Published online before print August 2, 2004, doi: 10.1161/01.CIR.0000138973.55605.38
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(Circulation. 2004;110:776-783.)
© 2004 American Heart Association, Inc.
Original Articles |
Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction
From INSERM U637-EA3759 (E.P., B.-G.K., P.B., S.R., A.M.G., J.-P.B.), IFR3, Montpellier, France, and the Division of Endocrinology and Diabetology and Laboratory of Clinical Chemistry (N.L., M.F.R.), University Hospital, Geneva, Switzerland.
Correspondence to Jean-Pierre Benitah, INSERM U637–EA3759, CHU A. de Villeneuve, 34295 Montpellier, France. E-mail benitah{at}montp.inserm.fr
Received October 28, 2003; de novo received January 29, 2004; revision received April 15, 2004; accepted April 16, 2004.
Background— Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development.
Methods and Results— Using whole-cell, patch-clamp and quantitative reverse transcription–polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca2+ current (ICa) and a decrease in K+ transient outward current (Ito) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca2+ channel 
1C subunit (Cav1.2) increased, and that of the K+ channel Kv4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. ICa density, Cav1.2, and Kv4.2 mRNA levels regained control levels, but Ito density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy.
Conclusions— Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.
Key Words: hypertrophy • action potentials • ion channels • remodeling • hormones
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