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NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS
Edited by
George Edward BillmanProfessor of Physiology and Cell Biology
The Ohio State University
InnodataFile Attachment9780470561409.jpg
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NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS
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NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS
Edited by
George Edward BillmanProfessor of Physiology and Cell Biology
The Ohio State University
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Copyright � 2010 by John Wiley & Sons, Inc. All rights reserved.
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Library of Congress Cataloging-in-Publication Data:
Novel therapeutic targets for antiarrhythmic drugs / [edited by] George E. Billman.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-26100-2 (cloth)
1. Myocardial depressants. 2. Arrhythmia–Chemotherapy. I. Billman, George E.
[DNLM: 1. Antiarrhythmia Agents. 2. Arrhythmias, Cardiac–drug therapy.
QV 150 N937 2010]
RM347.N68 2010
616.1028061–dc222009020796
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
http://www.copyright.comhttp://www.wiley.com/go/permissionshttp://www.wiley.com
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To Rosemary, friend, confidante, soul mate, and life partner—semper gaude.
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CONTENTS
Acknowledgments xix
Contributors xxi
1. Introduction 1George E. Billman
References 3
2. Myocardial Kþ Channels: Primary Determinants ofAction Potential Repolarization 5Noriko Niwa and Jeanne Nerbonne
2.1 Introduction 5
2.2 Action Potential Waveforms and Repolarizing Kþ Currents 72.3 Functional Diversity of Repolarizing Myocardial Kþ Channels 92.4 Molecular Diversity of Kþ Channel Subunits 122.5 Molecular Determinants of Functional Cardiac Ito Channels 16
2.6 Molecular Determinants of Functional Cardiac IK Channels 18
2.7 Molecular Determinants of Functional Cardiac Kir Channels 23
2.8 Other Potassium Currents Contributing to Action
Potential Repolarization 27
2.8.1 Myocardial Kþ Channel Functioning in MacromolecularProtein Complexes 28
References 32
3. The ‘‘Funny’’ Pacemaker Current 59
Andrea Barbuti, Annalisa Bucchi, Mirko Baruscotti, and
Dario DiFrancesco
3.1 Introduction: The Mechanism of Cardiac Pacemaking 59
3.2 The ‘‘Funny’’ Current 60
3.2.1 Historical Background 60
3.2.2 Biophysical Properties of the If Current 61
3.2.3 Autonomic Modulation 63
3.2.4 Cardiac Distribution of If 63
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3.3 Molecular Determinants of the If Current 64
3.3.1 HCN Clones and Pacemaker Channels 64
3.3.2 Identification of Structural Elements Involved in
Channel Gating 66
3.3.3 Regulation of Pacemaker Channel Activity: “Context”
Dependence and Protein-Protein Interactions 70
3.3.4 HCN Gene Regulation 71
3.4 Blockers of Funny Channels 72
3.4.1 Alinidine (ST567) 73
3.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49),
and Cilobradine (DK-AH269) 73
3.4.3 ZD7288 75
3.4.4 Ivabradine (S16257) 75
3.4.5 Effects of the Heart Rate Reducing Agents on HCN
Isoforms 78
3.5 Genetics of HCN Channels 78
3.5.1 HCN-KO Models 78
3.5.2 Pathologies Associated with HCN Dysfunctions 79
3.6 HCN-Based Biological Pacemakers 81
References 84
4. Arrhythmia Mechanisms in Ischemia and Infarction 101Ruben Coronel, Wen Dun, Penelope A. Boyden, and
Jacques M.T. de Bakker
4.1 Introduction 101
