LETHAL ARRHYTHMIAS RESULTING FROM MYOCARDIAL ISCHEMIA AND INFARCTION

DEVELOPMENTS IN CARDIOVASCULAR MEDICINE

Reiber, J.H.C., Serruys, P.W., Slager, C.].: Quantitative coronary and left ventricular cinean­giography. ISBN 0-89838-760-4.

Fagard, RH., Bekaert, I.E., eds.: Sports cardiology. ISBN 0-89838-782-5. Reiber, J.H.C., Serruys, P.W., eds.: State of the art in quantitative coronary arteriography.

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0-89838-815-5. Higler, H., Hombach, V., eds.: Invasive cardiovascular therapy. ISBN 0-89838-818-X. Serruys, P.W., Meester, G.T., eds.: Coronary angioplasty: a controlled model for ischemia.

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833-3. van Dam, Th., van Oosterom, A., eds.: Electrocardiographic body surface mapping. ISBN

0-89838-834-1. Spencer, M.P., ed.: Ultrasonic diagnosis of cerebrovascular disease. ISBN 0-89838-836-8. Legato, M.]., ed.: The stressed heart. ISBN 0-89838-849-X. Safar, M.E., ed.: Arterial and venous systems in essential hypertension. ISBN 0-89838-857-0. Roelandt,]., ed.: Digital techniques in echocardiography. ISBN 0-89838-861-9. Dhalla, N.S., Singal, P.K., Beamish, R.E., eds.: Pathophysiology of heart disease. ISBN

0-89838-864-3. Dhalla, N.S., Pierce, G.N., Beamish, RE., eds.: Heart function and metabolism. ISBN 0-

89838-865-1. Dhalla, N.S., Innes, I.R, Beamish, RE., eds.: Myocardial ischemia. ISBN 0-89838-866-X. Beamish, RE., Panagia, V., Dhalla, N.S., eds.: Pharmacological aspects of heart disease. ISBN

0-89838-867 -8. Ter Keurs, H.E.D.]., Tyberg,]. V., eds.: Mechanics of the circulation. ISBN 0-89838-870-8. Sideman, S., Beyar, R., eds.: Activation metabolism and perfusion of the heart. ISBN 0-89838-

871-6. Aliot, E., Lazzara, R, eds.: Ventricular tachycardias. ISBN 0-89838-881-3. Schneeweiss, A., Schettler, G.: Cardiovascular drug therapy in the elderly. ISBN 0-89838-883-

X. Chapman, ]. V., Sgalambro, A., eds.: Basic concepts in doppler echocardiography. ISBN 0-

89838-888-0. Chien, S., Dormandy,]., Ernst, E., Matrai, A., eds.: Clinical hemorheology. ISBN 0-89838-

807-4. Morganroth, ]., Moore, E. Neil, eds.: Congestive heart failure. ISBN 0-89838-955-0. Heintzen, P.H., Bursch, ].H., eds.: Progress in digital angiocardiography. ISBN 0-89838-965-

8. Scheinman, M., ed.: Catheter ablation of cardiac arrhythmias. ISBN 0-89838-967-4. Spaan, ].A.E., Bruschke, A.V.G., Gittenberger, A.C., eds.: Coronary circulation. ISBN 0-

89838-978-X. Bayes de Luna, A., ed.: Therapeutics in cardiology. ISBN 0-89838~981-X. Mirvis, D.M., ed.: Body Surface Electrocardiographic Mapping. ISBN 0-89838-983-6. Visser, c., Kan, G., Meltzer, R., eds.: Echocardiography in coronary artery disease. ISBN

0-89838-979-8. Singal, P.K., ed.: Oxygen Radicals in the Pathophysiology of Heart Disease. ISBN 0-89838-

375-7. Iwata, H., Lombardini, ].B., Segawa, T., eds.: Taurine and the heart. ISBN 0-89838-Mirvis, D.M., ed.: Body surface electrocariographic mapping. ISBN 0-89838-983-6. Morganroth, ]., Moore, E.N., eds.: Silent myocardial ischemia. ISBN 0-89838-380-3.

LETHAL ARRHYTHMIAS RESULTING FROM

MYOCARDIAL ISCHEMIA AND INFARCTION

[PROCEEDINGS OF THE SECOND RAPPAPORT SYMPOSIUM]

EDITED BY MICHAEL R. ROSEN and YORAM PALTI

~.

" KLUWER ACADEMIC PUBLISHERS GROUP

BOSTON IDORDRECHT ILANCASTER

Copyright 1989 by Kluwer Academic Publishers Softcover reprint of the hardcover 1 st edition 1989

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying, recording, or other­wise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, Massachusetts 02061.

Distributors for North America: Kluwer Academic Publishers 101 Philip Drive Assinippi Park Norwell, Massachusetts 02061 USA

Distributors for the UK and Ireland: Kluwer Academic Publishers Falcon House, Queen Square Lancaster LAI lRN, UNITED KINGDOM

Distributors for all other countries: Kluwer Academic Publishers Group Distribution Centre Post Office Box 322 3300 AH Dordrecht, THE NETHERLANDS

Library of Congress Cataloging-in-Publication Data

Rappaport Symposium (2nd: 1988: Haifa, Israel) Lethal arrhythmias resulting from myocardial ischemia and infarction: proceedings of the

Second Rappaport Symposium/edited by Michael R. Rosen, Yoram Palti. p. cm. - (Developments in cardiovascular medicine)

Symposium held in Haifa, Israel, March 13-16, 1988. Includes bibliographies and index.

ISBN-13: 978-1-4612-8916-6

DOl: 10.1007/978-1-4613-1649-7

e-ISBN-13: 978-1-4613-1649-7

1. Arrhythmia-Congresses. 2. Heart-Infarction-Complications and sequelae­Congresses. 3. Ischemia-Complications and sequelae-Congresses. I. Rosen, Michael R. (Michael Robert), 1938- . 11. Palti, Yoram. 111. Title. IV. Series.

[DNLM: 1. Arrhythmia-etiology-congresses. 2. Coronary Disease-complications -congresses. 3. Heart Arrest-congresses. 4. Myocardial Infarction-complications­congresses. WI DE997VME/WG 330 R221 1988L] RC685.A65R27 1988 616.1'28-dc19 DNLMIDLC for Library of Congress

This volume is dedicated to those who made the symposium possible: the

investigators, who generously donated their time and shared their intellect,

and the Rappaport family, who graciously supported the enterprise.

CONTENTS

Participants in the symposium

Editors' Introductions

I. IONIC DETERMINANTS OF ELECTRICAL ACTIVITY

1. Calcium current and excitation-contraction coupling in heart.

w. JONATHAN LEDERER, J.R. BERLIN, N.M. COHEN,

e.G. NICHOLS, G.L. SMITH AND M.B. CANNELL

2. Role of cytosolic calcium in the normal and ischemic heart: potential new insights from the second generation indicator, Indo-I.

WILLIAM T. CLUSIN, RAJENDRA MOHABIR AND HON-CHI LEE

3. Repetitive activity: origin of the Na + load and its physiologic effects. IRA S. COHEN, FANG CHANG AND RICHARD P. KLINE

