MODEL CONSTRUCTION FOR SIMULATION OF VULNERABLE PLAQUE DEVELOPMENT

INTRODUCTION In the United States, coronary artery disease is responsible for more than 400,000 annually. Plaque rupture is the principal cause of atherosclerosis in acute coronary syndromes. Early detection of vulnerable plaques is required for the prevention of coronary artery disease. However, current technique is lack of reliability and safety. Unstable plaque is composed of lipid-rich core which contains various crystals of cholesterol and thin fibrous cap with scarce smooth muscle cells. Approximately 40% of the vulnerable plaque is filled with lipid-rich core [1] and lipid-rich core are often found in the basal intima of the coronary artery. Some inflammatory cells like macrophages and T lymphocytes massively exists in fibrous cap. In addition, it contains lipoprotein cholesterol which may induce the activation of immune system and annihilate macrophages and smooth muscle cells due to high toxicity [1]. There are five major causes for the formation of vulnerable plaque such as thin fibrous cap, lipid rich core, shear stress, intraplaque hemorrhage and inflammation. The vulnerable plaque has a lipid-rich core which is covered by a fibrous cap. If the necrotic core occupies above 30% space of the plaque, the plaque is probably unstable and may cause atherothrombosis [1]. If the plaque grows too large, the fibrous cap will become thinner. Since the fibrous cap was composed of smooth muscle cells which are primary connective tissue cells in basal intima to support the stable structure of the plaque and type I, III collagen [2], the deterioration of the fibrous cap will lead to the shortage of smooth muscle cells and collagen. Then the plaque may become instable and form an obstruction in the artery to cause atherothrombosis. Rich collagen will provide great tensile stress to support the structure and without high concentration of collagen, the tensile stress will disrupt the fibrous cap and lead to the rupture of plaque [1]. The formation of lipid-rich core may be induced by the accumulation of the dead cells of macrophages in the basal intima because most lipid-rich cores are founded in the basal intima and macrophages tend to eliminate the lipids in the basal intima [3]. Additionally, some researchers found that high saturation of cholesterol may result in crystalline structure of cholesterol which causes the expansion of the plaque and fibrous cap [4]. The accumulation of lipoprotein cholesterol will stimulate the oxidation of lipoprotein and macrophages is activated due to the presence of oxidized lipoprotein. Since the lipoprotein is cytotoxic, the accumulation of dead macrophages will induce more macrophages to remove the dead cells. And then more dead cells are accumulated in the plaque and the dead cells provide large amount of lipid to promote the instability of the plaque [8]. Inflammation occurred in vulnerable plaque is likely induced by infiltration of macrophage and T-lymphocytes. Macrophages produce matrix metalloproteinases to degrade the collagen which loosens the stable structure of fibrous cap. Tlymphocytes produce CD 40 to stimulate the secretion of matrix metalloproteinases and they may also produce IFN-γ to disrupt the collagen synthesis [4]. In addition, NLRP3 inflammasome and IL-1β which activates systematic inflammation was induced by crystallization of cholesterol [4]. Carr et al. found that intraplaque hemorrhage appeared more frequently in the patients suffered from stenosis than the asymptomatic patients. Intraplaque hemorrhage is considered to provide free cholesterol to in the lipid-rich necrotic cells and increasing concentration of free cholesterol will induce the formation of cholesterol crystals which will expand the fibrous cap and lead to the rupture of plaque [4]. Since the dead cells of macrophages may not provide enough lipids to form the plaques, intraplaque hemorrhage may make great contributions to the formation of vulnerable plaque. In addition, shear stress may induce the dysfunction of endothelial cells and cause the imbalance between low density lipoprotein, which is for lipid input and high density lipoprotein, which is for lipid output. If the lipid input is bigger than lipid output, then, more lipid will accumulate in the cells and help to form lipid rich core. Furthermore, when the plaque size is very large and the fibrous cap is very thin, under certain high shear stress, the plaque will break.