Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart - A possible ionic mechanism for reduced excitability and postrepolarization refractoriness

Previously, we have shown abnormalities in (V) over bar (max) and in the recovery of (V) over bar (max) in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart (myocytes from the EBZ [IZs]). Thus, we sought to determine the characteristics of the whole-cell Na+ current I-Na) in IZs and compare them with the I-Na of cells from noninfarcted hearts (myocytes from noninfarcted epicardium [NZs]). I-Na was recorded using patch-clamp techniques under conditions that eliminated contaminating currents and con trolled I-Na for measurement (19 degrees C, 5 mmol/L [Na+](0)). Peak I-Na density (at -25 mV) was significantly reduced in IZs (4.9+/-0.44 pA/pF, n=36) versus NZs (12.8+/-0.55 pA/pF, n=54; P<.001), yet the half-maximal activation voltage (V-0.5), time course of decay, and time to peak I-Na were no different. However, in IZs, V-0.5 of the availability curve (I/I-max curve) was shifted significantly in the hyperpolarizing direction (-80.2+/-0.48 mV in NZs [n=45] versus -83.9+/-0.59 mV in IZs [n=27], P<.01). Inactivation of I-Na directly from a depolarized prepotential (-60 mV) was significantly accelerated in IZs versus NZs (fast and slow time constants [tau(1) and tau(2) respectively] were as follows: NZs [n=28], tau(1)=71.5+/-5.6 ms and tau(2)=243.7+/-17.1 ms; IZs [n=21], tau(1)=36.3+/-2.4 ms and tau(2)=153+/-11.3 ms; P<.001). Recovery of I-Na from inactivation was dependent on the holding potential (V-H) in both cell types but was significantly slower in IZs. At V-H= -90 mV, I-Na recovery had a lag in 18 (82%) of 22 IZs (with a 17.6+/-1.5-ms lag) versus 2 (9%) of 22 NZs (with 5.9- and 8.7-ms lags); at V-H=-100 mV, tau(1)=60.9+/-2.6 ms and tau(2)=352.8+/-28.1 ms in NZs (n=41) versus tau(2)=76.3+/-4.8 ms and tau(2)=464.3+/-47.2 ms in IZs (n=26) (P<.002 and P<.03, respectively); at V-H=-110 mV, tau(1)=33.4+/-1.8 ms and tau(2)=293.5+/-33.6 ms in NZs (n=21) versus tau(1)=44.3+/-2.9 ms and tau(2)=388.4+/-38 ms in IZs (n=18) (P<.002 and P<.07, respectively). In sum, I-Na is reduced, and its kinetics are altered in IZs. These changes may underlie the altered excitability and postrepolarization refractoriness of the ventricular fibers of the EBZ, thus contributing to reentrant arrhythmias in the infarcted heart.