4. Ionic changes associated with acute ischemia. LEONARD S. GETTES, TIMOTHY A. JOHNSON, WILLIAM F. FLEET AND

ICHIRO WATANABE

5. Mechanisms of reperfusion arrhythmias. HAROLD C. STRAUSS, RAYMOND YEE, JOSEPH A. HILL, JR. AND THOMAS L. WENGER

II. METABOLIC FACTORS IN ISCHEMIA

6. Ischemia and N a + IK + pump function. ANDRE G. KLEBER AND WAYNE E. CASCIO

7. Amphipathic lipid metabolites and arrhythmogenesis: a perspective. PETER B. CORR AND DAVID J. DOBMEYER

8. Free radicals and myocardial injury during ischemia and reperfusion: a short-lived phenomenon? DAVID J. HEARSE

9. Thyroid hormones and cardiac function. OFER BINAH, IRIT RUBINSTEIN, BELLA FELZEN, YECHIEL SWEED AND

SELA MAGER

IX

xv

1

3

13

31

41

55

75

77

91

105

117

vii

viii Contents

III. NEURAL AND HORMONAL FACTORS

10. Receptor mechanisms in ischemia and infarction. AUGUST M. WATANABE

11. Sympathetic-parasympathetic interactions in the normal heart. MATTHEW N. LEVY

12. Central nervous system modulation of cardiac rhythm. RICHARD L. VERRIER

13. Influence of ischemia and infarction on cardiac vagal and sympathetic innervation. DOUGLAS P. ZIPES

IV. ARRHYTHMOGENIC MECHANISMS

14. On the problem of anisotropic propagation in ventricular muscle. MARIO DELMAR, CARMEN DELGADO, DANTE CHIALVO, DONALD C. MICHAELS

AND JOSE JALIFE

129

131

137

149

165

179

181

15. Anisotropic reentry: A model of arrhythmias that may necessitate a new 199 approach to antiarrhythmic drug development. ANDREW L. WIT

16. Arrhythmias in the early ischemic period. MICHIEL J. JANSE

17. Arrhythmias and the healed myocardial infarction. ROBERT J. MYERBURG, SHINICHI KIMURA, PATRICIA L. KOZLOVSKIS, ARTHUR

L. BASSETT, HEIKKI HUIKURI AND AGUSTIN CASTELLANOS

215

229

V. STRATEGIES FOR PREDICTION, PREVENTION AND THERAPY 243

18. Clinical significance and limitations of ventricular late potentials. 245 GUNTER BREITHARDT, MARTIN BORGGREFE, ULRICH KARBENN AND

ANTONI MARTINEZ-RUBIO

19. Pacing to predict mechanism: transient entrainment and reentry. ALBERT L. WALDO AND RICHARD W. HENTHORN

20. The value of programmed electrical stimulation in triggered activity-induced arrhythmias. ANTON P.M. GORGELS, MARC A. VOS, PEDRO BRUGADA AND

HEIN J.J. WELLENS

21. Pharmacologic mechanisms in the treatment of arrhythmias due to ischemia and infarction. BRIAN F. HOFFMAN AND WALTER SPINELLI

22. Cardiac innervation and sudden death: new strategies for prevention. PETER J. SCHWARTZ

255

269

281

293

PARTICIPANTS IN THE SYMPOSIUM

Ofer Binah, Ph.D. Departments of Biophysics and Physiology Rappaport Family Institute for Research in the Medical Sciences Technion-Israel Institute of Technology Faculty of Medicine Efron Street-Post Office Box 9697 Haifa 31096 Israel

Dr. Gunter Breithardt Professor of Medicine (Cardiology) Direktor Medizinische Klinik und Poliklinik Innere Medizin C Westfalische Wilhelms Universitat Munster Albert-Schweitzer-Strabe 33 D-4400 Munster West Germany

William Clusin, M. D., Ph. D. Assistant Professor of Medicine and Physiology Falk Cardiovascular Research Center Stanford University School of Medicine 300 Pasteur Drive Stanford, California 94305

ix

x Contributing Authors

Ira S.Cohen, M.D., Ph.D. Professor of Physiology and Biophysics Health Sciences Center State University of New York at Stony Brook Stony Brook, New York 11794

Peter B. Corr, Ph.D. Associate Professor of Medicine and Pharmacology Department of Internal Medicine Cardiovascular Division Washington University School of Medicine 660 South Euclid A venue St. Louis, Missouri 63110

Leonard S. Gettes, M.D. Director, Divison of Cardiology University of North Carolina at Chapel Hill 349 Clinical Sciences Building, 229-H Chapel Hill, North Carolina 27514

Dr. David J. Hearse Professor The Rayne Institute The Medical School St. Thomas' Hospital London SE 1 7EH England

