For decades, cardiovascular research focused on DNA mutations and protein-level changes. A quieter revolution has been building at the RNA layer — where reversible chemical tags on messenger RNA fine-tune which genes get expressed, when, and how strongly. New evidence positions these epitranscriptomic modifications as central players in heart disease progression, potentially opening a class of precision targets that sits between genomics and classical pharmacology.

The review maps two dominant RNA modification systems — N6-methyladenosine (m6A) and 5-methylcytosine (m5C) — across six major cardiovascular conditions: atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease. Key enzymatic regulators follow distinct spatiotemporal patterns depending on disease stage and cell type. On the m6A axis, writers METTL3 and METTL14 deposit methyl groups, while erasers FTO and ALKBH5 remove them; reader proteins in the YTH family then interpret the marks to regulate RNA stability, splicing, translation, and degradation. The m5C pathway involves parallel writer-eraser-reader logic through NSUN2, DNMT2, TET2, ALYREF, and YBX1. The review further identifies emerging marks — m1A, m7G, m6Am, hm5C, and f5C — that extend this landscape into cap-dependent translation and oxidative cytosine signaling.

This synthesis is analytically significant because it reframes RNA methylation not as a secondary phenomenon but as a primary driver of pathological processes including endothelial dysfunction, inflammation, fibrosis, and metabolic remodeling. What elevates it beyond prior single-condition studies is the cross-disease comparison of regulator expression patterns, which suggests that the same molecular machinery produces divergent pathological outputs depending on cellular context. Preclinical therapeutic strategies — including AAV-based gene delivery targeting writers or erasers, pharmacological inhibition of FTO and METTL3, and stem cell approaches — show early efficacy signals, but human trial data remain absent. The observation that exercise may remodel the cardiac m6A landscape is intriguing but mechanistically underdeveloped. As a comprehensive review rather than an original trial, its primary value lies in hypothesis generation and biomarker prioritization rather than definitive causal evidence.