verbatim): This is a competitive renewal application to the National Heart, Lung, and Blood Institute, where it has been administered in the past, for a continuing ROl grant on """"""""Microscopic Discontinuities as a Basis for Arrhythinias."""""""" This renewal application is also designated in relation to Program Announcement 99-035 entitled """"""""Impact of Aging on Atrial Fibrillation Development"""""""" because the proposed research is intended to link the initiation of atrial reentrant arrhythmias to changes in atrial microstructure that occur during aging in association with the escalating incidence of atrial fibrifiation. The research is focused on determining the mechanisms that lead to reentrant arrhythmias when changes in cardiac microstructure occur secondary to aging and disease. Implicit in this objective, the long-term goal is to understand the interrelationships between cell-to-cell current flow, ionic current flow through cell membranes, current flow in interstitial space, and propagation phenomena. The hypothesis of the project is that changes in cardiac microstructure due to aging and disease produce loading mechanisms that create conduction disturbances which induce and maintain reentrant arrhythmias.
The specific aims are to: 1) determine how variations in the specific components of cardiac microstructure (e.g., distribution of gap junctions, cell morphology, variations of interstitial space) affect propagation at a cellular level; 2) develop a quantitative representation (model) of microscopic multidimensional propagation based on natural cell geometry, gap junction distribution, and interstitial space variations; and, 3) explore the sensitivity of conduction disturbances that occur with premature action potentials to variations in the different components of cardiac microstructure. Toward this end, we have established procedures to investigate these mechanisms by combining experimental measurements of intracellular, interstitial, and extracellular potentials with computer simulations that are based on multidimensional cellular models developed from documented microscopic substrates at different ages. Such computer models are essential since they provide a way to evaluate the role of the specific components of myocardial architecture at a microscopic level. Elucidation of the role of microscopic discontinuities has significant implications for new therapeutic approaches to arrhythmias associated with aging and structural heart disease.
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