NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS

Edited by

George Edward BillmanProfessor of Physiology and Cell Biology

The Ohio State University

InnodataFile Attachment9780470561409.jpg

NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS

NOVEL THERAPEUTICTARGETS FORANTIARRHYTHMIC DRUGS

Edited by

George Edward BillmanProfessor of Physiology and Cell Biology

The Ohio State University

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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

To Rosemary, friend, confidante, soul mate, and life partner—semper gaude.

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

vii

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

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

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

x CONTENTS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

conventional wisdom can blind. Sometimes to be a visionary, one simply has to open

one’s eyes.

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4 INTRODUCTION