HDAC inhibitors: Cardiotoxicity and paradoxical cardioprotective effect in ischemia-reperfusion myocardiocyte injury

Histone deacetylase inhibitors (HDACIs) are epigenetic drugs that regulate the acetylation status of histones and non-histone proteins, thereby leading to chromatin remodeling and transcriptional regulation of key apoptotic and cell cycle regulatory genes. There are currently five HDACIs clinically approved by the major regulatory authorities for treating hematological cancers, primarily as monotherapy. While HDACIs have been particularly effective in T-cell lymphomas, their clinical efficacies have not yet extended to solid tumors. The development of HDACIs continues, including for the treatment of a non-malignant conditions, with givinostat recently approved by the US FDA. However, the early development of HDACIs was limited by concerns about cardiotoxicity including QT interval prolongation. Yet, paradoxically, the latest research suggests some cardioprotective effect of HDACIs in ischemic heart disease or heart failure. This review presents the latest update about the cardiotoxicity of the clinically approved HDACIs. The mechanisms leading to HDACI-induced cardiotoxic adverse events and clinical strategies for their management are discussed. We will also deliberate the potential repurposing use of HDACIs and their HDAC isoform selectivity for treating ischemia-reperfusion cardiac muscle injury, cardiac hypertrophy, and fibrosis.