Regional Vulnerability of Cardiac Chambers to Radiotherapy: A Multi-Omics Perspective

The heart is highly vulnerable to radiotherapy (RT)-induced injury, leading to molecular and structural remodeling collectively termed radiation-induced cardiac toxicity (RICT). Although several biological pathways have been implicated, the regional, cardiac-specific molecular responses to radiation exposure remain incompletely understood. Here, a multi-omics approach was adopted to longitudinally characterise the unique responses to radiation of the heart base (including ventricular base and right atrium), or the heart apex. Ventricular base irradiation induced a cardiomyopathy phenotype, with pronounced molecular perturbations in metabolism and electrical conduction, while changes related to tissue structure were predominant following apex-directed RT. In the right atrium, irradiation drives fibrotic tissue remodelling, leading to an increased propensity for atrial fibrillation, underpinned by changes in sarcomere organisation. This study represents a comprehensive characterisation of differential spatiotemporal radiation effects in the heart and highlights biological and functional pathways that are potentially clinically actionable for cardiac radioprotection and monitoring.