A two-phase model of early fibrous cap formation in atherosclerosis

Abstract

Atherosclerotic plaque growth is characterised by chronic, non-resolving inflammation that promotes the accumulation of cellular debris and extracellular fat in the inner artery wall. This material is highly thrombogenic, and plaque rupture can lead to the formation of blood clots that occlude major arteries and cause myocardial infarction or stroke. In advanced plaques, vascular smooth muscle cells (SMCs) are recruited from deeper in the artery wall to synthesise a cap of fibrous tissue that stabilises the plaque and sequesters the thrombogenic plaque content from the bloodstream. The fibrous cap provides crucial protection against the clinical consequences of atherosclerosis, but the mechanisms of cap formation are poorly understood. In particular, it is unclear why certain plaques become stable and robust while others become fragile and dangerously vulnerable to rupture. We develop a multiphase model with non-standard boundary conditions to investigate early fibrous cap formation in the atherosclerotic plaque. The model is parameterised using data from a range of in vitro and in vivo studies, and includes highly nonlinear mechanisms of SMC proliferation and migration in response to an endothelium-derived chemical signal. We demonstrate that the model SMC population naturally evolves towards a steady-state, and predict a rate of cap formation and a final plaque SMC content consistent with experimental observations in mice. Parameter sensitivity simulations show that SMC proliferation makes a limited contribution to cap formation, and demonstrate that stable cap formation relies primarily on a critical balance between the rates of SMC recruitment to the plaque, chemotactic SMC migration within the plaque and SMC loss by apoptosis or phenotype change. This model represents the first detailed in silico study of fibrous cap formation in atherosclerosis, and establishes a multiphase modelling framework that can be readily extended to investigate many other aspects of plaque development.

Anti-Atherosclerosis Effect of Angong Niuhuang Pill via Regulating Th17/Treg Immune Balance and Inhibiting Chronic Inflammatory on ApoE-/- Mice Model of Early and Mid-Term Atherosclerosis

“…Atherosclerotic plaque, the morphological substrate of AS, is induced by multiple factors, including accumulation of VSMCs, macrophages and T lymphocytes (Andrés et al, 2012;Moore et al, 2013); the proliferation of VSMCs and connective tissue matrix such as collagen fibers and elastic fibers; deposition of cholesterol crystals and free cholesterol. All these factors contribute to formation of fragile arterial plaques (Watson et al, 2018). Maintaining stability of plaques and arresting expansion of vulnerable plaques are in the focus of current treatment for AS which has already formed.…”

A prediction tool for plaque progression based on patient-specific multi-physical modeling

“…Besides the developments of novel imaging techniques, mathematical modeling and numerical simulation have been proven useful for quantitatively assessing the dynamic changes of cellular and acellular components involved in the plaque microenvironment and predicting plaque growth and possible rupture [14,15]. In our previous studies, we have developed a multi-physical mathematical model by coupling lipid deposition, inflammation, neovascularization and intraplaque hemorrhage, to investigate the pathophysiological responses of plaques to dynamic changes in the microenvironment [16,17].…”

Image-Based Modeling for Atherosclerotic Coronary Plaque Progression and Vulnerability Research

“…Watson, M.G. et al (2018) are concerned about the formation of early fibrous caps in recent years [13]. The presentation of local maximum stress on plaque further confirmed the importance of thin fibrous cap [12].…”

“…Because of the obvious importance of the thin fibrous cap in plaque rupture process, it has been a focus of attention by many investigations. Watson, M.G. et al (2018) are concerned about the formation of early fibrous caps in recent years [13].…”