There is considerable evidence that the malignant ventricular arrhythmias which occur weeks or months following myocardial infarction are usually due to reentry. Our long term goal is to understand the cellular mechanisms of the slow discontinuous conduction which supports reentry. Recent clinical trials emphasize the need for new approaches to drug therapy. The following specific aims are directed to this goal. FIRST to determine the role of modulation of cell-to-cell electrotonic coupling in arrhythmogenesis nad antiarrhythmic action. SECOND, to determine the effect of transient ischemia on conduction in normal myocardium and on conduction in pre-existing infarcted myocardium. THIRD, to evaluate the role of refractoriness in changes in arrhythmogeneicity induced by agents which modify cell coupling. Multi-site simultaneous electrograms will be recorded from ventricular myocardium and from the infarcted region that has undergone occlusion and reperfusion of the left anterior descending coronary artery three to four weeks prior to study. Body surface potentials will be signal averaged to analyze late potentials and programmed ventricular extrastimulation employed to measure refractoriness and test susceptibility to arrhythmias. Heptanol, which decreases cell coupling, and angiotensin II which increases cell coupling, will be introduced into the coronary circulation to determine their effects on conduction, the appearance of late potentials and susceptibility to arrhythmias. Parallel experiments in vitro on normal and infarcted epicardial tissues will evaluate the effects of these agents on anisotropy. Direct effects of these agents on gap junctional function will be evaluated using current and voltage clamps in isolated ventricular myocyte pairs. Similar experiments measuring conduction, late potentials, inducibility of arrhythmias will evaluate the effects of ischemia superimposed on pre- existing infarction. These studies correlated at three levels of experimentation (isolated myocytes, tissue preparation and in situ) will produce new basic information that is not only important in terms of understanding the basic electrophysiology of conduction but will also provide the experimental basis and theoretical rationale for designing new modes of antiarrhythmic therapy based on the manipulation of cell coupling; current antiarrhythmic agents are designed to alter membrane properties.
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