Objectives: This study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF). Background: The role of mineralocorticoid in the pathogenesis of AF is unknown. Methods: We studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes. Results: We found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 ± 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 ± 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (-13.6 ± 2.9 pA/pF vs. -4.5 ± 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium. Conclusions: Expression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade.
|頁（從 - 到）||758-770|
|期刊||Journal of the American College of Cardiology|
|出版狀態||已發佈 - 2月 23 2010|
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