The chief aim of the proposed studies is to provide experimental data that will significantly advance our knowledge and understanding of the heterogeneities that exist in canine ventricular myocardium. Our primary objectives include full characterization of a unique subpopulation of cells in the deep subepicardial to midmyocardial layers of the ventricular wall (M cells) recently described by our laboratory as well as further definition of the distinctions between subepicardial and subendocardial tissues and cells. Also among our primary goals are several corollary subprojects designed to examine to what degree differences in the electrophysiology and pharmacology of these functionally distinct cell types contribute to electrocardiographic manifestations, physiologic function and the development of cardiac arrhythmias. Our approach is a multilevel one designed to provide and integrate information ranging from membrane electrophysiology to clinical electrocardiography. Electrocardiographic, action potential and conduction data will be obtained from the intact canine heart in vivo and compared with the results obtained from isolated thin sheets of tissue from various depths of the ventricular wall in vivo. These data will then be compared with action potential and voltage/patch clamp data from enzymatically dissociated myocytes. Establishment of complete profiles of the electrophysiologic characteristics and pharmacologic responsiveness of the various tissue and cell types spanning the ventricular wall is a fundamental goal of the project. Identification of regional (base, apex, septum, outflow tracts) distinctions is among our secondary aims. To achieve these goals effectively, we will strive to develop interdependent lines of investigation in parallel, so far as possible. These studies will advance our understanding of the bases for the electrocardiographic J, T and U waves and improve our understanding of the complex factors contributing to the development of cardiac rhythm disturbances. The results will also provide new information relative to mechanisms by which various drugs may exert their antiarrhythmic actions. Our long-range goal is to narrow the gap that currently exists in this area and to generate information that will contribute to a more definitive and less empiric approach in the medical management of cardiac arrhythmias.
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