Novel Therapeutic Targets for Antiarrhythmic Drugs

GEORGE EDWARD BILLMAN is a professor at The Ohio State University. He is currently an Associate Editor of Pharmacology and Therapeutics, an Editor of Experimental Physiology, and on the editorial boards of Journal of Cardiovascular Pharmacology and Journal of Applied Physiology. Dr. Billman has authored over 125 journal articles and has been an invited speaker at twenty national and international scientific meetings. He wrote the chapter "Cardiac Sarcolemmal ATP-Sensitive Potassium Channel Antagonists" in Drug Discovery Handbook (Wiley).

• Acknowledgments xixContributors xxi1. Introduction 1George E. BillmanReferences 32. Myocardial K+ Channels: Primary Determinants of Action Potential Repolarization 5Noriko Niwa and Jeanne Nerbonne2.1 Introduction 52.2 Action Potential Waveforms and Repolarizing K+ Currents 72.3 Functional Diversity of Repolarizing Myocardial K+ Channels 92.4 Molecular Diversity of K+ Channel Subunits 122.5 Molecular Determinants of Functional Cardiac Ito Channels 162.6 Molecular Determinants of Functional Cardiac IK Channels 182.7 Molecular Determinants of Functional Cardiac Kir Channels 232.8 Other Potassium Currents Contributing to Action Potential Repolarization 272.8.1 Myocardial K+ Channel Functioning in Macromolecular Protein Complexes 28References 323. The ‘‘Funny’’ Pacemaker Current 59Andrea Barbuti, Annalisa Bucchi, Mirko Baruscotti, and Dario DiFrancesco3.1 Introduction: The Mechanism of Cardiac Pacemaking 593.2 The ‘‘Funny’’ Current 603.2.1 Historical Background 603.2.2 Biophysical Properties of the If Current 613.2.3 Autonomic Modulation 633.2.4 Cardiac Distribution of If 633.3 Molecular Determinants of the If Current 643.3.1 HCN Clones and Pacemaker Channels 643.3.2 Identification of Structural Elements Involved in Channel Gating 663.3.3 Regulation of Pacemaker Channel Activity: “Context” Dependence and Protein-Protein Interactions 703.3.4 HCN Gene Regulation 713.4 Blockers of Funny Channels 723.4.1 Alinidine (ST567) 733.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49), and Cilobradine (DK-AH269) 733.4.3 ZD7288 753.4.4 Ivabradine (S16257) 753.4.5 Effects of the Heart Rate Reducing Agents on HCN Isoforms 783.5 Genetics of HCN Channels 783.5.1 HCN-KO Models 783.5.2 Pathologies Associated with HCN Dysfunctions 793.6 HCN-Based Biological Pacemakers 81References 844. Arrhythmia Mechanisms in Ischemia and Infarction 101Ruben Coronel, Wen Dun, Penelope A. Boyden, and Jacques M.T. de Bakker4.1 Introduction 1014.1.1 Modes of Ischemia, Phases of Arrhythmogenesis 1024.1.2 Trigger-Substrate-Modulating Factors 1034.2 Arrhythmogenesis in Acute Myocardial Ischemia 1034.2.1 Phase 1A 1034.2.2 Phase 1B 1134.2.3 Arrhythmogenic Mechanism: Trigger 1144.2.4 Catecholamines 1154.3 Arrhythmogenesis During the First Week Post MI 1154.3.1 Mechanisms 1154.3.2 The Subendocardial Purkinje Cell as a Trigger 24–48 H Post Occlusion 1164.3.3 Five Days Post-Occlusion: Epicardial Border Zone 1204.4 Arrhythmia Mechanisms in Chronic Infarction 1284.4.1 Reentry and Focal Mechanisms 1284.4.2 Heterogeneity of Ion Channel Expression in the Healthy Heart 1294.4.3 Remodeling in Chronic Myocardial Infarction 1314.4.4 Structural Remodeling 1334.4.5 Role of the Purkinje System 135References 1365. Antiarrhythmic Drug Classification 155Cynthia A. Carnes5.1 Introduction 1555.2 Sodium Channel Blockers 1555.2.1 Mixed Sodium Channel Blockers (Vaughan Williams Class Ia) 1565.3 Inhibitors of the Fast Sodium Current with Rapid Kinetics (Vaughan Williams Class Ib) 1585.3.1 Lidocaine 1585.3.2 Mexiletine 1595.4 Inhibitors of the Fast Sodium Current with Slow Kinetics (Vaughan Williams Class Ic) 1595.4.1 Flecainide 1595.4.2 Propafenone 1605.5 Inhibitors of Repolarizing K+ Currents (Vaughan Williams Class III) 1605.5.1 Dofetilide 1605.5.2 Sotalol 1615.5.3 Amiodarone 1615.5.4 Ibutilide 1625.6 IKur Blockers 1625.7 Inhibitors of Calcium Channels 1625.7.1 Verapamil