Novel Therapeutic Targets for Antiarrhythmic Drugs

✍ Scribed by George Edward Billman

• Year: 2010
• Tongue: English
• Leaves: 612
• Edition: 1
• Category: Library

✦ Synopsis

Profiles potential treatment approaches for cardiac arrhythmiasCardiac arrhythmias of ventricular origin are responsible for the deaths of nearly half a million Americans each year while atrial fibrillation accounts for about 2.3 million cases per year, a rate that is projected to increase 2.5 fold over the next half century. Effectively managing these cardiac rhythm disorders remains a major challenge for both caregivers and the pharmaceutical industry. Filling a gap in the current literature, Novel Therapeutic Targets for Antiarrhythmic Drugs presents the latest treatments for cardiac arrhythmias alongside comprehensive presentations of basic cardiac physiology and pharmacology.Written by leading experts in their research areas, this invaluable resource offers both practitioners and researchers a one-stop guide that brings together previously dispersed information. The text consists of four sections:Section One comprehensively reviews basic cardiac electrophysiology, the mechanisms responsible for arrhythmias in the setting of ischemia, and basic pharmacology of antiarrhythmic drugs.Section Two addresses safety pharmacology, including the concept of "repolarization reserve," safety challenges, and regulatory issues for the development of novel antiarrhythmic drugs.Section Three describes several novel pharmacological targets for antiarrhythmic drugs, including both ion channel and non-ion channel targets.Section Four describes promising non-pharmacological antiarrhythmic interventions including selective cardiac neural disruption or nerve stimulation, aerobic exercise training, and diet (omega-3 fatty acids).Offering an unparalleled look at the current state and future direction of cardiac arrhythmia treatment, Novel Therapeutic Targets for Antiarrhythmic Drugs provides an important resource to advanced students, working researchers, and busy professionals alike.

