly cannulates both left and right coro-nary ostia for continuous perfusion with blood car-dioplegia at 20°C [8]. The infusion rate is 200 ml/minuntil electrical activity ceases, then 40-60 ml/mindepending on cardiac size and degree of hypertrophy.Coselli at Baylor employs a similar strategy with thesystemic temperature between 28°C and 30°C andinfusion of cold blood cardioplegia directly into thecoronaries until the heart stops [9]. In some reopera-tions and in patients with coronary artery disease,retrograde cold blood cardioplegia is delivered via thecoronary sinus. Lytle at the Cleveland Clinic similarlyemploys systemic cooling to 28°C then antegradecold blood cardioplegia delivered directly into thecoronary ostia after aortic cross-clamping [10]. After

arresting the heart, retrograde cold blood cardioplegiais infused into the coronary sinus.

Miller of Stanford employs systemic cooling to28°C and uses cold blood cardioplegia infused directlyinto the coronary ostia [11]. Retrograde cardioplegiais delivered via the coronary sinus in the event of dif-fuse coronary artery disease, if the left main stem isshort, or if there are separate origins to the left anteriordescending and circumflex vessels. One liter of cardio-plegia is employed initially and the myocardial tem-perature measured to ensure that this is below 10°C.When the ischemic period exceeds 60 min or if themyocardial temperature rises, a further dose of car-dioplegia is used. Before release of the aortic cross-clamp, this group employs an infusion of between 500and 1000 ml of warm blood cardioplegia via a needleinto the Dacron graft and uses this maneuver to checkthe integrity of the anastomoses.

Two groups use lower systemic temperatures.

Griepp at Mount Sinai cools to 20°C, applies the cross-clamp, and delivers a single dose of antegrade coldcrystalloid cardioplegia directly into the coronaryostia [12]. This simple and effective approach is sup-plemented by topical hypothermia with iced saline.Kouchoukos reduces the temperature of the perfusateto 15°C for 8-10 min to permit gradual cooling ofthe myocardium and prevent early ventricular fibrilla-tion [13]. A probe is placed in the anterior septum

192 CHAPTER 22

to continuously monitor myocardial temperature.

When ventricular fibrillation occurs or after the per-

fusate temperature has stayed at 15°C for 2-3 min, the

aorta is clamped. Blood cardioplegia at 4°C is then

administered retrogradely through a ballooned-tipped

catheter into the coronary sinus. This is delivered at

250 ml/min for 3 min or until a myocardial tempera-

ture of 12-14°C is achieved. Simultaneously, a cooling

jacket is placed around the left ventricle to maintain

hypothermia. Additional infusions of cardioplegia are

given through the coronary sinus at 20- to 25-min

intervals during the period of aortic clamping. The

coronary arteries are not cannulated directly at any

stage.

These methods clearly differ in complexity but

provide the same exemplary results in the hands of

experienced surgeons. As a result, ischemic time no

longer features as a risk factor for hospital death. In

contemporary series CPB time, preoperative renal

failure, coronary artery disease NYHA Class IV, and

acute type A dissection are more likely to be associated

with an adverse outcome. A well-planned, elective

aortic root operation in a patient without advanced

heart failure or renal impairment is unlikely to result

in mortality. Failure to wean from CPB is more likely

to occur through malposition of the reimplanted cor-

onary ostia than inadequate myocardial protection.

References1 Westaby S, Katsumata T, Vaccari G. Aortic root replace-

ment with coronary button re-implantation: low risk andpredictable outcome. Eur J Cardiothorac Surg 2000; 17:259-65.

2 David TE, Feindel CM, Bos J. Repair of the aortic valvein patients with aortic insufficiency and aortic rootaneurysm. / Thorac Cardiovasc Surg 1995; 109:234-352.

3 Westaby S. Coagulation disturbances in profoundhypothermia: the influence of antifibrinolytic therapy.Setnin Thorac Cardiovasc Surg 1997; 9:246-56.

4 Kouchoukos NT, Wareing TH, Murphy SF et al. Sixteen-year experience with aortic root replacement: results of172 operations. Ann Thorac Surg 1991; 214:308-20.

5 Gott VL, Gillinou AM, Pyeritz RE et al. Aortic rootreplacement: risk factor analysis of a 17 year experiencewith 270 patients. / Thorac Cardiovasc Surg 1995; 109:536-45.

6 Westaby S, Katsumata T, Freitas E. Aortic valve conserva-tion in acute type A dissection. Ann Thorac Surg 1997; 64:1108-12.

7 Yun KL, Miller DC. Technique of aortic valve preserva-tion in acute type A aortic dissection. Oper Tech CardThorac Surg 1996; 1:68-81.

8 David TE. When, why and how should the native aorticvalve be preserved in patients with annulo-aortic ectasiaor Marfan syndrome. Semin Thorac Cardiovasc Surg1993; 5:93-6.

9 Coselli IS, Crawford ES. Composite aortic valve replace-ment and graft replacement of the ascending aorta pluscoronary ostial re-implantation: how I do it. SeminThorac Cardiovasc Surg 1993; 5:55-62.

10 Lytle BW. Composite aortic valve replacement and graftreplacement of the ascending aorta plus coronary ostialre-implantation: how I do it. Semin Thorac CardiovascSurg 1993; 5: 84-7.

11 Miller CD, Mitchell RS. Composite aortic valve replace-ment and graft replacement of the ascending aorta pluscoronary ostial re-implantation: how I do it. SeminThorac Cardiovasc Surg 1993; 5: 74-83.

12 Ergin MA, Griepp RB. Composite aortic valve replace-ment and graft replacement of the ascending aorta pluscoronary ostial re-implantation: how I do it. SeminThorac Cardiovasc Surg 1993; 5: 88-90.

13 Kouchoukos NT. Composite aortic valve replacementand graft replacement of the ascending aorta plus coron-ary ostial re-implantation: how I do it. Semin ThoracCardiovasc Surg 1993; 5:66-70.

CHAPTER 23

Myocardial protection in majoraortic surgery

Marc A. Schepensy MD, PhD e^ Andrea Nocchi, MD

Excluding the heart from the circulation means inter-ruption of the coronary artery blood flow and thisnecessitates myocardial protection. As in isolated car-diac surgery, this is very often the procedure in majoraortic surgery. Undeniably, myocardial protection inmajor aortic surgery is one of the cornerstones of suc-cess. In fact very complex aortic repairs are technicallypossible, but if the heart is neglected the results will beaccordingly bad. Preoperative myocardial ischemiashould be ruled out or treated before or during theaortic repair. This means that cardiac function has tobe evaluated carefully. All possible ways of protectingthe myocardium are discussed; our favored techniqueis then highlighted.

Cardiac surgery began in 1897 when Rehn (1849-1930) closed a cardiac perforation thus saving the lifeof the patient [1]. In 1950 Bigolow et al. introducedhypothermia and inflow occlusion in order to increasethe tolerable operative time [2]. The first heart-lungmachine was introduced in 1953 [3] and this startedthe modern era of heart surgery. The first elective car-diac arrest by potassium-rich solution was describedby Melrose et al. in 1955 [4]. Since then several tech-niques have been adopted, such as continuous coron-ary perfusion, fibrillatory and ischemic arrest, topicalor general hypothermia, and cardioplegic arrest. Incongenital and valvular surgery, potassium-rich car-dioplegia has been the method of choice since 1970. Itbecame routine for all intracardiac operations becauseenergy requirements were decreased and energy losseswere minimized during the arrest.

A lot of techniques have been adopted for use inaortic surgery also. Barnard and Schire in 1963 usedcardiopulmonary bypass and deep hypothermic cir-

culatory arrest in patients with aortic aneurysm anddissection [5]. In the beginning most interventions onthe ascending aorta were performed using continuouscoronary perfusion with cooled blood and a beatingheart throughout the whole procedure (with separatecannulas into both coronaries after excision of theaneurysm or with a continuously cross-clamped prox-imal nondilated aortic segment) [6]. Better under-standing of several aspects of myocardial protection incoronary artery surgery, together with awareness ofthe pathophysiology of reperfusion and oxygen freeradical scavengers, has led to new developments suchas the use of oxygenated cardioplegia solution, oxy-genated crystalloid cardioplegia, blood cardioplegia,and retrograde cardioplegia. The addition of mag-nesium or calcium channel blockers, or low-calciumsolutions, may help to stabilize cellular membranes.Acidosis by lactic acid during ischemia can be bufferedby sodium bicarbonate, phosphate, or tris(hydroxy-methyl)-amino-methane (THAM).

Arrhythmias can be avoided by using procainein the solution. Mannitol, albumin, or dexamethasonecan counteract myocardial edema. Blood in the solu-tion will act as a buffer; furthermore hemodilutioncan be reduced and oxygen can be added keepingthe myocardium oxygenated. Most surgeons per-forming aortic surgery have developed their ownpreferred method of cardioprotection, frequentlyadopted from their experience in coronary artery orvalve surgery.

The oxygen requirements of the heart are reducedwhen arrested and cooled (at 20°C) to 0.3 ml/100g/min versus 2-3 ml/100 g/min when fibrillating[7,8].

193

194 CHAPTER 23

The St Antonius method ofprotecting the myocardiumduring complex aortic surgery

Aortic root surgeryWe think it is essential to measure continuously thetemperature of the myocardium. For very extensiveaortic root surgery (acute type A aortic dissection,Bentall operations, valve-sparing operations, ascend-ing aortic replacement, arch replacement, elephanttrunk, combinations of the previous, redo cases,...),we prefer to use a single shot of cold crystalloid cardio-plegia (Cardioplegische Perfusionslosung, FreseniusKabi, Bad Homburg, Germany), aiming to reach aseptal myocardial temperature of about 10°C.

The route of administration (via the root or directlyinto both ostia of the coronary arteries) depends onthe pathology and the degree of aortic valve incompet-ence. In cases of dissection of the ascending aortaand aneurysm containing clots, we will never use rootdelivery but rather selective administration throughboth coronaries after having opened the root. Also incases of severe aortic valve incompetence higher thangrade I, we prefer selective cardioplegia through bothcoronaries; if the aortic valve insufficiency is less thangrade I and if the left ventricle is vented adequately,administration through the root can be an option.Distention of the left ventricle can lead to subendocar-dial ischemia and immediate postoperative problems.

The amount of cardioplegia given depends on thetemperature that the myocardium reaches. During thefirst delivery we aim to arrive at a septal temperatureof 10°C and this can be realized in most cases with only1 L of cardioplegia, always combined with externalcooling of the myocardium during the cardioplegicdelivery with cold (4°C) Ringer's acetate. During theintervention the heart is packed in three wet gauzes(one positioned at the posterior side of the heart, oneanteriorly, and one on the diaphragmatic side) with adevice (a simple tip of an ordinary infusion system)between the gauzes and the heart that continuouslyirrigates the pericardial contents with cold (4°C)Ringer's acetate. It is important not to discontinue thiscooling irrigation for long time periods because thetemperature of the heart will increase rapidly. Thiscooling is mostly sufficient to keep the septal tempera-ture of the myocardium as measured close to the leftanterior descending artery or the posterior descendingartery around 10-12°C for periods extending up to 3 h

of cardiac ischemia. Only if the myocardial tempera-ture rises above 15°C will we give another shot ofcardioplegia, but this is done only very rarely.

Regarding the location of the septal temperatureprobe, we choose the anterior septum because it is themost superficially located part of the myocardiumwithin the pericardium and it is easy to reach. Prob-ably it will rewarm first due to the warmth of the oper-ative lights and the fact that this part is exposed to awarmer environment. It is important to turn the oper-ating table 30 degrees to the left and slightly in anti-Trendelenburg allowing the whole heart to remaincontinuously immersed in iced water; in this way thebulk of the heart is below the cold fluid level thatfills the pericardium. This position of the table alsoprevents the water running into the superior part ofthe pericardium where we have to operate. If a myo-cardial region warms up early, we believe this can beavoided by repositioning the table. When coronaryartery stenosis greater than 50% is present (whichshould be evaluated preoperatively), care should betaken not to underestimate the maldistribution ofthe cardioplegia since this may lead to postoperativemyocardial ischemia [9].

Opponents of this cooling system might argue thatthe intervention resembles a continuous fight againstwater. However when the delivery and removal ofthe cold water (by a nasogastric tube positioned in thedeepest part of the pericardium, below the heart,with intermittent or continuous moderate suction) isperfectly in balance, it seems to be a very elegant andeasy way to keep the heart adequately protected forprolonged time periods without interrupting the sur-geon's main surgical activity on the aorta higher up. Inthis way the surgeon does not loose time in the repetit-ive administration of cardioplegia every 20 min or soand he/she can continue to work in a concentratedway.

We would caution against the use of ice slushwithout protecting the phrenic nerves (e.g. with a sur-gical glove) because phrenic nerve paralysis could bedisastrous.

We have no experience with retrograde delivery ofcardioplegia in major aortic surgery; although it maybe very effective, care should be taken of the distri-bution and preservation of the right ventricle sincethis can sometimes be a serious problem. With thistechnique, considerable amounts of cardioplegia mayhave been used yielding a high potassium level that

Myocardial protection in major aortic surgery 195

necessitates repetitive checking of blood gases andelectrolytes.

Descending thoracic orthoracoabdominal aortic surgeryIn cases of descending thoracic or thoracoabdominalaortic surgery (aneurysms, dissections, trauma,.. .) ,the surgeon has the option to use simple cross-clamping or left heart bypass. In both settings (as isalso the case in major abdominal aortic surgery) theheart will continue to beat and there is no reasonto give cardioplegia; however it is more complicatedthan that. Undoubtedly the former technique offerssuboptimal protection of distal organs such as thekidneys and spinal cord; the latter technique certainlygives the surgeon more possibilities for treating theseextensive diseases, with a lower risk of renal failure orparaplegia. It is known that cross-clamping the aortamight cause a serious increase in the afterload, withsevere rhythm disturbances and even acute left ven-tricular failure. Left heart bypass unloads the circula-tion and the heart, and in this way it certainly protectsthe myocardium compared to simple cross-clamping[10]. When extracorporeal circulation is used forthe treatment of descending thoracic or thoracoab-dominal aortic lesions through a left chest incision,cooling the body will induce first bradycardia andlater ventricular fibrillation. As long as the heart beats,there is no danger of distention. Therefore in thissituation, the slightest degree of aortic valve incom-petence will cause left ventricular distention. A leftventricular apical drain will overcome this very harm-ful effect to the heart. The administration of cardio-plegia in this setting is not necessary, the heart isperfused with oxygenated cold (about 15°C) bloodduring the cooling phase. If circulatory arrest is used,the period of arrest should be limited to 30 min or less

in view of the deleterious effects on the brain. Duringthis time period, there is no additional need to protectthe heart in another way, although one could attemptto give cardioplegia by cross-clamping the ascendingaorta and direct punction of the aortic root, althoughinfusing cardioplegia in a diseased aortic segment issometimes hazardous.

References

1 Rehn L. Uber penetrierende Herzwunden und Herznaht.Arch Klin Chir 1897; 55:315-17.

2 Bigolow WG, Lindays WK, Greenwood WF. Hypothermia—its possible role in cardiac surgery: an investigation offactors governing survival in dogs at low body tempera-tures. Ann Surg 1950; 132:1081-5.

3 Gibbon JH Jr. Application of a mechanical heart and lungapparatus to cardiac surgery. In: Recent Advances inCardiovascular Physiology and Surgery. Minneapolis:University of Minnesota, 1953:107-13.

4 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Electivecardiac arrest. Preliminary communication. Lancet 1955;ii:21.

5 Barnard CN, Schire V. The surgical treatment of acquiredaneurysms of the thoracic aorta. Thorax 1963; 18:101-5.

6 Sing MP, Bentall HH. Complete replacement of theascending aorta and the aortic valve for the treatment ofaortic aneurysm. / Thorac Cardiovasc Surg 1972; 63:218-25.

7 Buckberg GD. A proposed "solution" to the cardioplegiacontroversy. / Thorac Cardiovasc Surg 1979; 77:803—15.

8 Buckberg GD. Strategies and logic of cardioplegic deliv-ery to prevent, avoid, and reverse ischemic and perfusiondamage. / Thorac Cardiovasc Surg 1987; 93:127-39.

9 Svensson LG, Crawford ES. Aortic dissection and aorticaneurysm surgery: clinical observations, experimentalinvestigations and statistical analyzes. Part I. Curr ProblSurg 1992; 29: 819-912.

10 Schepens MA, Defauw JJ, Hamerlijnck RP, VermeulenFE. Use of a left heart bypass in the surgical repair ofthoracoabdominal aortic aneurysms. Ann Vase Surg1995; 9: 327-38.

CHAPTER 24

Recent advances in myocardialprotection for coronaryreoperations

Jan T. Christenson, MA, MD, PhD, PD, FETCS &AfksendiyosKalangos, MD, PHD, PD, FETCS

Challenges in reoperative coronaryartery bypass grafting

Reoperative coronary artery bypass grafting (CABG)is an important clinical entity. Previous studies havenoted an increase in the prevalence of redo CABGsurgery over time as the age of our patient popula-tion increases [1-4]. However, increasing use ofarterial conduits [5] and lipid-lowering agents [6,7]may result in a plateau in the number of reoperativeprocedures [8].

Coronary artery reoperation is a surgical chal-lenge because the risk profile of patients undergoingreoperation is increasing [2,9]. Inhospital mortalityand postoperative morbidity is higher than observedafter the first operation [10]. In the vast majority ofpatients, years have elapsed since the first operation,and more than one-third of the patients have lostearlier normal left ventricular function [11,12]. Nativecoronary vessel disease has progressed and vein-graftatherosclerosis has developed. Lesions in a vein graftto the left descending coronary artery have been reportedto predict a higher rate of death and cardiac eventsthan native vessel disease in the same distribution area[13]. With increased age other concomitant diseasesmay also have been added to a higher surgical risk, suchas diabetes, impaired renal function, and obstructiveairway disease. Reoperative CABG is always associatedwith the ubiquitous risk of re-entry sternotomy injuryto underlying structure, may they be patent grafts orthe heart itself. Commonly an advancement of native

coronary artery disease has occurred, often resultingin a more diffuse coronary artery disease that causesimpedance to coronary arterial runoff, which is a majordeterminant of adequacy of myocardial revascular-ization. There may be the presence of partially open,atherosclerotic saphenous vein grafts, which carries anincreased risk for distal embolization. There may be ashortage of adequate revascularization conduits, whichmay lead to inadequate or incomplete revasculariza-tion, compromising inflow to the myocardium. More-over the operative risk increases incrementally witheach subsequent coronary artery reoperation [14,15].The relationship between hospital morbidity andaortic cross-clamping time underscores the need foroptimal myocardial protection. Morbidity increaseswith cross-clamping time, regardless of cardioplegiamixture and the type of delivery [ 16].

The presence of high-grade obstructions in nat-ive coronary vessels and previously performed veingrafts, patent internal thoracic artery bypass grafts,and pericardial adhesions create unique challenges forcardioplegia delivery and myocardial preservation inthe reoperative CABG population.

Improved medical therapy, interventional cardio-logy, and complex coronary interventions save lives.Consequently, patients presenting for repeat CABGare typically older and often have severely reducedleft ventricular function. Prevention of postoperativemyocardial dysfunction is a primary goal of reoperativesurgery and technical details therefore should aim atminimizing this risk, which means that one should focus

196

Coronary reoperations 197

on the changing metabolic needs of the heart, prior to,during, as well as after surgical revascularization.

In reoperative CABG patients therefore, require-ments for the optimal myocardial management areparamount. Recent advances in surgical techniquesincluding avoidance of patent grafts and a plannedand organized recruitment of adequate bypass con-duits, appropriate use of cardiopulmonary bypass,optimal cardioplegic solutions delivered by the mostefficacious techniques at appropriate temperatures,and the role of preoperative intra-aortic ballooncounterpulsation in high-risk reoperative CABG willbe addressed.

Surgical considerations—no-touchtechnique/vein grafts/patentinternal thoracic artery (ITA) grafts

Redo CABG surgery may be required as a result ofgraft disease, progression of native coronary athero-sclerosis, or a combination of these factors [2,17,18].Increased risk at redo CABG is primarily due toatheroembolism from saphenous vein grafts, a widelyrecognized complication [17,19-21]. A patent LITAgraft at reoperation decreases operative mortality,mainly as a result of preserved anterior wall functionand absence of atherosclerotic embolization from theITA graft [22]. However, a patent ITA graft at reopera-tion may also create specific technical challenges.There is an increased risk of ITA graft injury duringreentry and dissection, and delivery of cardioplegia tothe anterior aspect of the heart may be inadequate[23]. Temporary occlusion of the ITA graft and useof retrograde cardioplegia delivery results most oftenin adequate myocardial protection. However, iden-tification and dissection of the ITA pedicle can behazardous and injury to the graft may occur. If theITA graft is not readily identified, systemic cooling hasbeen recommended until the ITA graft is identifiedand controlled [23].

Even when vein grafts are patent and athero-sclerotic, the first antegrade dose of cardioplegia isregarded as safe. However, these vein grafts shouldnot be manipulated externally because of the risk ofatheroembolism. Subsequent cardioplegia deliverythrough old, diseased grafts is not recommended.Patent atherosclerotic vein grafts should be dividedfirst and replaced immediately [ 10]. The entire opera-tion should be performed under one period of cross-

clamping [10,18,24]. This technique is preferred toconserve space on the aorta and to reduce the threatof atheroembolism, which may result from repeatedaortic manipulation. For patients with patent internalthoracic artery grafts from previous operation, aneffort should be made to temporarily occlude theITA pedicle, prior to the initial dose of cardioplegia[24], in order to achieve optimal myocardial protec-tion [10].

Cardiopulmonary bypass—cannulation/hypothermic versusnormothermic cardiopulmonarybypass

The employment of a flexible CPB, oftentimes usingfemoral/femoral bypass, perhaps even before openingthe sternum, is advocated. Core cooling is an acceptedpractice even though several recent reports have sug-gested that normothermic cardiopulmonary bypassprovides a good total body protection during cardiacsurgery and cold or warm cardioplegia is seeminglysufficient for adequate myocardial protection [25-27].Normothermic CPB has the advantage of less systemicinflammatory response and shorter CPB time [25,27].Hypothermic CPB could be considered if the patient'scerebrovascular status is such that an increased risk ofintraoperative stroke is anticipated.

Cardioplegia—delivery/temperature/solution/additives

Cardioplegia deliveryThe presence of high-grade obstructive disease inpreviously performed vein grafts together with oftenproximal native artery stenoses create unique challengesfor cardioplegia delivery and myocardial preservationin the reoperative CABG population. Initially antegradecardioplegia delivery was the standard method.

Retrograde cardioplegia was introduced to circum-vent the inhomogenous distribution of cardioplegiaassociated with antegrade delivery, particularly in thepresence of severe proximal coronary artery stenoses[20,28]. Retrograde cardioplegia may decrease the riskof atheroembolism during redo CABG. Retrogradedelivery has been hypothesized to result in less embol-ization than antegrade delivery [29], and anecdotalevidence suggests that retrograde delivery of cardio-plegia solution can dislodge atheroemboli that have

198 CHAPTER 24

already occurred. Unfortunately, evidence was broughtforward indicating that retrograde perfusion did notresult in adequate perfusion of the right ventricle anddid not provide as adequate capillary perfusion ofthe left ventricle as antegrade delivery [30-33]. Thisled to exploration of combined antegrade/retrogradecardioplegia delivery [34-36]. Ardehali and coworkersshowed that in the human heart as much as two-thirdsof retrograde cardioplegia is shunted through thethebesian veins and arterio-sinusoidal channels intothe ventricular cavities and they claim it has a nutritiveproperty [37]. This corresponds well with a paper byTaylor and Taylor [38] who show that even thoughthe human heart is an external pump it is indeed alsostructured as an internal pump.

In a series of 240 consecutive reoperations an intra/postoperative intra-aortic balloon pump was usedin 3.8% of high-risk patients when retrograde cardio-plegia was delivered versus 14.5% in high-risk patientswithout retrograde cardioplegia [ 1 ]. These results aresimilar to those presented by Athanasuleas et al. [39],and indicate the value of uniform cardioplegic deliveryin a difficult patient population.

Simultaneous antegrade/retrograde administrationwith continuous warm noncardioplegic blood wasintroduced in 1994 [40]. It was indicated that combinedantegrade and retrograde blood cardioplegia mightdecrease major morbidity incidence in comparisonwith antegrade blood or crystalloid cardioplegia [4].

Further refinement using the significant featuresof each of the previously described techniques wascombined in a method called integrated myocardialmanagement, proposed by Buckberg and coworkers[41 ]. A high-potassium amino-acid-enhanced mixtureis used for induction, either cold or warm, and duringthe warm terminal reperfusion in all cases. A lowpotassium nonsubstrate-enhanced cold solution isused for maintenance and cardioplegia is deliveredby both antegrade and retrograde routes.

Retrograde cardioplegia alone or in combinationwith antegrade cardioplegia resulted in a significantreduction of mortality in a study recently presentedby Borger et al. [8]. They concluded that the optimalmyocardial protection strategy for redo CABG mayberetrograde cardioplegia, supplemented by antegradeperfusion of new vein grafts, in particular to the rightcoronary artery (RCA).

Combined antegrade aortic root and retrogradecoronary sinus cardioplegia infusion is now the method

of choice for cardioplegic protection of the heart in thereoperative CABG patient [ 14]. No matter what type ofcardioplegia solution is used, the use of the antegrademethod to institute cardiac arrest, followed by sub-sequent sequential retrograde coronary sinus infusions,appears to maximize myocardial protection [42].Several excellent coronary sinus cardioplegia cannulasare available. During infusion on CPB, an elevation ofthe coronary sinus pressure usually indicates that thecoronary sinus cannulas are properly placed.

Cardioplegia solutionsThere continues to be considerable debate about thetype and constituents of various myocardial preserva-tion solutions. In general, it would appear that themajority of cardiac surgeons throughout the world nowfavor some form of blood cardioplegia for reopera-tions. In these high-risk reoperative CABG patients, itis thought that delivering as much oxygen as possibleto the usually dysfunctional left ventricle, in theserather long and complicated cases, should obviouslybe an advantage.

Oxygenated crystalloid cardioplegia has also beenadvocated [43], as have a variety of other cardio-plegia solutions. However, these solutions have notbeen proven to have any significant advantage overone type or another, provided that surgery is doneaccurately, and that the cardioplegia solution is ad-ministered both antegrade and retrograde. However,the infusion of small amounts of cardioplegia follow-ing completion of each vein graft to test the patencyof the anastomosis, and especially to provide cardio-plegia distal to coronary artery stenosis to furthercool the myocardium, is probably of importance[12,44].

Blood cardioplegia enhances myocardial protectionby reducing arrhythmias, maintaining myocardialhigh-energy phosphate content during ischemia, andimproving the rate of recovery of function. Bloodcardioplegia has emerged as the preferred cardio-protective strategy because of its versatility. A bloodvehicle for cardioplegic delivery blends rheology,buffering, and onconicity and antioxidant benefits[45] with its capacity to augment oxygen delivery, pre-vent ischemic injury, and limit reperfusion injury[41,46,47].

Blood cardioplegia delivered by antegrade andretrograde routes has become the most widely appliedtechnique worldwide [48].


Optimal cardioplegia temperatureThe standard method of delivering either blood orcrystalloid cardioplegia consisted of intermittent hypo-thermic (8-10°C) infusions. Cold blood cardioplegiais the mainstay of myocardial protection by decreasingmyocardial oxygen demand. However, Rosenkranz etal.showed that hypothermia does not reduce myocardialoxygen requirements much beyond the reductionachieved alone with hyperkalemic arrest [49]. Further-more, impaired preoperative ventricular function pres-ents a special problem and dysfunction may persist aftergrafting in ischemic energy-depleted hearts despite theavoidance of further injury with cold blood cardio-plegia. This led to the adoption of warm induction [50].However, normothermic cardioplegia has been shownto result in increased systolic function and preloadrecruitable stroke work compared to hypothermic car-dioplegia. In addition, warm blood cardioplegia resultsin a greater lactate and acid washout with reperfusioncompared to cold [51]. This led to the introductionof tepid (29°C) cardioplegia, which seems to extractthe positive effects from both extremes. Tepid cardio-plegia provides the metabolic benefit of cold cardio-plegia while permitting the immediate recovery of leftventricular function associated with normothermiccardioplegia [33,52].

Role of preoperative intra-aorticballoon counterpulsation

Intra-aortic balloon counterpulsation (IABC) isan established additional support to pharmacologictreatment of the failing heart after myocardial infarc-tion, unstable angina, and following cardiac surgery[12,53,54]. IABC therapy results in more favorablemyocardial supply and demand balance [55], reducesafterload, and augments the diastolic pressure [56,57],which in turn leads to an increased cardiac output.Augmented diastolic pressure results in redistributionof coronary blood flow toward ischemic areas of themyocardium [58,59]. Christakis and associates [60]reconfirmed suggestions earlier voiced by Gustensenet al. [61] and others [62,63] that use of preoperat-ive IABC could lead to a preoperative reduction ofmyocardial ischemia, thereby improving the outcomeof myocardial revascularization in patients with poorpreoperative left ventricular function. Several studieshave shown the efficacy of preoperative IABC therapyfor patients with severely compromised preoperative

function [64-67]. Furthermore the cost effectivenessof preoperative IABC therapy in high-risk patientshas been demonstrated [66,68]. Since a large pro-portion of patients admitted for reoperative CABGhave left ventricular dysfunction as well as other riskfactors mentioned above, preoperative IABC therapywas thought to be beneficial as an additional andintegrated part of myocardial protection for thiscohort of high-risk patients.

From a recent prospective randomized trial it wasshown that preoperative IABC therapy for high-riskreoperative CABG patients significantly improvedthe cardiac index, thus presenting patients with aless ischemic or in many cases even a nonischemicmyocardium at the time of aortic cross-clamping [69].

Furthermore it was reported that virtually allphysiologic parameters were more favorable in thosepatients who had received preoperative IABC therapy.As with prior studies, the time on CPB was signific-antly shorter (86 min vs. 110 min in the control group).The cardiac index was significantly higher duringthe first 48 h postoperatively, with only 16.7% of thetreatment group experiencing a low postoperativecardiac index compared with 54.2% of the controls.Only two patients (8.3%) in the preoperative IABCgroup also required counterpulsation support post-operatively, and in each of these instances the intra-aortic balloon was successfully removed on the firstpostoperative day. This contrasted with a total of 9(37.5%) of the control patients requiring postoperat-ive IABC support, for an average of 4.1 days (rangingfrom 2 to 8 days).

The improvement in postsurgical cardiac indexwas highly significant, as severely disturbed cardiacperformance can often lead to difficulty in weaningthe patient from CPB, resulting in a high rate ofpostoperative mortality. This was clearly reflectedin the absence of any hospital mortality among the24 patients who received preoperative IABC therapy,while four control patients (16.7%) died (P < 0.049),all between the first and fourth postoperative day.

The mean length of stay in the ICU was also sig-nificantly reduced in the postoperative IABC group—2.4 ± 0.8 days versus 4.5 + 2.2 days for the controls(P = 0.007). Finally, total hospital expenditures werereported that were lower for those patients who receivedpreoperative IABC therapy and few (4.2%) IABC-related complications (both instances of leg ischemia)occurred. Smaller sized balloon catheters (8F), better

200 CHAPTER 24

education and surveillance are major factors respons-ible for low lABC-related complications [70].

It was concluded that preoperative IABC therapysignificantly improved cardiac index, leading to a lessischemic or even nonischemic myocardium at the timeof aortic cross-clamping and thus overall improve-ment in patient outcome. An additional benefit of theimproved cardiac performance observed in this studywas an observed reduced requirement for pharmaco-logic inotropic support during the first 24 h followingCPB[69].

Summary

Despite continued improvements in cardioplegictechniques, low output syndrome following high-risk reoperative CABG remains an ongoing concern.With the use of different CPB techniques, oftentimesusing femoral/femoral bypass, even before openingthe sternum, antegrade/retrograde blood cardioplegia,and avoidance of the patent bypass grafts by the"no-touch" techniques, reoperative surgery risk forcoronary artery disease has decreased significantly. The

Table 24.1 Summary of integrated management of

reoperative CABG.

• Identification of high-risk patients, e.g. for perioperativestroke• Preoperative intra-aortic balloon counterpulsation forpatients with severe left ventricular dysfunction andunstable angina despite optimal medical regimen• Flexible cardiopulmonary bypass approach adjusted tothe individual patient• A single cross-clamping interval for construction of both

distal and proximal anastomoses

• No-touch surgical technique, ligation, and replacementof atherosclerotic vein grafts• Clamping of patent ITA grafts during delivery ofcardioplegia• Combined antegrade and retrograde tepid (29°C) bloodcardioplegia• An initial dose of the hyperkalemic cardioplegia solutionis administered through the aortic root to arrest the heart.This is followed by the continuous, retrogradeadministration of cardioplegia solution through an

indwelling coronary sinus catheter. Coronary sinus pressure

is continuously monitored to maintain a pressure ofapproximately 40 mmHg, which usually relates to acardioplegia flow rate of 150-200 ml/min

major bulk of patients succumbing after reoperativeCABG today are those who develop multisystemorgan failure in the late postoperative period [71]. It ispossible that the development of new additives withvarious properties may provide added protection,allowing for reduction of morbidity and mortalityfollowing redo CABG [71]. However, an alreadyestablished modality is probably underused. IABC hasbeen shown to diminish this risk of low post-operativecardiac output [72] and subsequent risk for multi-organ failure preoperatively [73,74], and should bepart of the integrated management in high-risk reoper-ative CABG surgery (Table 24.1).

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20 Savage EB, Cohn LH. "No touch" dissection, antegrade-retrograde blood cardioplegia, and single aortic cross-clampsignificantly reduce operative mortality of reoperativeCABG. Circulation 1994; 90: II-140-3.

21 Brener SJ, Loop FD, Lytle BW et al. A profile of candidatesfor repeat myocardial revascularization: implications forselection of treatment. / Thorac Cardiovasc Surg 1997;114:153-61.

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23 Gillinov AM, Casselman FP, Lytle BW et al. Injury to apatent left internal thoracic artery graft at coronaryreoperation. Ann Thorac Surg 1999; 67:382-6.

24 Graver JM, Hodakowsky GT, Shen Y et al. Third-timecoronary artery bypass operations: surgical strategy andresults. Ann ThoracSurg 1996; 62:1801-7.

25 Christenson JT, Maurice J, Simonet F, Velebit V,Schmuziger M. Normothermic versus hypothermic per-fusion during primary coronary artery bypass grafting.Cardiovasc Surg 1995; 3: 519-24.

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27 Singh AK, Feng WC, Bert AA, Rotenberg FA. Warm body,cold heart surgery. Clinical experience in 2817 patients.Eur J Cardiothorac Surg 1993; 7:225-30.

28 Rosengart TK, Krieger K, Lang SJ et al. Reoperativecoronary artery bypass surgery: improved preservationof myocardial function with retrograde cardioplegia.Circulation 1993; 88: II-330-5.

29 Gundry SR, Razzouk AJ, Vigesaa RE, Wang N, Bailey LL.Optimal delivery of cardioplegic solution for "redo"operations. / Thorac Cardiovasc Surg 1992; 103:896-901.

30 Partington MT, Acar C, Buckberg GD et al. Studies of ret-rograde cardioplegia. I. Capillary blood flow distributionto myocardium supplied by open and occluded arteries./ Thorac Cardiovasc Surg 1989; 97:605-12.

31 Menasche P, Subayi JB, Veyssie L et al. Efficacy of coron-ary sinus cardioplegia in patients with complete coronaryartery occlusions. Ann Thorac Surg 1991; 51:418-23.

32 Crooke GA, Harris LH, Grossi EA et al. Biventricular dis-tribution of cold blood cardioplegic solution administeredby different retrograde techniques. / Thorac CardiovascSurg 1991; 102:631-7.

33 Rao V, Ikonomidis JS, Weisel RD, Cohen G. Precondi-tioning to improve myocardial protection. Ann NYAcadSci 1996; 793:338-54.

34 Bhayana JN, Kalmbach T, Booth FV, Mentzer RM,Schimert G. Combined antegrade/retrograde cardio-plegia for myocardial protection: a clinical trial. / ThoracCardiovasc Surg 1989; 98:956-60.

35 Drinkwater DC, Laks H, Buckberg GD. A new simplifiedmethod of optimizing cardioplegic delivery without rightheart isolation. Antegrade/retrograde cardioplegia. / ThoracCardiovasc Surg 1990; 100:56-63.

36 Hayashida N, Weisel RD, Shirai T et al. Tepid antegradeand retrograde cardioplegia. Ann Thorac Surg 1995; 59:723-9.

37 Ardehali A, Laks H, Drinkwater DL, Gates RN, Kaczer E.Ventricular effluent of retrograde cardioplegia in humanhearts has transversed capillary beds. Ann Thorac Surg1995;60:78-82.

38 Taylor JR, Taylor AJ. The thebesian circulation to develop-ing conducting tissue, a nutrient-nodal hypothesis ofcardiogenesis. Can} Cardiol 1999; 15:859-66.

39 Athanasuleas CL, Riemer DW, Buckberg GD. The role ofintegrated myocardial management in reoperative coron-ary surgery. Sem Thorac Cardiovasc Surg 2001; 13: 33-7.

40 Ihnken K, Morita K, Buckberg GD et al. The safetyof simultaneous arterial and coronary sinus perfusion:experimental background and initial clinical results.JCard Surgl994; 9:15-25.

41 Buckberg GD, Beyersdorf F, Allen BS, Robertson JM.Integrated myocardial management. Background andinitial application. / Card Surg 1995; 10:68- 89.

42 Chitwood WR Jr. Retrograde cardioplegia: currentmethods. Ann Thorac Surg 1992; 53: 352-5.

43 Shanewise JS, Kosinski AS, Goto JA, Jones EL. Prospectiverandomized trial comparing blood and oxygenated crys-talloid cardioplegia in reoperative coronary artery bypassgrafting. / Thorac Cardiovasc Surg 1998; 115:1166-71.

44 Silverman NA, Schmitt MD, Levitsky S et al. Optimal intra-operative protection of myocardium distal to coronarystenoses. / Thorac Cardiovasc Surg 1984; 88:424-31.

45 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety ofprolonged aortic clamping with blood cardioplegia. III.Aspartate enrichment of glutamate-blood cardioplegia inenergy-depleted hearts after ischemic and reperfusioninjury. / Thorac Cardiovasc Surg 1986; 91:428-35.

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46 Robertson JM, Vinten-Johansen J, Buckberg GD et al.Safety of prolonged aortic clamping with blood cardio-plegia. I. Glutamate enrichment in normal hearts. /Thome Cardiovasc Surg 1984; 88:395-401.

47 Allen BS, Okamoto F, Buckberg GD et al. Studies ofcontrolled reperfusion after ischemia. XV. Immediatefunctional recovery after 6 hours of regional ischemiaby careful control of conditions of reperfusion and com-position of reperfusate. / Thorac Cardiovasc Surg 1986;92:621-35.

48 Robinson LA, Schwarz GD, Goddard DB et al. Myo-cardial protection for acquired heart disease surgery:results of a national survey. Ann Thorac Surg 1995; 59:361-72.

49 Rosenkranz ER, Okamoto F, Buckberg GD. Safety ofprolonged aortic clamping with blood cardioplegia.II. Glutamate enrichment in energy-depleted hearts.J Thorac Cardiovasc Surg 1984; 88: 395-401.

50 Buckberg GD, Brazier JR, Nelson RL et al. Studies ofthe effects of hypothermia on regional myocardial flowand metabolism during cardiopulmonary bypass. I. Theadequately perfused beating, fibrillating and arrestedheart. / Thorac Cardiovasc Surg 1977; 73: 87-94.

51 Hayashida N, Ikonomidis JS, Weisel RD et al. The optimalcardioplegic temperature. Ann Thorac Surg 1994; 58:961-71.

52 Hayashida N, Isomura T, Sato T et al. Minimally dilutedtepid blood cardioplegia. Ann Thorac Surg 1998; 65:615-21.

53 Aksnes J, Abdelnoor M, Platou ES, Fjeld NB. Mortalityin patients supported by intra-aortic balloon pump incourse of cardiac surgery was related to perioperativemyocardial infarction. Eur } Cardio-Thoracic Surg 1996;10:408-11.

54 Hammermeister KE, De Rouen TA, Dodge HT. Variablespredictive of survival in patients with coronary disease.Circulation 1979; 59:421-30.

55 Lazar HL, Yang XM, Rivers S et al. Retroperfusion andballoon support to improve coronary revascularization.J Cardiovasc Surge 1992; 23: 538-44.

56 Bolooki H. Clinical Application of Intraaortic BalloonPump. New York: Futura, 1984.

57 Weber KT, Janicki JS. Intraaortic balloon counterpulsation—a review of physiological principles, clinical results, anddevice safety. Ann Thorac Surg 1974; 17:602-36.

58 Gill CC, Wechsler A, Newman G, Oldman H. Augmenta-tion and redistribution of myocardial blood flow duringacute ischemia by intra-aortic balloon pumping. AnnThorac Surg 1975; 16: 44-53.

59 Watson JT, Willerson JT, Fixler DE, Sugg NL. Temporalchanges in collateral coronary blood flow in ischemic myo-cardium during intra-aortic balloon pumping. Circulation1974; 50 (Suppl): 11-249-54.

60 Christakis GT, Weisel RD, Fremes SE et al. Coronaryartery bypass grafting in patients with poor ventricularfunction. J Thorac Cardiovasc Surg 1992; 103:1083-92.

61 Gustensen J, Goldman BS, Scully HE, Huckell VF,Adelman AG. Evolving indications for preoperativeintraaortic balloon pump assistance. Ann Thorac Surg1976; 22: 535-46.

62 Christenson JT, Maurice J, Simonet F et al. Effect oflow left ventricular ejection fractions on the outcome ofprimary coronary bypass grafting in end-stage coronaryartery disease. / Cardiovasc Surg 1995; 36:45 -51.

63 Naunheim KS, Schwartz MT, Pennington DG et al.Intraaortic balloon pumping in patients requiring car-diac operations. Risk analysis and long-term follow up.J Thorac Cardiovasc Surg 1992; 104:1654-60.

64 Christenson JT, Simonet F, Badel P, Schmuziger M.Optimal timing of preoperative intra-aortic balloon pumpsupport in high risk coronary patients. A prospectiverandomized study. Ann Thorac Surg 1999; 68:934-9.

65 Christenson JT, Schmuziger M, Simonet F. Effectivesurgical management of high-risk coronary patientsusing preoperative intra-aortic balloon counterpulsationtherapy. Cardiovasc Surg 2001; 9: 383-90.

66 Dietl CA, Berkheimer MD, Woods EL et al. Efficacy andcost-effectiveness of preoperative IABP in patients withejection fraction of 0.25 or less. Ann Thorac Surg 1996;62:401-9.

67 Holman WL, Li Q, Kiefe CI et al. Prophylactic valueof preincision intra-aortic balloon pump. Analysis of astatewide experience. / Thorac Cardiovasc Surg 2000; 120:1112-19.

68 Christenson JT, Simonet F, Schmuziger M. Economicimpact of preoperative intra-aortic balloon pump therapyin high-risk coronary patients. Ann Thorac Surg 2000;70:510-15.

69 Christenson JT, Badel P, Simonet F, Schmuziger M.Preoperative intra-aortic balloon pump enhances cardiacperformance and improves the outcome of redo CABG.Ann Thorac Surg 1997; 64:1237-44.

70 Ferguson JJ, Cohen M, Freedman RJ et al The currentpractice of intra-aortic balloon counterpulsation: resultsfrom the Benchmark registry. J Am Coll Cardiol 2001;38:1456-62.

71 Cohen G, Borger MA, Weisel RD, Rao V. Intraoperativemyocardial protection: current trends and future per-spectives. Ann Thorac Surg 1999; 68:1995-2001.

72 Christenson JT, Simonet F, Badel P, Schmuziger M.Evaluation of preoperative intra-aortic balloon pumpsupport in high risk coronary patients. Eur J CardiothoracSurg 1997; 11:1097-103.

73 Christenson JT, Schmuziger M, Maurice J, Simonet F,Velebit V. Gastrointestinal complications after coronaryartery bypass grafting. / Thorac Cardiovasc Surg 1994;108:899-906.

74 Christenson JT, Simonet F, Schmuziger M, Badel P.Preoperative intra-aortic balloon counterpulsation (LABC)reduces the risk of gastrointestinal complications fol-lowing CABG in high-risk coronary patients. Today'sTherapeutic Trends 2001; 19:9-22.

CHAPTER 25

Myocardial protection duringminimally invasive cardiac surgery

Saqib Masroor, MD, MHS d- Kushagra Katariya, MD

This chapter reviews the current status of myocardialprotection during minimally invasive cardiac surgeryincluding robotic cardiac surgery. Obviously, the car-diac physiology and metabolism is similar no matterwhat the approach to the heart. The same principlesof myocardial preservation apply to minimally inva-sive surgery as to conventional cardiac surgery. Thepeculiar demands and critical technical issues arisefrom the limited access that a surgeon has to the leftventricle, aortic root, and coronary sinus, structurescrucial to aortic clamping/occlusion and delivery ofcardioplegia. In our discussion of minimally invasivecardiac surgery, we have excluded so-called "direct-access" minimally invasive mitral valve surgery suchas the techniques reported from the Brigham &Womens Hospital and the Cleveland Clinic [1,2].These approaches are still quite invasive and requiresome degree of partial sternotomy or thoracotomywith rib spreading and/or cartilage resection.

Evolution of minimally invasivecardiac surgery

Even though Carpentier et al. reported the firstvideo-assisted mitral valve repair in 1996 using ven-tricular fibrillation [3], enthusiasm in minimally inva-sive cardiac surgery did not catch on until the adventof port-access technology which allowed endovascularaortic occlusion, cardioplegia delivery, and left ven-tricular (LV) decompression [4]. Today, we can safelycross-clamp the aorta transthoracically or occludeit endovascularly and deliver cardioplegia either ante-grade or retrograde by percutaneous means. Thesedevelopments have been crucial to the successfulapplication of robotics to clinical cardiac surgery.

Finally, the cardiac surgeon's dream of totally endo-scopic cardiac surgery has come true in part due totechnologic advances in the field of robotics. The finemovements of the surgeon can now be transmitted toinstruments introduced through tiny 5-mm ports inthe chest wall. While the conduct of the operation mayseem futuristic, with the surgeon (not even scrubbed)sitting comfortably in front of the three-dimensionalviewing screen away from the patient, the basic prin-ciple of cardiac surgery has remained the same, i.e.myocardial protection.

Animal studies

Early studies in dogs by Schwartz et al. [5] demon-strated the adequacy of myocardial protection dur-ing closed chest cardiopulmonary bypass (CPB) andcardioplegic arrest. Using port-access technology, theexperimental group of animals underwent femoralvein-femoral artery CPB, endovascular aortic occlu-sion, and antegrade cold blood cardioplegic arrest.The heart was successfully vented through the aorticroot as well as a pulmonary artery. The latter wasvented through a catheter placed percutaneously viathe right internal jugular vein. The control group ofanimals underwent median sternotomy and openCPB. The authors showed that with cardiac arrest of60 min by intermittent delivery of cardioplegia every15 min, animals in both groups had similar post-CPBLV function as measured by the stroke work-diastoliclength relationship, the preload recruitable workarea, and elastance. Measuring myocardial tempera-tures in the right and left ventricular free walls, theauthors achieved similar degrees of hypothermia inboth groups of animals. Histologic and ultrastructural

203

204 CHAPTER 25

examination did not reveal any evidence of intra-cellular or intercellular edema, myofilament or mito-chondrial abnormalities, or membrane rupture.These results should be interpreted with caution,since longer periods of cardiac arrest (which are notuncommonly seen in robotic coronary surgery) werenot assessed in this study. Moreover, these werenormal hearts and thus not compromised by pre-existing LV hypertrophy or depressed LV function. Inaddition, the effect of nonhomogenous distributionof cardioplegia could not have been assessed in thesehearts with normal coronary arteries.

The same group later reported their results withsuccessful video-assisted thoracoscopic mitral valvereplacement in dogs using the port-access techniquefor CPB [6]. After induction of cardiac arrest by ante-grade cardioplegia, subsequent doses of cardioplegiawere delivered retrograde every 15 min, via a percuta-neously placed coronary sinus catheter. The meancross-clamp time was 55.6 + 10.3 min and the authorsreported a well-maintained postoperative LV function.

Since then, many reports have been publishedof successful conduct of minimally invasive/roboticcardiac surgery in humans with acceptable morbidityand mortality. The procedures have included totallyendoscopic coronary artery bypass (TECAB) [7-10],TECAB on a beating heart (TECAB-BH) [8,11,12],mitral valve repair and replacement [3,8,13-15], com-bined mitral valve/coronary bypass [16], atrial septaldefect (ASD) repair [17], and surgical treatment ofatrial fibrillation [18]. Cold blood cardioplegia ispreferentially used in most institutions, althoughcold crystalloid cardioplegia has also been reported.Ventricular fibrillation is now only used as a bail-outtechnique when there are problems with the deliveryof antegrade and retrograde cardioplegia solutionsduring the surgery. In subsequent sections we describethe strategies of myocardial protection as appliedto valvular and coronary surgery; however, data canbe extrapolated to other surgeries on the arrestedheart such as the ASD repairs and treatment of atrialfibillation.

Valve surgery

Minimally invasive mitral valve repair or replace-ment can be performed either by using video-assistedthoracoscopy or by totally endoscopic robotic tele-manipulation. Unfortunately most studies that have

been published in the literature emphasize the actualconduct and adequacy of the surgery. While they domention the complications associated with the pro-cedure, they fail to mention the presence or absenceof postoperative low cardiac output syndrome andthe postoperative use of inotropes. In one study only,Mohr et al. [ 14] describe their experience with minim-ally invasive mitral valve surgery using the Heartportdevice and a three-dimensional videothoracoscopicsystem. They used antegrade cold crystalloid cardio-plegia in 51 patients undergoing mitral valve repair orreplacement. Interestingly, two patients developedpersistent low cardiac output and died, nine patientsrequired prolonged inotropic support, and eight hadsupraventricular tachycardia. The mean cross-clamptime was 72 + 27 min and hospital mortality was 9.8%.Of the five patients who died, two died of persistentlow cardiac output—both these patients requiredadditional procedures after their mitral valve surgery.One patient was found to have aortic dissection uponweaning from CPB. Another patient had the ascend-ing aorta replaced after a median sternotomy but diedof persistently low cardiac output. The final patientunderwent successful mitral valve repair which failedon the third postoperative day. He then underwentmitral valve replacement (the paper does not mentionif this was done as an open or closed chest procedure)but the patient died of persistent low cardiac outputalso. Such findings have not been reported in otherreports which used cold blood cardioplegia [13,15].One explanation for these results may be inadequatemyocardial protection by cold crystalloid cardioplegiawhen longer cross-clamp times are encountered.

Deairing the heart can be a concern in minimallyinvasive surgery because of limited access to the leftventricle and the predilection of the right coronaryartery to air embolism in the minithoracotomy posi-tion. Attention to detail is important at this crucialstage of the operation. First of all, transesophagealechocardiography is important for accurate diagnosisof cavitary air and to monitor the success of the deair-ing maneuvers. Continuous CO2 insufflation shouldbe used during the procedure because it displacesair and is rapidly absorbed. In addition, the patientshould be aggressively ventilated and shaken from sideto side to remove residual air before unclamping theaorta. Once undamped, the aortic root should con-tinue to be vented until transesophageal echocardio-graphy reveals no residual air and the EGG reveals no

Minimally invasive cardiac surgery 205

ST elevation attributable to air embolism. Meticulousadherence to this protocol has allowed surgeons toachieve similar embolic stress rates between patientsoperated on with port-access or conventional sur-gery with no reported postoperative LV dysfunction[15,19].

Open chest beating heart valve surgery as astrategy for myocardial protection has been describedin Chapter 34. Minimally invasive surgery with CO2

insufflation produces an even lower risk for anysignificant air embolism. Moreover, the maneuver-ability of the endoscopic camera might afford a betterexposure of the valve being worked on. It will be inter-esting to see if in future beating heart valve surgery isindeed tried at any center as a myocardial protectionstrategy.

