BS01 Multi-omics approach to dissect the effect of radiotherapy on cardiac substructures

Radiation therapy (RT) plays a pivotal role in cancer treatment, constituting a vital aspect of the therapeutic protocol for over half of cancer patients. Despite continuous advancements in RT technology improving the precision and accuracy of RT, incident radiation results in the unavoidable exposure of surrounding normal tissues. In patients undergoing RT for thoracic tumours, radiation-induced cardiac toxicity (RICT) is a particular risk. RICT describes a spectrum of cardiac conditions including myocardial fibrosis, coronary artery disease and arrhythmias manifesting years after the completion of treatment. Recent clinical findings emphasize a robust correlation between cardiovascular outcomes and specific cardiac substructures with a notable focus on the base of the ventricle as a primary area of concern. This study aims to highlight early molecular and functional markers to create new guidelines in the monitoring of RICT patients. Micro-CT-guided 16 Gy single dose irradiation either of the heart apex or base was conducted in female C57/BL6J wild-type mice (WT, 12 weeks old). Cardiac function and conduction were monitored via echocardiography and electrocardiogram over 20 weeks. Langendorff-based pacing was performed at the final endpoint. 10 weeks after RT, we observed a reduction of Global Longitudinal Strain and a shortening in the QRS interval in the base-irradiated group, suggesting that these parameters could anticipate the later dysfunction and an initial remodelling within the conduction system. We investigated the potential molecular changes connected with this phenotype, using spatial transcriptomics. After RT, spatial transcriptomics highlighted a strong dysregulation of fibrosis and cardiac remodelling gene expression, which correlates with disrupted ion handling and instability in the conduction system. These findings indicate that early radiation-induced changes trigger molecular remodeling placing the heart in an unstable state that is prone to pathological alterations. These changes lead to a specific arrhythmogenic phenotype 20 weeks after radiation. Indeed, a higher propensity to develop atrial fibrillation was observed in base-irradiated mice. Bulk-RNAseq confirmed that base-irradiated mice showed a pronounced change in genes correlated with the conduction system at this time point. Remarkably, radiation at the apex provoked remodelling mainly in the extracellular matrix, highlighting the substructure-specific effect of radiation. This multi-omics study is unveiling potential new mechanisms, which may correlate with the development of RICT in patients and thus identifying potential new therapeutical targets to limit the effect of RT in cancer patients.

Conflict of Interest

no