Acknowledgments xix
Contributors xxi
1. Introduction 1
George E. Billman
References 3
2. Myocardial K+ Channels: Primary Determinants of Action Potential Repolarization 5
Noriko Niwa and Jeanne Nerbonne
2.1 Introduction 5
2.2 Action Potential Waveforms and Repolarizing K+ Currents 7
2.3 Functional Diversity of Repolarizing Myocardial K+ Channels 9
2.4 Molecular Diversity of K+ Channel Subunits 12
2.5 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 K+ Channel Functioning in Macromolecular Protein 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
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 101
Ruben 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 2448 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
5. Antiarrhythmic Drug Classification 155
Cynthia 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 K+ Currents (Vaughan Williams 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 171
Andras Varro
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 SodiumPotassium Pump Current (INa/K) 180
6.2.8 SodiumCalcium Exchanger Current (NCX) 180
6.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve 182
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 Novel Antiarrhythmic Drugs 201
Gary 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
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 ICHS7A 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 271
Takeshi Aiba and Gordon F. Tomaselli
9.1 Introduction 271
9.2 Molecular and Cellular Basis for Cardiac Excitability 271
9.3 Heart FailureEpidemiology and the Arrhythmia Connection 272
9.4 K+ Channel Remodeling in Heart Failure 274
9.4.1 Transient Outward Current (Ito) 274
9.4.2 Inward Rectifier K+ Current (IK1) 276
9.4.3 Delayed Rectifier K Currents (IKr and IKs) 277
9.5 Ca2+ Handling and Arrhythmia Risk 278
9.5.1 L-type Ca2+ Current ICa-L 278
9.5.2 Sarcoplasmic Recticulum Function 278
9.6 Intracellular [Na+] in HF 282
9.6.1 Cardiac INa in HF 282
9.6.2 Na+/K+ ATPase 283
9.7 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 Cardiac Arrhythmia and Failure: A Potential Therapeutic Target 299
Andriy E. Belevych, Dmitry Terentyev, and Sandor Gyorke
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 Na+/Ca2+ Exchange as an Antiarrhythmic Strategy 313
Gudrun 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 Caveatthe Consequences on Ca2+ Handling 328
11.7 Need for More Development 331
References 332
12. Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII)Modulation of Ion Currents and Potential Role for Arrhythmias 339
Dr. Lars S. Maier
12.1 Introduction 339
12.2 Evolving Role of Ca2+/CaMKII in the Heart 340
12.3 Activation of CaMKII 340
12.4 Role of CaMKII in ECC 342
12.4.1 Ca2+ Influx and ICa Facilitation 343
12.4.2 SR Ca2+ Release and SR Ca Leak 344
12.4.3 SR Ca2+ Uptake, FDAR, Acidosis 346
12.4.4 Na+ Channels 348
12.4.5 K+ 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 K+ Channel Blockade on APD and Arrhythmogenesis 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 381
George 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
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 413
Brian ORourke, 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 431
Anja 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
17. Novel Pharmacological Targets for the Management of Atrial Fibrillation 461
Alexander 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 INa Blockade 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 479
Arun Sridhar and Cynthia A. Carnes
18.1 Introduction 479
18.2 Molecular Biology of the Kv 1.5 Channels: 480
18.2.1 Kv 1.5 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 Kv 1.5 Blockers 488
18.5 Conclusions 490
References 490
19. Non-Pharmacologic Manipulation of the Autonomic Nervous System in Human for the Prevention of Life-Threatening Arrhythmias 495
Peter J. Schwartz
19.1 Introduction 495
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 Cardiac Autonomic Regulation and Susceptibility to Sudden Cardiac Death: A Nonpharmacological Approach for the Prevention of Ventricular Fibrillation 509
George 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 2-Adrenergic Receptor Activation and Susceptibility to VF 521
20.5 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 543
Barry 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
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
