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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 mol/L) protected cultured cardiomyocytes from cell death during exposure to H 2 O 2 (50 mol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferasemediated 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 Ϫ1 · d Ϫ1 (nϭ8) (18.6Ϯ1.8% and 11.8Ϯ1.1 mm Hg, respectively) compared with dogs receiving vehicle (nϭ8) (9.6Ϯ0.7% and 22Ϯ0.9 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. (Circulation. 2009;119:2568-2577.)Key Words: AMP-activated protein kinase Ⅲ heart failure Ⅲ metformin Ⅲ nitric oxide M etformin is widely used as an antidiabetic drug with an insulin-sensitizing effect. A large-scale clinical trial (the UK Prospective Diabetes Study [UKPDS] 34) has shown that metformin therapy decreased the risk of cardiovascular death and the incidence of myocardial infarction associated with diabetes mellitus, 1 suggesting that this drug may be useful for patients who have both cardiovascular disease and diabetes mellitus. Eurich and colleagues 2 recently reported the results of a meta-analysis showing that metformin was the only antidiabetic agent to reduce all-cause mortality without causing any harm in patients who had heart failure and diabetes mellitus. These results suggest that a tight link exists between cardiovascular disease and diabetes mellitus and that metformin has a cardioprotective effect. Metformin is known to activate AMP-activated protein kinase (AMPK), [3][4][5] which is expressed in various tissues, including the myocardium, and plays a central role in the regulation of energy metabolism under stress conditions. 6 AMPK is activated by ischemia/reperfusion, 7-9 as well as in hearts with pressure overload hypertrophy 10 and subseque...

.-We characterized the time course of the left ventricular (LV) geometric and functional changes after aortic banding, validated them by necropsy, and investigated the sensitivity of echocardiographic findings on LV hypertrophy. C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation; echocardiographic assessments were performed before or at 2, 4, 6, and 11 wk after surgery; and some of the mice were euthanized at the corresponding time points. There was a progressive increase in diastolic posterior wall thickness and LV systolic dimension; the percentage of LV fractional shortening (LV%FS) decreased progressively at 4 wk, whereas these parameters remained stable in sham-operated mice. Echo LV mass and LV%FS correlated well with actual whole heart mass and ratio of lung weight to body weight, respectively (r ϭ 0.765 and Ϫ0.749, respectively; P Ͻ 0.0001). These results suggest that the development of myocardial hypertrophy and systolic dysfunction is a time-dependent process. Echocardiographic assessment of myocardial hypertrophy and functional changes correlate well with the actual heart mass and lung mass. Echocardiography is sensitive enough to assess myocardial hypertrophy and heart functional changes induced by pressure overload in mice. myocardial; heart failure; left ventricular hypertrophy WITH THE ADVENT OF TRANSGENIC TECHNOLOGY, genetically altered mice with remarkable cardiovascular phenotypes have been commonly used in cardiovascular research, and it is an important approach to integrate a genetically engineered mouse with a pressure overload intervention to study the interplay of genes and pathophysiology of cardiac hypertrophy in vivo. However, the murine model of pressure overload by transverse aortic constriction (TAC) is not widely used because it is difficult to prepare the model in such a small animal; microsurgical techniques are thus required (3, 9, 11). Furthermore, it is critically important to develop approaches for accurate and reproducible measurements of cardiac morphology and function in the intact mice with pressure overload.Transthoracic echocardiography has been reported (5, 8, 14) as a reliable tool for monitoring the changes of cardiac geometry and function in vivo, but serial echocardiographic evaluation of myocardial hypertrophy in mice with TAC has not been extensively performed. Therefore, it is important to confirm the ability of echocardiography to distinguish between differences in severity of cardiac hypertrophy and myocardial function in TAC murine models.In the present study, we hypothesized that echocardiography is able to monitor the changes of left ventricular (LV) hypertrophy and has the sensitivity to distinguish between differences in severity of disease in TAC mice. To test this hypothesis, we established a murine model of TAC and assessed morphometric and functional characteristics with the use of echocardiography. Furthermore, we validated the results of echocardiographic heart mass by necropsy over a time course and checked the cor...

Abstract-Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A 1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio