Ventricular tachyarrhythmias which occur following myocardial infarction are thought to be reentrant and are dependent, in part, on abnormal impulse conduction. Recent work suggests that slow, discontinuous conduction in recently infarcted tissue may be due, in part, to altered passive membrane properties leading to chronic increased resistance to current flow between cells. The overall objective of this proposal is to define the cellular electrophysiologic basis for abnormal conduction in a chronic, canine infarct model and determine how interventions thought to modify the propensity toward arrhythmias (antiarrhythmic drugs, sublethal ischemic injury superimposed on chronic infarcted myocardium, increased preload) modify conduction, its cellular determinants and inducible arrhythmias. In vitro studies will focus upon the cellular mechanisms of slow, discontinuous conduction in chronic, infarcted canine myocardium. Our hypothesis is that abnormal passive membrane properties play a primary role in the slow conduction. Alterations in action potential parameters, the space constant and membrane time constant which occur in infarcts will be determined. Cable analysis will be used to determine whether alterations in passive membrane properties can account for the slow, abnormal conduction noted. In addition, the effects of antiarrhythmic drugs and superimposed sublethal ischemic injury on conduction, action potential parameters, and passive membrane properties will be determined. These in vitro determinations will be correlated to changes in local conduction characteristics, electrogram morphology, refractoriness and arrhythmia inducibility noted with the same interventions (antiarrhythmics, ischemia) in parallel in vivo experiments. The effects of increasing preload, a maneuver thought to be proarrhythmic, on conduction, refractoriness, electrogram characteristics and arrhythmia induction will be studied using isolated, perfused infarcted heart preparations. Changes in these parameters in both normal and infarcted myocardium will be determined and developing heterogeneity identified. These factors will be correlated to changes in inducibility of ventricular arrhythmias.
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