Heart failure currently affects more than two million Americans and its economic and human tool will continue to increase as the population ages. Strictly defined, heart failure is an inability to match cardiac output to physiological demand; however, roughly half of the early deaths following diagnosis are thoroughly cataclysmic arrhythmic events, or Sudden Cardiac Death (SCD). SCD is presumed to result from a set of primary cellular alterations that predispose the failing heart to a fatal electrical event. A leading hypothesis has been that prolongation of the cardiac action potential resulting from slowed repolarization shifts the cell into a vulnerable state. Two important changes with heart failure that could influence repolarization are a reduction in repolarizing K/+ currents and a slowed rat of removal of intracellular Ca/2+. The former involves a selective reduction in the transient outward K+ current (I/to/1) and the inward rectifier K+ current (I/k1) while the latter results from a decrease in the sarcoplasmic reticulum Ca/2+ ATPase (SERCA2a) and a increase in sarcolemmal Na/+/Ca/2+ exchange in the sarcoplasmic reticulum Ca/2+ ATPase (SERCA2a) and a increase in sarcolemmal Na/+/Ca/2+ exchange (NCX). The full scope of cellular alterations in heart failure can only be understood when all of the changes are considered together; changes in the action potential waveform will govern the triggered release of Ca/2+ from the sarcoplasmic reticulum and conversely, intracellular Ca/2+ will reshape the action potential. At present, little is known about the relative importance of each of these factors on the contour of the action potential and the intracellular Ca/2+ transient in normal or failing heart cells. The goal of the present application is to examine how varying each these factors (e.g., I/to, I/k1, SERCA2a, and NCX) affects the cellular action potential and Ca/2+ transient of each change to the integrated cell response. This effort will be aided by the parallel development of a comprehensive computer model of action potentials and Ca/2+ handling. Special attention will be paid to how the alterations contribute to the susceptibility of the cardiac cell to arrhythmias. The ultimate objective is to understand which changes associated with heart failure contribute most to the pathology of the disease, so as to precisely target therapy to the site(s) that correct both the electrophysiological and mechanical alterations of heart failure.
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