Abstract 1608: Metformin Improves Left Ventricular Function and Survival in Heart Failure Through AMPK-eNOS Activation
Background: Clinical studies have reported that the widely used anti-diabetic drug metformin reduces cardiac risk and improves clinical outcomes in patients with heart failure. The mechanisms by which metformin exerts these cardioprotective effects remain unclear and may be independent of its anti-hyperglycemic effects. We tested the hypothesis that chronic activation of AMPK and eNOS with low-dose metformin would exert beneficial effects on cardiac function and improve survival in in vivo murine models of heart failure.
Methods: Mice were subjected to permanent left coronary artery (LCA) occlusion or to 60 min LCA occlusion and reperfusion for 4 wk. High-resolution, 2-D echocardiography was performed at baseline and 4 wk post myocardial infarction (4 Wk Post) to measure left ventricular (LV) dimensions and ejection fraction.
Results: Metformin (125 μg/kg) significantly protected against LV structural and functional impairment following ischemia induced heart failure and improved survival in response to permanent LCA occlusion. Additionally, metformin increased myocardial AMPK phosphorylation, eNOS phosphorylation and PGC-1α expression. Furthermore, metformin therapy resulted in significant improvements in cardiac mitochondrial respiration and ATP synthesis. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS.
Conclusion: Metformin exerts beneficial effects in the setting of heart failure following acute myocardial infarction via the activation of AMPK-eNOS and downstream signaling.