Coronary artery bypass surgery

Coronary artery bypass has been performed bothon an arrested heart (TECAB) and more recently abeating heart (TECAB-BH). The operative strategyhas involved using either single or bilateral mammaryarteries to bypass lesions in a single- or double-vesseldistribution [7,8,12]. When working on the arrestedheart, cold crystalloid or blood cardioplegia has beenadministered in an antegrade fashion using the port-access technology. Dogan [7] has reported a mean cre-atine kinase MB fraction (CK-MB) level of 14.2 + 10.9U/L and 18.2 + 13.1 U/L 6 h after the procedure insingle-vessel and double-vessel TECAB. This is similarto what has been reported in literature with conven-tional coronary artery bypass (CABG) on an arrestedheart [20]. Interestingly, in the TECAB study [7], totalCK levels were 586 + 514 after a single-vessel opera-tion and 1797 + 1884 after a double-vessel operation.This correlates with a mean cross-clamp time of 61 +16 min for single-vessel and 99 + 55 min for double-vessel TECAB. The clinical significance of this differ-ence in CK-MB release between the two groups isunknown at present, but in patients undergoing per-cutaneous transluminal coronary angioplasty, eleva-tion of CK-MB was associated with a higher likelihoodof postprocedure cardiac events and mortality [21].We also know that the longer the cross-clamp time,the greater is the myocardial dysfunction and damage[22]. It can then be said that for single-vessel bypass,TECAB can be performed with a degree of myocardialprotection that is comparable to that achieved during

a conventional CABG. With double-vessel bypass, thecross-clamp times are more than double those withCABG, and hence there is an increased likelihoodof inadequate myocardial protection using the cur-rently available myocardial protection strategies.

Beating heart coronary surgery via mediansternotomy has been associated with up to 41% lowerCK-MB release compared to CABG, when the meancross-clamp times have been in the 40-min range.While this difference has not been shown to be clin-ically significant in the open chest approach, it mayreach clinical significance in the TECAB operation,where the cross-clamp times have been more thantwice as long and CK-MB release even higher. Thishypothesis has not been put to a test yet, sinceTECAB-BH is a relatively new and more technicallychallenging procedure. Myocardial preservation dur-ing TECAB-BH can be improved by using intracoro-nary shunts. Certain intraoperative pharmacologicinterventions might improve myocardial protectionalso. Beta-blockers can slow the heart rate whichdecreases myocardial oxygen consumption (with itsattendant beneficial effects on myocardial metabolismand preservation) and facilitates the conduct of thesurgery [23]. Adenosine can have a similar technicalbenefit of slowing the heart while also attenuating thereperfusion injury to the myocardium [23,24].

In conclusion, current data support the follow-ing inferences regarding myocardial protection inminimally invasive cardiac surgery:1 The technology for delivery of either antegrade orretrograde cardioplegia for minimally invasive cardiacsurgery is as reliable as that for open conventionalcardiac surgery.2 For periods of cardiac arrest of less than 60 min,adequate myocardial protection may be achieved in anarrested normal heart using either cold crystalloid orcold blood cardioplegia.3 The deficiencies of cold crystalloid cardioplegiabecome clinically apparent with longer cross-clamptimes, thereby increasing the morbidity and mortality.4 While a comparable degree of myocardial protec-tion can be achieved with either open or closed chestapproaches, the limitations of current myocardialprotection strategies in robotic surgery arise fromthe prolonged cross-clamp times associated with it.Stated in another way, open chest operations on theheart would probably have similar outcomes from amyocardial preservation standpoint (i.e. incidence

206 CHAPTER 25

of low cardiac output syndromes, arrhythmias) if they

involved similarly long periods of cardiac arrest.

5 Beating heart surgery as a myocardial protection

strategy can be a useful strategy in selected patients

requiring coronary artery bypass. However this proce-

dure demands a high degree of technical proficiency

and a steep learning curve.

6 Beating heart valve surgery is still just a concept in

minimally invasive cardiac surgery.

With continued research in the field of myocardial

protection and ischemia-reperfusion injury, and the

development of proximal and distal anastomotic

devices (to decrease the operative times in coronary

bypass surgery), the future of minimally invasive

cardiac surgery certainly holds great promise.

Acknowledgment

The authors wish to acknowledge the help of Mohan

Thanikachalam, MD, in the preparation of this

manuscript.

References1 Aklog L, Adams D, Couper GS et al. Techniques and

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3 Carpentier A, Loulmet D, Carpentier A. First open heartoperation (mitral valvuloplasty) under videosurgerythrough a minithoracotomy [French]. Comp Rend AcadSci 1996; 319:219-23.

4 Fann JI, Pompili MF, Stevens JH et al. Port-access cardiacoperations with cardioplegic arrest. Ann Thorac Surg1997;63(6Suppl):S35-9.

5 Schwartz DS, Ribakove GH, Grossi EA et al. Minim-ally invasive cardiopulmonary bypass with cardioplegicarrest: a closed chest technique with equivalent myocar-dial protection. / Thorac Cardiovasc Surg 1996; 111:556-66.

6 Schwartz DS, Ribakove GH, Grossi EA et al. Minimallyinvasive mitral valve replacement: port-access technique,feasibility and myocardial functional preservation. /Thorac Cardiovasc Surg 1997; 113:1022-31.

7 Dogan S, Aybek T, Andreben E et al. Totally endoscopiccoronary artery bypass grafting on cardiopulmonarybypass with robotically enhanced telemanipulation:report of forty-five cases. / Thorac Cardiovasc Surg 2002;123:1125-31.

8 Mohr FW, Falk V, Diegeler A et al. Computer-enhanced'Robotic' cardiac surgery: experience in 148 patients./ Thorac Cardiovasc Surg 2001; 121:842-53.

9 Damiano RJ, Ehrman WJ, Ducko CT et al. Initial UnitedStates clinical trial of robotically assisted endoscopiccoronary artery bytpass grafting. / Thorac Cardiovasc Surg2000;119:77-82.

10 Mohr FW, Falk V, Diegeler A, Autschbach R. Computer-enhanced coronary artery bypass surgery. / ThoracCardiovasc Surg 1999; 117:1212-15.

11 Kappert U, Cichon R, Schneider J et al. Closed-chestcoronary artery surgery on the beating heart with the useof a robotic system. / Thorac Cardiovasc Surg 2000; 120:809-11.

12 Boyd WD, Rayman R, Desai ND et al. Closed-chestcoronary artery bypass grafting on the beating heart withthe use of a computer-enhanced surgical robotic system./Thorac Cardiovasc Surg 2000; 120:807-9.

13 Schroeyers P, Wellens F, De Geest R et al. Minimally inva-sive video-assisted mitral valve surgery: our lessons after a4-year experience. Ann Thorac Surg 2001; 72: S1050—4.

14 Mohr FW, Falk V, Diegeler A et al. Minimally invasiveport-access mitral valve surgery. / Thorac Cardiovasc Surg1998:115:567-76.

15 Chitwood WR, Wixon CL, Elbeery JR et al. Video-assisted minimally invasive mitral valve surgery. / ThoracCardiovasc Surg 1997; 114:773-82.

16 Zimmerman-Klima PM, Philpott JM, Elbeery JR, LalikosJF, Chitwood WR, JR. Combined minimally invasivemitral valve repair and direct coronary artery bypass. Anew alternative to sternotomy. Chest 2002; 122:344-7.

17 Torraca L, Ismeno G, Quarti A, Alfieri O. Totally endo-scopic atrial septal defect closure with a robotic system:experience with seven cases. Heart Surg Forum 2002; 5:125-7.

18 Kottkamp H, Hindricks G, Autschbach R et al. Specificlinear left atrial lesions in atrial fibrillation. Intraoperat-ive radiofrequency ablation using minimally invasivesurgical techniques. JAm Coll Cardiol 2002; 40:475-80.

19 Schneider F, Onnasch JF, Falk V et al. Cerebral micro-emboli during minimally invasive and conventionalmitral valve operations. Ann Thorac Swrg2000;70:1094-7.

20 Dijk DV, Nierich AP, Jansen EWL et al. Early outcomeafter off-pump versus on-pump coronary bypass surgery.Results from a randomized study. Circulation 2001; 104:1761-6.

21 Califf RM, Abdelmeguid AE, Kuntz RE et al. Myonecrosisafter revascularization procedures. / Am Coll Cardiol1998; 31:241-51.

22 Kirklin JW, Conti VR, Blackstone EH. Prevention ofmyocardial damage during cardiac operations. N Engl}Med 1979; 301:135-41.

23 Chitwood WR, Wixon CL, Elbeery JR, Francalancia NA,Lust RM. Minimally invasive cardiac operations: adapt-ing cardioprotective strategies. Ann Thorac Surg 1999; 68:1974-7.

24 Owall A, Ehrenberg J, Brodin LA, Juhlin-Dannfelt A,Sollevi A. Effects of low-dose adenosine on myocardialperformance after coronary artery bypass surgery. AdaAnaesthesiolScand 1993; 37:140-8.

CHAPTER 26

Current concepts in pediatricmyocardial protection

Bradley S. Allen, MD

Repair of congenital heart defects is becoming morefrequent in infants and neonates. Despite majoradvances in the surgical correction of congenital car-diac disease, perioperative myocardial damage remainsthe most common cause of morbidity and deathfollowing technically successful cardiac operations [ 1-4]. As many as 90% of patients who do not survivethe perioperative period show varying combinationsof gross, microscopic, or histochemical myocardialnecrosis which is most severe in the subendocardiumof the left or right ventricle, depending on whichchamber is affected by the basic cardiac lesion [1,5].This necrosis occurs in the absence of coronaryartery obstruction and may affect the entire subendo-cardium in patients with valvular and congenitalheart disease. Poor protection can also lead to endo-cardial fibrosis with late cardiac dysfunction despite a"successful surgical outcome" [1]. Protection of theneonatal heart is further complicated by a reducedresponse to inotropic agents compared to the adult[2,4,6]. Thus, preservation of myocardial functionin neonates during cardiac operations assumes evengreater importance, because a perioperative insult isless well tolerated and more difficult to treat.

This chapter provides an overview of current con-cepts and recent advances in pediatric myocardialprotection, and details our experimental and sub-sequent clinical experience in protecting the pediatricheart undergoing operative repair. It examines themanagement of cardiopulmonary bypass prior toischemic arrest, and subsequent cardioplegic strategy,as both are critical to avoiding a perioperative injury.Only by optimizing protection can the patient fullybenefit from the successful surgical correction of anunderlying congenital abnormality.

Preoperative considerations

Pediatric hearts are usually subjected to physiologicstresses (i.e. hypoxia) that are quite different fromthose seen in the adult, and in some cases thesechanges can affect not only the heart, but also all organsystems. Experimentally, it has been demonstratedthat normal immature myocardium has a greatertolerance to ischemia when compared to maturemyocardium [2,4,7]. Nonetheless, in clinical practicethis is rarely observed, and the immature myocardiumis generally far more susceptible to injury during car-diac surgery [4,8-10]. This is almost certainly theresult of the negative effects upon the myocardium ofthe various abnormal physiologic conditions for whichoperations are undertaken. Nowhere are these effectsgreater than in the neonate, where a preoperativestress is almost always present prior to surgery. Inaddition, there may be intrinsic differences in myo-cardial energy reserves from one patient to another,regardless of preoperative conditions. For example,ATP levels may be reduced up to 50% in some"normal" unperturbed hearts [11]. These metabolicchanges are further influenced by the physiologicstresses of acute or chronic hypoxia, and pressure orvolume overload.

Volume and pressure overloadVolume overloading of the pediatric heart occurs inmany conditions, such as left-to-right shunts, singleventricle with mixed circulation, and severe atrioven-tricular valve insufficiency. The ability of the imma-ture myocardium to compensate for this is limited,as these hearts normally function at a high diastolicvolume, and therefore have a limited diastolic reserve

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208 CHAPTER 26

[4,6,12]. Ventricles hypertrophy and eventually dilate,their myocardial oxygen requirements increase, andtheir structural and metabolic properties change. Eachof these changes has a negative effect upon the responseof the myocardium to surgical stress or ischemia.

Similarly, congenital lesions that mechanicallyobstruct ventricular outflow or result in increasedarterial resistance lead to ventricular hypertrophy.Ventricular hypertrophy quickly causes reduceddiastolic compliance and results in lower high-energyphosphate levels and inefficient oxygen utilization[13-15]. Hypertrophy effects regional myocardialblood flow resulting in relative hypoperfusion of thesubendocardium, which may become ischemic duringtachycardia or exercise [1]. Marked hypertrophy canalso impair adequate cardioplegic distribution to thevulnerable subendocardium, as well as predispose toan ischemia-reperfusion injury with the initiation ofbypass [ 1 ]. As with volume overloading, these changesmake the heart more susceptible to an ischemic insult,and may negatively influence the function of theremaining ventricle.

HypoxiaHypoxia is a common physiologic stress in pediatricpatients, and is present in most neonates undergoingoperative repair. Acute hypoxia and acidosis mayoccur as a consequence of many congenital heartdefects, and can result in depletion of glycogen, ATP,and Kreb's cycle intermediates, leading to myocar-dial dysfunction [4,8-10,16]. Such substrate- andenergy-depleted hearts are far less tolerant of futureischemic insults. Significant acute hypoxia forces themyocardium to rely upon anerobic metabolism, andwhen acidosis is present, this further heightens thesedeleterious effects. Hypoxia may also cause a reducedresponse to catecholamines [2-4]. Chronic hypoxialeads to cyanosis, a condition frequently encounteredin infants and children undergoing open-heart sur-gery. In spite of compensatory mechanisms, cyanotichearts also develop substrate depletion and metabolicderangements when compared to normoxic hearts,resulting in a relatively greater intolerance to ischemia[2,4,8-10].

Reoxygenation and cardiopulmonary bypassmanagementBecause congenital malformations of the heart fre-quently lead to preoperative physiologic abnormal-

ities ("stress") that are quite different from those seenin the adult, the concerns during cardiopulmon-ary bypass are not necessarily the same. The mostcommon preoperative stress in adults is ischemia,secondary to coronary artery disease, and the majorconcern is avoidance of a "regional" myocardial reper-fusion injury with the reintroduction of blood [1]. Bycontrast, the most common preoperative stress inpediatric patients is hypoxia (cyanosis) [2,4,9,17]. Themajor concern therefore is whether a reoxygenationinjury (similar to a reperfusion injury) occurs with theabrupt reintroduction of oxygen. The occurrence ofsuch an injury could be even more detrimental, as itwould result in "global" damage, since hypoxia affectsthe entire body, not just the heart.

Cyanosis depletes the myocardium of endogen-ous antioxidants, and a growing body of experimentaland clinical evidence indicates that this may makethe cyanotic immature heart more susceptible to anoxygen-mediated injury when molecular oxygen isrestored [18-23]. The reversal of hypoxemia occurswith initiation of extracorporeal circulation and pre-cedes the surgical ischemia used for operative repairin children with cyanotic disease. The conventionalmethod of starting cardiopulmonary bypass (CPB) ininfants and children with hypoxemia is to abruptlyraise oxygen tension (Po2) to approximately 400-500 mmHg. Does this sudden reintroduction of oxy-gen cause an "unintended injury," and if so, can it beprevented? Such an injury might help explain why thecyanotic heart is more vulnerable and less tolerant tosubsequent surgical ischemia than the normoxic heart[4,8-10,23,24].

We initially examined the consequences of hypoxiaand reoxygenation using an in vivo piglet model tosimulate the hypoxic (cyanotic) infant undergoingsurgical repair [25,26]. Neonatal piglets underwent60 min of ventilator hypoxia by lowering the fractionof inspired oxygen to 8-10%, producing an arterialoxygen tension of 25-35 mmHg, and an oxygensaturation of 65-70%. This was a "pure" hypoxicstress without any evidence of ischemia [26]. Animalswere then abruptly reoxygenated by increasing theventilator fraction of inspired oxygen (Fio2) to 100%,or placed on cardiopulmonary bypass at a Fio2 of100%, simulating the usual clinical practice. Abruptreoxygenation by either method caused an oxygenfree radical mediated injury, resulting in a reductionin cardiac output, depressed left ventricular (LV)

Current concepts in pediatric myocardial protection 209

Figure 26.1 Percent recovery of end-systolic elastance (EES)compared to baseline values, at the end of hypoxia, andafter the abrupt reintroduction of oxygen (reoxygenation,100% Fio2), either by increasing the oxygen in theventilator or initiating cardiopulmonary bypass. * P< 0.05versus hypoxia.

Figure 26.3 Percent recovery of end-systolic elastance(EES) compared to baseline values in hypoxic animalsundergoing cardiopulmonary bypass, after abruptreoxygenation at a Po2 of 400-500 mmHg, gradualreoxygenation at a Po2 of 80-100 mmHg, orleukodepletion. * P< 0.05 versus Po2 400-500 mmHg.Reprinted from [24], with permission from Elsevier.

function, elevated pulmonary vascular resistance, and

pulmonary alveolar damage manifested by a reduc-

tion in the arterial/alveolar (a/A) ratio (Figure 26.1).

This injury was independent of the method of reoxy-

genation, and so it appears to be primarily related to

the sudden reintroduction of oxygen, and not the

effects of CPB. This unintended reoxygenation injury

could explain why hypoxic (cyanotic) infants are more

sensitive to surgical ischemia, and often experience

myocardial dysfunction despite performing an appar-

ently technically successful operation with "good"

myocardial protection [2,4,8-10,18,19,27].

Maintaining normoxemia (Po2 80-100 mmHg)

rather than hyperoxemia during the initiation of CPB

substantially reduces oxidant damage and decreases

the extent of myocardial dysfunction (Figures 26.2 &

26.3). These benefits coincide with the Po2-dependent

nature of the reoxygenation injury, because free rad-

ical production and myocardial injury after reoxygena-

tion of isolated heart preparations are proportionate

Figure 26.2 Myocardial tissue antioxidant reserve capacity(measurement of oxygen free radical production) inanimals undergoing cardiopulmonary bypass after abruptreoxygenation at a Po2 of 400-500 mmHg, gradualreoxygenation at a Po2 of 80-100 mmHg, orleukodepletion. * P< 0.05 versus Po2 400-500 mmHg.

to oxygen tension [28,29]. The avoidance of hyper-

oxemia during reoxygenation in cyanotic infants to

reduce injury may in a sense be comparable with

controlling the initial reperfusate following ischemia

to avoid a reperfusion injury [ 1,30].

Although white blood cells are involved mainly in

the maintenance of the immune system, under certain

pathologic conditions of altered physiology they may

cause damage to myocardial, pulmonary, and vascular

tissue [31-33]. Activated white cells have been shown

to play a major role in the generation of oxygen

free radicals after ischemia, and it seems logical they

should also be active in the reoxygenation injury, since

both ischemia and hypoxia subject tissue to low oxy-

gen levels [31,33,34]. The detrimental effects of white

blood cells (WBCs) can be prevented either by remov-

ing the leukocytes or blocking their actions. Leukocyte

depletion is a readily available method, which allows

the surgeon to safely minimize the harmful effects

of neutrophils, without risking side effects of phar-

macologic interventions aimed at altering leukocyte

function, or preventing the free radical injury through

the use of exogenous oxygen radical scavengers.

The effect of leukocyte removal was tested in

neonatal piglets following the same acute (60 min)

hypoxic stress [17,25,26]. When neutrophils were

reduced by a leukocyte-depleting filter, the detri-

mental effects of sudden reoxygenation were obviated,

with a marked reduction in oxygen free radical forma-tion, preservation of LV contractility and diastolic

compliance, maintenance of pulmonary alveolar cap-

illary gas exchange (a/A ratio), and only a slight rise in

pulmonary vascular resistance (Figures 26.2 & 26.3).

This occurred despite using an Fio2 of 100%. In fact,

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210 CHAPTER 26

the increase in pulmonary vascular resistance was evenless than in nonhypoxic (control) animals subjectedto CPB, suggesting that leukocyte nitration shouldbe used in all pediatric operations where postoper-ative pulmonary hypertension could be problematic.Several experimental and clinical studies support thisimplication, and in fact have documented a reductionin pulmonary injury with leukonltration even in non-cyanotic infants [35,36].

Clinical studiesDespite these findings, many surgeons still doubtthe existence and the clinical significance of suddenlyrestoring oxygen to the hypoxic heart. They point outthat the majority of studies, which have documentedthis injury, have utilized an acute hypoxic injury,which in contrast to the chronically hypoxic infant maynot allow sufficient time to develop compensatoryadaptation. This adaptation, they argue, may allow thechronically hypoxic patient to avoid an injury withthe reintroduction of oxygen. Nevertheless, the post-reoxygenation changes seen after acute hypoxemiaparallel those reported in cyanotic patients whoundergo reoxygenation during bypass [18,19]. More-over, a recent report by Corno and associates demon-strated an identical injury in animals subjected to2 weeks of chronic hypoxia [37]. Such an unintendedinjury may explain clinical reports showing thatcyanotic hearts are more vulnerable than noncyanotichearts to ischemia/reperfusion damage despite com-parable cardioplegic protection and shorter ischemictimes [2,4,8-10,38,39].

To more critically examine the clinical relevanceof the reoxygenation injury, myocardial tissue antiox-idant reserve capacity was analyzed in cyanotic andacyanotic patients before and 10 min after initiatingbypass [26,40]. This allows quantification of oxygenfree radical formation during reoxygenation, and isthe same test used in numerous experimental studiesof acute hypoxia. It therefore allows for a direct com-parison of acute versus chronic hypoxia [22,25,40—42].Furthermore, antioxidant reserve capacity also pre-dicts the ability of the heart to withstand a subsequentischemic challenge, and there appears to be direct link-age between antioxidant depletion, oxidant damage,and cardiac and pulmonary dysfunction [22,25,41,42].Normal hearts with abundant antioxidants developonly minor functional impairment after aortic clamp-ing, whereas hearts with a limited antioxidant reserve

Figure 26.4 Percent increase in myocardial tissueantioxidant reserve capacity in acyanotic and cyanoticinfants after reoxygenation using cardiopulmonary bypass.*P<0.05.

capacity exhibit marked contractile depression aftercardioplegic arrest [9,18,19,38,39,41,43].

There was no difference in prebypass myocardialantioxidant reserve capacity between cyanotic andacyanotic patients. This parallels our experimentalfindings after acute hypoxia [25]. Initiating bypassin low-risk acyanotic infants (atrial septal defect,ventricular septal defect) caused minimal change inthe antioxidant reserve capacity, inferring that in theabsence of hypoxia only a small quantity of oxygenfree radicals are generated. By contrast, abrupt reoxy-genation of cyanotic infants resulted in a significantdepletion of endogenous tissue antioxidants (Fig-ure 26.4). This suggests that abrupt reoxygenation ofchronically hypoxemic infants generates abundantoxygen free radicals, since prebypass endogenous tis-sue stores of antioxidants were not different betweenacyanotic and cyanotic hearts. This, again, parallelsour experimental studies [25].

Cyanotic infants reoxygenated using a Po2 of400-550 mmHg (Fio2 100%) had the greatest lossof myocardial antioxidant reserve capacity (highestmalondialdehyde formation) indicating the largestexposure to oxygen free radicals (Figure 26.5). More-over, the generation of malondialdehyde was four tosix times greater in cyanotic infants compared to acutehypoxic animals, implying a greater production ofoxygen free radicals with reoxygenation after chroniccyanosis [25,40]. This supports the experimental workof Corno and associates, who also observed greaterproduction of oxygen free radicals following chronichypoxia [37]. The most probable explanation forthese results is that chronically hypoxic animals (orpatients) often become ischemic during periods ofincreased stress (tachycardia) or exercise [21,44]. Thissubjects them to both a hypoxic and ischemic stress.By contrast, acute experimental hypoxia results inno ischemia [26]. It is therefore not surprising that


Figure 26.5 Percent increase in antioxidant reservecapacity in cyanotic infants after reoxygenation withcardiopulmonary bypass using a Po2 of 400-500 mmHg,gradual reoxygenation at a Po2 of 80-100 mmHg, or whiteblood cell (WBC) filtration. The more malondialdehyde(MDA, nmol/g protein) produced by an oxidant challenge(4 mmol t-butyl hydroperoxide), the greater the loss ofendogenous tissue antioxidants, indicating exposure toincreased levels of oxygen free radicals duringreoxygenation. * P<0.05. Reprinted from [35], withpermission from Society of Thoracic Surgeons.

a combination of hypoxia and ischemia results in

a more severe injury with reperfusion. This oxidantinjury probably explains why ventricular functionis often temporarily depressed in cyanotic infantsundergoing extracorporeal membrane oxygenation,even in the absence of surgical ischemia [45,46].

Initiating bypass using a normoxic strategy (Po2

80-100 mmHg) reduced the change in antioxidantreserve capacity, and using WBC filtration, which fur-ther lowered oxygen radical formation, maximizedthis effect (Figure 26.5). This is once again precisely

what was demonstrated in the experimental settingafter acute hypoxia, where a lower production ofoxygen free radicals correlated with an improvementin myocardial and pulmonary function [17,25,26].Although no patient reoxygenated with leukocyte-depleted blood had a substantial change in the antiox-idant reserve capacity, the generation of oxygen freeradicals was further suppressed by combining nor-moxia and WBC filtration [40]. Indeed, the antioxid-ant reserve capacity in these infants was unchangedfrom baseline values, and even lower than in acyanoticpatients, indicating the effects of lower oxygen levelsand white cell filtration are additive.

Based on this extensive experimental and clin-ical infrastructure, we currently recommend using anormoxic bypass strategy combined with leukodeple-tion in all hypoxic (cyanotic) patients (Table 26.1).We also use this strategy in normoxic patients withventricular hypertrophy or pulmonary hypertension.

Marked ventricular hypertrophy from pressure vol-ume overload can lead to subendocardial ischemia,

Table 26.1 Limiting the reoxygenation injury in clinical

practice.

Bypass protocol:

• Wash and leukodeplete blood prime

• Inline arterial filter

• Initiate bypass using normoxic management

(Po2 80-100 mmHg)

and a reperfusion injury can be limited by the samebypass strategy. Leukodepletion also reduces pul-monary injury even in noncyanotic patients, and so ithelps limit problems with postoperative pulmonaryhypertension [35,36]. The bypass circuit is primedand initiated using a normoxic strategy (Po2 80-100mmHg), and the Fio2 increased slowly over the next10-20 min to maintain a Po2 of 100-150 mmHg. Inclinical practice hyperoxemic bypass is performed

routinely but is likely never needed, because a Po2 of400-500 mmHg confers only negligible increase in O2

content compared to a Po2 of 100-150 mmHg. In bothinstances the oxygen saturation is essentially 100%.Moreover, a bypass Po2 greater than 180 mmHg hasbeen associated with impairment of peripheral perfu-sion [47]. If a blood prime is used, it is always washedand leukodepleted, and a leukodepleting filter isplaced in the arterial line for the entire procedure. Istrongly believe blood for the bypass prime should

always be leukodepleted, since oxygen free radical for-mation is greatest with the initial reintroduction ofoxygen. This is the most important time to limit WBCexposure. In addition, banked blood contains a largeamount of activated WBCs, which can cause pulmon-ary damage even in the absence of hypoxia [35,36].Inefficient WBC filters, coupled with leukodepletionduring times which are less critical, probably explainswhy some investigators have failed to demonstrate aclinical advantage with WBC filtration, despite over-whelming experimental evidence as to their benefit[25,26,35,40,48-50]. The bypass prime is also lefthypocalcemic, as we (unpublished data) and othershave demonstrated that hypocalcemia can substan-tially reduce the reperfusion/reoxygenation injurywith the initiation of bypass [51,52].

Cardioplegia

Cardioplegia application to pediatric congenital heartsurgery has made tremendous gains over the past

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212 CHAPTER 26

10 years. However, recovery and outcome statisticscontinue to point out the need for improvements inthis increasingly younger patient population. Neonatalmyocardial protection remains suboptimal, resultingin an increased operative mortality compared with theresults for older children and adults [2-4,9]. In gen-eral, improvements have benefitted from the adultcardiac experience. However, in view of the structural,functional, and metabolic differences, extrapolationof adult cardioprotective strategies to the neonate isfundamentally imprudent and potentially harmful[2,4,6,7,12,53]. Myocardial protective strategies andcardioplegia solutions must be studied in the infantheart if neonatal protection is to be truly optimized.

Despite the prevalence of hypoxia or other physio-logic changes in the neonatal population, few experi-mental studies have included "stressed" hearts whenexamining cardioplegia solutions in pediatric hearts.By contrast, in clinical practice, congenital lesionsusually result in hypoxia or pressure volume overload,and therefore, "normal" (nonstressed) hearts areprobably uncommon, especially in the neonatal popu-lation. Including stressed hearts in any investigationof cardioplegia solutions is extremely important, be-cause stressed hearts are less tolerant to ischemia, andmore sensitive to changes in the method of cardio-plegic protection [2—4,8,9]. They therefore provideinformation concerning the patients most vulnerableto postoperative dysfunction. This is why adult studiesoften use an acute ischemic stress to investigate car-dioplegia strategies, even though it does not exactlymimic the clinical conditions of chronic angina or car-diogenic shock [ 1 ]. However, since pediatric hearts donot usually experience severe preoperative ischemia,

the stress must be changed to one that is clinicallyrelevant, such as hypoxia.

The type of experimental model is also important,as there are marked differences between an in vivo andan isolated heart preparation. In contrast to studies inthe adult, most neonatal investigations have used anisolated heart model. Although this allows for preciseexperimental control, it does not mimic the clin-ical conditions of the operating room. For instance,bronchial blood return and noncoronary collateralflow are absent in the isolated heart but may have aprofound effect in the in vivo model, because the car-dioplegia solution may be washed away, changing thecellular environment [1,38,39]. Hypothermia, whichmay provide a dominate protective effect, is easier tomaintain in the isolated heart preparation, whereasthe heart is constantly rewarmed in the intact animalsetting [1,38,39]. Results from isolated heart prepara-tions may therefore be misleading, and not clinic-ally applicable. These differences probably explain theconflicting results obtained by different investigators,especially with regards to blood versus crystalloid solu-tions and cardioplegia calcium concentration [38,39].

Because of these concerns we investigated differentcardioplegic strategies in both "normal" (nonstressed)and "hypoxic" (stressed) neonatal hearts using an invivo intact animal model that simulates the operatingroom. Our warm and cold blood cardioplegia solu-tions are shown in Tables 26.2 and 26.3, and wemodified the solution, or the method of delivery, toinvestigate each component.

Blood versus crystalloidWhile blood cardioplegia predominates in the adult

Table 26.2 Warm induction and

reperfusate blood cardioplegia solution.

Reprinted from [24], with permission

from Elsevier.

Image Not Available


Table 26.3 Cold blood cardioplegia

solution. Reprinted from [24], with

permission from Elsevier.

* When mixed in a 4:1 ratio with blood.

patient undergoing open heart surgery, crystalloidcardioplegia is still widely used in the pediatric popu-lation, and most investigations have demonstratedlittle or no difference between blood and crystalloidcardioplegia [1,2,54-56]. Our studies support theseresults, as we also found that both blood andcrystalloid (St Thomas) cardioplegia provide excellentmyocardial protection of "normal" neonatal heartsnot subjected to a preoperative stress; with completepreservation of myocardial function [39]. However,subjecting the neonatal piglet to a hypoxic "stress"profoundly altered these results. Blood cardioplegiasolutions not only protected the heart from fur-

ther damage, but also facilitated repair of the injurycaused by hypoxia and reoxygenation; resulting incomplete preservation of myocardial and vascularfunction. Conversely, crystalloid cardioplegia solutionwas unable to adequately protect the hypoxic heart,resulting in postbypass myocardial and vasculardysfunction (Figure 26.6).

Blood cardioplegia has several advantages overcrystalloid cardioplegia, which help explain thesefindings [ 1 ]. With blood, the heart is arrested in an

oxygenated environment, so that no loss of high-energy phosphate stores occurs during the short

Figure 26.6 Blood versus crystalloid cardioplegia. Recoveryof LV systolic function in nonhypoxic (normal) and hypoxichearts undergoing 70 min of cardioplegic arrest withblood or crystalloid cardioplegia solution. Contractility ismeasured by the end-systolic elastance (EES) and expressedas a percentage of control (baseline) values. * P< 0.001.Reprinted from [42], with permission from Elsevier.

period of electromechanical activity before asystole[1]. By contrast, several investigators have reportedsignificant decreases in high-energy phosphates dur-ing the few heartbeats occurring during inductionwith crystalloid cardioplegia. When given as a warminduction, blood cardioplegia can "resuscitate" theinjured myocardium, thereby allowing it to bettertolerate the subsequent ischemia (see "Cardioplegicinduction" below) [1,57]. Blood cardioplegia providesoxygen and nutrients during multidose infusions toenhance cellular metabolism and replenish depletedenergy storage [1]. Lastly, since the hypoxic heartmay be more susceptible to a reperfusion injury afterischemia, use of a warm blood cardioplegic reper-fusate may limit this injury (see "Reperfusion" below).

Calcium and magnesiumAn important consideration regarding myocardialprotection is calcium concentration, because highlevels have been implicated as a major component incellular injury during ischemia and reperfusion [1,2,58,59]. The neonatal heart maybe more susceptibleto a calcium-mediated cellular injury because thesarcoplasmic reticulum of the immature myocardiumpossesses a diminished capacity to sequester calciumand because of different characteristics of the calciumtransport system [2,4,53]. Although hypocalcemiccardioplegia solutions provide superior protectionof adult hearts, the ideal cardioplegia calcium con-centration in newborns continues to be debated,and both hypocalcemic and normocalcemic solutionshave been shown to provide superior protection ofthe normal heart [ 1,2,4,54,60].

As in the case of blood versus crystalloid cardio-plegia, these seemingly conflicting results are probablysecondary to the experimental model (in vitro vs.in vivo) and the preoperative state of the heart. Ourstudies in nonhypoxic ("normal") hearts supportmost previous investigations, as we also saw complete

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214 CHAPTER 26

Figure 26.7 Hypocalcemic versus normocalcemiccardioplegia. Recovery of LV systolic function innonhypoxic (normal) and hypoxic hearts undergoing70 min of cardioplegic arrest with hypocalcemic (Low) ornormocalcemic (NL) cardioplegia solution. Contractility ismeasured by the end-systolic elastance (EES) and expressedas a percentage of control (baseline) values. * P< 0.001.Reprinted from [47], with permission from Elsevier.

preservation of myocardial and vascular functionwith either a normocalcemic or hypocalcemic bloodcardioplegia solution [1,2,4,38,54,60]. By contrast,subjecting the neonatal heart to hypoxia ("stress")profoundly altered the results. Hypocalcemic cardio-plegia solutions allowed for repair of the injury causedby hypoxia and reoxygenation, resulting in completepreservation of myocardial and vascular endothelial

cell function. Conversely, there was an increased cellu-lar injury when normocalcemic solutions were used toprotect hypoxic hearts, manifested by depression inpostbypass myocardial and endothelial cell function(Figure 26.7). These findings should not be surpris-ing, because an increased sensitivity to calcium was

also observed when adult hearts were subjected to anischemic stress [1,61].

In clinical practice, there are often transient fluxesin the cardioplegia ionized calcium concentration

due to variability in pH, hemodilution, temperature,potassium, and, perhaps most importantly, systemiccalcium levels in the bypass circuit. The ischemicneonatal myocardium is therefore at risk of exposureto potentially higher or lower cardioplegic calciumlevels than originally intended, which may increase therisk of a calcium-mediated injury. Any unintendedtransient calcium increase assumes even greater im-portance in pediatric myocardial protection because

immature myocytes are less able to handle a given cal-cium load when compared to the adult [2,53,58,60].In addition, despite concerns over calcium injury,many pediatric surgeons continue to use normocal-cemic cardioplegia solutions.

The addition of magnesium, which inhibits cellularcalcium entry, may solve this dilemma by preventing

damage from higher cardioplegic calcium concentra-tions. Magnesium is lost during ischemia, leading toan increase in postoperative arrhythmias and possibleimpairment of magnesium-dependent cellular reac-

tions [62-66]. Replacing extracellular magnesium byenriching cardiologic solutions has been shown todecrease the incidence of postoperative arrhythmias aswell as improve myocardial protection by a variety ofpathways [62-67]. The most important of these isprobably magnesium's ability to modulate intracellu-lar calcium levels by inhibiting calcium entry acrossthe cellular membrane, as well as displacing calciumfrom the binding sites of the sarcolemmal membrane[62-64,67]. This prevents mitochondrial calciumuptake, which can lead to uncoupling of oxidativephosphorylation with a decrease in ATP production.Postischemic calcium entry is further limited becausemagnesium prevents an influx of sodium, whichduring reperfusion is exchanged for calcium. Supple-mental magnesium can also facilitate asystole at lower

potassium concentrations [1]. This is importantbecause high potassium concentrations can damagevascular endothelial cells directly, as well as enhanceendothelial and myocyte calcium entry.

In the absence of magnesium enrichment, ahypocalcemic cardioplegia solution results in com-plete preservation of myocardial function in hypoxic(stressed) hearts [38,62]. Magnesium supplementa-tion was, however, found to be beneficial if thehypoxic (stressed) neonatal heart was protected with anormocalcemic cardioplegia solution [62]. Instead ofa significant cellular injury, magnesium enrichmentprotected the heart from further damage, resulting

in complete preservation of myocardial and vascularendothelial cell function (Figure 26.8). Magnesium,therefore, offsets the detrimental effects of high-calcium cardioplegia solutions in hypoxic hearts.Indeed, there appears to be a specific interrelation-ship between magnesium and calcium that has led tothe perception that magnesium may not be necessarywhen a hypocalcemic cardioplegia solution is utilized[62-64,67].

Whether magnesium enrichment can improve theprotection afforded by hypocalcemic blood cardio-plegia solution remained unanswered by this study,since hypoxic hearts regain complete function whenprotected with hypocalcemic cardioplegia alone. Inorder to answer this question, neonatal hearts had toundergo a more severe stress (hypoxia and ischemia).

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Figure 26.8 Postbypass percent recovery of end-systolicelastance (EES) compared to baseline in hypoxic neonatalpiglets undergoing 70 min of cardioplegic arrest. Note:Magnesium enrichment of the normocalcemic cardioplegiasolution offset the detrimental effects of high levels ofcalcium in hypoxic piglets, resulting in complete return ofsystolic function. * P< 0.001. Reprinted from [48], withpermission from Elsevier.

Hypoxia is associated with metabolic adaptations thatallow normal aerobic metabolism to persist in the rest-ing state. However, this compensatory mechanism isexpended readily with stress, as atrial pacing or cate-cholamine infusion causes myocardial lactate produc-tion, indicating ischemia with a shift toward anaerobicmetabolism [21,44]. This metabolic shift may occur

in cyanotic patients during the stresses of daily life,

such as exercise, emotional upset, and tachycardia, andbecome compounded during anoxic spells. A com-bined hypoxic-ischemic stress, therefore probablymore closely resembles the chronic hypoxic (cyanotic)patient, and was used to determine if magnesiumimproves hypocalcemic cardioplegia solutions [4,9,10,16,17,21,44,68].

Following an hypoxic-ischemic stress, neitherhypocalcemic blood cardioplegia without magnesiumnor normocalcemic cardioplegia with magnesiumwas able to provide adequate protection [69].

By contrast, adding magnesium to hypocalcemic car-dioplegia solutions substantially improved myocar-dial protection and allowed for complete recoveryof metabolic and myocardial function (Figure 26.9).This beneficial effect is similar to the improved resultsobtained in adults with calcium channel blockers,which also inhibit calcium entry [1,61]. Calciumchannel blockers, however, have a prolonged effect,

which may depress postoperative myocardial function,making them a less attractive cardioplegic additive.Because calcium and magnesium have an interrela-tionship, similar results might have been obtainedin the absence of magnesium by further lowering thecardioplegic calcium concentration. However, this ispotentially dangerous, as myocardial recovery may

Figure 26.9 Postbypass LV systolic function as measured bythe end-systolic elastance (EES) and expressed as percentof recovery of baseline in neonatal piglets undergoing ahypoxic-ischemic stress. Note: Hearts protected with ahypocalcemic cardioplegia solution alone exhibitedmarked loss of systolic function. By contrast, there iscomplete preservation of systolic function whenmagnesium is added to hypocalcemic cardioplegia solution.However, magnesium enrichment was not able to offsetthe detrimental effects of a normocalcemic cardioplegiasolution in hypoxic-ischemic hearts, resulting in diminishedsystolic function. * P< 0.001.

be reduced when the cardioplegic calcium is lessthan 100 mmol/L, and although unlikely, a calciumparadox can occur if levels are reduced to less than50 mmol/L [1,29,59,61,64]. The optimal dose ofmagnesium therefore probably depends on the car-dioplegic calcium concentration in as much as thebeneficial effects of magnesium and hypocalcemiaare additive as well as interdependent.

Operative strategyThe strategies for clinical cardioplegia may be separ-ated into the phases of (i) induction, (ii) maintenance,and (iii) reperfusion.

Cardioplegic inductionA brief (5 min) infusion of warm blood cardioplegiasolution can be used as a form of active resuscitationin energy-depleted (ischemic) adult hearts whichmust undergo subsequent aortic clamping [1,70,71].Normothermia (37°C) optimizes the rate of cellularrepair, and enrichment with the amino acids aspartateand glutamate improves oxygen utilization capacity,resulting in improvement in postoperative functionalrecovery and patient survival [1,71,72]. This extra

oxygen is used to repair ischemic cell damage, as wellas to replete energy stores, thereby allowing themyocardium to better tolerate the obligatory periodof aortic cross-clamping needed for cardiac repair.Warm blood cardioplegic induction is therefore oftena part of the myocardial protection strategy in adult

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216 CHAPTER 26

hearts subjected to a preoperative ischemic stress orhemodynamic instability [1,70,71]. In the "normal"infant myocardium, myocardial energy stores aregreater, and unlike adult hearts, preoperative ischemiais uncommon since there is no coronary occlusion[2,4,73]. This has led to the perception that warminduction, as well as amino acid supplementation, isunnecessary [2,4,73]. Pediatric hearts are, however,often stressed by other factors such as hypoxia, orpressure volume overload, which although differentfrom ischemia, can result in substrate and energydepletion [2,4,8,10,16,39,41,42].

In the nonhypoxic (normal) heart, we found car-dioplegic induction temperature was not important,as there was complete preservation of myocardialfunction and metabolic activity with either warm orcold induction [74]. There was also no significantincrease in oxygen uptake over basal metabolic ratesduring cardioplegic induction, indicating no increasedmetabolic activity during warm induction. This is notsurprising as nonhypoxic (normal) hearts should notneed to be resuscitated, and cold blood cardioplegiahas been shown to provide excellent myocardial pro-tection in normal neonatal hearts undergoing 2 h ofaortic cross-clamping [2,4,75].

Hearts subjected to the stress of hypoxia fol-lowed by reoxygenation, however, undergo an oxygen-mediated injury which depresses systolic and globalmyocardial function, and increases diastolic stiffnesssignificantly [25,39,41,42]. Cold cardioplegic induc-tion (with or without amino acids) prevents furtherdamage, but does not improve the injury caused byreoxygenation. Conversely, providing a warm cardio-plegic induction for 3-5 min facilitates repair of thehypoxic-reoxygenation injury resulting in completepreservation of myocardial function [74] (Figure26.10). However, the benefits of warm induction areonly realized if the cardioplegia contains the aminoacids aspartate and glutamate, as warm inductionwithout substrate enrichment was no better than coldinduction.

Quite interestingly, the oxygen uptake during warminduction in hypoxic neonatal hearts was not signi-ficantly increased over basal metabolic rates. There-fore, in contrast to adults, which increase oxygenuptake fivefold during warm induction, the primarymechanism of amino acid supplementation in hypoxic(stressed) neonatal piglets does not appear to be sec-ondary to increased metabolic activity [1,74]. This

Figure 26.10 Warm versus cold cardioplegic induction.

Recovery of LV systolic function in hypoxic hearts

undergoing reoxygenation on cardiopulmonary bypass

without ischemia or 70 min of cardioplegic arrest with an

aspartate/glutamate-enriched cardioplegic induction.

Contractility is measured by the end-systolic elastance (EES)

and expressed as a percentage of control (baseline) values.

* P< 0.001. Reprinted from [24], with permission from

Elsevier.

maybe due to the fact that ischemia and hypoxia resultin different myocardial injuries [42]. With ischemia,there is significant depletion of ATP resulting in theloss of cellular ionic gradients [1,15,30,70,76]. Warminduction allows the heart to generate substantialquantities of ATP, making it possible to re-establishthese ionic gradients, which explains the large increasein oxygen uptake seen in ischemic adult hearts dur-ing warm induction [1,70]. Conversely, in our acutehypoxic model there is no ischemia, as oxygen deliveryis maintained during hypoxia preserving ATP levels[26]. Since ATP levels are not reduced, there should beno loss of cellular ionic gradients. Therefore, oxygenuptake during warm induction does not need to besignificantly increased over basal levels, because cellu-lar ionic gradients do not need to be re-established.Evidence that amino acids can act through a mech-anism other than by increasing energy productioncould explain why some investigators have shown noactive incorporation of amino acids into the Krebscycle, despite substantial evidence that they improvemyocardial protection [1,2,77]. Nevertheless, chron-ically hypoxic or hypertrophied (pressure-volumeoverload) hearts can become ischemic during exerciseor periods of increased stress [ 1,4,8,9,16,21,44]. Warminduction may therefore be even more beneficialin the clinical setting, since these patients will havereduced ATP levels prior to ischemic arrest.

MaintenanceAll hearts receive some noncoronary collateral bloodflow via pericardial connections, and this may be even

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Table 26.4 Modified cold blood

maintenance (continuous) solution.

Reprinted from [24], with permission

from Elsevier.

more significant in the patient with aortopulmonary

collaterals [1,2]. The volume of this flow is variable,

but is sufficient to wash away all cardioplegia solu-

tions. Myocardial temperature increases after the

cardioplegia solution is discontinued, as the heart is

rewarmed by the noncoronary collateral blood flow,

which has the same temperature as the systemic per-

fusate. Efforts at controlling noncoronary collateral

flow by reducing either systemic flow rate or systemic

perfusion pressure, or by using profound levels of sys-

temic hypothermia (<25°C), must be tempered by the

recognition of the possible hematologic consequences

of deep hypothermia, and the potential deleterious

effects of hypoperfusion of other vital organs (brain

and kidney) at low systemic flow rates. Moreover,

recurrent ventricular activity is uncommon if systemic

temperature is kept between 25 and 30°C despite car-

dioplegic washout.

Periodic replenishment of the cardioplegia solution

at 10- to 20-min intervals counteracts noncoronary

collateral washout. Multidose cardioplegia is neces-

sary even if electromechanical activity does not return,

since low-level electrical activity may precede recur-rence of visible mechanical activity, and can lead to

delayed recovery if cardioplegic replenishment is not

provided [1,78]. Periodic replenishment: (i) main-

tains arrest; (ii) restores desired levels of hypothermia;

(iii) buffers acidosis; (iv) washes acid metabolites away

which inhibit continued anaerobiosis; (v) replenishes

high-energy phosphates if the cardioplegia solution is

oxygenated; (vi) restores substrates depleted during

ischemia; and (vii) counteracts edema with hyperos-

molarity. Replenishment of oxygenated cardioplegia

solutions over 2 min allows enough time for the heart

to use the delivered oxygen, and myocardial oxygen

uptake may exceed basal demands by as much as 10-

fold during each replenishment [ 1 ]. To further limit

ischemia, maintenance infusions can also be run

continuously when visualization is not impaired. For

this strategy, we utilize a new nonpotassium-modified

cardioplegia solution (Table 26.4; see "Modified inte-

grated cardioplegia" below).

ReperfusionAlthough ischemia alone undeniably leads to cell

death, most investigators believe that within clinical

relevance this injury occurs primarily during reperfu-

sion [1,79-82]. Cells that looked completely normal

at the end of ischemia, may show extensive functional,

metabolic, and structural alterations following reper-

fusion [1,72,83]. A reperfusion injury may contribute

to the impaired cardiac performance which develops

immediately after operation, and to the eventual

myocardial fibrosis which may result following surg-

ical correction of congenital or acquired cardiac dis-

eases [1,2,72,83]. The potential for this damage exists

during most pediatric cardiac procedures, because the

aorta must be clamped to produce a quiet, bloodless

field. Previous studies in adults have shown that the

fate of the ischemic myocardium is determined more

by the method of reperfusion than the duration

of ischemia itself [1,30,83]. The cardiac surgeon is in

the unique position to counteract this reperfusion

damage, since the conditions of reperfusion and the

composition of the reperfusate are under his/her

immediate control.

Follette was the first to show that postischemic

reperfusion damage after global ischemia could beavoided in adult hearts by substituting a brief warm

blood cardioplegic infusion during the initial phase

of reperfusion for the unmodified blood that would

normally be provided by aortic unclamping [83].

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218 CHAPTER 26

Applying these principles, Teoh etal. and Kirklin etal.

found that use of a warm blood cardioplegic reper-fusate improved metabolic and functional recovery,thereby decreasing mortality in adult patients under-going cardiac operations [72,84]. Warm blood cardio-plegia solutions are therefore often used in adulthearts to limit the reperfusion injury following surg-ical ischemia [1,70]. The use of a warm cardioplegicreperfusate, however, is rarely used in infants, perhapsdue to the belief that the infant heart is more toler-

ant to ischemia [2,4,73]. Experimentally, it has beendemonstrated that normal immature myocardiumhas a greater tolerance to ischemia when compared tomature myocardium [2,4,7]. Nonetheless, in clinicalpractice this is rarely observed, and several experi-mental and clinical studies have found that the hypoxicneonatal heart is more sensitive to ischemia than theadult [2-4,9,10,39].

Compared to uncontrolled reperfusion with normalblood, infusing a nonsubstrate-enriched warm blood

cardioplegic reperfusate for 3-5 min prior to remov-ing the aortic clamp slightly improved postbypassfunctional recovery in hypoxic piglets undergoing70 min of arrest. However, enriching the terminalwarm cardioplegic reperfusate with the amino acidsaspartate and glutamate vastly improved its efficacy,resulting in complete functional recovery [80] (Fig-ure 26.11). By contrast, Follette and others saw a muchgreater improvement with a warm reperfusate with-out amino acids in adults [1,83,84]. This increasedsensitivity to surgical ischemia in acutely hypoxicneonates undergoing cardioplegic arrest parallels thefindings in cyanotic infants and chronically hypoxicanimals [2,3,8-10,16]. Moreover, Taggart and associ-

Figure 26.11 The effect of different methods ofreperfusion on the recovery of LV systolic functionfollowing cardioplegic arrest as measured by the end-systolic elastance (EES) and expressed as percentage ofcontrol (baseline). * P< 0.001 versus unmodified blood;** P< 0.001 versus all groups. Reprinted from [68], withpermission from Elsevier.

ates recently demonstrated that both acyanotic andcyanotic infants undergoing corrective surgery weremore prone to a reperfusion injury compared toadults [85]. This may explain why Chaturvedi andcoworkers, using a conductance catheter to measurepressure-volume loops, demonstrated postoperativeventricular dysfunction even in infants undergoing

simple repair of an atrial septal defect when the heartwas protected by cold cardioplegia alone [86]. Use of awarm substrate-enriched cardioplegic reperfusate is

therefore probably indicated in all infants, and this isour current clinical practice.

White blood cell filtrationDespite the success of these studies, myocardial recov-ery was incomplete with our standard blood cardio-plegia solutions if the pediatric heart was subjected toa combination of hypoxia and ischemia [24,68,87]. Asmentioned previously, a combined hypoxic-ischemicstress probably more closely resembles the chronic

hypoxic (cyanotic) patient, as hypoxic hearts fre-quently become ischemic during periods of increasedstress or exercise [10,16,21,44,68]. This led us to lookfor additional modalities which might improve theefficacy of warm cardioplegia solutions in limitingreperfusion damage.

We were intrigued by the studies of Bryne and asso-ciates who demonstrated a reduction in reperfusiondamage by leukodepleting normal blood followingmyocardial ischemia, and wondered if WBC filtra-

tion might exhibit an adjunctive effect when usedin conjunction with cardioplegia solutions [31]. Weinvestigated the efficacy of leukodepleting our stand-ard substrate-enriched (Asp/Glut) blood cardioplegiasolution using neonatal piglets subjected to a hypoxic-ischemic stress followed by 70 min of cardioplegicarrest [87]. This is a more severe stress, and reperfus-ing the heart with normal (unmodified) blood byremoving the aortic cross-clamp caused substantial

oxygen free radical production, resulting in suchsignificant reperfusion damage that bypass couldnot be discontinued (Figure 26.12). Conversely, thereperfusion injury was reduced in hearts reperfusedwith our standard warm substrate-enriched bloodcardioplegia solution. These hearts, however, stillsustained a significant oxygen free radical mediatedreperfusion injury resulting in coronary vascular andmitochondrial damage, and depressed myocardialfunction (Figures 26.12 & 26.13). By contrast, oxygen

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Figure 26.12 Production of oxygen free radicals duringmyocardial reperfusion as measured by conjugated dienesin hypoxic-ischemic piglets reperfused with eitherunmodified blood, aspartate/glutamate (Asp/Glut) bloodcardioplegia alone, or leukodepleted Asp/Glut bloodcardioplegia (WBC filter). *P< 0.001.

Figure 26.13 Postbypass recovery of LV systolic function asmeasured by end-systolic elastance (EES) and expressed aspercentage of control (baseline) in hypoxic-ischemic pigletsprotected with aspartate/glutamate (asp/glut) bloodcardioplegia with or without a WBC filter. * P< 0.001.

Figure 26.14 Total WBC and neutrophil count in bloodcardioplegia pre and post the Pall BC-1 leukodepleting(WBC) filter. *P<0.001.

free radical production was almost eliminated if theblood cardioplegia was leukodepleted by passing it

through a cardioplegic (Pall BC-1, Pall Biomedical,Glencove, NY) WBC filter (Figure 26.12). This filter isvery efficient at removing WBCs in a single pass, andcan accommodate flows up to 500 ml/min, making itideal for blood cardioplegia (Figure 26.14). By avoid-ing the reperfusion injury, mitochondrial and vascularfunction were preserved, resulting in complete recov-ery of myocardial function (Figure 26.13).

Figure 26.15 Myocardial oxygen free radical formation(malondialdehyde) during cardioplegic reperfusion inpediatric patients. * P<0.05. Adapted from Sawa &Matsuda [XX].

Although experimental studies have shown the

efficacy of leukocyte-removal filters in attenuatingthe reperfusion injury, transfer to the clinical settinghas been slow [25,31,33,34,87]. Pearl et al. reportedthat leukocyte depletion improved graft function intransplanted human hearts [88]. However, Sawa and

Matsuda were the first to investigate leukocyte deple-tion as an adjunct to blood cardioplegia in pediatricpatients [89,90]. In 50 pediatric patients undergoingopen heart surgery for congenital heart disease, 25

received blood cardioplegia without leukocyte deple-tion (BCP group), whereas the remaining 25 receivedleukocyte-depleted blood cardioplegia (LDBCP). Thedifference in plasma concentrations of malondialde-hyde between coronary sinus effluent and arterialblood just after reperfusion in the LDBCP group wassignificantly lower than that in the BCP group, indi-cating lower oxygen free radical production withWBC filtration (Figure 26.15). The LDBCP group alsoshowed significantly lower plasma concentrations ofhuman heart fatty acid-binding protein and CK-MBthan did the BCP group, indicating less tissue damage,and the maximum dose of catecholamine neededfor hemodynamic stability was significantly smaller.These results parallel our experimental studies inneonatal hearts, and support the use of this modality

to reduce cardiac injury.With respect to the clinical application of leuko-

cyte-depleted blood cardioplegia, the direct insertionof the leukocyte removal filter into the cardioplegia

circuit is easy. No serious complications have occurredin any patient studies [17,25,26,40] (J Ortolano, per-sonal communication). From a clinical standpoint,the two major concerns of the WBC filtrations havebeen the possible increased rate of infection, especiallyin the setting of immunosuppression, and the con-

comitant platelet depletion. However, the total bodyWBC and platelet counts are minimally affected

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220 CHAPTER 26

because only approximately 20-30% of the total bloodvolume is filtered during cardioplegic infusions, andplatelet elimination with this filter is only about 60%[17,87,89] (J Ortolano, personal communication).Moreover, recent studies have demonstrated that neu-trophil depletion during surgery may actually decreasethe infection rate, and neutrophil levels quickly returnto normal by arrival in the ICU [ 25,40,91 ].

Certain limitations of the cardioplegic WBC filtermust be kept in mind. This filter requires approxim-ately 200 ml for priming, and this amount is large incomparison with the total volume used for primingthe pediatric CPB circuit. The increased primingvolume enhances hemodilution and may preventcardiac surgery without blood components in certainsubsets of low-risk pediatric patients. Consequently,WBC filtration of cardioplegia solutions may not beindicated in pediatric patients with excellent cardiacfunction who otherwise will not require a blood trans-fusion. A second limitation relates to the finite capa-city of the cardioplegia WBC filter. In neonates andinfants, it is possible to leukocyte deplete all cardio-plegic infusions without overloading the filter, as thevolume of cardioplegia is quite a bit less than in adults.However, older children and adults require muchlarger volumes of cardioplegia, and since the cardio-plegia WBC filter has a finite capacity, repeated car-dioplegic administration may lessen the ability of thefilter to effectively remove leukocytes during the crit-ical period of reperfusion. As such, the filter shouldprobably only be used for the terminal cardioplegicreperfusate in these older patient groups. Althoughthis approach has been shown to still significantlyimprove myocardial protection, the potential benefitmay be reduced [89,92]. This limitation is import-ant, as inappropriate use of WBC filters coupledwith leukodepletion during times which are less crit-ical probably explains why some investigators havefailed to demonstrate a clinical advantage with WBCfiltration of cardioplegia solutions. Hopefully, asmore surgeons realize the benefits of leukodepletion,filters will be developed with smaller priming volumesfor infants, while allowing for complete leukocytedepletion with multiple infusions in children andadults.

DistributionIn order to be effective, cardioplegia must beadequately distributed to all myocardial segments. It

is safer to clamp the aorta for up to 4 h with goodcardioplegic delivery, than for as little as 30 min whenthe same cold cardioplegia solution is given withinadequate distribution [ 1 ]. In the presence of cor-onary artery occlusion, improved protection has beendemonstrated with retrograde as opposed to ante-grade delivery techniques [1,93,94]. Fortunately, inthe vast majority of pediatric procedures, excellentcardioplegic distribution may be achieved using theantegrade approach alone, as coronary occlusion isnot an issue. Nonetheless, there may be an increasingrole for retrograde-delivered cardioplegia in pediatricpatients, particularly in situations where there is signi-ficant aortic insufficiency, or when frequent antegradeinfusions are impossible, such as during an arterialswitch procedure (see "Modified integrated cardiople-gia" below). Retrograde delivery may also be indic-ated in all patients with depressed function, or markedventricular or septal hypertrophy, since retrogradesupplies different myocardial beds, and providessuperior septal and subendocardial perfusion [ 1,93,95 ].

PressureAntegrade cardioplegia is often delivered without dir-ectly monitoring the infusion pressure. The surgeonor perfusionist can therefore only estimate the actualperfusion pressure [1,96]. This may result in cardio-plegia being delivered at a pressure that is higher orlower than desired. Furthermore, even if the pressureis monitored, the optimal cardioplegia infusion pres-sure remains essentially unknown, especially in neon-ates. Although a high cardioplegic perfusion pressureis thought to be deleterious, especially to ischemic tis-sue, the definition of high remains undefined [ 1,2,97].Nevertheless, an adequate cardioplegic pressure isneeded to insure distribution to all areas of the myo-cardium [ 1 ]. What pressure is required, and the con-sequences of even moderate elevation of cardioplegicinfusion pressure in neonatal hearts, is unknown,especially in the hypoxic (stressed) heart that may bemore prone to pressure injury [2,8,10,38,39].

In order to answer this question, we protectedneonatal hearts with blood cardioplegia deliveredeither at high (80-100 mmHg) or low (30-50 mmHg)pressure [98]. In nonhypoxic (noninjured) hearts, wefound complete preservation of myocardial and vas-cular function using either low or high cardioplegiainfusion pressure, indicating that either cardioplegiainfusion pressure provides good protection (Figure


Figure 26.16 Effect of different cardioplegic infusion

pressures on LV systolic function in normal (nonhypoxic)

and hypoxic hearts as measured by the end-systolic

elastance (EES) and expressed as percent recovery of

baseline values. * P< 0.001. Reprinted from [76], with

permission from Society of Thoracic Surgeons.

26.16). However, there was still an increase in myo-cardial edema even in normal (nonhypoxic) heartswhen an infusion pressure of 80-100 mmHg wasused. Although function was preserved, this impliessome myocardial damage as a result of higher infusionpressure. By contrast, subjecting the neonatal heart tohypoxia profoundly altered the effect different cardio-plegia infusion pressures had on the myocardium. Alow cardioplegia infusion pressure not only protectedthe heart from further damage, it also allowed the car-dioplegia to facilitate repair of the injury caused byhypoxia and reoxygenation, resulting in completepreservation of myocardial and vascular endothelial

cell function (Figure 26.16). This supports the safetyof a cardioplegic infusion pressure of 30-50 mmHg,and implies it is high enough to ensure adequate myo-cardial distribution, because without adequate dis-tribution, myocardial protection is poor. Conversely,protection was poor when cardioplegic infusions weredelivered at a slightly higher (80-100 mmHg) pres-sure. This was manifested by postbypass myocardialand vascular endothelial cell dysfunction, increasededema, and decreased ATP levels.

A pressure port is integrated into most adult com-mercial cardioplegia systems to allow monitoring ofthe cardioplegia delivery line. Before the availability ofantegrade (and retrograde) cannulas with a lumen fordirect pressure monitoring, intravascular pressureswere estimated by observing the pressure recorded onthe pressure port of the cardioplegic delivery system,and subtracting from it the known pressure drop inthe delivery system. This requires the perfusionist tointermittently calibrate the system (especially if differ-

ent-sized cannulas are used), and makes it necessaryto calculate intravascular pressure with each changein cardioplegic flow rate.

Direct intravascular pressure measurement is theonly reliable method for determining either aortic orcoronary sinus pressure during cardioplegic delivery

[1,99]. This conclusion was reached in adults byobtaining simultaneous measurement of intravascularpressure in either the aorta or coronary sinus duringcardioplegic infusions and comparing it to calculatedpressure from the known pressure drop in the tubingsystem at flow rates ranging from 50 to 300 ml/min[1,96,99]. This demonstrated that: (i) calculated pres-sure does not accurately reflect the measured intravas-cular pressure during either antegrade or retrogradedelivery; and (ii) the variability between calculated andmeasured intravascular pressure increases as eitherantegrade or retrograde cardioplegic flow rate is raised.This discrepancy between the calculated and meas-ured intravascular pressure probably results from dif-

ferences related to calibration with roller pumps, andwide fluctuations in cardioplegic delivery system pres-sure which can develop when temperature, flow, andviscosity are varied in systems containing rigid andcompliant components. Direct intravascular meas-urement circumvents this problem and provides thesurgeon with a more reliable pressure measurement[1,96,99]. With smaller cannulas and vascular beds,errors in calculating the cardioplegic infusion pressuremay be magnified, and change quicker in neonates.Direct aortic monitoring should be used in pediatricpatients to prevent inadvertent elevations in pressure,since even small changes in pressure may significantlyaffect neonatal myocardial protection, especially inthe hypoxic heart.

Modified integrated cardioplegiaFollowing cardioplegic arrest, most surgeons deliverintermittent cardioplegia every 10-20 min to main-tain myocardial arrest, restore hypothermia, bufferacidosis, and wash away acid metabolites [1,2]. Thisis traditional, but a dry field is not always requiredbetween cardioplegic doses. Therefore, to further limitischemia and improve protection, we introduced theconcept of "integrated" cardioplegia, which consistsof infusing a maintenance solution of unmodified cold(4°C) blood between intermittent cardioplegic doseswhenever visualization is not impaired by coronaryperfusion [1,94,100]. Cold unmodified blood is used

for the maintenance infusions, since hypothermiaalone tends to keep the heart arrested, it allows theinfusions to be safely interrupted when a dry field

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222 CHAPTER 26

is required for optimal visualization, and avoidsthe administration of large quantities of potassium.Despite excellent clinical results in adult patients, the"standard" integrated strategy has never been evalu-ated experimentally, and it is rarely used in pediatricpatients [ 1,94,100]. Indeed, several studies in pediatrichearts have suggested that multiple intermittent car-dioplegic infusions are no better, and may even beworse, than a single cold infusion [2,4,39]. Postoper-ative myocardial dysfunction, however, remains theprimary cause of morbidity and mortality in the pedi-atric patient, occurring most frequently in the pres-ence of cyanosis [2,4,9,10,101]. Hypoxic hearts aremore prone to accelerated depletion of ATP duringsurgical ischemia, as well as predisposed to a reoxy-genation injury with the reintroduction of oxygen[10,25,39]. They are also less able to tolerate myo-cardial ischemia [2,4,8-10,16,38,39]. Consequently,compared to the normoxic adult heart, the cyanotic(hypoxic) pediatric heart is more vulnerable toinadequacies in myocardial protection, and mightderive an even greater benefit from an integratedapproach which limits ischemia.

To parallel this experimentally, we used "stressed"(hypoxic-ischemic) neonatal hearts to evaluate theconventional techniques of: (i) intermittent cardio-plegia; and (ii) standard integrated protection. Thestandard integrated strategy, however, has the poten-tial problem of producing a reperfusion injury, sinceit exposes the ischemic heart to multiple infusionsof cold unmodified blood, which Rebeyka and asso-ciates showed is dangerous in infants [102]. We there-fore also evaluated a new approach, which replacesthe cold unmodified blood normally used for themaintenance infusions, with a cold modified (non-potassium, magnesium-enriched, CPD, THAM) bloodsolution (Table 26.4). We termed this the modified"integrated" strategy. Using a modified nonpotassium"cardioplegic-like" blood solution for the mainten-ance infusions has the potential advantage of reduc-ing any reperfusion injury, since cardioplegia limitsreperfusion damage following ischemia, and the heartis ischemic between cardioplegic doses [1,80,83].Hyperkalemia is avoided by not adding potassium,and the heart kept arrested by hypothermia, as well aschanges in magnesium and calcium. To more closelymimic clinical experience, we also determined if themethod of delivery (antegrade vs. retrograde) affectedresults. This simulates operations such as an arterial

Figure 26.17 Recovery of LV systolic function as measuredby end-systolic elastance (EES) and expressed as percentageof control (baseline) in stressed (hypoxic-ischemic) piglets.Note: Intermittent cardioplegia preserves function at thesame levels as stressed hearts not subjected to cardioplegicarrest. By contrast, adding maintenance infusions ofunmodified cold blood (standard integrated strategy)partially resuscitated the heart and improved contractility.However, this effect was maximized if a modified solutionwas used for the maintenance infusions (modifiedintegrated strategy) resulting in complete return ofsystolic function. * P<0.001 versus intermittent,** P< 0.001 versus all. Reprinted from [24], withpermission from Elsevier.

switch, where antegrade perfusion is not possible afterthe initial cardioplegia dose.

From this study we concluded that:1 The conventional techniques of intermittent multi-dose blood cardioplegia alone or with maintenanceinfusions of cold unmodified blood ("standard inte-grated" strategy) provides inadequate protection ofthe "stressed" (hypoxic-ischemic) neonatal heart.2 Infusing a cold, modified nonpotassium mainte-nance blood solution between intermittent cardio-plegia doses (modified integrated strategy) completelyresuscitates the "stressed" neonatal heart, restoringmyocardial, metabolic, and vascular function.3 The modified solution is equally effective deliveredantegrade or retrograde (Figure 26.17).

This implies that maintenance infusions of a coldmodified solution do more than just limit ischemiaduring cardioplegic arrest, they also actively resuscit-ate the stressed heart, since a modified maintenancesolution (modified integrated strategy) improvedrecovery to a greater extent than unmodified blood(standard integrated strategy), despite the fact thatboth of these approaches reduce ischemia equally byproviding oxygenated blood during myocardial arrest.

Previously, only warm blood cardioplegia has beendemonstrated to have the ability to resuscitate thestressed heart [ 1,57,94]. Why such a dramatic improve-ment occurs when a modified maintenance solution

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is infused at 4°C is unknown, but it suggests that thesolution is working through a mechanism which is notdependent on enzymatic activity. It is possible that thesame effect would have occurred if the modified solu-tion had been infused at normothermia. However,keeping the heart warm is potentially dangerous, as itis less tolerant to ischemic intervals any time infusionsare interrupted, or if cardioplegic distribution is notadequate to all myocardial segments. The mainte-nance infusions are always delivered at a measuredpressure of 30-50 mmHg, because infusing intermit-tent cardioplegia at higher pressures is detrimental tostressed neonatal hearts [98]. The modified solutionused for the maintenance infusions is based on ourmultidose cardioplegia solution, but the potassium isremoved to avoid postbypass hyperkalemia [1,38,39,94]. Moreover, potassium is probably not required,as the cold arrested heart tends to stay that way ifit is maintained at 4°C [1]. Nevertheless, to insuremyocardial quiescence, potassium cardioplegia is usu-ally given every 20-30 minutes, or whenever the con-tinuous infusions are interrupted, since the arrestedheart can develop small amplitude ventricular fibrilla-tion which is not always visible, but results inincreased oxygen consumption and ischemia [78].

This study also has implications concerningthe method of cardioplegic delivery. Compared toantegrade delivery, retrograde delivery may providesuperior perfusion of the vulnerable LV subendo-cardium and septum, especially in the setting of coron-ary occlusion or ventricular hypertrophy. This studysuggests that another reason for the pediatric heartsurgeon to use retrograde cardioplegia is to providecardioplegic delivery whenever frequent antegradeinfusions are not possible (i.e. arterial switches), as itseems to supply adequate protection at hypothermia.In contrast to adults, however, protection of the rightventricle is often more important in pediatrics dueto the frequent problems of right ventricular (RV)hypertrophy and postoperative pulmonary hyperten-sion [2,4]. The pediatric surgeon must therefore becareful about relying solely on retrograde delivery,since it may not supply adequate nutritive flow to theRV free wall, especially at normothermia [93,103,104]. This is the reason we always deliver at least a por-tion of the terminal warm reperfusate (hot shot) ante-grade, as it helps compensate for any inadequacies inRV free wall protection by repairing cellular damagethat may have occurred during cold cardioplegic

arrest. Nevertheless, in patients with marked ventricu-lar hypertrophy, the surgeon should also considerdelivering a portion of the warm reperfusate retro-grade, as antegrade delivery to the septum and sub-endocardium may be compromised in this setting.Inadequate septal protection can significantly impairRV function, since the septum is responsible for asubstantial part of RV function [ 105].

Clinical studies

We have now incorporated the above principlesinto our clinical practice at the Heart Institute forChildren and the University of Illinois at Chicago. Weuse a blood plasma bypass prime in neonates andyoung infants, and a crystalloid prime in children. Thebypass calcium levels are not normalized, but allowedto become hypocalcemic, because a hypocalcemicprime helps limit the reoxygenation/reperfusioninjury that can occur with the initiation of bypass[51,52]. As described earlier (see "Reoxygenation andcardiopulmonary bypass management" above), weutilize a normoxic bypass strategy, always leukode-plete the bypass prime when blood is used, and placean inline arterial WBC filter in all cyanotic and high-risk (i.e. pulmonary hypertension) patients. Theblood cardioplegia solutions are similar to the ones inour experimental studies (Tables 26.2-26.4). How-ever, in order to deliver the desired calcium concen-tration, we have reduced the amount of citrate. Thecardioplegic calcium level is the concentration ofcalcium after it is mixed with blood from the bypassprime. Using citrate reduces calcium levels. If one usesa normocalcemic bypass prime, as in our experimentalstudies, then the amount of citrate should be thesame as depicted in Tables 26.2 and 26.3. However, ifthe bypass circuit is kept hypocalcemic (as we do inour clinical practice), then the amount of citrate inthe cardioplegia solution is reduced to achieve thesesame levels. Nevertheless, it is important not to let thedelivered calcium level become too low. Levels lowerthan 0.2 mmol/L may be detrimental to myocardialprotection, as well as predispose to a calcium paradox.Furthermore, if all the available calcium is bound,excess citrate will then bind with magnesium, result-ing in extremely low calcium and magnesium levels.

To offset any problem with higher than intendedcardioplegic calcium levels, we add magnesium to ourcardioplegia solutions, as magnesium can limit the

224 CHAPTER 26

detrimental effects of calcium, especially during thecritical period of reperfusion. Magnesium may haveseveral other benefits. Normothermic hearts requirehigher potassium levels to maintain myocardial arrestduring cardioplegia induction or terminal reperfusion(hot shot) [1]. Because high potassium levels candirectly injure endothelial cells, as well as predisposeto calcium influx, magnesium allows the potassiumconcentration to be reduced while maintaining myo-cardial arrest [29,59,62,63]. When the heart is warm,ion fluxes and cellular reactions are faster, and the cellis more susceptible to a calcium-mediated reperfusioninjury [1]. Because magnesium competes with cal-cium, it should be beneficial during these critical times[63,64]. Magnesium should also provide greater pro-tection against postoperative arrhythmias, and Hearseand others have documented that cardioplegic mag-nesium concentrations as high as 16 mEq/L are safein both adult and pediatric patients [63-67]. To thebest of our knowledge, we have never had a prob-lem with postbypass hypermagnesemia. Nevertheless,to offset any potential problems, we always normal-ize the systemic ionic calcium in the upper rangeof normal prior to discontinuing cardiopulmonarybypass, as any adverse effects of hypermagnesemia areeasily reversed by calcium. Moreover, magnesium israpidly depleted by ultrafiltration, and levels are usu-ally normal by arrival in the ICU.

Our clinical cardioplegia protocol consists of 3-5 min of cold induction, followed by 2-min coldmultidose infusions every 10-15 min, with finallyall patients receiving a 3- to 5-min terminal warmsubstrate-enriched reperfusate prior to removing theaortic cross-clamp. A cold modified (nonpotassium)blood maintenance solution is always infused contin-uously whenever it does not impair optimal visual-ization (modified integrated strategy). We are juststarting to use a 3- to 5-min warm induction in high-risk patients. Infusions are given antegrade wheneverpossible, but retrograde delivery is used in all patientswhere antegrade infusions are not possible at leastevery 10-15 min (i.e. arterial switch), or if there ismarked septal hypertrophy. However, at least a por-tion of the terminal warm reperfusate is always givenantegrade. Cardioplegia is delivered at a continuouslymeasured aortic root or coronary sinus pressureof 30-50 mmHg. I also believe a cardioplegic WBCfilter is extremely important, especially during theterminal warm reperfusate, and plan to use them

routinely once a filter with a prime less than 100 mm3

is introduced.To assess the clinical efficacy of this approach, we

retrospectively examined all patients undergoing anopen-heart procedure at The Heart Institute forChildren or University of Illinois Chicago during a 2-year period. There were 567 patients with an overallmortality of 5%, and most importantly, almost nopatient died as a result of postoperative myocardialfailure (Table 26.5). To better assess the validity ofour bypass and cardioplegia strategy, we performed amore detailed examination of all patients undergo-ing a Norwood procedure between July 1996 andDecember 2001, since these patients are very high risk,and their hearts are severely stressed. These dates werechosen as this is when we began to routinely use botha bypass strategy of normoxia and leukodepletion,as well as modified integrated cardioplegic protec-tion. There were 93 patients, 51 with a diagnosis ofhypoplastic left heart syndrome (HLHS), and 42 witha variant (HLHV) of hypoplastic left heart syndrome.The overall survival was 77% (75% HLHS, 81%HLHV). More importantly, there was excellent pre-servation of myocardial function, both initially, asassessed by echocardiogram, and several months later,when evaluated by angiogram prior to the Glenn pro-cedure (Table 26.6). This is in contrast to other reportswhich often describe depressed myocardial func-tion following successful repair of cyanotic lesions[2,4,9,106,107]. Indeed, the surgical survival in the 38patients undergoing a Norwood procedure in the2 years prior to instituting this strategy (January 1993to June 1996) was only 53%. The only major changeswe made between these two time intervals was theroutine use of a leukodepleted normoxic bypass strat-egy, and infusing a continuous modified maintenancecardioplegia solution (modified integrated strategy)during the period of myocardial ischemia. I acknowl-edge that other factors might have accounted forthe increased survival and improved postoperativecardiac function. However, despite lack of a controlgroup, I believe these results, as well as the extensiveexperimental infrastructure, support the safety andefficacy of this approach.

In conclusion, significant advances have beenmade in the technical performance of operations forcongenital heart disease, but postoperative organdysfunction remains problematic, especially in cyan-otic infants [2-4,9,10]. These studies provide direct


Table 26.5 Clinical results. Reprinted

from [24], with permission from Elsevier.Operation

Closure ventricular septal defect

Closure atrial septal defect

Aortic valve procedures

RV outflow tract reconstruction

Fontan procedure

Norwood procedure

Repair tetralogy of Fallot

Bidirectional Glenn shunt

Atrioventricular canal repair

Rastelli repair

Arterial switch

Mitral valve procedure

Ross procedure

Repair total anomalous venous return

Aortic arch reconstruction

Anomalous coronary repair

Ebstein's repair

Repair truncus arteriosis

Double switch procedure

Repair interrupted aortic arch

Repair tetralogy of Fallot/atrioventricular canal

Kono's procedure

Age distribution

Neonates (<1 month)

Infants (1-12 months)

Children (<12 months)

Mortality*

Number

106

71

53

53

49

39

39

36

33

16

15

14

8

8

4

4

4

4

3

3

3

2

79

205

283

29 (29/568)

* Mortality rate = 5%.

Table 26.6 Norwood operation clinical results.

93 patients (7/1/96 to 12/31/2001)

51 HLHS, 42 HLHV

Age 7 days (range 2-44 days)

Weight 3090 g (range 1680-5195 g)

Overall perioperative survival 77% (72/93 patients)

HLHS 75%, HLHV 81%

HLHS right ventricular function

Fractional shortening (Echo); preoperative 37 ± 8% vs.

postoperative 35 + 9%

Ejection fraction (angiogram) at time of Glenn shunt

56 ± 8%

Priorperioperative survival 53% (1/1/93 to 6/30/96,

38 patients)

HLHS, hypoplastic left heart syndrome; HLHV, hypoplastic

left heart variant; Echo, echocardiogram.

evidence that: (i) an unintended oxygen free radicalmediated injury occurs in cyanotic infants with theinitiation of bypass resulting in myocardial and pul-monary damage; (ii) this reoxygenation injury can bereduced by using a bypass strategy which incorporatesnormoxia and WBC filtration; and (iii) excellent pro-tection of the hypoxic-ischemic heart is possible byusing a comprehensive blood cardioplegic strategy.Incorporating these strategies into operative manage-ment will allow surgeons to limit damage in thesehigh-risk infants, leading to a reduction in morbidityand mortality.

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99 Buckberg GD, Allen BS, Beyersdorf F. Blood cardio-plegic strategies during adult cardiac operations. In:Piper HM, Preusse CJ, eds. Ischemia-Reperfusion inCardiac Surgery. Kluwer Academic: Norwell, Mass,1993:181-227.

100 Buckberg GD, Beyersdorf F, Allen BS, Robertson JR.Integrated myocardial management. Background andinitial application. / Cardiac Surg 1995; 10:68-89.

101 Fujiwara T, Kurtts T, Anderson W, Heinke J, Mayer JEJr. Myocardial protection in cyanotic neonatal lambs./ Thorac Cardiovasc Surg 1988; 96: 700-10.

102 Rebeyka I, Hanan SA, Borges MR et al. Rapid coolingcontracture of the myocardium. / Thorac CardiovascSurg 1990; 100:240-9.

103 Gates RN, Laks H, Drinkwater DC et al. The microvas-cular distribution of cardioplegia solution in the pigletheart-retrograde vs. antegrade delivery. / ThoracCardiovasc Surg 1993; 105: 845-53.

104 Partington MT, Acar C, Buckberg G et al. Studies of ret-rograde cardioplegia II. Nutritive blood flow distribu-tion in normal and jeopardized myocardium. / ThoracSurg 1989; 97:613.

105 Buckberg GD, Coghlan HC, Hoffman JIE, Torent-Quasp F. The structure and function of the helical heartand its buttress wrapping. VII. Critical importance ofthe septum for right ventricular function. Semin ThoracCardiovasc Surg 2001; 13:402-16.

106 Jarmakani JM, Graham TP, Canent RV, Jewett PH. Leftheart function in children with tetralogy of Fallot beforeand after palliative or corrective surgery. Circulation1972; 46:478-90.

107 Rocchini AP, Keane JF, Cantaneda AR, Nadas AS.Left ventricular function following attempted surgicalrepair of tetralogy of Fallot. Circulation 1978; 57: 798-802.

CHAPTER 27

Myocardial preconditioning in theexperimental model: a new strategyto improve myocardial protection

Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD,& Hong-Ling Li, MD, MSC

Open-heart operations require a period of electivecardioplegic arrest to facilitate the surgical repair.Although current methods of inducing and maintain-ing arrest using hyperkalemic cardioplegia solutionsare effective, postreperfusion depression of myocar-dial performance remains an important cause of post-operative morbidity and mortality. In 1986, Murryet al. [1] described the phenomenon of ischemicpreconditioning in dogs in which a brief period ofregional myocardial ischemia made the heart moretolerant to a subsequent, more prolonged period ofischemia. The molecular mechanisms responsible forischemic preconditioning are presently incompletelyunderstood, although several studies have shown thatactivated distinct isoforms of the enzymes proteinkinase C (PKC), tyrosine kinase (TK), and nitricoxide (NO) may be important effectors required forpreconditioning to occur [2-5] and may be targetsfor pharmacologic induction of the preconditionedphenotype. Similarly, several mediators released fromthe ischemic myocardium during ischemia and reper-fusion, including adenosine and bradykinin [6], maybe important initiators of the preconditioned statewhen given exogenously prior to a period of pro-longed ischemia. These observations lead us to con-clude that pharmacologic agents given before or incombination with hyperkalemic cardioplegia mightbe a strategy to reduce or prevent postreperfusionmyocardial depression after surgical procedures.

This chapter reviews our hypothesis that myocar-dial ischemia tolerance can be improved by pretreat-

ing the heart with agents that activate the distinctmolecular pathways that have been associated withthe ischemic preconditioning phenomenon and maybe a new approach towards protecting the heartduring open-heart surgery. The first portion of thischapter will outline the preconditioning phenomenonand describe our current understanding of the mole-cular mechanisms responsible for preconditioning themyocyte in response to ischemia or cell stress. Severalrecent reviews in the literature describe the mole-cular mechanisms behind the preconditioning phe-nomenon in greater detail [7-11], which is beyondthe scope of this chapter. In the second part of thischapter, we will first describe experimental workconducted in our research laboratory that suggeststhat pretreating the heart with pharmacologic agentsbefore and during cardioplegic arrest can improvemyocardial ischemia tolerance by mechanisms thathave been associated with mediating the ischemic pre-conditioning process. Then we will review a seriesof studies from our laboratory that suggest that thesuperior ischemia tolerance noted in the immatureheart compared to the adult heart may be due to morehighly activated molecular mechanisms of the precon-ditioning phenomenon in the immature animal.

The discovery of ischemicpreconditioning

In 1981, Reimer [12] noted that repletion of ATPfollowing a brief episode of ischemia occurred very

230

Experimental myocardial preconditioning 231

slowly, suggesting that repeated ischemic episodesmight lead to cumulative myocyte injury. Surpris-ingly, however, further ischemic episodes did not pro-duce any additional depletion, indicating that the rateof ATP breakdown rate must have been reduced dur-ing the subsequent ischemic periods. Subsequently,Reimer [13] noted that four 10-min periods of tran-sient ischemia resulted in less myocardial necrosisthan that seen in hearts exposed to a single 40-minperiod of coronary occlusion.

Murry et al. [1] extended these observations byshowing that four 5-min periods of coronary occlu-sion, each separated by 5 min of reperfusion, led toa significant reduction in infarct size following asubsequent period of prolonged regional coronaryischemia. They called this method of enhancingischemic tolerance "preconditioning with ischemia",which has been reproduced in most animal speciesincluding humans [14-18].

General biology of ischemicpreconditioning

The four aspects of the general biology of ischemicpreconditioning to be considered are: (i) the numberand duration of preconditioning episodes of ischemiarequired to precondition the heart; (ii) the durationof reperfusion that is needed between ischemic pre-conditioning episodes; (iii) the duration of the sub-sequent period of sustained ischemia during whichmyocyte death can be prevented; and (iv) the breadthof protection by ischemic preconditioning.

Although the original preconditioning protocolwas composed of four 5-min episodes of ischemia [ 1 ],there is general agreement that preconditioning can beinduced with a variety of protocols. Single or multiplecoronary occlusions of 2.5, 5, or 10 min have beenshown to be protective in dogs [16,19,20], rabbits[15,21], pigs [22], and rats [23,24]. Although multiplebrief periods of ischemia appear to be superior tosingle ischemic episodes in inducing the precondi-tioned phenotype, there appears to be a diminishingreturn after more than four ischemia episodes.

The minimum duration of reperfusion requiredbetween the preconditioning episode and the pro-longed period of ischemia has not been established.Studies have shown a limitation of necrosis when5-min periods of reperfusion were used and a markeddecrease in ischemic metabolism when longer (20-

min) reperfusion periods are used [1]. By contrast,protection is substantially attenuated if the period ofprolonged ischemia is delayed for 2 h after the precon-ditioning episodes [19]. In the rat, the effects of pre-conditioning with three, 3-min coronary occlusionswere largely lost when the period of intervening reper-fusion was extended from 5 min to 1 h. This phe-nomenon is often referred to as early preconditioning,due to the limited envelope of the protection period,and appears to be induced by activation of mediatorsalready present in the myocyte and independent ofmRNA expression and protein synthesis. It is char-acterized by being nearly immediate in onset, but thebenefit is of limited duration.

By contrast, if one exposes the heart to severalrepetitions of multiple brief ischemia-reperfusioncycles, a more longlasting period of ischemia toleranceis induced (delayed preconditioning). This processrequires the activation of more complex signal trans-duction pathways that may involve gene activationand synthesis of as of yet incompletely defined effectorproteins [9,25,26].

Ischemic preconditioning has classically been stud-ied using myocardial necrosis as an endpoint [ 1,16,22].In addition, preconditioning offers a wide rangeof protection against the complications of ischemia-reperfusion including regional and global myocardialdysfunction and a reduction in reperfusion arrhyth-mias. Several studies have demonstrated that pre-conditioning can enhance the recovery of contractilefunction in addition to reducing infarct size in themyocardial "region at risk" [27-32].

Proposed signal transductionpathways for ischemicpreconditioning

Although ischemic preconditioning has been exten-sively studied, its mechanisms of induction, the mole-cular pathways that mediate the signal transduction,and the end effector of the process are incompletelyunderstood. Several recent reviews in the literatureprovide more complete details of the evolving under-standing of the preconditioning phenomenon [7-11 ].

The preconditioned phenotype can be triggeredby a number of initiator agents that are released locallyin ischemic myocardium, including adenosine, acetyl-choline, bradykinin, norepinephrine, nitric oxide,reactive oxygen species, opioid receptor activators,

232 CHAPTER 27

Figure 27.1 Molecular pathways.Proposed molecular pathways leadingto the early preconditioned state. PKC,protein kinase C; TK, tyrosine kinase;MAP kinase, mitogen-activated proteinkinase; KATP channel, ATP-sensitivepotassium channel; NO, nitric oxide.

etc. [6,33-36]. In addition, the preconditioned statecan be activated in response to cell stress (heat, pacing,cell-surface tension, etc.). These initiator substancesbind to G-protein linked cell membrane receptors,which via phospholipase-C and phospholipase-Damplify the signal by the activation of a complex,and incompletely defined, signal transduction path-way (Figure 27.1). The signal transduction pathwayrequires the activation of families of serine-threonineprotein kinases including protein kinase C (PKC)[2,4,6,37], tyrosine kinase (TK) [5,37,38], and themitogen-activated protein kinases (MAPK) [39,40].The signal appears to be regulated by the activation ofspecific isoforms of each of the kinase families such asPKC-e, Src-TK [39], and p38 MAPK [40], p44/p42MAPK [41], and JNK [42], members of the MAPKsuperfamily. Kinase activation presumably leads tophosphorylation of as yet unidentified proteins [43],which may regulate the early preconditioned pheno-type and appear to participate in the pharmacologic-ally induced preconditioned state. Kinase activationmay also amplify the preconditioning signal by activa-tion of inducible nitric oxide synthase (iNOS) result-ing in generation of NO (Figure 27.2). In vascularendothelial cells and myocytes, bradykinin activatesconstitutive (endothelial) NO synthase (eNOS) result-ing in nitric oxide (NO) generation [44,45]. In an ele-gant series of studies using a model of late ischemicpreconditioning, Bolli and associates [39,46,47] sug-

gested that NO is a required mediator of ischemicpreconditioning and is responsible for activating themore distal signal transduction pathways leading tothe preconditioned state. Bolli et al. [47], Jones et al.[48], and Takano et al. [33] demonstrated that theinitial ischemic preconditioning stimulus results inrelease of NO via activation of eNOS. NO reacts withreactive oxygen species (ROS), such as oxygen radical(O2~), formed during reperfusion of ischemic myo-cardium, which then combine to generate peroxyni-trite (ONOO~) [46,48]. Pretreatment of the heartwith NOS inhibitors or oxygen radical scavengersblock early and late preconditioning. NO, ROS, andperoxynitrite induce the translocation and activationof PKCe, which plays a critical role in the precondi-tioning signal transduction pathway. The protect-ive effects of late preconditioning are then amplifiedby activation of a TK-dependent signal cascade whichresults in activation of iNOS gene product as evid-enced by an increase in iNOS mRNA [48,49]. NOgeneration then may in turn activate nuclear tran-scription factors including nuclear factor KB (NF-KB)[25,26,43,50] and heat-shock protein (HSP-27) [51].Activated transcription factors appear to turn on sev-eral genes that may account for the more prolonged-acting phenomenon of delayed preconditioning.

The terminal effect (end effector) of the precondi-tioning signal transduction pathway is not completelyunderstood, although the majority of evidence points


Figure 27.2 Proposed molecularpathway for bradykinin (BK)pretreatment resulting inpreconditioning the heart. eNOS,endothelial nitric oxide synthase; iNOS,inducible nitric oxide synthase; ROS,reactive oxygen species; NFicB, nuclearfactor KB; PKC, protein kinase C; NO,nitric oxide; KATP, ATP-sensitivepotassium channel. Reprinted fromAnnals of Thoracic Surgery, Vol. 70, FengJ, Li H, Rosenkranz E. Bradykinin protectsthe rabbit heart after cardioplegicischemia via NO-dependent pathways,pp. 2119-2124, © 2000, with permissionfrom Society of Thoracic Surgeons.

to the ATP-sensitive potassium (KATP) channel play-ing this role [10,11,35,52-54]. The KATP channelis found in both myocyte sarcolemmal membranes

and mitochondrial membranes, the latter of whichappears to be the true end effector of both ischemiaand pharmacologically induced preconditioned phe-notypes [55-60] (see p. 249).

Cellular effects of preconditioning

Precisely what determines the development of irre-versible myocyte injury during ischemia and follow-ing reperfusion is not known, although injury to themitochondria is likely since abnormalities of energymetabolism and calcium homeostasis appear to beof central importance. Preconditioning in many waysresults in a downcycling of the metabolic state of themyocyte. The preconditioning stimulus leads to areduction in myocardial ATP content by approxim-

ately 30% [ 1 ]. However, during subsequent prolongedischemic episodes, the rate of decline of ATP and crea-tine phosphate are reduced. Thereafter, levels of both

ATP and creatine phosphate do not differ significantlyfrom controls. Exposure of myocardium to a briefstress results in a rapid adaptation, which is character-

ized by decreased energy utilization by one or mul-tiple metabolic pathways during a subsequent episodeof ischemia [1,61,62] (Figure 27.1). Similarly, thereis less accumulation of glycolytic products duringischemia, indicating a reduced rate of glycolysis andtherefore a reduced rate of ATP hydrolysis.

Carbohydrate metabolismThe preconditioned phenotype is characterized bya reduction in energy utilization and energy genera-tion, including by glycolysis. However, precondition-ing may enhance subsequent recovery of myocardialfunction by enhancing postreperfusion glucose uptakevia activation of glucose transport proteins [63]. Wehave demonstrated that pharmacologic precondition-ing with bradykinin enhances translocation of glucosetransporter 4 via PKC-dependent pathways, whichmay play a mechanistic role in enhancing ischemiatolerance (see p. 246).

Concurrent stunningBrief episodes of ischemia and reperfusion can produce

a profound but reversible depression of contractilefunction, called myocardial stunning [62,64]. Duringischemia the actin-myosin ATPase reduces ATP and

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234 CHAPTER 27

it was suggested that preconditioning might act bystunning the heart, thereby reducing energy demandduring the subsequent prolonged ischemic challenge[65,66]. However, this hypothesis has become lessattractive for several reasons. While the classical, earlyprotective effects of preconditioning last for one totwo hours, it takes substantially longer, often severaldays, to achieve full recovery from stunning. Others[7,18] have shown a clear dissociation between the tem-poral profiles of recovery from the two processes.

Free radicals and reactiveoxygen speciesReactive oxygen species (ROS) have long been associ-ated with the damage caused by ischemia and reperfu-sion. There is strong evidence implicating ROS as atrigger of and mediator for the preconditioning stim-ulus and signal transduction pathways [67], parti-cularly in relation to the opening of mitochondrialKATP channels [68-70]. Similarly, preconditionedmitochondria generate less ROS after reperfusion.ROS generation during the brief ischemia-reperfusioncycles have also been linked to the induction ofdelayed preconditioning since administration of 2-mercaptopropionyl glycine (2-MPG), which inhibitsROS production, or free radical scavengers such assuperoxide dismutase and catalase during the precon-ditioning stimulus, prevent the anti-infarction effectsof preconditioning [46,49,71].

Genetic mechanismsAs noted above, the time course of induction andmaintenance of early preconditioning is too brief toallow for new protein generation or gene activation.By contrast, evidence suggests that repeated cycles ofischemia-reperfusion result in gene activation via theactivation of transcription factors [25,26,43,50]. Thus,a brief episode of ischemia might induce the transcrip-tion of new mRNA and subsequent synthesis of oneor more proteins that protect the myocardium [9].Activation of target genes, as evidenced by increasedlevels of mRNA and protein transcription, includesiNOS, cyclooxygenase-2 (COX-2) [72], aldolasereductase [73], Mn superoxide dismutase (SOD) [74],and HSP-27 [9,51]. These gene products then mayserve to reduce the injury associated with ROS gener-ated during reperfusion (aldolase, SOD), or serve toinduce or amplify preconditioning (iNOS, HSP-27).Future studies employing applied genomics and pro-

teomics utilizing microchip arrays hold promise inidentifying genes and gene products that are activatedby various preconditioning stimuli.

Experimental studies ofpharmacologic preconditioning

Shortly after the description of the precondition-ing phenomenon by Murry [1], several investigatorsbegan evaluating the potential for clinically harness-ing this powerful process, particularly by means ofpharmacologic induction. Since the preconditioningphenomenon has been demonstrated in most animalspecies and several different organ systems, numerousapproaches have been taken to determine if humanmyocardium can be ischemically preconditioned, andif so, could pharmacologic agents be employed toelectively induce the preconditioned phenotype tomitigate the effects of ischemic episodes incurred byacute coronary syndromes or during cardiac surgery[8,18,75,76].

In vitro studies have confirmed that human atrialand ventricular myocytes can be preconditioned,involving the same metabolic pathways identified inanimal models [77-80]. In clinical situations, severalexamples of preconditioning have been proposed. Ithad long been recognized that patients with symp-toms of angina have a lower mortality rate and com-plication rate (shock, arrhythmias, etc.) after an acutemyocardial infarction, which may represent precondi-tioning, induced by the preceding angina episodes[81,82]. Similarly, patients with "warm-up angina"frequently note a decrease in their exercise-relatedsymptoms and a reduction in ST-segment changesprior to a second period of exercise if they have hadangina symptoms at the initiation of exercise [83,84].This reduction in symptoms lasts for 1-2 h, which is asimilar duration to the beneficial effects of classical,early preconditioning as discussed earlier [85]. Sim-ilarly, diabetic patients treated with oral sulfonylureaantihyperglycemic agents, such as glibenclamide,have been shown to have a disproportionately highincidence or death after myocardial infarction. Thisappears to be due to the pharmacological mechan-ism of their action, which involves inhibition of theKATP channel, which appears to be an important endeffector of preconditioning as discussed above [86].

Examples of ischemic and pharmacologic pre-conditioning have also been shown clinically during


coronary angioplasty and cardiac surgery. Severalinvestigators have reported a reduction or eliminationof angina, ST-segment elevation, enzyme release, etc.after successive balloon inflations during percuta-neous transluminal angioplasty (PTCA). This benefitof repeated episodes of brief ischemia and reperfusionduring PTCA is out of proportion to the presence ofcollateral vessels and has a duration of benefit that isquite similar to that seen in experimental models ofearly preconditioning (1-2 h) [87-90]. In addition,the benefits of repeated balloon inflations duringPTCA can be blocked by preangioplasty administra-tion of glibenclamide [91] (KATPblocker) or inducedby the pretreatment administration of intracoron-ary bradykinin which has been shown to be a potenttrigger of preconditioning [76]. During cardiacsurgery, preservation of ATP, a reduction of troponinT release, and better global and regional myocardialfunction have been suggested by several studies inwhich a preconditioning protocol was employed priorto the period of prolonged aortic cross-clamping.Protocols have involved repeated cycles of 2-3 min ofaortic cross-clamping followed by 2-5 min of reperfu-sion [18,92-94].

It is important to recognize that at the present timewe cannot draw direct mechanistic parallels betweenthe ischemic preconditioning process and pharmaco-logic treatments that are aimed at improving globalmyocardial function after cardiac surgery. There isevidence that although many parts of the induction ofthe preconditioning cascade and mediators involvedin the intracellular transduction of the signal arefound both in ischemic preconditioning and pharma-cologic preconditioning, other data suggest that thereis a divergence of the molecular pathways dependingon the triggering event (i.e. ischemia vs. a pharmaco-logic agent). Further research will be required to moreclearly define the relationships between the varioustriggers of preconditioning, the sequential and parallelintracellular cascades that mediate the signal andthe end effectors of the signal that are responsible forconferring the preconditioned phenotype. Despitethese limitations in our knowledge, our laboratoryhas focused on studying the preconditioning phe-nomenon as it can be applied to: (i) pharmacologicpretreatment of the heart prior to simulated cardiacsurgery; and (ii) understanding why the immatureheart is innately more tolerant than the mature heartto equivalent periods of myocardial ischemia. The

remainder of this chapter will review our findings andsummarize our understanding of how pharmacologicpreconditioning may by employed as an importantadjunct to or substitute for traditional methods ofintraoperative myocardial protection.

Pharmacologic pretreatment toimprove myocardial ischemiatolerance

As discussed earlier, several mediators releasedby ischemic myocardium, including adenosine andbradykinin, can induce the preconditioned phenotypein the heart when administered exogenously before aperiod of more prolonged ischemia. These observa-tions lead us to test the hypothesis that pretreating theheart with bradykinin before a period of cardioplegicarrest would improve postreperfusion myocardialfunction. Utilizing the isolated rabbit heart as a model(described below), we have confirmed this hypothesisand have identified some of the molecular pathwaysinvolved in the mediation of bradykinin-inducedpharmacologic preconditioning.

Bradykinin as a pharmacologicpreconditioning agentBradykinin is a member of a family of kinins that arepeptides released by the myocardium during ischemiaand it is activated by cleavage from a precursor peptidecatalyzed by the enzyme kallikrein [95]. The heart hasan intrinsic kallikrein-kinin system that under normalcircumstances produces very low concentrations ofbradykinin in the plasma. Active bradykinin is rapidlydegraded (<15 s) principally by kininase II that isthe same enzyme as angiotensin converting enzyme(ACE) [96]. Therefore, bradykinin is an attractiveagent to use as a pretreatment in that it is rapidlydegraded and as such, should have few if any systemicside effects.

Bradykinin exerts several cardioprotective effects,including: an increase in coronary blood flow [97]; animprovement in ventricular performance [36]; adecrease in reperfusion arrhythmias [98]; a reductionin lactate dehydrogenase and creatine kinase release[99]; a reduction in tissue ATP depletion [99]; and areduction in infarction size [100]. These beneficialeffects occur via stimulation of the bradykinin B2

receptor, since administration of HOE 140, a select-ive inhibitor of the bradykinin B2 receptor, before

236 CHAPTER 27

ischemic preconditioning abolished its salutary effects[100]. Bradykinin may also play an important rolein protecting the human heart from ischemia. ACEinhibitors reduce infarct size and mortality associatedwith myocardial ischemia [95,96] by increasing thelevel of bradykinin in coronary sinus blood [45].

There is accumulating evidence that bradykininimproves myocardial tolerance to ischemia throughmolecular mechanisms that have been associatedwith ischemic preconditioning. These pathways havebeen discussed earlier in this chapter and are out-lined in Figure 27.1. Downey and others [15,101]have demonstrated that several mediators, includingbradykinin, trigger preconditioning in the rabbit heartby this receptor-mediated process. After the receptoris activated, an intracellular signal transduction cas-cade is initiated, which in the rabbit involves activa-tion of the PKC family of serine-threonine kinases[99]. Discrete PKC isoforms translocate from thecytosol to the cell membrane after ischemic precondi-tioning, resulting in PKC activation [45]. ActivatedPKC in turn phosphorylates downstream substrateproteins that propagate the intracellular signal, result-ing in enhanced resistance to myocardial ischemia.

The PKC hypothesis has been a focus of contro-versy despite extensive laboratory investigation. PKCinhibitors effectively block preconditioning in rat,rabbits, and humans, but less reliably in dogs and pigs[ 14]. It has recently been shown that activation of bothTK and PKC are required for ischemic precondition-ing of rat [15], rabbit [2,15], and pig [4] hearts. Inkeeping with this observation, neither PKC nor TKinhibition alone prevented ischemic preconditioning.Only combined inhibition of both kinases preventedpreconditioning, suggesting that both kinases playparallel roles in mediating preconditioning [4]. Theprecise interaction between PKC and TK activationafter receptor activation is unresolved [5]. TK plays aninitiating role for many cell functions that occur inresponse to environmental stress, including ischemia.Parallel receptor TK-dependent pathways and PKC-dependent pathways may be activated simultaneouslyor individually by a specific preconditioning stimulus.This is supported by studies that have demonstratedthat TK activation can directly phosphorylate PLC,resulting in diacyl glycerol phosphate (DAG)-inducedPKC activation [102]. Alternatively, TK may beactivated downstream from PKC, as evidenced byincreases in TK activity after direct PKC activation [5].

Propagation of the signal beyond PKC and TK appearsto involve activation of the discrete mitogen-activatedprotein kinase called p38MAP-kinase [103,104].Activated p38MAP-kinase phosphorylates severalsubstrates including transcription factors and otherkinases, which in turn phosphorylate the end effectorsof the preconditioning stimulus [ 104].

As discussed earlier in this chapter, NO has beenidentified as both a trigger and a mediator of delayedischemic preconditioning. Activation of endothelialbradykinin receptors leads to the formation of pro-staglandin I2 (PGI2) and NO in cultured endothelialcells [ 105 ]. In anesthetized dogs, infusion of bradykininproduces an increase in coronary blood flow by stimu-lating B2 receptors and the release of NO [106].

Bradykinin also has beneficial metabolic effects innormal and ischemic hearts, including preservation oftissue ATP, creatine phosphate, and glycogen, as wellas reducing lactate production. Bradykinin also hasbeen shown to potentiate the effects of insulin on glu-cose uptake, activation of glucose transporters, andglucose oxidation [107,108]. Exogenous bradykininexhibits an insulin-like effect on glucose metabolismand potentiates insulin-stimulated glucose uptake inskeletal and cardiac muscle [109-113].

Experimental model used in bradykininpretreatment studiesNew Zealand white rabbits (1.5-2.0 kg) were used inthis series of studies. Rabbits were anesthetized withsodium pentobarbital (60 mg/kg, IV), anticoagulatedwith heparin (2000 U/kg, IV), and the heart wasrapidly exposed. The aorta was cannulated and theheart was retrogradely perfused in situ to avoidischemia. The heart was then excised and mounted inan organ chamber on a Langendorff perfusion system.The heart was retrogradely perfused at 75 mmHg witha modified Krebs-Henseleit buffer (KHB) which wasequilibrated with 95% O2 and 5% CO2, adjusted to apH of 7.35-7.4. Myocardial temperature was main-tained at 37°C by regulation of the organ chambertemperature.

Mean coronary flow (ml/min) was measured bytimed collection of effluent from the right ventricleexiting the heart from the severed pulmonary artery.Isovolumetric measurement of left ventricular (LV)performance was made using a compliant latex bal-loon connected to a pressure transducer which wasinserted in the left ventricle across the mitral valve. A


Figure 27.3 Standard protocol for pharmacologic preconditioning with bradykinin. CP, cardioplegic infusion.

calibrated syringe attached to the pressure transducersystem was used to fill the balloon with a volumeof saline needed to maintain a left ventricular end-diastolic pressure (LVEDP) of 10 mmHg during mea-surement of baseline LV performance and was usedfor subsequent measurements of LV performance afterreperfusion. Left ventricular performance was assessedby the measurement of left ventricular developed pres-sure (LVDP, mmHg) and LVEDP (mmHg). Positiveand negative first derivatives of LVDP (+dP/dt and-dP/dt, mmHg/s) were calculated as indices of ven-tricular contractility and compliance, respectively.

A standard protocol was used (Figure 27.3) inwhich hearts were stabilized for 20 min on Langendorffretrograde perfusion after which baseline measure-ment of LV performance and coronary flow wererecorded. According to the specific protocol beingtested, hearts received differing treatments. Controlhearts received standard KHB during the entire pre-treatment period. Pretreatment agents, with or with-out metabolic inhibitors, were administered duringthe 20-min pretreatment interval. At the conclusion ofthe 20-min pretreatment period, LV performance andCF were measured again in all hearts to determine ifpretreatment altered these parameters compared tobaseline measurements. All hearts then underwent 50min of cardioplegic arrest induced with St Thomas'cardioplegia solution which was gassed with 95% O2

and 5% CO2 at pH 7.4 and infused at 60 mmHg via aseparate perfusion column. The time to mechanicalarrest was recorded. The cardioplegia solution wassupplemented with the same dose of pretreatmentagents and metabolic inhibitors that was used duringthe pretreatment interval. After conclusion of thecardioplegic ischemic period, postreperfusion LV per-formance and CF were recorded and compared topreischemic values.

Advantages and limitations of the isolatedheart preparationThe primary advantage of the isolated perfused heartis the elimination of extrinsic neural input and hor-

monal factors. A disadvantage of the isolated heartperfused with low-viscosity media lacking red cells isthe abnormally high coronary flow rate as comparedto the blood-perfused heart. Most of the energy needsof the in vivo myocardium are met through the oxida-tion of plasma free fatty acids, lactate, and glucose.In isolated hearts, glucose is the substrate used inthe perfusion fluid and results in a limited store ofhigh-energy phosphate. The Langendorff preparationis stable and can be maintained for many hours,although it does not perform external work whilebeating. The work output and oxygen requirementof the Langendorff preparation is considerably lessthan the ejecting heart in vivo. In spite of these limita-tions, the isolated rat heart perfused with glucose hasbeen widely used in studies of myocardial metabolismin both normal and pathologic conditions.

Bradykinin pretreatment improvesischemia tolerance of the rabbit heartUtilizing the model outlined above, we performeda series of experiments to test the hypothesis thatbradykinin pretreatment and cardioplegia supple-mentation would improve the ischemia tolerance ofthe isolated rabbit heart exposed to a period of warm,cardioplegic ischemia. The subsequent sections ofthis portion of the chapter present data that supportthis conclusion and demonstrate the mechanisms ofits action.

Recovery of ventricular performanceand coronary flow in bradykinin-pretreated heartsBradykinin pretreatment was administered in a doseof 0.1 [imol for 10 min prior to arresting the heart withSt Thomas' cardioplegia solution that was also sup-plemented with 0.1 umol bradykinin (Figure 27.4).Postreperfusion recovery of LV performance and cor-onary flow are show in Figures 27.5-27.9. Bradykininpretreatment resulted in a significant increase in base-line coronary flow (CF) and a slight increase in LVDPprior to ischemia (Figures 27.5 & 27.9). Bradykinin

238 CHAPTER 27

Figure 27.4 Experimental protocol: group 1 hearts received no pretreatment before arrest with St Thomas' cardioplegiasolution (StTCP). Group 2 hearts were pretreated with bradykinin (BK) before arrest with StTCP supplemented with BK.Hatched bars, ischemic period; KHB, Krebs-Henseleit buffer.

Figure 27.5 Recovery of left ventricular developed pressure Figure 27.6 Recovery of LV contractility (+dP/dt).(LVDP). Bradykinin (BK) significantly improved the recovery Bradykinin (BK) pretreatment significantly improved theof LVDP throughout the period of reperfusion. recovery of contractility compared to control hearts.

Figure 27.7 Recovery of left ventricular end-diastolicpressure (LVEDP). LVEDP rose significantly in both groupsof hearts during ischemia and declined during reperfusion.LVEDP was significantly lower in the bradykinin-treatedhearts. BK, bradykinin.

Figure 27.8 Recovery of LV compliance (-dP/dt). Bradykinin(BK) pretreatment significantly improved the recovery ofcompliance compared to untreated control hearts.


Figure 27.9 Recovery of coronary flow (CF). Bradykinin (BK)increased coronary flow during the pretreatment periodand significantly improved its recovery during reperfusion.

pretreatment significantly improved the recovery ofsystolic performance throughout the entire period ofreperfusion after 50 min of cardioplegic arrest. At theend of 60 min of reperfusion, the recovery of LVDP

(53 ± 5 mmHg vs. 27 + 4 mmHg, P < 0.01; Figure27.5), and +dP/dtm3x (1025 ± 93 mmHg/s vs. 507 ± 85mmHg/s, P < 0.01; Figure 27.6) were significantlyenhanced by bradykinin pretreatment compared tocontrol hearts. The continuous recovery of LVEDPand -dP/dtmax in the two study groups is presented inFigures 27.7 and 27.8, respectively. LVEDP remainedat baseline level in bradykinin-pretreated hearts dur-ing the stabilization and pretreatment intervals. Dur-ing cardioplegic ischemia, LVEDP rose significantly inboth groups and then gradually declined during the60-min period of reperfusion. Ventricular compli-ance, as measured by-dP/dtmax, showed a gradual riseduring reperfusion. After 60 min of reperfusion,bradykinin-treated hearts had a significantly lowerLVEDP (28 + 3 mmHg vs. 52 ± 5 mmHg, P< 0.01) anda higher -dP/dtmax (669 ± 60 mmHg/s vs. 368 ± 65mmHg/s, P < 0.05) than control hearts. Figure 27.9shows the profile for the recovery of CF. Bradykininpretreatment improved the recovery of CF through-out the entire period of reperfusion, and at the endof 60 min of reperfusion, the recovery of CF wassignificantly enhanced in pretreated hearts.

In the next series of studies, we looked at the mech-anisms by which bradykinin pretreatment improvedpostischemic recovery of ventricular performance inour model. By using specific inhibitors of discrete sitesin the molecular pathways that have been associated

with the preconditioning cascade (Figure 27.1), wetested the hypothesis that bradykinin pretreatmentof the heart triggers molecular signal transductionpathways that are similar to those involved in ischemicpreconditioning.

Bradykinin pretreatment activatesprotein kinase CActivation of specific PKC isoforms, such as PKCe,has been shown to be a key step for triggering andmediating ischemic preconditioning [3,6,14,37,46].

For PKC to become active, it must be translocatedfrom the cytosol fraction of cell proteins to the cellmembrane. Thus, this study tested the hypothesesthat: (i) bradykinin pretreatment of the heart results inactivation of PKC; (ii) activation of PKCe results fromits translocation from the cytosol to membrane frac-tions; and (iii) the beneficial effects of bradykininpretreatment could be blocked by pretreatment withan inhibitor of PKC.

PKC activationTo quantify PKC activation, adult rabbit hearts wereplaced on Langendorff retrograde perfusion. Controlhearts remained perfused with KHB for a total of40 min without further interventions. Bradykinin-treated hearts received an infusion of 0.1 |0,molbradykinin for 5 min followed by 30 min of KHB. PKCactivation was then blocked in a third group of heartsthat received a 5-min infusion of both 0.1 (imolbradykinin and 20 jlmol chelerythrine, a specific PKCblocker, followed by 30 min of KHB. At the end ofeach experiment, hearts were immediately frozen inliquid nitrogen. Protein fractions from frozen heartsamples were purified and the cytosol and membranefractions separated by centrifugation. PKC activitywas quantified in each of the fractions using an ELISA(enzyme-linked immonosorbent assay) system thatutilizes synthetic PKC pseudosubstrate and mono-clonal antibody that recognizes the phosphorylatedform of the pseudosubstrate. Activity was expressed asoptical density (OD) read on a spectrophotometer at492 nm. As shown in Figure 27.10, bradykinin pre-treatment for 5 min led to a significant increase of

PKC activity in the membrane fraction (0.99 ± 0.07 vs.0.66 ± 0.08 OD, P < 0.05). This increase in PKC activ-ity in the membrane fraction was accompanied by adecrease in enzyme activity in the cytosol fraction. Bycontrast, pretreatment with chelerythrine abolished

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Figure 27.10 Protein kinase C activity in the cytosol and membrane protein fractions. Bradykinin pretreatment (black bar)significantly increased the PKC activity in the membrane fraction, which was accompanied by a parallel decrease in thecytosol fraction, presumably due to translocation of PKC from the cytosol to the membrane. Chelerythrine (Chel) blockedthe activation of PKC in the membrane fraction.

the bradykinin-induced increase in PKC activity in themembrane fraction (0.69 + 0.02 vs. 0.66 ± 0.08 OD) inmembrane fractions. Chelerythrine also reduced PKCactivity in the cytosol fractions (0.87 ± 0.02 vs. 1.15 ±0.02 OD,P< 0.05).

PKCe translocationTissue samples from the hearts in the previous experi-ment were analyzed by Western immunoblotting toquantify the amount of PKCe in the cytosol and mem-brane fractions to confirm that PKC activation wasthe result of translocation of this discrete isoformof the enzyme. Proteins were separated by SDS-PAGE technique and then transferred to polyvinyli-denedifluoride (PVDF) membranes, which wereincubated first with monoclonal mouse-anti rabbitPKCe antibody and then with horseradish peroxidase-conjugated secondary antibody. The labeled bandswere visualized colorimetrically, quantified by an imagescanning densitometer, and reported as densitometer

units. The content of PKCe in the cytosol and mem-brane fractions for each of the groups is shown inFigure 27.11. Administration of bradykinin for 5 mininduced significant PKCe translocation from thecytosol fraction (untreated controls 0.91 ± 0.13 OD vs.5 min bradykinin 0.46 ± 0.07 OD, P < 0.05) to themembrane fraction (untreated controls 0.55 ± 0.03 ODvs. bradykinin 1.32 ± 0.30, P < 0.05). Chelerythrineblocked the translocation of PKCe that was inducedby bradykinin. These results corresponded nicely tothe PKC activation measured in the previous study.

Ventricular performance and coronary flowTo determine if PKC inhibition altered the efficacyof bradykinin pretreatment in improving the recoveryor ventricular performance after ischemia and reper-fusion, we pretreated hearts with a combination of0.1 (ilmol bradykinin and 20 (irnol chelerythrine for10 min prior to a period of 50 min of cardioplegicischemia using the same protocol described earlier.


Figure 27.11 Content of PKCe in the cytosol and membrane protein fractions. Bradykinin pretreatment resulted intranslocation of PKCe from the cytosol to the membrane fraction. This parallels the greater activation of PKC shownin Figure 27.9. Chelerythrine (Chel) blocked translocation of PKCe. PKC translocation did not occur in untreatedcontrol hearts.

Prior pilot studies confirmed that chelerythrine in thedoses used did not alter baseline ventricular perform-ance or coronary flow in the normal heart. As shownin Figures 27.12 and 27.13, PKC inhibition by com-bining chelerythrine with bradykinin abolished theprotection afforded by bradykinin pretreatment. The

recovery of ventricular systolic (LVDP and +dP/dt)and diastolic (LVEDP and -dP/df) function in heartstreated with the combination of chelerythrine andbradykinin was no different from control hearts. Thiswas not due to an alteration in coronary flow, sincethis did not differ in chelerythrine-treated hearts com-pared to those receiving bradykinin alone. The resultsof this series of studies confirmed that bradykinin pre-treatment activated PKC as a part of the mechanism of

its induction of protection from cardioplegic ischemia.Limitations of these studies included our inability tomeasure the isolated activity of the PKCe isoformactivity in contrast to total PKC activity. In addition,chelerythrine is not completely specific for PKC, andmay have caused low-grade inhibition of other serine-threonine protein kinases.

Bradykinin pretreatment activatestyrosine kinaseOver 1000 tyrosine kinases have been identified whichplay a variety of roles in normal cell function [9]. Innoncardiac tissues, the Src family of tyrosine kinaseshas been shown to play an important role in response

to stress and tyrosine kinase activation has beenidentified as a part of the triggering and signal trans-duction cascade that mediates the ischemic precon-ditioning phenomenon [4,5,39,44,114]. This study

tested the hypothesis that bradykinin pretreatmentimproved postischemic myocardial function by acti-vating the molecular pathways associated within thepreconditioning phenomenon, including activation

of tyrosine kinase.The same isolated adult rabbit heart model described

earlier was used in this study. Bradykinin-treatedhearts received 0.1 (imol bradykinin for 10 min, fol-lowed by 50 min of cardioplegic ischemia inducedby an infusion of 0.1 (imol bradykinin-enrichedSt Thomas' cardioplegia solution. As shown in Fig-ures 27.5-27.9, bradykinin pretreatment resulted in

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Figure 27.12 Recovery of left ventricular systolic performance after PKC inhibition. Bradykinin pretreatment significantlyimproved the recovery of left ventricular developed pressure (LVDP) and contractility (+dP/df) compared to untreatedcontrol hearts. PKC inhibition with chelerythrine (Chel) attenuated the benefits of bradykinin after reperfusion.

Figure 27.13 Recovery of left ventricular diastolic performance after PKC inhibition. Bradykinin pretreatment alsoimproved the recovery of left ventricular end-diastolic pressure (LVEDP) and compliance (-dP/dt) after reperfusion, whichwas attenuated by PKC inhibition by the coadministration of chelerythrine (Chel).


Figure 27.14 Experimental protocol. Group 1 hearts received no pretreatment before undergoing 50 min of cardioplegicischemia. Group 2 hearts were pretreated with the combination of bradykinin (BK) and genistein (Gen), a blocker oftyrosine kinase. StTCP, St Thomas' cardioplegia solution; KHB, Krebs-Henseleit buffer.

a significant improvement in the recovery of postre-perfusion ventricular performance and a return ofcoronary flow compared to nonpretreated controlhearts. Seven additional hearts were exposed to40 (imol genistein, a selective inhibitor of tyrosinekinase [115], before being pretreated with 0.1 |0,molbradykinin (Figure 27.14). These hearts were thenarrested with St Thomas' cardioplegia solution thatcontained both bradykinin and genistein. In pilot

Figure 27.15 Recovery of left ventricular developedpressure (LVDP) after pretreatment with bradykinin andgenistein. Bradykinin pretreatment resulted in a significantimprovement in the recovery of LVDP compared to control.Blocking tyrosine with genistein prevented the salutaryeffect of bradykinin. Reprinted from Annals of ThoracicSurgery, Vol. 68, Feng J, Rosenkranz E. Bradykininpretreatment improves ischemia tolerance of the rabbitheart by tyrosine kinase mediated pathways,pp. 1567-1572. © 1999, with permission from the Societyof Thoracic Surgeons.

Figure 27.16 Recovery of LV compliance (-dP/dt) afterpretreatment with bradykinin and genistein. Bradykininpretreatment resulted in a significant improvement in therecovery of-dP/dtcompared to control. Blocking tyrosinekinase with genistein prevented the salutary effect ofbradykinin. Reprinted from Annals of Thoracic Surgery,Vol. 68, Feng \, Rosenkranz E. Bradykinin pretreatmentimproves ischemia tolerance of the rabbit heart by tyrosinekinase mediated pathways, pp. 1567-1572. © 1999, withpermission from the Society of Thoracic Surgeons.

studies, 40 jimol genistein had no effect on ventri-cular performance or coronary flow in the normalLangendorff-perfused rabbit heart. As shown inFigures 27.15-27.17, genistein blocked the beneficialeffects of bradykinin pretreatment. Recovery of sys-tolic and diastolic ventricular function and coronaryflow in these hearts did not differ from nonpretreatedcontrol hearts. The results of this study confirmed thattyrosine kinase activation participates in the mole-cular pathway responsible for bradykinin's salutary

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Figure 27.17 Recovery of coronary flow (CF) afterpretreatment with bradykinin and genistein. Bradykininpretreatment resulted in a significant improvement in therecovery of coronary flow compared to control. Blockingtyrosine kinase with genistein prevented the salutary effectof bradykinin. Reprinted from Annals of Thoracic Surgery.Vol. 68, Feng J, Rosenkranz E. Bradykinin pretreatmentimproves ischemia tolerance of the rabbit heart by tyrosinekinase mediated pathways, pp. 1567-1572. © 1999, withpermission from the Society of Thoracic Surgeons.

effect on the recovery or postischemic ventricularperformance. Limitations of this study included ourinability to determine where in the signal transductionsequence tyrosine kinase was located. In addition, wedo not know which tyrosine kinase isoform was beingactivated by bradykinin and we did not measure tyro-sine kinase activity.

Bradykinin pretreatment requiresactivation of nitric oxideActivation of the bradykinin B2 receptor in vascularendothelial cells and in myocytes results in nitric oxide(NO) generation due to activation of the endothelial(eNOS) and inducible (iNOS) isoforms of nitric oxidesynthase (NOS), respectively [44,45]. As detailed ear-lier in this chapter, NO generated during ischemic pre-conditioning has been shown to reduce the incidenceof ischemia- and reperfusion-associated arrhythmiasand is associated with triggering the induction of thelate form of ischemic preconditioning [9,47-49]. NOreleased by ischemic endothelium or supplied endo-genously in nonischemic hearts from NO donors haveboth been shown to activate PKCe which is requiredfor the preconditioning signal transduction cascade

[46,116]. The role of NO as a trigger and mediatorof the early phase of ischemic preconditioning is lesscertain. This study tested the hypotheses that: (i)bradykinin pretreatment of the heart activates thebradykinin B2 receptor and induces the precondi-tioned state of the rabbit heart via molecular pathwaysthat involve generation of nitric oxide; and (ii) thebenefits of bradykinin pretreatment can be preventedby administration of either B2 receptor blocker (HOE140) or an inhibitor of NOS (N-Q-nitro-L-arginine-methyl ester (L-NAME)).

Our standard model of the isolated adult rabbitheart and the experimental protocol described earlierwere employed in this study as well (Figure 27.18).Control hearts received no pretreatment prior toinducing arrest with standard St Thomas' cardioplegiasolution. Bradykinin-pretreated hearts received a10-min infusion of 0.1 urno! bradykinin prior to50 min of arrest with bradykinin-enriched St Thomas'cardioplegia solution. To confirm that bradykinininduced protection from ischemia via activation of thebradykinin B2 receptor, six hearts were treated with0.1 Jlmol HOE 140, a selective bradykinin B2 receptorantagonist, prior to pretreatment with 0.1 Limolbradykinin and cardioplegic arrest with St Thomas'cardioplegia solution containing both HOE 140 andbradykinin. Finally, to confirm that bradykinin's salut-ary affect required activation on NOS, seven heartswere treated with 100 [imol L-NAME, an inhibitor ofboth iNOS and eNOS, prior to 0.1 n,mol bradykininpretreatment and cardioplegic arrest.

Both HOE 140 and L-NAME prevented the bene-ficial effects of pretreating the heart with bradykininprior to cardioplegic ischemia. As shown in Figures27.19 and 27.20, the recovery of ventricular systolicand diastolic performance after reperfusion was equi-valent to that seen in nonpretreated control hearts.The results of this study demonstrated that the bene-ficial effects of bradykinin pretreatment of the heartprior to a prolonged period of global ischemia aremediated via NO, presumably produced by activationof eNOS in response to the triggering signal inducedby activation of the bradykinin B2 receptor. As shownin Figure 27.2, we believe that bradykinin pretreat-ment results in activation of eNOS and generation ofNO. NO then may act as a second messenger betweenthe vascular endothelium and the myocyte resultingin activation of the PKC- and TK-dependent signaltransduction pathway leading to the preconditioned

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Figure 27.18 Experimental protocol. Group 1 hearts received no pretreatment. Group 2 hearts were pretreated withbradykinin (BK) before undergoing 50 min of ischemia and 60 min of reperfusion. Group 3 hearts received a combinationof bradykinin and HOE 140, a blockerof thebradykinin B2 receptor. Group 4 hearts received a combination of bradykininand /V-a-nitro-L-arginine-methyl ester (i-NAME). KHB, Krebs-Henseleit buffer; STCP, St Thomas' cardioplegia; CP,cardioplegia. Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J, Li, H, Rosenkranz E. Bradykinin protects therabbit heart after cardioplegic ischemia via NO-dependent pathways, pp. 2119-2124. © 2000, with permission fromthe Society of Thoracic Surgeons.

Figure 27.19 Recovery of left ventricular developedpressure (LVDP) after pretreatment with bradykinin (BK) incombination with HOE 140 or i-NAME. As shown earlier,bradykinin pretreatment improved the recovery of LVDPafter reperfusion compared to untreated control hearts. Bycontrast, blockade of the bradykinin B2 receptor with HOE140, or blockade of nitric oxide synthase with L-NAMEprevented the benefit of bradykinin pretreatment.Reprinted from Annals of Thoracic Surgery, Vol. 70, Feng J,Li H, Rosenkranz E. Bradykinin protects the rabbit heartafter cardioplegic ischemia via NO-dependent pathways,pp. 2119-2124. ©2000, with permission from the Societyof Thoracic Surgeons.

Figure 27.20 Recovery of left ventricular end-diastolicpressure (LVEDP) after pretreatment with bradykinin (BK)in combination with HOE 140 or i-NAME. As shown earlier,bradykinin pretreatment improved the recovery of LVEDPafter reperfusion compared to untreated control hearts. Bycontrast, blockade of the bradykinin B2 receptor with HOE140, or blockade of nitric oxide synthase with i-NAME,negated the benefit of bradykinin pretreatment. Reprintedfrom Annals of Thoracic Surgery, Vol. 70, Feng J, Li H,Rosenkranz E. Bradykinin protects the rabbit heart aftercardioplegic ischemia via NO-dependent pathways, pp.2119-2124. © 2000, with perm ission from the Society ofThoracic Surgeons.

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246 CHAPTER 27

state. Coadministration of L-NAME blocked NO gen-eration, which prevented activation of the proposedprotective mechanisms.

Limitations of this study included our inability tomeasure NOS activity. In addition, we cannot deter-mine if bradykinin is acting on iNOS or eNOS, sinceL-NAME inhibits all isoforms of NOS. In this study,we did not measure activation of PKC or TK, and assuch we cannot prove that NO resulted in their activa-tion. Finally, it is possible that NO directly activatesthe KATP channel independent of the signal transduc-tion cascade outlined above.

Bradykinin induces translocation ofglucose transporter 4In skeletal muscle and adipocytes [109] bradykininincreases glucose uptake due to enhanced transloca-tion of glucose transporters 1 and 4 (GLUT 1 and 4)from intracellular membrane pools to the sarcolem-mal membranes. Both GLUT 1 and GLUT 4 must betranslocated from intracellular membrane fractionsto sarcolemmal membrane fractions for activation,which results in an increase in glucose transport.In cardiac myocytes, GLUT 1 is responsible for basalglucose uptake, whereas GLUT 4 is responsible forinsulin-induced glucose transport [117-119]. In alltissues, including the heart, insulin results in theactivation of tyrosine kinase, which in turn activatesphosphatidylinositol 3-kinase (PI3-K) leading to thetranslocation of GLUT 1 and 4 to the sarcolemmalmembrane [ 120]. As described earlier, we have shownthat bradykinin pretreatment results in tyrosine kinaseactivation in order to induce myocardial ischemiatolerance in the isolated adult rabbit heart. This groupof studies tested the hypotheses that; (i) bradykininpretreatment induces GLUT 4 translocation in rabbitmyocardium; and (ii) bradykinin-induced GLUT 4translocation requires activation of both PKC andPI3-K.

GLUT 4 translocationThe first study in this series quantified the changes inGLUT 4 protein content in the myocardial intracellu-lar and sarcolemmal membrane fractions in responseto bradykinin pretreatment. Control adult rabbithearts were perfused on a Langendorff apparatus withstandard KHB for 20 min. Five other hearts were pre-treated with 0.1 (imol bradykinin for 10 min followedby 10 min of perfusion with standard KHB. Tissue

samples were then processed by differential sucrosegradient centrifugation to separate high-densitymembranes (sarcolemmal membrane fraction) fromthe low-density membranes (intracellular membranefraction). Western immunoblotting was used to quan-tify the GLUT 4 content in the two membrane popu-lations. Aliquots were loaded onto 10% SDS-PAGEgels and the protein blots were transferred to PVDPmembrane. The membrane was first incubated withmonoclonal mouse antirat GLUT 4 primary antibodyand then with horseradish peroxidase-conjugatedsecondary antibody. The immunolabeled bands werevisualized colorimetrically and the protein quantifiedby scanning image densitometry. As shown in Figure27.21, bradykinin pretreatment resulted in a twofoldincrease in GLUT 4 content in the sarcolemmal mem-brane fraction of the bradykinin-treated hearts com-pared to the control hearts. This was associated witha proportional decrease in the GLUT 4 protein con-tent of the intracellular membrane fraction in thebradykinin-treated hearts (Figure 27.22), suggestingthat GLUT 4 was translocated from the intracellularto the sarcolemmal fractions.

PI3K activityThe second study in this series was aimed at determin-ing if bradykinin-stimulated GLUT 4 translocationoccurred via the same metabolic pathways associatedwith insulin, namely PI3-K activation. We first meas-ured the activation of PI3-K in bradykinin-pretreatedhearts by Western immunoblotting. Whole tissueprotein samples were obtained from control heartsperfused with standard KHB for 5 min and fromhearts pretreated with 0.1 (imol bradykinin for 5 min.Proteins were separated in SDS-PAGE, transferredto PVDF membranes, the immunoblots resolved withmonoclonal antibody that recognized the phosphory-lated (activated) form of PI3-K, and then the proteincontent of the bands was quantified by laser scanningdensitometry. As shown in Figure 27.23, bradykininpretreatment resulted in a threefold increase inPI3-K activity compared to nonpretreated hearts(0.43 densitometer units (DU) vs. 1.16 DU). We thentested the effect PI3-K inhibition had on the recoveryof ventricular performance after cardioplegic ischemiaand reperfusion in bradykinin-pretreated hearts.Utilizing our standard isolated heart model andprotocol (Figure 27.3), hearts were pretreated with3 [imol wortmannin, an inhibitor of PI3-K, prior to


Figure 27.21 Translocation of glucosetransporter 4 (GLUT 4) to thesarcolemmal membrane fraction. Heartstreated with bradykinin had asignificantly greater amount of GLUT 4protein translocated to the sarcolemmalmembrane than untreated controlhearts.

Figure 27.22 Glucose transporter 4(GLUT 4) content in the intracellularmembrane fraction. Bradykinin-treatedhearts had a significant reduction inGLUT4 content in the intracellularmembrane fraction, which likelyrepresents translocation of GLUT 4protein to the sarcolemmal membranefraction as shown in Figure 27.21.

pretreatment with 0.1 Jimol bradykinin and 50 min of

cardioplegic ischemia with St Thomas' solution sup-

plemented with both wortmannin and bradykinin.

The recovery of ventricular performance compared

to control hearts (no pretreatment) and bradykinin-

pretreated hearts is shown in Figure 27.24. PI3-K

inhibition completely prevented the beneficial effectof bradykinin. These results support our hypothesis

that bradykinin activates PI3-K as part of the molecu-

lar pathway by which it reduces ischemic injury.

GLUT 4 translocation requires PKC activationOur next study tested the hypothesis that PKC

activation is required for bradykinin-induced GLUT

4 translocation and activation. Control hearts received

no pretreatment. Six other hearts were pretreated

with 0.1 (imol bradykinin for 10 min. Six others

received 20 umol chelerythrine, a PKC inhibitor,

before bradykinin pretreatment and then in combina-

tion with bradykinin pretreatment for 10 min. After

10 min of KHB perfusion, subcellular membrane

248 CHAPTER 27

Figure 27.23 Phosphatidylinositol 3-kinase (PI3-K)activation. Bradykinin-treated hearts had a significantincrease in PI3-K activity compared to untreated controlhearts.

Figure 27.24 Recovery of left ventricular developedpressure (LVDP) after pretreatment with bradykinin aloneor in combination with wortmannin (Wort). As shownearlier, bradykinin pretreatment resulted in significantlybetter recovery of LVDP after ischemia and reperfusioncompared to untreated control hearts. By contrast, heartstreated with the combination of bradykinin andwortmannin, an inhibitor of PI3-K, had poorer recovery,which was equivalent to untreated control hearts.

fractions were prepared in all hearts by differentialcentrifugation and GLUT 4 content in sarcolemmaland intracellular membrane fractions were measuredby Western immunoblotting as described earlier. As

Figure 27.25 Glucose transporter 4 (GLUT 4) content in thesarcolemmal membrane protein fraction of hearts treatedwith bradykinin with or without chelerythrine (Chel).Heart treated with bradykinin had a significantly greatertranslocation of GLUT 4 protein to the sarcolemmalmembrane fraction compared to untreated controls.By contrast, hearts treated with the combination ofbradykinin and chelerythrine, an inhibitor of proteinkinase C (PKC), did not have translocation of GLUT 4.

shown in Figures 27.25 and 27.26, bradykinin pre-treatment significantly increased GLUT 4 content inthe sarcolemmal fraction, which was accompanied byan equivalent decrease of GLUT 4 in the intracellularmembrane fraction. By contrast, pretreatment withchelerythrine prevented bradykinin-induced trans-location of GLUT 4 from the intracellular membraneto the sarcolemmal membrane fraction.

From this series of studies, we concluded that in theheart, there are similarities in insulin and bradykininsignal transduction pathways. Thus, both insulin andbradykinin may activate tyrosine kinase, PKC, andMAP kinase [109,110,121,122], as well as increasethe release of NO from endothelium and myocytes[45,108,123]. NO increases the rate of glucose trans-port and metabolism in skeletal muscle, independentof its vasodilatory effects. Bradykinin has also beenshown to mimic insulin-induced translocation of glu-cose transporters in insulin-resistant rat hearts [124].Our data supports the contention that bradykininstimulates glucose uptake via translocation of GLUT4, mediated by PKC and PI3-K-dependent pathways,


Figure 27.26 Glucose transporter 4 (GLUT 4) content in theintracellular membrane protein fraction of hearts treatedwith bradykinin with or without chelerythrine (Chel).Hearts treated with bradykinin had a significant decreasein GLUT 4 protein in the intracellular membrane fractioncompared to untreated controls due to its translocationto the sarcolemmal fraction (Figure 27.25). By contrast,hearts treated with the combination of bradykinin andchelerythrine, an inhibitor of protein kinase C (PKC), didnot have a decrease in intracellular GLUT 4 protein,suggesting that PKC activation is required for translocationof GLUT 4 protein from the intracellular to the sarcolemmalmembrane.

and may represent one of the mechanisms responsiblefor bradykinin's salutary effects as a pretreatmentprior to global myocardial ischemia.

The KATP channel as an end effector ofthe preconditioning phenomenonAs discussed earlier, the KATP channel has beenproposed as the end effector of the ischemic precon-ditioning phenomenon, responsible for conveying

protection from subsequent ischemic episodes [10,11,52,54,55,59,60,125,126]. The KATP channel is foundin most tissues and opens in response to depletion ofintracellular ATP. The channel appears to play severalregulatory roles, including adjustment of membrane

potentials by regulating the flux of potassium and cal-cium ions across cell and organelle membranes. Theevidence for opening these channels that are involvedin preconditioning comes from studies in whichblocking these channels prevented the effects of bothischemic preconditioning [127-129] and pharmaco-

logic preconditioning induced by adenosine [54,125,128,130] or acetylcholine [131]. In addition, treatinghearts with KATP channel-openers mimics precondi-tioning, and several of the putative triggers of ischemicpreconditioning, including bradykinin, have beenshown to open KATP channels in myocytes [35,52,57,70,127,132-134].

Administration of pharmacologic potassium chan-nel openers (PCOs) has been shown to improve myo-cardial ischemia tolerance [127] and have been used incardioplegia solutions [135-140]. Cardiac myocytescontain two distinct KATP channels, one in the sar-colemmal membrane (sarc-KATP) and the other, inthe mitochondrial inner membrane (mito-KATP).Opening of sarc-KATP channels shortens the actionpotential duration, which inhibits calcium entry intothe myocytes via L-type channels and preventscalcium overloading during reperfusion. Membranehyperpolarization also inhibits calcium entry into thecell by preventing the reversal of the sodium-calciumexchanger that normally extrudes calcium in exchangefor sodium [55-57,132,133,135-142].

These processes were initially considered to be themechanism by which PCOs induced cardioprotec-tion. However, studies by Grover demonstrated thatshortening of action potential duration is not a pre-requisite for the cardioprotective effect of PCOs orischemic preconditioning, suggesting that the mechan-ism of cardioprotection is more likely due to an intra-cellular effect on the mito-KATP channel, not thesarco-KATP channel [55,57,132,133,141]. Althoughthe mechanism responsible for the protective effects ofmito-KATP channel opening has not been elucidated,several potential mechanisms have been proposed.Opening of the mito-KATP channel leads to depolar-ization of the intramitochondrial membrane, whichcauses a transient swelling of the intramitochondrialspace. This leads to increased respiration via the elec-tron transport chain and a subsequent increase in ATPproduction. Mitochondrial membrane depolarizationreduces calcium entry, thus reducing calcium over-loading of the mitochondria, which is typically seen inhearts undergoing a reperfusion injury. Finally, open-ing the mito-KATP channel may induce potassiuminflux into mitochondria and result in a burst of freeradical generation that sets the myocardium in a pre-conditioned state [10,55,69,142,143].

Based on these observations, we hypothesized

that combining a mito-KATP channel opener with

250 CHAPTER 27

Figure 27.27 Experimental protocol. Control hearts received no pretreatment prior to undergoing 50 min of ischemia.Hearts pretreated with the KATP channel opener diazoxide (DZ) received 10 min of DZ pretreatment and DZ supplementedcardioplegia. Hearts treated with 5-hydroxydecanoate (5-HD), an inhibitor of the mitochondrial KATP channel, received 5-HD alone for 10 min then in combination with DZ for an additional 10 min and finally the combination of 5-HD and DZ incombination with St Thomas' cardioplegia (STCP). CP, cardioplegia; KHB, Krebs-Henseleit buffer. Reprinted withpermission from Feng J, Li H, Rosenkranz ER. Diazoxide protects the rabbit heart following cardioplegic ischemia.Molecular and Cellular Biochemistry 2002; 233:133-138.

cardioplegia may have an additive protective effect onthe ischemic rabbit heart. To test this hypothesis, wefirst looked at the efficacy of enriching cardioplegiasolution with diazoxide, a selective mito-KATP chan-nel opener, in terms of protecting the rabbit heart fromglobal ischemia [133]. We then tested whether pre-treatment with sodium 5-hydroxydecanoate (5-HD),a selective mitochondrial KATP channel blocker,could prevent the protective effects of diazoxide. Ourstandard protocol was used (Figure 27.27). Controlhearts received no pretreatment. Diazoxide-pretreatedhearts received 30 (imol diazoxide-enriched KHB.5-HD treated hearts received 100 (imol 5-HD priorto pretreatment with a combination of 30 jllmol dia-zoxide and 100 |0,mol 5-HD. After 50 min of cardio-plegic arrest with St Thomas' cardioplegia solutionthat contained either diazoxide alone or the combina-tion of diazoxide and 5-HD, postreperfusion LV per-formance and CF were determined and comparedbetween the pretreatment groups.

Pretreatment with diazoxide alone resulted in asignificant increase in coronary flow prior to cardio-plegic arrest, which was prevented when 5-HD wascombined with diazoxide (Figure 27.28). As shown inFigures 27.29 and 27.30, the recovery of systolic anddiastolic ventricular performance was significantlyimproved in response to pretreatment with diazoxide

Figure 27.28 Recovery of coronary flow in heartstreated with diazoxide and 5-hydroxydecanoate (5-HD).Diazoxide pretreatment resulted in a significant increasein coronary flow prior to ischemia, which was attenuatedby the combined treatment with diazoxide and 5-HD.After reperfusion, diazoxide-treated hearts had asignificantly better recovery of coronary flowcompared to control hearts. This benefit of diazoxidepretreatment was lost in hearts treated with 5-HD.Reprinted with permission from Feng J, Li, H RosenkranzER. Diazoxide protects the rabbit heart followingcardioplegic ischemia. Molecular and CellularBiochemistry 2002; 233:133-138.

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Figure 27.29 Recovery of left ventricular developedpressure (LVDP) in hearts treated with diazoxide with orwithout 5-hydroxydecanoate (5-HD). Hearts treated withdiazoxide had a significantly better recovery of LVDP afterreperfusion compared to untreated control hearts. Thisbenefit of diazoxide was prevented in hearts treated with5-HD. Reprinted with permission from Feng J, Li H,Rosenkranz ER. Diazoxide protects the rabbit heartfollowing cardioplegic ischemia. Molecular and CellularBiochemistry 2002; 233:133-138.

Figure 27.30 Recovery of left ventricular end-diastolicpressure (LVEDP) in hearts treated with diazoxide with orwithout 5-hydroxydecanoate (5-HD). Hearts treated withdiazoxide had a significantly lower LVEDP after reperfusioncompared to untreated control hearts. This benefit ofdiazoxide was lost in hearts treated with 5-HD. Reprintedwith permission from Feng J, Li H, Rosenkranz ER.Diazoxide protects the rabbit heart following cardioplegicischemia. Molecular and Cellular Biochemistry 2002; 233:133-138.

and diazoxide-enriched cardioplegia solution, whichwas completely prevented by the addition of 5-HD.There were no significant differences in the recoveryof 5-HD-treated hearts compared to nonpretreated

control hearts. Figure 27.28 shows the profile for therecovery of coronary flow during 60 min of reper-fusion in the three groups. Diazoxide pretreatmentsignificantly improved the recovery of coronary flowthroughout the entire period of reperfusion. By con-trast, pretreatment with 5-HD also blocked this effectof diazoxide on the recovery during reperfusion.

The benefits of diazoxide pretreatment mimic thoseseen with ischemic preconditioning against infarction.Diazoxide is 1000-2000 times more potent in openingthe mito-KATP channel compared to the sarc-KATPchannel, and recent studies by Liu et al. [56,60] andSato et al. [57] confirmed that diazoxide is a selectivemito-KATP opener in the rabbit myocardium. Theresults of our study extend these observations bydemonstrating that diazoxide combined with hyper-kalemic cardioplegia improved the myocardial func-

tional recovery.

ConclusionsThe studies reviewed in the preceding section con-firmed our initial hypothesis that bradykinin pre-treatment could improve the recovery of ventricularfunction after a period of global myocardial ischemia.Our studies, combined with those in the literature,support the hypothesis that bradykinin activates anumber of the molecular pathways that have beenshown to be involved in triggering and mediating theischemic preconditioning phenomenon. Further workis needed to determine the sequence of the molecularpathways involved and to determine the end effectof the signal transduction pathway that confers thepreconditioned phenotype. Once this data is in hand,surgeons will be able to more rationally combinepharmacologic preconditioning with more traditionalmethods of perioperative myocardial protection.

Is the immature heart"preconditioned" to tolerateischemia?

Cardiac surgical procedures on adults and childrenrequire a quiescent, bloodless surgical field to carryout the operation. Aortic cross-clamping with cardio-plegic arrest has been the standard approach forseveral decades and has been associated with good

outcomes in adult patients in whom the majority ofmyocardial protective strategies have been developed.By contrast, postoperative myocardial dysfunction

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252 CHAPTER 27

remains a clinical problem in pediatric patients.Several studies suggest that the methods of cardio-plegic arrest and the composition of the cardioplegiasolutions may be responsible for this discrepancycompared to the adult patients [ 144-153].

Experimental studies suggest that the immatureheart tolerates ischemia better then the mature heartdue to endogenous metabolic advantages in theimmature heart [144-148], including greater glyco-gen stores and more prolonged anerobic utilization ofglucose, amino acids, and lactate for both aerobicand anerobic ATP generation [149,154-156]. Duringischemia, ATP depletion is delayed due to bothdecreased utilization and slower catabolism by 5'-nucleotidase [155,157]. Postischemic reperfusion isbetter tolerated by the immature heart due to lessorganelle and cell membrane damage caused by oxy-gen free radicals and by calcium paradox [158]. Inaddition, there is recent data that suggests that theimmature heart may possess endogenous activationof molecular pathways that have been associated withthe ischemic preconditioning phenomenon [149,156,159,160]. We have conducted a series of experimentsaimed at testing the hypotheses that the immatureheart is inherently more tolerant of ischemia becauseit can more avidly call upon molecular pathways thathave been associated with the preconditioning phe-nomenon. Paradoxically, these molecular pathwaysappear to become less active with maturation [161,162].

PKCe is upregulated in the neonatalheartThe ischemically preconditioned adult heart sharesmany of the metabolic advantages inherent in theimmature heart, including reduced utilization of ATPduring ischemia and less cell and organelle damageafter reperfusion [61]. Based on these observations, wehypothesized that the immature heart is endogenouslypreconditioned, possessing greater stress-inducedactivation of the signal transduction enzymes, particu-larly PKCe, which are responsible for ischemic pre-conditioning. To test this hypothesis, we performed aseries of studies designed to characterize the effects ofage on the isolated rabbit heart's tolerance to ischemiaas measured by the return of heart performance after20 min of global ischemia. Secondly, we evaluated therole played by PKCe in the age-dependent variation inischemia tolerance by measuring the basal level ofPKCe activity in both the neonatal and the adult heart

and quantifying its translocation to the membranefraction in response to ischemia and reperfusion.

Experimental model and methodsNew Zealand white rabbits (7-to 10-day-old-neonates,130-150 g, or adults, 1.5-2.5 kg) were used in thesestudies. Neonatal rabbit hearts were perfused on aLangendorff apparatus at a perfusion pressure of45 mmHg with a modified Krebs-Henseleit buffer(KHB). Adult rabbits were perfused at 75 mmHg withthe same modified KHB. Mean coronary flow (CF,ml/min) and indices of LV performance were assessedin neonatal and adult rabbit hearts as described earlierin this chapter.

A standard protocol was used throughout the study(Figure 27.31). All hearts were stabilized for 20 min onLangendorff retrograde perfusion, after which base-line measurement of LV performance and coronaryflow were recorded. Control neonatal and adult heartswere perfused for 60 min without ischemia. Ischemicneonatal and adult hearts underwent 20 min ofunprotected ischemia at 37°C without reperfusion.Finally, ischemic/reperfused neonatal and adult heartsunderwent 20 min of unprotected ischemia at 37°Cfollowed by 30 min of KHB reperfusion. Recovery ofLV performance and coronary flow were measured inthe hearts undergoing ischemia and reperfusion. Atthe end of each experiment, all hearts were immedi-ately frozen in liquid nitrogen and stored at -80°C forsubsequent PKCe analysis. PKC activity was quantifiedin each of the fractions using an ELISA system thatwas described earlier in this chapter. Western immun-oblotting was used to quantify PKCe translocationfrom the cytosol to the membrane as described earlier.

Recovery of LV function after ischemia andreperfusionThe recovery of both systolic and diastolic LV perfor-mance (Figures 27.32 & 27.33) was significantly betterin the newborn rabbit hearts compared to their adultcounterparts. Neonatal hearts had complete recoveryof both systolic and diastolic ventricular function bythe end of the 30-min reperfusion period. By contrast,LV systolic performance in the adult hearts remained30-40% below preischemic level at the end of reper-fusion. Diastolic function gradually improved, butremained below preischemic level at the end of reper-fusion. Coronary flow returned to near preischemiclevel in both newborn and adult hearts.


Figure 27.31 Experimental protocol. Control hearts underwent perfusion with Krebs-Henseleit buffer (KHB) withoutischemia, after which a sample was obtained for measurement of protein kinase C (PKC) activity and content. Heartsundergoing ischemia alone underwent 20 min of ischemia without reperfusion, after which a sample was obtained for PKCactivity and content. Hearts undergoing ischemia and reperfusion underwent 20 min of ischemia followed by 30 min ofreperfusion, after which a sample was obtained.

Figure 27.32 Recovery of left ventricular developedpressure (LVDP) in neonatal versus adult hearts. Neonatalhearts had complete recovery of LVDP after ischemiacompared to 60% recovery in adult hearts.

PKCe content and activity in cytosol andmembrane protein fractionsFigures 27.34 and 27.35 show the relative content ofPKCe in the cytosol and membrane fractions obtainedfrom the control, ischemia, and ischemic/reperfusedgroups. Before ischemia, there was no significant

Figure 27.33 Recovery of left ventricular end-diastolicpressure (LVEDP) in neonatal versus adult hearts. LVEDPin neonatal hearts returned to baseline values afterreperfusion. By contrast, LVEDP remained significantlyelevated in adult hearts.

difference between adult or neonatal hearts in theircontent of PKCe in the membrane or cytosol frac-tions. In both neonatal and adult hearts, PKCe cont-ent of the cytosol protein fraction was unchanged

254 CHAPTER 27

Figure 27.34 PKCe content in cytosolprotein fraction. PKCe remainedunchanged in neonatal and adult heartsduring ischemia, compared to baselinecontrol values. After reperfusion, PKCeincreased in the cytosol of neonatalhearts, but decreased in adult hearts.

Figure 27.35 PKCe content in themembrane protein fraction. PKCeincreased significantly in the membranefraction of neonatal hearts duringischemia and reperfusion. By contrast,PKCe declined during these time periodsin adult hearts. These findings suggestthat PKCetranslocation occurred inneonatal hearts and may be responsiblefor the greater ischemia toleranceseen in neonatal hearts as shown inFigures 27.32 and 27.33.

during ischemia. In neonatal hearts, however, PKCewas translocated to the membrane fraction duringischemia, resulting in a significant increase in PKCecontent. After reperfusion, PKCe rose significantlyin both the cytosol and membrane fractions in theneonatal hearts. By contrast, in the adult hearts, PKCedeclined in both fractions during reperfusion. PKCactivity paralleled these findings. As shown in Figure27.36, membrane fraction PKC activity rose signific-antly in the neonatal hearts both during ischemia andduring reperfusion, which was paralleled by a propor-tionate fall in cytosol fraction PKC activity. By con-trast, membrane fraction PKC activity was unchangedin the adult hearts during ischemia and reperfusion(Figure 27.37).

From these data we concluded that the neonatalrabbit heart is more tolerant to the stress of unpro-tected ischemia due to its greater activation of themolecular pathways that have also been associatedwith ischemic preconditioning. Although baseline

Figure 27.36 PKC activity in neonatal hearts. PKC activityincreased in the membrane protein fraction duringischemia and reperfusion, with a parallel decline in PKCactivity in the cytosol protein fraction. These findingscorrespond with the translocation of PKCe noted inFigures 27.34 and 27.35.


Figure 27.37 PKC activity in adult hearts. PKC activity didnot change significantly in the cytosol or membraneprotein fractions during ischemia or reperfusion.

levels of PKCe in the membrane and cytosol fractionsof the neonatal and adult hearts were equivalentbefore ischemia, neonatal hearts showed a signific-antly greater translocation of PKCe from the cytosolto the membrane fraction and a significant increase in

membrane PKC activity during ischemia and reperfu-sion. By contrast, PKCe content declined and PKCactivity was unchanged in both fractions in the adulthearts. We believe this confirms our hypothesis that

the better ischemia tolerance of the neonatal heart isdue to greater activation of endogenous molecularmechanisms associated with preconditioning whichappears to decline with maturation. A limitation ofthis study was our inability to measure the specificactivity of the PKCe isoform.

KATP channel opening improvesischemia tolerance in the immatureheartTo further study the mechanisms by which the imma-ture heart tolerates ischemia better than the maturerabbit heart, we looked into the role that the KATPchannel may play in this process. Our first study testedthe hypothesis that the KATP channel is "endoge-

nously activated" in the immature heart or it maybe more responsive to ischemia than in the adultheart. This study was designed to determine if KATPchannel blockade before unprotected global myo-cardial ischemia would reduce postischemic recoveryof LV performance. Seven control neonatal rabbitsreceived an intraperitoneal injection of 2 ml of normalsaline 10 min before sacrifice. Five other neonatal rab-bits received an intraperitoneal injection of 0.3 mg/kgglibenclamide, a KATP blocker, 10 min before

sacrifice. The hearts from both groups of rabbits wereretrogradely perfused on a Langendorff apparatus at37°C for 20 min, after which baseline preischemia LVperformance and coronary flow were recorded. Heartsfrom control rabbits received only KHB. Hearts fromthe glibenclamide-pretreated rabbits received KHBsupplemented with 10 junol glibenclamide. All heartswere then subjected to 20 min of 37°C global ischemiaand were then reperfused with KHB without addi-tional supplementation. After 10 min of reperfusion,recovery of LV performance and coronary flowwere measured. Glibenclamide pretreatment signific-antly reduced baseline LV developed pressure and+dP/drmax before global ischemia (Figure 27.38). After10 min of unprotected 37°C ischemia and 20 min

Figure 27.38 Recovery of LVperformance after glibenclamidepretreatment. Blockade of KATP channelactivation by administration ofglibenclamide resulted in a significantdecrease in the recovery of LV developedpressure and LV contractility (+dP/dr).Reprinted from Journal of SurgicalResearch, Vol. 90, Feng J, Li H,Rosenkranz E. Pinacidil pretreatmentextends ischemia tolerance to neonatalrabbit hearts, pp. 131-137. © 2000,with permission from Elsevier.

256 CHAPTER 27

of reperfusion, untreated control hearts recovered84% of preischemic LV systolic function (LVDP and+dP/dtmax), 91% of compliance (-dP/dtmax), and 96%of CF. By contrast, glibenclamide-pretreated heartshad significantly poorer recovery of LV systolic func-tion after ischemia and reperfusion. LVDP and +dP/dfrecovered only 67% and 62% of their preischemicvalues while -dP/dfmax and CF recovered 78% and77% of preischemic values. These data confirmed thatinhibition of KATP channel activation with gliben-clamide significantly reduced the recovery of LV per-formance after normothermic ischemia in neonatalhearts. Recovery of LV performance in untreatedadult rabbit hearts was 54% of preischemic values,which was not significantly different from that seen inthe immature hearts in which the KATP channel hadbeen blocked. Therefore, increased endogenous KATPchannel activation may contribute to the greaterischemia tolerance of immature rabbit hearts. Thisfinding is consistent with recent studies reported byBaker et al. [156] using isolated neonatal rabbit heartsin which they found that the benefit of ischemicpreconditioning was prevented by KATP inhibitionwith 5-hydrodecanoate. It is important to note that

in our study the animals were pretreated with KATPinhibitor before the heart was isolated. This was doneto prevent an ischemic preconditioning stimulusduring removal of the heart. This is the most likelyreason why baseline preischemia LV performance inglibenclamide-pretreated hearts was significantly lessthan that in untreated hearts.

