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Background: Several studies have shown that the modulation of fibrotic scar in cardiac diseases has beneficial effects on cardiac arrhythmias. In addition, recent reports suggest a potential role of mineralocorticoid receptor upregulation in atrial fibrillation (AF). The role of spironolactone, a mineralocorticoid receptor blocker and a potent antifibrotic agent, in AF is as yet unexplored. The aim of this study was to determine if spironolactone, a mineralocorticoid receptor blocker with potent antifibrotic properties, has beneficial effects on AF. Hypothesis: Spironolactone therapy in patients with atrial fibrillation provides additional clinical benefits in addition to the current conventional pharmacological agents. Methods: A comprehensive retrospective analysis was performed on 83 patients with AF, including 23 who were treated with spironolactone for ≥3 months. The combined primary outcome of hospitalization for AF or direct current cardioversion (DCCV) was compared between patients treated with spironolactone in addition to the usual care for AF and those receiving conventional medical therapy alone. Results: Patients receiving spironolactone had significantly fewer primary outcome events (AF-related hospitalizations or DCCV) (22% vs 53%, P = 0.027). Conclusions: Spironolactone therapy is associated with a reduction in the burden of AF, as reflected by a combination of hospitalizations for AF and DCCV. Larger randomized controlled studies should be performed to evaluate the efficacy and safety of spironolactone as an adjunctive therapy for patients with AF. © 2011 Wiley Periodicals, Inc. This work was supported by American Heart Association grants 0705170Y, 0830313N (RHN), and 0640084N (JAH), and National Institutes of Health grants HL-075173, HL-090842, and HL-080144 (JAH). The authors have no other funding, financial relationships, or conflicts of interest to disclose.