Metabo-epigenetic signalling in Heart Failure

HDAC signalling in cardiometabolic disease: Heart Failure with preserved Ejection Fraction (HFpEF) is an age-associated disease that is driven by metabolic and hemodynamic risk factors such as obesity and arterial hypertension. About 30 million people suffer worldwide from this disease, and currently there is with SGLT2 inhibitors only one treatment option with no clear evidence for an improved long-term survival. Pan-inhibitors of histone deacetylases (pan-HDACi) have been shown to improve cardiac diastolic function in animal models but HDACi inhibit multiple HDAC enzymes and by this cause many side effects that hindered so far the use of these anti-cancer compounds in cardiovascular disease. Thus, the identification of the underlying HDAC isoform and the mechanism of action might lead to new therapeutic approaches. In this talk I will describe how we identified one HDAC isoform that causes many cardiometabolic features of HFpEF. Specific enzymatic and allosteric inhibitors have preventive and therapeutic effects in at least two mouse models for HFpEF. Oxidative modification has arisen as a critical activation mechanism that can be more specifically targeted than enzymatic inhibition. These results led to a new translational program for the development of specific HDAC inhibitors that will be optimized for the treatment of HFpEF.