The Role of Myocardial Heterogeneity in Maintenance and Termination of Cardiac Arrhythmias

Sudden cardiac death resulting from cardiac arrest is the leading cause of death in the industrialized world and is normally attributed to ventricular arrhythmias. Several clinical trials have demonstrated the efficacy of defibrillation therapy and the superiority of implantable cardioverter defibrillator (ICD) therapy over pharmacologic treatments for those at high risk for ventricular tachycardia and fibrillation (VT/VF). High-risk patients generally have one or more clinical indicators for ICD implantation including a history of ischemic heart disease and prior myocardial infarction or cardiomyopathy. These conditions may involve scarring of the myocardium and/or hypertrophy, which create a heterogeneous substrate and can promote VT/VF. However, many basic studies on arrhythmia maintenance and defibrillation are carried out on healthy animal hearts. To further improve upon defibrillation therapy for those high-risk patients, the mechanisms of arrhythmias and defibrillation must be studied in appropriate animal models of human disease. This dissertation will report on arrhythmia maintenance and defibrillation in three clinically relevant animal models including rabbit models of acute and chronic myocardial infarction and a transgenic rabbit model (beta-myosin heavy chain-Q403) of human hypertrophic cardiomyopathy. Using fluorescent optical mapping combined with structural and molecular imaging techniques, underlying mechanisms contributing to arrhythmia were elucidated and new, lower energy algorithms for defibrillation were explored.