4.1.1 Modes of Ischemia, Phases of Arrhythmogenesis 102
4.1.2 Trigger-Substrate-Modulating Factors 103
4.2 Arrhythmogenesis in Acute Myocardial Ischemia 103
4.2.1 Phase 1A 103
4.2.2 Phase 1B 113
4.2.3 Arrhythmogenic Mechanism: Trigger 114
4.2.4 Catecholamines 115
4.3 Arrhythmogenesis During the First Week Post MI 115
4.3.1 Mechanisms 115
4.3.2 The Subendocardial Purkinje Cell as a Trigger
24–48 H Post Occlusion 116
4.3.3 Five Days Post-Occlusion: Epicardial Border Zone 120
4.4 Arrhythmia Mechanisms in Chronic Infarction 128
4.4.1 Reentry and Focal Mechanisms 128
4.4.2 Heterogeneity of Ion Channel Expression in the
Healthy Heart 129
4.4.3 Remodeling in Chronic Myocardial Infarction 131
4.4.4 Structural Remodeling 133
4.4.5 Role of the Purkinje System 135
References 136
viii CONTENTS
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5. Antiarrhythmic Drug Classification 155Cynthia A. Carnes
5.1 Introduction 155
5.2 Sodium Channel Blockers 155
5.2.1 Mixed Sodium Channel Blockers (Vaughan Williams
Class Ia) 156
5.3 Inhibitors of the Fast Sodium Current with Rapid Kinetics
(Vaughan Williams Class Ib) 158
5.3.1 Lidocaine 158
5.3.2 Mexiletine 159
5.4 Inhibitors of the Fast Sodium Current with Slow Kinetics
(Vaughan Williams Class Ic) 159
5.4.1 Flecainide 159
5.4.2 Propafenone 160
5.5 Inhibitors of Repolarizing Kþ Currents (VaughanWilliams Class III) 160
5.5.1 Dofetilide 160
5.5.2 Sotalol 161
5.5.3 Amiodarone 161
5.5.4 Ibutilide 162
5.6 IKur Blockers 162
5.7 Inhibitors of Calcium Channels 162
5.7.1 Verapamil and Diltiazem 162
5.8 Inhibitors of Adrenergically-Modulated Electrophysiology 163
5.8.1 Funny Current (If) Inhibitors 163
5.8.2 Beta-Adrenergic Receptor Antagonists 164
5.9 Adenosine 164
5.10 Digoxin 165
5.11 Conclusions 165
References 165
6. Repolarization Reserve and Proarrhythmic Risk 171Andr�as Varró
6.1 Definitions and Background 171
6.2 The Major Players Contributing to Repolarization Reserve 175
6.2.1 Inward Sodium Current (INa) 175
6.2.2 Inward L-Type Calcium Current (ICa,L) 176
6.2.3 Rapid Delayed Rectifier Outward Potassium Current (IKr) 177
6.2.4 Slow Delayed Rectifier Outward Potassium Current (IKs) 178
6.2.5 Inward Rectifier Potassium Current (Ik1) 179
6.2.6 Transient Outward Potassium Current (Ito) 180
6.2.7 Sodium—Potassium Pump Current (INa/K) 180
6.2.8 Sodium–Calcium Exchanger Current (NCX) 180
6.3 Mechanism of Arrhythmia Caused By Decreased
Repolarization Reserve 182
CONTENTS ix
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6.4 Clinical Significance of the Reduced Repolarization Reserve 183
6.4.1 Genetic Defects 184
6.4.2 Heart Failure 185
6.4.3 Diabetes Mellitus 185
6.4.4 Gender 186
6.4.5 Renal Failure 187
6.4.6 Hypokalemia 187
6.4.7 Hypothyroidism 187
6.4.8 Competitive Athletes 188
6.5 Repolarization Reserve as a Dynamically Changing Factor 188
6.6 How to Measure the Repolarization Reserve 189
6.7 Pharmacological Modulation of the Repolarization Reserve 191
6.8 Conclusion 193
References 194
7. Safety Challenges in the Development of NovelAntiarrhythmic Drugs 201Gary Gintant and Zhi Su
7.1 Introduction 201
7.2 Review of Basic Functional Cardiac Electrophysiology 202
7.2.1 Normal Pacemaker Activity 203
7.2.2 Atrioventricular Conduction 204
7.2.3 Ventricular Repolarization: Effects on the QT Interval 204
7.2.4 Electrophysiologic Lessons Learned from
Long QT Syndromes 205
7.3 Safety Pharmacology Perspectives on Developing
Antiarrhythmic Drugs 206
7.3.1. Part A. On-Target (Primary Pharmacodynamic) versus
Off-Target (Secondary Pharmacodynamic)
Considerations 206
