{"product_id":"novel-therapeutic-targets-for-antiarrhythmic-drugs-isbn-9780470261002","title":"Novel Therapeutic Targets for Antiarrhythmic Drugs","description":"\u003cp\u003e\u003cb\u003ePROFILES POTENTIAL TREATMENT APPROACHES FOR CARDIAC ARRHYTHMIAS\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003eCardiac 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, \u003ci\u003eNovel Therapeutic Targets for Antiarrhythmic Drugs\u003c\/i\u003e presents the latest treatments for cardiac arrhythmias alongside comprehensive presentations of basic cardiac physiology and pharmacology. \u003c\/p\u003e\u003cp\u003eWritten 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: \u003c\/p\u003e\u003cul\u003e \u003cli\u003e\n\u003cb\u003eSection One\u003c\/b\u003e comprehensively reviews basic cardiac electrophysiology, the mechanisms responsible for arrhythmias in the setting of ischemia, and basic pharmacology of antiarrhythmic drugs.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Two\u003c\/b\u003e addresses safety pharmacology, including the concept of \"repolarization reserve,\" safety challenges, and regulatory issues for the development of novel antiarrhythmic drugs.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Three\u003c\/b\u003e describes several novel pharmacological targets for antiarrhythmic drugs, including both ion channel and non-ion channel targets.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Four\u003c\/b\u003e describes promising non-pharmacological antiarrhythmic interventions including selective cardiac neural disruption or nerve stimulation, aerobic exercise training, and diet (omega-3 fatty acids).\u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eOffering an unparalleled look at the current state and future direction of cardiac arrhythmia treatment, \u003ci\u003eNovel Therapeutic Targets for Antiarrhythmic Drugs\u003c\/i\u003e provides an important resource to advanced students, working researchers, and busy professionals alike. \u003c\/p\u003e\u003cp\u003eAcknowledgments xix\u003c\/p\u003e \u003cp\u003eContributors xxi\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1. Introduction 1\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGeorge E. Billman\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eReferences 3\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2. Myocardial K\u003csup\u003e+ \u003c\/sup\u003eChannels: Primary Determinants of Action Potential Repolarization 5\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eNoriko Niwa and Jeanne Nerbonne\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 5\u003c\/p\u003e \u003cp\u003e2.2 Action Potential Waveforms and Repolarizing K\u003csup\u003e+\u003c\/sup\u003e Currents 7\u003c\/p\u003e \u003cp\u003e2.3 Functional Diversity of Repolarizing Myocardial K\u003csup\u003e+\u003c\/sup\u003e Channels 9\u003c\/p\u003e \u003cp\u003e2.4 Molecular Diversity of K\u003csup\u003e+\u003c\/sup\u003e Channel Subunits 12\u003c\/p\u003e \u003cp\u003e2.5 Molecular Determinants of Functional Cardiac I\u003csub\u003eto\u003c\/sub\u003e Channels 16\u003c\/p\u003e \u003cp\u003e2.6 Molecular Determinants of Functional Cardiac I\u003csub\u003eK\u003c\/sub\u003e Channels 18\u003c\/p\u003e \u003cp\u003e2.7 Molecular Determinants of Functional Cardiac Kir Channels 23\u003c\/p\u003e \u003cp\u003e2.8 Other Potassium Currents Contributing to Action Potential Repolarization 27\u003c\/p\u003e \u003cp\u003e2.8.1 Myocardial K\u003csup\u003e+\u003c\/sup\u003e Channel Functioning in Macromolecular Protein Complexes 28\u003c\/p\u003e \u003cp\u003eReferences 32\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3. The ‘‘Funny’’ Pacemaker Current 59\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAndrea Barbuti, Annalisa Bucchi, Mirko Baruscotti, and Dario DiFrancesco\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction: The Mechanism of Cardiac Pacemaking 59\u003c\/p\u003e \u003cp\u003e3.2 The ‘‘Funny’’ Current 60\u003c\/p\u003e \u003cp\u003e3.2.1 Historical Background 60\u003c\/p\u003e \u003cp\u003e3.2.2 Biophysical Properties of the I\u003csub\u003ef\u003c\/sub\u003e Current 61\u003c\/p\u003e \u003cp\u003e3.2.3 Autonomic Modulation 63\u003c\/p\u003e \u003cp\u003e3.2.4 Cardiac Distribution of I\u003csub\u003ef\u003c\/sub\u003e 63\u003c\/p\u003e \u003cp\u003e3.3 Molecular Determinants of the I\u003csub\u003ef\u003c\/sub\u003e Current 64\u003c\/p\u003e \u003cp\u003e3.3.1 HCN Clones and Pacemaker Channels 64\u003c\/p\u003e \u003cp\u003e3.3.2 Identification of Structural Elements Involved in Channel Gating 66\u003c\/p\u003e \u003cp\u003e3.3.3 Regulation of Pacemaker Channel Activity: “Context” Dependence and Protein-Protein Interactions 70\u003c\/p\u003e \u003cp\u003e3.3.4 HCN Gene Regulation 71\u003c\/p\u003e \u003cp\u003e3.4 Blockers of Funny Channels 72\u003c\/p\u003e \u003cp\u003e3.4.1 Alinidine (ST567) 73\u003c\/p\u003e \u003cp\u003e3.