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(1) Purpose/Objective: The heart remains one of the most critical dose limiting organs in patients receiving radiotherapy for thoracic indications. Clinical studies have demonstrated regional variations in the radiosensitivity of heart with the base being a differentially radiosensitive region. In this study we aimed to apply a translationally relevant mouse model of regional radiosensitivity to characterise late occurring gene expression changes using spatial transcriptomics.
(2) Materials and Methods: Aged female C57BL/6 mice were irradiated 16 Gy delivered to the cranial third of the heart using a 6 x 9 mm parallel opposed beam geometry on a small animal radiotherapy research platform (SARRP). Echocardiography was performed and tissues were collected at 30 weeks for spatial transcriptomics analysis to map gene expression changes occurring in different region of the irradiated heart. Cardiac regions were manually annotated on to the capture slides and the gene expression profiles compared across different regions.
(3) Results: Base irradiation showed significant time dependent loss of cardiac including functional effects left ventricular ejection fraction (LVEF), fractional shortening and myocardial performance index (MPI) (p < 0.01) that did not correlate with mean heart dose (MHD) or the volume of the heart receiving 5 Gy (V5, R2 < 0.1). UMAP analysis identified regions of the heart based on distinct gene expression patterns. Regional specific analysis identified 131 genes in the atria and 28 genes in the ventricular region that were differentially expressed compared to unirradiated tissue. In the right atrium the three most significantly activated biological processes were extracellular matrix structure and organisation, circulatory system development and regulation of cell population and proliferation. No biological processes were significantly downregulated. Network analysis showed that the five most significantly dysregulated genes were Fn1, Timp1, Cav1, Vwf and TagLn.
(4) Conclusion: We provide the first evidence of spatially resolved gene expression changes in irradiated tissues. Examination of the regional radiation responses in the heart can further our understanding of radiosensitivity in the cardiac base towards the development of actionable targets for pharmacological intervention or improving cardiac dose constraints.