New research suggests that histone deacetylase (HDAC) inhibition might improve cardiopulmonary structure and function in heart failure with preserved ejection fraction (HFpEF). In a cat model of slow-progressive, pressure overload-induced diastolic dysfunction, which recapitulates features of human HFpEF, daily treatment with the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 2 months reduced left ventricular (LV) hypertrophy and left atrial size, increased myofibril relaxation ex vivo and LV relaxation in vivo, and improved LV systolic and diastolic function and pulmonary structure and function compared with vehicle-treated cats. Mechanistically, SAHA treatment reduced the acetylation of mitochondrial metabolic enzymes, leading to increased mitochondrial respiration. These results suggest that HDAC inhibition with SAHA, which has FDA approval for the treatment of cutaneous T cell lymphoma, might be beneficial for improving adverse cardiopulmonary remodelling in HFpEF.