Electrical remodeling of the epicardial border zone in the canine infarcted heart: a computational analysis

1 Department of Pharmacology and 2 Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York 10032; and 3 Department of Computer Systems, New York City College of Technology, City University of New York, New York, New York 11201 The density and kinetics of several ionic currents of cells isolated from the epicardial border zone of the infarcted heart (IZs) are markedly different from cells from the noninfarcted canine epicardium (NZs). To understand how these changes in channel function affect the action potential of the IZ cell as well as its response to antiarrhythmic agents, we developed a new ionic model of the action potential of a cell that survives in the infarct (IZ) and one of a normal epicardial cell (NZ) using formulations based on experimental measurements. The difference in action potential duration (APD) between NZ and IZ cells during steady-state stimulation (basic cycle length = 250 ms) was 6 ms (156 ms in NZ and 162 ms in IZ). However, because IZs exhibit postrepolarization refractoriness, the difference in the effective refractory period (ERP), calculated using a propagation model of a single fiber of 100 cells, was 43 ms (156 ms in NZ and 199 ms in IZ). Either an increase in L-type Ca 2+ current (to simulate the effects of BAY Y5959) or a decrease of both or either delayed rectifier currents (e.g., to simulate the effects of azimilide, sotalol, and chromanol) had significant effects on NZ ERP. In contrast, the effects of these agents in IZs were minor, in agreement with measurements in the in situ canine infarcted heart. Therefore 1 ) because IZs exhibit postrepolarization refractoriness, conclusions drawn from APD measurements cannot be extrapolated directly to ERPs; 2 ) ionic currents that are the major determinants of APD and the ERP in NZs are less important in IZs; and 3 ) differential effects of either BAY Y5959 or azimilide in NZs versus IZs are predicted to decrease ERP dispersion and in so doing prevent initiation of arrhythmias in a substrate of inhomogeneous APD/ERPs. computer model; infarction; postrepolarization refractoriness; antiarrhythmic drugs