Abstract
BackgroundAbout 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.ResultsWe 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.ConclusionsWe 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.
Highlights
About 6 million Americans suffer from heart failure and 70% of heart failure cases are caused by myocardial infarction (MI)
We established a set of nonlinear differential equations to characterize the regulatory relationship for macrophage activation in the left ventricle post-myocardial infarction using physical chemistry laws
1) All monocytes that migrate to the infarct region are differentiated to unactivated macrophages [10]
Summary
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. Myocardial infarction is defined by pathology as myocytes necrosis and apoptosis due to prolonged ischemia. Myocytes apoptosis appears in the first 6 to 8 hours post-MI, and necrosis occurs in 12 hrs to 4 days post-MI [1]. Necrosis responsible for extracellular matrix (ECM) destruction and construction, respectively, the transition and dynamic balance between two macrophage phenotypes might lead to the balance between ECM destruction and construction, and determine the ECM remodeling post-MI.[4] characterizing macrophage activation pattern is essential to better understand the ECM remodeling post-MI
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