Mathematical modeling and stability analysis of macrophage activation in left ventricular remodeling post-myocardial infarction

Background: About 6 million Americans suffer from heart failure and 70% of heart failure cases are caused by myocardial infarction (MI). Following myocardial infarction, increased cytokines induce two major types of macrophages: classically activated macrophages which contribute to extracellular matrix destruction and alternatively activated macrophages which contribute to extracellular matrix construction. Though experimental results have shown the transitions between these two types of macrophages, little is known about the dynamic progression of macrophages activation. Therefore, the objective of this study is to analyze macrophage activation patterns post-MI. Results: We have collected experimental data from adult C57 mice and built a framework to represent the regulatory relationships among cytokines and macrophages. A set of differential equations were established to characterize the regulatory relationships for macrophage activation in the left ventricle post-MI based on the physical chemistry laws. We further validated the mathematical model by comparing our computational results with experimental results reported in the literature. By applying Lyaponuv stability analysis, the established mathematical model demonstrated global stability in homeostasis situation and bounded response to myocardial infarction. Conclusions: We have established and validated a mathematical model for macrophage activation post-MI. The stability analysis provided a possible strategy to intervene the balance of classically and alternatively activated macrophages in this study. The results will lay a strong foundation to understand the mechanisms of left ventricular remodelling post-MI.