Diminished Ca <sup>2+</sup> and Ba <sup>2+</sup> Currents in Myocytes Surviving in the Epicardial Border Zone of the 5-Day Infarcted Canine Heart
Authors: Rajesh Aggarwal, Penelope A. Boyden
Journal: Circulation Research (1995)

Abstract Ventricular arrhythmias frequently occur in patients suffering from ischemic heart disease. In a canine model developed to understand the pathoelectrophysiological mechanisms of the ischemia-related arrhythmias, electrical stimulation can initiate and terminate reentrant ventricular tachyarrhythmias, which arise in surviving subepicardial muscle fibers (epicardial border zone [EBZ] fibers) of the left ventricle 5 days after coronary artery occlusion. Both the structural and electrical changes occurring in the EBZ provide the important substrate for generation of reentrant ventricular tachyarrhythmias. In this study, we tested the hypothesis that abnormalities exist in the electrophysiological properties of macroscopic Ca 2+ currents in myocytes isolated from the EBZ of the 5-day infarcted canine heart (IZs). We recorded the T-type (I Ca,T ) and L-type (I Ca,L ) Ca 2+ currents by using the whole-cell voltage-clamp technique with either Ca 2+ or Ba 2+ (5 mmol/L) as the charge carrier and under experimental conditions (Na + - and K + -free solutions, 10 mmol/L intracellular EGTA) that eliminated contamination by other currents. When Ca 2+ served as the charge carrier, the density of peak I Ca,T in IZs (0.89±0.5 pA/pF, n=28) was similar to that in myocytes from normal noninfarcted hearts (NZs) (1.1±0.5 pA/pF, n=32). Although no changes existed in the properties of I Ca,T , dramatic changes occurred in the density and function of I Ca,L in IZs compared with NZs. Density of peak I Ca,L at a holding potential of −40 mV (8-second clamp-step interval) was significantly reduced in IZs (4.6±1.5 pA/pF, n=40) compared with NZs (7.2±1.6 pA/pF, n=53). The reduction in peak I Ca,L density was not attributable to altered steady state inactivation relations or a delay in recovery of I Ca,L from inactivation. The time course of decay of peak I Ca,L was described by a biexponential function in both cell types, with the fast and slow time constants (τ 1 and τ 2 , respectively) of decay being significantly faster in IZs (τ 1, 12.3±3.6 ms; τ 2 , 55.1±31.1 ms) than in NZs (τ 1 , 16.1±4.1 ms; τ 2 , 85.2±51.7 ms). In addition, rapid clamp stimulation (at 1-s intervals) of cells produced a larger frequency-dependent decrease of peak I Ca,L density in IZs than NZs, suggesting that at more physiologically relevant rates, little I Ca,L may be activated. Finally, a significant reduction and acceleration of decay of the I Ca,L persisted even when Ca 2+ was substituted by equimolar Ba 2+ as the charge carrier. These latter findings suggest that the reduced peak I Ca,L density in IZs may be due to a decrease in the number of functional channels, which also show an alteration in the voltage-dependent inactivation process. In summary, we have shown that chronic changes exist in the electrophysiological properties of I Ca,L in cells that survive in the infarcted heart. Such changes could contribute to the altered repolarization of action potentials of myocytes from EBZs of the 5-day infarcted canine heart.