The past 10 years of research have significantly advanced our understanding of the functions and modes of regulation of HDACs in the heart. The next wave of discovery will likely focus on translating these basic, mechanistic findings into novel therapeutics for heart failure. This process would be greatly facilitated by the discovery of the pathological HDAC(s) in the heart. Genetic studies have implicated HDAC2 as a positive regulator of heart failure, but the results remain equivocal. Assessing the activity of new generations of isoform-selective HDAC inhibitors in animal models of heart failure will likely provide more definitive answers. Furthermore, these pharmacology studies will establish whether iso-form-selective HDAC inhibition widens the therapeutic index to a level that is acceptable for the treatment of a chronic indication such as heart failure.

Once the pathological HDAC(s) have been identified, it will be important to determine how it regulates heart failure. Does it simply repress cardioprotective genes via deacetylation of histones, or does it deacetylate nonhistone substrates to altered cardiac signaling? Finally, it remains to be determined whether the beneficial effects of HDAC inhibitors in the heart are mediated solely by effects on myocytes or involve nonmyocytes as well. In this regard, it seems likely that the profound efficacy of HDAC inhibitors in models of heart failure is due to the ability of the compounds to affect multiple cells types (e.g., myocytes, fibroblasts, epithelial cells, inflammatory cells) and pathological mechanisms (e.g., myocyte hypertrophy, inflammation, apoptosis, autophagy and fibrosis). This next phase of research on HDACs in the heart should set the stage for clinical assessment of HDAC inhibitors in patients with cardiovascular disease.

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