Atherosclerotic Plaque Adhesion Strength and its role in Plaque Rupture

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 1, 2. 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 Wang3, and we created a numerical model to apply the cohesive zone 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 previously4,3, 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. 20155 was designed to test the use of cohesive zones by implementing a specific traction separation law, assuming the parameter values of the behavior laws of the plaque and the cohesive zone using values from the 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

atherosclerotic plaque adhesion strength and its role in plaque rupture

La rupture de plaque athérosclérotique est une complication grave, menant à des conséquences mortelles. En raison de la complexité du processus, les mécanismes de rupture de la plaque sont encore mal connus. Dans cette thèse, l'approche technique innovante pour mesurer la force d'adhérence développée précédemment sera appliquée à des souris. Elle comprend un protocole de délamination à petite échelle pour mesurer la résistance adhésive des plaques d'athérosclérose. Notre équipe à USC a été la première à effectuer ce type de mesures sur des souris. Une autre innovation de notre travail impliquera l'application d'un modèle de zone cohésive pour décrire le comportement de délamination des plaques athérosclérotiques dans une gamme de conditions physiologiques et physiopathologiques, en utilisant un modèle numérique 2D. Bien que l'approche de la zone cohésive ait été largement utilisée pour modéliser la mécanique des fractures, elle a rarement été appliquée pour décrire la rupture des plaques athérosclérotiques. L'étude de la délamination des plaques (Leng.2015) a été conçue pour tester l'utilisation de zones cohésives en mettant en œuvre une loi de séparation de traction spécifique, en supposant les valeurs des paramètres des lois de comportement de la plaque et de la zone cohésive en utilisant des valeurs de la littérature. L'innovation dans notre approche est d'utiliser une simple loi de séparation de la traction pour étudier le comportement des plaques et identifier leurs propriétés. Des résultats expérimentaux de délamination des plaques ont été utilisés dans la définition des lois de traction-séparation de la zone cohésive.Atherosclerosis is the underlying cause of many cardiovascular diseases. Plaque rupture is a serious complication of advanced atherosclerosis, leading to life-threatening consequences. 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, the innovative technical approach to measure the adhesive strength developed previously, will be applied 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 was the first to perform these types of measurements on mice. 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, it was rarely applied to describe failure of atherosclerotic plaques. The study of plaque delamination (Leng.2015) was designed to test the use of cohesive zones by implementing a specific traction separation law, assuming the parameter values of the behavior laws of the plaque and the cohesive zone using values from the 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

force d’adhesion des plaques atherosclerotique et son role dans le detachement des plaques

Atherosclerosis is the underlying cause of many cardiovascular diseases. Plaque rupture is a serious complication of advanced atherosclerosis, leading to life-threatening consequences. 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, the innovative technical approach to measure the adhesive strength developed previously, will be applied 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 was the first to perform these types of measurements on mice. 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, it was rarely applied to describe failure of atherosclerotic plaques. The study of plaque delamination (Leng.2015) was designed to test the use of cohesive zones by implementing a specific traction separation law, assuming the parameter values of the behavior laws of the plaque and the cohesive zone using values from the 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.La rupture de plaque athérosclérotique est une complication grave, menant à des conséquences mortelles. En raison de la complexité du processus, les mécanismes de rupture de la plaque sont encore mal connus. Dans cette thèse, l'approche technique innovante pour mesurer la force d'adhérence développée précédemment sera appliquée à des souris. Elle comprend un protocole de délamination à petite échelle pour mesurer la résistance adhésive des plaques d'athérosclérose. Notre équipe à USC a été la première à effectuer ce type de mesures sur des souris. Une autre innovation de notre travail impliquera l'application d'un modèle de zone cohésive pour décrire le comportement de délamination des plaques athérosclérotiques dans une gamme de conditions physiologiques et physiopathologiques, en utilisant un modèle numérique 2D. Bien que l'approche de la zone cohésive ait été largement utilisée pour modéliser la mécanique des fractures, elle a rarement été appliquée pour décrire la rupture des plaques athérosclérotiques. L'étude de la délamination des plaques (Leng.2015) a été conçue pour tester l'utilisation de zones cohésives en mettant en œuvre une loi de séparation de traction spécifique, en supposant les valeurs des paramètres des lois de comportement de la plaque et de la zone cohésive en utilisant des valeurs de la littérature. L'innovation dans notre approche est d'utiliser une simple loi de séparation de la traction pour étudier le comportement des plaques et identifier leurs propriétés. Des résultats expérimentaux de délamination des plaques ont été utilisés dans la définition des lois de traction-séparation de la zone cohésive

Atherosclerotic Plaque Delamination: Experiments and 2D Finite Element Model to Simulate Plaque Peeling in Two Strains of Transgenic Mice

International audienceFinite element analyses using cohesive zone models (CZM) can be used to predict the fracture of atherosclerotic plaques but this requires setting appropriate values of the model parameters. In this study, material parameters of a CZM were identified for the first time on two groups of mice (ApoE-/- and ApoE-/- Col8-/-) using the measured force-displacement curves acquired during delamination tests. To this end, a 2D finite-element model of each plaque was solved using an explicit integration scheme. Each constituent of the plaque was modeled with a neo-Hookean strain energy density function and a CZM was used for the interface. The model parameters were calibrated by minimizing the quadratic deviation between the experimental force displacement curves and the model predictions. The elastic parameter of the plaque and the CZM interfacial parameter were successfully identified for a cohort of 11 mice. The results revealed that only the elastic parameter was significantly different between the two groups, ApoE-/- Col8-/- plaques being less stiff than ApoE-/- plaques. Finally, this study demonstrated that a simple 2D finite element model with cohesive elements can reproduce fairly well the plaque peeling global response. Future work will focus on understanding the main biological determinants of regional and inter-individual variations of the material parameters used in the model