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

Zhengyi Wang, William Kutschke, Kenneth E. Richardson, Mohsen Karimi, Joseph A Hill

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1657-1663
Number of pages7
JournalCirculation
Volume104
Issue number14
DOIs
StatePublished - Oct 2 2001

Keywords

  • Action potentials
  • Arrhythmia
  • Calcium
  • Electrophysiology
  • Hypertrophy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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