Cardiac arrhythmias are a major cause of death and disability, and yet their underlying mechanisms remain incompletely understood. In addition, treatment of arrhythmias by drugs and by non-pharmacological interventions (e.g. pacing, defibrillation) remains largely empiric and the efficiency is unpredictable. The long term objective of the proposed studies is to elucidate, at the cellular and tissue levels, the mechanisms that underlie cardiac excitation and arrhythmogenesis and the mechanisms of interventions (pharmacological and electrical) that lead to termination of arrhythmias. Our premise is that better understanding of the mechanisms is necessary for the development of better therapeutic interventions. Our approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations.
The specific aims are: 1) To complete the development of a dynamic model of the ventricular action potential based on recent data from single cell and single channel preparations and on experimental measurements of subcellular processes such as calcium fluxes in the sarcoplasmic reticulum. 2) To study, using this model, the mechanisms of arrhythmogenic activity of the single cell including afterdepolarizations (early and delayed) and triggered activity and the effects of various pharmacological interventions on these activities. 3) To study, using the action potential model in conjunction with models of propagation in cardiac tissue, the mechanisms of propagation through a segment of depressed (e.g. ischemic) myocardium and related arrhythmogenic phenomena (slow conduction, conduction block, reflected reentry). 4) To elucidate the mechanisms of termination of circus-movement reentry including spontaneous termination, and termination by electrical and pharmacological interventions. 5) To examine the relative importance of myocardial structure (anisotropy) and nonuniformities of repolarization in the initiation and sustenance of reentry in the setting of chronic infarction, and to elucidate the nature of conduction at the center of the reentrant circuit in relation to these factors.
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