doi: 10.1161/hc3901.095766
(Circulation. 2001;104:1657.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy
Role of Calcineurin
Departments of Internal Medicine (Z.W., W.K., J.A.H.), Pharmacology (J.A.H.), and Surgery (M.K.), and the Interdisciplinary Graduate Program in Molecular Biology (K.E.R., J.A.H.), University of Iowa College of Medicine, and the Department of Veterans Affairs (J.A.H.), Iowa City, Iowa.
Correspondence to Joseph A. Hill, MD, PhD, Cardiovascular Division, University of Iowa College of Medicine, E318GH, UIHC, 200 Hawkins Dr, Iowa City, IA 52242-1081. E-mail joseph-hill{at}uiowa.edu
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.
Key Words: calcium • electrophysiology • action potentials • arrhythmia • hypertrophy
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