Natalia Atzemian, Ludovica Di Venanzio, Shafeeq Ahmed Mohammed, Sarah Costantino, Frank Ruschitzka, Francesco Paneni
Cardiovascular disease reflects not only genetic predisposition and haemodynamic stress but also reversible alterations in chromatin organisation and transcriptional programming, a layer of regulation that is, in principle, amenable to pharmacological intervention. Purpose-built epigenetic drugs, DNA methyltransferase inhibitors, histone deacetylase inhibitors, histone acetyltransferase inhibitors, bromodomain and extraterminal domain inhibitors, enhancer of zeste homolog 2 inhibitors, and RNA-based therapeutics, target this machinery directly. In parallel, established cardiovascular therapies, including statins, renin-angiotensin-aldosterone system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, antithrombotic agents, sodium-glucose cotransporter-2 inhibitors, and incretin-based therapies, appear to modulate the epigenome as an underappreciated component of their action, a concept termed "pharmaco-epigenetics". This review appraises both axes side by side, with explicit attention to clinical maturity, including the level of evidence, human validation, development stage, and the interpretation of hypothesis-generating findings. Key translational barriers, cardiac-targeted delivery, biomarkers of target engagement, and interindividual epigenetic variability, are outlined alongside priorities for future trial design.