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49), and Cilobradine (DK-AH269) 73\u003c\/p\u003e \u003cp\u003e3.4.3 ZD7288 75\u003c\/p\u003e \u003cp\u003e3.4.4 Ivabradine (S16257) 75\u003c\/p\u003e \u003cp\u003e3.4.5 Effects of the Heart Rate Reducing Agents on HCN Isoforms 78\u003c\/p\u003e \u003cp\u003e3.5 Genetics of HCN Channels 78\u003c\/p\u003e \u003cp\u003e3.5.1 HCN-KO Models 78\u003c\/p\u003e \u003cp\u003e3.5.2 Pathologies Associated with HCN Dysfunctions 79\u003c\/p\u003e \u003cp\u003e3.6 HCN-Based Biological Pacemakers 81\u003c\/p\u003e \u003cp\u003eReferences 84\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4. Arrhythmia Mechanisms in Ischemia and Infarction 101\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eRuben Coronel, Wen Dun, Penelope A. Boyden, and Jacques M.T. de Bakker\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 101\u003c\/p\u003e \u003cp\u003e4.1.1 Modes of Ischemia, Phases of Arrhythmogenesis 102\u003c\/p\u003e \u003cp\u003e4.1.2 Trigger-Substrate-Modulating Factors 103\u003c\/p\u003e \u003cp\u003e4.2 Arrhythmogenesis in Acute Myocardial Ischemia 103\u003c\/p\u003e \u003cp\u003e4.2.1 Phase 1A 103\u003c\/p\u003e \u003cp\u003e4.2.2 Phase 1B 113\u003c\/p\u003e \u003cp\u003e4.2.3 Arrhythmogenic Mechanism: Trigger 114\u003c\/p\u003e \u003cp\u003e4.2.4 Catecholamines 115\u003c\/p\u003e \u003cp\u003e4.3 Arrhythmogenesis During the First Week Post MI 115\u003c\/p\u003e \u003cp\u003e4.3.1 Mechanisms 115\u003c\/p\u003e \u003cp\u003e4.3.2 The Subendocardial Purkinje Cell as a Trigger 24–48 H Post Occlusion 116\u003c\/p\u003e \u003cp\u003e4.3.3 Five Days Post-Occlusion: Epicardial Border Zone 120\u003c\/p\u003e \u003cp\u003e4.4 Arrhythmia Mechanisms in Chronic Infarction 128\u003c\/p\u003e \u003cp\u003e4.4.1 Reentry and Focal Mechanisms 128\u003c\/p\u003e \u003cp\u003e4.4.2 Heterogeneity of Ion Channel Expression in the Healthy Heart 129\u003c\/p\u003e \u003cp\u003e4.4.3 Remodeling in Chronic Myocardial Infarction 131\u003c\/p\u003e \u003cp\u003e4.4.4 Structural Remodeling 133\u003c\/p\u003e \u003cp\u003e4.4.5 Role of the Purkinje System 135\u003c\/p\u003e \u003cp\u003eReferences 136\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5. Antiarrhythmic Drug Classification 155\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eCynthia A. Carnes\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 155\u003c\/p\u003e \u003cp\u003e5.2 Sodium Channel Blockers 155\u003c\/p\u003e \u003cp\u003e5.2.1 Mixed Sodium Channel Blockers (Vaughan Williams Class Ia) 156\u003c\/p\u003e \u003cp\u003e5.3 Inhibitors of the Fast Sodium Current with Rapid Kinetics (Vaughan Williams Class Ib) 158\u003c\/p\u003e \u003cp\u003e5.3.1 Lidocaine 158\u003c\/p\u003e \u003cp\u003e5.3.2 Mexiletine 159\u003c\/p\u003e \u003cp\u003e5.4 Inhibitors of the Fast Sodium Current with Slow Kinetics (Vaughan Williams Class Ic) 159\u003c\/p\u003e \u003cp\u003e5.4.1 Flecainide 159\u003c\/p\u003e \u003cp\u003e5.4.2 Propafenone 160\u003c\/p\u003e \u003cp\u003e5.5 Inhibitors of Repolarizing K\u003csup\u003e+\u003c\/sup\u003e Currents (Vaughan Williams Class III) 160\u003c\/p\u003e \u003cp\u003e5.5.1 Dofetilide 160\u003c\/p\u003e \u003cp\u003e5.5.2 Sotalol 161\u003c\/p\u003e \u003cp\u003e5.5.3 Amiodarone 161\u003c\/p\u003e \u003cp\u003e5.5.4 Ibutilide 162\u003c\/p\u003e \u003cp\u003e5.6 I\u003csub\u003eKur\u003c\/sub\u003e Blockers 162\u003c\/p\u003e \u003cp\u003e5.7 Inhibitors of Calcium Channels 162\u003c\/p\u003e \u003cp\u003e5.7.1 Verapamil and Diltiazem 162\u003c\/p\u003e \u003cp\u003e5.8 Inhibitors of Adrenergically-Modulated Electrophysiology 163\u003c\/p\u003e \u003cp\u003e5.8.1 Funny