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(Circulation Research. 2009;104:403.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure

Susheel Gundewar, John W. Calvert, Saurabh Jha, Iris Toedt-Pingel, Sang Yong Ji, Denise Nunez, Arun Ramachandran, Mauricio Anaya-Cisneros, Rong Tian, David J. Lefer

From the Department of Medicine (S.G., J.W.C., S.J., I.T.-P., S.Y.J., D.N., A.R., M.A.-C., D.J.L.), Division of Cardiology; and Department of Pathology (D.J.L.), Albert Einstein College of Medicine, Bronx, NY; and Nuclear Magnetic Resonance Laboratory for Physiological Chemistry (R.T.), Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to David J. Lefer, PhD, Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Crawford Long Hospital, 550 Peachtree St NE, Atlanta, GA 30308. E-mail dlefer{at}emory.edu

Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors 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 antihyperglycemic effects. We tested the hypothesis that chronic activation of AMP-activated protein kinase (AMPK) with low-dose metformin exerts beneficial effects on cardiac function and survival in in vivo murine models of heart failure. Mice were subjected to permanent left coronary artery occlusion or to 60 minutes left coronary artery occlusion followed by reperfusion for 4 weeks. High-resolution, 2D echocardiography was performed at baseline and 4 weeks after myocardial infarction to assess left ventricular dimensions and function. Metformin (125 µg/kg) administered to mice at ischemia and then daily improved survival by 47% (P<0.05 versus vehicle) at 4 weeks following permanent left coronary artery occlusion. Additionally, metformin given at reperfusion and then daily preserved left ventricular dimensions and left ventricular ejection fraction (P<0.01 versus vehicle) at 4 weeks. The improvement in cardiac structure and function was associated with increases in AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation, as well as increased peroxisome proliferator-activated receptor- coactivator (PGC)-1 expression in cardiac myocytes. Furthermore, metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis compared to vehicle. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS. This study demonstrates that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1, in a murine model of heart failure.

Key Words: myocardial ischemia • heart failure • metformin • nitric oxide

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