Background: The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved EF (HFpEF) are not well characterized. Methods and Results: Consecutive, prospectively identified HFpEF (Framingham HF criteria, EF ≥50%) patients (N=562) from Olmsted County, Minnesota underwent echocardiography at HF diagnosis and follow-up for cause specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion (TAPSE) and by semi-quantitative (normal, mild RVD or moderate-severe RVD) 2D assessment. Whether RVD was defined by semi-quantitative assessment or TAPSE ≤ 15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers and chronic diuretic therapy. At echo, patients with RVD had slightly lower LVEF, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure (PASP), and more severe RV enlargement and tricuspid valve regurgitation. Adjusting for age, sex, PASP and comorbidities, the presence of any RVD by semi-quantitative assessment was associated with higher all-cause (hazard ratio (HR) = 1.35 (1.03-1.77; p=0.03)) and cardiovascular (HR=1.85 (1.20-2.80; p=0.006)) mortality and higher first (HR=1.99 (1.35-2.90; p=0.0006) and multiple (HR=1.81 (1.18-2.78; p=0.007) HF hospitalization rates. RVD defined by TAPSE values showed similar but weaker associations with mortality and HF hospitalizations. Conclusions: In the community, RVD is common in HFpEF patients, associated with clinical and echocardiographic evidence of more advanced HF and predictive of poorer outcomes.

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...

An infusion as PEGylated liposomes augmented the cardioprotective effects of adenosine against ischemia/reperfusion injury and reduced its unfavorable hemodynamic effects. Liposomes are promising for developing new treatments for acute MI.