Current (I\u003csub\u003ef\u003c\/sub\u003e) Inhibitors 163\u003c\/p\u003e \u003cp\u003e5.8.2 Beta-Adrenergic Receptor Antagonists 164\u003c\/p\u003e \u003cp\u003e5.9 Adenosine 164\u003c\/p\u003e \u003cp\u003e5.10 Digoxin 165\u003c\/p\u003e \u003cp\u003e5.11 Conclusions 165\u003c\/p\u003e \u003cp\u003eReferences 165\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6. Repolarization Reserve and Proarrhythmic Risk 171\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAndrás Varr\u003c\/i\u003eó\u003c\/p\u003e \u003cp\u003e6.1 Definitions and Background 171\u003c\/p\u003e \u003cp\u003e6.2 The Major Players Contributing to Repolarization Reserve 175\u003c\/p\u003e \u003cp\u003e6.2.1 Inward Sodium Current (I\u003csub\u003eNa\u003c\/sub\u003e) 175\u003c\/p\u003e \u003cp\u003e6.2.2 Inward L-Type Calcium Current (I\u003csub\u003eCa,L\u003c\/sub\u003e) 176\u003c\/p\u003e \u003cp\u003e6.2.3 Rapid Delayed Rectifier Outward Potassium Current (I\u003csub\u003eKr\u003c\/sub\u003e) 177\u003c\/p\u003e \u003cp\u003e6.2.4 Slow Delayed Rectifier Outward Potassium Current (I\u003csub\u003eKs\u003c\/sub\u003e) 178\u003c\/p\u003e \u003cp\u003e6.2.5 Inward Rectifier Potassium Current (I\u003csub\u003ek1\u003c\/sub\u003e) 179\u003c\/p\u003e \u003cp\u003e6.2.6 Transient Outward Potassium Current (I\u003csub\u003eto\u003c\/sub\u003e) 180\u003c\/p\u003e \u003cp\u003e6.2.7 Sodium—Potassium Pump Current (I\u003csub\u003eNa\/K\u003c\/sub\u003e) 180\u003c\/p\u003e \u003cp\u003e6.2.8 Sodium–Calcium Exchanger Current (NCX) 180\u003c\/p\u003e \u003cp\u003e6.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve 182\u003c\/p\u003e \u003cp\u003e6.4 Clinical Significance of the Reduced Repolarization Reserve 183\u003c\/p\u003e \u003cp\u003e6.4.1 Genetic Defects 184\u003c\/p\u003e \u003cp\u003e6.4.2 Heart Failure 185\u003c\/p\u003e \u003cp\u003e6.4.3 Diabetes Mellitus 185\u003c\/p\u003e \u003cp\u003e6.4.4 Gender 186\u003c\/p\u003e \u003cp\u003e6.4.5 Renal Failure 187\u003c\/p\u003e \u003cp\u003e6.4.6 Hypokalemia 187\u003c\/p\u003e \u003cp\u003e6.4.7 Hypothyroidism 187\u003c\/p\u003e \u003cp\u003e6.4.8 Competitive Athletes 188\u003c\/p\u003e \u003cp\u003e6.5 Repolarization Reserve as a Dynamically Changing Factor 188\u003c\/p\u003e \u003cp\u003e6.6 How to Measure the Repolarization Reserve 189\u003c\/p\u003e \u003cp\u003e6.7 Pharmacological Modulation of the Repolarization Reserve 191\u003c\/p\u003e \u003cp\u003e6.8 Conclusion 193\u003c\/p\u003e \u003cp\u003eReferences 194\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7. Safety Challenges in the Development of Novel Antiarrhythmic Drugs 201\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGary Gintant and Zhi Su\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 201\u003c\/p\u003e \u003cp\u003e7.2 Review of Basic Functional Cardiac Electrophysiology 202\u003c\/p\u003e \u003cp\u003e7.2.1 Normal Pacemaker Activity 203\u003c\/p\u003e \u003cp\u003e7.2.2 Atrioventricular Conduction 204\u003c\/p\u003e \u003cp\u003e7.2.3 Ventricular Repolarization: Effects on the QT Interval 204\u003c\/p\u003e \u003cp\u003e7.2.4 Electrophysiologic Lessons Learned from Long QT Syndromes 205\u003c\/p\u003e \u003cp\u003e7.3 Safety Pharmacology Perspectives on Developing Antiarrhythmic Drugs 206\u003c\/p\u003e \u003cp\u003e7.3.1. Part A. On-Target (Primary Pharmacodynamic) versus Off-Target (Secondary Pharmacodynamic) Considerations 206\u003c\/p\u003e \u003cp\u003e7.3.2 Part B. General Considerations 207\u003c\/p\u003e \u003cp\u003e7.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs 208\u003c\/p\u003e \u003cp\u003e7.4.1 Sodium Channel Block Reduces the Incidence of Ventricular Premature Depolarizations But Increases Mortality 208\u003c\/p\u003e \u003cp\u003e7.4.2 Delayed Ventricular Repolarization with d-Sotalol Increases Mortality in Patients with Left Ventricular Dysfunction and Remote Myocardial Infarction: The SWORD and DIAMOND Trials 210\u003c\/p\u003e \u003cp\u003e7.4.3 Ranolazine: An Antianginal Agent with a Novel Electrophysiologic Action and Potential Antiarrhythmic Properties 213\u003c\/p\u003e \u003cp\u003e7.5 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs 217\u003c\/p\u003e \u003cp\u003e7.5.1 Introduction 217\u003c\/p\u003e \u003cp\u003e7.5.2. Lessons Learned with Azimilide, a