Exercise-specific epigenetic effects on cardiovascular health.

Exercise is widely prescribed to prevent cardiovascular disease, which encompasses a heterogeneous spectrum of disorders involving vascular dysfunction, myocardial injury and remodeling, inflammation, and electrophysiological disturbances; however, its benefits are not uniformly dose-dependent. While aerobic and resistance training generally elicit sustained cardioprotective adaptations, evidence from ultra-endurance exercise suggests a distinct physiological regime in which repeated extreme load, prolonged duration and individual susceptibility may precipitate maladaptive remodeling. Here we synthesize an epigenetic remodeling framework to reconcile these divergent outcomes and to explain how exercise modality, intensity and exposure duration may influence the balance between cardiovascular adaptation and vulnerability. We systematically examine epigenetic pathways, including DNA methylation, histone modifications and non-coding RNA-mediated regulation, through which aerobic exercise and resistance training may modulate vascular function, myocardial metabolism, inflammation and fibrosis. We then contrast these signatures with those reported in ultra-endurance settings, highlighting mechanistic patterns associated with transient myocardial damage markers, arrhythmogenic substrates and adverse structural remodeling in susceptible individuals. We further discuss emerging sex-specific epigenetic mechanisms that may contribute to differential cardiovascular disease trajectories under ultra-high-intensity endurance stress. Finally, we outline key limitations in current evidence, including incomplete causal epigenetic chains, heavy reliance on experimental models, peripheral tissues and elite athlete cohorts, limited tissue-specific evidence and a paucity of longitudinal population studies. Addressing these gaps will be essential for translating epigenetic insights into risk-stratified and individualized exercise prescriptions that maximize cardioprotection while minimizing potential risk.