Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest via AMPK Activation

Sudden cardiac arrest (SCA) affects over 600,000 individuals annually in the United States and is associated with substantial mortality. After resuscitation, multi-system organ damage is common and largely attributable to ischemia-reperfusion injury. The anti-diabetic drug metformin improves cardiac outcomes in models of myocardial ischemia and ischemia-reperfusion. In this study, we evaluated the role of metformin pretreatment in a mouse model of SCA. We found that two weeks of metformin pretreatment protects cardiac ejection fraction and reduces acute kidney injury post-SCA in non-diabetic mice. Further, metformin pretreatment prior to SCA activates AMPK signaling and is associated with altered mitochondrial dynamics and markers of autophagy following arrest. Direct AMPK activation and inhibition studies demonstrate that activation is necessary and sufficient for metformin-mediated protection of cardiac and renal tissues in this model. We were unable to demonstrate cardiac improvement with a single-dose metformin rescue therapy. Importantly, the protective findings translate into patients. We retrospectively evaluated the extent of cardiac and kidney damage in diabetic patients resuscitated from SCA. Metformin-treated patients have less evidence of heart and kidney damage after arrest than diabetics who have not received metformin. Together, these data support AMPK activation as a preventive mechanism in ischemia-reperfusion injury. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes