Congestive heart failure is a common, highly lethal cardiovascular disorder claiming over 200,000 lives a year. As many as 50% of the deaths in heart failure patients are sudden. Many of the sudden deaths are the result of ventricular tachyarrhythmias. Methods designed to identify patients at risk been remarkably unrewarding. Consequently, attempts to intervene and prevent sudden death in these patients have been unsuccessful. The failure to impact on the incidence of sudden death in heart failure patients stems largely from out lack of understanding of the basic mechanisms of arrhythmogenesis in the cohort. This proposal will explore the role of abnormalities of repolarization in sudden death that occurs in heart failure patients. This proposal includes a comprehensive search for potential 'markers' of sudden cardiac death risk. We will examine repolarizing K+ channel genes in failing and normal human hearts, and invasive electrophysiologic and electrocardiographic measures of ventricular repolarization in patients. The ultimate aim is to investigate the link between abnormal K+ current expression in human heart failure, action potential prolongation, and abnormalities of repolarization in the intact heart. In this context, this proposal tests the following specific hypotheses: 1. Human heart failure is characterized by prolongation, and increased spatial and temporal dispersion of repolarization, these abnormalities are potentially arrhythmogenic, and thus predictive of an increased risk for sudden death. 2. Prolongation of repolarization is related to reduced function of two repolarizing K+ currents, Ik1 and Ito, and this is the result of decreased K+ channel gene expression. 3 Quantitation of K+ channel transcripts in endomyocardial biopsy samples is possible and a useful molecular marker of the repolarization abnormality in human heart failure.
Showing the most recent 10 out of 114 publications
