Following myocardial infarction, the mechanical properties of the healing infarct are a critical determinant of ventricular performance, infarct expansion, aneurysm formation and rupture, and ventricular remodeling. Specifically, recent studies have shown that myocardial scar tissue is anisotropic (stiffer in one direction than in others) and suggested that this anisotropy helps to preserve ventricular function. The primary goal of this proposal is to establish the physical mechanisms by which collagen fiber structure, crosslinking, edema, and fibroblast tension determine mechanical anisotropy and to identify their relative importance over the course of postinfarction healing. The proposed studies will progress from an innovative collagen gel model system that reproduces physiologic levels of scar anisotropy to in vitro tissue testing to in vivo functional studies. Work under Specific Aim 1 will utilize state-of-the art biaxial testing to determine the mechanisms by which crosslinking, edema, and fibroblast force generation modify mechanical anisotropy in fibroblast-populated collagen gels, testing the hypotheses: A) Pyridinoline crosslinking modifies anisotropy by limiting shearing between collagen fibers; B) Interstitial edema reduces anisotropy by applying an isotropic prestress to the collagen matrix; and C) Fibroblasts reduce anisotropy by generating an isotropic active stress on the collagen matrix. Next, myocardial scar tissue will be tested in vitro in Specific Aim 2 to determine the relative importance of crosslinking, edema, and fibroblast force generation as determinants of anisotropy during postinfarction healing in the rat, testing the hypotheses: A) Edema and fibroblast force are the primary determinants of anisotropy in the first days; B) Collagen fiber structure is the primary determinant of anisotropy at 1-2 weeks; and C) Pyridinoline crosslinking is a critical determinant of anisotropy at later time points. Finally, Specific Aim 3 will test the hypothesis that acutely reducing anisotropy impairs ventricular function at intermediate and late stages of postinfarction healing in the rat. The resulting fundamental quantitative understanding of structure-function relationships in myocardial scar tissue will be critical to future attempts to understand and predict the effects of medical, surgical, and regenerative therapies as well as to attempts to modify or replace myocardial scar tissue using tissue engineering methods.
| Haggart, Charles R; Ames, Elizabeth G; Lee, Jae K et al. (2014) Effects of stretch and shortening on gene expression in intact myocardium. Physiol Genomics 46:57-65 |
| Rouillard, Andrew D; Holmes, Jeffrey W (2014) Mechanical boundary conditions bias fibroblast invasion in a collagen-fibrin wound model. Biophys J 106:932-43 |
| Ames, E G; Lawson, M J; Mackey, A J et al. (2013) Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy. J Mol Cell Cardiol 62:99-107 |
| Chandran, Preethi L; Paik, David C; Holmes, Jeffrey W (2012) Structural mechanism for alteration of collagen gel mechanics by glutaraldehyde crosslinking. Connect Tissue Res 53:285-97 |
| Ateshian, Gerard A; Morrison 3rd, Barclay; Holmes, Jeffrey W et al. (2012) Mechanics of Cell Growth. Mech Res Commun 42:118-125 |
| Fomovsky, Gregory M; Rouillard, Andrew D; Holmes, Jeffrey W (2012) Regional mechanics determine collagen fiber structure in healing myocardial infarcts. J Mol Cell Cardiol 52:1083-90 |
| Rouillard, Andrew D; Holmes, Jeffrey W (2012) Mechanical regulation of fibroblast migration and collagen remodelling in healing myocardial infarcts. J Physiol 590:4585-602 |
| Fomovsky, Gregory M; Clark, Samantha A; Parker, Katherine M et al. (2012) Anisotropic reinforcement of acute anteroapical infarcts improves pump function. Circ Heart Fail 5:515-22 |
| Fomovsky, Gregory M; Macadangdang, Jesse R; Ailawadi, Gorav et al. (2011) Model-based design of mechanical therapies for myocardial infarction. J Cardiovasc Transl Res 4:82-91 |
| Fomovsky, Gregory M; Holmes, Jeffrey W (2010) Evolution of scar structure, mechanics, and ventricular function after myocardial infarction in the rat. Am J Physiol Heart Circ Physiol 298:H221-8 |
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