✦ Table of Contents

NOVEL THERAPEUTIC TARGETS FOR ANTIARRHYTHMIC DRUGS......Page 3
CONTENTS......Page 9
Acknowledgments......Page 21
Contributors......Page 23
1. Introduction......Page 27
References......Page 29
2.1 Introduction......Page 31
2.2 Action Potential Waveforms and Repolarizing K(+) Currents......Page 33
2.3 Functional Diversity of Repolarizing Myocardial K(+) Channels......Page 35
2.4 Molecular Diversity of K(+) Channel Subunits......Page 38
2.5 Molecular Determinants of Functional Cardiac I(to) Channels......Page 42
2.6 Molecular Determinants of Functional Cardiac I(K) Channels......Page 44
2.7 Molecular Determinants of Functional Cardiac Kir Channels......Page 49
2.8 Other Potassium Currents Contributing to Action Potential Repolarization......Page 53
2.8.1 Myocardial K(+) Channel Functioning in Macromolecular Protein Complexes......Page 54
References......Page 58
3.1 Introduction: The Mechanism of Cardiac Pacemaking......Page 85
3.2.1 Historical Background......Page 86
3.2.2 Biophysical Properties of the I(f) Current......Page 87
3.2.4 Cardiac Distribution of I(f)......Page 89
3.3.1 HCN Clones and Pacemaker Channels......Page 90
3.3.2 Identification of Structural Elements Involved in Channel Gating......Page 92
3.3.3 Regulation of Pacemaker Channel Activity: “Context” Dependence and Protein-Protein Interactions......Page 96
3.3.4 HCN Gene Regulation......Page 97
3.4 Blockers of Funny Channels......Page 98
3.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49), and Cilobradine (DK-AH269)......Page 99
3.4.4 Ivabradine (S16257)......Page 101
3.5.1 HCN-KO Models......Page 104
3.5.2 Pathologies Associated with HCN Dysfunctions......Page 105
3.6 HCN-Based Biological Pacemakers......Page 107
References......Page 110
4.1 Introduction......Page 127
4.1.1 Modes of Ischemia, Phases of Arrhythmogenesis......Page 128
4.2.1 Phase 1A......Page 129
4.2.2 Phase 1B......Page 139
4.2.3 Arrhythmogenic Mechanism: Trigger......Page 140
4.3.1 Mechanisms......Page 141
4.3.2 The Subendocardial Purkinje Cell as a Trigger 24–48 H Post Occlusion......Page 142
4.3.3 Five Days Post-Occlusion: Epicardial Border Zone......Page 146
4.4.1 Reentry and Focal Mechanisms......Page 154
4.4.2 Heterogeneity of Ion Channel Expression in the Healthy Heart......Page 155
4.4.3 Remodeling in Chronic Myocardial Infarction......Page 157
4.4.4 Structural Remodeling......Page 159
4.4.5 Role of the Purkinje System......Page 161
References......Page 162
5.2 Sodium Channel Blockers......Page 181
5.2.1 Mixed Sodium Channel Blockers (Vaughan Williams Class Ia)......Page 182
5.3.1 Lidocaine......Page 184
5.4.1 Flecainide......Page 185
5.5.1 Dofetilide......Page 186
5.5.3 Amiodarone......Page 187
5.7.1 Verapamil and Diltiazem......Page 188
5.8.1 Funny Current (I(f)) Inhibitors......Page 189
5.9 Adenosine......Page 190
References......Page 191
6.1 Definitions and Background......Page 197
6.2.1 Inward Sodium Current (I(Na))......Page 201
6.2.2 Inward L-Type Calcium Current (I(Ca,L))......Page 202
6.2.3 Rapid Delayed Rectifier Outward Potassium Current (I(Kr))......Page 203
6.2.4 Slow Delayed Rectifier Outward Potassium Current (I(Ks))......Page 204
6.2.5 Inward Rectifier Potassium Current (I(k1))......Page 205
6.2.8 Sodium–Calcium Exchanger Current (NCX)......Page 206
6.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve......Page 208
6.4 Clinical Significance of the Reduced Repolarization Reserve......Page 209
6.4.1 Genetic Defects......Page 210
6.4.3 Diabetes Mellitus......Page 211
6.4.4 Gender......Page 212
6.4.7 Hypothyroidism......Page 213
6.5 Repolarization Reserve as a Dynamically Changing Factor......Page 214
6.6 How to Measure the Repolarization Reserve......Page 215
6.7 Pharmacological Modulation of the Repolarization Reserve......Page 217
6.8 Conclusion......Page 219
References......Page 220
7.1 Introduction......Page 227
7.2 Review of Basic Functional Cardiac Electrophysiology......Page 228
7.2.1 Normal Pacemaker Activity......Page 229
7.2.3 Ventricular Repolarization: Effects on the QT Interval......Page 230
7.2.4 Electrophysiologic Lessons Learned from Long QT Syndromes......Page 231
7.3.1. Part A. On-Target (Primary Pharmacodynamic) versus Off-Target (Secondary Pharmacodynamic) Considerations......Page 232
7.3.2 Part B. General Considerations......Page 233
7.4.1 Sodium Channel Block Reduces the Incidence of Ventricular Premature Depolarizations But Increases Mortality......Page 234
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......Page 236
7.4.3 Ranolazine: An Antianginal Agent with a Novel Electrophysiologic Action and Potential Antiarrhythmic Properties......Page 239
7.5.1 Introduction......Page 243
7.5.2. Lessons Learned with Azimilide, a Class III Drug that Reduces the Delayed Rectifier Currents I(Kr) and I(Ks)......Page 244
7.5.3 Atrial Repolarizing Delaying Agents. Experience with Vernakalant, a Drug that Blocks Multiple Cardiac Currents (Including the Atrial-Specific Repolarizing Current I(Kur))......Page 246
References......Page 248
8.1 Introduction......Page 259
8.2.1 Ion Channels and Arrhythmogenesis......Page 260
8.2.2 Antiarrhythmic Agents......Page 262
8.3.1 CAST: Background, Clinical Findings, and Aftermath......Page 263
8.3.2 Torsades de Pointes and hERG Channel Inhibition: Safety Pharmacology Concern with Critical Impact on Antiarrhythmic Development......Page 265
8.3.3 Recent Clinical Trials......Page 268
8.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment......Page 270
8.4.1 ICH—S7A and S7B; E14......Page 271
8.4.2 Additional Regulatory Guidance......Page 274
8.4.3 Clinical Management Guidelines and Related Considerations About Patient Populations......Page 276
8.4.4 Consortia Efforts to Address Safety Concerns Related to Antiarrhythmic Drug Development......Page 279
8.4.5 The Unmet Medical Need: Challenges and Opportunities......Page 280
References......Page 282
9.2 Molecular and Cellular Basis for Cardiac Excitability......Page 297
9.3 Heart Failure—Epidemiology and the Arrhythmia Connection......Page 298
9.4.1 Transient Outward Current (I(to))......Page 300
9.4.2 Inward Rectifier K(+) Current (I(K1))......Page 302
9.4.3 Delayed Rectifier K Currents (I(Kr) and I(Ks))......Page 303
9.5.2 Sarcoplasmic Recticulum Function......Page 304
9.6.1 Cardiac I(Na) in HF......Page 308
9.7 Gap Junctions and Connexins......Page 309
9.8 Autonomic Signaling......Page 310
9.9 Calmodulin Kinase......Page 311
References......Page 312
10.1 Introduction......Page 325
10.2 Activation and Deactivation of Ryanodine Receptors During Normal Excitation-Contraction Coupling......Page 326
10.3 Defective Ryanodine Receptor Function is Linked to Proarrhythmic Delayed Afterdepolarizations and Calcium Alternans......Page 327
10.4 Genetic and Acquired Defects in Ryanodine Receptors......Page 328
10.5 Effects of Thiol-Modifying Agents on Ryanodine Receptors......Page 329
10.6 Reactive Oxygen Species Production and Oxidative Stress in Cardiac Disease......Page 330
10.7 Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Heart Failure......Page 331
10.8 Therapeutic Potential of Normalizing Ryanodine Receptor Function......Page 332
References......Page 334
11.1 Introduction......Page 339
11.2 Why Target NCX in Arrhythmias?......Page 340
11.3 When Do We See Triggered Arrhythmias?......Page 343
11.4 What Drugs are Available?......Page 344
11.5 Experience with NCX Inhibitors......Page 347
11.6 Caveat—the Consequences on Ca(2+) Handling......Page 354
11.7 Need for More Development......Page 357
References......Page 358
12.1 Introduction......Page 365
12.3 Activation of CaMKII......Page 366
12.4 Role of CaMKII in ECC......Page 368
12.4.1 Ca(2+) Influx and I(Ca) Facilitation......Page 369
12.4.2 SR Ca(2+) Release and SR Ca Leak......Page 370
12.4.3 SR Ca(2+) Uptake, FDAR, Acidosis......Page 372
12.4.4 Na(+) Channels......Page 374
12.4.5 K(+) Channels......Page 379
12.5 Role of CaMKII for Arrhythmias......Page 380
12.6 Summary......Page 381
References......Page 382
13.1 Introduction......Page 393
13.2.2 I(Kr) Blockade......Page 397
13.2.4 I(K1) Blockade......Page 398
13.2.5 I(to) Blockade......Page 399
13.2.6 I(KATP) Blockade......Page 400
References......Page 401
14.1 Introduction......Page 407
14.2 Effects of Myocardial Ischemia on Extracellular Potassium......Page 408
14.3 Effect of Extracellular Potassium on Ventricular Rhythm......Page 412
14.4.1 Nonselective ATP-sensitive Potassium Channel Antagonists......Page 413
14.4.2 Selective ATP-sensitive Potassium Channel Antagonist......Page 416
14.4.3 Proarrhythmic Effects of ATP-sensitive Potassium Channel Agonists......Page 423
References......Page 427
15.1 Introduction......Page 439
15.2.1 Automacity......Page 440
15.2.2 Triggered Arrhythmias......Page 441
15.3 Ischemia-Reperfusion Arrhythmias......Page 443
15.4 Mitochondrial Criticality: The Root of Ischemia-Reperfusion Arrhythmias......Page 444
15.5 K(ATP) Activation and Arrhythmias......Page 446
15.6 Metabolic Sinks and Reperfusion Arrhythmias......Page 448
15.8 Mitochondria as Therapeutic Targets......Page 449
References......Page 450
16.1 Introduction......Page 457
16.2 The Development of Gap Junction Modulators and AAPs......Page 459
16.3 Molecular Mechanisms of Action of AAPs......Page 462
16.4 Antiarrhythmic Effects of AAPs......Page 465
16.4.2 Atrial fibrillation......Page 470
16.4.3 Others......Page 471
16.5 Site- and Condition-Specific Effects of AAPs; Effects in Ischemia or Simulated Ischemia......Page 472
16.7 Short Overview About Cardiac Gap Junctions......Page 473
16.8 Gap Junction Modulation as a New Antiarrhythmic Principle......Page 478
References......Page 479
17.1 Introduction......Page 487
17.2.1 The Ultrarapid Delayed Rectifier Potassium Current (I(Kur))......Page 488
17.2.3 The Early Sodium Current (I(Na))......Page 490
17.2.5 Other Potential Atrial-Selective Ion Channel Targets for the Treatment AF......Page 493
17.3 Upstream Therapy Targets for Atrial Fibrillation......Page 494
17.4 Gap Junction as Targets for AF Therapy......Page 495
17.5 Intracellular Calcium Handling and AF......Page 496
References......Page 497
18.1 Introduction......Page 505
18.2.1 K(v)1.5 Activation and Inactivation......Page 506
18.2.2 Where Does I(Kur) Fit Into the Cardiac Action Potential?......Page 508
18.3 I(Kur) as a Therapeutic Target......Page 511
18.4.1 Mixed Channel Blockers......Page 512
18.4.2 Mixed Channel Blockers......Page 513
18.4.3 Selective Kv1.5 Blockers......Page 514
References......Page 516
19.1 Introduction......Page 521
19.2.1 Experimental Background......Page 522
19.2.2 Clinical Evidence......Page 523
19.3.1 Experimental Background......Page 526
19.3.2 Clinical Evidence......Page 527
References......Page 530
20.1 Introduction......Page 535
20.2.1 Clinical Studies......Page 536
20.2.2 Experimental Studies......Page 541
20.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death......Page 544
20.4 β(2)-Adrenergic Receptor Activation and Susceptibility to VF......Page 547
20.5 Effect of Exercise Conditioning on Cardiac Autonomic Regulation......Page 549
20.6 Effect of Exercise Training on Myocyte Calcium Regulation......Page 554
20.7 Summary and Conclusions......Page 556
References......Page 557
21.1 Introduction......Page 569
21.2.2 Dietary Fatty Acids......Page 570
21.3.1 Ion Channel Blockade......Page 571
21.3.2 Direct Membrane Effects......Page 573
21.4 Animal Studies......Page 574
21.4.2 Dietary Supplementation with n-3 PUFAs......Page 575
21.5.1 Observational Studies......Page 576
21.5.2 Randomized Trials......Page 577
21.5.4 Summary......Page 581
References......Page 582
General Index......Page 593
Index of Drug and Chemical Names......Page 601