Electrical remodeling in pressure-overload cardiac hypertrophy - Role of calcineurin

Background-Myocyte hypertrophy accompanies many forms of heart disease, but its contribution to electrical remodeling is unknown. Methods and Results-We studied mouse hearts subjected to pressure overload by surgical thoracic aortic banding. In unbanded control hearts, action pot ential duration (APD) was significantly longer in subendocardial myocytes c ompared with subepicardial myocytes. Hypertrophy-associated APD prolongatio n was significantly greater in subendocardial myocytes compared with subepi cardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clam p recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward curr ent (It,,) than did subepicardial cells. Hypertrophy was not associated wit h significant changes in It., sustained current, or inward rectifier curren t densities, but peak L-type Ca2+ current density (I-Ca,I-L) increased 26% (P <0.05). Recovery from Ica,L inactivation was accelerated in hypertrophie d myocytes. Inhibition of calcineurin with cyclosporin A prevented increase s in heart mass and myocyte size but was associated with an intermediate AP D. The hypertrophy-associated increase in ICU and the accelerated recovery from inactivation were blocked by cyclosporin A. Conclusions-These data reveal regional variation in the electrophysiologica l response within the left ventricle by way of a mechanism involving upregu lated Ca2+ current and calcineurin. Furthermore, these results reveal parti al uncoupling of electrophysiological and structural remodeling in hypertro phy.