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

• DOI: 10.1161/circulationaha.104.503706
• Publication Date: 2005-06-07T00:25:45Z
• Authors: Antoine Ouvrard-P...; Yannis Sainte-Marie; Jean-Pierre Bénitah; Romain Perrier; Christelle Soukaseum; Aurelie Nguyen Di...; Anne Royer; Khai Le Quang; Flavien Charpentier; Sophie Demolombe; Fatima Mechta-Gri...; Ahmed T. Beggah; Pierre Maison-Bla...; Marie-Edith Oblin; Claude Delcayre; Glenn I. Fishman; Nicolette Farman; Brigitte Escoubet; Frederic Jaisser
• Keywords: [SDV]Life Sciences [q-bio]; Critical Illness; Mice, Transgenic; arrhythmia; mineralocorticoid receptors; Ion Channels; Death, Sudden; Electrocardiography; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Myocytes, Cardiac; RNA, Messenger; aldosterone; hormones; Myocardium; ion channels; Arrhythmias, Cardiac; 3. Good health; [SDV] Life Sciences [q-bio]; Electrophysiology; Disease Models, Animal; Receptors, Mineralocorticoid; Gene Expression Regulation; Calcium

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.