Local heart irradiation of ApoE−/− mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis

Abstract: Background and purpose: Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. Material and methods: Hypercholesterolemic and atherosclerosis-prone ApoE−/− mice received local heart irradiation with a single dose of 0, 2, 8 or 16Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40weeks. Results: Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40weeks after 8 and 16Gy. Microvascular density decreased at both follow-up time-points after 8 and 16Gy. Remaining vessels had decreased alkaline phosphatase activity (2–16Gy) and increased von Willebrand Factor expression (16Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16Gy, with foam cell accumulations at 20weeks, and fibrosis and protein leakage at 40weeks. Despite an accelerated coronary atherosclerotic lesion development at 20weeks after 16Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20weeks. Conclusions: The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE−/− mice was maintained. [Copyright &y& Elsevier]