Abstract
Introduction: Radiation therapy (RT) is used in the treatment of approximately 50% of cancer patients. Thoracic RT is commonly used in breast cancer, Hodgkin’s lymphoma, head and neck and lung cancers among others. Unfortunately, the benefits of RT are often out-weighed by the by-stander cardiovascular risks and associated non-relapse mortality in cancer survivors. Hence, the development of cardiovascular disease (CVD) in patients receiving RT remains an important clinical problem. The base of the heart has been shown to be dose-sensitive wherein basal irradiation is associated with lower patient survival in lung-cancer patients treated with curative-intent RT. Although the mechanisms for RT-induced CVD are poorly understood, direct injury to the coronary arteries endothelium has been implicated. Hypothesis and Results: We hypothesized that irradiation harms heart tissue differentially depending upon the specific region that receives radiation. In order to test this hypothesis, we irradiated different regions of the heart and measured the development of atherosclerotic plaques as compared to control unirradiated mice. Apolipoprotein E knockout (ApoE -/- ) mice were irradiated with 16Gy to the base, apex or to the whole heart. Our results demonstrate that the base of the heart has significantly greater sensitivity to irradiation as compared to the apex, and develops atherosclerotic lesions that are equivalent to those produced by whole heart irradiation at 20 weeks post-RT. In addition, a greater number of plaques are present in the base of the heart after whole heart and basal irradiation compared to unirradiated controls at 40 weeks post-RT. Atherosclerotic plaques with subendothelial macrophage foam cell accumulation and fibrin deposits were also observed at 20 and 40 weeks post basal or whole heart RT. Ongoing studies are testing the effect of high-fat diet on the development of differential RT-induced atherosclerotic plaques in ApoE -/- mice and their correlation with heart function. Conclusion: Our studies strengthen the argument for advanced RT techniques to shield the base of the heart from radiation exposure to minimize RT-induced CVD and improve the quality of life and survival of cancer patients receiving RT.
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