Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

Nepali, P. R.; Mathieu, M.; Kitz, S.; Nakauchi, C.; Gabriels, K.; Russell, J.; Monette, S.; te Poele, J. A.; Heeneman, S.; Rimner, A.; Qiu, Y.; Kurland, I. J.; Stewart, F. A.; Jaimes, E. A.; Haimovitz-Friedman, A.

doi:10.1101/2021.04.08.438992

bioRxiv · 10.1101/2021.04.08.438992

Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

Nepali, P. R.·Mathieu, M.·Kitz, S.·Nakauchi, C.·Gabriels, K.·Russell, J.·Monette, S.·te Poele, J. A.·Heeneman, S.·Rimner, A.·Qiu, Y.·Kurland, I. J.·Stewart, F. A.·Jaimes, E. A.·Haimovitz-Friedman, A.

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Abstract

Clinical studies have identified cardiac exposure as an independent predictor for cardiovascular mortality in patients treated with radiation therapy (RT) for thoracic malignancies. Although the mechanisms are not completely understood, the available evidence indicate that direct injury to the coronary arteries endothelium is implicated. In these studies we tested the hypothesis that different areas of the heart are more sensitive to the effects of RT on the formation of atherosclerotic plaque in apolipoprotein E deficient (ApoE-/-) mice, a well validated model of atherosclerosis. MethodsApoE-/- mice on a high fat diet (HFD) received 16Gy cardiac irradiation targeted to the whole or partial (apical or basal) region of the heart at 9 weeks or 16 weeks of age. Atherosclerotic lesions and inflammatory changes in the hearts as compared to control unirradiated mice were assessed eight weeks following radiation. ResultsAfter either basal or whole heart RT at 9 weeks of age the number of subendocardial atherosclerotic lesions at the heart base was higher as compared to unirradiated mice. Irradiation of the apex did not increase the number of subendocardial atherosclerotic lesions in any region. After basal RT at 16 weeks of age the number of coronary and subendocardial atherosclerotic lesions was higher as compared to controls. Neither apical or whole heart RT had an impact on the development or acceleration of lesions in the basal region of the hearts of 16 week old mice, thus demonstrating the adverse impact of basal irradiation. Infiltration of inflammatory cells (CD45+ and CD3+) and enhanced expression of endothelial adhesion molecules (CD31), were differentially and locally regulated based upon the site of irradiation. In support of a role of eicosanoid mediators for base or whole heart atherogenic irradiation effects, apex irradiation eicosanoid mediators are not clearly atherogenic, in contrast to eicosanoid mediators detected in serum after base heart irradiation. These results indicate that the base of the heart is significantly more prone to the development of atherosclerotic lesions in the coronary arteries post-RT. ConclusionOur results indicate that the base of the heart is more susuceptible to development of RT-induced atherosclerotic lesions and therefore avoidance from RT direct exposure to this area may reduce the risk for atherosclerotic disease in patients undergoing RT.

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Nepali, P. R., Mathieu, M., Kitz, S., Nakauchi, C., Gabriels, K., Russell, J., Monette, S., te Poele, J. A., Heeneman, S., Rimner, A., Qiu, Y., Kurland, I. J., Stewart, F. A., Jaimes, E. A., Haimovitz-Friedman, A.. 2021-04-09. Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis. https://doi.org/10.1101/2021.04.08.438992

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