Pinacidil pretreatment improvesischemia tolerance of the neonatalheartOur next series of studies tested the role of KATPchannel openers either as cardioplegic agents alone oras additives to cardioplegia solutions used to protectimmature rabbit hearts. We first tested the hypothesisthat pinacidil, a potassium channel opener, is amore effective cardioplegic agent than St Thomas'cardioplegia solution during global ischemia in theimmature myocardium. Neonatal rabbit hearts wereretrogradely perfused at 45 mmHg KHB for 20 minand were then divided into three groups according tothe pretreatment they received (Figure 27.39). Sixcontrol hearts received standard KHB during theentire pretreatment period. Six pinacidil-pretreated

Figure 27.39 Experimental protocol. Control hearts received no pretreatment prior to 90 min of ischemic arrest. Pinacidil-treated hearts were pretreated with pinacidil, a KATP channel opener, as the only pretreatment prior to 90 min ofischemia. St Thomas' cardioplegia (StTCP) treated hearts received a 3-min infusion of StTCP before 90 min of ischemia.Reprinted from Journal of Surgical Research, Vol. 109, Feng J, Li H, Rosenkranz E. K(ATP) channel opener protects neonatalrabbit heart better than St Thomas' solution, pp. 69-73. © 2003, with permission from Elsevier.

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Figure 27.40 Recovery of left ventricular developedpressure (LVDP) after reperfusion. Neonatal heartspretreated with pinacidil had significantly better recoveryof LVDP than hearts treated with StTCP. Reprinted fromJournal of Surgical Research, Vol. 109, Feng J, Li H,Rosenkranz E. K(ATP) channel opener protects neonatalrabbit heart better than St Thomas' solution, pp. 69-73. ©2003, with permission from Elsevier.

Figure 27.41 Recovery of left ventricular end-diastolicpressure (LVEDP) after reperfusion. Neonatal heartspretreated with pinacidil or StTCP had significantly betterrecovery of left ventricular diastolic function (LVEDP) afterreperfusion, compared to untreated control hearts.Reprinted from Journal of Surgical Research, Vol. 109, FengJ, Li H, Rosenkranz E. K(ATP) channel opener protectsneonatal rabbit heart better than St Thomas' solution,pp. 69-73. © 2003, with permission from Elsevier.

hearts received 50 ^imol pinacidil-enriched KHBduring the 3-min pretreatment interval without StThomas' cardioplegia solution at the onset of ischemia.Five others received a 3-min infusion of St Thomas'cardioplegia solution at the onset of ischemia. Allhearts were then subjected to a simulated 90-minoperation during which no further cardioplegia solu-tion was administrated. Postreperfusion LV perform-

ance and coronary flow were recorded at the end of60 min of reperfusion and were compared to baselinevalues.

The 3-min infusion of pinacidil significantlyincreased baseline coronary flow prior to ischemia,compared to untreated control hearts. Pinacidil treat-ment significantly improved the recovery of systolicperformance compared to untreated control heartsthroughout the period of reperfusion (Figure 27.40).At the end of 60 min of reperfusion, the recovery of

LVDP (47 + 3.8 mmHg vs. 32 ± 2.5 mmHg, P < 0.05)and +dP/dtmax (885.4 ± 74 mmHg/s vs. 643.7 ± 65mmHg/s, P < 0.05), were significantly greater inpinacidil-treated hearts compared to untreated con-trol hearts (Figure 27.41). By contrast, St Thomas' car-dioplegia did not significantly improve the recoveryof systolic function compared to untreated controlhearts (LVDP: 39 ± 4.1 vs. 32 ± 2.5 mmHg; + dP/dfmax:716.2 + 81 mmHg/s vs. 643.7 ± 65 mmHg/s) or hearts

treated with pinacidil. By contrast, both pinacidil and

St Thomas' cardioplegia significantly enhanced therecovery of diastolic function compared to untreatedcontrol hearts (Figure 27.41). At 60 min of reperfu-sion, -dP/dtmax was significantly higher in pinacidil-treated hearts (994.2 + 86 mmHg/s) and St Thomas'cardioplegia-treated hearts (877.4 + 73 mmHg/s)compared to untreated control hearts (673.6 ± 69mmHg/s, P < 0.05). Similarly, postreperfusion LVEDPin pinacidil-treated (10.5 ± 0.9 mmHg, P < 0.05) andSt Thomas' cardioplegia-treated hearts (11.8 ± 0.6mmHg, P < 0.05) were significantly lower thanuntreated control hearts (17.4+1.2 mmHg). Finally,the recovery of coronary flow was significantly greaterin both the pinacidil (5.9 + 0.4 ml/min, P < 0.05) andSt Thomas' cardioplegia-treated (5.7 ± 0.3 ml/min,P < 0.05) hearts, compared to the untreated controlhearts (4.2 ± 0.2 ml/min).

The results of this study confirmed that St Thomas'

cardioplegia solution does not protect the neonatalheart as effectively as it protects the mature, adultheart. Secondly, pretreatment of the heart with theKATP channel opener pinacidil provided superiorprotection from global ischemia than St Thomas'solution, in that it preserved both systolic and diastolic

function after reperfusion.Pinacidil is both a sarc-KATP and mito-KATP

channel opener. As discussed earlier, opening of the

mito-KATP channel plays a more important role

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258 CHAPTER 27

in conferring protection from myocardial ischemia[10,56,60,133] by reducing mitochondria! calciumoverload and causing matrix swelling, which enhancesATP synthesis and stimulates mitochondrial respira-tion [52,55]. Opening of mito-KATP channels mayalso reduce the deleterious effects of ischemia bycausing a degree of mitochondrial uncoupling whichreduces the production of cytotoxic reactive oxygenspecies (ROS) during reperfusion [69]. Uncouplingalso decreases mitochondrial ATP production, whichmay in turn stimulate glycolytic ATP production andenhance glucose uptake. We concluded from thesedata that KATP channel opening agents used as a pre-treatment, or as an additive to cardioplegia solution,may be an important new approach to intraoperativeprotection of the immature heart during open heartsurgery.

Conclusions

This series of studies in the immature heart sug-gest that mechanisms that have been associated withthe ischemic preconditioning phenomenon may beendogenously activated in the immature animal andmay explain why the immature heart is more tolerantto ischemic stress than the adult heart. Why shouldthis phenotype exist in the immature heart? The fetalheart functions normally in an environment of lowoxygen tension and it would make ideologic sensethat the metabolic defense mechanisms that protectthe heart from low oxygen supply would be mostactive in the fetus by activation of genes that code forthe needed enzymes. When the fetus emerges as anewborn into an oxygenated environment, some ofthese genes may be downregulated since an environ-ment rich in oxygen allows aerobic metabolism toprovide the energy needed for normal cardiac func-tion. Downregulation of these genes may occur overtime, and thus may still be active in the neonate butbecome less active as the neonate matures. Similarly,neonates with cyanotic heart defects may maintaintheir "fetal phenotype" and not mature in terms oftheir loss of ischemia tolerance, since recent data sug-gest that hearts from cyanotic animals possess thegreatest ischemia tolerance compared to acyanoticor adult hearts [159]. Finally, the ischemic precondi-tioning phenomenon may represent reactivation ofthese "fetal genes" that transiently reproduce the fetalheart's tolerance to periods of low oxygen tension

during periods of ischemia. If future research provesthese speculations to be true, then new pharmacologicapproaches aimed at specifically activating these genesand their products may revolutionize our currentthinking and approaches towards protecting the heartduring open heart surgery.

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102 Kim H, Kim J, Zilberstien A et al. PDGF stimulation ofinositol phospholipid hydrolysis requires PLC-gammalphosphorylation on tyrosine residues 783 and 1254.Cell 1991; 65:435-41.

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109 Isami S, Kishikawa H, Araki Eetal Bradykinin enhancesGLUT4 translocation through the increase of insulinreceptor tyrosine kinase in primary adipocytes: evidencethat bradykinin stimulates the insulin signaling path-way. Diabetologia 1996; 39:412-20.

110 Miyata T, Taguchi T, Uehara M et al. Bradykinin poten-tiates insulin-stimulated glucose uptake and enhancesinsulin signal through the bradykinin B2 receptor in dog

262 CHAPTER 27

skeletal muscle and rat L6 myoblasts. Eur J Endocrinol1998; 138:344-52.

111 Dietze G, Wicklmayr M, Rett K et al. Potential role ofbradykinin in forearm muscle metabolism in humans.Diabetes 1996; 45 (Suppl 1): SI 10-14.

112 Rosen P, Ecke J, Reinauer H. Influence of bradykinin onglucose uptake and metabolism studied in isolated car-diac myocytes and isolated perfused rat hearts. Hoppe-SeylersZFurPhysiolChem 1983; 364:1431-8.

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114 Zhao L, Weber P, Comerfield M, Elliott G. Potentialrole of tyrosine kinase phosphorylation of myocardialinducible nitric oxide synthase in delayed precondition-ing by monophosphoryl lipid A (MLA). Circulation1997; 98 (Suppl I): 256.

115 Imagawa J, Baxter G, Yellon D. Genistein, a tyrosinekinase inhibitor, blocks the "second window of protec-tion" 48 hours after ischemic preconditioning. / MolCell Cardiol 1997; 29:1885-93.

116 Feng J, Li H, Rosenkranz E. Bradykinin protects the rab-bit heart after cardioplegic ischemia via NO-dependentpathways. Ann Thorac Surg 2000; 70:2119-24.

117 Gould G, Holman G. The glucose transporter family:structure, function, and tissue-specific expression.Biochemjl993; 295: 329-41.

118 Holman G, Kasuga M. From receptor to transporter:insulin signaling to glucose transport. Diabetologia1997; 40:991-1003.

119 Shepherd P, Kahn B. Glucose transporters and insulinaction—implications for insulin resistance and diabetesmellitus. NEnglJMed 1999; 341:248-57.

120 Shepherd P, Withers D, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signaling.Biochemfl998; 333:471-90.

121 Braiman L, Sheffi-Friedman L, Bak A et al. Tyrosinephosphorylation of specific protein kinase C isoenzymesparticipates in insulin stimulation of glucose transportin primary cultures of rat skeletal muscle. Diabetes 1999;48:1922-9.

122 Haring H, Tippmer S, Kellerer M et al. Modulation ofinsulin receptor signaling. Potential mechanisms of across talk between bradykinin and the insulin receptor.Diabetes 1996; 45 (Suppl 1): SI 15-19.

123 Roy D, Perreault M, Marette A. Insulin stimulation ofglucose uptake in skeletal muscles and adipose tissues invivo is NO dependent. AmJPhysiol 1998; 274: E692-9.

124 Rett K, Wicklmayr M, Dietze G, Haring H. Insulin-induced glucose transporter (GLUT1 and GLUT4)translocation in cardiac muscle tissue is mimicked bybradykinin. Diabetes 1996; 45 (Suppl 1): S66-9.

125 Baxter G, Yellon D. ATP-sensitive K channels mediatethe delayed cardioprotective effect of adenosine Alreceptor activation. JMol Cell Cardiol 1999; 31:981-9.

126 Gross G, Fryer R, Mitochondrial KATP channels: trig-gers or distal effectors of ischemic or pharmacologicpreconditioning? CircRes 2000; 87:431-3.

127 Gross G, Auchampach J. Blockade of ATP-sensitivepotassium channels prevents myocardial precondition-ing in dogs. Circ Res 1992; 70:223-33.

128 Auchampach J, Grover G, Gross G. Blockade ofischemic preconditioning in dogs by the novel ATPdependent potassium channel antagonist, sodium 5-hydroxydecanoate. CardiovascRes 1992; 26:1054-66.

129 Auchampach J, Grover G, Gross G. Blockade ofischemic preconditioning in dogs by the novel ATPdependent potassium channel antagonist 5-hydroxyde-canoate. Cardiovasc Res 1992; 26:1054-62.

130 Yao Z, Gross G. A comparison of adenosine-inducedcardioprotection and ischemic preconditioning in dogs.Efficacy, time course, and role of KATP channels.Circulation 1994; 89:1229-305.

131 Yao Z, Gross G. Acetylcholine mimics ischemic pre-conditioning via a glibenclamide-sensitive mechanismin dogs. AmJPhysiol 1993; 264: H2221-5.

132 Grover G, D'Alonzo A, Parham C, Darbenzio R.Cardioprotection with the KATP opener cromakalim isnot correlated with ischemic myocardial action poten-tial duration. / Cardiovasc Pharmacol 1995; 26:145-52.

133 Garlid K, Paucek P, Yarov-Yarovoy V et al. Cardio-protective effect of diazoxide and its interactionwith mitochondrial ATP-sensitive K channels: possiblemechanism of cardioprotection. Circ Res 1997; 81:1072-82.

134 Szewczyk A, Mikolajek B, Pikula S, Nalecz M. Potassiumchannel openers induce mitochondrial matrix volumechanges via activation of ATP-sensitive channel. Pol JPharmacol 1993; 45:437-43.

135 Galinanes M, Shattock M, Hearse D. Effects ofpotassium channel modulation during global ischaemiain isolated rat heart with and without cardioplegia.CardiovascRes 1992; 26:1063-8.

136 Cohen N, Wise R, Wechsler A, Damiano R. Electivecardiac arrest with a hyperpolarizing adenosine triphos-phate-sensitive potassium channel opener. A novelform of myocardial protection? / Thorac Cardiovas Surg1993; 106:317-28.

137 Menasche P, Kevelaitis E, Mouas C et al. Precondition-ing with potassium channel openers. A new concept forenhancing cardioplegic protection? / Thorac CardiovascSurg 1995; 110:1606-13.

138 Feng J, Li H, Rosenkranz E. Pinacidil pretreatmentextends ischemia tolerance to neonatal rabbit hearts.J Surg Res 2000; 90:131-7.

139 Pignac J, Bourgouin J, Dumont L. Cold cardioplegiaand the K+ channel modulator aprikalim (RP 52891):improved cardioprotection in isolated ischemic rabbithearts. Can JPhysiol Pharmacol 1994; 72:126-32.

140 Dorman B, Hebbar L, Clair M et al. Potassium channelopener-augmented cardioplegia: protection of myocytecontractility with chronic left ventricular function.Circulation 1997; 96 (Suppl II): II253-9.

141 Wang Y, Hirai K, Ashraf M. Activation of mitochondrialATP-sensitive K channel for cardiac protection againstischemic injury is dependent on protein kinase C activ-ity. CircRes 1999; 85: 731-41.


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144 Avkiran M, Hearse D. Protection of the myocardiumduring global ischemia: is crystalloid cardioplegia effec-tive in the immature myocardium? / Thorac CardiovascSurg 1989; 97:220-8.

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146 Baker J, Boerboom LGO. Cardioplegia-induced damageto ischemic immature myocardium is independentof oxygen availability. Ann Thorac Surg 1990; 50: 934-9.

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153 Wittnich C, Maitland A, Vincente W, Salerno T. Not allneonatal hearts are equally protected from ischemiaduring hypothermia. Ann Thorac Surg 1991; 52:1000-4.

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155 Grosso M, Banerjee A, St Cyr J et al. Cardiac 5'-nucleoti-dase activity increases with age and inversely relates torecovery from ischemia. / Thorac Cardiovasc Surg 1992;103:206-9.

156 Baker J, Curry B, Olinger G, Gross G. Increasedtolerance of the chronically hypoxic immature heart toischemia: contribution of the KATP channel. Circula-tion 1997; 95:1278-85.

157 Pridjian A, Bove E, Boiling S et al. Developmentalchanges in myocardial protection in response to 5'-nucleotidase inhibition. / Thorac Cardiovas Surg 1994;107:520-6.

158 Liu H, Gala P, Anderson S. Ischemic preconditioning,effects of pH, Na and Ca in newborn rabbit hearts dur-ing ischemia and reperfusion. / Mol Cell Cardiol 1998;30:685-97.

159 Rafiee P, Shi Y, Kong X et al. Activation of proteinkinases in chronically hypoxic infant human and rabbithearts. Role in cardioprotection. Circulation 2002; 106:239-45.

160 Awad W, Shattock M, Chambers D. Ischemic precondi-tioning in immature myocardium. Circulation 1998; 98(Suppl II:): 11206-13.

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162 Burns P, Krukenkamp I, Caldarone C et al. Isthe preconditioning response conserved in senescentmyocardium? Ann Thorac Surg 1996; 61:925—9.

CHAPTER 28

New concepts in myocardialprotection in pediatriccardiac surgery

Bindu Bittira, MD, MSC, DominiqueShum-Tim, MD, MSc,Christo I. Tchervenkov, MD

Introduction

The practice of safe and effective cardiac surgery isnot possible without adequate myocardial protection.Over the years, many studies have been carried out toexamine previous techniques for myocardial protec-tion and to refine novel ones such that complex andlong procedures may be performed with decreasingmorbidity and mortality. This chapter will attempt tohighlight the most recent advances in the protectionof the pediatric myocardium during and followingcardiac surgery. The scientific and clinical evolutionof cardioplegia (techniques and composition) will becovered, focusing on the most recently published liter-ature. Finally, the revolutionary concept of primarycorrective surgery versus palliative surgery will alsobe reinterpreted in light of these recent methods ofmyocardial protection.

The immature versus the adultmyocardium

There are numerous structural features and signi-ficant metabolic differences between the immatureand adult myocardium, which greatly influence andaffect their responses to ischemia and various pro-tective methods. There are a great number of papersdescribing the differences between mature and imma-ture myocytes in terms of anatomy, physiology, andpharmacology. However, since many of these are fromanimal experiments, the relevance of these experi-mental data to clinical application is not clear [ 1,2].

Immature hearts have greater surface area to wallthickness ratios and smaller myocardial cells. Imma-ture myocardial cells are composed of noncontractileelements including nuclei, mitochondria, and mem-branes [3,4]. Metabolically, immature hearts consistof fewer mitochondria than those of adults but havehigher aerobic activities with increased cytochrome coxidase activity. During development, the myocytesbecome more complex in their external shape with themyofibrils becoming larger and reorienting along thelongitudinal direction of the cell [5]. Immature heartsalso have more glycogen content, and depend lesson fatty acids as a fuel source with a greater anerobicglycolytic capacity than in adults [6].

With the differences in the content of these calcium-dependent organelles, such as the sarcoplasmic reti-culum and the transverse tubular system, functionaldifferences are noted in the immature myocardialresponse to calcium channel blockers, as well as toinotropic agents [7]. Since the immature myocardiumdiffers in its sensitivity to extracellular calcium duringnormal contraction and during ischemia, the responseof the immature myocardium to many pharmacologicagents differs from that of adult hearts. This makesintraoperative and postoperative regulation of bloodpressure and cardiac output more challenging [8,9].

Biochemical changes also occur during myocar-dial maturation. The immature heart has a greaterglycolytic capacity than the adult, due to its abilityto use various substrates for oxidation, includingcarbohydrates, medium- and short-chain fatty acids,ketones, and amino acids [ 10]. The relative protection

264

Pediatric myocardial protection: new concepts 265

afforded by the immature myocardium to anoxicischemia has been associated with its increased abilityto use anerobic glycolysis to produce energy. How-ever, the principal substrates used in the matureheart are long-chain fatty acids. Additionally, maturemyocardium has a more complex mitochondrialcrystal pattern with several more complex enzymesinvolved in fatty acid metabolism [ 10].

Responses to global myocardialischemia

Despite numerous investigations [4,6,11], whetherthe immature heart is less sensitive or not to the effectsof hypoxia and ischemia than the adult heart remainsunsettled. However there are, as discussed earlier,distinguishing characteristics between the two, whichmay have an important effect on the immature myo-cardial response to ischemia. In the ischemic myo-cardium, all oxygen-dependent processes cease almostimmediately. While anerobic glycolysis initially gen-erates some ATP, this process is inadequate for theenergy required for normal physiologic events. Whileimmature hearts are capable of greater glycolyticactivity than adult hearts, there is greater lactate pro-duction, which leads to a fall in tissue pH [12]. Thisprevents the production of ATP via the glycolyticpathway, and as ionic intracellular gradients are dis-rupted, intracellular edema and cell lysis occur. Therole of myocardial protection is to prevent irreversiblecell death and to promote a physiologic transition tonormal contractile function following reperfusion.

The differences in myocardial calcium metabolismallow younger myocardium to work more efficientlythan adult myocardium for the volume of oxygenconsumed. This is in part due to the differences insarcoplasmic reticulum content and T-tubules betweenthe adult and pediatric hearts [13]. In mature myocar-dium, the sarcoplasmic reticulum is the predomin-ant source of calcium ions for excitation-contractioncoupling, while the sarcoplasmic reticulum of theimmature heart is more poorly developed. The imma-ture myocardial cell is deficient in T-tubules and isincapable of internal release and reuptake of calciumfor contraction and is instead dependent on trans-membrane calcium transport for the developmentof tension. This greater dependence on the trans-sarcolemmal movement of calcium as a source ofcalcium available for contraction translates to more

intracellular calcium concentrations through theNa+-Ca2+exchange mechanism which further enhancesNa+-K+ ATPase activity [13]. These developmentaldifferences in the methods of calcium handling haveimportant implications in the response to ischemiadue to the role of calcium in irreversible cardiac injuryafter ischemia and reperfusion.

In addition to the structural differences betweenadult and pediatric hearts, many biochemical mechan-isms account for infant hearts having an improvedtolerance of global ischemia when compared to adulthearts. In comparison to adult myocardium, youngermyocardium exhibits less ATP breakdown afterglobal ischemia and reperfusion [14]. There is alsoless 5'-nucleotidase activity in pediatric than adulthearts, correlating with a better functional recoveryafter global ischemia. Newborn hearts exhibit greaterquantities of conjugated dienes after normothermicischemia and reperfusion than adult hearts do, sug-gesting that younger hearts generate more free radicalsthan their adult counterparts. The importance ofthis free radical injury before and after cardiopul-monary bypass has been challenged by investigators[13-15,16], but nonetheless has important implica-tions in the administration of cardioplegia solutions.

Important work has shown the differences in pro-tection offered to older and younger hearts with theuse of particular cardioplegia solutions. Immaturemyocardium was not as well protected by both Roeand Bretschneider solutions [17], while superior pro-tection was seen with St Thomas' and Tyers solutions.The absence of calcium in Bretschneider and Roesolutions, which are used in adult myocardial protec-tion, may explain this discrepancy. Other studies,however, negate these findings, showing that calciumand sodium contents of cardioplegia solutions offerlittle benefit in functional preservation [ 18].

Recent work suggests that prearrest cold perfusionadversely affects postischemic myocardial recovery[19]. The exact mechanism by which this contrac-ture occurs after prolonged cold perfusion remainsunknown, although the loss of intracellular calciumhomeostasis has been implicated [20]. Another con-trast between pediatric and adult myocardium is intheir response to multidose cardioplegia. While adulthearts subjected to longer periods of global ischemiabenefit from periodic readministration of cardio-plegia, immature hearts may be subjected to moreischemic damage [21-23] with multiple doses.

266 CHAPTER 28

Cardioplegia

The concept of myocardial protection has been evolv-ing since its introduction in the 1950s. Since crystal-loid cardioplegia was first introduced into the clinicalsetting, results of open-heart surgery for adult patientshave improved significantly. However, pediatric car-diac surgeons are still in conflict over the optimaltechniques of myocardial protection, since most arebased on experimental and clinical work carried outon adult hearts.

A host of new adjuncts to cardioplegia solutionsand new modes of delivery, as well as controversialissues regarding temperature and sites of adminis-tration, have been debated over the past few years.Experimental and clinical investigations have increasedour understanding of cold blood cardioplegia, warmblood cardioplegic reperfusion with warm induction,antegrade and retrograde delivery, and continuous,cold, noncardioplegic blood perfusion in the adultpopulation. Although these techniques were origin-ally designed to protect the adult heart, some of themhave been adapted for pediatric cardiac surgery [24].While these current methods of myocardial pro-tection during adult open-heart surgery have showngood myocardial preservation [25,26], myocardialprotection in pediatric cardiac surgery may be sub-optimal, resulting in greater morbidity and mortality[27]. Despite the anatomic, architectural and phy-siologic differences between the two age groups, veryfew comprehensive studies have been performed toassess the effects of cardioplegia on the immatureheart.

Crystalloid cardioplegiaOne experimental study [19] which reflected thedifferences in cardiopulmonary bypass and surgicalmanagement in the pediatric population, suggestedthat prolonged cold perfusion of the nonarrested new-born heart in preparation to reach deep hypothermiaprior to aortic cross-clamping, impaired functionalrecovery and was therefore detrimental. This studywas designed to identify the consequences of perfus-ing a nonarrested newborn heart under hypothermicconditions for a prolonged period of time. In eachcase, newborn piglets were randomly assigned to fourgroups and subjected to varying periods of cold perfu-sion with or without ischemic insult. The hearts werestudied in a crystalloid perfused Langendorff heart

model and examined histologically for ultrastructuraldamage to the myocardial cells. The results showedthat in the groups subjected to prolonged cooling, thefunctional recovery was significantly impaired. Whenfurther followed by a period of ischemic arrest, themyocardial injury was potentiated, and severe con-tracture resulted. The effects of prolonged myocardialcold perfusion before cardiac arrest was offered as oneexplanation for the suboptimal myocardial protectionseen in neonates.

In addition, Imura et al. [28] showed that high-potassium, cold-cardioplegia solution commonlyused to protect adult hearts, had variable degreesof myocardial protection, depending on the age andlevel of cyanosis of the child. The authors monitoredmyocardial metabolic changes following ischemiain acyanotic children undergoing open-heart surgeryusing St Thomas' cardioplegia solution. They usedpostoperative troponin I as a measure of reperfusioninjury as well as other intraoperative and post-operative clinical parameters to determine the sub-sequent clinical outcome. These parameters included:an intraoperative requirement for inotropes to weanpatients from cardiopulmonary bypass; postoperativeinotropic support; length of inotropic and ventil-atory support; as well as intensive care and hospitalstay. Myocardial biopsies were also collected from theright ventricular free wall and adenine nucleotides,purines, lactate, and free amino acids were measuredin all biopsies collected. For the first time, they wereable to show that the outcome after pediatric open-heart surgery is age dependent. Children showedmore resistance to reperfusion injury than neonates.However, cyanotic children had a significantly worseoutcome and more reperfusion injury compared toacyanotic children.

The most recent studies all suggest that a singledose, rather than multiple doses of cardioplegia solu-tion result in improved recovery of function afterischemia. No additional protection was offered whenmultiple doses of St Thomas' cardioplegia solutionwere compared with a single dose in the neonatalrabbit [29], while other investigators found worserecovery of function with multiple, rather than singledoses of St Thomas' cardioplegia solution [30]. Cur-rent cardioplegic techniques have improved based onthis experimental data, showing that cold-crystalloidcardioplegia in pediatric cardiac surgery is associ-ated with significant ischemic stress and subsequent


myocardial injury [27], depending also on the age andpathophysiology of the child's condition.

The introduction of warm myocardial protectionhad a striking impact on modern cardiac surgery, rep-resenting a radical change from a conventional idea.The benefits of combined antegrade-retrograde infu-sion of blood cardioplegia solution are well knownin adult coronary and valvular heart operations, andmany of these advantages are applicable to pediatricpatients. Myocardial perfusion with warm blood wasapplied successfully in a clinical setting by Lichtenstein,Salerno and associates in Toronto, Canada [31,32].They used continuous, antegrade or retrograde per-fusion of the heart with warm (37°C) hyperkalemicblood to arrest the heart's electromechanical activity,with results comparable to those achieved with coldischemic arrest.

Cardioplegia administrationOne of the first studies to show the safety of combinedantegrade-retrograde infusion of blood cardioplegiasolution in pediatric patients was conducted byDrinkwater et al. [33] They reported the safety ofretrograde in conjunction with antegrade infusion ofblood cardioplegia solution in 123 pediatric patientswhose ages ranged from 1 week to 16 years and whoseweights, correspondingly, ranged from 3.6 to 72.7 kg.A cardioplegia cannula, modified for pediatric use,was introduced in one of two ways at the time of oper-ation. For patients with bicaval cannulation and rightatriotomy, the retrograde cannula was directly intro-duced into the coronary sinus without the malleablestylet. For larger patients (> 15-20 kg) with a singlevenous cannula, it was introduced over the styletthrough a pursestring suture in the atrial wall. Thisinitial positive experience showed that this combinedtechnique could provide adequate myocardial protec-tion with excellent surgical outcome in the repair ofcomplex, congenital heart malformations.

Since retrograde cardioplegia delivery was firstreported clinically by Lillehei et al. [34] and repro-posed by Menasche [35], the essential problem as towhether retrograde perfusion of the coronary sinusprovides adequate nutrient flow to the heart, espe-cially the right coronary artery, remains unsolved.Despite the multitude of studies, the use of retrogradecardioplegia in adults did not gain popularity untilthe late 1970s, when various authors documentedinadequate myocardial protection during antegrade

cardioplegic infusion in the presence of coronaryartery stenosis [34]. Yet its application in the pediatricpopulation remains limited, because coronary arterystenosis is rarely encountered in this age group.

Blood cardioplegiaBlood cardioplegia, since its introduction in 1977,has played a dominant role in adult cardiac surgery.However, the role and advantages of blood cardio-plegia in pediatric cardiac surgery have been less welldefined, leaving pediatric cardiac surgeons dividedin their use of blood versus crystalloid cardioplegiasolutions [36]. Corno and coworkers found that inthe neonatal piglet model, cardioplegia solutions con-taining blood improved functional recovery whencompared with crystalloid cardioplegia solutions orhypothermia alone [37]. This addition of blood to car-dioplegia solutions may be beneficial as a result of theprovision of free radical scavenging capacity throughthe catalase in red blood cells and the buffering cap-acity of blood proteins. However, the superiority ofblood cardioplegia in pediatric cardiac surgery has notpreviously been challenged in a controlled clinical trialuntil recently. Young et al. [38] administered multipledoses of cold (4°C) blood cardioplegia solution ante-gradely in addition to topical cooling during ischemicarrest in 138 pediatric patients (ages ranging from1 day to 15 years). The technical disadvantage ofusing retrograde and warm blood cardioplegia forsome pediatric patients, especially newborn infants,prompted the use of blood as an additive to thecurrent cardioplegic strategy. Systemic hypothermicperfusion of 30°C was achieved in all patients; theaorta was cross-clamped and antegrade cardioplegiaadministered. Although the optimum systemic per-fusate temperature at which aortic cross-clampingshould occur has been raised by some investigators[36,38^0], the authors chose a moderately hypother-mic temperature for aortic cross-clamping. Despitethe significant limitations of this study, it suggestedthat the use of a blood cardioplegic strategy for con-genital heart disease offered no obvious benefitswhen only antegrade hypothermic dosing was used[41]. The study also failed to show any benefit ofblood cardioplegia in cyanotic patients. The use ofblood cardioplegia failed to show any significantadvantages using the clinical criteria in this particularstudy. Crystalloid cardioplegia was associated withless inotropic support although no better ventricular

268 CHAPTER 28

function was found when compared with bloodcardioplegia.

Substrate enhancementSince ischemia has been known to reduce the level ofhigh-energy phosphates in the myocardial cell and thelevel of ATP has been correlated to the recovery duringthe reperfusion period, investigators have attemptedto enhance the levels of phosphate precursors so thatATP levels may be readily restored [42]. There is someevidence that the addition of adenosine to cardio-plegia solutions [43,44] or its administration duringreperfusion [45] may result in better recovery of ATPlevels and contribute to overall improved functionduring the postischemic recovery period. Similarly,the rationale for the addition of glucose in cardio-plegia solutions was to provide substrate to be used bythe ischemic cell. However, as noted earlier, multiplecardioplegia doses may provide more substrate formetabolism, but have been associated with either noimprovement or a worse outcome in the pediatricmyocardium.

The integrated approach to cardioplegiaWhile the integrated cardioplegic approach usingwarm, cold, antegrade and retrograde techniques inaddition to substrate enhancement may be beneficialfor the pediatric population, the efficacy of these inte-grated cardioplegic techniques has not been assessedin clinical trials in neonates or young infants. Never-theless, there are compelling reasons for adapting ablood cardioplegic strategy, as experimental evidencehas suggested the superiority of blood cardioplegia forcyanotic patients [38,46]. Since the duration of aorticcross-clamping time is a major determining factor inthe outcome of various cardioplegic strategies in theclinical setting, considering these variations, furtherstudies need to be done to elucidate the potentialbenefits of various substrate enhancements, precondi-tioning agents, or hyperpolarizing substances.

One such study by Borowski et al. [47] assessed thetechnical applicability and clinical value of continu-ous coronary perfusion with oxygenated blood as amethod for myocardial protection. Thirty pediatricpatients underwent open-heart procedures on thebeating heart for the repair of simple and complexcardiac malformations using a self-designed perfusionsystem. It uses a pressure- and volume-controlledcontinuous hypothermic coronary perfusion in com-

bination with ultra short betaj-receptor blockade(esmolol) and nitroglycerin for myocardial protec-tion. They found that this technique was feasible forthe repair of simple and complex malformations.However, in small children under 3 years of age, therepair of interventricular defects is technically morechallenging with the use of this technique than withconventional cardioplegic arrest.

While no recent consensus exists about the idealcomposition of cardioplegia, a nationwide survey ofinstitutions in the United States showed that bloodcardioplegia in conjunction with hypothermia was thestrategy mostly used for pediatric myocardial protec-tion in the past decade [48,49]. The administration ofcardioplegia was guided more by formulas than clin-ical criteria, with circulatory arrest being used morefrequently in larger institutions. Still, ongoing clinicaltrials abound, attempting to clarify the effectivenessof various substrate enhancement strategies [47] inorder to provide better cardiac performance in thepostoperative period.

New advances in mechanicaldevices that improvecardioprotective strategies

Classification of the major areas of research can bemade into two distinct areas of myocardial protection:(i) pharmacologic support, as in the form of substrateenhancement, which has been outlined previously, aswell as infusion of platelet activating factor antagonists(PAFA); and (ii) mechanical delivery systems and theaddition of filters incorporated in the delivery pump.

The earliest methods of cardioplegic deliveryincluded infusions of concentrated solutions directlyinto the aortic root via hand-held syringes. Unfortun-ately, such methods caused a heterogeneous distri-bution of solutions and the need for more preciseand controlled delivery techniques to ensure uniformdistributions and cardiac standstill. Since then, thepressurized bag technique and roller pump deliveryhave been used for the delivery of both blood andcrystalloid cardioplegia. There has also been tre-mendous variation in the type of delivery cannulasthat have been used over the past four decades. In1956, Lillehei et al. [34] described the administrationof hypothermic crystalloid cardioplegia via direct can-nulation into the coronary sinus, achieving retrogradeflow in those with aortic regurgitation. However,


the aortic root administration techniques providedsimple methods of cardioplegic delivery for eithercongenital heart disease or acquired valvular dysfunc-tion. This format is most often accomplished by plac-ing a large bore (12-18 gauge) needle directly in theaortic root several centimeters above the aortic valve.A variation of this involves direct cannulation of thecoronary ostia. However, the several devices availableto cannulate the coronary ostium for cardioplegicdelivery in adults are not useful in pediatric patients. Ifthe catheter tip is the same as or slightly larger than thecoronary ostium, then ostial damage is prone to occur[50]. Chiu et al. [51] have successfully used the DLP4Fr pediatric cardioplegic cannula during the arterialswitch operation. Although retrograde cardioplegiahas been advocated in this setting, the authors showedthe versatility of their cannula, which was used beforeand after their aortotomy. In view of the difficulties inneonatal myocardial protection and easy catheter dis-location and the hazard of coronary sinus injury usingretrograde infusion, the authors utilized a pediatriccannula for antegrade aortic infusion of cardioplegia,and inserted the same cannula into the coronaryostium for direct injection after the aortotomy.

FiltersThe need to assure the purity and safety of bloodcardioplegia solutions, as well as recent work thathas shown injury from both reperfusion and theinflammatory reaction, has prompted the use of filtersdirectly in the cardioplegic heat exchanger devices[52]. The use of leukocyte-depleting filters added intothe cardioplegic circuit for reducing neutrophil-mediated reperfusion injury seems promising [16].The most recent clinical interest has focused on theevaluation of the use of leukocyte-depleted blood car-dioplegia and mechanical neutrophil depletion forpediatric heart surgery. However, the concern remainsof inducing neutrophil-mediated reperfusion injuryfor every administration of blood cardioplegia duringfurther reoperation. While the possible cytotoxicity ofblood cardioplegia as a risk for myocardial reperfu-sion injury has not been quantified, the risk remainseven under conditions of cold blood cardioplegiaadministered to hypothermic myocardium duringcardioplegic arrest.

Hayashi et al. [53] studied the effect of leukocytedepletion in a clinical setting, and have shown thatit reduced the extent of myocardial damage after

reperfusion. While blood cardioplegia is consideredsuperior to crystalloid cardioplegia in certain aspects,it contains leukocytes and platelets, potentially caus-ing capillary plugging after myocardial ischemia andreperfusion during cardioplegia administration. Theauthors were able to show the clinical myocardial pro-tective effect of leukocyte-depleted blood cardioplegiaby evaluating plasma concentrations of malondialde-hyde, human heart fatty acid-binding protein, andmaximum creatine kinase-MB (CK-MB) levels [53].Although leukocyte-depleted blood cardioplegia mayprovide better cardioprotection, the mechanism ofcytotoxicity to blood cardioplegia remains unclearand more work needs to be done before frequent useof leukocyte depletion is recommended.

The use of leukocyte-depleting filters in thecardiopulmonary bypass line as well as infusion ofthe platelet-activating factor antagonist (PAPA) CV-6209 to prevent activation of polymorphonuclearleukocytes has been studied in the chronic cyanoticanimal model for congenital heart disease. Leukocyte-depleted perfusion was shown to decrease operat-ive morbidity and mortality, reduce inotropic drugrequirements, and increase left ventricular contract-ility [54]. The role of platelet activating factor antag-onism in protecting against reperfusion injury to themyocardium has also been favorable [55,56]. Sawaand associates [56] showed that with controlled reper-fusion, CV-3988 was more effective than terminalleukocyte depletion, suggesting that neutrophils mayplay a more minor role in myocardial reperfusioninjury than platelet activating factor.

The compensatory changes to the myocardiumoffered by chronic hypoxia and the myocardialresponse to oxygen free radical injury was studiedby Allen et al. [57] in the context of leukocyte deple-tion as well. The reoxygenation injury, characterizedby a decrease in systolic contractility, a decrease indiastolic compliance, and increased pulmonary vascu-lar resistance, was seen with abrupt reoxygenation andreperfusion following 1-2 h of acute hypoxia. Thisreoxygenation injury has been shown to be modul-ated by oxygen free radicals and can be modified byleukocyte depletion or by reoxygenating at a loweroxygen concentration [56,57]. In this study, whiteblood cell filtration substantially reduced the numberof leukocytes before and after cardiopulmonary bypasswas initiated for 30 min. While there are limitationswithin this study, it did show evidence of decreased

270 CHAPTER 28

oxygen free radical production by decreasing theoxygen concentration in the circulation during car-diopulmonary bypass or more effectively by leukocytefiltration.

In addition to mechanical devices which may alterthe injury caused by oxygen-derived free radicals,substances such as d-alpha-tocopherol (vitamin E)have also been studied [58]. Newborn piglet heartswere pretreated with vitamin E given by oral gavagefor 4 days before perfusion studies were carried out.The postischemic functional recovery of vitaminE-pretreated groups was improved significantly in aLangendorff heart model. The study showed that oralvitamin E improved the ischemic tolerance of thenewborn myocardium and therefore might be con-sidered a valuable, effective and inexpensive methodof myocardial protection [58].

UltrafiltrationCardiopulmonary bypass in neonates and infantsusing hypothermia with hemodilution is associatedwith a host of vascular changes. There may be atremendous capillary leak syndrome with an increasein total body water, tissue edema, and organ dysfunc-tion affecting the brain, lungs, and heart. Capillaryleak, which is caused by a systemic inflammatoryresponse, is a result of the contact of blood elementsto the nonendothelialized synthetic surfaces of thecardiopulmonary bypass circuit [59]. Ultrafiltration isone of the more novel concepts in myocardial pro-tection, affecting not only intraoperative myocardialfunctioning but also postoperative hemodynamics.

A number of strategies have been employed toreduce capillary leak and the accumulation of extra-vascular water during bypass. These include highhematocrits at relatively high temperatures, postoper-ative peritoneal dialysis, postoperative continuousarteriovenous hemofiltration, infusion of the salvagedcircuit volume, and aggressive diuresis [60]. Conven-tional Ultrafiltration is carried out during the rewarm-ing phase of cardiopulmonary bypass [61]. Recently,modified Ultrafiltration (MUF) has been used to limitthe deleterious effects of cardiopulmonary bypass aswell. The recognized benefits are multiple, and includeimprovements in left ventricular function, an increasedhematocrit and subsequent decrease in transfusionrequirements, improved hemostasis, modification ofcomplement activation, improved pulmonary com-pliance, and cerebral metabolic recovery [62-64].

Modified UltrafiltrationIn MUF, the cardiopulmonary bypass circuit is alteredso that blood is pumped in a retrograde fashion fromthe aortic cannula through the hemocentrator, andreturned to the right atrium. This results in warmed,hemoconcentrated oxygenated blood returning tothe heart and pulmonary vasculature. The benefitsof MUF when compared with standard Ultrafiltrationwere first shown by Naik et al. [64,65] in 1991, asmeasured by bioelectrical impedance and later con-firmed in 1993. In their studies, fluid balance, totalbody water (TBW), and hemodynamics were evalu-ated postoperatively. There was a reduction in bloodloss, improved hemostasis, a reduction in bloodproduct transfusion, and a reduction in TBW in theMUF group. Other investigators have overwhelminglysupported these findings [66], and the benefits on thecardiovascular system have also been shown [67].Davies et al. [68] measured weight, left ventricularsystolic function, myocardial cross-sectional area,and inotropic drug support in infants undergoingcardiopulmonary bypass with and without MUF.He showed that the increase in end-diastolic lengthand fall in end-diastolic pressure seen after MUF isconsistent with an improvement in left ventricularcompliance resulting from a reduction in myocardialedema. The improvement in hemodynamics seen inall patients after MUF was correlated with a fall in totalbody water, and subsequent increase in hematocritvalues as well as improved left ventricular systolicfunction, which continued for at least 24 h postoper-atively. While this study was conducted in patientsundergoing hypothermia and hemodiluted cardio-pulmonary bypass with crystalloid cardioplegia, itprovokes the testing of MUF with either warm car-diopulmonary bypass or blood cardioplegia, to seewhether there will be a further improvement in post-cardiopulmonary bypass systolic function. The MUFtechnique therefore represents a major improvementin the management of patients who are at a high riskof fluid accumulation.

Hypothermia and circulatory arrestversus low-flow cardiopulmonarybypass

Systemic hypothermia has been regarded as an essen-tial component of cardiac surgery. Hypothermia offerstissue and organ protection by decreasing metabolic


requirements during cardiopulmonary bypass andcardiac arrest, and provides a margin of safety in theevent of technical difficulties developing with thecardiopulmonary bypass circuit. In pediatric cardiacsurgery, there is often the need for adequate intracar-diac exposure in a bloodless field, and a reductionin perfusion flow rate to counteract the high volumeof left heart return, particularly in cyanotic children.However, the optimal temperature and flow at whichbypass should be conducted is still debated. Des-pite the technical advantages offered by both deephypothermic circulatory arrest and low-flow bypass,there are reports which show their damaging effects.Flow reduction negatively affects parenchymal cells,endothelial cells, and inflammatory cells [69]. Flowreduction also impairs the organ function alreadycompromised by hypothermia. Several deleteriouseffects of cardiopulmonary bypass are also exagger-ated by reduced perfusion flow rates and hypother-mia, including metabolic acidosis, neurologic sequela,reduced platelet aggregation, and increased vascularresistance.

Based on this theory, Corno et al. [70] investigatedthe possibility of performing surgical procedures forcongenital heart defects under normothermic (37°C)high-flow (3.0 L/m2/min) leukocyte-depleted per-fusion. The inconvenience of inadequate surgicalvisualization, using the normothermic high-flow tech-nique, was overcome with proper surgical exposure,adequate cannulation, and venous drainage. Thistechnique balanced the benefits of ideal intracardiacexposure and surgical comfort with more physiologiclevels of tissue perfusion, and was a viable alternativeoption.

While a lot of interest in hypothermic arresthas concentrated on the neurologic outcome [71-74], few authors have looked at the postoperativecourse and non-neurologic hemodynamic profilesfollowing the perioperative effects of deep hypo-thermic circulatory arrest (DHCA) and low-flowcardiopulmonary bypass in neonates and infants.Wernovsky et al. [75] studied patients randomlyassigned to either low-flow (50 cm3/kg/min) bypassor circulatory arrest. Cardiac output, mean systemicarterial, pulmonary arterial, and right and left atrialpressures were recorded. Perfusion strategy did nothave an impact on the postoperative hemodynamicsin the end. However, the patient population waslimited to those undergoing the arterial switch opera-

tion and therefore either circulatory arrest or low-flow bypass strategies could be used with equalfacility. The authors cautioned the use of low-flowbypass in other types of neonatal and infant sur-geries as longer support times may have increasedthe chances of total body fluid overload. Clearlythe decision to balance the technical advantages offacilitating a complete repair under circulatory arrestversus the risks of prolonged low-flow cardiopul-monary bypass must be decided on an individualbasis.

Palliation versus early repair

Newly developed variations on previous techniquesfor cardioplegic composition and administration aswell as postoperative care have allowed for the com-plete repair of many congenital heart defects in theneonatal or early infancy period. However, theoptimal age for complete repair of most congenitalheart defects remains undefined and controversial.

Palliative procedures were first introduced whenthe condition of the child or the congenital morpho-logy of the malformations were such that completerepair of the defect was impossible or unsafe. Sincethen, palliation has been an accepted mode of therapyin the treatment of these patients with congenitalheart disease. However, with the greater number ofcorrective operations which are now available, therole of palliation versus initial corrective surgery haschanged.

The surgical literature is filled with numeroussuccessful reports of correction for a variety of com-plex congenital defects. In fact, complete repairs ofsuch defects as atrioventricular canal, tetralogy ofFallot (with or without pulmonary atresia), truncusarteriosus, and transposition of the great arteries areconsidered routine, and postoperative evaluation ofthe quality of life of these children often surpassesthose who have undergone staged procedures. Withthe advent of new options for not only myocardialprotection but also protection of the brain and otherorgans as well, more importance is being given to prim-ary repair of congenital lesions. Therefore, primaryanatomic and physiologic repair in early life, in orderto avoid the chronic volume and pressure overloadand persistent cyanosis associated with palliativeprocedures, may actually provide the best strategyof myocardial protection.

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73 Norwood W, Norwood C, Castaneda AR. Cerebralanoxia. Effect of deep hypothermia and pH. Surgery 1979;86:203-9.

74 Swain JA. Metabolism of the heart and brain duringhypothermic cardiopulmonary bypass. Ann Thome Surg1991; 51:105-9.

75 Wernovsky G, Wypij D, Jonas RA et al Postoperativecourse and hemodynamic profile after the arterial switchoperation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest.Circulation 1995; 92:2226-35.

CHAPTER 29

Extracardiac Fontan: theimportance of avoidingcardioplegic arrest

Carlo F. Marcelletti, MD & Raul F. Abella, MD

Single ventricle repair resulting in right heart bypassmay be applicable in the management of a variety ofcomplex congenital cardiac anomalies. Over the years,a number of modifications of the original Fontan pro-cedure have been proposed in an effort to improveoutcome.

During the past 10 years, we have focused our atten-tion on two main issues: the concept of staging towardthe Fontan procedure, which has proven to reduce thenumber and impact of risk factors present when sucha procedure is performed, and the development of asurgical technique that is simple and easy to teach, thetotal extracardiac Fontan repair.

The Fontan procedure by means of an extracardiacconduit was initially proposed for patients presentingwith anomalies of intra-atrial anatomy, such as pul-monary and systemic venous return, auricular juxta-position hypoplasia, or atresia of the atrioventricularleft valve or common atrioventricular valve [1]. Inaddition to this preliminary experience and becauseof the uneventful outcome of these patients, we ex-tended this technique to all patients, with a functionalanatomic single ventricle. In our early experience wewere quite concerned about this novel procedurebased on the implementation of an artificial conduitinto the systemic venous pathway because of the pos-sible risks of late stenosis and thrombus formation.The extracardiac modified Fontan has a number oftheoretical advantages. Because the conduit is con-structed outside the heart, the operation may beperformed with the patient supported on cardiopul-monary bypass (CPB) without arresting the heart. In

selected patients, the extracardiac Fontan may beaccomplished without the use of CBP.

A close and careful follow-up including exam-inations was conducted in 231 patients; the first 64patients had been operated using the initial techniqueof cardiocirculatory arrest and the remaining 167patients underwent the new approach without cardiacarrest.

Myocardial protection andmanagement in patients with afunctional single ventricle

No single method of myocardial management isunequivocally the best. Many different methods arein use by surgeons obtaining good results. We usedtwo principal approaches:1 Staging towards the Fontan procedure.2 Fontan procedure without cardioplegic arrest inmoderate hypothermic perfusion.

Ventricular hypertrophy is a widely known riskfactor of the Fontan operation for complex cardiacanomalies. Ventricular hypertrophy alters both dias-tolic function [2] and threshold sensitivity to ischemicdamage of the systemic ventricles [3], thereby affect-ing its crucial role of negative pump mechanism in theFontan circulation.

It is worth noting that this myocardial lesion hasbeen reported in patients who have complex cardiacanomalies. Even after a Fontan operation problemscan manifest as one of two acute complications. One isa relative increase in ventricular mass after sudden

275

276 CHAPTER 29

normalization of volume overload [4], and the secondis a result of inadequate myocardial protection duringthe operation.

Staging toward the Fontanprocedure

Surgical management of children with single ventric-ular physiology has continued to evolve. Many institu-tions have adopted various approaches with improvedearly clinical outcome. Staging the Fontan operationwith the bidirectional Glenn anastomosis, and thedeliberate creation of a residual right-to-left atrialshunt, have undoubtedly contributed significantlyto an improved early outcome in these patients andpermitted the extracardiac approach of the Fontanprocedure.

The ideal candidates for the Fontan procedureshould have a normal pulmonary vascular bedwith low pulmonary artery pressure, low pulmonaryvascular resistance, absence of distortions of pulmon-ary arteries, absence of anomalous pulmonary venousconnections, and normal or near-normal functionof the single ventricle (i.e. without severe ventricularhypertrophy or dilatation related to pressure orvolume overload) [2]. Many of these patients undergothe Fontan procedure after one or more surgicalpalliations.

The potential effects of previous surgery must beconsidered, such as chronic volume overload second-ary to systemic to pulmonary artery shunt and/oratrioventricular valve regurgitation, and chronic pres-sure overload secondary to pulmonary artery bandingand/or subaortic obstruction. These hemodynamicchanges may cause ventricular hypertrophy with earlycompromise of cardiac function.

It is clear that correct timing in patients with a uni-ventricular heart (UVH) is paramount in both theearly and late outcome of surgical treatment. No mat-ter which type of UVH the patient has, the goal is tokeep the patient alive until approximately 2 years ofage, at that time a total cavopulmonary connectioncan be accomplished since the systolic and diastolicfunction of the single ventricle has been preserved.

First stage and associated proceduresBidirectional cavopulmonary anastomosis (BCPA)brings the advantage of dramatically reducing thevolume load of the systemic ventricle to normal values,

and diverting desaturated blood only to the lungs,increasing the effective pulmonary blood flow. Con-sidering the persistence of systemic venous drainagefrom the inferior vena cava (IVC) directly into theatrial cavity provides an adequate filling pressure forthe single ventricle, independent from any restriction,and from the passage of blood through the pulmonaryvascular bed [5,6]. The first stage can be performedprimarily in cyanotic patients older than 3 monthswho have single ventricle physiology and are eitherextremely cyanotic or have an excessive volume load.This usually results in signs of congestive heart failure.For the child who has an ideal balance of pulmonaryand systemic blood flow, we generally wait until atleast 9 months of age. The objective of this first stageis to treat or eliminate all the possible risk factors toallow the Fontan circulation. The first stage of thebidirectional Glenn procedure increases the effectivepulmonary blood flow and eliminates ventricularvolume [5].

Patch enlargement of the pulmonary arteriesThe most frequent site of pulmonary artery stenosisis the origin of the left pulmonary artery in corres-pondence to the insertion of a formerly patent ductusarteriosus whose retraction causes a true coarctationof the pulmonary artery. Less frequently, a stenosisor distortion is found involving the right (or left)pulmonary artery due to a previous systemic topulmonary artery shunt. The anastomotic site of thesuperior vena cava (SVC) can be used for resolutionin many of the latter stenoses, but if the stenosesare peripheral and involve the branches, a patch isrequired.

