Abstract 468: Sirt1 Ameliorates High Fat Diet-induced Diastolic Heart Failure

Abstract

Approximately half of heart failure patients are diagnosed with diastolic heart failure, which is characterized by impaired relaxation. Cardiac fibrosis is observed in diastolic heart failure patients, which may promote diastolic dysfunction due to increased LV stiffness. Sirt1 is a protein deacetylase that regulates cardiac fibrosis. However, the role of Sirt1 in diastolic heart failure remains unknown. Since obesity is a significant risk factor for diastolic heart failure, we employed a high fat diet (HFD)-induced obese mouse model and cardiac-specific Sirt1 knockout (Sirt1cKO) and overexpression (Sirt1cTG) mice to define the role of Sirt1 in diastolic heart failure. Diastolic dysfunction induced by 1 and 3 months of HFD consumption was exacerbated in Sirt1cKO, evidenced by an increased end-diastolic pressure-volume relationship (EDPVR), an index of diastolic dysfunction obtained by pressure-volume loop analysis (EDPVR: wild-type mice (WT) Normal Diet (ND): 0.069; WT HFD (3 months): 0.11; Sirt1cKO ND: 0.063: Sirt1cKO HFD: 0.18*, p<0.05 vs WT HFD). Consistently, HFD-induced diastolic dysfunction is ameliorated in Sirt1cTG mice (EDPVR: WT ND: 0.062; WT HFD: 0.11; Sirt1cTG ND: 0.061: Sirt1cTG HFD: 0.056*, p<0.05 vs WT HFD). HFD-induced cardiac fibrosis was promoted in Sirt1cKO but ameliorated in Sirt1cTG mice. Moreover, exogenous expression of Sirt1 via adeno-associated virus vector ameliorated HFD-induced diastolic dysfunction and fibrosis (Figure). These results suggest that Sirt1 ameliorates diastolic heart failure, possibly through inhibition of cardiac fibrosis.