Class III Drug that Reduces the Delayed Rectifier Currents I\u003csub\u003eKr\u003c\/sub\u003e and I\u003csub\u003eKs\u003c\/sub\u003e 218\u003c\/p\u003e \u003cp\u003e7.5.3 Atrial Repolarizing Delaying Agents. Experience with Vernakalant, a Drug that Blocks Multiple Cardiac Currents (Including the Atrial-Specific Repolarizing Current I\u003csub\u003eKur\u003c\/sub\u003e) 220\u003c\/p\u003e \u003cp\u003eReferences 222\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8. Safety Pharmacology and Regulatory Issues in the Development of Antiarrhythmic Medications 233\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eArmando Lagrutta and Joseph J. Salata\u003c\/i\u003e\u003cb\u003e\u003ci\u003e\u003cbr\u003e\u003cbr\u003e\u003c\/i\u003e\u003c\/b\u003e8.1 Introduction 233\u003c\/p\u003e \u003cp\u003e8.2 Basic Physiological Considerations 234\u003c\/p\u003e \u003cp\u003e8.2.1 Ion Channels and Arrhythmogenesis 234\u003c\/p\u003e \u003cp\u003e8.2.2 Antiarrhythmic Agents 236\u003c\/p\u003e \u003cp\u003e8.3 Historical Considerations 237\u003c\/p\u003e \u003cp\u003e8.3.1 CAST: Background, Clinical Findings, and Aftermath 237\u003c\/p\u003e \u003cp\u003e8.3.2 Torsades de Pointes and hERG Channel Inhibition: Safety Pharmacology Concern with Critical Impact on Antiarrhythmic Development 239\u003c\/p\u003e \u003cp\u003e8.3.3 Recent Clinical Trials 242\u003c\/p\u003e \u003cp\u003e8.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment 244\u003c\/p\u003e \u003cp\u003e8.4.1 ICH—S7A and S7B; E14 245\u003c\/p\u003e \u003cp\u003e8.4.2 Additional Regulatory Guidance 248\u003c\/p\u003e \u003cp\u003e8.4.3 Clinical Management Guidelines and Related Considerations About Patient Populations 250\u003c\/p\u003e \u003cp\u003e8.4.4 Consortia Efforts to Address Safety Concerns Related to Antiarrhythmic Drug Development 253\u003c\/p\u003e \u003cp\u003e8.4.5 The Unmet Medical Need: Challenges and Opportunities 254\u003c\/p\u003e \u003cp\u003eReferences 256\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9. Ion Channel Remodeling and Arrhythmias 271\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eTakeshi Aiba and Gordon F. Tomaselli\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 271\u003c\/p\u003e \u003cp\u003e9.2 Molecular and Cellular Basis for Cardiac Excitability 271\u003c\/p\u003e \u003cp\u003e9.3 Heart Failure—Epidemiology and the Arrhythmia Connection 272\u003c\/p\u003e \u003cp\u003e9.4 K\u003csup\u003e+\u003c\/sup\u003e Channel Remodeling in Heart Failure 274\u003c\/p\u003e \u003cp\u003e9.4.1 Transient Outward Current (I\u003csub\u003eto\u003c\/sub\u003e) 274\u003c\/p\u003e \u003cp\u003e9.4.2 Inward Rectifier K\u003csup\u003e+\u003c\/sup\u003e Current (I\u003csub\u003eK1\u003c\/sub\u003e) 276\u003c\/p\u003e \u003cp\u003e9.4.3 Delayed Rectifier K Currents (I\u003csub\u003eKr\u003c\/sub\u003e and I\u003csub\u003eKs\u003c\/sub\u003e) 277\u003c\/p\u003e \u003cp\u003e9.5 Ca\u003csup\u003e2+\u003c\/sup\u003e Handling and Arrhythmia Risk 278\u003c\/p\u003e \u003cp\u003e9.5.1 L-type Ca\u003csup\u003e2+\u003c\/sup\u003e Current I\u003csub\u003eCa-L \u003c\/sub\u003e278\u003c\/p\u003e \u003cp\u003e9.5.2 Sarcoplasmic Recticulum Function 278\u003c\/p\u003e \u003cp\u003e9.6 Intracellular [Na\u003csup\u003e+\u003c\/sup\u003e] in HF 282\u003c\/p\u003e \u003cp\u003e9.6.1 Cardiac I\u003csub\u003eNa\u003c\/sub\u003e in HF 282\u003c\/p\u003e \u003cp\u003e9.6.2 Na\u003csup\u003e+\u003c\/sup\u003e\/K\u003csup\u003e+\u003c\/sup\u003e ATPase 283\u003c\/p\u003e \u003cp\u003e9.7 Gap Junctions and Connexins 283\u003c\/p\u003e \u003cp\u003e9.8 Autonomic Signaling 284\u003c\/p\u003e \u003cp\u003e9.9 Calmodulin Kinase 285\u003c\/p\u003e \u003cp\u003e9.10 Conclusions 286\u003c\/p\u003e \u003cp\u003eReferences 286\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10. Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Failure: A Potential Therapeutic Target 299\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAndriy E. Belevych, Dmitry Terentyev, and Sandor Györke\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 299\u003c\/p\u003e \u003cp\u003e10.2 Activation and Deactivation of Ryanodine Receptors During Normal Excitation-Contraction Coupling 300\u003c\/p\u003e \u003cp\u003e10.3 Defective Ryanodine Receptor Function is Linked to Proarrhythmic Delayed Afterdepolarizations and Calcium Alternans 301\u003c\/p\u003e \u003cp\u003e10.4 Genetic and Acquired Defects in Ryanodine Receptors 302\u003c\/p\u003e \u003cp\u003e10.5 Effects of Thiol-Modifying Agents on Ryanodine Receptors 303\u003c\/p\u003e \u003cp\u003e10.6 Reactive Oxygen Species Production and Oxidative Stress in Cardiac Disease 304\u003c\/p\u003e \u003cp\u003e10.7 Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Heart Failure 305\u003c\/p\u003e \u003cp\u003e10.8 Therapeutic Potential of Normalizing Ryanodine Receptor Function 306\u003c\/p\u003e \u003cp\u003eReferences 308\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11. Targeting Na\u003csup\u003e+\u003c\/sup\u003e\/Ca\u003csup\u003e2+ \u003c\/sup\u003eExchange as an Antiarrhythmic Strategy 313\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGudrun Antoons, Rik Willems, and Karin R. Sipido\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 313\u003c\/p\u003e \u003cp\u003e11.2 Why Target NCX in Arrhythmias? 314\u003c\/p\u003e \u003cp\u003e11.3 When Do We See Triggered Arrhythmias? 317\u003c\/p\u003e \u003cp\u003e11.4 What Drugs are Available? 318\u003c\/p\u003e \u003cp\u003e11.5 Experience with NCX Inhibitors 321\u003c\/p\u003e \u003cp\u003e11.6 Caveat—the Consequences on Ca\u003csup\u003e2+\u003c\/sup\u003e Handling 328\u003c\/p\u003e \u003cp\u003e11.7 Need for More Development 331\u003c\/p\u003e \u003cp\u003eReferences 332\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12. Calcium\/Calmodulin-Dependent Protein Kinase II (CaMKII)—Modulation of Ion Currents and Potential Role for Arrhythmias 339\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDr. Lars S. Maier\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 339\u003c\/p\u003e \u003cp\u003e12.2 Evolving Role of Ca\u003csup\u003e2+\u003c\/sup\u003e\/CaMKII in the Heart 340\u003c\/p\u003e \u003cp\u003e12.3 Activation of CaMKII 340\u003c\/p\u003e \u003cp\u003e12.4 Role of CaMKII in ECC 342\u003c\/p\u003e \u003cp\u003e12.4.1 Ca\u003csup\u003e2+\u003c\/sup\u003e Influx and I\u003csub\u003eCa\u003c\/sub\u003e Facilitation 343\u003c\/p\u003e \u003cp\u003e12.4.2 SR Ca\u003csup\u003e2+\u003c\/sup\u003e Release and SR Ca Leak 344\u003c\/p\u003e \u003cp\u003e12.4.3 SR Ca\u003csup\u003e2+\u003c\/sup\u003e Uptake, FDAR, Acidosis 346\u003c\/p\u003e \u003cp\u003e12.4.4 Na\u003csup\u003e+ \u003c\/sup\u003eChannels 348\u003c\/p\u003e \u003cp\u003e12.4.5 K\u003csup\u003e+\u003c\/sup\u003e Channels 353\u003c\/p\u003e \u003cp\u003e12.5 Role of CaMKII for Arrhythmias 354\u003c\/p\u003e \u003cp\u003e12.6 Summary 355\u003c\/p\u003e \u003cp\u003eAcknowledgments 356\u003c\/p\u003e \u003cp\u003eReferences 356\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13. Selective Targeting of Ventricular Potassium Channels for Arrhythmia Suppression: Feasible or Risible? 367\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eHugh Clements-Jewery and Michael Curtis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 367\u003c\/p\u003e \u003cp\u003e13.2 Effects of K\u003csup\u003e+\u003c\/sup\u003e Channel Blockade on APD and Arrhythmogenesis 371\u003c\/p\u003e \u003cp\u003e13.2.1 I\u003csub\u003eKur\u003c\/sub\u003e Blockade 371\u003c\/p\u003e \u003cp\u003e13.2.2 I\u003csub\u003eKr\u003c\/sub\u003e Blockade 371\u003c\/p\u003e \u003cp\u003e13.2.3 I\u003csub\u003eKs\u003c\/sub\u003e Blockade 372\u003c\/p\u003e \u003cp\u003e13.2.4 I\u003csub\u003eK1\u003c\/sub\u003e Blockade 372\u003c\/p\u003e \u003cp\u003e13.2.5 I\u003csub\u003eto\u003c\/sub\u003e Blockade 373\u003c\/p\u003e \u003cp\u003e13.2.6 I\u003csub\u003eKATP\u003c\/sub\u003e Blockade 374\u003c\/p\u003e \u003cp\u003e13.3 Conclusions\/Future Directions 375\u003c\/p\u003e \u003cp\u003eReferences 375\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14. Cardiac Sarcolemmal ATP-sensitive Potassium Channel Antagonists: A Class of Drugs that May Selectively Target the Ischemic Myocardium 381\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGeorge E. Billman\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 381\u003c\/p\u003e \u003cp\u003e14.2 Effects of Myocardial Ischemia on Extracellular Potassium 382\u003c\/p\u003e \u003cp\u003e14.3 Effect of Extracellular Potassium on Ventricular Rhythm 386\u003c\/p\u003e \u003cp\u003e14.4 Effect of ATP-sensitive Potassium Channel Antagonists on Ventricular Arrhythmias 387\u003c\/p\u003e \u003cp\u003e14.4.1 Nonselective ATP-sensitive Potassium Channel Antagonists 387\u003c\/p\u003e \u003cp\u003e14.4.2 Selective ATP-sensitive Potassium Channel Antagonist 390\u003c\/p\u003e \u003cp\u003e14.4.3 Proarrhythmic Effects of ATP-sensitive Potassium Channel Agonists 397\u003c\/p\u003e \u003cp\u003e14.5 Summary 401\u003c\/p\u003e \u003cp\u003eReferences 401\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15. Mitochondrial Origin of Ischemia-Reperfusion Arrhythmias 413\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBrian O’Rourke, PHD\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 413\u003c\/p\u003e \u003cp\u003e15.2 Mechanisms of Arrhythmias 414\u003c\/p\u003e \u003cp\u003e15.2.1 Automacity 414\u003c\/p\u003e \u003cp\u003e15.2.2 Triggered Arrhythmias 415\u003c\/p\u003e \u003cp\u003e15.3 Ischemia-Reperfusion Arrhythmias 417\u003c\/p\u003e \u003cp\u003e15.4 Mitochondrial Criticality: The Root of Ischemia-Reperfusion Arrhythmias 418\u003c\/p\u003e \u003cp\u003e15.5 K\u003csub\u003eATP\u003c\/sub\u003e Activation and Arrhythmias 420\u003c\/p\u003e \u003cp\u003e15.6 Metabolic Sinks and Reperfusion Arrhythmias 422\u003c\/p\u003e \u003cp\u003e15.7 Antioxidant Depletion 423\u003c\/p\u003e \u003cp\u003e15.8 Mitochondria as Therapeutic Targets 423\u003c\/p\u003e \u003cp\u003eReferences 424\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16. Cardiac Gap Junctions: A New Target for New Antiarrhythmic Drugs: Gap Junction Modulators 431\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAnja Hagen and Stefan Dhein\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 431\u003c\/p\u003e \u003cp\u003e16.2 The Development of Gap Junction Modulators and AAPs 433\u003c\/p\u003e \u003cp\u003e16.3 Molecular Mechanisms of Action of AAPs 436\u003c\/p\u003e \u003cp\u003e16.4 Antiarrhythmic Effects of AAPs 439\u003c\/p\u003e \u003cp\u003e16.4.1 Ventricular Fibrillation and Ventricular Tachycardia 444\u003c\/p\u003e \u003cp\u003e16.4.2 Atrial fibrillation 444\u003c\/p\u003e \u003cp\u003e16.4.3 Others 445\u003c\/p\u003e \u003cp\u003e16.5 Site- and Condition-Specific Effects of AAPs; Effects in Ischemia or Simulated Ischemia 446\u003c\/p\u003e \u003cp\u003e16.6 Chemistry of AAPs 447\u003c\/p\u003e \u003cp\u003e16.7 Short Overview About Cardiac Gap Junctions 447\u003c\/p\u003e \u003cp\u003e16.8 Gap Junction Modulation as a New Antiarrhythmic Principle 452\u003c\/p\u003e \u003cp\u003eReferences 453\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17. Novel Pharmacological Targets for the Management of Atrial Fibrillation 461\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAlexander Burashnikov and Charles Antzelevitch\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 461\u003c\/p\u003e \u003cp\u003e17.2 Novel Ion Channel Targets for Atrial Fibrillation Treatment 462\u003c\/p\u003e \u003cp\u003e17.2.1 The Ultrarapid Delayed Rectifier Potassium Current (I\u003csub\u003eKur\u003c\/sub\u003e) 462\u003c\/p\u003e \u003cp\u003e17.2.2 The Acetylcholine-Regulated Inward Rectifying Potassium Current (I\u003csub\u003eK-ACh\u003c\/sub\u003e) and the Constitutively Active (CA) I\u003csub\u003eK-ACh \u003c\/sub\u003e464\u003c\/p\u003e \u003cp\u003e17.2.3 The Early Sodium Current (I\u003csub\u003eNa\u003c\/sub\u003e) 464\u003c\/p\u003e \u003cp\u003e17.2.4 Block I\u003csub\u003eKr\u003c\/sub\u003e and Its Relation to Atrial Selectivity of I\u003csub\u003eNa\u003c\/sub\u003e Blockade 467\u003c\/p\u003e \u003cp\u003e17.2.5 Other Potential Atrial-Selective Ion Channel Targets for the Treatment AF 467\u003c\/p\u003e \u003cp\u003e17.2.6 Influence of Atrial- Selective Agents on Ventricular Arrhythmias? 468\u003c\/p\u003e \u003cp\u003e17.3 Upstream Therapy Targets for Atrial Fibrillation 468\u003c\/p\u003e \u003cp\u003e17.4 Gap Junction as Targets for AF Therapy 469\u003c\/p\u003e \u003cp\u003e17.5 Intracellular Calcium Handling and AF 470\u003c\/p\u003e \u003cp\u003eReferences 471\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18. I\u003csub\u003eKur\u003c\/sub\u003e, Ultra-rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias 479\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eArun Sridhar and Cynthia A. Carnes\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 479\u003c\/p\u003e \u003cp\u003e18.2 Molecular Biology of the K\u003csub\u003ev \u003c\/sub\u003e1.5 Channels: 480\u003c\/p\u003e \u003cp\u003e18.2.1 K\u003csub\u003ev \u003c\/sub\u003e1.5 Activation and Inactivation 480\u003c\/p\u003e \u003cp\u003e18.2.2 Where Does I\u003csub\u003eKur\u003c\/sub\u003e Fit Into the Cardiac Action Potential? 