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

• Published in: Circulation research 2009-02, Vol.104 (3), p.403-411
• Main Authors: Gundewar, Susheel, Calvert, John W, Jha, Saurabh, Toedt-Pingel, Iris, Ji, Sang Yong, Nunez, Denise, Ramachandran, Arun, Anaya-Cisneros, Mauricio, Tian, Rong, Lefer, David J
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Cell Respiration - drug effects; Coronary heart disease; Disease Models, Animal; Echocardiography; Female; Fundamental and applied biological sciences. Psychology; Heart; Heart Failure - diagnostic imaging; Heart Failure - drug therapy; Heart Failure - metabolism; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hypoglycemic Agents - pharmacology; Male; Medical sciences; Membrane Proteins - drug effects; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria - metabolism; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoproteins - drug effects; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.190918

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