Atrioseptectomy can either be performed from theopening of the cavoatrial junction after division of theSVC, or from the opening of the pursestring suture ofatrial cannulation, when circulatory arrest is used, andthe cannula is removed. The opening is pushed downtoward the atrial septum and the septum primum isgrasped, pulled up, and resected. Complete resec-tion of the septum primum is generally an adequateatrioseptectomy [7].

Main pulmonary artery (MPA) to aortaanastomosisPatients with previous pulmonary artery bandingare prone to develop subaortic obstruction; there-fore, since 1986, our policy has been to associate

Extracardiac Fontan 277

an MPA to an aorta anastomosis at the time of aBCPA[8].

Second stage Fontan extracardiac

Extracardiac Fontan with cardioplegia andcardiocirculatory arrestOur group described the technique of a total rightbypass by means of interposition of an extracardiacconduit in 1990 [1]. In the last 10 years many modi-fications have been made to the original approach.We used deep hypothermia and circulatory arrest in64 patients. After median sternotomy CPB was insti-tuted by means of aortic cannulation and a single rightatrial cannula. Cardiac standstill occurred under deephypothermia, and circulatory arrest was achieved.The IVC was transected, and care was taken to avoiddamage to the right coronary artery, and the atrialstump of the IVC was oversewn with a running suture.Preclotted Dacron conduit was anastomosed end-to-end to the stump of the transected IVC with a runningsuture. The distal end of the conduit was anastomosedend-to-side to the inferior aspect of the right pul-monary artery which was opened with a longitudinalincision. The conduit connecting the IVC to the pul-monary artery (PA) remained completely extracardiac.Atrial septectomy, when required, was performedthrough the atrial stump of the transected IVC.Cardiopulmonary bypass was reinstituted with theatrial cannula now draining the pulmonary venousreturn plus the coronary sinus return. No particulardifficulties in venous drainage relating to use of a singleleft atrial cannula during rewarming were observed.Thirty-six patients received crystalloid cardioplegiaand 28 patients received blood cardioplegia. The meanaortic cross-clamp time was 34 min (range 15-80 min).

ResultsSeven hospital deaths occurred (10.9%) in this initialperiod, the principal cause being myocardial damagein five patients all of whom had a combination of ven-tricular pressure or volume overload with myocardialhypertrophy before total extracardiac cavopulmonaryconnection (TECC).

Postoperative treatmentMean pulmonary artery pressure was 12 ± 4 mmHg(range 4-24 mmHg), the mean arterial oxygen satura-tion 82% ± 7.5% (range 51-95%), and the mean end-

diastolic ventricular pressure 8 ± 3 mmHg (range2-16 mmHg). The mean duration of mechanical ven-tilation was 28.3 h (1-96 h) excluding seven patients inwhom ventilatory support was prolonged (100 h).Prolonged pleural and peritoneal effusions, definedas more than 10 days of drainage, or the need formultiple drainage procedures, occurred in 22 patients(33%). All patients received inotropic agents for 72 h.

Modification of the extracardiacFontan without cardioplegic arrest

Tolerance of the hypertrophiedventricle to ischemiaDamage from a period of ischemia may result froma prolonged period (many days) of both systolic anddiastolic dysfunction without muscle necrosis [9,10].This condition is now termed myocardial stunningor myocardial hibernation [11,12]. Ischemic damageinvolves the myocardial cells, the vascular endothe-lium, and the specialized conduction cells.

Overall reviews of the damage from myocardialischemia and of the potentially damaging effect ofreperfusion are available [13,14]. The switch fromaerobic to anerobic glycolysis occurs within secondsof the onset of ischemia, and clearly reduces the levelof high-energy phosphates in the myocardial cell[15-18]. Calcium plays a key role in reperfusion injury[14]. The stiffness of cardiac muscle resulting fromuncontrolled reperfusion after a period of ischemiaresults from the massive influx of calcium into mito-chondria and the cytoplasm of myocytes, as well asfrom edema and capillary disruption [19-21]. Theobservation is that of highly reactive oxygen species(free radicals) having destructive effects on cellularmembranes that are generated during reperfusionafter the ischemia period.

All these events of ischemic damage have biggerrepercussions in hypertrophied ventricles. For thesereasons we avoid the use of cardioplegia in patientswithUVH.

The Fontan procedure is frequently performedin patients who have undergone at least one mediansternotomy and therefore have large mediastinaladhesions found at resternotomy. We used this pro-cedure without cardioplegic arrest in 167 patients.Cardiopulmonary bypass is initiated using femoralvein cannulation and single arterial cannulation. Thevenous cannulas should be kept as far away from the

278 CHAPTER 29

Figure 29.1 The SVC cannulation site should be high.Cannulation of the femoral vein is obligatory in order tocarry out this technique.

heart as possible. This is important to allow forsufficient room in placing the extracardiac conduit.The inferior cannulation should invariably be in thefemoral vein, to permit inferior anastomosis to theconduit and IVC. The SVC cannulation site shouldalso be high at the SVC-innominate vein junction(Figure 29.1). It is important to encircle the SVC fol-lowing cannulation. This cannulation allows decreas-ing cerebral venous pressure and increasing cerebralperfusion pressure. We use continuous perfusionwithout aortic cross-clamping; the surgical procedureis totally extracardiac since the atrioseptectomy had

Figure 29.2 The anastomosis between the PTFE stretch andthe inferior surface of the right pulmonary artery.

been already performed at the BCPA stage. The opera-tion is preformed in either moderate hypothermia oron a beating heart. The left ventricle is vented with acannula placed in the right atrium.

The border of the right pulmonary artery is incisedalong its entire length (Figure 29.2). The incision mustreach the confluence of the pulmonary artery and theleft pulmonary artery origin must be seen. The PTFEstretch conduit (we have never used a diameter lessthan 18 mm or greater than 22 mm) is cut slightlyoblique to direct the IVC blood flow toward theconfluence of the pulmonary arteries and suturedin place using a monofilament running suture. ThePTFE stretch conduit is pulled down toward theIVC and cut slightly short to put the IVC and rightpulmonary artery under gentle traction. The correctlength of the conduit varies between 3 and 5 cmaccording to the patient's anatomy.

The anastomosis with the IVC is performed with arunning 6-0 prolene suture (Figure 29.3). If the IVC isnot present, as is the case in patients with left iso-merism and azygos continuation, the surgery is thesame because the hepatic veins usually join togetherbefore reaching the atrium. A separate vein is some-times present; in such cases, the vein should be "unifo-calized" with the others to create a common singlevein. When good staging is performed for singleventricular repair, the last step (extracardiac conduit)becomes a relatively simple procedure. The meanbypass time was 25 min (range 15-50 min). Theshorter period on bypass certainly played a positiverole in early success.


Figure 29.3 End-to-end anastomosis between theextracardiac conduit and the IVC. This surgical technique istotally extracardiac.

UltrafiltrationAfter bypass, significant accumulation of total bodywater may occur. This edema is distributed not only inthe periphery, but also in vital areas such as brain,heart, gut, and lung. This increase in total body watercan be partially controlled by limiting the excessamount of crystalloid given with the pump prime,and also by removing fluid using various meansduring or after CPB. The technique of ultrafiltrationis performed in the immediate postbypass period.Most commonly, blood is removed from the aorticcannula, passed through a hemofilter, and returnedas oxygenated, hemoconcentrated, and ultrafilteredblood to the cannula in the right atrium. Ultrafiltra-tion improves intrinsic ventricular systolic function,improves diastolic compliance, increases blood pres-sure, and decreases inotropic drug use in the earlypostoperative period [22]. Ultrafiltration was per-formed in all patients after CBP as an important formof myocardial protection.

ResultsEight hospital deaths occurred (4.7%). The principalcause was myocardial in three patients, pulmonary

Figure 29.4 Duration of mechanical ventilatory support.Improvement in cardiorespiratory function in patientswithout cardioplegic arrest.

artery distortion or hypoplasia appeared to be thecause of death in two patients, and heart failure inthe other three patients.

Postoperative treatmentMean pulmonary artery pressure was 11 ± 4 mmHg(range 5-20 mmHg), mean arterial oxygen saturation

90% ± 6.7% (range 67-97%), and mean end-diastolicventricular pressure 5 ± 2 mmHg (range 3-11 mmHg).The mean duration of mechanical ventilation was9.9 h (1-54 h) (Figure 29.4).

Prolonged pleural and peritoneal effusions, definedas more than 10 days of drainage or a need for multipledrainage procedures occurred in 33 patients (20%). Inthis group of patients only 5% underwent the fenes-tration procedure (Figure 29.5). All patients receivedinotropic agents (mean 35.4 h) (Figure 29.6).

Extracardiac Fontan operationwithout cardiopulmonary bypass

Cardiopulmonary bypass is known to activate inflam-matory mediators, increase lung water, and decreaseright ventricular compliance. These unfavorable effectsof cardiopulmonary bypass can increase pulmonaryvascular resistance and decrease pulmonary bloodflow after cavopulmonary connection. If intracardiac

repair is not necessary, the extracardiac total cavopul-monary connection could be performed without car-diopulmonary bypass. Several centers have begun touse this technique [23-25], which is one that shouldbe in the pediatric cardiac surgeon's armamentarium.

280 CHAPTER 29

Figure 29.5 Decrease of the effusion in 13% of patientsin whom the surgical technique was performed withoutcardioplegic arrest. In 5% of the patients it was necessaryto carry out the fenestration procedure.

Figure 29.6 Duration of inotropic support. Improvementof ventricular function in the group of patients operatedon without cardioplegic arrest.

The ability to perform the extracardiac conduit Fontanprocedure without cardiopulmonary bypass dependson a number of variables. The indications for per-forming this technique are not well established [23].With this technique, it was found that time to extuba-tion, length of ICU stay, and hospital stay were notstatistically different in comparison with patients inwhom cardiopulmonary bypass was used [25]. Weprefer the approach which employs a short duration

for cardiopulmonary bypass without the need forcardioplegia.

Summary

Patients with a functional anatomic single ventricleundergo the Fontan procedure after one or more sur-gical palliations. Chronic volume overload secondaryto systemic to pulmonary artery shunt and chronicpressure overload secondary to pulmonary arterybanding result in an increase in ventricular cavitysize followed by a proportional increase in eccentrichypertrophy, altering both systolic and diastolicfunction [5].

Myocardial protection begins with staging towardthe Fontan procedure. The aim of this first stage is toprepare the myocardium and eliminate all possiblerisk factors to allow the Fontan circulation. In the firststage we performed BCPA, with all the associated pro-cedures (patch enlargement of the pulmonary arteries,main pulmonary artery to aorta anastomosis) andintracardiac surgery (atrioseptectomy). This approachreduces the volume load of the systemic ventricle tonormal values and diverts desaturated blood to thelung, thus increasing effective pulmonary blood flow.The second important form of myocardial protectionis performance of the Fontan procedure using anextracardiac conduit. This technique has several theo-retical and practical advantages. In our experience,one of the most important benefits of the extracardiacconduit approach has been the ability to complete theFontan circulation without cardioplegic arrest. Thistechnique is easy to reproduce and enables cardiopul-monary bypass time to be reduced, while preservingsystolic and diastolic ventricular function. With thistechnique substantial improvements in early post-operative outcome are achieved.

References1 Marcelletti C, Corno A, Ginnico S et al. Inferior vena

cava—pulmonary artery extracardiac conduit. A newform of right heart bypass. / Thorac Cardiovascular Surg1990; 100:228-32.

2 Giannico S, lorio FS, Carotti A et al. Staging toward theFontan operation. Semin Thorac Cardiovascular Surg1994; 6:13-16.

3 Di Donato R, Amodeo A, Di Carlo DD et al. StagedFontan operation for complex cardiac anomalies withsubaortic obstruction. / Thorac Cardiovasc Surg 1993;105: 398-405.


4 Martelletti CF, lorio FS, Abella RF. Late results of extra-cardiac Fontan repair. In: Pediatric Cardiac Surgery Annualof Seminars in Thoracic and Cardiovascular Surgery, Vol 2.Philadelphia, PA: Saunders, 1999: 31-141.

5 Albanese S, Carotti A, Di Donato R et al. Bidirectionalcavopulmonary anastomosis in patients under two yearsof age. / Thorac Cardiovasc Surg 1992; 104:904-9.

6 Mazzera E, Corno A, Picardo S et al. Bidirectionalcavopulmonary shunts: clinical applications as stagedor definitive palliation. Ann Thorac Surg 1989; 47: 415-20.

7 lorio FS, Marcelletti C, Hanley FL et al. Current approachfor cavopulmonary conection. In: Operative Techniquesin Cardiac and Thoracic Surgery. A Comparative Atlas,Vol 2. Philadelphia, PA: Saunders, 1997:196-204.

8 Di Carlo DD, Di Donato RM, Carotti A et al. Evaluationof the Damus-Kaye-Stansel operation in infancy. AnnThorac Surg 1991; 52:1148-53.

9 Ellis SG, Henschke CI, Sandor T, Wynne J et al. Timecourse of functional and biochemical recovery ofmyocardium salvaged by reperfusion. / Am Coll Cardiol1983; 1:1047-55.

10 Heyndrickx GR, Millard RW, McRitchie RJ et al.Regional myocardial function and electrophysiologicalalterations after brief coronary artery occlusion in dogs.JClin Invest 1975; 56:978-85.

11 Braunwald E. The stunned myocardium. Newer insightsinto mechanisms and clinical implications [letter]./ Thorac Cardiovasc Surg 1990; 100: 310-11.

12 Braunwald E, Kloner RA. The stunned myocardium: pro-longed postischemic ventricular dysfunction. Circulation1982;66:1146-49.

13 Hearse DJ, Braimbrige MV, Jynge P. Ischemia and reper-fusion: the progression and prevention of tissue injury.In: Protection of the Ischemic Myocardium: Cardioplegia.New York: Raven Press, 1981: 21.

14 Nayler W, Elz JS. Reperfusion injury: Laboratory artifactor clinical dilemma? Circulation 1986; 74:215-21.

15 Clark BJ III, Woodford EJ, Malec EJ et al. Effects of pota-sium cardioplegia on high-energy phosphate kineticsduring circulatory arrest with deep hypothermia in thenewborn piglet heart. / Thorac Cardiovasc Surg 1991; 101:342-49.

16 Jarmakani JM, Nakazawa M, Nagatomo T et al. Effectof hypoxia on mechanical function in the neonatalmammalian heart. Am JPhysiol 1978; 235: H469.

17 Murphy CE, Salter DR, Morris JJ et al. Age-related differ-ences in adenine nucleotide metabolism during in vivoglobal ischemia. SurgForum 1986; 37:288.

18 Starnes VA, Hammon JW Jr, Lupinetti FM et al. Functionand metabolic preservation of immature myocardiumwith Verapamil following global ischemia. Ann ThoracSurg 1982; 34:58-65.

19 Beyersdorf F, Okamoto F, Buckberg GD etal. Studies onprolonged acute regional ischemia. II. Implications ofprogression from dyskinesia to akinesia in the ischemicsegment. / Thorac Cardiovasc Surg 1989; 98:224-33.

20 Buja LM, Chien KR, Burton KP et al. Membrane damagein ischemia. AdvExpMed Biol 1982; 161:421-31.

21 Castaneda AR, Jonas RA, Mayer JE, Hanley FL. CardiacSurgery of the Neonate and Infant. Philadelphia, PA:Saunders, 1994:41-64.

22 Davies MJ, Nguyen K, Gaynor JW et al. Modifiedultrafiltration improves left ventricular systolic func-tion in infants after cardiopulmonary bypass. / ThoracCardiovasc Surg 1998; 115:361-70.

23 McElhinney DB, Petrossian E, Reddy VM et al. Extra-cardiac conduit Fontan procedure without cardiopul-monary bypass. Ann Thorac Surg 1998; 66:1826-8.

24 Okabe H, Nagata N, Kaneko Y et al. Extracardiac cavo-pulmonary connection of Fontan procedure with auto-logous pedkled pericardium without cardiopulmonarybypass. / Thorac Cardiovasc Surg 1998; 116:1073-5.

25 Tarn VKH, Miller BE, Murphy K. Modified Fontan with-out use of cardiopulmonary bypass. Ann Thorac Surg1999;68:1698-703.

CHAPTER 30

Preservative cardioplegic solutionsin cardiac transplantation:recent advances

RomualdoJ. Segurolajr, MD & Rosemary F. Kelly, MD

Introduction

This chapter considers the current advances in preser-vation solutions used for cardiac transplantation.Poor tolerance of the myocardium to prolonged coldischemia remains a major concern in heart transplan-tation. There is a known correlation between earlypatient survival and duration of cold ischemic times.One-year mortality rates increase after transplanta-tion of hearts subjected to more than 3.5 h of ischemia,and clinical graft viability is still limited to 4—6 h ofheart preservation [1]. Clinical methods of myocar-dial preservation for cardiac transplantation are dis-cussed in detail in Chapter 31. Although methods ofimproving graft function include methods of con-tinuous hypothermic perfusion, effective cardioplegicsolutions for myocardial protection are the first stepin any successful preservation protocol, and will bethe focus of this chapter.

Perf usate composition

There is considerable variability in the type of heartpreservation solutions used in the United States, withno consensus regarding the optimal preservationsolution [2]. Cardioplegia is used to stop the heartsafely, it diminishes the myocardial energy require-ments, creates an environment for continued energyproduction, and counteracts the deleterious effects ofischemia. The active components found in nearly allpreservation solutions include potassium to arrest theheart, sodium and chloride for ion exchange, glucoseto provide a substrate for anerobic metabolism, and

bicarbonate to buffer the ischemic acidosis [3].Although glucose has been used in preservationsolutions as the metabolic substrate, documentationis lacking that hypothermic hearts consume exogen-ous glucose during cardioplegic conditions [4].Indeed, the dominant protective effects of hypother-mia and mechanical cardiac arrest may mask thesuboptimal composition of solutions used for cardiacpreservation.

Even with the most advanced methods of myo-cardial protection, ischemic tissue injury progressesexponentially with time, thus emphasizing the im-portance of an expeditiously performed operation.An increase in donor organ myocardial ischemia isknown to affect early graft function and patient sur-vival [5]. Diastolic function has been reported to bemore sensitive to ischemic damage, and its deteriora-tion occurs earlier than systolic dysfunction [6].During cardiac surgery or cardiac transplantation theheart must be protected against ischemic and reperfu-sion injury in order to preserve postoperative func-tion. Ischemic effect on the myocardium appears to beminimal if kept under 4 h [7]. The optimal preserva-tion solution for donor cardiac allograft procurementwould minimize, or even eliminate, any structuralor functional damage to the myocardium due toischemia and reperfusion. It is a solution that hasyet to be developed.

There are currently more than 160 preservationsolutions used clinically in cardiac transplantation [2].The most common preservation solutions are Plegisol,University of Wisconsin, Stanford, Roe, Collins,Krebs, and St Thomas. The most common additives in

282

Cardioplegia in cardiac transplantation 283

customized solutions are gluconate, acetate, lidocaine(lignocaine), albumin, and insulin. Demmy et al. ana-lyzed the pattern of usage and related survival of thesecommonly used solutions [2]. In their retrospectivestudy, they reported that among 167 solutions used in137 different transplant centers between June 1994and February 1995, the most common solutions werethe traditionally cited ones (55%), and the remainderwere customized.

Univariate analysis of this data regarding survivalsuggests that survival rates are not equal for all com-monly used solutions, but no difference was noted incustomized solutions. Krebs' solution fared the bestand the clinical advantage of the Stanford solutionpreviously shown was not evident [8]. Intracellularsolutions were defined as having sodium content ofless than 70 mmol/L. These solutions with intracellularcomposition had a 1-month survival benefit but didnot have a 1-year survival over extracellular solutions.Logistic regression to adjust for the effects of donorand recipient risk factors upon cardiac transplantationonly confirmed a significantly lower odds of mortalityat 1 month when comparing intra- versus extracellularsolutions. This difference was lost thereafter. One ofthe important factors involved in the decline of dias-tolic function after ischemia is interstitial edema,which may occur especially with the extracellular typeof crystalloid cardioplegic solutions [9].

However, this decline in diastolic function withextracellular solutions found in the animal model hasnot been evident in the clinical situation. In fact, asfollow-up to the clinical survey, Demmy et al. furtherstudied the impact of intra- versus extracellular pre-servation solutions on a rat heart model [10]. Again,the data supported the superiority of certain intra-cellular formulations, but that the evidence of optimalorgan preservation is difficult to judge clinically usinghemodynamic values routinely available. Obviously,such considerations as technical problems, patientselection, variation in donor heart quality, programvolume, and patient comorbid conditions dramat-ically affect outcome, making it difficult to clearlyestablish solution-related problems [2].

There are several common cardioplegic additivescurrently used clinically that offer additional pro-tection to the myocardium. Mannitol is an osmoticagent used to prevent cellular edema. Lidocaine(lignocaine) and procaine stabilize cell membranes,induce arrest, and suppress arrhythmias. Calcium

maintains cell membrane integrity and prevents cal-cium paradox. Magnesium induces arrest and stabil-izes membranes. Glutamate and aspartate providesubstrate for the Krebs' cycle. Nitroglycerine acts asa nitric oxide donor and promotes coronary vasodi-latation. Methylprednisolone reduces cellular edema.Calcium channel blockers stabilize membranes. High-energy phosphates provide energy to the myocardium.Experimentally, these agents have demonstrated areduction in the degree of ischemia-reperfusioninjury, and improved myocardial recovery. Thoughadditives should clearly demonstrate their clinicalbenefit, few formulas have been so studied in theclinical arena.

Other additives incorporated into cardioplegicsolutions include amino acids that can be metabolizedto citric acid cycle intermediates [11]. Segel et al.studied the addition of pyruvate to preservation solu-tion in a rabbit model [12]. The hearts preservedwith pyruvate-containing crystalloid had better post-transplantation function, although there was slightloss in compliance and decreased contractile functioncompared to controls. Other experimental work onlong-term preservation has incorporated substratesfor oxidative metabolism into cardioplegic solutions[13,14]. Overall the results remain somewhat equivo-cal as to benefits and depend on the animal modelutilized.

Histidine-tryptophan-ketoglutarate (HTK) solu-tion is a preservation solution that relies heavily onamino acid substrates. It may be an effective pre-servation solution due to the high buffering capa-city provided by histidine/histidine-hydrochloridethat suppresses ischemia-induced acidosis [15]. Thedecrease in acidosis inhibits ATP degradation duringhypothermic storage. In addition, the ketoglutarateand tryptophan in HTK solution are effective addi-tives in protecting the myocardium during ischemia[16]. In an animal model, the myocardial tissue levelof ATP was significantly higher in hearts preservedwith the HTK compared to University of Wisconsinsolution [17]. In addition, the solution has beenmodified by the addition of hyaluronidase thatresulted in superior cardioprotective qualities com-pared to HTK solution with cold storage up to 24 h inthe rat and rabbit hearts [ 18]. As with other solutions,however, prospective clinical studies are unavailablethat clearly demonstrate the advantage of HTK solu-tion over other solutions.

284 CHAPTER 30

Mechanism of ischemia-reperfusion injury

Understanding the mechanisms of ischemia-reperfu-sion injury during organ procurement is critical to theimprovement of future preservation techniques. Evenunder hypothermic conditions used during trans-portation of the donor organ, myocardial cells main-tain a level of metabolic activity. The initial phase oforgan procurement involves a prolonged ischemicevent requiring anerobic metabolism to support anymyocardial metabolic activity during storage. Duringthis phase, intracellular acidosis occurs, which ispoorly tolerated by myocardial cells. Resultant edemaformation during ischemia and upon reperfusion is amorphologic sign of severe myocyte membrane dam-age and is associated with a disturbance of the ionicbalance of cell membranes [19]. Clearly, myocardialedema impairs both coronary circulation and systolicperformance [20]. The ability to preserve graft func-tion following prolonged ischemia is critical toimproving cardiac transplantation outcomes. Thoughcurrent preservation strategies do employ antioxidantadditives, optimization of the preservation solutionsinvolves understanding and alteration of the variousmechanisms of tissue injury that can occur withtransplantation.

Ischemia-reperfusion injury is an important mech-anism of organ injury in heart transplantation. Celldamage from ischemia primes the tissue for the sub-sequent damage from reperfusion, with reperfusionresulting in even greater injury than ischemia alone.The mechanism of ischemia-reperfusion injury inheart transplantation is a complex series of events.Prolonged ischemia results in the activation of pro-teases, particularly lysosomal enzymes, which leadto biological and morphological damage to the myo-cardium. This is then associated with a decrease inglycogen stores, depletion of high-energy phosphatecompounds, ionic imbalances, local release of cate-cholamine, accumulation of lactic acid, and deteriora-tion of cellular function. Reperfusion after ischemiacauses additional damage to the myocardium throughthe production of free radicals and activation ofenzymes, which causes cellular damage and depres-sion of the left ventricular function.

The ischemic phase of heart transplantation leadsto anaerobic metabolism that results in depletionof ATP. Depletion of ATP alters membrane ionic

ATP-dependent pumps, thereby increasing the entryof calcium, sodium and water into the cell [21]. Thismassive calcium overload leads to: (i) activation ofproteases, lipase, and phospholipases; (ii) ATP usageby activation of ATPases; and (iii) inhibition of mito-chondrial oxidative phosphorylation. Ischemia alsocauses the catabolism of adenine nucleotides resultingin an accumulation of hypoxanthine within the cells[22]. At the same time, ischemia is associated withthe proteolytic conversion of xanthine/hypoxanthinedehydrogenase to xanthine/hypoxanthine oxidase,which primes the cell for free radical production uponreperfusion with oxygenated blood [23].

Upon reperfusion, xanthine oxidase metabolizeshypoxanthine and xanthine to uric acid, and in theprocess generates superoxide radical and hydrogenperoxide. The superoxide radical may then react in theion-catalyzed Fenton reaction to form highly react-ive hydroxyl radicals [24]. Studies of reoxygenatedhuman and bovine endothelial cells show release ofsuperoxide anion and hydroxyl radical. These freeradicals cause lipid peroxidation, protein sulfhydryloxidation, and cross-linking, which leads to enzymeactivation and subsequent extravasation of intravas-cular components, signifying alteration of barrierfunction [25]. Membrane injury then results in releaseof intracellular enzymes from the myocytes, causingcell injury and death.

Vulnerability to oxidant damage increases as theburst of reactive oxygen species during ischemia-reperfusion overwhelms endogenous antioxidants.Normally, organs contain ubiquitous endogenousoxygen radical scavengers such as superoxide dismu-tase, reduced glutathione, catalase, and vitamins Cand E, which counteract the effects of such toxic oxy-gen species as superoxide, hydrogen peroxide, andhydroxyl radical. Ischemia depletes tissue levels ofthese naturally occurring barriers to oxidant injuryand increases vulnerability to reoxygenation injury,especially as reoxygenation further reduces antioxid-ant availability [26,27].

Following the initial injury of ischemia-reperfusion, the activation of neutrophils significantlyamplifies tissue injury. There are several well-definedpathways of neutrophil activation. Early endothelialcell membrane injury promotes neutrophil adherenceand activation, leading to capillary plugging, reducedflow, and release of oxidants. This neutrophil activa-tion may then contribute to myocardial stunning,


resulting in low-output syndrome following trans-plantation [28].

One particularly important pathway of neutrophilactivation is through platelet activating factor (PAF)formation. This PAF formation is a result of theincreased intracellular calcium concentration thatoccurs with ischemia-reperfusion injury, causingphospholipase A2 activation. Activated phospholipaseA2 hydrolyzes arachidonic-containing phospholipids,including a PAF precursor. Formation of PAF resultsin activated endothelial cell presenting PAF to theneutrophil receptor, which causes neutrophil aggre-gation. In addition, oxygen free radicals generatedduring ischemia-reperfusion cause prolonged andinappropriate expression of P-selectin on the surfaceof endothelial cells. The coexpression of P-selectin andPAF mediates a joint process of neutrophil tether-ing and activation [29]. Neutrophils attached to theendothelial cells become polarized and able to releaseproteolytic enzymes as well as reactive oxygen species,both of which induce cell damage.

Another pathway of neutrophil activation includesreactive oxygen intermediates stimulating interleukin8 (IL-8), which in turn induces the transmigration andaggregation of neutrophils [30,31]. At the same time,complement activation by ischemic tissue generatesC3a and C5a, which causes vascular leakage andenhances activation and infiltration of leukocytes. Thecomplement activation disrupts vascular endothelialcell function and leads to tissue injury. Thus,amplification of organ injury continues during reper-fusion through activation of neutrophils and thecomplement system. All these pathways are potentialpoints of intervention for eliminating organ injuryfollowing procurement and transplantation.

Interventions to reduce ischemia-reperfusion injury

Cardiac preservation solutions have included addit-ives that attenuate tissue injury from ischemia-reperfusion. Yet despite the additives and improvedunderstanding of various mechanisms of ischemia-reperfusion injury, the clinical limitation of 4-6 h ofischemic time persists. Although the different stepsinvolved in the ischemia-reperfusion cascade permitdistinct points of intervention, no critical step hasbeen defined that results in the elimination of suchinjury. Many interventions are in the experimental

stage and require further refinement before clinicalapplication is possible.

Free radical scavengers or inhibitors are importantadditives. Several additives have been included inexperimental and clinical preservation solutionswith varying success in experimental animal models.Extrapolation of experimental findings to clinicalevents requires a reasonable perspective of the limita-tions of laboratory methods. Inhibitors of reactiveoxygen species production include superoxide dis-mutase and allopurinol. AUopurinol has been usedclinically in University of Wisconsin solution, thoughimproved outcomes have not been directly linked tothis additive in cardiac transplantation. Free radicalscavengers include glutathione, nitric oxide, lazaroids,and vitamin E. Inhibition of the Fenton reaction withiron chelators may reduce the formation of the highlyreactive hydroxyl radical. All of these additives haveshown improved graft function in experimental stud-ies, but have not yet been incorporated into a clinicalpreservation strategy.

What may be even more important to limitingischemia-reperfusion injury is inhibition or deactiva-tion of neutrophils. In a rabbit model, neutrophilswere sequestered in transplanted hearts within 4 hafter transplantation, but not in hearts transplantedwithin 1 h of ischemic time [32]. This suggests thatneutrophil-mediated reperfusion injury may be animportant component in heart graft failure whenischemic times are prolonged. Neutrophils play a cen-tral role in tissue injury through amplification of thereperfusion injury. Targeting the adhesion moleculesusing monoclonal antibodies inhibits the cellularinteraction between neutrophils and endothelial cells,and limits reperfusion injury. Similarly, a monoclonalantibody against IL-8 prevents neutrophil activationand aggregation. In addition, protease inhibitors mayinactivate the cytotoxic enzymes released from activ-ated neutrophils. It is also possible to use mechanicalfiltration of neutrophils during cardiopulmonarybypass [33]. Although each of the methods discussedhas experimental merit in reducing graft injury, theyhave not yet been available clinically.

Inhibition of complement activation may also havea potential role in heart transplantation. Soluble com-plement receptor type 1 inhibits the activation of theclassic and alternate pathways. These interventionsmay limit the amplification of injury that occursduring reperfusion. There is less experimental data

286 CHAPTER 30

currently available for this mechanism of interven-tion, but further study is indicated.

The role of nitric oxide remains unclear despiteextensive study, as the data are somewhat conflicting.Nitric oxide causes vasodilatation, reduces plateletaggregation, and reduces neutrophil activation.Sodium nitroprusside administered with cardioplegicsolution and with reperfusion in a rat heart model wasfound to improve donor heart preservation. However,the inducible enzymatic pathway of nitric oxide pro-duction is associated with tissue injury. The abilityto inhibit inducible nitric oxide synthetase can be pro-tective during ischemia. Due to the conflict in inform-ation, the clinical application of nitric oxide in hearttransplantation remains limited and it is not routinelyutilized as an additive in preservation techniques.

Hyperpolarized cardiac arrest

A separate area of investigation has focused on thedevelopment of cardioplegic solutions directed at pro-longing the tolerance of the myocardium to ischemiaby maintaining the heart in a state of "reversible injury."It has been suggested that the depolarizing nature ofhyperkalemic solutions results in ionic imbalancecaused by continuing transmembrane fluxes [34].This imbalance may increase the impact of ischemia-reperfusion injury on the myocardium. An alternativeto hyperkalemic cardioplegia is to arrest the heart in ahyperpolarized state, which maintains the membraneof the myocardium near the resting membrane poten-tial [34].

Hyperkalemic cardioplegic solutions are the cur-rent clinical standard and have an elevated potassiumconcentration ranging between 12 and 25 mmol/L. Asthe resting membrane potential of cardiac cells isaround -90 mV, these hyperkalemic solutions lead toa depolarization of the membrane potential to about-50 mV. At this membrane potential the sodiumchannels are also inactivated and the heart arrested ina flaccid diastolic state [35]. However, at this mem-brane potential, other ionic mechanisms such assodium-hydrogen exchange may cause a slow influx ofsodium. This sodium influx could lead to calciumoverload during reperfusion, which is toxic to themyocardium [36].

Hyperpolarization results in complete arrest of thesinus node. This potassium agonistic property willoffer a more complete and persistent arrest of the

heart. Recognition of this mechanism launched theidea of using hyperpolarizing instead of depolarizingagents for the induction of cardiac arrest with cardio-plegia. The resultant hyperpolarized state offers abalanced transmembrane gradient, which will main-tain ionic balances during ischemia. Polarized arresthas been associated with reduced ionic imbalanceand improved recovery of cardiac function [37].

It is possible to achieve this hyperpolarized stateusing various drugs. These drugs include adenosine,sodium channel blockers (procaine, tetrodotoxin, andlidocaine (lignocaine)), or potassium channel openers(nicorandil and pinacidil). Multiple animal studieshave demonstrated that using adenosine cardioplegicsolutions alone or in combination with potassiumreduces the time to myocardial arrest and recoveryafter reperfusion is significantly better [38-40].

Adenosine has been shown to be protective tothe ischemia-reperfused myocardium. The additionof adenosine deaminase inhibitor to cardioplegiasolution resulted in improved functional recoveryfollowing cold storage in a dose-dependent fashion.It appears to inhibit adenosine catabolism via areceptor-mediated mechanism [41].

Potassium channel openers as well have beenstudied in multiple animal models but results havebeen conflicting [42]. Potassium channel openersare thought to exert their protective effect by induc-ing hyperpolarization of the myocardial cells. It isassumed that hyperpolarization represents a restingmembrane potential that is more negative, as by open-ing the potassium channels should move the restingmembrane potential toward the potassium equilibr-ium potential.

Alternatively, a hyperpolarized state may beachieved by blocking sodium channels. Studies havesuggested that the depolarized arrest induced bytetrodotoxin reduced metabolic demands on ischemichearts by a larger factor than depolarized arrest byhyperkalemia. Extracellular potassium accumulationwas significantly reduced in hearts arrested withtetrodotoxin compared to hyperkalemic arrest [43].

Myocardial protection during cardiac transplanta-tion has been successfully accomplished with potas-sium-dependent cardioplegia, but this predisposes toionic imbalances and, hence, reperfusion irritability.Arresting the heart in a hyperpolarized state theo-retically reduces these ionic imbalances and there-fore decreases the rate of postischemic irritability.


However, the profibrillatory effects of the hyperpolar-izing agents are well established. Therefore, despitepromising experimental data, considerable additionalstudies will be required to make hyperpolarized arresta clinical standard.

Ischemic preconditioning

Brief periods of myocardial ischemia separated byreperfusion increase myocardial tolerance to infarction—a phenomenon termed "ischemic preconditioning"[44]. Preconditioning has been shown to: (i) causepreservation of myocardial high-energy phosphates;(ii) attenuate intramyocardial acidosis; and (iii)reduce the rate of anaerobic glycolysis and subsequentaccumulation of lactate during prolonged ischemicinsult. It has been identified as a successful strategyfor improving preservation of cardiac allografts andmay be an important adjunct to cardiac preserva-tion strategies [45,46]. Single or repeated periods ofischemia may have a protective effect during moreprolonged ischemic episodes by the induction ofendogenous antioxidants [47]. In a rat model, precon-ditioning was noted to offer additional protection tothe myocardium by preventing increase in diastolicstiffness following cardioplegic arrest with St Thomas'Hospital solution [48]. Though the extent of addedprotection to hypothermic arrest from precondition-ing may be relatively small compared to protectionobserved after unprotected normothermic ischemia,this conclusion has been challenged [48,49].

Possible mechanisms underlying the endogenousprotection of ischemic preconditioning are: (i) reduc-tion of lactate accumulation; (ii) increase in adenosinerelease; (iii) enhancement of cell salvage of ATP; (iv)the opening of ATP-sensitive potassium channels; and(v) the inhibition of intracellular calcium overload.Ischemic preconditioning is thought to cause a pro-tein kinase C-mediated activation of mitochondrialpotassium adenosine triphosphate (KATP) channels[ 50 ]. It has been postulated that the entry of potassiumthrough these open channels dissipates the mem-brane potential normally established across the innermitochondrial membrane by the proton pump. Thisin turn would decrease the calcium uptake into themitochondria, which is a major determinant of post-ischemic function [51,52]. This idea is consistentwith the ability of preconditioning to reduce calciumoverload in the myocardium.

Another major metabolic consequence of ischemicpreconditioning is reduction of intracellular acidosis,which then results in reduced myocardial edema. Thesodium (Na+)/hydrogen (H+) exchange is also affectedby the reduction in intracellular acidosis, and its activ-ity is reduced with a noted decrease in intracellularsodium [53]. However, the protection afforded tomyocytes by preconditioning does not appear toextend to endothelial cells, as endothelium-dependentcoronary responses are unaffected by preconditioning[49,54].

Diazoxide is a drug that duplicates the beneficialeffects of preconditioning on postischemic functionby selective opening of the mitochondrial KATP chan-nels. This effect supports the role of KATP channels asmediators of the cardioprotective effects of ischemicpreconditioning [52]. Subsequently, the beneficialaction of diazoxide involves a reduction in intracellu-lar calcium overload. However, diazoxide adminis-tered in the postischemic period failed to improverecovery of the myocardial function and this may bedue to another effect of diazoxide, which includesreduction in ATP synthesis.

By contrast, study of another mitochondrial KATPchannel activator, nicorandil, showed significantbeneficial effects in cold-stored hearts [55]. The bestmethod of administration for these drugs appears tobe in conjunction with a cardioplegic solution, as thedrugs may exert a hypotensive effect that would bedetrimental if given prior to donor organ procurement.

Recently, reduction in calcium overload by inhibit-ing the (Na+-H+) exchanger has been investigated[56]. This antiport allows the extrusion of intracellularprotons in exchange for sodium ions. In ischemia-reperfusion, the depletion of ATP leads to impairedefflux of sodium ions through the ATP-driven Na+-potassium (K+) ATPase. The increased intracellularsodium results in calcium (Ca2+) overload because ofthe increased calcium influx through the Na+-Ca+2

exchanger. It is possible to blunt the ischemia-reperfusion injury using Na+-H+ exchanger inhibitors[56]. This has not been used clinically in the trans-plantation setting, but may become an importantadditive to cardioplegic solutions or upon reperfusion.

The choice of a Na+-H+ exchanger inhibitor may bebetter than a potassium channel opener (diazoxide)for improving preservation of cold-stored hearts.Cariporide is a Na+-H+ exchange inhibitor that hasbeen studied experimentally in rat hearts [49]. When

288 CHAPTER 30

cariporide was added to the cardioplegia solutionas well as the reperfusate, the myocardial protectiveeffects were similar to preconditioning. In additionto limiting sodium-driven calcium overload, Na+-H+

exchanger inhibitors prevent the alkaline overshootoccurring during reperfusion, and the hypercontrac-ture of myofilaments. The improved outcome wasnoted in both small and large animal models [49,57].In particular, the combination of ischemic precondi-tioning with the addition of cariporide to cardioplegiaand upon reperfusion had the greatest impact onpreservation of postischemic cardiac function [49].

Protease inhibitor

As discussed, prolonged ischemia results in activationof proteases, which in turn leads to biological andmorphological damage to the myocardium. Aprotinin,a protease inhibitor, may protect the myocardiumfrom ischemia-reperfusion injury by suppressing therelease of lysosomal enzymes during ischemia [58].It may preserve adenine nucleotide and adenosinetriphosphate as well as stabilize tissue cyclic adenosinemonophosphate levels in hearts preserved at 4°C for6 h followed by reperfusion [59]. However, in thisstudy, despite better biological and morphologicalintegrity in the aprotinin-preserved hearts, the func-tional recovery of the left ventricle was slow. Thisunexpected result suggests that the utilization ofaprotinin in preservation solution may be somewhatlimited.

Gene therapy

Gene transfer techniques are a potential adjunct tocardioplegia and cardiac preservation by allowing thetransfer of protective proteins and enzymes to thetransplanted heart. The delivery techniques and trans-fection rates have greatly improved recently. However,gene therapy requires further refinement in experi-mental models before it is clinically applicable in hearttransplantation.

Heat shock proteins (HSP) are a family of inducibleintracellular proteins that have a protective role forcells exposed to environmental stress and that havebeen transfected and studied in heart transplantationanimal models. Levels of HSP are known to increase inischemia-reperfusion injury. Mechanisms that increaseHSP, induce free radical scavengers, and attenuate

apoptosis lead to the protection of ventricular andendothelial function after ischemia-reperfusion injury[60—62]. In a clinical study, patients with high initialmyocardial levels of inducible HSP 70 had a higherdegree of cardioprotection during cardiac surgery[63]. In a rat model, HSP 70 was successfully trans-fected into donor hearts [64]. There was improvedpreservation of ventricular and endothelial functionin HSP 70 gene-transfected hearts. Therefore it is pos-sible that HSP may have a role in the clinical setting asan adjunct to cardioplegia for myocardial protection.

Gene transfer techniques have also been used fortransfection of free radical production inhibitors suchas manganese-superoxide dismutase. This enzyme canconfer a protective effect for ischemia-reperfusioninjury. The method of gene transfer uses coronaryartery infusion of the hemagglutinating virus of Japanliposome during cardioplegic arrest at the time oforgan harvest [65]. The rat hearts transfected withmanganese-superoxide dismutase showed a significantimprovement in tolerance to ischemia-reperfusioninjury. This model may provide a new tool for genetransfer that improves preservation techniques. It ispossible that future clinical advances in transfectiontechniques may allow a more rapid induction of suchprotein expression as HSP 70 and superoxide dismutaseby introduction into the heart by catheter techniquesprior to organ donation [66].

Conclusion

There continue to be significant advances in myocar-dial protection for cardiac transplantation. The alter-ations in cardioplegic ionic composition and solutionadditives have demonstrated potential improvementin preservation strategies using animal models, andhave shown promise in the clinical arena. In particu-lar, reduction in ischemia-reperfusion injury withantioxidant additives has been extensively studiedand utilized. In addition, the reduction in neutrophilactivation appears to limit the amplification of injuryduring reperfusion, and is an important area of inves-tigation. As an adjunct to cardioplegia and hypothermia,the use of ischemic preconditioning in cardiac trans-plantation has intriguing possibilities, especially giventhe ease with which it can be incorporated clinicallyboth pharmacologically and technically. The same istrue for the potential role of gene transfer therapy. Con-tinued investigations in the laboratory and clinical


arenas remain a vital part of improving preservationstrategies and patient outcomes in heart transplanta-tion. These advances in preservation techniques willpositively impact cardiac transplantation by prolong-ing ischemic tolerance during organ procurement aswell as improving graft function following implantation.

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CHAPTER 31

Myocardial preservation in clinicalcardiac transplantation: an update

Louis B. Louis TV, MD, Xiao-Shi Qi, MD, PHD, & Si M. Pham,MD, FAGS

Advances over the past five decades have made hearttransplantation an effective treatment for end-stageheart disease. The 1-year patient and graft survivalhas approached 90%. However, primary graft failurecontinues to account for approximately 25% of earlyrecipient death, and is mainly due to inadequatemyocardial preservation. Although there have beensome recent advances in extending the ischemic timeof the donor heart, myocardial preservation for clin-ical heart transplantation still depends on the use ofhypothermic cardiac arrest and static storage. Withthis technique, acceptable results can be achieved in4-6 h [ 1-3]. Cases of prolonged preservation up to 8 hhave been reported in pediatric hearts [2], howeverischemic times greater than 5 h are associated withpoor survival [4]. In this chapter, we will review thecurrent techniques of myocardial preservation forclinical heart transplantation, organizing myocardialpreservation into the four distinct stages as suggestedby Buckberg: preharvest, cardioplegic arrest, storage,and reperfusion [5].

Preharvest donor management

It is now clear that brain death results in significanthormonal imbalance in the donor, and suboptimaldonor management can result in myocardial injury.Therefore, donor management plays an importantrole in a successful strategy of myocardial preserva-tion. Myocardial preservation for cardiac transplanta-tion commences as soon as a donor is identified.The primary goal of donor management is to maintain

and optimize cardiac function of the donor. Braindead donors experience severe disruption of the hypo-thalamic-pituitary-adrenal axis, hypovolemia, andelectrolyte abnormalities [6]. Volume replacement,correction of acid-base disturbances, and electrolyteabnormalities, are the initial steps for maintainingproper organ function. However, attention must bepaid to the remainder of the disrupted endocrineaxis, particularly to antidiuretic hormone (ADH) andthyroid hormone [7]. Loss of ADH, which results indiabetes insipidus, polyuria, dehydration, hyperna-tremia, hypokalemia, and hyperosmolarity, is a hall-mark of brain injury. Administration of syntheticADH will promptly correct the sequelae of diabetesinsipidus. In addition, synthetic arginine vasopressin(1-2 units per hour) will potentiate the effects ofepinephrine. When brain dead patients were treatedwith epinephrine and vasopressin versus epinephrinealone, they survived a mean length of 24 days com-pared with only 48 h [8]. Currently, synthetic ADH iscommonly used in brain dead donors [9].

Another hormone important in the brain deaddonor is thyroid hormone. Thyroxine (T4) is nor-mally converted to the metabolically active triiodothy-ronine (T3). While T3 does not have an intrinsicinotropic effect on the normal heart, it improves ven-tricular function after ischemia [10]. Using a modelof isolated atrial myocardium, Timek et al. demon-strated that T3 reversed the depressed myocardialcontractility due to prolonged exposure to cate-cholamines (as typically occurs in brain dead organdonors) [11]. Additionally, T3 acts at the peripheral

292

Clinical cardiac transplantation 293

level to decrease the breakdown of catecholamines. Ithas been shown that a majority of brain dead donorsare T3 deficient, and that supplementation with T3(2 |lg; Triostat, SmithKline Beecham Pharmaceuticals,Pittsburgh, PA), cortisol (100 mg), and insulin(20 units) at hourly intervals significantly stabilizesthe hemodynamic status of these donors, makingthem suitable candidates for cardiac donation [6].Jeevanandam et al. demonstrated that T3 replacement(0.2 |lg/kg bolus every hour for a total of 3 doses)improved cardiac function and stabilized the hemo-dynamic status of heart donors [12]. Wheeldon et al.demonstrated that an aggressive approach to donormanagement that includes invasive hemodynamicmonitoring, fluid resuscitation, and hormonal replace-ment (methylprednisolone, insulin, arginine vaso-pressin, and triiodothyronine) resulted in better cardiacfunction and increased the rate of cardiac donationin marginal donors [13]. Through this standardizedapproach, they increased the number of organs avail-able for transplantation by 30% [14,15]. Furthermore,when aggressive treatment was applied to donors whoinitially fell outside the minimum acceptance criteriaon arrival, 44 of 52 initially unacceptable donors wereable to provide useful organs [ 13].

Elevated peripheral levels of the cardiac-specifictroponins I and T have recently been shown to be riskfactors for primary graft failure. A peripheral troponinI greater than 1.6 (ig/L and a peripheral troponin Tgreater than 0.1 |lg/L is associated with an odds ratiofor acute graft failure of 42.7 and 56.9, respectively [ 16].

Caution is indicated with donors who have adocumented history of hypertension and ventricularhypertrophy. In a retrospective review of 37 patientswho received donor hearts with left ventricular hyper-trophy (LVH) compared to a cohort of 221 patientsreceiving optimal hearts, there was decreased survivalin recipients of LVH hearts at 2 months (86.4% com-pared with 91%) and 12 months (73% vs. 86.9%) [17].Inferior survival rates were observed when donors hadknown hypertension, ischemic time greater than 180min, LVH by EGG, and moderate LVH by echocardio-graphic criteria [17]. Precise measurement of LV wallthickness by echocardiography should be consideredin addition to EGG in all donors to estimate the sever-ity of LVH. Donor hearts with LVH may be usedselectively, particularly if there are no EGG criteriaand if ischemia time is short.

Cardioplegic arrest

The current technique of myocardial preservation forclinical transplantation typically includes infusion ofcold cardioplegia to achieve electromechanical arrest,immersion of the heart in cold crystalloid or cardio-plegic solution before implantation (static hypother-mic storage), infusion of various solutions during theimplantation, and reperfusion of the transplantedheart.

Types of cardioplegiaA wide variety of cardioplegia solutions have beenused to preserve the donor heart in clinical trans-plantation. A retrospective study of all active cardiactransplant programs in the United States from 1987 to1992 showed that of 143 programs, there were 167 dif-ferent preservation solutions in use [18]. Cardioplegiasolutions are divided into two types based on theirionic composition of sodium and potassium—intra-cellular-type or extracellular-type. Intracellular-typesolutions, such as University of Wisconsin (UW,ViaSpan, Dupont, Wilmington, DE) and Euro-Collins(EC, Fresenius AG, Bad Hamburg, Germany) solu-tion, have low sodium (below 70 mmol/L), and highpotassium contents (between 30 and 125 mmol/L).These solutions mimic the intracellular ionic milieu,inducing rapid cardiac arrest by reducing the potassiumgradient. Bretschneider solution (HTK, Custodiol,Koehler Chemie GmbH, Alsbach, Germany) is alsoconsidered an intracellular solution based on itssodium concentration; however, cardiac arrest is in-duced by histidine. Extracellular-type solutions suchas Celsior (SangStat Medical Corporation, Fremont,CA) or Plegisol (St Thomas II, Abbott Laboratories,Abbott Park, IL) solutions have sodium concentra-tions greater than or equal to 70 mmol/L, and apotassium concentration between 5 and 30 mmol/L.Table 31.1 depicts the compositions of commonlyused cardioplegia solutions.

There is a paucity of large, randomized, controlledtrials designed to test the efficacy of cardioplegia solu-tions. Reported data are either from retrospectivestudies or from small controlled single center trials; asa result, conclusions are sometimes contradictory.

A retrospective study of 9401 patients who receivedheart transplants between 1987 and 1992 concludedthat the adjusted 1 -month odds ratio for mortality was

294 CHAPTER 31

Table 31.1 Compositions of common heart preservation solutions.

Cardioplegia

Content (mmol/L)*

Na

K

Mg

Ca

Glucose

Dextrose (g/L)

Lactobionate

Raffinose

Hydroxyethylstarch (g/L)

Manitol

Glutamate

Ketoglutarate

Tryptophan

Phosphate

Bicarbonate

Histidine

Glutathione

Adenosine

Allopurinol

Procaine

Insulin (U/L)

Dexamethasone (mg/L)

Methylprednisolone

(mg/L)

PH

Osmolarity (mosmol)

EC [74] UW[74]

10 30

115 125

- 5

- -

198 -

-

- 100

- 30

- 50

- -

- -

- -

-

100 25

10 -

- -

- 3

- 5

- 1

- -

100

16

-

7.4 7.4

406 320

HTK [74] Celsior[75] STH-1 [28] Plegisol [76] Roe [2]

15 100 144 110 27

10 15 20 16 20

4 13 16 16 6

0.015 0.25 2.2 1.2 -_ _ _ _ _

- - - - 50

- 80 - - -_ _ _ _ _

- - - - -

30 60 - -

- 20 - -1 _ _ _ _

2

- - - -- - - 10 Variablet

180 30 - - -

- 3 - - -_ _ _ _ _

- - - - -_ _ 1 _ _

- - - - -

- - - - -

- - - - 250

7.2 7.3 5.5-7.0 7.8 7.4

310 320 300-320 320 323

Stanford [77]

30

30

-

—

50 g

-

-

—

-

12. 5 g/L

—

-

-

-

60

-

—

—

-

-

-

-

-

7.8

431

EC, Euro-collins; UW, University of Wisconsin; HTK, Bretschneider; STH-1, St Thomas' Hospital.

