Combining Experimental and Mathematical Modeling to Reveal Mechanisms of Macrophage‐Dependent Left Ventricular Remodeling

Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches. We developed the first mathematical model to study LV remodeling post‐MI by quantifying the dynamic balance between extracellular matrix (ECM) construction and destruction. Our experimental results of post‐MI ECM gene expression and plasma analyte levels in C57/BL6J mice and cardiac fibroblast ECM gene responses to transforming growth factor‐β 1 (TGF‐β 1 ) showed that key factors in LV remodeling included macrophages, fibroblasts, TGF‐β 1 , matrix metalloproteinase‐9, and collagen content. The mathematical model incorporated these key factors and demonstrated that TGF‐β 1 stimuli and MMP‐9 interventions with different strengths and interfering time lead to different LV remodeling responses. The predictions fell within the range of experimental measurements for these interventions, providing validation for the model. In conclusion, our results demonstrate that the balance between ECM synthesis and degradation controlled by interactions of specific key factors determine net LV remodeling outcomes. Our mathematical model based on the balance between ECM construction and destruction predicts remodeling outcomes and provides a useful tool to study post‐MI LV regulatory mechanisms. The authors acknowledge grant support from NSF 0644646, 0602834 (to HH), NIH R01 HL75360 and AHA GIA 0855119F (to MLL), NSF 0649172 and NIH 1SC2 HL101430 (to YJ).