The applicant's have shown that structural remodeling of gap junctions, characterized by increased connexin43 along the lateral myocyte membranes, occurs in reentrant circuits that cause ventricular tachycardia in canine infarcted hearts. This discovery has led to this proposal in which the objectives are; 1) to determine the role of gap junction structural remodeling and altered gap junction physiology (electrophysiological remodeling) that occur as a consequence of myocardial infarction, in causing slow an discontinuous conduction necessary for reentrant excitation and 2) to determine how remodeled gap junctions in reentrant circuits affect the response of ventricular arryhthmias to anti-arrhythmic drugs. To accomplish these objectives, a canine infarct model of reentrant circuits in the epicardial border zone will be investigated with different methodologies designed to elucidate structured, electrophysiology and pharmacology of gap junctions. These include in vivo activation mapping, immunolocalization of connexin proteins, and measurements of transjunctional conductances in myocyte cell pairs from the infarct border zone. The different methods will be integrated to investigate the following questions. Does the pattern of structural gap junction remodeling determine the size, shape and location of reentrant circuits and the kinds of arrhythmias which occur? How does gap junctional remodeling of influence propagation of electrical activity i.e. does it cause discontinuous conduction and conduction block? Is structural remodeling associated with reduction in transjunctional conductance that contributes to slow conduction? Are remodeled gap junctions more sensitive to changes in intracellular calcium, possibly explaining the occurrence of conduction block during rapid heart rates or after pharmacologically increasing the L-type calcium current? Does an increased sensitivity of remodeled gap junctions to pH play a role in causing slow activation and conduction in regions with poor gap junction coupling? And, are remodeled gap junctions a sensitive target for drug induced termination of reentrant arrhythmias? When the answers to those questions are obtained, the applicants assert that they will have a comprehensive picture of the electrophysiological and pharmacological consequences of gap junctional remodeling in ischemic heart disease. Gap junctions will be shown to be an important target for drug development to prevent sudden arrhythmic death.
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