482\u003c\/p\u003e \u003cp\u003e18.2.3 Adrenergic Modulation of I\u003csub\u003eKur\u003c\/sub\u003e 485\u003c\/p\u003e \u003cp\u003e18.3 I\u003csub\u003eKur\u003c\/sub\u003e as a Therapeutic Target 485\u003c\/p\u003e \u003cp\u003e18.4 Organic Blockers of I\u003csub\u003eKur\u003c\/sub\u003e 486\u003c\/p\u003e \u003cp\u003e18.4.1 Mixed Channel Blockers 486\u003c\/p\u003e \u003cp\u003e18.4.2 Mixed Channel Blockers 487\u003c\/p\u003e \u003cp\u003e18.4.3 Selective K\u003csub\u003ev \u003c\/sub\u003e1.5 Blockers 488\u003c\/p\u003e \u003cp\u003e18.5 Conclusions 490\u003c\/p\u003e \u003cp\u003eReferences 490\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19. Non-Pharmacologic Manipulation of the Autonomic Nervous System in Human for the Prevention of Life-Threatening Arrhythmias 495\u003cbr\u003e\u003c\/b\u003e\u003ci\u003ePeter J. Schwartz\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 495\u003c\/p\u003e \u003cp\u003e19.2 Sympathetic Nervous System 496\u003c\/p\u003e \u003cp\u003e19.2.1 Experimental Background 496\u003c\/p\u003e \u003cp\u003e19.2.2 Clinical Evidence 497\u003c\/p\u003e \u003cp\u003e19.3 Parasympathetic Nervous System 500\u003c\/p\u003e \u003cp\u003e19.3.1 Experimental Background 500\u003c\/p\u003e \u003cp\u003e19.3.2 Clinical Evidence 501\u003c\/p\u003e \u003cp\u003e19.4 Conclusion 504\u003c\/p\u003e \u003cp\u003eAcknowledgement 504\u003c\/p\u003e \u003cp\u003eReferences 504\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20. 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\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGeorge E. Billman\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 509\u003c\/p\u003e \u003cp\u003e20.2 Exercise and Susceptibility to Sudden Death 510\u003c\/p\u003e \u003cp\u003e20.2.1 Clinical Studies 510\u003c\/p\u003e \u003cp\u003e20.2.2 Experimental Studies 515\u003c\/p\u003e \u003cp\u003e20.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death 518\u003c\/p\u003e \u003cp\u003e20.4 β\u003csub\u003e2\u003c\/sub\u003e-Adrenergic Receptor Activation and Susceptibility to VF 521\u003c\/p\u003e \u003cp\u003e20.5 Effect of Exercise Conditioning on Cardiac Autonomic Regulation 523\u003c\/p\u003e \u003cp\u003e20.6 Effect of Exercise Training on Myocyte Calcium Regulation 528\u003c\/p\u003e \u003cp\u003e20.7 Summary and Conclusions 530\u003c\/p\u003e \u003cp\u003eReferences 531\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21. Dietary Omega-3 Fatty Acids as a Nonpharmacological Antiarrhythmic Intervention 543\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBarry London and J. Michael Frangiskakis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 Introduction 543\u003c\/p\u003e \u003cp\u003e21.2 Fatty Acid Metabolism 544\u003c\/p\u003e \u003cp\u003e21.2.1 Nomenclature 544\u003c\/p\u003e \u003cp\u003e21.2.2 Dietary Fatty Acids 544\u003c\/p\u003e \u003cp\u003e21.2.3 Roles of Polyunsaturated Fatty Acids 545\u003c\/p\u003e \u003cp\u003e21.3 Cellular Mechanisms 545\u003c\/p\u003e \u003cp\u003e21.3.1 Ion Channel Blockade 545\u003c\/p\u003e \u003cp\u003e21.3.2 Direct Membrane Effects 547\u003c\/p\u003e \u003cp\u003e21.3.3 Phosphorylation 548\u003c\/p\u003e \u003cp\u003e21.3.4 Inflammation 548\u003c\/p\u003e \u003cp\u003e21.3.5 Summary 548\u003c\/p\u003e \u003cp\u003e21.4 Animal Studies 548\u003c\/p\u003e \u003cp\u003e21.4.1 Acute Intravenous Effects of n-3 PUFAs 549\u003c\/p\u003e \u003cp\u003e21.4.2 Dietary Supplementation with n-3 PUFAs 549\u003c\/p\u003e \u003cp\u003e21.5 Clinical Studies 550\u003c\/p\u003e \u003cp\u003e21.5.1 Observational Studies 550\u003c\/p\u003e \u003cp\u003e21.5.2 Randomized Trials 551\u003c\/p\u003e \u003cp\u003e21.5.3 Surrogate Markers for Arrhythmias 555\u003c\/p\u003e \u003cp\u003e21.5.4 Summary 555\u003c\/p\u003e \u003cp\u003e21.6 Future Directions 556\u003c\/p\u003e \u003cp\u003eReferences 