Givinostat inhibits in vitro differentiation of cardiac fibroadipogenic precursors from a mouse model of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease and one of the leading causes of sudden cardiac death in young individuals and athletes. Current treatments focus on preventing arrhythmias and sudden cardiac death, but no effective therapy targeting disease progression is available. Myocardial replacement with fibro-fatty tissue, a hallmark of ACM, is primarily driven by the activation of cardiac fibroadipogenic precursors (cFAPs). Here, we evaluate the efficacy of a pan inhibitor of histone deacetylases (givinostat) in reducing cFAP proliferation and differentiation. These cells were found to be enriched in the hearts of a transgenic ACM murine model (Tg-hQ), which overexpresses the DSG2 p.Q558* mutation, compared to wild-type (WT) controls. We observed that givinostat reduced the proliferation of both Tg-hQ and WT isolated cFAPS. Additionally, cFAPS were induced to differentiate into adipocytes or fibroblasts and treated with givinostat. The drug treatment led to a reduction in the number of adipocytes under pro-adipogenic conditions. RNA sequencing analysis revealed a significant downregulation of key regulators of adipogenic differentiation and lipid metabolism (Pparg, Cebpa and Adipoq). In parallel, cells cultured under pro-fibrotic conditions showed decreased expression of genes encoding components of the extracellular matrix (Col1a1, Col6a1 and Postn) upon givinostat treatment. Overall, these results support the potential of givinostat in modulating cFAP proliferation and differentiation in vitro, warranting further in vivo studies to assess its impact on fibro-fatty tissue replacement in ACM.