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.


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 (I(to)) than did subepicardial cells. Hypertrophy was not associated with significant changes in I(to), sustained current, or inward rectifier current densities, but peak L-type Ca(2+) current density (I(Ca,L)) increased 26% (P<0.05). Recovery from I(Ca,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 I(Ca,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 Ca(2+) current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
Wang
Z
Z
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Kutschke
W
W
Richardson
K E
KE
Karimi
M
M
Hill
J A
JA
D000200:Action Potentials; D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004553:Electric Conductivity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D011312:Pressure; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D019703:Calcineurin; D011188:Potassium; D002118:Calcium