* All measurements mmol/L unless stated otherwise,

t Adjust to pH of 7.4.

lower in recipients whose donor hearts were preservedwith intracellular-type solutions [18]. However, therewas no difference in survival at the 1- or 2-year timepoints. In another retrospective study, Stringham etal.compared UW and Stanford solutions in 66 hearttransplants whose ischemic time was greater than 3 h[19]. Of these 66 hearts, 17 were preserved withStanford solution and 49 with UW solution. Theyshowed no difference in primary graft failure, hospitalstay, or survival rates. However, the time to wean frombypass after cross-clamp removal was nearly twice aslong with Stanford solution than with UW (80.6 vs.44.3 min), and the average need for inotropic supportover the first eight post-transplant hours was signific-antly higher with Stanford solution than UW [ 19].

Wildhirt et al. performed a single-center, prospect-ive, randomized trial, comparing the efficacy of UWsolution (n = 20) and Celsior solution (n = 21) hearttransplant recipients [20]. The mean ischemic timewas 197 ± 13 min and 210 ± 13 min in the Celsiorand UW groups, respectively. There was an increasedneed for vasodilator and catecholamine therapy inthe immediate postoperative period in patients whohad received Celsior solution, but no difference inmyocardial performance, endothelial function, ormortality at 1 month after transplantation. Totalischemic time correlated with impaired endothelialfunction in the Celsior but not in the UW group.Endothelin and inducible nitric oxide synthase(iNOS) gene expression were significantly higher in


the Celsior group. Another single-center clinical trial,conducted in Poland, comparing Celsior (n = 28, meanischemic time 221 ± 8.6 min), HTK (n - 132, meanischemic time 109 ± 3.5 min), and UW (n = 64,mean ischemic time 216 ± 5.4 min) solutions, failedto demonstrate any significant difference in mortality,or hemodynamic support required following trans-plant [21].

In the only multicenter, randomized, controlledtrial to date, Celsior (n = 64, mean ischemic time 3.3 ±1.0 h) proved to be as safe and effective as conven-tional solutions (n = 67, mean ischemic time 3.1 ± 1.0h) for myocardial preservation prior to transplanta-tion [22]. There was no difference in primary graftfailure rate or inotropic support required in the peri-operative period. Significantly fewer patients in theCelsior group developed at least one cardiac-relatedserious adverse event (13% vs. 25%).

Blood cardioplegia has been used to preserve heartsfor transplantation with some benefit. A recentprospective, randomized, clinical trial comparing theefficacy of crystalloid (n = 27, ischemic time 176 ± 51min) versus blood cardioplegia (n — 20, ischemic time180 ± 58 min) demonstrated that blood cardioplegiawas associated with a lower incidence of right heartfailure, cardiac rhythm dysfunction, and laboratoryevidence of ischemia [23]. However, there were nodifferences in operative mortality rates, and require-ment for inotropic support or mechanical assistancebetween the two groups. Considering the more com-plicated logistics and the marginal benefits gainedfrom the use of blood cardioplegia in the transplantsetting, it is unlikely that blood cardioplegia will gainwide acceptance for preservation of heart donors.

Because endothelial injury accelerates the develop-ment of coronary allograft vasculopathy (CAV) [24],the possible deleterious effect of high potassium con-centration of UW solution on the coronary endothe-lium has been a concern. In a retrospective studyinvolving 195 heart transplant recipients (100 receivedStanford solution, and 95 UW solution), Drinkwateret al. from the University of California in Los Angeles(UCLA) reported that UW solution is associated witha higher incidence of allograft vasculopathy by multi-variate analysis [25]. However, several subsequentstudies have not shown this to be the case. Stringhamet al. [26] retrospectively reviewed the outcomes ofheart recipients who received hearts preserved witheither UW solution (n = 94) or Stanford (n = 65) and

demonstrated that the incidence and the severity ofallograft vasculopathy were similar between groups at3 years after transplantation. Furthermore, deathsattributed to CAV were equal in each group. Recently,Marelli etal. from UCLA reported their 17-year experi-ence with 1803 heart transplants at a single institution[27]. These authors reported no difference in freedomfrom coronary artery disease at 5 years after transplan-tation in hearts preserved with UW solution (from1994 to 2002) compared with hearts preserved withStanford solution (before 1994). However, death dueto allograft vasculopathy was significantly higher inthe latter group.

Delivery pressureMonitoring of delivery pressure is important, as thecardioplegia solution is often given at high pressurefollowing aortic clamping to ensure rapid diastolicarrest. With standard setup in clinical practice, itis easy to exceed 200 mmHg in the aortic root. Ithas been demonstrated that high delivery pressureis deleterious to the myocardium. Katayama et al.reported that the mean recovery of cardiac outputand coronary endothelial function in rodent heartsdecreased with increasing cardioplegic delivery pres-sure [28]. Delivery pressures higher than 120 cmH2O(88.2 mmHg) cause coronary smooth muscle con-striction. Using an adult porcine model, Irtun et al.reported that high cardioplegic delivery pressure(175 mmHg) resulted in a more rapid diastolic arrest,but was associated with poorer myocardial recoverythan low pressure (75 mmHg) [29]. Drinkwater et al.demonstrated that delivery pressures greater than120 mmHg caused marked myocardial dysfunction ina neonatal pig, and recommended that cardioplegiashould be administered at less than 80 mmHg for atotal volume of 10-15 ml/kg [30].

Storage

The current storage stage involves immersion of thedonor heart in cold crystalloid or cardioplegia solu-tions, a technique that is sometimes referred to as statichypothermic storage. Hypothermia preserves organfunction by slowing enzymatic reaction rates, and therate at which intracellular enzymes degrade cellularcomponents [31]. Most euthermic enzymes will showa 1.5-2-fold decrease in enzymatic metabolism foreach 10°C decrease in temperature [32]. Hypothermia

296 CHAPTER 31

does not prevent cell death; it merely delays it, andshould be considered a double-edged sword. By de-creasing enzymatic function, hypothermia also slowsdown processes that would be considered beneficial,such as the synthesis of ATP. The limitation of statichypothermic storage has prompted the search foralternatives, such as coronary artery perfusion, to pro-long myocardial preservation for transplantation.

Coronary perfusion with oxygen-carrying solutionshas three basic advantages over static hypothermicstorage. Firstly, it prevents ischemia, anerobic meta-bolism, and reperfusion injury. Secondly, nutritionalsupplementation and provision of substrate can bemore effectively delivered to myocardial cells. Lastly,continuous perfusion preservation effects the clear-ance of metabolic waste products from the coronarycirculation [33]. Continuous cold perfusion has beenshown to be superior to static hypothermic storage inseveral studies. Canine hearts perfused with UW solu-tion for 12 h required significantly less inotropic sup-port after transplantation compared with hearts thathad been stored in UW solution [34]. After 24 h ofcontinuous cold perfusion, rabbit hearts preservedwith UW solution regained 93% of LV developingpressures compared with only 35% in the control(static storage) group [35]. Likewise, porcine heartsdemonstrated significantly better function when per-fused for 6, 12, and 24 h compared to nonperfusedcontrols. It should be noted that at the 6 h time point,there was no discernible functional difference, butthere was metabolic evidence for injury in the non-perfused controls [36]. Continuous coronary perfu-sion during storage has not been adopted for clinicalheart transplantation because of the complexity of theequipment required. However, several recent studiesinvolving simpler equipment have showed promise.Using a simple portable perfusion system, Oshima etal. demonstrated that perfused canine hearts recov-ered faster and had less damage after 12 h of ischemiathan controls (static storage) [37]. These results havebeen reproduced in canine hearts for up to 24 h ofischemia [38,39].

Reperfusion

The role of antioxidantsReperfusion, the final phase of myocardial preserva-tion, is the point at which the heart may sustain

the greatest amount of injury. Ischemia-reperfusioninjury involves a complex series of interactions at boththe molecular and cellular levels. As ATP is consumedduring ischemia, there is a build up of hypoxanthine.Once the graft is reperfused with oxygen rich blood,a burst of oxygen free radicals is produced by theendothelial xanthine oxidase pathway, resulting inlipid peroxidation [40,41]. This cascade of oxygenfree radical injury leads to increased permeability ofcellular membranes, and intracellular edema. Thesarcoplasmic reticulum, and thus calcium transport,is damaged by peroxidation, as is mitochondrialoxidative phosphorylation. Inflammatory mediatorssuch as prostaglandins, leukotrienes, and thrombox-anes, produced by the injured cells, and as a result ofcardiopulmonary bypass, act as chemotactic factorsfor leukocytes, amplifying oxygen free radical injury.

The protective role of oxygen radical scavengersin myocardial preservation has been well recognized[42-44], and oxygen radical scavengers, such asreduced glutathione, polyethelene glycol, and mani-tol, either alone or in combination, have beenincluded in several cardioplegic solutions. Amongother oxygen radical scavengers that have been stud-ied extensively in recent years are the lazaroid com-pounds. These compounds act both as antioxidantsand calcium antagonists, and protect tissue from lipidperoxidation. It has been reported that lazaroid com-pounds reduce free radical-mediated injury in variousorgans [45-49]. Takahashi et al. demonstrated thatintravenous administration of the lazaroid compoundU-74389G 30 min prior to reperfusion resulted in bet-ter cardiac function and less myocardial damage incanine hearts [50]. These data suggesting that novelinhibitors of lipid peroxidation may further reducethe ischemia-reperfusion injury and enhance myocar-dial protection for clinical cardiac transplantation.

Another strategy to minimize oxygen radical injuryis to reduce the exposure of the ischemic heart toleukocytes during the initial reperfusion period. Theuse of a leukocyte filter in the cardiopulmonary bypasscircuit has been shown to decrease injury associatedwith oxygen free radicals, and improve function fol-lowing bypass [51]. In an animal study with longischemic time (4 h), leukocyte depletion resulted inimproved functional recovery, as well as improvedendothelial function [52]. Yamamoto et al. reportedthat reperfusion with leukocyte-depleted blood


improved coronary endothelial function, and reducedmyocardial injury, in a canine heart transplant model[53]. Clinical data from bypass surgery also demon-strated that leukocyte nitration correlated with im-proved cardiac and lung function following surgery[54]. In a randomized, controlled, clinical trial, reper-fusion of transplanted hearts with leukocyte-depletedreperfusate was associated with less release of the crea-tine kinase MB fraction (CK-MB) (and thromboxaneB2), indicating a lesser degree of ischemia-reperfusioninjury. There was no difference in the graft survivalrate or requirement for inotropic support; however,the ischemic times were rather short in this study(mean 152 min) [55].

Endothelial dysfunction also contributes to reper-fusion injury, as impaired endothelial-dependentvascular relaxation via reduced nitric oxide produc-tion may significantly reduce coronary blood flow.Administration of nitric oxide, its substrate L-arginine,and various nitric oxide donors to the reperfusate hasreduced ischemia-reperfusion injury in animal mod-els [56-59]. However, nitric oxide may have deleteri-ous effects on the ischemic myocardium because of itspropensity to convert to peroxynitrite and causes lipidperoxidation. Using a canine model of orthotopicheart transplantation, Tanoue et al. examined whetheradding the organic nitric oxide donor nitroglycerin(NTG) to UW solution caused deleterious effects oncoronary endothelial and LV function. After 24 hof cold storage in either UW solution alone or UWsolution augmented with NTG (0.1 mg/ml), cardiacfunction was significantly better in the NTG group,but levels of lipid peroxide in the NTG group weresignificantly higher, implying peroxynitrite forma-tion. The overall effect of NTG was cardioprotective,and seems to outweigh any effect of lipid peroxidation[60]. Newer nitric oxide donors also exhibit a protec-tive effect on the myocardium. Rodent hearts pre-served with an extracellular solution augmented withthe nitric oxide donor diethylamine NONOate hadsignificantly better coronary artery flow and cardiacfunction than controls [61]. Another novel nitricoxide donor is FK409. It is the first spontaneous nitricoxide donor that is able to increase plasma guanosine3':5'-cyclic monophosphate [62,63]. Mohara et al.demonstrated that the administration of FK409 dur-ing reperfusion ameliorated ischemia-reperfusioninjury in a canine heart transplant model [64,65].

Post-transplant cardiac function was better in theFK409 group as compared with controls. The FK409group is associated with a lower endothelin-1 level,and better preservation of the capillary basal lamina,glycogen granules, and mitochondrial structures.

Intraoperative administration oftriiodothyronine (T3) during hearttransplantationIt has been shown that patients with heart failure havea decrease in free T3. The low free T3 state has alsobeen observed during and following cardiac opera-tions that require the use of cardiopulmonary bypass[66,67]. Therefore in the immediate post-transplantperiod, heart recipients may have significant T3deficiency. It is recommended that T3 be administeredintraoperatively before reperfusion of the donor heartto prevent relapse of the hemodynamic-metabolicabnormality observed in the donor [68]. Although thebenefits of intraoperative T3-administration are welldocumented in adult and pediatric cardiac surgicalpatients [69,70], there is a paucity of data supportingthe beneficial effects of intraoperative T3 in hearttransplantation. In a small randomized study in whichT3 (0.2 [ig/kg bolus, 0.4 (ig/kg infusion over 6 h) wasadministered immediately before donor heart reper-fusion, Jeevanandam et al. reported that recipients inthe T3 groups required less inotropic supports, andhad less coronary lactate production than the placebogroup [71].

Reperfusion pressureThe mechanical aspects of reperfusion have also beenshown to play an important role in myocardial preser-vation. High initial reperfusion pressure (60 mmHg)leads to endothelial damage, possibly due to shearforces inflicted upon vulnerable endothelium [72].Low initial reperfusion pressures followed by gradualincrease have been shown to lead to significant im-provement in mechanical and endothelial functionin lamb hearts [73]. Low pressure retrograde reperfu-sion before unclamping of the aorta may also helpremove debris and air from the coronary circulation[3]. Because of these potential benefits, it is recom-mended that there is a short period (3-5 min) of lowreperfusion (preferably via the coronary sinus) withsubstrate-enhanced, leukocyte-depleted blood reper-fusate before unclamping the aorta [3].

298 CHAPTER 31

Summary

For the sake of simplicity myocardial preservation for

heart transplantation can be divided into four stages:

preharvest donor management, cadioplegic arrest,

storage, and reperfusion.

In the donor management stage, in addition to cor-

rection of fluid and electrolytes, hormonal replace-

ment (with steroids, insulin, T3, and catecholamines)

and invasive hemodynamic monitoring have been

shown to improve myocardial function, resulting in

successful usage of a high percentage (85%) of donors

who were initially considered unacceptable.

A variety of cardioplegia solutions have been used

to arrest the heart during the cardioplegic arrest

stage with similar efficacy. This is, in part, due to the

relatively short ischemic interval. However, current

data indicate a detrimental effect of high cardioplegic

delivery pressure. A delivery pressure of 80 mmHg

seems to be optimal. In the storage stage, although

continuous coronary perfusion with oxygen carrying

solutions have been shown to be superior to static

hypothermic storage, it has not been adopted widely

in clinical heart transplantation because of the com-

plexity of the equipment required. Simpler devices

developed in recent years, along with the ever-

increasing need to maximize the use of donors, have

prompted a renewed research interest in this area.

In the reperfusion stage, in addition to the use of

substrate-enhanced reperfusate, low initial reperfusion

pressure with leukocyte-depleted blood and intraop-

erative administration of T3 before reperfusion of the

transplanted heart have been shown to be beneficial. It

must be emphasized that not every cardiac recipient or

donor requires all the treatments outlined. However,

these treatments may help reduce the incidence of

primary graft failure, especially in marginal donors.

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43 Wicomb WN, Hill JD, Avery J et al Optimal cardioplegiaand 24-hour heart storage with simplified UW solutioncontaining polyethylene glycol. Transplantation 1990;49:261-4.

44 Menasche P, Grousset C, Gauduel Y et al. A comparat-ive study of free radical scavengers in cardioplegic solu-tions. Improved protection with peroxidase. / ThoracCardiovasc Surg 1986; 92:264-71.

45 Moreyra AE, Conway RS, Wilson AC et al Attenuationof myocardial stunning in isolated rat hearts by a 21-aminosteroid lazaroid (U74389G). J Cardiovasc Pharmacol1996; 28:659-64.

46 Ishizaki N, Zhu Y, Zhang S et al. Comparison of variouslazaroid compounds for protection against ischemic liverinjury. Transplant Proc 1997; 29:1333-4.

47 Nishida T, Morita S, Miyamoto K et al. Lazaroid(U74500A) prevents vascular and myocardial dysfunc-tion after 24-hour heart preservation. A study based oncross-circulated blood-perfused rabbit hearts. Circula-tion 1996; 94:11326-31.

48 Tanoue Y, Morita S, Ochiai Y et al Successful twenty-four-hour canine lung preservation with lazaroidU74500A.J Heart Lung Transplant 1996; 15:43-50.

49 Sasaki S, Alessandrini F, Lodi R et al. Improvement ofpulmonary graft after storage for twenty-four hours by invivo administration of lazaroid U74389G: functional andmorphologic analysis. / Heart Lung Transplant 1996; 15:35-42.

50 Takahashi T, Takeyoshi I, Hasegawa Y et al Cardio-protective effects of lazaroid U-74389G on ischemia-reperfusion injury in canine hearts. / Heart LungTransplant 1999; 18:285-91.

51 Boiling KS, Halldorsson A, Allen BS et al Prevention ofthe hypoxic reoxygenation injury with the use of a leuko-cyte-depleting filter. 7 Thorac Cardiovasc Surg 1997; 113:1081-9; discussion 1089-90.

300 CHAPTER 31

52 Okazaki Y, Cao ZL, Ohtsubo S et al. Leukocyte-depletedreperfusion after long cardioplegic arrest attenuatesischemia-reperfusion injury of the coronary endotheliumand myocardium in rabbit hearts. Eur] Cardiothorac Surg2000; 18:90-7.

53 Yamamoto H, Moriyama Y, Hisatomi K et al. A leukocytedepleting filter reduces endothelial cell dysfunction andimproves transplanted canine heart function. / HeartLung Transplant 2001; 20:670-8.

54 Hachida M, Hanayama N, Okamura T et al. The role ofleukocyte depletion in reducing injury to myocardiumand lung during cardiopulmonary bypass. ASAIOJ1995;41:M291-4.

55 Pearl JM, Drinkwater DC, Laks H et al. Leukocyte-depleted reperfusion of transplanted human hearts: arandomized, double-blind clinical trial. / Heart LungTransplant 1992; 11:1082-92.

56 Pinsky DJ, Oz MC, Koga S et al. Cardiac preservation isenhanced in a heterotopic rat transplant model by sup-plementing the nitric oxide pathway. / Clin Invest 1994;93:2291-7.

57 Szabo G, Bahrle S, Batkai S et al. L-arginine: effect onreperfusion injury after heart transplantation. World JSurg 1998; 22: 791-7.

58 Baxter K, Howden B, Saunder A et al. Improved cardiacpreservation by the addition of nitroglycerine to colloid-free University of Wisconsin solution (MUW). / HeartLung Transplant 1999; 18: 769-74.

59 Baxter K, Howden BO, Jablonski P. Heart preservationwith celsior solution improved by the addition of nitro-glycerine. Transplantation 2001; 71:1380-4.

60 Tanoue Y, Morita S, Ochiai Y et al. Nitroglycerin as anitric oxide donor accelerates lipid peroxidation but pre-serves ventricular function in a canine model of ortho-topic heart transplantation. / Thorac Cardiovasc Surg1999; 118: 547-56.

61 Du ZY, Hicks M, Jansz P et al. The nitric oxide donor,diethylamine NONOate, enhances preservation of thedonor rat heart. / Heart Lung Transplant 1998; 17:1113-20.

62 Hino M, Takase S, Itoh Y et al. Structure and synthesis ofFK409, a novel vasodilator isolated from Streptomyces as asemiartificial fermentation product. Chem Pharm Bull1989; 37:2864-6.

63 Yamada H, Yoneyama F, Satoh K et al. Car-diohemodynamic effect of FK409, a novel highly potentnitrovasodilator, in anesthetized dogs. Eur J Pharmacol1991;205:81-3.

64 Mohara J, Oshima K, Tsutsumi H et al. FK409 enhancespost-transplant cardiac function following 12-hour coldpreservation. Transplant Proc 2000; 32: 2407-8.

65 Mohara }, Oshima K, Tsutsumi H et al. FK409 amelio-rates ischemia-reperfusion injury in heart transplanta-tion following 12-hour cold preservation. / Heart LungTransplant 2000; 19:694-700.

66 Reichert MG, Verzino KG. Triiodothyronine supplemen-tation in patients undergoing cardiopulmonary bypass.Pharmacotherapy2001;2l: 1368-74.

67 Reinhardt W, Mocker V, Jockenhovel F et al. Influence ofcoronary artery bypass surgery on thyroid hormoneparameters. Hormone Res 1997; 47:1-8.

68 Novitzky D. Novel actions of thyroid hormone: the roleof triiodothyronine in cardiac transplantation. Thyroid1996; 6:531-6.

69 Mullis-Jansson SL, Argenziano M, Corwin S et al. Arandomized double-blind study of the effect of tri-iodothyronine on cardiac function and morbidity aftercoronary bypass surgery. / Thorac Cardiovasc Surg 1999;117:1128-34.

70 Bettendorf M, Schmidt KG, Grulich-Henn J et al.Tri-iodothyronine treatment in children after cardiacsurgery: a double-blind, randomised, placebo-controlledstudy. Lancet 2000; 356: 529-34.

71 Jeevanandam V. Triiodothyronine spectrum of use inheart transplantation. Thyroid 1997; 7:139-45.

72 Sawatari K. Myocardial preservation in the immatureheart. In: Castaneda A, Jonas R, Myaer J, Hanley F, eds.Cardiac Surgery of the Neonate and Infant. Philadelphia,PA: WB Saunders 1994:41-53.

73 Sawatari K, Kadoba K, Bergner KA et al. Influence of ini-tial reperfusion pressure after hypothermic cardioplegicischemia on endothelial modulation of coronary tone inneonatal lambs. Impaired coronary vasodilator responseto acetylcholine. / Thorac Cardiovasc Surg 1991; 101:777-82.

74 Muhlbacher F, Langer F, Mittermayer C. Preservationsolutions for transplantation. Transplant Proc 1999; 31:2069-70.

75 Menasche P, Termignon JL, Pradier F et al. Experimentalevaluation of Celsior, a new heart preservation solution.Eur J Cardiothorac Surg 1994; 8:207-13.

76 Bernard M, Caus T, Sciaky M et al. Optimized cardiacgraft preservation: a comparative experimental studyusing P-31 magnetic resonance spectroscopy and bio-chemical analyzes. / Heart Lung Transplant 1999; 18:572-81.

77 Collins GM, Peterson T, Wicomb WN et al. Experimentalobservations on the mode of action of "intracellular"flush solution. ] Surg Res 1984; 36:1-8.

CHAPTER 32

Myocardial protection during leftventricular assist deviceimplantation

Aftab R. Kherani, MD, Mehmet C. Oz, MD, & Yoshifumi Naka,MD, PhD

As success with left ventricular assist device (LVAD)implantation has increased, attention now focusesmore on the subtle techniques required to make theprocedure reproducible with minimal morbidity[1,2]. A major debate over the optimal implantationprocedure concerns the risks and benefits of arrestingthe heart and the subsequent importance of myocar-dial protection. While the left heart should not beneglected, particularly in those patients who are can-didates for bridge to recovery, the focus of protectionshould be on the right ventricle.

Left ventricular assist deviceimplantation

It is important to note that a complete cross-clamp isnot routinely applied during LVAD implantation. Inthese cases, myocardial protection is not an issue asthe heart is not arrested. Typically, a coring knife isused to create the apical defect once the patient is onbypass. A Teflon graft is secured on the apex, and theinflow cannula is inserted through it. Next, a partialoccluding clamp is applied onto the right lateralsurface of the aorta. Then a longitudinal aortotomyis made to fit the diameter of the outflow graft.Following this the anastomosis to the outflow graft isperformed. The device is then activated at a fixed rateof 50 beats per minute while weaning off cardiopul-monary bypass.

To minimize the risk of air embolism to the rightcoronary artery and maximize protection of the right

ventricle, deairing plays an important role. To thisend, several precautions are taken [3]. First, the LVADis filled with blood by giving volume to the patientwhen the outflow is connected, using the device as avent. Second, a 14-g aortic root cannula, on suction, isplaced into the outflow graft to evacuate air. Third, thepatient is placed in exaggerated Trendelenburg posi-tion and kept volume-loaded while the hand pumpis used to deair. Fourth, transesophageal echocardio-graphy is utilized to identify air bubbles, especially inthe aortic root, and the outflow graft is sometimespartially clamped distal to the root vent to trap airbubbles. Fifth, when actuating the device, the root ventis kept on suction to further evacuate air until weaningoff cardiopulmonary bypass. Finally, the entire surgi-cal field, especially the inflow, is kept under fluid whenweaning off cardiopulmonary bypass, thereby mini-mizing the chance that air enters the device.

Slowly weaning off bypass and careful deairingare critical to minimizing the extent of right ven-tricular damage that may occur during implantation.Preservation of right ventricular function is a majorpriority during this procedure. To this end, someadvocate cannulation of the left atrial appendage tocreate a right to left side oxygenated shunt. Once onbypass, the cannula is then connected to the cardiople-gia system, in line with the oxygenator reservoir. Thisarrangement can deliver up to 2 L of oxygenated bloodper minute to the left atrium [4]. Our concern withthis method centers on the risk of air embolus thatmay arise during left atrial cannulation.

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Our specific technique to maximize right heart pro-tection involves deairing using the hand pump. Evenwith meticulous deairing small air bubbles may arise.They can embolize to the right coronary artery, caus-ing right ventricular dysfunction. This can lead to avicious cycle, as right-sided dysfunction will result indecreased left-sided filling, predisposing to increasedair being sucked into the system, leading to furtherembolization. After sufficient deairing, we decreasecardiopulmonary bypass flow to 2 L/min while givingthe patient volume. Next, we initiate the LVAD.During this time, we maintain bypass flow at 2 L/minfor a few minutes to support the right ventricle as wellas maintaining systemic blood pressure for the elimi-nation of air bubbles in the right coronary artery. Wethen gradually wean the patient off cardiopulmonarybypass as we confirm stable right ventricular function.During these periods, the LVAD is switched to automode as LVAD flow reaches 4 L/min. For this pro-cedure, we liberally give volume to achieve our targetcentral venous pressure of 15 mmHg. To maintaina reasonable mean arterial pressure as well as maximalright ventricular support, we routinely use milrin-one (Sanofi-Synthelabo, Malvern, PA), dobutamine(Eli Lilly, Indianapolis, IN), arginine vasopressin(Novartis, East Hanover, NJ), norepinephrine (AbbottLaboratories, Abbott Park, IL), and nitric oxide(Cayman Chemical, Ann Arbor, MI).

How and when to arrestThe procedure described above delineates a typicalLVAD implantation that avoids arresting of theheart. In situations where complete cross-clampingand arrest are necessary during device implantation,it is the practice at our institution to give one dose ofcardioplegia antegrade followed by creation of theoutflow anastomosis and subsequent release of theclamp on the aorta. We use high-dose cardioplegiacontaining 126 mEq/L potassium chloride, 15 mEq/Lsodium bicarbonate with 5% dextrose and 20% man-nitol added, which is mixed one to four with blood.The heart may then be perfused and warmed duringthe inflow procedure. Rewarming allows the heart torecover from the arrest. In cases where arrest is indi-cated, the tenants surrounding deairing and rightventricular protection also apply.

There are mainly three circumstances in whicharresting the heart is necessary. The first is in the pres-

Figure 32.1 Aortic valve repair with creation of a bicuspidvalve. Reprinted from Annals of Thoracic Surgery, Vol. 71,Rao Vet a/. Surgical management of valvular disease inpatients requiring left ventricular assist device support,pp. 1448-1453. © 2001, with permission from Society ofThoracic Surgeons.

ence of aortic valvular pathology, which previouslywas a contraindication to LVAD placement. In casesof aortic insufficiency, cardioplegia is given antegradeuntil the heart fibrillates. The aortotomy made for theoutflow anastomosis is extended longitudinally, andadditional cardioplegia is given directly down thecoronary ostia. The valve is then repaired by creating abicuspid orifice (Figure 32.1).

Alternatively, the three cusps of the native valvemay simply be oversewn. If the LVAD recipient has amechanical aortic valve, a Dacron patch is sewn to theaortic aspect of the valve (Figure 32.2), preventingleaflet motion and thereby limiting thrombus migra-tion formed on the ventricular aspect of the outflowtract [5]. In these patients, high-dose cardioplegia isalso given antegrade (1000 cm3) prior to creation ofthe aortotomy.

The second situation in which arrest of the heartis necessary during LVAD implantation is whenthere is not enough space on the ascending aorta to

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LVAD implantation 303

Figure 32.2 Prevention of thromboembolism by Dacrongraft closure of mechanical aortic valve prosthesis.Reprinted from Annals of Thoracic Surgery, Vol. 71,Rao Vet a/. Surgical management of valvular disease inpatients requiring left ventricular assist device support,pp. 1448-1453. © 2001, with permission from Society ofThoracic Surgeons.

accommodate a partial occluding clamp. This can betrue in patients where the ascending aorta is simplytoo small to accommodate a partial occluding clampor when the ascending aorta is cluttered with several

grafts from previous coronary artery bypass surgerythat precludes the placement of such a clamp. In thesecases, 1000 cm3 of high-dose cardioplegia is givenantegrade. In patients who previously have undergonecoronary artery bypass grafting, great care should betaken to preserve the graft to the right coronary artery.If it does not have a graft but has a significant lesion,then it should be bypassed at this time.

The third situation requiring attention to myocar-dial protection is when coronary artery bypass graftingis required during LVAD implantation. This occursin the setting of acute myocardial infarction and car-diogenic shock even with intra-aortic balloon pumpsupport. These patients experience extremely highmortality with conventional medical and/or surgicaltherapy [6]; we believe that they can benefit from LVADimplantation. As discussed in the previous paragraph,

the right coronary artery should be bypassed if it hasa significant lesion. In addition, we graft at least onemajor left coronary artery to avoid postoperativeangina and infarction which can lead to ventriculartachyarrhythmia. Proximal anastomoses can be per-formed on the ascending aorta, leaving enough roomfor placement of a partial occluding clamp and cre-ation of the LVAD outflow anastomosis. Coronaryartery bypass grafting can be completed with a singledose of antegrade cardioplegia. Then the aortic clampmay be released, resuming coronary circulation.During the period of rewarming and reperfusion,the remainder of the implantation procedure can beperformed.

LVADs have established a well-defined niche in themanagement of heart failure. Today, devices are foundin patients who were not previously candidates forimplantation. With some of these patients, the heartmust be arrested during implantation. In these situa-

tions myocardial protection becomes an issue, espe-cially for the right heart. Various modifications existbut in our experience, a single dose of antegradecardioplegia is sufficient. By stressing the importanceof myocardial protection during LVAD implantation,a broader spectrum of patients is now eligible forthe device.

References1 Sun BC, Catanese KA, Spanier TB et al. 100 long-term

implantable left ventricular assist devices: the ColumbiaPresbyterian interim experience. Ann Thorac Surg 1997;68:688-94.

2 Goldstein DJ. Intracorporeal support: Thermo Cardio-systems ventricular assist devices. In: Goldstein DJ, OzMC, eds. Cardiac Assist Devices. Armonk, NY: Futura,2000:307-21.

3 Oz MC, Goldstein DJ, Rose EA. Preperitoneal placementof ventricular assist devices: an illustrated stepwiseapproach./ Card Surg 1995; 10:288-94.

4 Van Meter CH, Robbins RJ, Ochsner JL. Technique ofright heart protection and deairing during Heartmatevented electric LVAD implantation. Ann Thorac Surg1997;63:1191-2.

5 Rao V, Slater JP, Edwards NM et al. Surgical managementof valvular disease in patients requiring left ventriculardevice support. Ann Thorac Surg 2001; 71:1448-53.

6 Hochman JS, Sleeper LA, White HD et al. One-yearsurvival following early revascularization for cardiogenicshock. JAMA 2001; 285:190-2.

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CHAPTER 33

Gene therapy for myocardialprotection

Said F. Yassin, MD d* Christopher G. McGregor, MD

Introduction

Therapeutic gene therapy is likely to dramatically altermedical practice in the coming decades [1]. Multipleclinical applications are possible, as great progress hasbeen made in genomics and molecular medicine.Based on our current knowledge about human genesand cellular communication mechanisms, combinedwith current and developing abilities to deliver genes,and the development of mechanisms to control sub-sequent gene expression by promoters, the potentialof genetic engineering seems to have no limits. Theoptimization of vectors and delivery systems, as well asmethods of monitoring gene expression, are requiredto achieve these ends.

In cardiac surgery, gene therapy has the potential todeliver prolonged focused localized therapy to theheart without generalized systemic side effects. This ispotentially beneficial in heart transplantation wheregene therapy to the heart prior to implantation intothe recipient could produce organ-specific immuno-suppression and eliminate the need for systemicimmunosuppression. Another potential applicationfor gene therapy is protection and resuscitation ofthe myocardium during routine cardiac surgery andafter coronary ischemic events. Ischemia-reperfusioninjury is the major pathophysiological phenomenonin these circumstances where reoxygenation of theischemic myocardium results in the formation ofreactive oxygen species, leading to activation of theinflammatory cascade, myocyte injury, and endothe-lial dysfunction. The accumulation of oxygen freeradicals during reperfusion may eventually depletethe buffering capabilities of endogenous antioxidant

systems, leading to impairment of contractile functionresulting in circulatory failure. Gene therapy could beapplied to limit such free radical-induced myocardialinjury.

Gene delivery

Direct injection into the myocardial siteThis is effective and was one of the first methodsused for gene delivery. It has been proven that highlevels of protein expression can be achieved by thismethod as far as 1.5 cm from the site of vectoradministration, and this expression was shown tolast for at least 14 days after the myocardial injectionof adenovirus vectors without significant transfixionof a distant organ or compromising cardiac function[2].

Perf usion of the vector through thecoronary circulationThis can be performed percutaneously with afluoroscopically guided catheter [3], or directly dur-ing open-heart or in-heart transplant surgery. Ahighly efficient gene transfer method was describedusing hypothermic coronary circulation of the aden-oviral vector by means of a peristaltic pump for 5 min[4,5].

Direct exposure of the treated organ tothe virusThis method was shown to be successful for trans-fection of saphenous vein grafts with endothelial nitricoxide synthase carried on adenoviral vector beforebypass surgery to prevent graft atherosclerosis [6].

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Gene therapy for myocardial protection 305

Indirect transducing cells in vitro thatare subsequently implanted intospecific sites in vivo [7]Attempts to inject myocytes from Myo-D-

transformed fibroblasts into infarcts to repopulatethe areas of damaged myocardium are underway.Other examples are transplanting neonatal myocytesto repopulate infarcts [8], and repopulation of thedenuded endothelium with engineered endothelialor smooth muscle cells.

Systemic intravenous injection ofviral vector with a myocardial-specif icpromoter (like myosin light chainpromoter) to drive the transgeneto express mRNA specifically in theheart [9]Systemic intravenous injection of recombinant aden-ovirus which is extremely efficient and selective to theliver was studied for transferring superoxide dismu-tase gene, and resulted in expression of superoxidedismutase protein in the liver; the protein was secretedfrom hepatocytes with relatively modest plasma levelactivities. However, truly supraphysiological plasmalevels (up to 100-fold over baseline) were obtained bydisplacing the recombinant enzyme from its heparansulfate proteoglycan binding sites by dextran sulfate

or heparin [10]. In theory, recombinant techniquescould be used to add the secretory and heparin-binding domain of extracellular superoxide dismutaseto any therapeutic protein. Liver-directed gene trans-fer would then lead to modest resting plasma levelsthat could be rapidly increased when needed withsimple intravenous injection of dextran or heparin.This method also alleviates concerns regarding thepossibility of myocardial inflammation and its poten-tial impact on myocardial stunning and precondition-ing. This observation provides the basis for a methodto control gene therapy at the post-translation leveland for simultaneous protection of multiple organsfrom ischemia-reperfusion injury.

Vectors

LiposomesLiposomes were one of the first vectors to be used—they can transfect nondividing cells like myocytes,the transfection is fast which makes them practical for

intraoperative use without requiring modifications ofthe current techniques, and they do not incite a hostimmune response which allows retreatment. In com-parison to viral vectors, liposomes have the advantageof freedom from infectious risk or wild-type recombi-nation. The feasibility of liposome transfection hasbeen shown with equivalent gene expression in alldistributions in the heart (the vast majority of thecoronary arteries cells and the coronary sinus cells),and demonstrated at least 7 days after transfection[5,11-13].

Viral vectorsHemagglutinating virus of Japan inactivated by ultra-violet irradiation and combined with active DNAliposome has been transferred to the nuclei of theendothelial cells and myocytes in all layers of themyocardium, by means of in vivo coronary infusion ofthe virus during cardioplegic arrest. The nontoxicityand lack of antigenicity of this virus has been proven

[14].Adenovirus vectors are recombinant vectors in

which the gene of interest is inserted into the viralchromosome and one or more genes are removed toprevent viral reproduction. Although pathology dueto replication is eliminated, the majority of viral genesremain, resulting in expression of viral proteins in

the target cells. Adenoviral vectors have been used forgene transfer by direct intramuscular injection andvia intracoronary infusion in both small and largemammals [15-17]. Gene transfection by adenovirusis excellent even in nondividing cells; however, inthese studies gene expression was often transient andaccompanied by cell-mediated immune response andcell toxicity, a significant disadvantage for myocardialprotection [18].

This has led to the development of an improvedvector, the adeno-associated virus vectors, a defectiveDNA virus that in nature requires coinfection withadenovirus for efficient replication and spread. Defect-ive viral vectors contain no viral genes but permitpackaging of foreign gene into a viral coat. This allowsefficient transfer of genes without toxic or immuno-logic side effects due to the viral genes' expression [3].

In a recent study Phillips et al. demonstrated that aheart-specific promoter MLC-2v incorporated intoadeno-associated virus vector can drive a therapeutic(angiotensin type 1 receptor antisense) and reporter

306 CHAPTER 33

gene (green fluorescence protein) specifically in theheart after systemic injection. DNA measurementshowed that the vector was taken up into multipletissues; the transgene protein mRNA, however, wasonly expressed in heart tissue. To switch on the virustransgene during ischemia they inserted a hypoxiaresponse element, which upregulates transcriptionwhen oxygen levels are low. By adding additionalhypoxia inducible factors and using double plasmid,400-fold gene amplification in 1% O2 could beachieved. This construct was suggested as a prototype"vigilant vector" to switch on therapeutic genes inspecific tissue with physiological signals [9]. Severalother on-off switches have been developed, includingtetracycline-controlled transcription [19], and viralvectors with expression cassettes containing cortico-steroid-response promoters [20], which might allowthe physician in the future to regulate the onset andthe duration of gene products' expression in previ-ously transfected genes.

Retroviral vectors can integrate the gene of interestinto the genome of the target cell and provide longgene expression; transfection in these cases, however,is efficient only in actively dividing cells. Also the incid-ence of T-cell lymphoma as a result of contaminationwith a wild-type retrovirus has been reported in mon-keys transfected with retrovirus [21,22].

Many other viruses including disabled pathogenssuch as herpes viruses are being studied as potentialgene delivery vectors [23]. As these vectors are pro-gressively developed in the future, they give hopethat therapeutic genes could be delivered safely andefficiently to cardiac cells. Similarly, if highly efficientliposome preparations suitable for use in man weredeveloped, this would be an equally valid therapeuticapproach.

Therapeutic genes

Multiple preventive and therapeutic strategies havebeen trialled experimentally. An approach aimed atpotentiating endogenous antioxidant reserves couldbe used as a preventive measure against myocardialinjury induced by ischemia-reperfusion.

Heat shock proteinsHeat shock proteins are a family of intracellularproteins which are observed in all organisms studied,from prokaryotic bacteria to mammals including man.

These proteins are synthesized by normal unstressedcells, with a number of them acting as molecularchaperones (ensuring correct protein folding of otherproteins within the cell) and others playing a role inprotein degradation [24]. Although initially identifiedon the basis of their induction by elevation in temper-ature, these proteins are in fact induced by a widerange of stressful stimuli including a variety of viralinfections, ethanol, steroids, heavy metals, anoxia,ischemia, and free radical generators. This associationsuggests that heat shock proteins have a critical func-tion in the cell's response to stress and in assisting thecell to protect itself from such stress. Heat shockprotein 70 (each heat shock protein is named accord-ing to its mass in kilodaltons) is induced in dogs'hearts exposed to ischemia, pressure or volume over-load, and drugs such as vasopressin, angiotensin, orisoproterenol [25-27]. Moreover, heat shock proteins'expression is elevated in human hearts of patients withunstable angina and dilated cardiomyopathy [27,28].Several studies demonstrate that heat shock proteinshave protective effects on the myocardial cells withdecreased reperfusion injury measured by creatinekinase release, improved recovery of contractile func-tion, and reduction in infarct size following ischemiain hearts exposed to these proteins compared to con-trols, an effect that was shown to correlate with theamount of the heat shock protein induced [27-31].Subsequent studies reported the generation of trans-genie mice which overexpressed heat shock protein 70in the heart and demonstrated that such overexpres-sion was able to protect the heart against the damag-ing effects of ischemia [32]. Heat shock protein 32(hemeoxygenase-1) is one of three identified iso-forms, products of three distinct genes. They are therate-limiting enzymes in the degradation of heme tobilirubin, carbon monoxide, and iron. These catalyticproducts exert wide-ranging antioxidant and cyto-protective effects [33,34]. Furthermore, hearts fromhemeoxygenase-1 knockout mice show enhancedinfarct formation following hypoxia [35]; converselycardiac-specific overexpression of hemeoxygenase-1leads to attenuated myocardial injury after ischemicperfusion injury in transgenic mice [36], and induc-tion of the enzyme by exogenous heme before anischemic episode markedly reduces infarct size [37].

The mechanisms mediating the protective effectsof heat shock proteins are molecular chaperoning,attenuation of cardiac cells' apoptosis, protection of


the integrity of the microtubules and the actin cyto-skeleton of the myocardial and endothelial cells,and enhancing the production and stimulating theactivity of endothelial nitric oxide synthase (eNOS)[38-40].

It has been shown that heat shock protein 70 genewithin plasmid vector can be delivered to the heartwithin a plasmid, or viral vector, via intracoronaryperfusion, conferring effective protection againstsubsequent ischemia-reperfusion injuries [38,41].Adenoviral-mediated gene delivery of humanhemeoxygenase-1 gene to rat hearts has also beenshown to prolong transgene expression and, con-sequently, exert long-term myocardial protectiondemonstrated by dramatic reduction in infarct sizeafter ischemia [42].

Antioxidant enzymesConsiderable experimental evidence suggests thatreactive oxygen species, such as superoxide anion O2

and hydrogen peroxide H2O2, are generated duringreperfusion of the ischemic myocardium and play animportant role in the initiation of the myocardialischemia-reperfusion injury resulting in myocardialstunning and subsequently myocardial infarction.Under normal conditions the myocardium is equippedwith enzyme systems that efficiently metabolize thesereactive species. However, when subjected to ischemiaand reperfusion, there is excessive production of freeradicals that may overwhelm the antioxidant defensemechanism, combined with depletion of these enzymesduring ischemia, which also prevents the cellularreconstitution of these systems [43].

The vast majority of animal studies examining therole of antioxidant enzymes in protecting the myo-cardium from ischemia-reperfusion injury have usedsuperoxide dismutase, either alone or in combinationwith other antioxidants or antioxidant enzymes.

Superoxide dismutase provides antioxidant pro-tection by inactivating O2, sparing nitric oxide fromdestruction, and preventing O2 from forming moredestructive reactive oxygen species, such as peroxyni-trite and its reaction products, including hydroxylradical (OH).

Careful examination of the distribution kineticsof superoxide dismutase indicate that the interstitiallevels rather than the plasma levels of this enzyme areprimarily responsible for protection against ischemia-reperfusion injury [44].

Extracellular superoxide dismutase type C is asecretory isoenzyme that binds to heparan sulfateproteoglycans on cellular surfaces and has, in contrastto the intracellular isoenzyme, natural affinity for theendothelium and interstitial space and a long vascularhalf life, which provides more consistent cardiopro-tection than freely soluble isoforms. Gene therapywith extracellular superoxide dismutase gene as singleantioxidant enzyme is an efficient and consistentmyocardial protection method and was proven todecrease infarct size and regional myocardial dysfunc-tion after ischemic injury in mice, conscious rabbits,and pigs [10,45-47].

Catalase is another antioxidant enzyme that hasbeen studied widely for its potential cardioprotectiveeffects by converting hydrogen peroxide (H2O2, areactive oxygen) to water and oxygen and preventingthe formation of highly reactive hydroxyl radical(OH). Detoxification of hydrogen peroxide in themyocardium is mainly accomplished by the glu-tathione peroxidase enzyme system, which is depletedduring myocardial ischemia and reperfusion. There-fore, the capacity for hydrogen peroxide degradationis greatly diminished in the heart following ischemia.Although catalase levels in the myocardium are low,it is the major antioxidant enzyme in other tissues.Studies have shown that it participates to a significantextent in detoxification of hydrogen peroxide duringperiods of ischemia. Initial attempts have been madeto increase antioxidant supplies by administrationintravenously or by addition to the pump perfusateduring cardiopulmonary bypass. Exogenous antioxid-ant enzyme administration, however, is limited bythe ability of the myocytes to internalize these largemolecules [48].

Gene transfection of catalase DNA into themyocardium via adenovirus vector can achieve highlevels of catalase expression and significantly increasecatalase activity in the myocardium. This was shownto result in the preservation of the contractile functionin rabbit heart during reperfusion after ischemicinjury [49].

Nitric oxide synthaseOverexpressing nitric oxide synthase with a singleintraoperative dose of liposomes was shown to inhibitnuclear factor-KB (NF-KB), a proinflammatory tran-scriptional activation factor for E-selectin and vascu-lar cell adhesion molecule 1, resulting in inhibition of

308 CHAPTER 33

leukocyte infiltration and ischemia-reperfusion injury[11]. Adenoviral transfection of inducible nitric oxidesynthase has been effective in inhibiting aortic allograftarteriopathy [50], whereas endothelial nitric oxidesynthase has been used to inhibit neointimal forma-tion in balloon injury models [51 ].

Immunosuppressive cytokines andadhesion moleculesThe activation of NF-KB was implicated in cellulardamage after ischemia. NF-KB is a crucial transcrip-tional activator of many genes whose expression isrelated to ischemia-reperfusion injury, such as tumornecrosis factor a, interleukin 10, and intracellularadhesion molecule 1 [52]. In vivo transfection of asynthetic double-stranded deoxynucleotide with high-affinity to NF-KB "decoy oligodeoxynucleotides"results in binding of the transcriptional factor andblocking the activation of genes mediating myocardialinjury. This effect was shown to provide effective ther-apy for myocardial injury when given before induc-tion of ischemia or immediately after reperfusion, ashearts of treated rats had significant reduction of neu-trophil adherence to endothelial cells, tissue levels ofinterleukin 8 resulting in significantly higher postis-chemic coronary flow, a higher percentage of leftventricular functional recovery, and reduction in theextent of myocardial infarction [53,54].

The NF-KB decoy was also shown to have the sameprotective effect on the brain during circulatory arrest,with evidence of attenuating neuronal damage afterglobal brain ischemia by using in vivo transfection ofdecoy, which was successfully introduced into thenuclei of the neurons by infusing the carrying vector(hemagglutinating virus of Japan-liposome complex)through the carotid artery and across the blood-brain barrier. This might have a potential for wideclinical applications, such as retrograde perfusion ofcerebroplegia [55].

Apoptosis regulatorsApoptosis, the predominant mode of cardiac celldeath, is positively and negatively regulated by the Bcl-2 family of proteins. Proapoptotic proteins includeBax, Bak, Bcl-XS, Bad, Bid, Bik, Bim, Hrk, and Bok,whereas antiapoptotic proteins include Bcl-2, Bel-XL,Bcl-w, Mcl-1, and Al/Bfl-1. Bcl-2 is a 26-kDa proteinlocalized to the cytoplasmic face of the mitochondrialouter membrane, endoplasmic reticulum, and nuclear

envelope. Bcl-2 has been shown to prevent cyto-chrome c release, caspase activation, and cell death.Regulation of apoptosis is highly dependent on theratio of antiapoptotic to proapoptotic proteins. Bcl-2is capable of preventing p53-induced programmedcell death of neonatal ventricular myocytes. The Hcl-2protein plays an antiapoptotic role by inhibiting theformation of the mitochondrial permeability transi-tion pores, which promote contact between the innerand the outer membranes of the mitochondria andplay a critical role in apoptosis. It was also suggestedthat Bcl-2 might have a role in maintaining calciumhomeostasis and stable mitochondrial membranepotential to offset pathologic insult. Although theexact mechanism is not clear yet, overexpression ofBcl-2 in the hearts of transgenic mice resulted insignificantly improved myocardial protection andfunctional recovery after ischemia-reperfusion injuryinduced by ligation of the coronary artery; this wasdemonstrated by a threefold decrease in lactate dehy-drogenase released, a decrease in the infarct sizes, andleft ventricular developed pressure [56].

The Akt is a proto-oncogene, a serine/threonineprotein kinase, with antiapoptotic activity resultingfrom its ability to inactivate proapoptotic molecules,including Bad and caspase 9, and to activate potentialprosurvival molecules, such as IKKa. Rat heartstransfected with the Akt gene were shown to havesignificantly smaller infarct areas following ischemia-reperfusion injury [57].

As further progress is made in understanding thepathophysiology of ischemia-reperfusion heart injuryand in developing methods for safe and efficient genedelivery to the heart, we are heading toward develop-ing an effective gene therapy for myocardial protec-tion. Such a therapy would incorporate genetic targetsfor preventing myocardial injury and restoring theinjured myocardium. The development of tissue-specific and regulatable transgene expression, suchthat the therapeutic enzyme would be produced onlywhere and when needed, will avert potential cytotoxiceffects associated with constitutive expression of thetherapeutic enzyme.

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CHAPTER 34

Aortic and mitral valve surgeryon the beating heart

Marco Ricci, MD, Pierluca Lombardi, MD, Michael O. Sigler, MD,Giuseppe D'Ancona, MD, & TomasA. Salerno, MD

Introduction

Coronary artery bypass grafting (CABG) on the beat-ing heart has been recently revived as an alternativeto conventional myocardial revascularization per-formed on cardiopulmonary bypass (CPB) and on thearrested heart [1,2]. Despite its increasing popul-arity many surgeons, at least initially, accepted thistechnique with substantial skepticism [3,4]. Amongothers, their contrary view to beating heart CABG wasdue to the fact that they felt that a motionless andbloodless field was an indispensable component ofcoronary artery surgery. Furthermore, as a result ofthe progressive improvement in perioperative andlong-term results of conventional CABG on thearrested heart [5], many surgeons remained reluctantto embrace a new procedure of unproven efficacy [3].As technical advances have been made in the field ofbeating heart coronary revascularization, and as theexperience with beating heart CABG has accumulated,there has been increasing evidence to suggest that CPBand cardioplegic arrest are not, in reality, indispens-able adjuncts to coronary operations [ 1,2 ].

Similarly, the surgical strategies used by the vastmajority of surgeons in aortic and mitral valve opera-tions have invariably encompassed the use of somesort of cardioplegic arrest, with only a few recentsporadic exceptions [6,7]. As techniques in cardiacsurgery have evolved during the last two or threedecades, much attention has focused on experimenta-tion with new strategies of cardioplegic arrest [8], andon the introduction of new techniques of minimallyinvasive valvular operations on the arrested heart

[9,10]. The introduction and popularization of cardio-plegic solutions have replaced the original methods ofmyocardial protection initially proposed and utilizedduring the early days of cardiac surgery, in which theheart was arrested by a combination of ischemia andhypothermia [11]. As this technique was found toprovide only limited and suboptimal protection of themyocardium during the interruption of coronary bloodflow, in recent years a multitude of new strategiesof myocardial protection have been introduced andinvestigated, both clinically and experimentally [8].

