Abstract 19116: Efficacy of a Small Molecule HDAC Inhibitor in a Model of Diastolic Dysfunction with Preserved Ejection Fraction

Abstract

Heart failure (HF) is a major health problem and growing economic burden worldwide. Of the patients with HF, ∼50% suffer from heart failure with preserved ejection fraction (HFpEF), also known as diastolic HF. Current standards-of-care for systolic HF provide little to no benefit to patients with HFpEF. Histone deacetylase inhibitors (HDACi) have been shown to improve systolic function in a variety of rodent models of HF. However, the impact of HDACi on diastolic function remains poorly understood. This study assessed the efficacy of an HDACi in a rat model of HFpEF. Dahl salt-sensitive (DSS) rats were fed low salt (LS, 0.4% NaCl) or high salt (HS, 4.0% NaCl) diets for 10 weeks. Rats were treated either with vehicle (LS and HS groups) or the pan-HDAC inhibitor, ITF2357, at 3 and 30 mg/kg (HS groups). Serial echocardiography was performed to assess left ventricle (LV) dimensions and function. At study endpoint, pressure-volume analyses were performed to further quantify effects of HS and HDACi on hemodynamic properties. HS feeding caused hypertension, cardiac hypertrophy and diastolic dysfunction, as shown by a 30% reduction of E/A and E’/A’ from baseline (measured by flow and tissue Doppler), a 27% increase of isovolumic relaxation time (IVRT), and a significant increase in LV end-diastolic pressure (LVEDP). EF was preserved in HS fed animals. ITF2357 was well tolerated and did not cause hematological side effects. ITF2357 dose-dependently prevented diastolic dysfunction of the heart; E/A and E’/A’ decreased 14% and 5% from baseline with low and high doses of ITF2357, respectively. Efficacy of ITF2357 was also observed at the level of IVRT and LVEDP. HDAC inhibition-mediated improvement in cardiac function and hemodynamics occurred independently of effects on cardiac hypertrophy and systemic hypertension. These data suggest that HDACs play a critical role in the pathogenesis of diastolic HF and that small molecule HDAC inhibitor have potential as novel therapeutics for HFpEF