7.3.2 Part B. General Considerations 207
7.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs 208
7.4.1 Sodium Channel Block Reduces the Incidence of
Ventricular Premature Depolarizations But Increases
Mortality 208
7.4.2 Delayed Ventricular Repolarization with d-Sotalol
Increases Mortality in Patients with Left Ventricular
Dysfunction and Remote Myocardial Infarction:
The SWORD and DIAMOND Trials 210
7.4.3 Ranolazine: An Antianginal Agent with a Novel
Electrophysiologic Action and Potential Antiarrhythmic
Properties 213
7.5 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs 217
7.5.1 Introduction 217
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7.5.2. Lessons Learned with Azimilide, a Class III
Drug that Reduces the Delayed Rectifier Currents
IKr and IKs 218
7.5.3 Atrial Repolarizing Delaying Agents. Experience with
Vernakalant, a Drug that Blocks Multiple Cardiac
Currents (Including the Atrial-Specific Repolarizing
Current IKur) 220
References 222
8. Safety Pharmacology and Regulatory Issues in the
Development of Antiarrhythmic Medications 233
Armando Lagrutta and Joseph J. Salata
8.1 Introduction 233
8.2 Basic Physiological Considerations 234
8.2.1 Ion Channels and Arrhythmogenesis 234
8.2.2 Antiarrhythmic Agents 236
8.3 Historical Considerations 237
8.3.1 CAST: Background, Clinical Findings, and Aftermath 237
8.3.2 Torsades de Pointes and hERG Channel Inhibition:
Safety Pharmacology Concern with Critical Impact on
Antiarrhythmic Development 239
8.3.3 Recent Clinical Trials 242
8.4 Opportunities for Antiarrhythmic Drug Development in the
Present Regulatory Environment 244
8.4.1 ICH—S7A and S7B; E14 245
8.4.2 Additional Regulatory Guidance 248
8.4.3 Clinical Management Guidelines and Related
Considerations About Patient Populations 250
8.4.4 Consortia Efforts to Address Safety Concerns
Related to Antiarrhythmic Drug Development 253
8.4.5 The Unmet Medical Need: Challenges
and Opportunities 254
References 256
9. Ion Channel Remodeling and Arrhythmias 271Takeshi Aiba and Gordon F. Tomaselli
9.1 Introduction 271
9.2 Molecular and Cellular Basis for Cardiac Excitability 271
9.3 Heart Failure—Epidemiology and the Arrhythmia Connection 272
9.4 Kþ Channel Remodeling in Heart Failure 2749.4.1 Transient Outward Current (Ito) 274
9.4.2 Inward Rectifier Kþ Current (IK1) 2769.4.3 Delayed Rectifier K Currents (IKr and IKs) 277
CONTENTS xi
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9.5 Ca2þ Handling and Arrhythmia Risk 2789.5.1 L-type Ca2þ Current ICa-L 2789.5.2 Sarcoplasmic Recticulum Function 278
9.6 Intracellular [Naþ ] in HF 2829.6.1 Cardiac INa in HF 282
9.6.2 Naþ /Kþ ATPase 2839.7 Gap Junctions and Connexins 283
9.8 Autonomic Signaling 284
9.9 Calmodulin Kinase 285
9.10 Conclusions 286
References 286
10. Redox Modification of Ryanodine Receptors in CardiacArrhythmia and Failure: A Potential Therapeutic Target 299
Andriy E. Belevych, Dmitry Terentyev, and Sandor Gy€orke
10.1 Introduction 299
10.2 Activation and Deactivation of Ryanodine Receptors
During Normal Excitation-Contraction Coupling 300
10.3 Defective Ryanodine Receptor Function is Linked to
Proarrhythmic Delayed Afterdepolarizations and Calcium
Alternans 301
10.4 Genetic and Acquired Defects in Ryanodine Receptors 302
10.5 Effects of Thiol-Modifying Agents on Ryanodine
Receptors 303
10.6 Reactive Oxygen Species Production and Oxidative
Stress in Cardiac Disease 304
10.7 Redox Modification of Ryanodine Receptors in Cardiac
Arrhythmia and Heart Failure 305
10.8 Therapeutic Potential of Normalizing Ryanodine
