Advection-dominated models of atherosclerotic plaque composition: The impacts of cell death and cholesterol toxicity.

Advanced atherosclerotic plaques are characterised by a large necrotic core containing highly inflammatory lipids and debris from dead cells. In large plaques, newly recruited macrophages fail to penetrate this core, and instead push existing material deeper inside the plaque. In this paper, we consider two multiphase models for early atherosclerotic plaque growth, and we analyse their behaviour in the limiting regime where bulk advection drives mass transport of cells and lipids. In this regime, the dynamics of the deep plaque can be approximated by a system of advection-reaction equations. By applying the method of characteristics to these equations, we derive a set of ODEs that describes the evolution of individual segments of plaque tissue. We apply this approximation to a simple 1D three-phase model comprising macrophage foam cells, dead cells, and modified LDL, and we investigate how plaque tissue composition depends on the relative rates of cell death and efferocytosis (cell recycling). We also consider a six-phase model in which death rates depend on intracellular cholesterol content. We use this model to study the effects of cholesterol-induced toxicity, and the beneficial effects of high density lipoproteins (HDL), which can remove excess cholesterol from macrophages. We show that for both multiphase models, the advection-reaction approximations capture key structural features of the full model solutions, including the relative proportions of live and dead cells, and persistent spatial heterogeneities that arise from time-varying boundary influxes of LDL and HDL.