ESTRO 2024 - Abstract Book

S5273 ESTRO 2024 Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH. The sparing effect is similarly present for both acute and late damage. The study is ongoing. Radiobiology - Normal tissue radiobiology

Keywords: FLASH, Spread-out Bragg peak, toxicity

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Entresto as a novel radioprotectant in a partial heart irradiation mouse model

Gerard M Walls 1 , Mihaela Ghita 1 , Narainrit Karuna 2 , Kevin S Edgar 2 , Kathryn H Brown 1 , Rachel Queen 3 , Chris J Watson 2 , Karl T Butterworth 1 1 Queen's University Belfast, Patrick G Johnston Centre for Cancer Research, Belfast, United Kingdom. 2 Queen's University Belfast, Wellcome Wolfson Institute for Experimental Medicine, Belfast, United Kingdom. 3 Newcastle University, Bioinformatic Support Unit, Newcastle, United Kingdom

Purpose/Objective:

Radiation cardiotoxicity (RC) is an important treatment sequela for patients with intrathoracic cancer. Depending on the dose and distribution of radiation, acute coronary syndrome, heart failure, arrhythmias, valvulopathy and pericardial disease can each manifest, with onset typically in the months–years after treatment, and often with a chronic component. Despite modern radiotherapy technology, avoidance of incidental cardiac irradiation is not possible to due to intimate tumour proximity for many patients.

While multiple pre-clinical and clinical studies investigating established cardiology biomarkers such as B-type natriuretic peptide (BNP) in RC were negative, other natriuretic peptides have not been thoroughly examined. Atrial natriuretic peptide (ANP) has gained interest in recent years for its role in heart failure. In response to mechanical stress, atrial cardiomyocytes release additional ANP, which acts on myocytes and fibroblasts of the myocardium and systemic vasculature to improve contractility, reduce harmful remodelling and decrease vascular tone. The landmark trial of Entresto in 2016 showed that blockade of the enzyme nepriliysin, which degrades ANP, reduces heart failure hospitalisation by 20%, and death by 5%. Pre-clinical studies have verified the on-target effect of Entresto on ANP elevation. Given historical data that ANP levels decrease acutely post-irradiation, we hypothesised that Entresto may alleviate the cardiomyopathy phenotype in a partial heart irradiation mouse model, as measured by structural, functional and spatial transcriptomic endpoints.

Material/Methods:

Female 8-week old C57BL/6J mice were randomly assigned to receive sham irradiation (controls), sham irradiation plus Entresto (Entresto-only), irradiation (XRT-only) or irradiation plus Entresto (XRT+Entresto). Irradiated mice received a 20 Gy single-fraction to the superior 2/3 of the heart as a 90º arc field arrangement using a small animal radiotherapy research platform (SARRP, Xstrahl). The mean heart dose delivered is representative of a bulky stage