Potential ionic mechanism for repolarization differences between canine right and left atrium

Abstract

Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current (I(Kr)) was greater in the LA (eg, 1.83+/-0.10 pA/pF at +20 mV) than in the RA (1.15+/-0.07 pA/pF, P<0.01; n=16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca(2+), and transient outward K(+) currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go-related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD- and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I(Kr) than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I(Kr) may participate in the ability of the LA to act as a "driver region" for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy.