Abstract 451: Radiation Induced Atherosclerosis on Mice

Abstract

Rationale: The high prevalence of cardiovascular disease (CVD) in cancer survivors after ionizing radiation (IR) therapy has long been recognized, but the mechanism for this is unknown. Previous studies reported that the plaques in IR therapy survivors exhibit characteristics of increased instability without changes in the plaque size. Objective: To study the mechanism of IR induced CVD in humans, we decided to develop an IR mouse model that mimics human CV events. Methods and Results: We fed LDLR-/- mice or C57 mice with a single injection of adeno -associated virus vector(AAV) encoding a gain-of function of PCSK9 with a high fat diet, then irradiated the mice with different doses of IR (2 Gy, 5 Gy, 10 Gy). Whole body radiation was given 2 Gy, while localized IR to the neck and thoracic area was given at 5 Gy (1 time) or 10Gy (weekly 5 Gy, twice).About 2~3 weeks after the IR treatment, we performed left partial carotid artery ligation (PCL), and 3 weeks later examined the extent of plaque formation and cardiac abnormality by comparing those detected in non-irradiated control mice. The lesion area ratio between the partially ligated left carotid artery (LCA) and the right carotid artery (RCA) was significantly increased in the IR-treated group compared to the non-IR-treated group (3.1 ± 0.3 vs.1.8 ± 0.4, n = 7-8, p = 0.03). In addition, the lesion in the IR-treated of mice had significantly larger necrotic cores with a thinner fibrous cap when compared to those in non-irradiate mice. Furthermore, IR-treated mice showed cardiac hypertrophy, in which we found a significant increase of the wall thickness of mid-to small sized arteries as well as perivascular fibrosis, which were not noticed in the non-IR-treated mice. Conclusions: Our results demonstrate that IR not only increases atherosclerotic and vulnerable plaque formation but also cardiac hypertrophy with mid- and micro-vascular wall swelling. The increase of mid- and micro-vascular wall thickness may explain the heart failure preserved heart failure, which is observed in the majority of heart failure patients after IR treatment.