NOVEL THERAPEUTIC TARGETS FOR ANTIARRHYTHMIC DRUGS -- CONTENTS -- Acknowledgments -- Contributors -- 1. Introduction -- References -- 2. Myocardial K(+) Channels: Primary Determinants of Action Potential Repolarization -- 2.1 Introduction -- 2.2 Action Potential Waveforms and Repolarizing K(+) Currents -- 2.3 Functional Diversity of Repolarizing Myocardial K(+) Channels -- 2.4 Molecular Diversity of K(+) Channel Subunits -- 2.5 Molecular Determinants of Functional Cardiac I(to) Channels -- 2.6 Molecular Determinants of Functional Cardiac I(K) Channels -- 2.7 Molecular Determinants of Functional Cardiac Kir Channels -- 2.8 Other Potassium Currents Contributing to Action Potential Repolarization -- 2.8.1 Myocardial K(+) Channel Functioning in Macromolecular Protein Complexes -- References -- 3. The "Funny" Pacemaker Current -- 3.1 Introduction: The Mechanism of Cardiac Pacemaking -- 3.2 The "Funny" Current -- 3.2.1 Historical Background -- 3.2.2 Biophysical Properties of the I(f) Current -- 3.2.3 Autonomic Modulation -- 3.2.4 Cardiac Distribution of I(f) -- 3.3 Molecular Determinants of the I(f) Current -- 3.3.1 HCN Clones and Pacemaker Channels -- 3.3.2 Identification of Structural Elements Involved in Channel Gating -- 3.3.3 Regulation of Pacemaker Channel Activity: "Context" Dependence and Protein-Protein Interactions -- 3.3.4 HCN Gene Regulation -- 3.4 Blockers of Funny Channels -- 3.4.1 Alinidine (ST567) -- 3.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49), and Cilobradine (DK-AH269) -- 3.4.3 ZD7288 -- 3.4.4 Ivabradine (S16257) -- 3.4.5 Effects of the Heart Rate Reducing Agents on HCN Isoforms -- 3.5 Genetics of HCN Channels -- 3.5.1 HCN-KO Models -- 3.5.2 Pathologies Associated with HCN Dysfunctions -- 3.6 HCN-Based Biological Pacemakers -- References -- 4. Arrhythmia Mechanisms in Ischemia and Infarction -- 4.1 Introduction.

4.1.1 Modes of Ischemia, Phases of Arrhythmogenesis -- 4.1.2 Trigger-Substrate-Modulating Factors -- 4.2 Arrhythmogenesis in Acute Myocardial Ischemia -- 4.2.1 Phase 1A -- 4.2.2 Phase 1B -- 4.2.3 Arrhythmogenic Mechanism: Trigger -- 4.2.4 Catecholamines -- 4.3 Arrhythmogenesis During the First Week Post MI -- 4.3.1 Mechanisms -- 4.3.2 The Subendocardial Purkinje Cell as a Trigger 24-48 H Post Occlusion -- 4.3.3 Five Days Post-Occlusion: Epicardial Border Zone -- 4.4 Arrhythmia Mechanisms in Chronic Infarction -- 4.4.1 Reentry and Focal Mechanisms -- 4.4.2 Heterogeneity of Ion Channel Expression in the Healthy Heart -- 4.4.3 Remodeling in Chronic Myocardial Infarction -- 4.4.4 Structural Remodeling -- 4.4.5 Role of the Purkinje System -- References -- 5. Antiarrhythmic Drug Classification -- 5.1 Introduction -- 5.2 Sodium Channel Blockers -- 5.2.1 Mixed Sodium Channel Blockers (Vaughan Williams Class Ia) -- 5.3 Inhibitors of the Fast Sodium Current with Rapid Kinetics (Vaughan Williams Class Ib) -- 5.3.1 Lidocaine -- 5.3.2 Mexiletine -- 5.4 Inhibitors of the Fast Sodium Current with Slow Kinetics (Vaughan Williams Class Ic) -- 5.4.1 Flecainide -- 5.4.2 Propafenone -- 5.5 Inhibitors of Repolarizing K(+) Currents (Vaughan Williams Class III) -- 5.5.1 Dofetilide -- 5.5.2 Sotalol -- 5.5.3 Amiodarone -- 5.5.4 Ibutilide -- 5.6 I(Kur) Blockers -- 5.7 Inhibitors of Calcium Channels -- 5.7.1 Verapamil and Diltiazem -- 5.8 Inhibitors of Adrenergically-Modulated Electrophysiology -- 5.8.1 Funny Current (I(f)) Inhibitors -- 5.8.2 Beta-Adrenergic Receptor Antagonists -- 5.9 Adenosine -- 5.10 Digoxin -- 5.11 Conclusions -- References -- 6. Repolarization Reserve and Proarrhythmic Risk -- 6.1 Definitions and Background -- 6.2 The Major Players Contributing to Repolarization Reserve -- 6.2.1 Inward Sodium Current (I(Na)).

