Patients with myocardial hypertrophy are prone to lethal ventricular tachyarrhythmias but the pathophysiology of these arrhythmias is unknown. Previous studies in a variety of models have shown increased disparity of repolarization, conduction abnormalities and triggered automaticity, any of which could be responsible for an increase propensity for arrhythmias. Most of these studies were performed in vitro, so the relation between the electrophysiologic findings and the propensity for arrhythmias was conjectural. Other studies have revealed increased arrhythmia vulnerability, but the responsible electrophysiologic changes were not determined. The proposed experiments will test the hypothesis that left ventricular hypertrophy results in electrophysiologic changes that predispose to ventricular tachyarrhythmias. Puppies, 6-12 weeks old will undergo banding or sham procedures. Part I of the project will test the hypothesis that spontaneous arrhythmias occur more frequently in hypertrophied dogs, and ventricular tachyarrhythmias are more often inducible. Serial 24-hour ECG monitoring and programmed stimulation will be performed every three months after banding or sham procedures for one year. Arrhythmia variables will be correlated with echocardiographic estimates of left ventricular mass. After the 12 month studies the dogs will undergo studies in Parts II, III and/or IV. The hypothesis that dogs with LVH have increased disparity of recovery properties will be addressed in Part II by measuring activation-recovery intervals from unipolar electrodes distributed on the epicardial endocardial surfaces by means of a multisite recording and analysis system. These measurements will be validated by refractory period determinations. Abnormal conduction could also promote arrhythmiogenesis. Disturbance in conduction will be evaluated by examining activation sequence and transmural and epicardial surface conduction times using multisite electrode arrays. In Part III, to test the hypothesis that metabolic or drug-induced abnormalities are particularly proarrhythmic in the presence of hypertrophy, the proarrhythmic effects of three interventions that are clinically relevant will be evaluated: ischemia, digitalis toxicity and diuretic induced hypokalemia. Finally, in part IV of the project the mechanisms of the arrhythmia will be investigated by examining the response to pacing maneuvers and by determination of the electrical activation sequence using a multisite computer mapping system.
