# Epigenetic Drugs Splitomicin, Suberohydroxamic Acid, CPTH6, BVT-948, and PBIT Moderate Fibro-Fatty Development in Arrhythmogenic Cardiomyopathy

## TL;DR

This study identifies five epigenetic drugs that reduce fibro-fatty changes in heart cells from arrhythmogenic cardiomyopathy patients, offering new therapeutic potential.

## Contribution

The study is the first to screen epigenetic drugs for their effect on fibro-fatty differentiation in ACM patient-derived cells.

## Key findings

- Five epigenetic drugs reduced adipogenic differentiation in ACM CMSCs.
- BVT-948 and CPTH6 also reduced collagen production in these cells.
- The drugs showed potential for adjunctive therapy in ACM management.

## Abstract

Arrhythmogenic cardiomyopathy (ACM) is a cardiac disorder manifesting through electrical and contractile dysfunction of the ventricles, characterized by fibro-fatty substitution of the myocardium. Cardiac mesenchymal stromal cells (CMSCs) are key contributors to this remodeling. In clinical management, several pharmacological approaches address ACM arrhythmias and heart failure, but, to date, none specifically target fibro-adipose replacement. Despite genetic origin, several studies have reported that non-genetic aspects influence ACM phenotype, including epigenetic factors. Little is known about their mechanisms in ACM and their potential therapeutic applications. In this work, we aimed to test whether, by perturbing the epigenetic landscape of ACM CMSCs, we could influence their propensity to fibro-fatty differentiation. We conducted a hypothesis-free screening of 157 epigenetic drugs on CMSCs, isolated from ACM patients. Through fluorescence assays, we evaluated lipid droplet accumulation, collagen deposition, and cell viability. Of the 157 drugs screened, five (splitomicin, suberohydroxamic acid, CPTH6, BVT-948, and PBIT) attenuated adipogenic differentiation of ACM CMSCs, with BVT-948 and CPTH6 also reducing collagen production. Overall, this study identified specific epigenetic drugs that were effective in reducing the fibro-fatty phenotype of ACM stromal cells, thus offering potential for adjunctive therapies in the clinical management of ACM patients.