6.2.2 Inward L-Type Calcium Current (I(Ca,L)) -- 6.2.3 Rapid Delayed Rectifier Outward Potassium Current (I(Kr)) -- 6.2.4 Slow Delayed Rectifier Outward Potassium Current (I(Ks)) -- 6.2.5 Inward Rectifier Potassium Current (I(k1)) -- 6.2.6 Transient Outward Potassium Current (I(to)) -- 6.2.7 Sodium-Potassium Pump Current (I(Na/K)) -- 6.2.8 Sodium-Calcium Exchanger Current (NCX) -- 6.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve -- 6.4 Clinical Significance of the Reduced Repolarization Reserve -- 6.4.1 Genetic Defects -- 6.4.2 Heart Failure -- 6.4.3 Diabetes Mellitus -- 6.4.4 Gender -- 6.4.5 Renal Failure -- 6.4.6 Hypokalemia -- 6.4.7 Hypothyroidism -- 6.4.8 Competitive Athletes -- 6.5 Repolarization Reserve as a Dynamically Changing Factor -- 6.6 How to Measure the Repolarization Reserve -- 6.7 Pharmacological Modulation of the Repolarization Reserve -- 6.8 Conclusion -- References -- 7. Safety Challenges in the Development of Novel Antiarrhythmic Drugs -- 7.1 Introduction -- 7.2 Review of Basic Functional Cardiac Electrophysiology -- 7.2.1 Normal Pacemaker Activity -- 7.2.2 Atrioventricular Conduction -- 7.2.3 Ventricular Repolarization: Effects on the QT Interval -- 7.2.4 Electrophysiologic Lessons Learned from Long QT Syndromes -- 7.3 Safety Pharmacology Perspectives on Developing Antiarrhythmic Drugs -- 7.3.1. Part A. On-Target (Primary Pharmacodynamic) versus Off-Target (Secondary Pharmacodynamic) Considerations -- 7.3.2 Part B. General Considerations -- 7.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs -- 7.4.1 Sodium Channel Block Reduces the Incidence of Ventricular Premature Depolarizations But Increases Mortality -- 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.

7.4.3 Ranolazine: An Antianginal Agent with a Novel Electrophysiologic Action and Potential Antiarrhythmic Properties -- 7.5 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs -- 7.5.1 Introduction -- 7.5.2. Lessons Learned with Azimilide, a Class III Drug that Reduces the Delayed Rectifier Currents I(Kr) and I(Ks) -- 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)) -- References -- 8. Safety Pharmacology and Regulatory Issues in the Development of Antiarrhythmic Medications -- 8.1 Introduction -- 8.2 Basic Physiological Considerations -- 8.2.1 Ion Channels and Arrhythmogenesis -- 8.2.2 Antiarrhythmic Agents -- 8.3 Historical Considerations -- 8.3.1 CAST: Background, Clinical Findings, and Aftermath -- 8.3.2 Torsades de Pointes and hERG Channel Inhibition: Safety Pharmacology Concern with Critical Impact on Antiarrhythmic Development -- 8.3.3 Recent Clinical Trials -- 8.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment -- 8.4.1 ICH-S7A and S7B -- E14 -- 8.4.2 Additional Regulatory Guidance -- 8.4.3 Clinical Management Guidelines and Related Considerations About Patient Populations -- 8.4.4 Consortia Efforts to Address Safety Concerns Related to Antiarrhythmic Drug Development -- 8.4.5 The Unmet Medical Need: Challenges and Opportunities -- References -- 9. Ion Channel Remodeling and Arrhythmias -- 9.1 Introduction -- 9.2 Molecular and Cellular Basis for Cardiac Excitability -- 9.3 Heart Failure-Epidemiology and the Arrhythmia Connection -- 9.4 K(+) Channel Remodeling in Heart Failure -- 9.4.1 Transient Outward Current (I(to)) -- 9.4.2 Inward Rectifier K(+) Current (I(K1)) -- 9.4.3 Delayed Rectifier K Currents (I(Kr) and I(Ks)) -- 9.5 Ca(2+) Handling and Arrhythmia Risk.

9.5.1 L-type Ca(2+) Current I(Ca-L) -- 9.5.2 Sarcoplasmic Recticulum Function -- 9.6 Intracellular [Na(+)] in HF -- 9.6.1 Cardiac I(Na) in HF -- 9.6.2 Na(+)/K(+) ATPase -- 9.7 Gap Junctions and Connexins -- 9.8 Autonomic Signaling -- 9.9 Calmodulin Kinase -- 9.10 Conclusions -- References -- 10. Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Failure: A Potential Therapeutic Target -- 10.1 Introduction -- 10.2 Activation and Deactivation of Ryanodine Receptors During Normal Excitation-Contraction Coupling -- 10.3 Defective Ryanodine Receptor Function is Linked to Proarrhythmic Delayed Afterdepolarizations and Calcium Alternans -- 10.4 Genetic and Acquired Defects in Ryanodine Receptors -- 10.5 Effects of Thiol-Modifying Agents on Ryanodine Receptors -- 10.6 Reactive Oxygen Species Production and Oxidative Stress in Cardiac Disease -- 10.7 Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Heart Failure -- 10.8 Therapeutic Potential of Normalizing Ryanodine Receptor Function -- References -- 11. Targeting Na(+)/Ca(2+) Exchange as an Antiarrhythmic Strategy -- 11.1 Introduction -- 11.2 Why Target NCX in Arrhythmias? -- 11.3 When Do We See Triggered Arrhythmias? -- 11.4 What Drugs are Available? -- 11.5 Experience with NCX Inhibitors -- 11.6 Caveat-the Consequences on Ca(2+) Handling -- 11.7 Need for More Development -- References -- 12. Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII)-Modulation of Ion Currents and Potential Role for Arrhythmias -- 12.1 Introduction -- 12.2 Evolving Role of Ca(2+)/CaMKII in the Heart -- 12.3 Activation of CaMKII -- 12.4 Role of CaMKII in ECC -- 12.4.1 Ca(2+) Influx and I(Ca) Facilitation -- 12.4.2 SR Ca(2+) Release and SR Ca Leak -- 12.4.3 SR Ca(2+) Uptake, FDAR, Acidosis -- 12.4.4 Na(+) Channels -- 12.4.5 K(+) Channels -- 12.5 Role of CaMKII for Arrhythmias -- 12.6 Summary.

Acknowledgments.