Selective class IIa HDAC inhibition reverses diastolic dysfunction in cardiometabolic HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent cardiometabolic syndrome with yet no effective therapies. Here, we report that selectively class IIa histone deacetylases (HDACs) but no other classes of HDACs are enzymatically activated in hearts from HFpEF patients and cardiometabolic HFpEF animal models. Cell type-specific and enzymatic activity-specific genetic loss-of-function models of the cardiomyocyte-enriched class IIa HDAC family member HDAC4 and the pharmacological class IIa HDAC-selective inhibitor TMP195 prevent and reverse diastolic dysfunction and exercise intolerance in cardiometabolic HFpEF in vivo. In contrast to pan-HDAC inhibition no adverse effects are observed. Despite its well-known non-enzymatic role as transcriptional repressor, we found that specifically enzymatic activation of HDAC4 has little direct effects on cardiomyocyte-intrinsic gene expression. Instead, non-epigenetic actions lead to endothelial activation via altered cardiocrine signaling. We discovered that selective enzymatic class IIa HDAC inhibition is a new therapeutic concept to combat cardiac HFpEF.