Lethal ventricular arrhythmias represent an important source of increased mortality in patients with severe congestive heart failure. It has been suspected and recent experiments from this laboratory confirm that myocardial stretch may be a potent stimulus of ventricular ectopic beats and tachyarrhythmias. Myocardial stretch resulting from pressure or volume overload associated with myriad cardiac disorders may therefore be an important trigger of life-threatening arrhythmias in patient populations most at risk of sudden death. The long-term objectives of this research proposal are to achieve a better understanding of the mechanisms perfused canine hearts will be subjected to mechanical stretch imposed by a ventricular volume servo-pump system which allows precise experimental control of the timing, contour, and amplitude of the ventricular deformation. Monophasic action potentials recorded from the epicardial surface and the ventricular electrogram are monitored to determine stretch- induced changes in electrophysiological properties of the myocardium and arrhythmogenesis. Computer simulation of the arterial tree and preloading system will facilitate evaluation of the suspected potentiating effects of high ventricular load. The possibility that existing antiarrhythmic agents may prove useful in the suppression of these arrhythmias will be systematically evaluated. The role of intracellular Ca2+ overload in mechancoelectrical feedback will be tested using pharmacologic agents which block gated Ca2+ entry and sarcoplasmic reticulum Ca2+ release. Lastly, vulnerability to stretch-induced arrhythmias will be determined in ventricles with regional ischemia or infarction, and in a model of global hypokinesis and dilatation produced by chronic rapid ventricular pacing. It is anticipated that the proposed work will provide clinically relevant information regarding fundamental but as yet poorly understood mechanisms may lead to new treatment strategies for patients at risk of sudden death.