While the common denominator for these tech-niques has remained the induction and maintenanceof cardioplegic arrest, much of the debate has focusedon many other variables such as composition ofthe cardioplegia perfusate (i.e. blood vs. crystalloid),concentration of the constituents, route of delivery(antegrade vs. retrograde), and temperature of theperfusate (i.e. warm vs. cold) [ 12].

Data from the literature have shown that many ofthese techniques have stood the test of time, and thatthey have proved to provide safe and effective myocar-dial protection in many diverse cardiac operations.In certain patients, however, the enhancement ofmyocardial protection and maximal preservation ofventricular function remains a challenge. In fact, inthe presence of severely compromised left ventricular(LV) function preoperatively, exposure of the alreadycompromised myocardium to any additional ischemicinsult could lead to severe postoperative ventriculardysfunction [ 13]. This may be of particular significancewhen prolonged periods of aortic cross-clamping areanticipated (i.e. simultaneous aortic and mitral valve

311

312 CHAPTER 34

surgery, valve surgery, and CABG, etc.). In this per-spective, the cardioprotective strategy behind beatingheart valve operations, which is described in thischapter, was designed to enhance myocardial protec-tion and promote myocardial recovery, especially inpatients at risk of developing postoperative myocar-dial dysfunction.

Rationale for avoiding cardioplegicarrest in aortic and mitral valveoperations

A large body of clinical and experimental evidence hasshown that myocardial ischemic injury during cardiacoperations may be effectively prevented by substanti-ally reducing the myocardial oxygen demand duringthe interruption of coronary blood flow [ 14]. Althoughwith many variants, this has been traditionally accom-plished by the vast majority of surgeons by a combina-tion of electromechanical arrest, hypothermia, andavoidance of cardiac distension (or reduction in walltension) [12], which are used in concert in an attemptto minimize the imbalance between myocardial oxy-gen supply and demand. As many of the strategies cur-rently used by contemporary surgeons in various valveoperations are extensively described in the literature,and are also addressed in other chapters in this book, athorough description of their rationale, biochemicalbackground, and clinical applications will not be givenin this chapter.

The elimination of the electrical and mechanicalmyocardial activity accomplished by using many ofthe techniques currently available has been shown toconsistently reduce myocardial oxygen demand andconsumption during aortic cross-clamping. However,myocardial ischemic injury may be less effectivelyprevented during cardiac procedures requiring, forexample, prolonged periods of aortic cross-clamping.In these situations, such as those in which both mitraland aortic valve replacement are undertaken con-comitantly, prolonged myocardial ischemia mayresult in profound metabolic derangement, and ulti-mately ischemic injury, irrespective of the strategy ofmyocardial protection used [15]. The susceptibility ofthe myocardium to ischemic injury may be enhancedby the presence of coexisting adverse variables, such ascoronary artery disease, myocardial hypertrophy, andpoor LV function [12]. In these situations, preserva-tion of adequate coronary perfusion throughout the

procedure, and maintenance of the heart in a beating-empty, normothermic state, should be viewed as anattractive alternative, as it could prevent the deleteri-ous effects of a protracted ischemic time on an alreadycompromised myocardial substrate.

"Beating heart" surgery and"warm heart" surgery

The theoretical and conceptual framework behind thestrategy of performing aortic and mitral valve opera-tions on the beating heart, in many ways, is notentirely new. In fact, the principles supporting thisstrategy further extend those previously described forwarm heart surgery [15—17], in which myocardialprotection was accomplished by inducing electrome-chanical arrest at normothermia, keeping the heartcontinuously perfused with oxygenated and hyper-kalemic blood perfusate throughout the operation [ 16].As originally conceived, this strategy was designed toenhance protection of the myocardium by reducingsubstantially myocardial oxygen demand (electrome-chanical arrest), while maximizing oxygen supply(maintenance of coronary perfusion) [17]. Further-more, the elimination of any supply—demand mismatchwas compounded by the advantages of normothermia[15], and by the avoidance of reperfusion injury [15].In turn, normothermia was largely responsible formaintaining many of the myocardial enzymatic path-ways functioning at a normal, or near-normal, state[ 15], and for optimizing the oxygen dissociation curveand oxygen delivery to the myocardial substrate [15].This innovative approach stood in sharp contrast toother widely adopted methods of myocardial protec-tion of the 1980s and 1990s, which all shared in com-mon the presence of some degree of supply-demandmismatch, of variable duration and severity, as wellas the potential for myocardial anoxia, anaerobicmetabolism, reperfusion injury, and ultimately myo-cardial ischemic injury.

In the strategy proposed and described herein (beat-ing heart surgery), myocardial protection is promotedessentially by maintaining the heart in a beating-empty and continuously perfused state, by usingeither antegrade coronary flow or a combination ofantegrade-retrograde flow. As a result, as in warm heartsurgery, the principles behind beating heart surgerycan be fundamentally simplified to the theoretical andactual elimination of any degree of supply-demand

Beating heart valve surgery 313

mismatch. In warm heart surgery, the amount of oxy-gen supplied to the myocardium was found to exceedthat utilized by the arrested, normothermic heart(approximately 1 cm3/lOO g/min) [14], so that con-tinuous perfusion with oxygenated, normothermic,and hyperkalemic blood perfusate could be advanta-geously reduced, or even interrupted, for short per-iods of time as needed [ 18]. In this regard, studies haveshown that periods of interruption of myocardialperfusion of up to 10 min were associated with fullmyocardial metabolic recovery [18]. By contrast, inbeating heart surgery the heart remains in a normo-thermic, beating-empty state, which is associated withoxygen requirements of approximately 5-6 cm3/100g/min at heart rates of 70-80/min, which are substan-tially greater than those of the arrested normothermicheart (1 cm3/lOO g/min) [14]. Such oxygen require-ments of normothermic, beating-empty hearts mayfurther increase at higher heart rates. Incidentally, forthis specific reason we avoid using the misnomer"beating, non-working" heart, as this term would mis-takenly describe a situation in which the myocardiumis, in fact, contracting and thus working, althoughwithout generating any stroke volume. However, inbeating heart surgery, despite myocardial oxygenconsumption remaining substantial, oxygen supplyapproximates that of normal physiologic conditions,as the heart remains continuously perfused at ratessimilar to those of physiologically perfused hearts. As apostulate, coronary blood flow and oxygen supplymust be preserved without interruption, in order tomeet ongoing demands. Secondly, there is a strict rela-tionship between heart rate and myocardial oxygenconsumption at normothermia. As a result, duringbeating heart operations the heart rate has to be care-fully monitored, and faster rates should be controlledeither pharmacologically or by slightly drifting downthe bypass temperature (34.5-35°C). However, itshould also be noted that oxygen consumption of thebeating-empty, normothermic heart (5-6 cm3/100 g/min) is markedly lower than that of the beating-full, normally working, normothermic heart (8-9 cm3/100 g/min) [14]. This further shifts the ratio supplydemand upward, and further extends the safely withwhich operations on beating-empty, normothermic,and continuously perfused hearts can be conducted.As in warm heart surgery, an important considerationin beating heart surgery is the elimination of anyreperfusion injury, since the heart remains continu-

ously perfused [15]. Furthermore, the beating-emptystate may also prevent the occurrence of myocardialedema, often described after cardioplegic arrest, which,in turn, may have detrimental effects on myocardialcontractility and postoperative ventricular functionbased on these considerations. The aim of this chapteris to describe a variety of alternative techniques forperforming aortic and mitral valve operations, primaryor preoperative, with or without concomitant CABG,which all have in common the strategy of myocardialprotection (beating heart surgery).

Aortic valve operations on thebeating heart

The surgical technique of aortic valve repair orreplacement used by our group does not differ fromthose already described extensively in the literature byothers. As a result, they will not be discussed in thissection, which will focus exclusively on the strategyof myocardial protection. As previously described,this consists of keeping the heart in a beating-emptyand continuously perfused state. Many of the stepsof the operation are essentially similar to those ofconventional operations. Standard cannulation of theascending aorta and right atrium ('two-stage' singlevenous cannula) is performed. The patient is placedon CPB and kept normothermic (35-37°C). A stan-dard catheter with self-inflating balloon is insertedthrough the coronary sinus for retrograde, high-flowperfusion with normothermic, oxygenated blood. Theretrograde catheter is usually secured and stabilized byusing a single 4-0 prolene stitch placed around thecoronary sinus free wall, as previously described byour group [19]. This effectively prevents catheter dis-lodgement and, in our experience, is not associatedwith any notable shortcomings [19]. The retrogradeline is connected to a manifold, to which additionalperfusion catheters (1 or 2) can be attached. Thesewill be used for simultaneous perfusion through thecoronary ostia. Some of the technical details of theoperation are illustrated in Figure 34.1. After properCPB is established, an LV venting catheter is theninserted through the right superior pulmonary vein toboth avoid distension of the left ventricle and improvevisibility in the surgical field. The aorta is then cross-clamped. Retrograde perfusion with normothermic(35-37°C), oxygenated blood is immediately com-menced through the coronary sinus catheter.

314 CHAPTER 34

Figure 34.1 Aortic valve surgery on the beating-emptyheart. For explanation see the text.

Flows of 300-350 cm3/min are normally delivered.An attempt is made at keeping coronary sinus perfu-sion pressures at less than 60-70 mmHg. The aorticroot is immediately opened in the usual fashion and,after clearing the blood from the field, both coronaryostia are inspected. Cannulation of at least one of thecoronary ostia is established (usually the left) by usinga self-inflating balloon catheter. The catheter is con-nected to the manifold along with the CS catheter.Antegrade normothermic oxygenated blood througha single coronary ostia is then delivered simultaneouslywith retrograde perfusion, at a total rate of 350-400 cm3/min. Once simultaneous antegrade/retrogradeperfusion is commenced, the right coronary ostia(usually not cannulated) is inspected to ensure that anadequate amount of effluent is coming back from thecoronary circulation. In our experience, we favor can-nulation of the left coronary ostia to enhance adequateLV perfusion, and also because a perfusion catheterplaced in the left ostia tends to dislodge less frequentlythan one placed in the right ostia. Surgery on the aorticvalve is then performed while the heart is kept normo-thermic and beating-empty. The EGG is monitoredthroughout the procedure. Normal sinus rhythm (NSR)is frequently preserved, and is often indicative of pro-per coronary perfusion. Upon completion, the aortic

root is closed. The antegrade left coronary catheter isretrieved, while the heart is supported for a very shortperiod of time solely on retrograde flow. After deair-ing, the aorta is undamped and retrograde perfusiondiscontinued. A venting catheter is also inserted in theaortic root to completely deair the left chambers.

While this strategy of myocardial protection mayseem cumbersome, especially in regard to poor visual-ization, it presents several distinct advantages. In ourexperience it may be particularly advantageous inpatients with aortic regurgitation and markedly com-promised ventricular function. In fact, after establish-ing CPB, the heart is kept at normothermia andbeating, thus avoiding LV distention. Although visual-ization is somewhat inferior to that obtained on thearrested heart, in our experience it remains certainlyadequate to perform valve surgery. The LV ventingcatheter, as previously described, maintains the leftventricle empty. As a result, much of the blood in thefield arises from the coronary ostia that has not beencannulated for antegrade perfusion (normally theright), and can be easily recovered by the LV vent asit falls by gravity into the left ventricle.

As previously stated, when using this strategyof myocardial protection, the heart is maintainedcontinuously perfused by simultaneous antegrade-retrograde perfusion with normothermic, oxygenatedblood. Some of the principles upon which this strategyis based were recently reported in the literature byTian and Deslauriers [20,21]. In one of their recentexperimental studies [21], these investigators estab-lished whether simultaneous antegrade-retrogradecardioplegia, with the antegrade component deliveredthrough a single coronary artery, could result inadequate perfusion of the entire myocardium in pighearts. The distribution of the cardioplegic perfusatewas assessed both by magnetic resonance (MR) tech-nique and by analysing the quantity and character-istics of the blood recovered from the nonperfusedcoronary artery. In this original study, simultaneousantegrade-retrograde cardioplegia delivered throughthe coronary sinus (CS) and a single coronary arteryresulted in adequate and homogeneous perfusion ofthe entire heart, irrespective of the coronary arteryused [21]. This was in sharp contrast to what wasobserved after isolated perfusion through the CS, orthrough a single coronary artery, as both techniquesfailed to provide adequate and homogeneous perfu-sion of all areas of myocardium, leaving some regions


underperfused or not perfused at all. Of note, the ade-quacy of isolated retrograde delivery of cardioplegicperfusate in reaching all areas of myocardium hasbeen previously questioned, based on both experi-mental and clinical evidence [22,23]. Despite theseimportant findings obtained in the experimental model,and after using cardioplegia as opposed to normother-mic blood, it is conceivable that these data could verywell be extrapolated and applied to the clinical modeldescribed herein. In addition to providing adequatemyocardial perfusion in normal hearts, simultaneousantegrade-retrograde perfusion has been shown toalso enhance perfusion of areas of myocardium sup-plied by occluded coronary arteries [20]. This may beof great relevance, especially in elderly patients under-going valve operations, in whom coexistent coronaryartery disease is not infrequent, although in many ofthese patients we would favor CABG as the first step.As such, the results of this investigation constitutethe conceptual framework upon which our strategy ofmyocardial protection was conceived.

As there is evidence to suggest that isolated perfu-sion through the CS would inadequately support theentire myocardium in a beating-empty heart at nor-mothermia, we do not favor the approach describedby others [6] in which myocardial perfusion is sup-ported solely by the retrograde route. Conversely,while coronary perfusion through both coronary ostiawould adequately support the myocardium at least inthe absence of coronary artery disease, the presence oftwo coronary catheters in the operative field couldmake aortic valve surgery cumbersome and moretime-consuming. As such, the strategy of maintainingmyocardial perfusion through the CS and only onecoronary ostia facilitates surgery, as only one coronarycatheter crosses the operative field, while it promotesadequate perfusion of all areas of myocardium.

In summary, aortic valve operations can be per-formed on the beating heart. Simultaneous retrogradeand antegrade perfusion with normothermic oxy-genated blood through the coronary sinus and a singlecoronary artery provides adequate blood supply of thebeating-empty, non-working heart. Myocardial oxy-gen supply is kept at a normal or near-normal state,while oxygen consumption is reduced to approximately60-70% of that of a normal, beating-full heart (from8 to 9 cm3/100 g/min to 5-6 crrvVlOO g/min) [14].Thus, any supply-demand mismatch is eliminatedthroughout the procedure.

Patients that may particularly benefit from thisapproach are those requiring aortic valve replacementfor aortic insufficiency, those presenting with verypoor ventricular function, and those with renal failurerequiring hemodialysis. Also, patients in whom pro-longed periods of aortic cross-clamping are anticip-ated (double valve replacement, valve grafting, andCABG) could benefit from this approach. In thesepatients, however, the strategy described herein isfurther modified, and it will be described in a follow-ing section in this chapter (see "Concomitant valvesurgery and coronary artery bypass grafting on thebeating heart" below). Patients with renal failure maybenefit a great deal from the beating heart approach, ascardioplegia and the risk of hyperkalemia are avoidedaltogether.

Mitral valve operations on thebeating heartMany of the principles of myocardial protectiondescribed for beating heart aortic valve proceduresapply to mitral valve operations on the beating heart.As in aortic valve surgery, the heart is kept beating-empty at normothermia throughout the procedure.Bicaval cannulation is used and a deairing catheter isplaced into the aortic root and kept on very low suc-tion. When the trans-septal approach is chosen, it isnecessary to use caval tapes, which must be snaredprior to entering the right atrium. In contrast to aorticvalve operations coronary blood supply is providedphysiologically through the aortic root and coronaryostia, as the aorta is not cross-clamped (Figure 34.2).As a result, our approach differs from that previouslydescribed for solely retrograde perfusion through theCS. This contrary view to isolated retrograde perfu-sion is supported by the fact that—as previously men-tioned for aortic valve operations—there is increasingevidence to suggest that this strategy may lead tomaldistribution of the perfusate and malperfusionof the myocardium, with the consequential potentialfor myocardial ischemic injury [22,23]. While avoid-ing aortic cross-clamping and maintaining the heartcontinuously perfused through the aortic root areassociated with several distinct advantages, the con-duct of the operation has been refined to avoid therisk of air embolization. The procedure (Figure 34.2)is routinely commenced by standard aortic cannula-tion, and suction is used throughout the operation.

316 CHAPTER 34

Figure 34.2 Mitral valve replacement on the beating-empyheart. For explanation see the text.

Cardiopulmonary bypass at normothermia (35-37°C)is then established. When the posterior approachthrough the interatrial groove is used to expose themitral valve, the superior vena cava (SVC) andinferior vena cava (IVC) are not encircled with tapes.Therefore blood coming back to the right atriumthrough the CS is drained and returned to the CPBreservoir; thus keeping the right-sided chamber of theatrium opened, a floppy cardiotomy sucker can beinserted into the CS to collect the coronary effluentand improve visibility. The main concerns of beat-ing heart mitral valve surgery without aortic cross-clamping are the avoidance of air embolism, whosesignificance is obvious, and the avoidance of aorticinsufficiency, and which may be induced by the retrac-tor used to expose the mitral valve. The avoidance ofair embolism obviously represents a major concern,and to prevent this dreadful complication the operat-ive strategy must be discussed in detail beforehandwith both the anesthesiologist and the perfusiontechnician. In addition, several principles must befollowed: (i) the patient is placed and maintained inTrendelenburg position for the entire duration of theoperation, until the left atrium is closed; (ii) an aorticroot venting catheter is kept on low suction through-out the operation; (iii) during CPB, perfusion pres-sures must be maintained above 80-90 mmHg; (iv) avery short period of fibrillatory arrest (less than 1 min)is used while the left atrium is entered, but only inpatients in whom the mitral valve is competent (i.e.mitral valve surgery for mitral stenosis). In the pres-

ence of severe mitral insufficiency, the left atrium canbe entered while the heart is beating, when the recom-mendations described above are carefully followed.However, it is also important that, as soon as the leftatrium is opened, a cardiotomy sucker is placed intothe left ventricle through the mitral valve, so as todecompress the left ventricle and further eliminate therisk of air embolism. In our view, as long as the leftventricle is kept beating-empty and properly decom-pressed, and perfusion pressures are maintained above80-90 mmHg, air embolization is effectively prevented.Conversely, in patients presenting with a competentmitral valve, air embolism could occur when the leftatrium is entered. As a result, this strategy is modifiedby inducing a very brief period (normally less than aminute) of ventricular fibrillation with a fibrillator,during which access to the left atrium is rapidlygained. A cardiotomy sucker is then placed throughthe mitral valve into the left ventricle. Once the leftventricle is decompressed, the heart can be safelydefibrillated. In our view, such a brief period of ven-tricular fibrillation is of no consequence in respect tomyocardial protection. Also, following this strategywe have not observed any adverse neurologic eventwhich could have been ascribed with certainty to airembolism. Although the clinical results of our seriesof patients who underwent mitral valve operationson the beating heart are currently under investigationand will not be presented in this chapter, we haveobserved only one case of adverse neurologic out-come that was unlikely to have been caused by airembolism. This involved a patient in renal failure whounderwent double-valve replacement for severe anddiffuse calcific degeneration of both mitral and aorticvalves.

After the left atrium is entered and the LV cavityhas been decompressed, a "mitral" retractor is placedto gain adequate exposure of the mitral valve. It is atthis point, however, that improper placement of theretractor or excessive traction may alter the geometryof the aortic root, leading to torrential aortic insuffi-ciency. Aortic insufficiency, which may be furtherenhanced by high perfusion pressures, could alsoadversely affect coronary perfusion. Importantly, severeaortic regurgitation would inevitably compromisevisualization and could preclude the performanceof mitral valve surgery on the beating heart. For thesame reasons, the presence of moderate or severeaortic insufficiency preoperatively may also preclude


this approach, unless the strategy of the operationis modified so as to perform aortic valve surgery con-comitantly. The technical modifications adopted inthe setting of combined aortic and mitral valve surgerywill be discussed below (see "Combined aortic andmitral valve operations on the beating heart"). In thesesituations, when both mitral and aortic valve surgeryare contemplated in a patient with aortic insufficiency,it may be preferable to clamp the aorta and establishperfusion of the myocardium through the antegrade(single coronary ostia) and retrograde route simulta-neously, in a fashion similar to that previously describedfor aortic valve surgery on the beating heart. Once themitral retractor is placed into position and aorticregurgitation is avoided, the mitral valve can berepaired, or replaced, as planned. During the proce-dure, visualization is improved by using two floppycardiotomy suckers, one placed in the left ventriclethrough the mitral orifice, and a second one placed inthe left atrium at the bottom of the well. In contrastto mitral valve repair on the arrested heart, repair ofthe mitral valve on the beating heart is facilitated bythe fact that the geometry of the mitral valve apparatusclosely resembles that of hearts under normal physio-logic conditions. Thus, the quality of the repair canbe tested more effectively than in the arrested heart.After the mitral valve is repaired or replaced, a floppycardiotomy sucker is left through the mitral orificeso as to keep the left ventricle empty and prevent LVejection, while the left atrium is closed. At last, the LVvent is removed, while the root vent is kept constantlyon gentle suction to complete deairing, and the opera-tion is completed in the usual fashion.

In patients with concomitant coronary artery disease,this strategy can be modified by using a retrogradecatheter in the CS as an adjunct in myocardial perfu-sion. In reality, we rarely, if ever, use this strategy inthe presence of concomitant coronary disease, as wewould normally perform CABG on the beating heart(with or without CPB) prior to addressing the mitralvalve (see "Concomitant valve surgery and coronaryartery bypass grafting on the beating heart" below). Asa result, once coronary revascularization is accom-plished, the heart is kept perfused through the aorticroot (coronary ostia and newly constructed grafts) asmitral valve surgery is performed. However, using anadditional source of coronary blood supply throughthe coronary sinus may be advantageous in patientspresenting with coronary disease that, for whatever

reason, does not lend itself to coronary revasculariza-tion. In fact, studies from the literature have shownthat myocardial perfusion of areas of myocardiumsupported by occluded coronary arteries is superiorwhen simultaneous antegrade-retrograde perfusion isused, in contrast to isolated antegrade perfusion [20].

In summary, mitral valve surgery can be performedusing the beating heart technique as the strategy ofmyocardial protection. Patients who may benefitfrom this approach include those presenting withvery compromised ventricular function, especiallywhen prolonged periods of aortic cross-clampingare anticipated. The presence of moderate or severeaortic insufficiency may preclude this approach forthe reasons described above.

Combined aortic and mitral valveoperations on the beating heart

Although the principles described for aortic andmitral operations on the beating heart also apply topatients requiring combined procedures, a few tech-nical modifications are necessary. When concomitantaortic and mitral valve surgery are contemplated, thetheoretical advantages of the beating heart approachare obvious. Prolonged periods of ischemia, whichwould be the consequence of many of the strategies ofcardioplegic arrest, are avoided, and exchanged forprolonged periods during which the heart remainsperfused, thus eliminating the potential for ischemicinjury. In these situations, after proper CPB at nor-mothermia is established, the "mitral" portion of theoperation (repair or replacement) is performed beforethe "aortic" portion, as is the case in conventionaloperations on the arrested heart. However, the strat-egy of myocardial perfusion and the conduct of theoperation differ, based on whether the patient pre-sents with or without aortic insufficiency. In patientswith moderate or severe aortic insufficiency, in whommitral and aortic valve replacement are contemplatedconcomitantly, myocardial perfusion is accomplishedin a manner similar to that described for isolated oper-ations on the aortic valve. Cardiopulmonary bypassat normothermia is initiated. An LV vent through theright superior pulmonary vein is inserted. Then theaorta is cross-clamped and retrograde, high-flow per-fusion is commenced while the aortic root is opened.The left coronary ostia is cannulated, and simultane-ous antegrade-retrograde perfusion is delivered, while

318 CHAPTER 34

the heart is kept beating-empty. At this point, the leftatrium is entered, and mitral valve surgery performed.The left atrium is then closed leaving a floppy car-diotomy sucker in it. The attention is directed to theaortic valve, which is excised and replaced, venting theleft ventricle through the left ventricular outflow tract.At completion, the aortic root is closed, deairing isperformed, and the aorta is undamped, discontinuingretrograde perfusion.

Alternatively, in patients without aortic insuffici-ency, the first portion of the operation (mitral valvesurgery) can be performed with the aorta undamped,the patient in Trendelenburg position, high perfusionpressures (above 80-90 mmHg), the aortic root venton very gentle suction, and the myocardium perfusedthrough the aortic root, as previously described forisolated mitral valve operations. Once the mitral portionof the operation is completed, retrograde perfusionthrough the CS is begun, the aorta is clamped, theaortic root is opened, and simultaneous antegrade-retrograde perfusion is established, as described above.In essence, the presence or absence of aortic regurgita-tion dictates the strategy of the first part of the opera-tion, during which the mitral valve is dealt with.

Concomitant valve surgery andcoronary artery bypass graftingon the beating heart

In the presence of coronary artery disease amenablefor surgical revascularization, we routinely initiate theoperation by performing CABG on the beating heart,without CPB. Various techniques of beating heartcoronary surgery are employed, as previously described[1,24]. The next step encompasses the institution ofCPB, and performance of valve surgery on CPB, onthe beating heart. Only in a minority of patients havewe observed deterioration of the hemodynamic para-meters during the performance of CABG withoutCPB. In these situations, we establish CPB and we per-form coronary revascularization on bypass, while theheart is perfused and beating.

The operation then proceeds as previously describedfor beating heart aortic and mitral valve procedures.In patients requiring aortic valve replacement con-comitantly with CABG, after constructing distalanastomoses we routinely perform the aortic valveprocedure while the heart is perfused by a combina-tion of antegrade perfusion (through the grafts and

through one coronary ostia) and retrograde perfusion(catheter in the coronary sinus). When aortic valvereplacement is completed and the aortic root is closed,the proximal anastomoses of newly constructed coro-nary grafts are constructed.

In patients necessitating a mitral valve procedureand CABG, distal anastomoses and then proximalanastomoses are performed first, with or withoutCPB. Subsequently, after establishment of CPB, theoperation proceeds as previously described for mitralvalve operations on the beating heart, so that the heartis perfused from the aortic root without clamping theaorta (both through the coronary ostia and throughthe newly constructed coronary grafts).

Conclusions

As sicker and older patients are referred for cardiacsurgery, surgical techniques evolve and new cardio-protective strategies are proposed. For several decades,cardiac surgeons have focused on refining techniquesof myocardial protection during cardioplegic arrest,either by introducing new cardioplegic solutions or bymodifying their modalities of delivery. Also, with therecent advent of minimally invasive valve surgery, agreat deal of attention has centred on the magnitude ofthe operative approach, and on the length of the surgi-cal incision. In aortic and mitral valve surgery, morelimited and sometimes cumbersome surgical incisionshave been advocated. Although many of these tech-niques have enjoyed the consensus of some patients,their real value should be weighted against theirpotential disadvantages, such as the risk of longer per-iods of aortic cross-clamping and cardioplegic arrest.While in many patients the impact of such adversevariables may be difficult to establish, and is perhapsof modest clinical relevance, in others it can unneces-sarily increase the risk of both myocardial ischemicinjury and postoperative ventricular dysfunction. Inthis perspective, if it is agreed that maximal preserva-tion of myocardial function should be viewed as oneof the main priorities in cardiac operations, then the"minimal invasiveness" of some of these "minimallyinvasive" valve operations could be questioned, astheir use remains associated with a risk of myocardialinjury that is equal to, or even greater than, that ofconventional operations. In our view, minimally inva-sive valve operations are most notably those designedto minimize the risks of the operation and to preserve


maximally myocardial function, rather than those

in which cosmetic considerations are prioritized. As

a result, beating heart techniques of aortic and mitral

valve surgery may play an important role in expand-

ing the armamentarium of cardiac surgeons. In fact,

although their efficacy remains to be proven, these

techniques have been conceived and designed to

maximally preserve ventricular function. This may be

of great importance, especially in patients presenting

with severe preoperative ventricular dysfunction, or

in those requiring procedures in which prolonged

periods of aortic cross-clamping are required. To date,

there is no conclusive scientific evidence to prove or

dispute the superiority of this strategy of myocardial

protection over other widely adopted conventional

strategies. Nevertheless, the validity of the principles

supporting beating heart surgery, the advantages of

having the heart beating-empty and continuously per-

fused at normothermia throughout the period of aor-

tic cross-clamping, and the consequential advantages

of eliminating any supply-demand mismatch, cannot

be disputed. As the clinical data relative to the use of

these techniques for both aortic and mitral valve

surgery are currently under review, and they will be

the object of publications in the future, they will not be

presented herein. However, our preliminary experience

of beating heart valve surgery, which now consists

of well over 100 patients operated on in the context of

various clinical conditions, seems to suggest that this

approach is associated with early favorable results.

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Exposure and mechanical stabilization in off-pump cor-onary artery bypass grafting via sternotomy. Ann ThoracSurg2000; 70: 1736-40.

2 Mack MJ. Minimally invasive and robotic surgery. JAMA2001; 285: 568-72.

3 Cooley DA. Con: beating heart surgery for coronaryrevascularization: is it the most important developmentsince the introduction of the heart-lung machine? AnnThorac Surg 2000; 70:1779-81.

4 Cosgrove DM. Is coronary reoperation without thepump an advantage? Ann Thorac Surg 1993; 55:329.

5 Estafanous FG, Loop FD, Higgins TL et al. Increased riskand decreased morbidity of coronary artery bypass graft-ing between 1986 and 1994. Ann Thorac Surg 1998; 65:383-9.

6 Gersak B. Mitral valve repair or replacement on thebeating heart. Heart Surg Forum 2000; 3:232-7.

7 Downing SW, Herzog WA Jr, McLaughlin JS, Gilbert TP.Beating-heart mitral value surgery: prelimary model and

methodology. / Thorac Cardiovasc Surg 2002; 123:1141-46.

8 Buckberg GD. Cardioplegia solutions—unproven herbalapproach versus scientific study. Semin Thorac CardiovascSurg 2001; 13:52-5.

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10 Gillinov AM, Banbury MK, Cosgrove DM. Hemister-notomy approach for aortic and mitral valve surgery.JCard Surg 2000; 15:15-20.

11 Shumway NE, Lower R. Hypothermia for extendedperiods of anoxic arrest. Surg Forum 1959; 10: 563.

12 Buckberg GD. Update on current techniques of myocar-dial protection. Ann Thorac Surg 1995; 60: 805-14.

13 Christakis GT, Weisel RD, Fremes SE et al. Coronaryartery bypass grafting in patients with poor ventricularfunction. Cardiovascular Surgeons of the University ofToronto. / Thorac Cardiovasc Surg 1992; 103:1083-91.

14 Buckberg GD, Brazier JR, Nelson RL et al. Studies on theeffects of hypothermia on regional myocardial blood flowand metabolism during cardiopulmonary bypass. I. Theadequately perfused beating, fibrillating, and arrestedheart. / Thorac Cardiovasc Surg 1977; 73: 87-94.

15 Salerno TA. Myocardial temperature managementduring aortic clamping for cardiac surgery-protection,preoccupation, and perspective. / Thorac Cardiovasc Surg1992; 103:1019-28.

16 Salerno TA. Continuous blood cardioplegia: option forthe future or return to the past. /Mo/ Cell Cardiol 1990;22(supplV):849.

17 Salerno TA, Houck JP, Barrozo CAM et al. Retrogradecontinuous warm blood cardioplegia: a new concept inmyocardial protection. Ann Thorac Surg 1991; 51:245-7.

18 Tiang G, Xiang B, Butler KW et al. A3 ' P nuclear magneticresonance study of intermittent warm blood cardiople-gia. J Thorac Cardiovasc Surg 1995; 109:1155-63.

19 Lessana A, Pargaonkar S, Hu HQ et al. External stabiliza-tion of coronary sinus catheter. / Card Surg 1995; 10:95-7.

20 Tian G, Shen J, Sun J et al. Does simultaneous antegrade/retrograde cardioplegia improve myocardial perfusion inthe area at risk? A magnetic resonance perfusion imagingstudy in isolated pig hearts. / Thorac Cardiovasc Surg1998; 115:913-24.

21 Tian G, Dai G, Xiang B et al. Effect on myocardial perfu-sion of simultaneous delivery of cardioplegic solutionthrough a single coronary artery and the coronary sinus.I Thorac Cardiovasc Surg 2001; 122:1004-10.

22 Ye J, Sun J, Shell J et al. Does retrograde warm bloodcardioplegia provide equal protection to both ventricles?A magnetic resonance spectroscopy study in pigs.Circulation 1997; 96: II210-1 IS.

23 Hoffenberg EF, YeJ, Sun J etal. Antegrade and retrogradecontinuous warm blood cardioplegia: a 31P magneticresonance study. Ann Thorac Surg 1995; 60:1203—9.

24 Soltoski P, Bergsland J, Salerno TA et al. Techniques ofexposure and stabilization in off-pump coronary arterybypass grafting. / Card Surg 1999:14:392-400.

Index

N-acetylcysteine 27adenosine 50,54,99adenosine receptors 19adenosine triphosphate (ATP) 33,45 - 6

see also potassium-ATP channelsadhesion molecules 308allopurinol 110amiloride 27AMISTADI trial 50AMISTADII trial 50anastomosis

coronary sinus perfusion 153left anterior descending coronary artery 138-40main pulmonary artery to aorta 276-7

anesthetic preconditioning 33-42cytokine response 36-8,37inflammatory response to myocardial ischemia 35-6ischemia-reperfusion injury 34-5,34,35neutrophilic inflammatory response to myocardial

ischemia 38-40,39oxidants as neutrophilic mediators 40

angioplasty 46-9angiotensin blockers 46-7angiotensin converting enzyme 235anipamil 21antegrade cardioplegia 82-3

intermittent cold crystalloid 72intermittent warm blood 75-81

antioxidant enzymes 307antioxidants 20,27

cardiac transplantation 296-7antiplatelet Ilb-IIIa inhibitors 49aortic cross-clamping, intermittent 53-8

operative technique 54,55,56pathophysiology 54

aortic root surgery 189-92aortic surgery 193-5

St Antonius method 194-5aortic valve surgery

aortic insufficiency 168aortic stenosis 167-8beatingheart 313-15,314cardioplegia 176-7

cold versus warm 184 - 6,184,185intermittent warm blood cardioplegia 181-8

minimally invasive 176-8myocardial protection 182—3redo operations 177-8

apoptosis regulators 308L-arginine 106atrial septal defect 2

beating heart surgery 16,311—19CABG 119-25,126-33

continuous perfusion through coronary sinus 152-9myocardial infarction 144 -51on-pump 141-2

on-pumpCABG 141-2dilated cardiomyopathy 160—6

valvular surgery 311-19aortic valve 313-15,314combined aortic/mitral valve 317-18combined with CABG 318mitral valve 315-17,376

Beck, Claude 2,5benidipine 21Bernard, Claude 1beta-blockers

reduction of myocardial oxygen requirement 47valvular surgery 167-73

beta-carotene 20blood cardioplegia see cold blood cardioplegia; warm blood

cardioplegiabradykinin

activation of nitric oxide 244-6,245experimental studies 236-7,237improvement of ischemia tolerance 237as preconditioning agent 233,235-6protein kinase C activation 239-41,240,241,242recovery of ventricular performance and coronary flow

237-9,238,239translocation of glucose transporter 4 246-9,247,248,

249tyrosine kinase activation 241,243—4,243,244

bradykinin receptors 19

CABG see coronary artery bypass graftcalcium 213-15,214,275calcium channel blockers 27

in cardioplegia 101-2,102and ischemia-reperfusion injury 20-1

calcium homeostasis, in myocardial stunning 101calyculinA 23cantharidin 23carbohydrate metabolism 233cardiac arrest 120cardiac hypertrophy 181

myocardial metabolic state in 182susceptibility to ischemia-reperfusion 182

cardiac transplantation 292-300cardioplegia 293-5,294preharvest donor management 292 -3

321

322 Index

reperfusion 296-7antioxidants in 296-7triiodothyronine administration 297

storage 295-6cardioplegia 3,120

antegrade 75-81,82-3avoidance in Fontan procedure 275- 81CABG reoperation 197-9calcium channel blockade 101-2,102calcium and magnesium 213-15,214,215cardiac transplantation 293-5,294cold blood 212-13,213,217,267-8combined antegrade/retrograde 85-6,85,86continuous 4-5crystalloid 4,72,205,212-13,213

pediatric surgery 212-13,213,266-7hyperpolarization 286-7intermittent warm blood see intermittent warm blood

cardioplegiamagnetic resonance spectroscopy 59-60minimally invasive valvular surgery 174-5,174,176-7pediatric surgery 211-12,212,266-8

distribution 220induction 215-16,276,267infusion pressure 220-1,221maintenance 216-17,217

reintroduction of 3-4retrograde 5,83-5,152-9substrate enhancement 94-118

pediatric surgery 268valvular surgery 169-70,174-5,174,176-7warm blood 4,59-69,70-4,75-81,168-70,312-13see also miniplegia

cardiopulmonary bypassangioplasty 48beating heart surgery 120-2,122low-flow, in pediatric surgery 270-1reoperative CABG 197systemic inflammatory syndrome 122

cardiovascular physiology 1-2cariporide 22,27CARISA trial 46L-carnitine 96-7catalase 20,27chlorpromazine 22cinanserin 27closed heart surgery 2coenzymeQIO 97cold blood cardioplegia 4,212-13,213,217,267-8collateralizing vessels 129 -30complement cascade 103-11

L-arginine 106endothelial dysfunction 105endothelin 107-8,107neutrophil activation 104nitric oxide donors 106nitric oxide pathway 105-6,105reactive oxygen species 108 -11,109steroid therapy 104-5tetrahydrobiopterin 106-7

complement inhibitors 51continuous cardioplegia 4-5continuous retrograde warm blood cardioplegia 72coronary artery bypass graft 16,119-25

adverse effects 122-3

avoidance of myocardial ischemia 134—43beating heart surgery 120-2,122,126-7,134-43cardioplegia

intermittent antegrade warm blood cardioplegia 78-9,79

reoperation 197-9warm versus cold 123,124,183-4

combined with valvular surgery 318coronary sinus perfusion 152-9minimally invasive 205-6with myocardial infarction 144 - 51myocardial protection 119-20,126-33off-pump 126-7on-pump 141-2perfusion-assisted 127,130-1,131reoperation 196-201totally endoscopic 204

coronary sinus perfusion 48-9,152-9avoidance of ischemia 153-5,756cardiac wall stabilization 153conversion to cardiopulmonary bypass 156distal anastomosis 153follow-up 155hemodynamic stability 153initial assessment 153intraoperative complications 156maintenance of normothermia 152-3operative techniques 153preoperative preparation 152results 155-6revascularization assessment 155sequence of grafting 155

crystalloid cardioplegia 4,72,205pediatric surgery 212-13,213,266-7

cyanosis 208cytokines

immunosuppression 308and ischemia-reperfusion injury 24myocardial ischemia 36-8,37

deferoxamine 108-9descending thoracic surgery 195diazoxide 250,257dihydropyridines 21dilated cardiomyopathy 160-6

etiology 161history 160-1operative procedures 161—4

endoventricular circular patch plasty 162,163partial left ventriculectomy 162septal anterior ventricular exclusion 162,163,164

results 164,165diltiazem 27DV-7028 27

elastase 122endothelial dysfunction 105endothelin 107-8,707entoxifylline 23-4,27esmolol 168-9excitation-contraction coupling 99-100,700

fatty acid oxidation inhibitors 46felodipine 21filters 269-70

Index 323

Fontan procedure 275-81cardioplegia and cardiocirculatory arrest 277main pulmonary artery to aorta anastomosis 276-7patch enlargement of pulmonary arteries 276patients with functional single ventricle 275-6postoperative treatment 277results 277staging 276-7without cardioplegia 277—9

postoperative treatment 279results 279tolerance to ischemia 277-9,278,279ultrafiltration 279

without cardiopulmonary bypass 279-80,280fostriecin 23,27free radicals

generation in warm blood cardioplegia 77-8,78ischemic preconditioning 234production in open-heart surgery 77

G-protein-linked phospholipase C-coupled receptors 19gene therapy 288,304-10

gene delivery 304-5therapeutic genes

antioxidant enzymes 307apoptosis regulators 308cytokines and adhesion molecules 308heat shock proteins 306-7nitric oxide synthase 307-8

vectorsliposomes 305perfusion in coronary circulation 304viral 305-6

Gibbon, John 2glucose insulin potassium 44-5glucose transporter 4 246-9

PI3K activity 246-7,248protein kinase C activation 247-9,248,249translocation 246-7,247

glutamate-aspartate 96glutathione 20,27,110glutathione peroxidase 20

HALT-MI trial 50heart-lung machine 2heat shock proteins 306-7hemodynamic changes during heart manipulation 128-9histidine-tryptophan-ketoglutarate 97history 1-12

blood cardioplegia 4cardioplegia 3closed heart surgery 2continuous cardioplegia 4-5early cardiac physiology 1—2open heart surgery 2-3reassessment of myocardial damage 3-4retrograde cardioplegia 5

HOE 140 244-6,245hydrogen peroxide 20hydroxyl radical 20hyperpolarized cardioplegia 286-7hypothermia 14,46

pediatric surgery 270-1see also cold blood cardioplegia

hypoxia 208-11,209,210,211

ICS 205-930 27immature myocardium

cardioplegia 266-8administration of 267blood 267-8crystalloid 266-7integrated approach to 268substrate enhancement 268

hypothermia/circulatory arrest versus low-flowcardiopulmonary bypass 270-1

mechanical devices for cardioprotection 268-70filters 269-70modified ultrafiltration 270ultrafiltration 270

palliation versus early repair 271response to ischemia 265tolerance to ischemia 251-8

pinacidil pretreatment 256-8,256,257potassium-ATP channel opening 255-6,255upregulation of protein kinase C 252-5,253,254,255

versus adult myocardium 264-5see also pediatric surgery

inflammatory mediators 122inflammatory response to ischemia 35-6,38-40,39,103inorganic phosphate, and cardioplegia 65insulin, and myocardial metabolism 95-6intercellular adhesion molecule 1 (ICAM-1) 36interleukin-6 36,122interleukin-10 122intermittent antegrade cold crystalloid cardioplegia 72intermittent antegrade warm blood cardioplegia 75-81

coronary artery bypass grafting 78 -9,79metabolic studies 77-8,78surgical technique and delivery protocol 76-7,76,77valve surgery 79-80,80

intermittent warm blood cardioplegia 59-69antegrade see intermittent antegrade warm blood

cardioplegiaaortic valve surgery 181-8effect on myocardial energy metabolism 60—2,61heterogeneous ischemic changes during 62-6,63,64,65,

66minimum perfusion pressure 66—7,67

intra-aortic balloon counterpulsation 199 —200intra-aortic balloon pump 47-8intracoronary shunts 128ischemia

cytokines in 36-8,37inflammatory response to 35-6,38-40,39intraoperative 134-43response of immature myocardium to 265tolerance to

by immature myocardium 251—8improvement by bradykinin 237

ischemia-reperfusion injury 18-32,119-20cardiac hypertrophy 182cardiac transplantation 284-6causes of 26cell biology of cardiac myocytes in 34-5,34,35ion exchange during 34mechanism of 284-5oxidants as neutrophilic mediators 40preconditioning see ischemic preconditioningreduction of 49-51,285-6

5-HT receptor antagonists 24—5,27

324 Index

adenosine 50antioxidants 20,27antiplatelet Ilb-IIIa inhibitors 49calcium channel blockers 20-1,27complement inhibitors 51leukocyte receptor monoclonal antibody 50magnesium 49-50MAP kinase inhibitors 22-3,27phosphodiesterase inhibitors 23-4,27phospholipase A2 inhibitors 21-2,27protein phosphatase inhibitors 23,27sodium-hydrogen exchanger inhibitors 22,27,49

ischemic preconditioning 19 -20,98 -9,98anesthetic see anesthetic preconditioningbiology of 231cardiac transplantation 287-8cellular effects of 233-4

carbohydrate metabolism 233concurrent stunning 233-4free radicals and reactive oxygen species 234genetic mechanisms 234

discovery of 230—1experimental studies 234-5off-pump CABG 127-8preconditioning agents 44-6

adenosine 99bradykinin 235-51fatty acid oxidation inhibitors 46glucose insulin potassium 44-5hypothermia 46nicorandil 99potassium-ATP channel antagonists 45potassium-ATP channel openers 98-9,249-51,250,

251signal transduction pathways 231—3,232,233see also substrate enhancement

ketamine 38ketanserin 27

lacidipine 21lactate dehydrogenase 38left anterior descending coronary artery, anastomosis

138-40left ventricular assist device implantation 301-3Leicester Intravenous Magnesium Intervention Trial

(LIMIT-2) 50leukocyte receptor monoclonal antibody 50leukocyte-adhesion molecules 39LIMA suture 136,137,138lipopolysaccharide-induced CXC chemokine 38liposomes 305LY53857 27lysophosphatidylcholine 21

magnesium 49-50pediatric surgery 213-15,214,215

magnetic resonance spectroscopy 59-60manoalide 21MAP kinase inhibitors 22-3,27MAPkinases 35,232MDL28 27mechanical objectives of cardiac surgery 13-17Melrose solution 3miancerin 27

minimally invasive cardiac surgery 203-6animal studies 203-4CABG surgery 205-6evolution of 203see also minimally invasive valvular surgery

minimally invasive valvular surgery 174 - 80,204 -5aortic valve 176-8cardioplegic delivery 174-5,174,176-7chest incisions 175 - 6,175,176mitral valve 178-9,178muscular mass and metabolism 174reperfusion 175tricuspid valve 179-80

minimum perfusion pressure in cardioplegia 66-7,67

miniplegia 88-93clinical and experimental studies 91-2,91perfusion technique 89-90,90rheologic and biologic issues 88-9see also cardioplegia

mitogen-activated protein kinases see MAP kinasesmitral regurgitation 168mitral valve surgery

beating heart 315-17,316limited sternotomy 178minimally invasive surgery 178-9mitral stenosis 168redo operations 179right anterior thoracotomy 178-9

MR-256 22myocardial damage 3-4myocardial infarction 43-52

beating heart surgery 144 -51increased resistance to

fatty acid oxidation inhibitors 46glucose insulin potassium 43-4hypothermia 46ischemic preconditioning 43potassium-ATP channel agonists 45

indications for CABG 145-6reduction of oxygen requirements 46—9

angiotensin blockers 46—7beta-blockers 47cardiopulmonary bypass support 48coronary retroperfusion 48-9intra-aortic balloon pump 47- 8

reduction of reperfusion injury 49—51adenosine 50antiplatelet Ilb-IIIa inhibitors 49complement inhibitors 51leukocyte receptor monoclonal antibody 50magnesium 49-50sodium-hydrogen exchanger 49

timing and mechanism of reperfusion 43-4myocardial ischemia see ischemiamyocardial metabolism 95-7,95

and cardioplegia 60-2,61objectives of cardiac surgery 13-17see also substrate enhancement

myocardial preconditioning see ischemic preconditioningmyocardial shunts 128myocardial stunning 99-103

disruption of calcium homeostasis 101excitation-contraction coupling 99-100,100and ischemic preconditioning 233-4

Index 325

L-type calcium channel blockade 101-2,102sodium-hydrogen exchanger inhibitors 103

L-NAME 244-6,245neutrophil activation 104nicorandil 99nifedipine 21,27nitecapine 110-11nitric oxide 24,230

activation 244-6,245and complement activation 105—6,105

nitric oxide donors 106nitric oxide synthase 307— 8normothermia 152-3normoxemia 209nuclear factor kappa B 38

off-pump CABG 126continuous perfusion through coronary sinus 152 - 9distal anastomosis construction 129 - 30myocardial injury 126-7perfusion-assisted 127,130-1,131

okadaicacid 23on-pump beating heart surgery

CABG 141-2dilated cardiomyopathy 160-6

open heart surgery 2-3opioid receptors 19oxidants, as neutrophilic mediators 40

pediatric surgery 207-29,264-74cardioplegia 211-12,212

blood versus crystalloid 212-13,213calcium and magnesium 213-15,214,215distribution 220induction 215-16,216infusion pressure 220-1,22]maintenance 216-17,217

clinical studies 223-5,225hypoxia 208-11,209,210,211modified integrated cardioplegia 221—3,222preoperative considerations 207reperfusion 217-18,218volume and pressure overload 207-8white blood cell filtration 218 -20,219see also immature myocardium

perfusate composition 282-3perfusion-assisted CABG 127,130-1,131pFOX see fatty acid oxidation inhibitorsphosphocreatine, and cardioplegia 65phosphodiesterase inhibitors 23-4,27phospholipase A2 inhibitors 21-2,27pinacidil 256-8,256,257platelet activating factor 39potassium-ATP channel agonists 98 -9

ischemia tolerance in immature myocardium 255-6,255potassium-ATP channels 19

in ischemic preconditioning 45—6,249-51,250,251preservation solutions 282—91

gene therapy 287hyperpolarized cardiac arrest 286-7ischemic preconditioning 287-8perfusate composition 282-3protease inhibitor 287reduction of ischemia-reperfusion injury 285-6

propofol 37protease inhibitors 288protein kinase C 19,230,239-41

activation 239-2040,240,247-9,248,249translocation 240,241upregulation in neonatal heart 252-5,253,254,255ventricular performance and coronary flow 240-1,

242protein phosphatase inhibitors 23,27

ranolazine 46reactive oxygen species 234

allopurinol 110and complement activation 108-11,109deferoxamine 108-9glutathione 110as mediators of ischemia-reperfusion injury 20,

40nitecapine 110-11

renin-angiotensin system 47reoperation

aortic valve surgery 177-8CABG 196-201mitral valve surgery 179

reoxygenation 208-10,209,210reperfusion 43-4

cardiac transplantation 297see also ischemia-myocardial perfusion injury

retrograde cardioplegia 5,83-5,152-9retrograde perfusion see retrograde cardioplegiaRinger, Sydney 1

St Antonius method of myocardial protection 194-5SB-203580 27septal anterior ventricular exclusion 163serotonin receptor antagonists 24-5,27sevoflurane 37SHOCK trial 48,146SM-20550 27sodium-hydrogen exchanger 22,49sodium-hydrogen exchanger inhibitors 22,27,49

myocardial stunning 103stenosis see arterial stenosissteroid therapy 104-5stone heart 3,13substrate enhancement 94-118

L-carnitine 96-7coenzymeQIO 97glutamate-aspartate 96histidine-tryptophan-ketoglutarate 97immature myocardium 268insulin 95-6in pediatric surgery 268see also ischemic preconditioning

superoxide anion 20superoxide dismutase 20,27surgery

closed 2objectives of 13-17open 2

systemic inflammatory syndrome 122

taurine 20tetrahydrobiopterin 106-7thoracoabdominal aortic surgery 195

326 Index

totally endoscopic coronary artery bypass (TECAB) 204,205

beating heart 205tricuspid valve surgery 179 - 80triiodothyronine, administration in cardiac transplantation

297troponin 121tumor necrosis factor alpha 19,36tyrosine kinase 19,230,241,243-4,243,244

ultrafiltration 270Fontan procedure 279modified 270

valvular surgeryaortic valve see aortic valve surgeryavoidance of cardioplegia 312beating heart 311-19

aortic valve 313-15,314combined aortic/mitral valve 317-18combined with CABG 318mitral valve 315-17,316

beta-blockers in 167-73cardioplegia 79-80,80,168-70,174-5,174,176-7,

312-13minimally invasive 174-80,204-5mitral valve see mitral valve surgerytricuspid valve 179-80

vanadate 27verpamil 27viral vectors for gene therapy 305-6vitamin A 20vitamin C (ascorbic acid) 20vitamin E (alpha-tocopherol) 20,27

warm blood cardioplegia 4,70-4,75-81,168-70,312-13anatomy and physiology 70-1clinical trials 71-2,71intermittent see intermittent warm blood cardioplegiavalvular surgery 167-73

warm heart surgery see warm blood cardioplegiawhite blood cell nitration 218-20,219

yohimbine 27

Myocardial protection 2004

Health & Medicine

Transcript of Myocardial protection 2004