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(Circulation. 2009;119:2568-2577.)
© 2009 American Heart Association, Inc.

Heart Failure

Metformin Prevents Progression of Heart Failure in Dogs

Role of AMP-Activated Protein Kinase

Hideyuki Sasaki, MD; Hiroshi Asanuma, MD, PhD; Masashi Fujita, MD, PhD; Hiroyuki Takahama, MD, PhD; Masakatsu Wakeno, MD, PhD; Shin Ito, MD; Akiko Ogai, BS; Masanori Asakura, MD, PhD; Jiyoong Kim, MD; Tetsuo Minamino, MD, PhD; Seiji Takashima, MD, PhD; Shoji Sanada, MD, PhD; Masaru Sugimachi, MD, PhD; Kazuo Komamura, MD, PhD; Naoki Mochizuki, MD, PhD; Masafumi Kitakaze, MD, PhD

From the Department of Cardiovascular Medicine, National Cardiovascular Center (H.S., H.A., H.T., M.W., S.I., A.O., M.A., J.K., K.K., M.K.) and Departments of Structural Analysis (H.S., H.T., M.W., S.I., N.M.) and Cardiovascular Dynamics (M.S., K.K.), Research Institute, National Cardiovascular Center, Suita, Osaka; Departments of Bioregulatory Medicine (H.S., H.T., M.W., S.I., N.M.) and Cardiovascular Medicine (M.F., T.M., S.T., S.S.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan; and Department of Emergency Room Medicine, Kinki University School of Medicine, Osaka-Sayama (H.A.), Osaka, Japan.

Correspondence to Masafumi Kitakaze, MD, PhD, Department of Cardiovascular Medicine, National Cardiovascular Center, 5–7–1 Fujishirodai, Suita, Osaka 565–8565, Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

Received August 23, 2007; accepted February 24, 2009.

Background— Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs.

Methods and Results— Treatment with metformin (10 µmol/L) protected cultured cardiomyocytes from cell death during exposure to H₂O₂ (50 µmol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg · kg^–1 · d^–1 (n=8) (18.6±1.8% and 11.8±1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6±0.7% and 22±0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure.

Conclusions— Metformin attenuated oxidative stress–induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure.

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CLINICAL PERSPECTIVE

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