Following myocardial infarction, the mechanical properties of the healing scar are a critical determinant of left ventricular function, infarct expansion, aneurysm formation and rupture, and ventricular remodeling. Until recently, the only therapeutic options for addressing these consequences were pharmacologic. However, in the past few years, the introduction of a range of options for modifying the cardiac mechanical environment has fundamentally altered our options for clinical postinfarction therapy. The dynamic in vivo cardiac mechanical environment is now just as valid a potential therapeutic target as hormone receptors or signaling cascades. In principle, if mechanical signals that govern scar healing, infarct expansion, aneurysm formation, or ventricular remodeling can be identified, they can be modified. Therefore, one major goal of our work on mechanics of healing infarcts is to provide a better understanding of the evolution of scar structure and mechanics as a platform for designing and appropriately applying therapies to improve ventricular function and to prevent infarct expansion, aneurysm formation, and adverse left ventricular remodeling. Considerable evidence also suggests that the interaction between healing infarcts and the surrounding myocardium works in the other direction: mechanical stimuli applied to the infarct by the myocardium can direct the development of infarct structure and mechanical properties. In particular, our work under the initial funding period of this project (12/01/03 - 11/30/07) revealed a striking correlation between scar structural and mechanical anisotropy in different animal models and the deformation patterns experienced by healing infarcts in those models. We hypothesize that mechanical environment governs the development of anisotropy in healing infarcts and represents a potentially important therapeutic target for directing infarct healing to optimize ventricular function and help prevent long-term adverse remodeling. The work proposed here will test this hypothesis using a combination of unique in vitro model systems and a new innovative approach to manipulating the mechanical environment of healing myocardial infarcts in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075639-06
Application #
7851309
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2003-12-09
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$456,483
Indirect Cost
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Rouillard, Andrew D; Holmes, Jeffrey W (2014) Mechanical boundary conditions bias fibroblast invasion in a collagen-fibrin wound model. Biophys J 106:932-43
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
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
Ateshian, Gerard A; Morrison 3rd, Barclay; Holmes, Jeffrey W et al. (2012) Mechanics of Cell Growth. Mech Res Commun 42:118-125
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
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; 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; 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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