Receptor Function 306
References 308
11. Targeting Naþ /Ca2þ Exchange as anAntiarrhythmic Strategy 313Gudrun Antoons, Rik Willems, and Karin R. Sipido
11.1 Introduction 313
11.2 Why Target NCX in Arrhythmias? 314
11.3 When Do We See Triggered Arrhythmias? 317
11.4 What Drugs are Available? 318
11.5 Experience with NCX Inhibitors 321
11.6 Caveat—the Consequences on Ca2þ Handling 32811.7 Need for More Development 331
References 332
xii CONTENTS
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12. Calcium/Calmodulin-Dependent Protein Kinase II
(CaMKII)—Modulation of Ion Currents and Potential Role
for Arrhythmias 339Dr. Lars S. Maier
12.1 Introduction 339
12.2 Evolving Role of Ca2þ /CaMKII in the Heart 34012.3 Activation of CaMKII 340
12.4 Role of CaMKII in ECC 342
12.4.1 Ca2þ Influx and ICa Facilitation 34312.4.2 SR Ca2þ Release and SR Ca Leak 34412.4.3 SR Ca2þ Uptake, FDAR, Acidosis 34612.4.4 Naþ Channels 34812.4.5 Kþ Channels 353
12.5 Role of CaMKII for Arrhythmias 354
12.6 Summary 355
Acknowledgments 356
References 356
13. Selective Targeting of Ventricular Potassium Channels
for Arrhythmia Suppression: Feasible or Risible? 367
Hugh Clements-Jewery and Michael Curtis
13.1 Introduction 367
13.2 Effects of Kþ Channel Blockade on APD andArrhythmogenesis 371
13.2.1 IKur Blockade 371
13.2.2 IKr Blockade 371
13.2.3 IKs Blockade 372
13.2.4 IK1 Blockade 372
13.2.5 Ito Blockade 373
13.2.6 IKATP Blockade 374
13.3 Conclusions/Future Directions 375
References 375
14. Cardiac Sarcolemmal ATP-sensitive Potassium Channel
Antagonists: A Class of Drugs that May Selectively
Target the Ischemic Myocardium 381George E. Billman
14.1 Introduction 381
14.2 Effects of Myocardial Ischemia on Extracellular
Potassium 382
14.3 Effect of Extracellular Potassium on Ventricular Rhythm 386
CONTENTS xiii
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14.4 Effect of ATP-sensitive Potassium Channel Antagonists
on Ventricular Arrhythmias 387
14.4.1 Nonselective ATP-sensitive Potassium Channel
Antagonists 387
14.4.2 Selective ATP-sensitive Potassium Channel
Antagonist 390
14.4.3 Proarrhythmic Effects of ATP-sensitive Potassium
Channel Agonists 397
14.5 Summary 401
References 401
15. Mitochondrial Origin of Ischemia-Reperfusion Arrhythmias 413Brian O’Rourke, PHD
15.1 Introduction 413
15.2 Mechanisms of Arrhythmias 414
15.2.1 Automacity 414
15.2.2 Triggered Arrhythmias 415
15.3 Ischemia-Reperfusion Arrhythmias 417
15.4 Mitochondrial Criticality: The Root of
Ischemia-Reperfusion Arrhythmias 418
15.5 KATP Activation and Arrhythmias 420
15.6 Metabolic Sinks and Reperfusion Arrhythmias 422
15.7 Antioxidant Depletion 423
15.8 Mitochondria as Therapeutic Targets 423
References 424
16. Cardiac Gap Junctions: A New Target for New
Antiarrhythmic Drugs: Gap Junction Modulators 431Anja Hagen and Stefan Dhein
16.1 Introduction 431
16.2 The Development of Gap Junction Modulators and AAPs 433
16.3 Molecular Mechanisms of Action of AAPs 436
16.4 Antiarrhythmic Effects of AAPs 439
16.4.1 Ventricular Fibrillation and Ventricular Tachycardia 444
16.4.2 Atrial fibrillation 444
16.4.3 Others 445
16.5 Site- and Condition-Specific Effects of AAPs; Effects
in Ischemia or Simulated Ischemia 446
16.6 Chemistry of AAPs 447
16.7 Short Overview About Cardiac Gap Junctions 447
16.8 Gap Junction Modulation as a New Antiarrhythmic
Principle 452
References 453
xiv CONTENTS
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17. Novel Pharmacological Targets for the Management
