Mineralocorticoid Receptor Antagonism Reduces Atrial Arrhythmias Post- Cardiac Surgery and Attenuates Atrial Stress Responses to Cardioplegic Arrest

BACKGROUND: Postoperative atrial fibrillation occurs in ~40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We evaluated the association of preopera tive MRA use with postoperative atrial fibrillation and investigated atrial cell types modulated by MRAs during cold preservation.METHODS: We studied 19 042 cardiac surgery patients at Mayo Clinic. Propensity 1:3 matching identified 298 MRA users and 894 non- users. A subgroup analysis of patients on any preoperative diuretic was performed to isolate cardiac- specific effects of MRAs, matching 298 MRA users to 894 non- MRA diuretic users. AF recurrence was assessed for up to 6- years. Single- nucleus RNA sequencing (snRNA- seq) was performed on human donor atria exposed to canrenone (a water- soluble MRA) during cold preservation with ex- vivo reperfusion, and expression profiles were compared with atria from patients with AF. RESULTS: After matching, preoperative MRA use was associated with a lower incidence of postoperative atrial fibrillation (19.8% versus 31.8%, P<0.001). In the diuretic- only subgroup, MRA users also had lower postoperative atrial fibrillation (19.8% versus 33.2%, P<0.001). MRA use was associated with a reduced incidence of paroxysmal and chronic AF at 6- years. snRNA- seq identified a cardiomyocyte subpopulation, CM2, with high mineralocorticoid receptor expression where canrenone sup pressed cold preservation- induced mineralocorticoid receptor target gene expression, which was conversely elevated in chronic AF. Canrenone also attenuated stress- response in atrial macrophages and pericytes. CONCLUSIONS: Preoperative MRAs were associated with reduced postoperative and long- term AF after cardiac surgery. Mechanistically, our ex- vivo human atrial model revealed that MRAs suppress mineralocorticoid receptor - driven atrial stress responses, particularly in conduction- relevant cardiomyocytes.