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(Circulation. 2005;111:3025-3033.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias

Antoine Ouvrard-Pascaud, PhD^*; Yannis Sainte-Marie^*; Jean-Pierre Bénitah, PhD; Romain Perrier, MS; Christelle Soukaseum; Aurelie Nguyen Dinh Cat, MS; Anne Royer, MS; Khai Le Quang, MS; Flavien Charpentier, PhD; Sophie Demolombe, PhD; Fatima Mechta-Grigoriou, PhD; Ahmed T. Beggah, PhD; Pierre Maison-Blanche, MD; Marie-Edith Oblin, PhD; Claude Delcayre, PhD; Glenn I. Fishman, MD; Nicolette Farman, MD, PhD; Brigitte Escoubet, MD, PhD; Frederic Jaisser, MD, PhD

From INSERM AVENIR, Collège de France, Paris, France (A.O.-P., Y.S.-M., C.S., A.N., F.J.); INSERM U637, Montpellier, France (J.P.B., R.P.); INSERM U533, Medical School, Nantes, France (A.R., K.L.Q., F.C., S.D.); Unit of Gene Expression and Disease, Department of Developmental Biology, Pasteur Institute, Paris, France (F.M.-G.); INSERM U478, X (A.T.B., M.-E.O., N.F.) and INSERM U426–CEFI IFR02, AP-HP–Bichat Hospital, Paris 7 University (P.M.-B., B.E.), X. Bichat Medical School, Paris, France; INSERM U572, Lariboisiere Hospital, Paris, France (C.D.); and Leon H. Charney Division of Cardiology, New York University School of Medicine, New York (G.I.F.).

Correspondence to Frederic Jaisser, INSERM AVENIR, IFR 52, Collège de France, 11 Place Marcellin Berthelot, 75231 Paris, France. E-mail frederic.jaisser{at}college-de-france.fr

Received August 31, 2004; revision received February 1, 2005; accepted February 23, 2005.

Background— Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood.

Methods and Results— To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias.

Conclusions— Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death.

Key Words: aldosterone • arrhythmia • hormones • ion channels • mineralocorticoid receptors

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