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

TLDR

Life‑threatening arrhythmias are a leading cause of death, most commonly acquired in heart disease, and while aldosterone contributes to heart‑failure morbidity, its precise cardiac mechanisms remain unclear. The study aimed to determine the role of the mineralocorticoid receptor in the heart independent of aldosteronemia by creating a transgenic mouse with cardiac‑specific overexpression of human MR. This was achieved by generating a conditional cardiac‑specific transgenic mouse model that overexpresses human MR without altering systemic aldosterone levels. Cardiac MR overexpression caused ion‑channel remodeling, prolonged ventricular repolarization, and lethal arrhythmias that were prevented by the MR antagonist spironolactone, demonstrating that MR activation drives arrhythmogenesis and offers a target for prevention.

Abstract

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.