Speaker
Description
Atherosclerotic plaques are a leading cause of heart attacks and strokes. Macrophage proliferation drives plaque growth, but whether this promotes stability or triggers sudden destabilisation remains unresolved. Using bifurcation analysis of a lipid-structured atherosclerosis model \cite{chambers_lipid-structured_2024}, we uncover the nonlinear dynamics governing this transition.
Our main contribution is that the reduced dynamics remain meaningful beyond previously identified validity limits. Combining numerical bifurcation with fast–slow analysis and Fenichel's theory, we identify a saddle-node bifurcation at infinity. This creates a sharp threshold where proliferation balances emigration. Below this balance, the system stabilises in a biologically reasonable state; above it, macrophage numbers and lipid load grow unboundedly, causing runaway inflammation and plaque instability. Determinant and eigenvalue trends corroborate this bifurcation.
Parameter investigations suggest that increased proliferation or reduced emigration raises macrophage accumulation and necrotic core lipid content. Efferocytosis modulates downstream severity but does not shift the threshold. These findings reconcile conflicting views: proliferation is protective when emigration provides an adequate balance. Co-targeting reduced proliferation and enhanced emigration could maintain plaque stability and reduce cardiovascular risk, which is a prediction warranting experimental investigation.
Bibliography
@article{chambers_lipid-structured_2024,
title = {A {Lipid}-{Structured} {Model} of {Atherosclerosis} with {Macrophage} {Proliferation}},
volume = {86},
issn = {0092-8240, 1522-9602},
url = {https://link.springer.com/10.1007/s11538-024-01333-w},
doi = {10.1007/s11538-024-01333-w},
abstract = {Abstract
Atherosclerotic plaques are fatty deposits that form in the walls of major arteries and are one of the major causes of heart attacks and strokes. Macrophages are the main immune cells in plaques and macrophage dynamics influence whether plaques grow or regress. Macrophage proliferation is a key process in atherosclerosis, particularly in the development of mid-stage plaques, but very few mathematical models include proliferation. In this paper we reframe the lipid-structured model of Ford et al. (J Theor Biol 479:48–63, 2019.
https://doi.org/10.1016/j.jtbi.2019.07.003
) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable. Steady state analysis indicates that proliferation assists in reducing eventual necrotic core lipid content and spreads the lipid load of the macrophage population amongst the cells. The contribution of plaque macrophages from proliferation relative to recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (defined as having the same lipid content and cell numbers) recruitment-dominant plaque in the way lipid is distributed amongst the macrophages. The macrophage lipid distribution of an equivalent proliferation-dominant plaque is less skewed and exhibits a local maximum near the endogenous lipid content.},
language = {en},
number = {8},
urldate = {2026-03-04},
journal = {Bulletin of Mathematical Biology},
author = {Chambers, Keith L. and Watson, Michael G. and Myerscough, Mary R.},
month = aug,
year = {2024},
pages = {104},
}
