Atherosclerotic Plaque Adhesion Strength and Its Role in Plaque Rupture

摘要

Cardiovascular diseases are disorders affecting the blood vessels and the heart. According to the World Health Organization, cardiovascular diseases are one of the leading causes of death worldwide. They are responsible for over 17.1 million deaths per year worldwide, representing 31.5% of deaths. Atherosclerosis, a chronic inflammatory disorder affecting large arteries, is the underlying cause of many cardiovascular diseases. Plaque rupture is a serious complication of advanced atherosclerosis, often leading to life-threatening clinical consequences such as myocardial infarction (heart attack) or stroke. 75% of newly developed myocardial infarction cases are caused by atherosclerotic plaque rupture. It affects approximately 1.1 million people in the USA per year, with a 40% fatality rate; 220,000 of these deaths occur without hospitalization. Over the past few decades, the mechanisms of atherosclerotic plaque progression and formation have been widely studied. However, due to the complexity of the process, plaque rupture mechanisms are still poorly understood.;In this thesis, a novel hypothesis regarding mechanisms of plaque rupture is proposed. Specifically, we hypothesize that the adhesive strength of the bond between the plaque and the vascular wall is an important determinant of atherosclerotic plaque stability (resistance to rupture). We also expect adhesive strength to be a function of plaque composition and extracellular matrix (ECM) organization at the plaque-media interface. This proposed mode of rupture is called delamination or plaque peeling.;Mouse plaque peeling experiments were very challenging and they needed time to be performed and validated. Thus, due to similarity of the experimental protocol, we used experimental data obtained on the dissection of human coronary artery specimens by Ying Wang, and we created a numerical model to apply the cohesive model technique to this problem. Arterial dissection is a rare but potentially fatal condition in which blood passes through the inner lining and between the layers of the arterial wall. It results in separation of the different layers, creating a false lumen in the process. The advantages to performing a primary study on arterial dissection were first to apply the cohesive zone models to a less complex problem than atherosclerosis.;The innovative technical approach to measure the adhesive strength developed previously, will be applied in this thesis to mice. It includes a micro-scale peel experiment protocol to measure adhesive strength of mouse atherosclerotic plaques during delamination from the underlying vessel wall. Our team at USC, as far as we know, was the first to perform these types of measurements on mice. The use of mice in our experiments presents the advantage that the extracellular matrix composition could be systematically changed using transgenic strains, altered diet, or drug treatments. Different mouse strains or models could then be used and the mechanical properties will be studied on each type.;Another innovation of our work will involve application of a cohesive zone model to describe delamination behavior of atherosclerotic plaques under a range of physiological and pathophysiological conditions, using a 2D numerical model. While the cohesive zone approach has been widely used to model fracture mechanics in classic engineering materials, it was rarely applied to describe failure of atherosclerotic plaques. The study of plaque delamination by Leng et al. 2015 was designated to test the use of cohesive zone by implementing a specific traction separation law, assuming the parameter values of the behavior laws of the plaque and the cohesive zone using values by literature. Innovation in our approach is to use a simple traction separation law to study the behavior of plaques and identifying their properties. Experimental results of delamination of the plaques were used in the definition of traction-separation laws of the cohesive zone.