Left Ventricular Hypertrophy

Abstract

Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.