The electrophysiologic behavior of the heart is highly heterogeneous. It has been, and continues to be, the goal of this Program to define mechanisms underlying this heterogeneity. In the last period of support, substantial progress has been made toward this goal. The present renewal application has been restructured to focus specifically on cardiac potassium channels, testing the overall working hypothesis that variability in expression or function of these channels is an important determinant of heterogenous repolarization both in health and in disease. The studies proposed will incorporate both conventional molecular and electrophysiologic techniques as well as new techniques in which Program investigators and collaborators have developed considerable expertise in the last period of support; these include generation of genetically-modified mice, in situ hybridization, the molecular genetics of cardiac ion channels, and spin labeling/EPR technology. In each Project, preliminary data that attest to feasibility are presented, and specific hypotheses relating to the mechanisms underlying heterogeneous function or expression of cardiac K plus channels are proposed for testing. The experimental models include wild-type and mutant channels in heterologous expression systems, the use of genetically-modified animals, and studies in human subjects. The focus of the central theme of cardiac potassium channels allows a high degree of scientific interchange among Projects; this includes the use of shared reagents, as well as the likelihood that results in one Project influence the scientific direction in others. Dysfunction of cardiac potassium channels is increasingly recognized to play a role in the genesis of cardiac arrhythmias. The studies proposed in this Program will help elucidate mechanisms underlying this dysfunction, and therefore point to novel approaches to therapy.
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