Dr. Anton P.M. Gorgels Experimentele Cardiologie Academisch Rijksuniversiteit Limburg Annadal1 Maastricht 6201BX The Netherlands

Brian Hoffman, M.D. David Hosack Professor and Chairman Department of Pharmacology College of Physicians and Surgeons Columbia University 630 West 168th Street New York, New York 10032

Jose Jalife, M.D. Professor Department of Pharmacology College of Medicine State University of New York Health Science Center 766 Irving A venue Syracuse, New York 13210

Dr. MichielJ. Janse Professor Klinische en Experimentele Cardiologie Academisch Ziekenhuis Bij de Universiteit van Amsterdam Academisch Medisch Centrum Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Dr. Andre G. Kleber Physiologisches Institut Universitat Bern Buehlplatz 5 3012 Bern Switzerland

W. Jonathan Lederer, M.D., Ph.D. Associate Professor Department of Physiology University of Maryland School of Medicine 660 West Redwood Street Baltimore, Maryland 21201

Matthew N. Levy, M.D. Chief, Investigative Medicine The Mt. Sinai Medical Center One Mt. Sinai Drive Cleveland, Ohio 44106

xi

xii Contributing Authors

Robert Myerburg, M.D. Professor of Medicine and Physiology Director, Division of Cardiology University of Miami School of Medicine Post Office Box 16960 Miami, Florida 33101

Yoram Palti, M.D., Ph.D. Director, Rappaport Family Institute for Research in the Medical Sciences Technion-Israel Institute of Technology Efron Street, Post Office Box 9697 Haifa 31096 Israel

Michael R. Rosen, M. D. Professor of Pharmacology and Pediatrics Department of Pharmacology Columbia University College of Physicians and Surgeons 630 West 168th Street, P&S 7-517 New York, New York 10032

Peter J. Schwartz, M.D. Associate Professor of Medicine Instituto di Clinical Medica Generale e Terapia Medica Universita di Milano Centro di Fisiologia Clinica e Ipertensione Via Fancesco Sforza 35 20122 Milano Italy

Harold Strauss, M.D. Department of Medicine Duke University Medical School Box 3845 Durham, North Carolina 27710

Richard L. Verrier, Ph.D. Professor of Pharmacology Georgetown University School of Medicine Medical-Dental Building C-Y02 4900 Reservoir A venue Washington, D. C. 20007

Albert L. Waldo, M.D. Pritchard Professor of Cardiology and Professor of Medicine Department of Medicine Case Western Reserve University School of Medicine University Hospitals of Cleveland 2074 Abington Road Cleveland, Ohio 44106

August M. Watanabe, M.D. Professor of Medicine and Pharmacology Indiana University School of Medicine 1100 West Michigan Street Indianapolis, Indiana 46223

Andrew L. Wit, Ph.D. Professor Department of Pharmacology Columbia University College of Physicians & Surgeons 630 West 168th Street New York, New York 10032

Douglas P. Zipes, M.D. Professor of Medicine Director, Cardiovascular Research Indiana University School of Medicine 1100 West Michigan Street Indianapolis, Indiana 46223

xiii

EDITORS' INTRODUCTIONS

For some years I have wondered what it would be like to gather a small group of outstanding investigators and to place them in a room for a few days with nothing to do but talk to one another. Therefore, I was elated when Y oram Palti telephoned me two years ago with just this plan in mind. The format we agreed to was simple-to bring such a group of investigators to the Rappaport Institute of the Technion, to closet them in a conference room, and to set aside a period of time during which each could express his views about what he considered to be a critical aspect of his research. No slides would be permitted-only verbal communication and liberal use of a blackboard. Moreover, interruptions would not only be permitted but also encouraged; after each investigator began to talk, others in the group could interrupt at will. We felt that if the group dynamics worked out appropriate­ly, then no one would be able to complete his planned remarks, but the resultant discussions would lead us to new insights and directions concerning research.

