Ionizing radiation-induced remodelling of the heart: Cellular pathways and crosstalk relevant to stereotactic arrhythmia radioablation (STAR).

Stereotactic arrhythmia radioablation (STAR) has emerged as a promising non-invasive therapy for refractory ventricular tachycardia, yet its biological mechanisms remain poorly defined. While conventional catheter ablation achieves arrhythmia control through structural remodelling, radiotherapy was initially assumed to act similarly. However, STAR reduces ventricular arrhythmia burden within weeks, preceding the development of radiation-induced structural remodelling. This temporal mismatch indicates that early anti-arrhythmic effects are probably driven by functional adaptations. Human tissue findings and preclinical large- and small-animal models have provided the first insights into how the myocardium responds to focal high-dose radiation, yet experimental data on STAR's underlying cellular mechanisms remain limited. Across these studies, a consistent observation is the temporal dissociation between early functional effects and delayed structural remodelling, which provides a key framework for interpretating STAR's anti-arrhythmic action. In this review, we synthesize current evidence on cell-type-specific responses to ionizing radiation by integrating insights from the emerging STAR literature, oncology and radiation heart disease models. By linking time-resolved cellular responses to clinical observations, we aim to distinguish mechanisms most relevant to early therapeutic effects from those contributing to delayed remodelling, and to define key knowledge gaps for guiding safe and effective clinical implementation.