Cardiac radiotherapy-induced epigenetic memory underlies electrophysiologic and metabolic reprogramming.

Summary

Using in vivo and in vitro models, the authors show that a single high-dose fraction of cardiac irradiation induces durable epigenetic remodeling with increased Scn5a (NaV1.5) expression and chromatin accessibility, explaining sustained conduction velocity gains after STAR. Radiation triggered dose-dependent, cell-autonomous changes in repolarization, Ca2+ flux, and mitochondrial respiration, linking epigenetic memory to electrophysiologic and metabolic reprogramming.

Key Findings

• Single-fraction irradiation increased Scn5a (NaV1.5) expression and chromatin accessibility, consistent with higher conduction velocity after STAR.
• Epigenomic and transcriptomic remodeling encompassed pathways in repolarization, Ca2+ handling, and metabolism.
• Dose-dependent, cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration mapped to radiation-induced epigenetic memory.

Clinical Implications

Mechanistic insights support parameter optimization (dose, targeting) for STAR to maximize conduction benefits while anticipating metabolic effects. Biomarkers (e.g., SCN5A expression or chromatin signatures) could guide patient selection and response monitoring.

Limitations

• Preclinical models; lack of prospective human validation of proposed biomarkers
• Long-term safety and off-target epigenetic effects were not assessed clinically

Future Directions

Prospective human studies correlating radiation dose/targeting with epigenetic signatures and conduction outcomes; development of minimally invasive biomarkers to guide STAR.