Abstract 360: Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest

Introduction: Sudden cardiac arrest (SCA) affects over 600,000 Americans yearly with substantial mortality. After resuscitation, multiple system organ damage is common. Metformin has previously demonstrated ischemic protection in cardiac and renal tissues. We retrospectively evaluated kidney damage and cardiac function in a cohort of diabetic SCA patients. We also developed a mouse model of SCA that replicates human pathology and pretreated with metformin to evaluate the molecular changes driving these outcomes. Methods: We performed a retrospective analysis of patients admitted to a single center from 2010 to 2019 after resuscitation from SCA. We included those with a known diabetes prior to arrest. We extracted home medications from nursing and pharmacy medication reconciliations. Our primary exposure of interest was pre-arrest metformin use (vs no or other medications). We compared first day and maximum serum creatinine (SCr) during hospitalization, as well as cardiac ejection fraction (EF) after arrest. To explore the mechanisms underlying these changes, we developed a mouse model of SCA to compare metformin vs non-treated SCA mice. We evaluated EF and renal endpoints including SCr, BUN, and tubular damage 1-day after SCA. Tissues were collected for molecular and histologic studies. Results: We identified 360 diabetic patients of whom 151 (42%) were prescribed metformin at the time of SCA. There were no differences in age, sex, pre-arrest SCr or pre-arrest A1c between metformin and non-metformin treated patients. After SCA, metformin-treated patients had significantly lower initial SCr when compared to non-metformin patients (1.5±0.1 vs 1.7±0.1), 1-day SCr (1.4±0.1 vs 1.7±0.1), max creatinine (1.9±0.1 vs 2.2±0.1 ), and higher EF (49±2 vs 43±2). In the mouse study, pretreatment with metformin group found significantly lower 1-day SCr than non-treated mice (0.40±0.05 vs 1.52±0.22), BUN (64.8±8.2 vs 156.0±39.8), and histologic injury score (0.17±0.71 vs 3.33±0.29), as well as improved 1-day EF (49.6±3.7 vs 38.8±4.5). Conclusions: Our data support a renal- and cardio-protective role for metformin after SCA. Future studies will explore biochemical changes driving protection in the mouse with the goal of discovering translatable therapies.