Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

Systolic heart failure (heart failure with reduced ejection fraction) manifests as insufficient blood pumping due to contractile dysfunction. Impaired cardiac relaxation also contributes to a form of heart failure termed heart failure with preserved ejection fraction. Jeong et al. tested whether histone deacetylase inhibition, which has shown efficacy in some models of systolic heart failure, could prevent diastolic dysfunction. Inhibitor treatment improved cardiac relaxation without altering blood pressure or fibrosis in rodent models of hypertension- and aging-induced diastolic dysfunction with preserved ejection fraction. The authors determined that acetylation/deacetylation of myofibrils directly altered relaxation but not contraction, suggesting a mechanism for the development of diastolic dysfunction and a potential therapeutic target.There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor–mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.