HDL and plaque regression in a multiphase model of early atherosclerosis.

Atherosclerosis is a chronic disease of the arteries characterised by the accumulation of lipids and lipid-engorged cells in the artery wall. Early plaque growth is aggravated by the deposition of low density lipoproteins (LDL) in the wall and the subsequent immune response. High density lipoproteins (HDL) counterbalance the effects of LDL by accepting cholesterol from macrophages and removing it from the plaque. In this paper, we develop a free boundary multiphase model to investigate the effects of LDL and HDL on early plaque development. We examine how the rates of LDL and HDL deposition affect cholesterol accumulation in macrophages, and how this impacts cell death rates and emigration. We identify a region of LDL-HDL parameter space where plaque growth stabilises for low LDL and high HDL influxes, due to macrophage emigration and HDL clearance that counterbalances the influx of new cells and cholesterol. We explore how the efferocytic uptake of dead cells and the recruitment of new macrophages affect plaque development for a range of LDL and HDL influxes. Finally, we consider how changes in the LDL-HDL profile can change the course of plaque development. We show that changes towards lower LDL and higher HDL can slow plaque growth and even induce regression. We find that these changes have less effect on larger, more established plaques, and that temporary changes will only slow plaque growth in the short term.

Macrophage Anti-inflammatory Behaviour in a Multiphase Model of Atherosclerotic Plaque Development.

Atherosclerosis is an inflammatory disease characterised by the formation of plaques, which are deposits of lipids and cholesterol-laden macrophages that form in the artery wall. The inflammation is often non-resolving, due in large part to changes in normal macrophage anti-inflammatory behaviour that are induced by the toxic plaque microenvironment. These changes include higher death rates, defective efferocytic uptake of dead cells, and reduced rates of emigration. We develop a free boundary multiphase model for early atherosclerotic plaques, and we use it to investigate the effects of impaired macrophage anti-inflammatory behaviour on plaque structure and growth. We find that high rates of cell death relative to efferocytic uptake results in a plaque populated mostly by dead cells. We also find that emigration can potentially slow or halt plaque growth by allowing material to exit the plaque, but this is contingent on the availability of live macrophage foam cells in the deep plaque. Finally, we introduce an additional bead species to model macrophage tagging via microspheres, and we use the extended model to explore how high rates of cell death and low rates of efferocytosis and emigration prevent the clearance of macrophages from the plaque.