Sudden cardiac death is the single leading cause of heart failure mortality. The working hypothesis of our SCOR program is as follows: Delayed and dispersed repolarization in failing myocardium predisposes to fatal ventricular arrhythmias. Project 1 addresses this hypothesis by probing the biological basis of normal and abnormal repolarization. The overall goals are, first, ti dissect the relative roles of various genetically-defined potassium currents in the process of cardiac repolarization; second, to use that information to probe arrhythmic mechanisms at a cellular level; and a third, to lay the groundwork for gene therapy of complex excitability disorders. The project relies on transfer of ion channel genes and proteins into adult ventricular myocytes as central technologies for probing repolarization. While we rely predominantly on human or canine myocytes as central technologies for probing repolarization. While we rely predominantly on human or canine myocytes, from both normal and failing hearts, other mammalian species will be used as needed to probe specific aspects from both normal and failing hearts, other mammalian species will be used as needed to probe specific aspects of repolarization. A variety of wild-type and dominant-negative channel constructs will be introduced into myocytes by viral gene transfer or somatic cell fusion, and the functional consequences characterized. Selective enhancement or suppression of defined potassium current components will enable systematic assessment of the role of each component in the repolarization process. The findings will be interpreted in the context of biophysically- detailed models of the cardiac action potential. The information gained at a cellular level will guide gene transfer experiments designed to alter cardiac excitability in vivo, in a graded and reversible manner. Thus, Project 1 will not only increase our understanding of the molecular basis of cardiac repolarization; it will also take the first steps towards putting that information to practical therapeutic use.
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