556\u003c\/p\u003e \u003cp\u003eGeneral Index 567\u003c\/p\u003e \u003cp\u003eIndex of Drug and Chemical Names 575\u003c\/p\u003e  \"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)\u003cbr\u003e \u003cbr\u003e  \u003cp\u003e\u003cb\u003eGEORGE EDWARD BILLMAN\u003c\/b\u003e is a professor at The Ohio State University. He is currently an Associate Editor of \u003ci\u003ePharmacology and Therapeutics\u003c\/i\u003e, an Editor of \u003ci\u003eExperimental Physiology\u003c\/i\u003e, and on the editorial boards of Journal of \u003ci\u003eCardiovascular Pharmacology\u003c\/i\u003e and \u003ci\u003eJournal of Applied Physiology\u003c\/i\u003e. 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 \u003ci\u003eDrug Discovery Handbook\u003c\/i\u003e (Wiley).   \u003c\/p\u003e\u003cp\u003e\u003cb\u003ePROFILES POTENTIAL TREATMENT APPROACHES FOR CARDIAC ARRHYTHMIAS\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003eCardiac 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, \u003ci\u003eNovel Therapeutic Targets for Antiarrhythmic Drugs\u003c\/i\u003e presents the latest treatments for cardiac arrhythmias alongside comprehensive presentations of basic cardiac physiology and pharmacology. \u003c\/p\u003e\u003cp\u003eWritten 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: \u003c\/p\u003e\u003cul\u003e \u003cli\u003e\n\u003cb\u003eSection One\u003c\/b\u003e comprehensively reviews basic cardiac electrophysiology, the mechanisms responsible for arrhythmias in the setting of ischemia, and basic pharmacology of antiarrhythmic drugs.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Two\u003c\/b\u003e addresses safety pharmacology, including the concept of \"repolarization reserve,\" safety challenges, and regulatory issues for the development of novel antiarrhythmic drugs.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Three\u003c\/b\u003e describes several novel pharmacological targets for antiarrhythmic drugs, including both ion channel and non-ion channel targets.\u003c\/li\u003e \u003cli\u003e\n\u003cb\u003eSection Four\u003c\/b\u003e describes promising non-pharmacological antiarrhythmic interventions including selective cardiac neural disruption or nerve stimulation, aerobic exercise training, and diet (omega-3 fatty acids).\u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eOffering an unparalleled look at the current state and future direction of cardiac arrhythmia treatment, \u003ci\u003eNovel Therapeutic Targets for Antiarrhythmic Drugs\u003c\/i\u003e provides an important resource to advanced students, working researchers, and busy professionals alike.    \"George Billman has assembled a terrific book that will serve the needs of students, clinical and research faculty with interests in cardiac arrhythmias, antiarrhythmic drugs and ion channel biology.\" \u003cbr\u003e —\u003cb\u003eMark E. Anderson\u003c\/b\u003e, M.D., Ph.D. Professor, Departments of Internal Medicine and Molecular Physiology \u0026amp; Biophysics Head, Department of Internal Medicine François M. Abboud Chair in Internal Medicine  \u003c\/p\u003e\u003cp\u003e\"The information presented in each individual chapter is of superb quality, still providing the information in such a detailed way that even the knowledge of the specialists in the field will be challenged. The topics covered, however, are so broad that the mentioned specialist will also find chapters of great interest to his common knowledge in other fields. In this era of PubMed, the younger scientists will be pleased to find detailed referencing, including papers going back many decades, revealing information well in the last century. Therefore, I recommend this book to individuals still interested in the mechanism behind arrhythmias and the way that this knowledge can be applied to new therapeutic strategies.\"\u003cbr\u003e —\u003cb\u003eMarc Vos\u003c\/b\u003e, PhD, University Medical Center Utrecht\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989700788453,"sku":"NP9780470261002","price":214.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9780470261002.jpg?v=1761785160","url":"https:\/\/k12savings.com\/es\/products\/novel-therapeutic-targets-for-antiarrhythmic-drugs-isbn-9780470261002","provider":"K12savings","version":"1.0","type":"link"}