This is a new proposal for research that is intended to link the initiation of reentrant arrhythmias to microscopic cellular structure. To date, most research has been dominated by exploring arrhythmogenesis as related to modulation of active membrane properties (ion channel behavior). An essential link remaining to be made is the relationship between the ion channel currents and the initiating macroscopic reentrant events. That link can be made only by investigating propagation at a cellular level. However, at present this is an unexplored area; there is essentially no information available about abnormal or normal propagation at a microscopic level (less than 200 micromoles). The research is focused on exploring the sensitivity of arrhythmogenic potential to cell morphology and the distribution of the cellular connections.
The specific aims are to: l) establish an experimental basis for cardiac propagation at a cellular level; 2) develop a quantitative representation (model) of microscopic multidimensional propagation based on natural differences in cell geometry and the distribution of the cellular connections; and, 3) explore the sensitivity of the major determinants of conduction (e.g., sodium current, Vmax) and macroscopic conduction events to variations in cellular geometry and the topology of the side-to-side connections between cells and small groups of cells. The most common cause of tachyarrhythmias in patients is some form of reentry. The background results for this project indicate that changes in the distribution of the connections between cells, previously considered of minor importance, create new microscopic structural mechanisms that cause reentry. These new structural mechanisms appear to be as important in causing reentry as the classical mechanism of inhomogeneities of repolarization. Consequently, this project has direct clinical applicability in the evaluation of drugs and interventional procedures in patients with tachyarrhythmias. The project is designed to study the interrelationships between cell-to- cell current flow, ionic current flow through cell membranes, the extracellular potential field, and propagation phenomena. Experimentally, transmembrane potentials and extracellular potentials will be measured with high temporal and spatial resolution at a microscopic level. The effects of normal and altered initial conditions of the ion channel currents will be evaluated. Theoretically, multidimensional cellular models of propagation will be developed. Such models are essential since they provide the linear passive properties at a cellular level that are necessary to link the ion channel currents to the macroscopic propagation events. The major focus will be on exploring the sensitivity of macroscopic propagation events to changes in cell geometry and the loss of side-to-side electrical connections between fibers that occur with aging.
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