of Atrial Fibrillation 461Alexander Burashnikov and Charles Antzelevitch
17.1 Introduction 461
17.2 Novel Ion Channel Targets for Atrial Fibrillation Treatment 462
17.2.1 The Ultrarapid Delayed Rectifier Potassium
Current (IKur) 462
17.2.2 The Acetylcholine-Regulated Inward Rectifying
Potassium Current (IK-ACh) and the Constitutively
Active (CA) IK-ACh 464
17.2.3 The Early Sodium Current (INa) 464
17.2.4 Block IKr and Its Relation to Atrial Selectivity of INaBlockade 467
17.2.5 Other Potential Atrial-Selective Ion Channel Targets for
the Treatment AF 467
17.2.6 Influence of Atrial- Selective Agents on Ventricular
Arrhythmias? 468
17.3 Upstream Therapy Targets for Atrial Fibrillation 468
17.4 Gap Junction as Targets for AF Therapy 469
17.5 Intracellular Calcium Handling and AF 470
References 471
18. IKur, Ultra-rapid Delayed Rectifier Potassium Current:
A Therapeutic Target for Atrial Arrhythmias 479Arun Sridhar and Cynthia A. Carnes
18.1 Introduction 479
18.2 Molecular Biology of the Kv1.5 Channels: 480
18.2.1 Kv1.5 Activation and Inactivation 480
18.2.2 Where Does IKur Fit Into the Cardiac Action Potential? 482
18.2.3 Adrenergic Modulation of IKur 485
18.3 IKur as a Therapeutic Target 485
18.4 Organic Blockers of IKur 486
18.4.1 Mixed Channel Blockers 486
18.4.2 Mixed Channel Blockers 487
18.4.3 Selective Kv1.5 Blockers 488
18.5 Conclusions 490
References 490
19. Non-Pharmacologic Manipulation of the Autonomic
Nervous System in Human for the Prevention of Life-ThreateningArrhythmias 495
Peter J. Schwartz
19.1 Introduction 495
CONTENTS xv
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19.2 Sympathetic Nervous System 496
19.2.1 Experimental Background 496
19.2.2 Clinical Evidence 497
19.3 Parasympathetic Nervous System 500
19.3.1 Experimental Background 500
19.3.2 Clinical Evidence 501
19.4 Conclusion 504
Acknowledgement 504
References 504
20. Effects of Endurance Exercise Training on CardiacAutonomic Regulation and Susceptibility to Sudden Cardiac
Death: A Nonpharmacological Approach for the Prevention
of Ventricular Fibrillation 509George E. Billman
20.1 Introduction 509
20.2 Exercise and Susceptibility to Sudden Death 510
20.2.1 Clinical Studies 510
20.2.2 Experimental Studies 515
20.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death 518
20.4 b2-Adrenergic Receptor Activation and Susceptibility to VF 52120.5 Effect of Exercise Conditioning on Cardiac
Autonomic Regulation 523
20.6 Effect of Exercise Training on Myocyte Calcium Regulation 528
20.7 Summary and Conclusions 530
References 531
21. Dietary Omega-3 Fatty Acids as a Nonpharmacological
Antiarrhythmic Intervention 543Barry London and J. Michael Frangiskakis
21.1 Introduction 543
21.2 Fatty Acid Metabolism 544
21.2.1 Nomenclature 544
21.2.2 Dietary Fatty Acids 544
21.2.3 Roles of Polyunsaturated Fatty Acids 545
21.3 Cellular Mechanisms 545
21.3.1 Ion Channel Blockade 545
21.3.2 Direct Membrane Effects 547
21.3.3 Phosphorylation 548
21.3.4 Inflammation 548
21.3.5 Summary 548
21.4 Animal Studies 548
21.4.1 Acute Intravenous Effects of n-3 PUFAs 549
xvi CONTENTS
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21.4.2 Dietary Supplementation with n-3 PUFAs 549
21.5 Clinical Studies 550
21.5.1 Observational Studies 550
21.5.2 Randomized Trials 551
21.5.3 Surrogate Markers for Arrhythmias 555
21.5.4 Summary 555
21.6 Future Directions 556
References 556
General Index 567
Index of Drug and Chemical Names 575
CONTENTS xvii
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ACKNOWLEDGMENTS
