SIRT3 deficiency impairs mitochondrial and contractile function in the heart.

Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography. Four weeks following transverse aortic constriction, ejection fraction was further decreased in SIRT3(-/-) mice compared to WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis. In isolated working hearts, a decrease in cardiac function in SIRT3(-/-) mice was accompanied by a decrease in palmitate oxidation, glucose oxidation, and oxygen consumption, whereas rates of glycolysis were increased. Respiratory capacity and ATP synthesis were decreased in cardiac mitochondria of SIRT3(-/-) mice. HPLC measurements revealed a decrease of the myocardial ATP/AMP ratio and of myocardial energy charge. Using LC-MS/MS, we identified increased acetylation of 84 mitochondrial proteins, including 6 enzymes of fatty acid import and oxidation, 50 subunits of the electron transport chain, and 3 enzymes of the tricarboxylic acid cycle. Lack of SIRT3 impairs mitochondrial and contractile function in the heart, likely due to increased acetylation of various energy metabolic proteins and subsequent myocardial energy depletion.

Right ventricular systolic dysfunction and its prognostic value in heart failure with preserved ejection fraction.

OBJECTIVE: The prognostic impact of right ventricular systolic dysfunction (RVSD) in heart failure (HF) with preserved ejection fraction (HFPEF) is not sufficiently understood. This pilot study evaluates the prevalence and prognostic impact of RVSD in HFPEF. METHODS: Ninety-five consecutive patients, admitted due to HF within one year were included and followed up for 12 months. Patients were classified based on left ventricular ejection fraction (LVEF) into two groups: HFPEF (LVEF >40%; n = 54), and heart failure with reduced ejection fraction (HFREF) (LVEF < or = 40%; n = 41). RVSD was defined as peak systolic tricuspid annular velocity (S') <10.8 cm/s. RESULTS: The prevalence of RVSD was 22% vs 59%, in HFPEF vs HFREF, respectively (P < 0.001). Patients with HFPEF and RVSD had significantly higher one-year all-cause mortality compared to HFPEF with normal RV function (41.7% vs. 4.8%, P = 0.004). The same trend was found in HFREF (33.3% vs. 5.9%, P = 0.057). A similar outcome was obser ved in cardiovascular mortality (H FPEF 33.3% vs. 0%, P = 0.002 and HFREF 20.8% vs. 0%, P= 0.06). RVSD was the only independent predictor of all-cause one-year mortality in patients with HFPEF (HR 11.5, 95% Cl 2.2 to 59.5, p = 0.004). CONCLUSION: RVSD is an independent predictor of all-cause mortality in HFPEF. Patients with HFPEF and RVSD had significantly higher one-year all-cause and cardiovascular mortality than those with normal RV function.