The objective of this research is to undertake a comprehensive study of the ways in which properties of single sinus and atrial cardiac cells such as voltage-dependent membrane currents, ion pumping mechanisms, calcium buffering and release systems, and inter-cellular gap junction conductance, influence the generation and propagation of electrical activity in models of the sinus node, atrium, and combined sinus node - atrial networks. Cell models will be based on whole-cell voltage-clamp data obtained from sinus and atrial cells isolated from rabbit heart. Networks will be modeled as two-dimensional lattices, with neighboring cells interconnected by resistors representing gap junctions. Network stat equations will be integrated on a massively parallel supercomputer, the Connection Machine CM-2, in order to facilitate simulation of very large systems of cells. The models will be used to study the mechanisms which influence the generation and propagation of pacemaker activity in normal cardiac tissue. Mechanisms giving rise to arrhythmias in localized groups of cells, and factors affecting the propagation of arrhythmic activity through model networks will also be investigated. The proposed research will enhance our basic understanding of both normal and abnormal cardiac dynamics, and is unique in that it represents an attempt to understand the "macroscopic" properties of large networks of cardiac cells give detailed descriptions of the "microscopic" behavior of individual cells.