As John Donne, the 17th century, British metaphysical poet and Anglican Priest so
beautifully stated, “No man is an island, entire in itself. . .” (from Mediation XVII),this book results from the efforts of many. I wish to express my gratitude to many
individuals who not only assisted in the preparation of this book but also guided me
alongmy life’s journey. First, I wish to thankmy parents who nurturedmy curiosity as
well as my wife and children for their love and support in both the good times and the
bad. I also thank the faculty of the Department of Physiology and Biophysics at the
University of Kentucky for their support while I earned my doctorate degree. In
particular, I wish to acknowledge Dr. James Zolman, who taught me how to analyze
research articles critically and interpret statistical results accurately. I am deeply
indebted tomymentor, Dr. David C. Randall, who gaveme the freedom to fail and the
support to succeed. My career development was enhanced even more by my
postdoctoral advisor Dr. H. Lowell Stone (deceased) at the University of Oklahoma,
who taught me the art of “grantsmanship” and gave me the opportunity to pursue
independent research interests that led to my first grant. I also appreciate the help and
good humor of Dr. M. Jack Keyl (deceased), whose infectious enthusiasm kept
research fun and exciting, even in those all too common times when experiments did
notwork as planned and funding fell short of expected. Iwould not be the scientist that
I am today without the guidance and support of the individuals mentioned above.
Finally, I wish to thankMr. Jonathan Rose for inviting me towrite this book and to the
authors of the individual chapters; truly without their contributions, this book would
not have been possible.
xix
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CONTRIBUTORS
Takeshi Aiba, M.D., Ph.D.
Johns Hopkins University
Gudrun Antoons, Ph.D.
Laboratory of Experimental Cardiology
Catholic University of Leuven (KUL)
Belgium
Charles Antzelevitch, Ph.D., F.A.C.C., F.A.H.A., F.H.R.S.
Executive Director and Director of Research
Gordon K. Moe Scholar
Masonic Medical Research Laboratory
Andrea Barbuti, Ph.D.
Departmento of Biomolecular Sciences and Biotechnology
Universit�a degli Studi di Milano
Mirko Baruscotti, Ph.D.
Departmento of Biomolecular Sciences and Biotechnology
Universit�a degli Studi di Milano, Italy
Andriy E. Belevych, Ph.D.Davis Heart and Lung Research Institute
The Ohio State University Medical Center
George E. Billman, Ph.D, F.A.H.A.Department of Physiology and Cell Biology
The Ohio State University
Penelope A. Boyden, Ph.D.
Department of Pharmacology
Center for Molecular Therapeutics
Columbia College of Physicians and Surgeons
Annalisa Bucchi, Ph.D.Departmento of Biomolecular Sciences and Biotechnology
Universit�a degli Studi di Milano, Italy
xxi
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Alexander Burashnikov, Ph.D.
Masonic Medical Research Laboratory
Cynthia A. Carnes, Pharm.D., Ph.D., F.A.H.A., F.H.R.S.College of Pharmacy
The Ohio State University
Hugh Clements-Jewery, Ph.D.
Division of Functional Biology
West Virginia School of Osteopathic Medicine
Ruben Coronel, M.D., Ph.D.Department of Experimental Cardiology
Academic Medical Center, The Netherlands
Michael Curtis, Ph.D, F.H.E.A., F.B.Pharmcol.S
Cardiovascular Division
Rayne Institute
St. Thomas’ Hospital
King’s College London
United Kingdom
Jacques M.T. de Bakker, Ph.D.
Department of Experimental Cardiology
Academic Medical Center, The Netherlands
Stefan Dhein, M.D., Ph.D.
