Cellular determinants of action potential prolongation in heart failure

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Over 4 million Americans suffer from heart failure and more than 400,000 die annually. The incidence and prevalence will continue to increase with the aging of the U.S. population. Despite remarkable improvements in medical therapy, the prognosis of patients with myocardial failure remains poor with greater than 80% six-year mortality. Of the deaths in patients with heart failure, 50% are sudden and unexpected. Electrical remodeling resulting in action potential prolongation is a recurring feature of heart failure. Action potential prolongation, while initially adaptive is ultimately detrimental predisposing to malignant ventricular arrhythmias and increased intracellular Ca2+ load. Two important changes in the failing heart could influence action potential duration and therefore repolarization: a reduction in repolarizing K currents, and slowed removal of intracellular Ca2+. Transmural differences in action potential duration and profile, K current expression and Ca2+ transients have been demonstrated in normal hearts. There is little information regarding the transmural changes in K currents and Ca2+ handling in heart failure, nor how the transmural alterations impact on overall heterogeneity of repolarization. The goals of this proposal are three-fold: 1. Characterize the cellular electrophysiological abnormalities. that alter repolarization in the failing heart. 2. Characterize the cellular electrophysiological abnormalities that alter repolarization in the failing heart. 2. Characterize the molecular basis of the alterations in the transmural distribution of K currents and Ca2+ handling in the failing heart. 3. Characterize the biophysical basis of increased action potential duration variability (APDV) in the failing heart and determine if the known increase in the variability of the QT interval in the failing heart has its basis in exaggerated APDV. Ultimately we seek to determine which of the changes in the cellular electrophysiological properties most importantly influence the arrythmic pre-disposition of the failing heart. Understanding the cellular electrophysiological changes in heart failure will improve our ability to prevent sudden death, the most catastrophic complication of heart failure.