This is a renewal request for a Program Project Grant focusing on cardiac electrophysiology and cardiac contractility with the goal of developing new and useful insight, diagnostic methods, and treatment of cardiac disease. To this end, the work is conducted by a tightly-knit group of investigators from varied disciplines including physicians, physiologists, engineers, physicists, and computer scientists. The central theme of the program is to determine the functional role of anatomical complexities in the electrical and mechanical behavior of the heart. Recent work in this program led to the hypothesis that propagation in cardiac muscle is discontinuous due to recurrent discontinuities of intracellular resistivity that affect the membrane currents. Based on this finding, work is proposed to develop new theory and information about propagation in cardiac muscle. New biophysical models have been developed that allow detailed electrical measurements of propagation and repolarization in anisotropic muscle, as well as of total heart electrical activity. With these methods our objective is to develop conceptual and mathematical models which will provide new information about the origin and prepetuation of arrhythmias, the use of extracellular (rather than intracellular) potentials for detailed study of propagation abnormalities, and to understand the origin of body surface potentials on a quantitative basis. The ultimate goal of the cardiac muscle mechanic studies is to obtain a complete description of th changes in cardiac contractility in normal and abnormal states, and to understand their origin at the sarcomere level.
This aim will be pursued through in vitro studies of the dynamic properties of sarcomere shortening to estimate the time-course and kinetics of cross-bridge formation and dissociation in trabeeculae and by study of contractility in single cardiac cells. Only through such studies, where sarcomere length and loading are known, can the basic mechanical properties of the heart be determined.
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