ESTRO 2024 - Abstract Book

S5265 ESTRO 2024 Furthermore, several comorbidities have been found to exacerbate RICT in cancer patients, with hypertension being a commonly implicated condition 4 . However, to date, RICT has not been thoroughly evaluated in preclinical models of hypertension, and specific treatment plans for hypertensive cancer patients are still absent. So, the second aim of this project is the investigation of the effect of hypertension at the cardiac level in response to RT. Radiobiology - Normal tissue radiobiology

Material/Methods:

Micro-CT-guided 16Gy single 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 unconscious ECG, respectively, for 20 weeks. At the endpoint, ex-vivo pacing was adopted to identify propensity to arrhythmia and samples were taken for RNAseq. To evaluate the impact of hypertension, aged (56 weeks) mice heterozygous for Plasma membrane calcium ATPase 1 (PMCA1) and age-matched controls were used. PMCA1 strongly associates with hypertension in GWAS studies, with effects on age-related hypertension pheno-copied in mice 5 . After echocardiography and ECG, in vivo pacing was performed at the final endpoint.

Results:

Over the 20 weeks, we found that Global Longitudinal Strain (GLS), a widely used clinical parameter for cardiac performance, was a reliable marker of the effect of RICT. In particular, 10 weeks after RT, we observed a reduction of GLS in the base-irradiated group compared to the control, suggesting that this parameter could anticipate the later dysfunction. At the same time point, ECG analysis highlighted substantial changes in QRS interval in base irradiated mice, showing a shortening of the time required for the impulse to travel from the base to the lower part of the ventricle. Interestingly, at the final endpoint, cardiac tissue and conduction showed total remodelling, which was able to sustain the normal function of the heart. Bulk-RNAseq of irradiated cardiac tissues demonstrated substantial remodelling that differs across specific cardiac compartments in WT animals. Base irradiated mice showed a pronounced change in genes correlated with the conduction system (e.g. RyR2; Cacna1c), while radiation at the apex provoked remodelling mainly in the extracellular matrix (e.g. Col18a1; IGTb2). In particular, RNA expression of several important ion channels involved in cardiac conduction was decreased in the irradiated-base group. These expression changes induced a higher susceptibility to arrhythmias, as demonstrated by the ex-vivo pacing analysis, where the base-irradiated group showed a higher percentage of atrial fibrillation events. These findings suggest that radiation is able to determine initial changes leading to a molecular remodelling that puts the heart into an unstable status inclined to pathological remodelling. Aged PMCA1Ht and control mice did not show any differences in cardiac conduction and function. However, histological analysis highlighted that after radiation to the base, PMCA1Ht mice showed stronger fibrotic phenotype and increased tissue hypertrophy, highlighting that hypertension could exacerbate the impact of RT.

Conclusion:

This study highlighted the unique remodeling in separated cardiac substructures occurring after radiotherapy. RT causes gene expression and functional changes that differ according to the irradiated substructure. Base irradiation drives changes in gene expression associated with conduction that may mechanistically link with clinical observations of morbidity associated with RT to this region. Hypertension could exacerbate and speed up the tissue remodeling occurring after RT.

Keywords: RICT, cardiac substructures, conduction system

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