Abstract 400: Statin and Ezetimibe Differently Affect Spontaneous Atherothrombotic Occlusion in a Rabbit Model of Plaque Erosion

Background: Atherothrombosis of a coronary artery with plaque erosion is a major cause of acute coronary syndrome; however, its pathological mechanism and the effects of lipid-lowering therapy are unknown. We have recently reported the CuVIC Trial showing that ezetimibe added to statins improves coronary endothelial function associated with reductions in serum oxysterols in patients after coronary stenting (Takase, et al. ATVB 2017, in press). Methods and Results: We performed balloon injury in iliofemoral arteries in male Japanese white rabbits fed with high cholesterol diet and infused with angiotensin II. We examined the occurrence of atherothrombosis by echography 3 times/week, which were subsequently confirmed by angiography. Histochemical analysis revealed the lack of PECAM1-positive endothelial layer in the atherothrombotic sites. In treatment protocol, animals were divided into 3 groups; 1. Control, 2. Ezetimibe 0.6 mg/kg/day, and 3. Rosuvastatin 1.0 mg/kg/day, resulting total cholesterol 2514+/-179, 1716+/-111, and 1403+/-174, respectively after 8 weeks. Oral treatment with Ezetimibe significantly reduced atherothrombotic occlusion. Although there was no difference in the extent of arterial stenosis among 3 groups, treatment with ezetimibe was associated with better re-endothelialization and less tissue factor (TF)-positive areas in the intima. Serum oxysterols including 7-ketocholesterol (7KC) were lower in the Ezetimibe group. Serum from the model rabbits or 7KC induced TF in cultured SMCs. TF induction by the serum from the Ezetimibe group was significantly less compared with other groups. Conclusions: We established a valid animal model of spontaneous atherothromobotic occlusion in rabbits, which mimicked plaque erosion observed in human coronary arteries. Reduction in serum oxysterols with ezetimibe may prevent atherothrombosis from plaque erosion, by accelerating re-endothelialization and inhibiting TF expression in injured arteries.