Heart Centre Leipzig
University of Leipzig
Germany
Dario DiFrancesco, Ph.D.
Departmento of Biomolecular Sciences and Biotechnology
Universit�a degli Studi di Milano, Italy
Wen Dun, Ph.D.
Department of Pharmacology
Center for Molecular Therapeutics
Columbia College of Physicians and Surgeons
J. Michael Frangiskakis, M.D., Ph.DUPMC Cardiovascular Institute
University of Pittsburgh
Gary Gintant, Ph.D.Department of Integrative Pharmacology
Abbot Laboratories
Sandor Gy€orke, Ph.D.Davis Heart and Lung Research Institute
The Ohio State University Medical Center
xxii CONTRIBUTORS
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Anja Hagen, Ph.D.
University of Leipzig
University Hospital for Children and Adolescents
Germany
Armando Lagrutta, Ph.D.
Senior Investigator, Safety and Exploratory Pharmacology
Merck Research Laboratories
Barry London, M.D., Ph.D.
UPMC Cardiovascular Institute
University of Pittsburgh
Lars S. Maier, M.D.
Department of Cardiology and Pneumology / Heart Center
Georg-August-University G€ottingenGermany
Jeanne Nerbonne, Ph.D.Department of Molecular Biology and Pharmacology
Washington University
School of Medicine
Noriko Niwa, Ph.D.
Department of Molecular Biology and Pharmacology
Washington University
School of Medicine
Brian O’Rourke, Ph.D.
Division of Cardiology
Department of Medicine
Johns Hopkins University
Peter J. Schwartz, M.D.
Professor and Chairman
Department of Cardiology
Fondazione IRCCS Policlinico S. Matteo
Italy
Joseph J. Salata, Ph.D.
Director, Safety and Exploratory Pharmacology
Safety Assessment
Merck Research Laboratories
Arun Sridhar, Ph.D.
Safety Pharmacology GlaxoSmithKline United Kingdom
Karin R. Sipido, M.D., Ph.D.
Laboratory of Experimental Cardiology
Catholic University of Leuven (KUL)
Belgium
CONTRIBUTORS xxiii
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Zhi Su, Ph.D.
Department of Integrative Pharmacology
Abbot Laboratories
Dmitry Terentyev, Ph.D.
Davis Heart and Lung Research Institute
The Ohio State University Medical Center
Gordon F. Tomaselli, M.D.
Michel Mirowski MD Professor of Cardiology
Chair of Cardiology
Johns Hopkins University
Andr�as Varró, M.D., Ph.D., Sc.D.Department of Pharmacology and Pharmacotherapy
University of Szeged
Albert Szent-Gy€orgyi Medical Center, Hungary
Rik Willems, M.D.
Department of Cardiology
University Hospital of Leuven
Belgium
xxiv CONTRIBUTORS
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CHAPTER 1
Introduction
GEORGE E. BILLMAN
“. . . ignorance more frequently begets confidence than does knowledge: it is those whoknow little, and not those who know much, who so positively assert that this or that
problem will never be solved by science.” Charles Darwin [1]
“Thegreatest failure – not trying in the first place.The best angle to approach problems is
the try-angle.” Jean Shirer Ingold [2]
The effective management of cardiac arrhythmias, either of atrial or ventricular
origin, remains a major challenge for the cardiologist. Sudden cardiac death (defined
as unexpected death from cardiac causes that occurs within 1 hour of the onset of
symptoms [3]) remains the leading cause of death in industrially developed countries,
and it accounts for between 300,000 and 500,000 deaths each year in the United
States [4–6]. Holter monitoring studies reveal that these sudden deaths most fre-
quently (up to 93%) resulted from ventricular tachyarrhythmias [7–9]. In a similar
manner, atrial fibrillation is the most common rhythm disorder contributing to a
substantial mortality, as well as a reduction in the quality of life, among these
patients [10, 11]. Atrial fibrillation currently accounts for about 2.3 million cases in
the United States and has been projected to increase by 2.5 fold over the next half
century [12]. Indeed, the prevalence of this arrhythmia increases with each decade
of life (0.5% patient population between the ages of 50 to 59 years climbing to almost
9% at age 80–89 years) and contributes to approximately one quarter of ischemic
strokes in the elderly population [10, 11]. The economic impact associated with the
morbidity andmortality resulting from cardiac arrhythmias is enormous (incremental
cost per quality-adjusted life-year as much as U.S. $558,000 [13]).
