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(Circulation. 2004;109:1898-1903.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Constitutive Cardiac Overexpression of Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Delays Myocardial Failure After Myocardial Infarction in Rats at a Cost of Increased Acute Arrhythmias

Ying Chen, MD; Brigitte Escoubet, MD, PhD; Fabrice Prunier, MD; Julien Amour, MD; Warner S. Simonides, PhD; Benoît Vivien, MD, PhD; Christophe Lenoir; Michèle Heimburger, PhD; Christine Choqueux; Barnabas Gellen, MD; Bruno Riou, MD, PhD; Jean-Baptiste Michel, MD, PhD; Wolfgang M. Franz, MD, PhD; Jean-Jacques Mercadier, MD, PhD

From INSERM U 460 (Y.C., F.P., M.H., C.C., J.-B.M., J.-J.M.) and U 426, CEFI, IFR 02, AP-HP (B.E., J.-J.M.), Xavier Bichat Medical School, University of Paris 7; INSERM U 572, Hôpital Lariboisière (C.L.); the Laboratory of Experimental Anesthesiology, Departments of Anesthesiology (J.A., B.V.) and Emergency Medicine and Surgery (B.R.), Groupe Hospitalier Pitié-Salpêtrière, AP-HP, University of Paris 6, Paris, France; the Laboratory of Physiology, VU University Medical Center, Amsterdam, the Netherlands (W.S.S.); and Ludwig Maximilian University of Munich, Germany (B.G., W.M.F.). Dr Prunier is now at the Department of Cardiology, University Hospital, Angers, France.

Correspondence to Dr J.-J. Mercadier, INSERM U460, G.H. Bichat–Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. E-mail jjmercadier{at}wanadoo.fr

Received October 8, 2003; revision received December 30, 2003; accepted January 8, 2004.

Background— Heart failure often complicates myocardial infarction (MI), and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) is underexpressed in the failing myocardium. We examined the effect of preexisting cardiac SERCA2a protein overexpression on rat survival and left ventricular (LV) remodeling after MI.

Methods and Results— Baseline myocardial SERCA2a expression was 37% higher in transgenic (TG) rats than in their wild-type (WT) controls, consistent with enhanced myocardial function. The mortality rate of TG rats during the 24 hours after surgical MI was higher than that of WT rats (71% versus 35%, P<0.001), associated with a higher frequency of ventricular arrhythmias, and was normalized by lidocaine treatment. The increased acute-phase mortality in TG rats was not accompanied by increased 6-month mortality. Function of the noninfarcted myocardium, as assessed by tissue Doppler imaging, was higher in TG rats than in WT rats for up to 1 month after MI, a beneficial effect no longer observed at 3 months. LV remodeling and global function were similar in TG and WT rats. No difference in papillary muscle function was found at 6 months.

Conclusions— Constitutive cardiac SERCA2a overexpression has a transient beneficial effect on remote myocardium function in rat MI, with no improvement in LV global function or prevention of LV remodeling and failure. This benefit is associated with a higher risk of acute mortality, which is prevented by lidocaine treatment.

Key Words: contractility • arrhythmia, ventricular • heart failure • myocardial infarction • echocardiography

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