Combined experimental and mathematical modeling of macrophage driven left ventricle remodeling post MI

Biological complexity and limited quantitative measurements impose major challenges to standard engineering methodologies for modeling of biological pathways. A new approach is presented to describe the dynamics of the left ventricle (LV) remodeling process post myocardial infarction (MI) in terms of the experimental measurements. MI is a leading cause of congestive heart failure, and currently there is a lack of biomarkers to predict how the left ventricle (LV) will respond to injury. The objective of this study is to measure extracellular matrix (ECM) gene levels in the LV post-MI to identify candidate factors that are predictive of remodeling post MI. Left ventricle from unoperated control mice (n=6) and the remote and infarct regions from 7 day post-MI mice (n=7) were studied. Of the 84 genes evaluated, 51 were differentially expressed in the post-MI LV. Significantly up regulated genes included alpha1 collagen I and Spp1 (osteopontin; all pLt0.05). In the plasma, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and Spp1 (osteopontin) levels increased post-MI (all p<0.05). Data analysis illustrated those changes in expression of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), osteopontin (Spp1), and collagen correlated with each other. Mathematical simulation further illustrated the interaction among these factors and transforming growth factor beta (TGF-beta). In conclusion, the 5 proteins identified may be useful macrophage-dependent biomarkers for predicting changes in LV remodeling post-MI. The novelty of this study lies in the combination of experimental results with mathematical model.