Despite the enormity of this problem, the development of safe and effective
antiarrhythmic agents remains elusive. In fact, several initially promising antiar-
rhythmic drugs have actually been shown to increase, rather than to decrease, the risk
Novel Therapeutic Targets for Antiarrhythmic Drugs, Edited by George Edward BillmanCopyright � 2010 John Wiley & Sons, Inc.
1
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for arrhythmic death in patients recovering frommyocardial infarction. For example,
the Cardiac Arrhythmia Suppression Trial (CAST study [14]) demonstrated that,
although class I antiarrhythmic drugs (i.e., drugs that block sodium channels)
effectively suppressed premature ventricular contractions, some of these compounds
(flecainide and encainide) increased the risk for arrhythmic cardiac death. In a
similar manner, many class III antiarrhythmic drugs (drugs that prolong refractory
period, most likely via modulation of potassium channels) have been shown to
prolong QT interval, to promote the life-threatening tachyarrhythmia torsades de
pointes (i.e., polymorphic ventricular tachycardia in which the QRS waves seem to
“twist” around the baseline), and to increase cardiac mortality in some patient
populations [15, 16]. Unfortunately, only a few drugs have been clinically proven to
reduce cardiac mortality in high-risk patients, such as patients recovering from
myocardial infarction. To date, only b-adrenergic receptor antagonists and amio-darone, which is a class III antiarrhythmic drug that also blocks b-adrenergicreceptors, have been shown to reduce sudden cardiac death [5, 17–21]. However,
even optimal pharmacological therapy does not completely suppress malignant
ventricular arrhythmias. For example, mortality after myocardial infarction remains
high among patients with substantial ventricular dysfunction, even when placed on
b-adrenergic receptor antagonist therapy [21]. The 1-year mortality is 10% or higher,with sudden death accounting for approximately one third of the deaths in these
high-risk patients [21]. Furthermore, the long-term use of amiodarone is limited
because of adverse side effects that include pulmonary fibrous, hepatotoxicity, and
thyroid toxicity [22]. Given the adverse actions of many antiarrhythmic medications,
as well as the partial protection afforded by even the best agents (e.g., b-adrenergicreceptor antagonists), it is obvious that more effective antiarrrhythmic therapies must
be developed.
Old ideas never truly die, just the people who hold them. Eventually, newer ideas
gain acceptance as the younger generation replaces the older generation. The major
obstacle to progress often results from the inertia of conventional thinking [23]. This
book attempts to overcome this inertia by describing some novel approaches for the
management of arrhythmias. The primary focus of the book will be on ventricular
arrhythmias, but a few chapters will also address aspects of atrial arrhythmias (see
Chapters 3, 17, and 18). The book is divided into four sections. The first section opens
with a comprehensive review of basic cardiac electrophysiology (Chapters 2 and 3)
and mechanisms responsible for arrhythmias in the setting of ischemia (Chapter 4)
and closes with a review of basic pharmacology, focusing on the classification of
antiarrhythmic drugs (Chapter 5). Section two addresses safety pharmacology: the
concept of “repolarization reserve” (Chapter 6), safety challenges (Chapter 7), and
regulatory issues (Chapter 8) for the development of novel antiarrhythmic drugs.
Section three describes several novel pharmacological targets for antiarrhythmic
drugs (Chapters 9–18). Finally, section four describes a few promising nonpharma-
cological antiarrhythmic interventions, including selective cardiac neural disruption
or nerve stimulation (Chapter 19), endurance exercise training (Chapter 20), and
dietary supplements (omega-3 polyunsaturated fatty acids, Chapter 21). The reader
is encouraged to approach each chapter with an open mind, for the prejudice of
2 INTRODUCTION
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conventional wisdom can blind. Sometimes to be a visionary, one simply has to open
one’s eyes.
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4 INTRODUCTION