and Diltiazem 1625.8 Inhibitors of Adrenergically-Modulated Electrophysiology 1635.8.1 Funny Current (If) Inhibitors 1635.8.2 Beta-Adrenergic Receptor Antagonists 1645.9 Adenosine 1645.10 Digoxin 1655.11 Conclusions 165References 1656. Repolarization Reserve and Proarrhythmic Risk 171András Varró6.1 Definitions and Background 1716.2 The Major Players Contributing to Repolarization Reserve 1756.2.1 Inward Sodium Current (INa) 1756.2.2 Inward L-Type Calcium Current (ICa,L) 1766.2.3 Rapid Delayed Rectifier Outward Potassium Current (IKr) 1776.2.4 Slow Delayed Rectifier Outward Potassium Current (IKs) 1786.2.5 Inward Rectifier Potassium Current (Ik1) 1796.2.6 Transient Outward Potassium Current (Ito) 1806.2.7 Sodium—Potassium Pump Current (INa/K) 1806.2.8 Sodium–Calcium Exchanger Current (NCX) 1806.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve 1826.4 Clinical Significance of the Reduced Repolarization Reserve 1836.4.1 Genetic Defects 1846.4.2 Heart Failure 1856.4.3 Diabetes Mellitus 1856.4.4 Gender 1866.4.5 Renal Failure 1876.4.6 Hypokalemia 1876.4.7 Hypothyroidism 1876.4.8 Competitive Athletes 1886.5 Repolarization Reserve as a Dynamically Changing Factor 1886.6 How to Measure the Repolarization Reserve 1896.7 Pharmacological Modulation of the Repolarization Reserve 1916.8 Conclusion 193References 1947. Safety Challenges in the Development of Novel Antiarrhythmic Drugs 201Gary Gintant and Zhi Su7.1 Introduction 2017.2 Review of Basic Functional Cardiac Electrophysiology 2027.2.1 Normal Pacemaker Activity 2037.2.2 Atrioventricular Conduction 2047.2.3 Ventricular Repolarization: Effects on the QT Interval 2047.2.4 Electrophysiologic Lessons Learned from Long QT Syndromes 2057.3 Safety Pharmacology Perspectives on Developing Antiarrhythmic Drugs 2067.3.1. Part A. On-Target (Primary Pharmacodynamic) versus Off-Target (Secondary Pharmacodynamic) Considerations 2067.3.2 Part B. General Considerations 2077.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs 2087.4.1 Sodium Channel Block Reduces the Incidence of Ventricular Premature Depolarizations But Increases Mortality 2087.4.2 Delayed Ventricular Repolarization with d-Sotalol Increases Mortality in Patients with Left Ventricular Dysfunction and Remote Myocardial Infarction: The SWORD and DIAMOND Trials 2107.4.3 Ranolazine: An Antianginal Agent with a Novel Electrophysiologic Action and Potential Antiarrhythmic Properties 2137.5 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs 2177.5.1 Introduction 2177.5.2. Lessons Learned with Azimilide, a Class III Drug that Reduces the Delayed Rectifier Currents IKr and IKs 2187.5.3 Atrial Repolarizing Delaying Agents. Experience with Vernakalant, a Drug that Blocks Multiple Cardiac Currents (Including the Atrial-Specific Repolarizing Current IKur) 220References 2228. Safety Pharmacology and Regulatory Issues in the Development of Antiarrhythmic Medications 233Armando Lagrutta and Joseph J. Salata8.1 Introduction 2338.2 Basic Physiological Considerations 2348.2.1 Ion Channels and Arrhythmogenesis 2348.2.2 Antiarrhythmic Agents 2368.3 Historical Considerations 2378.3.1 CAST: Background, Clinical Findings, and Aftermath 2378.3.2 Torsades de Pointes and hERG Channel Inhibition: Safety Pharmacology Concern with Critical Impact on Antiarrhythmic Development 2398.3.3 Recent Clinical Trials 2428.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment 2448.4.1 ICH—S7A and S7B; E14 2458.4.2 Additional Regulatory Guidance 2488.4.3 Clinical Management Guidelines and Related Considerations About Patient Populations 2508.4.4 Consortia Efforts to Address Safety Concerns Related to Antiarrhythmic Drug Development 2538.4.5 The Unmet Medical Need: Challenges and Opportunities 254References 2569. Ion Channel Remodeling and Arrhythmias 271Takeshi Aiba and Gordon F. Tomaselli9.1 Introduction 2719.2 Molecular and Cellular Basis for Cardiac Excitability 2719.3 Heart Failure—Epidemiology and the Arrhythmia Connection 2729.4 K+ Channel Remodeling in Heart Failure 2749.4.1 Transient Outward Current (Ito) 2749.4.2 Inward Rectifier K+ Current (IK1) 2769.4.3 Delayed Rectifier K Currents (IKr and IKs) 2779.5 Ca2+ Handling and Arrhythmia Risk 2789.5.1 L-type Ca2+ Current ICa-L 2789.5.2 Sarcoplasmic Recticulum Function 2789.6 Intracellular [Na+] in HF 2829.6.1 Cardiac INa in HF 2829.6.2 Na+/K+ ATPase 2839.7 Gap Junctions and Connexins 2839.8 Autonomic Signaling 2849.9 Calmodulin Kinase 2859.10 Conclusions 286References 28610. Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Failure: A Potential Therapeutic Target 299Andriy E. Belevych, Dmitry Terentyev, and Sandor Györke10.1 Introduction 29910.2 Activation and Deactivation of Ryanodine Receptors During Normal Excitation-Contraction Coupling 30010.3 Defective Ryanodine Receptor Function is Linked to Proarrhythmic Delayed Afterdepolarizations and Calcium Alternans 30110.4 Genetic and Acquired Defects in Ryanodine Receptors 30210.5 Effects of Thiol-Modifying Agents on Ryanodine Receptors 30310.6 Reactive Oxygen Species Production and Oxidative Stress in Cardiac Disease 30410.7 Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Heart Failure 30510.8 Therapeutic Potential of Normalizing Ryanodine Receptor Function 306References 30811. Targeting Na+/Ca2+ Exchange as an Antiarrhythmic Strategy 313Gudrun Antoons, Rik Willems, and Karin R. Sipido11.1 Introduction 31311.2 Why Target NCX in Arrhythmias? 31411.3 When Do We See Triggered Arrhythmias? 31711.4 What Drugs are Available? 31811.5 Experience with NCX Inhibitors 32111.6 Caveat—the Consequences on Ca2+ Handling 32811.7 Need for More Development 331References 33212. Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII)—Modulation of Ion Currents and Potential Role for Arrhythmias 339Dr. Lars S. Maier12.1 Introduction 33912.2 Evolving Role of Ca2+/CaMKII in the Heart 34012.3 Activation of CaMKII 34012.4 Role of CaMKII in ECC 34212.4.1 Ca2+ Influx and ICa Facilitation 34312.4.2 SR Ca2+ Release and SR Ca Leak 34412.4.3 SR Ca2+ Uptake, FDAR, Acidosis 34612.4.4 Na+ Channels 34812.4.5 K+ Channels 35312.5 Role of CaMKII for Arrhythmias 35412.6 Summary 355Acknowledgments 356References 35613. Selective Targeting of Ventricular Potassium Channels for Arrhythmia Suppression: Feasible or Risible? 367Hugh Clements-Jewery and Michael Curtis13.1 Introduction 36713.2 Effects of K+ Channel Blockade on APD and Arrhythmogenesis 37113.2.1 IKur Blockade 37113.2.2 IKr Blockade 37113.2.3 IKs Blockade 37213.2.4 IK1 Blockade 37213.2.5 Ito Blockade 37313.2.6 IKATP Blockade 37413.3 Conclusions/Future Directions 375References 37514. Cardiac Sarcolemmal ATP-sensitive Potassium Channel Antagonists: A Class of Drugs that May Selectively Target the Ischemic Myocardium 381George E. Billman14.1 Introduction 38114.2 Effects of Myocardial Ischemia on Extracellular Potassium 38214.3 Effect of Extracellular Potassium on Ventricular Rhythm 38614.4 Effect of ATP-sensitive Potassium Channel Antagonists on Ventricular Arrhythmias 38714.4.1 Nonselective ATP-sensitive Potassium Channel Antagonists 38714.4.2 Selective ATP-sensitive Potassium Channel Antagonist 39014.4.3 Proarrhythmic Effects of ATP-sensitive Potassium Channel Agonists 39714.5 Summary 401References 40115. Mitochondrial Origin of Ischemia-Reperfusion Arrhythmias 413Brian O’Rourke, PHD15.1 Introduction 41315.2 Mechanisms of Arrhythmias 41415.2.1 Automacity 41415.2.2 Triggered Arrhythmias 41515.3 Ischemia-Reperfusion Arrhythmias 41715.4 Mitochondrial Criticality: The Root of Ischemia-Reperfusion Arrhythmias 41815.5 KATP Activation and Arrhythmias 42015.6 Metabolic Sinks and Reperfusion Arrhythmias 42215.7 Antioxidant Depletion 42315.8 Mitochondria as Therapeutic Targets 423References 42416. Cardiac Gap Junctions: A New Target for New Antiarrhythmic Drugs: Gap Junction Modulators 431Anja Hagen and Stefan Dhein16.1 Introduction 43116.2 The Development of Gap Junction Modulators