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

Facchi, C.; Nugroho, A.; Al-Othman, S.; Abumanhal-Masarweh, H.; Murtuza Baker, S.; Zeef, L.; Walls, G. M.; Xing, D.; Morrell-Neal, I.; King, K.; Chelu, A.; Prehar, S.; Forster, D.; Ghita-Pettigrew, M.; Hadjidemetriou, M.; D'Souza, A.; Venetucci, L.; Butterworth, K. T.; Cartwright, E. J.; Williams, K. J.

doi:10.1101/2025.10.13.681218

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bioRxiv · 10.1101/2025.10.13.681218

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

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Abstract

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.

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Facchi, C., Nugroho, A., Al-Othman, S., Abumanhal-Masarweh, H., Murtuza Baker, S., Zeef, L., Walls, G. M., Xing, D., Morrell-Neal, I., King, K., Chelu, A., Prehar, S., Forster, D., Ghita-Pettigrew, M., Hadjidemetriou, M., D'Souza, A., Venetucci, L., Butterworth, K. T., Cartwright, E. J., Williams, K. J.. 2025-10-14. Regional Vulnerability of Cardiac Chambers to Radiotherapy: A Multi-Omics Perspective. https://doi.org/10.1101/2025.10.13.681218

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