Since the order of the meeting was obviously based on chaos, we belived that some form of structure had to be imposed to maintain an overall focus. The first attempt at structure was the theme of the meeting itself: Lethal Arrhythmias in the Setting of Myocardial Ischemia and Infarction. Certainly, this is an important topic, but having settled on it, we decided to interpret it in the loosest possible sense. That is, rather than consider arrhythmias alone, we included a diversity of factors that might modulate them: neuroendocrine,

xv

xvi Editors' Introductions

metabolic, and ionic. This approach, in turn, required the participation of a diversity of investigator interests and skills. Hence, we invited clinical and basic investigators whose research interests ranged from studies of membrane patches to studies of the patient. This diversity of interests concerned us. How often have we attended meetings where the clinical scientists talk only to each other, the basic scientists do the same, and there is a minimum of interaction? This concern led us to the second aspect of the structure; that is, all partici­pants were requested to remain in the meeting room throughout the duration of the meeting. It is of interest that the request was followed, with a minimum of comings and goings, and clinically and basically oriented individuals found a variety of ground for common discussion. As for the third aspect of the structure, you are holding it in your hands. We believed that to prepare for the meeting, it would be helpful if each individual would write a position paper. We requested an essay, not highly illustrated or referenced, and not necessarily balanced in terms of one's field of research. Ideally, we wanted it to highlight exciting areas of investigation now occurring and to stress directions for future research. These papers were distributed to all partici­pants, one month before the meeting, and provided an initial framework for the participants' consideration.

No tapes or other permanent records were made at the meeting, except for the continual taking of notes by all participants. Based on the discussions and ideas generated, as well as the active participation by all present, my prejudice is to think that the meeting was successful. This book, which contains only a fraction of the ideas stated, nonetheless, serves as an indicator and partial transcript of what transpired.

There are many people for me to thank: first of all my co-editor and co-director of the meeting, Y oram Palti, without whose interest the meeting could never have been conceived and carried out; second, the Rappaport family and the Technion, for their support of the meeting; third, Haia Ganzarski and Rina Banks, whose tireless administrative efforts were re­quired to arrange arrival, departure, and all that occurred in between. Finally, and most important, I would like to thank the participants themselves, for their efforts in preparing for the meeting (including submitting their papers for this volume), for their willingness to share their ideas and fantasies­armed only with blackboard and chalk-before a highly critical cohort of peers, and without whose abilities at communication and criticism there simply would have been no meeting.

Michael R. Rosen Haifa March 17, 1988

xvii

The research program of the Rappaport Institute for Research in the Medical Sciences gives priority to the cardiovascular system. Since this area is staffed at the Institute by relatively young scientists, we asked Mike Rosen for assistance with its development. Mike provided us not only with develop­mental guidance, but also served as the driving force and spirit behind the organization of the second Rappaport Symposium, which was dedicated to Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction.

The symposium topic, which is of prime medical importance, is of special interest to our cardiovascular researchers, most of whom are concerned with cardiac electrophysiology and/or ischemia. I believe the panel of scientists that assembled here represented the ultimate researchers in their fields and were well balanced between clinical and basic sciences. With his charming but firm leadership, Mike managed to conduct the meetings to use the talents, experience, wisdom, and humor of the participants to the utmost. Thus, I feel that we have experienced a stimulating, informative, and at the same time, pleasant meeting.

I am taking this opportunity to thank the participants in the symposium for their scientific contributions and for the friendship they extended to us. I am sure that I speak for all of them when I thank the Institute staff that helped to organize the symposium. I especially want to thank the Meeting Secretary Haia Ganzarski who put forth tireless efforts, used good taste, and exhibited high spirits to ensure that every moment was an enjoyable one.

xviii Editors' Introductions

I hope that the meeting will encourage further interactions and cooperation among all the participants and will benefit each individual's scientific progress and the progress of the medical community as a whole.

Finally, we are grateful to the Rappaport Family for supporting this sym­posium among their many projects that support medical science in Israel and elsewhere.

Yoram Palti Haifa March 17, 1988