This proposal is a continuation of studies designed to examine the electrophysiologic responses underlying the development of lethal arrhythmias in the post-infarct canine heart that is subjected to an acute ischemic event. Programmed electrical stimulation of the post-infarcted heart will be imployed in conjunction with intramyocardial composite electrode recordings to examine simultaneous electrical activity in the previously injured as well as the acutely ischemic myocardium. The similarity in response of the canine heart to that observed with the clinical use of programmed electrical stimulation makes this a valuable experimental method for the pre-clinical assessment of antiarrhythmic drug action in the setting of myocardial ischemic injury. Our laboratory has developed and successfully employed a canin model of """"""""sudden coronary death"""""""" in which ventricular fibrillation develops in response to a transient ischemic episode at a site remote from the infarct related vessel. We will continue to employ this model to study regional electrical events that precede the onset of ventricular fibrillation and the manner in which such alterations are modified by selected pharmacologic agents demonstrated to possess antiarrhythmic and/or antifibrillatory properties. Both experimental approaches, programmed electrical stimulation and the spontaneous development of ventricular fibrillation, provide unique opportunities to study selected pharmacologic interventions for their potential to prevent ventricular fibrillation as opposed to those agents that reduce the frequency of premature ventricular complexes and/or modify the cardiac response to provocative electrical stimuli. The animal models will also be employed to continue our investigations into the influence of pharmacologic and surgical modifications of cardiac autonomic nervous system imput with respect to the ability to alter the susceptibility of the injured heart to the induction of tachyarrhythmia and/or ventricular fibrillation. These studies will emphasize the importance of analyzing the actions of drugs on ischemically injured myocardium which serves as the substrate for life-threatening (reentrant/triggered) arrhythmias and the development of ventricular fibrillation as opposed to pharmacologic studies on normal cardiac tissue. The long term goal of the research proposal is to provide a rational basis for designing and evaluating potential pharmacologic interventions for the prevention of lethal cardiac arrhythmias. The animal species to be used in these studies is the mongrel dog.
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