Despite enormous progress identifying the molecular basis for many of the ionic currents in the heart, a fully integrated understanding of the physiological basis for cardiac excitation is lacking. This gap in knowledge is underscored by the observation that two-thirds of all-cause cardiac mortality in the United States is due to sudden cardiac death. Our laboratory is interested in understanding the basis for normal cardiac rhythmicity and the pathological processes that result in arrhythmogenesis. We have been particularly interested in the role of gap junction channels in cardiac electrophysiology. During the previous funding period, we generated a number of genetically engineered murine models of altered gap junction channel expression in the heart. Our initial characterization of these mice resulted in several fundamental discoveries related to: the role of gap junctions channels in maintaining normal cardiac rhythmicity; the demonstration of a direct link between aberrant gap junction expression and arrhythmogenesis; and the demonstration of a relationship between aberrant gap junction expression and contractile dysfunction. However, our studies have raised as many questions as they have answered about the nature of cardiac impulse propagation and the function of gap junction channels in the heart. Accordingly, this renewal will build upon our previous work and further define the mechanisms through which gap junction channels and perhaps other coupling mechanisms in the heart contribute to normal cardiac physiology and pathophysiology. To achieve this overall goal, we will pursue the following specific aims: 1) To define the nature of impulse propagation in the murine heart; 2) To characterize the relationship between cell coupling and excitability in the murine heart; 3) To define the mechanisms by which cellular uncoupling in the myocardium forms a highly arrhythmogenic substrate. ? ?
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