Jeffrey Holmes
Computational Modeling of Myocardial Infarct Healing
Abstract
The mechanics of healing myocardial infarcts are a critical determinant of left ventricular function. We recently showed that infarcts healing in different mechanical environments develop different collagen fiber structures and mechanical properties. We developed an agent-based model to evaluate the mechanisms by which mechanical environment directs collagen deposition and remodeling by cardiac fibroblasts and to better understand the effects of therapeutic interventions on the evolving scar structure. Parameters for this model were derived from a combination of published literature and new experiments in engineered tissue-equivalents, focusing particularly on features of cell-matrix interaction such as contact guidance and collagen remodeling. Our results suggest that different environmental cues regulate scar formation in different tissues. In contrast to previous models of skin wound healing showing that chemokine gradients are a dominant regulator of scar formation, we find that mechanical environment is the dominant regulator of evolving scar structure following myocardial infarction. Our results suggest that a number of regenerative and device therapies that alter infarct mechanics, including stem cell injection, polymer injection, surgical reinforcement, and peri-infarct pacing, will also alter scar structure. Our computational model of infarct healing should enable in silico screening of novel therapies for potential adverse effects on scar formation.
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