Abstract 12442: Hypercholesterolemia and Angiotensin II Induces Spontaneous Atherothrombotic Occlusion of balloon-injured Rabbit Iliac Arteries; Effects of Lipid-Lowering Therapies

Abstract

Background: Atherothrombotic occlusion of a coronary artery with an intact fibrous cap is a major cause of acute coronary syndrome that is attributed to plaque erosion. We developed an animal model of spontaneous atherothrombotic occlusion of fibrous cap-intact arteries in rabbits. Methods and Results: We performed balloon injury in bilateral iliofemoral arteries in male Japanese white rabbits fed with high (2 %) cholesterol diet and infused with angiotensin II (50 ng/kg/min). Animals were divided into 3 groups; 1. no treatment, 2. Ezetimibe 0.6 mg/kg/day, and 3. Rosuvastatin 1.0 mg/kg/day. We examined the occurrence of atherothrombosis by high-resolution ultrasonograpy (Vevo2100) 3 times/week. (Fig. A) After the occurrence of acute thrombotic occlusion, the presence of thrombosis was confirmed by angiographic and histopathologic examination. Histochemical analysis in the atherothrombotic sites revealed; 1) no severe stenosis (% stenosis: 49±7), 2) no plaque rupture or lipid core, and 3) no PECAM1-positive endothelial layer. Interestingly, there were smooth muscle-like cells (αSMA+/SM1, SM2, SMemb and calponin-) with tissue factor expression at the neointima-thrombus interface. Oral treatment with Ezetimibe but not Rosuvastatin significantly reduced the incidence of atherothrombotic occlusion (Fig. B). Serum from the model rabbits induced TF in cultured rat smooth muscle cells. TF induction by serum from Ezetimibe-treated rabbits was significantly less compared with those from animals without treatment or with Rosuvastatin treatment (Fig. C). Conclusions: We established for the first time an appropriate animal model of spontaneous atherothromobotic occlusion in rabbits, which mimicked the pathological features of plaque erosion observed in human coronary arteries. This model may provide a clue to a mechanistic understanding and potential therapeutic approaches for plaque erosion.