The goal of the proposed research is to define the functional role of Cx43 in normal cardiac conduction and to delineate the role of altered coupling at gap junctions in the pathogenesis of conduction disturbances and arrhythmias. Proposed experiments will be performed using mice that are heterozygous for a null allele for the gene encoding the major cardiac gap junction protein, Cx43 (Cx43 plus/minus mice). These mice produce 50 percent of the wildtype level of Cx43 and have significant reduction in the number of gap junction interconnecting ventricular myocytes. The functional consequence of reduced Cx43 expression in adult mice is a 25-30 percent slowing of ventricular conduction velocity. Whereas the electrophysiological phenotype in Cx43 plus/minus mice is subtle under physiological conditions, a more dramatic phenotype can be elicited under pathophysiological condition. In response to acute regional ischemia, Cx43 plus/minus mice exhibit accelerated onset and increased incidence, frequency and duration of ventricular arrhythmias. The proposed research is focused on defining mechanisms by which reduced coupling promotes arrhythmias in accute and chronic ischemic heart disease. Studies in Specific Aim 1 will elucidate the mechanistic relationship between the rate and extent of electrical uncoupling at gap junctions and development of ventricular tachyarrhythmias induced by acute ischemia. Studies in Specific Aim 2 will define arrhythmia mechanisms in Cx43 plus/minus following acute coronary occlusion and delineate the roles of Cx43 and altered cell-to- cell coupling in electrical triggering events and sustained conduction abnormalities that underlie initiation and maintenance of ventricular arrhythmias in the setting of acute myocardial ischemia.
In Specific Aim 3, the role of gap junction remodeling in the pathogenesis of arrhythmias in chronic ischemic heart disease will be elucidated by comparing arrhythmogenesis in Cx43 plus/minus and wildtype mice with healed myocardial infarcts. And in Specific Aim 4, molecular and structural determinants of conduction will be delineated using neonatal mouse ventricular myocytes grown in patterned arrays of defined structure and packing geometry, and analyzed by high resolution optical mapping. The results of the proposed research will define mechanisms by which reduced coupling promotes ventricular tachyarrhythmias in mouse models of acute and chronic ischemic heart disease in patients.
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