Project Summary/Abstract It is estimated that half of the ~5 million patients in the United States who suffer from heart failure (HF) have HF with preserved ejection fraction (HFpEF), which is also referred to as diastolic heart failure. Hypertension is a major risk factor for the development of HFpEF. Unfortunately, large clinical trials have revealed that standard-of-care HF medications fail to reduce hospitalization rates or improve lifespan in patients with HFpEF. Thus, HFpEF remains a major unmet medical need. Our group has a longstanding interest in elucidating the cardiac functions of a family of enzymes known as histone deacetylases (HDACs), which serve crucial roles as epigenetic regulators of gene expression. Our preliminary data demonstrate remarkable ability of a small molecule HDAC inhibitor to prevent and reverse diastolic cardiac dysfunction in rodent models of systemic hypertension. Surprisingly, HDAC inhibition appears to improve diastolic function of the heart by enhancing relaxation of the contractile units (myofibrils), revealing a non-canonical, non-epigenetic function for HDACs in the control of cardiac relaxation. Three independent specific aims are designed to significantly extend this new field of cardiac research, and test the overall hypothesis that non-genomic actions of HDACs govern relaxation of the heart, and are critically involved in the pathogenesis of HFpEF.