Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

Abstract

To determine the mechanisms associated with the development of atherosclerotic lesions in the heart after exposure to radiation therapy (RT). We hypothesize that accelerated development of cardiovascular disease (CVD) post-RT depends upon the region of the heart exposed to radiation.C57Bl/6 mice are naturally resistant to atherosclerosis. Apolipoprotein E is a multifunctional protein and its deficiency results in atherosclerosis in mice. Therefore, Apolipoprotein E knockout (ApoE-/-) mice are more suitable to investigate the development of atherosclerosis after radiation. Thus, 9 or 16 weeks old male ApoE-/- mice on a high fat diet (HFD) received 16Gy cardiac RT targeted to the whole or partial (apical or basal) region of the heart. Atherosclerotic lesions and inflammatory changes in the hearts and aortas were assessed using immunohistochemistry eight weeks following radiation and compared to control unirradiated mice.Our studies demonstrate that atherosclerotic lesion formation is accelerated by cardiac RT. We found that (1) Subendocardial atherosclerotic lesions at the base of heart of 9 weeks old mice after basal irradiation (7.8 ± 2.49) are comparable to those formed post-whole heart irradiation (12.2 ± 3.29). (2) Basal cardiac irradiation led to a greater number of atherosclerotic lesions in the basal coronary arteries (29.33 ± 5.48) and basal subendocardial vasculature (6.66 ± 2.07) as compared to unirradiated controls in 16 weeks old mice at 8 weeks post-RT. (3) Apical or whole heart irradiation had no impact on the development or acceleration of lesions in the basal region of the hearts in 16-week-old mice, thus demonstrating the adverse impact of basal irradiation. (4) Infiltration of inflammatory cells (CD45+ and CD3+) and enhanced expression of endothelial adhesion molecules (CD31+) after RT were differentially and locally regulated based upon the irradiation site. These results are indicative of a long-term inflammatory response to RT which may be crucial in the development of CVD. (5) Basal irradiation led to a significant increase in aortic atherosclerotic lesions in 16 weeks old mice as compared to the 9 weeks old mice. Thus, development of aortic atherosclerotic lesions could be a result of a combination of factors including age, diet and area of the heart irradiated.Our results indicate that the base of the heart in the 16 weeks old ApoE-/- mice on HFD was more prone to development of RT-induced atherosclerotic lesions and thus omitting this area from RT direct exposure may improve the quality of life for cancer patients receiving thoracic RT.