TY - JOUR
T1 - Electrical remodeling in pressure-overload cardiac hypertrophy
T2 - Role of calcineurin
AU - Wang, Zhengyi
AU - Kutschke, William
AU - Richardson, Kenneth E.
AU - Karimi, Mohsen
AU - Hill, Joseph A
PY - 2001/10/2
Y1 - 2001/10/2
N2 - 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 potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (Ito) than did subepicardial cells. Hypertrophy was not associated with significant changes in Ito, sustained current, or inward rectifier current densities, but peak L-type Ca2+ current density (ICa,L) increased 26% (P<0.05). Recovery from ICa,L inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in ICa,L and the accelerated recovery from inactivation were blocked by cyclosporin A. Conclusions - These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca2+ current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
AB - 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 potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (Ito) than did subepicardial cells. Hypertrophy was not associated with significant changes in Ito, sustained current, or inward rectifier current densities, but peak L-type Ca2+ current density (ICa,L) increased 26% (P<0.05). Recovery from ICa,L inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in ICa,L and the accelerated recovery from inactivation were blocked by cyclosporin A. Conclusions - These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca2+ current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
KW - Action potentials
KW - Arrhythmia
KW - Calcium
KW - Electrophysiology
KW - Hypertrophy
UR - http://www.scopus.com/inward/record.url?scp=0035797834&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035797834&partnerID=8YFLogxK
U2 - 10.1161/hc3901.095766
DO - 10.1161/hc3901.095766
M3 - Article
C2 - 11581145
AN - SCOPUS:0035797834
SN - 0009-7322
VL - 104
SP - 1657
EP - 1663
JO - Circulation
JF - Circulation
IS - 14
ER -