Abstract 565: The Activation of AMP-Activated Protein Kinase Ameliorates the Severity of Heart Failure in Dogs

Backgrounds; Since AMP-activated protein kinase (AMPK) is activated in the pressure-overloaded hypertrophic hearts, we investigated whether the activation of AMPK caused by metformin attenuates the progression of heart failure induced by rapid pacing in dogs and decreases cellular damage caused by oxidative stress in neonatal rat cardiac myocytes. Methods and Results; Heart failure was induced by right ventricular (RV) pacing at 230 bpm for 4 weeks in dogs. Treatment of dogs with metformin (100mg/kg/day, orally, n=8, Met group) for 4 weeks prevented significantly the progression of pacing-induced heart failure evaluated by echocardiographical and hemodynamic measurement compared with the control group (n=8). Left ventricular (LV) diastolic and systolic dimension (LVDd and LVDs) were smaller (32.8±0.4 and 26.7±0.9 mm, respectively) and fractional shortening (FS) and ejection fraction (EF) were preserved in Met group (18.6±1.8 and 45.5±3.5 %, respectively) compared with the control group (LVDd and LVDs; 36.5±1.0 and 33.0±1.0 mm, FS and EF; 9.6±0.7 and 27.0±1.9 %, p2 O 2 exposure (50μmol/L). These effects were blunted by an AMPK inhibitor, compound-C (20μmol/L), suggesting that the activation of AMPK increased the cellular viability during H 2 O 2 exposure. Conclusions; Metformin that activates AMPK prevented the progression of heart failure induced by rapid pacing in dogs and attenuated the cellular damage against H 2 O 2 exposure in cardiac myocytes. AMPK may be one of new targets for preventing heart failure in clinical settings.