and AAPs 43316.3 Molecular Mechanisms of Action of AAPs 43616.4 Antiarrhythmic Effects of AAPs 43916.4.1 Ventricular Fibrillation and Ventricular Tachycardia 44416.4.2 Atrial fibrillation 44416.4.3 Others 44516.5 Site- and Condition-Specific Effects of AAPs; Effects in Ischemia or Simulated Ischemia 44616.6 Chemistry of AAPs 44716.7 Short Overview About Cardiac Gap Junctions 44716.8 Gap Junction Modulation as a New Antiarrhythmic Principle 452References 45317. Novel Pharmacological Targets for the Management of Atrial Fibrillation 461Alexander Burashnikov and Charles Antzelevitch17.1 Introduction 46117.2 Novel Ion Channel Targets for Atrial Fibrillation Treatment 46217.2.1 The Ultrarapid Delayed Rectifier Potassium Current (IKur) 46217.2.2 The Acetylcholine-Regulated Inward Rectifying Potassium Current (IK-ACh) and the Constitutively Active (CA) IK-ACh 46417.2.3 The Early Sodium Current (INa) 46417.2.4 Block IKr and Its Relation to Atrial Selectivity of INa Blockade 46717.2.5 Other Potential Atrial-Selective Ion Channel Targets for the Treatment AF 46717.2.6 Influence of Atrial- Selective Agents on Ventricular Arrhythmias? 46817.3 Upstream Therapy Targets for Atrial Fibrillation 46817.4 Gap Junction as Targets for AF Therapy 46917.5 Intracellular Calcium Handling and AF 470References 47118. IKur, Ultra-rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias 479Arun Sridhar and Cynthia A. Carnes18.1 Introduction 47918.2 Molecular Biology of the Kv 1.5 Channels: 48018.2.1 Kv 1.5 Activation and Inactivation 48018.2.2 Where Does IKur Fit Into the Cardiac Action Potential? 48218.2.3 Adrenergic Modulation of IKur 48518.3 IKur as a Therapeutic Target 48518.4 Organic Blockers of IKur 48618.4.1 Mixed Channel Blockers 48618.4.2 Mixed Channel Blockers 48718.4.3 Selective Kv 1.5 Blockers 48818.5 Conclusions 490References 49019. Non-Pharmacologic Manipulation of the Autonomic Nervous System in Human for the Prevention of Life-Threatening Arrhythmias 495Peter J. Schwartz19.1 Introduction 49519.2 Sympathetic Nervous System 49619.2.1 Experimental Background 49619.2.2 Clinical Evidence 49719.3 Parasympathetic Nervous System 50019.3.1 Experimental Background 50019.3.2 Clinical Evidence 50119.4 Conclusion 504Acknowledgement 504References 50420. Effects of Endurance Exercise Training on Cardiac Autonomic Regulation and Susceptibility to Sudden Cardiac Death: A Nonpharmacological Approach for the Prevention of Ventricular Fibrillation 509George E. Billman20.1 Introduction 50920.2 Exercise and Susceptibility to Sudden Death 51020.2.1 Clinical Studies 51020.2.2 Experimental Studies 51520.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death 51820.4 β2-Adrenergic Receptor Activation and Susceptibility to VF 52120.5 Effect of Exercise Conditioning on Cardiac Autonomic Regulation 52320.6 Effect of Exercise Training on Myocyte Calcium Regulation 52820.7 Summary and Conclusions 530References 53121. Dietary Omega-3 Fatty Acids as a Nonpharmacological Antiarrhythmic Intervention 543Barry London and J. Michael Frangiskakis21.1 Introduction 54321.2 Fatty Acid Metabolism 54421.2.1 Nomenclature 54421.2.2 Dietary Fatty Acids 54421.2.3 Roles of Polyunsaturated Fatty Acids 54521.3 Cellular Mechanisms 54521.3.1 Ion Channel Blockade 54521.3.2 Direct Membrane Effects 54721.3.3 Phosphorylation 54821.3.4 Inflammation 54821.3.5 Summary 54821.4 Animal Studies 54821.4.1 Acute Intravenous Effects of n-3 PUFAs 54921.4.2 Dietary Supplementation with n-3 PUFAs 54921.5 Clinical Studies 55021.5.1 Observational Studies 55021.5.2 Randomized Trials 55121.5.3 Surrogate Markers for Arrhythmias 55521.5.4 Summary 55521.6 Future Directions 556References 556General Index 567Index of Drug and Chemical Names 575

"In Summary, the book is a good, comprehensive reference for knowledge on arrhythmia and its treatment, and is considered as worthwhile addition to the literature on cardiac arrhythmia and antiarrhythmic drugs." (ChemMedChem, July 2010)