The goal of the proposed research is to test the hypothesis that the development of lethal ventricular arrhythmias in patients depends, in part, on characteristic alterations in the structure and molecular composition of gap junctions in hearts that have undergone remodeling after acute myocardial infarction or in dilated cardiomyopathy. The activities of three investigators will be combined to use molecular biological, immunocytochemical, morphometric, and electrophysiological approaches to characterize intercellular coupling in the normal heart an to delineate mechanisms leading to development of anatomic substrates of lethal arrhythmias. We will characterize distinct spatial distributions and molecular phenotypes of gap junctions that confer specific impulse propagation properties on atrial and ventricular muscle and the nodes an bundles of the conduction system. These studies will implicate regulatory mechanisms that will be tested in other components of the grant and will significantly advance computer simulations of propagation in two-dimensional models of myocardium. We will also characterize remodeling of the spatial distribution and molecular composition of gap junctions in healed canine infarct border zones, regions known to be the site of abnormal impulse propagation critical to the development of monomorphic reentrant ventricular tachycardia. A detailed analysis of the relation between altered tissue structure delineated with microscopi resolution and critical abnormalities of impulse propagation will be performed. Mechanisms underlying pathophysiologically relevant alterations in gap junctions in diseased myocardium will be elucidated in detail using cultured myocytes grown under defined conditions and exposed to mechanical and humoral mediators of hypertrophy. The specifi receptors and intracellular pathways that transduce signals to enhance expression of gap junction protein genes as well as the transcriptional and post-transcriptional mechanisms underlying enhanced gene expression will be characterized. Results of the proposed research should clarify the structure and function of myocardial gap junctions and identify mechanisms of altered electrical coupling in the diseased heart. They should also facilitate development of novel therapy designed to modulate intercellular coupling in patients.
Showing the most recent 10 out of 32 publications
