Congestive heart failure (CHF) causes the death of 250,000 Americans each year. The majority of cases result from myocardial infarction (MI) induced left ventricular (LV) remodeling. Remodeling is manifest by LV dilatation and global loss of contractile function;significant mitral regurgitation (ischemic mitral regurgitation- IMR) develops in at least 35% of these patients and may exacerbate the phenomenon. The goal of this project is use well characterized and clinically relevant ovine infarction models to elucidate the mechanism of post MI remodeling to an extent that has not been previously possible. We will focus on two common mechanical sequelae of MI: infarct expansion and IMR.
In Specific Aim 1, we test the hypothesis that infarct expansion (stretching) drives LV remodeling by increasing stress in the borderzone (BZ) myocardium. Increased BZ stress produces a self-perpetuating phenomenon by decreasing contractile strain in the region and causing inherent changes in myocyte and extracellular matrix biology that allows for propagation of the abnormal stress fields to progressively more remote myocardial regions. We have developed innovative and powerful technical capabilities to quantitatively assess all components of this pathologic cascade. Optical flow mapping of tagged MRI images will be used to measure truly 3D myocardial strains. Myocardial stress distribution will be calculated using state-of-the-art finite element analysis based on the MRI strain data. Infarct material properties will be measured using biaxial mechanical testing.
In Specific Aim 1 three therapeutic approaches to limit infarct expansion early after MI will be studied: heart wrapping with the Acorn CSD(R), infarct reperfusion and calcium hydroxyapatite microsphere gel injection.
In Specific Aim 2 using the same tools we focus on treating the chronically remodeled heart and test the hypothesis that even small (<4.5%) fractional changes in LV wall volume (caused by calcium hydroxyapatite microsphere gel injection) can significantly improve cardiac mechanics when optimally located.
In Specific Aim 3 we focus on the chronically remodeled heart with IMR and test the hypothesis that surgical repair techniques that are designed to increase mitral leaflet curvature (and theoretically reduce leaflet/chordal stress) will be superior to flat ring annuloplasty in improving regional and global LV function in severely remodeled hearts with established IMR. Saddle-shaped annuloplasty and leaflet augmentation will be used to manipulate leaflet curvature. A novel 3D echocardiography based approach to measuring leaflet geometry will be used.

Public Health Relevance

This project seeks to determine the mechanism of post infarction left ventricular remodeling. The contribution of infarct expansion and ischemic mitral regurgitation will be studied. Powerful new imaging and analytic tools will be used to elucidate how time- dependent changes in infarct material properties and mitral-ventricular interactions influence regional myocardial stress distribution, regional contractile function and regional myocyte and extracellular matrix biology. The affect of novel early and late therapies on the remodeling process will also be assessed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063954-13
Application #
8447531
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Schwartz, Lisa
Project Start
1999-12-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$565,534
Indirect Cost
$206,465
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mojsejenko, Dimitri; McGarvey, Jeremy R; Dorsey, Shauna M et al. (2015) Estimating passive mechanical properties in a myocardial infarction using MRI and finite element simulations. Biomech Model Mechanobiol 14:633-47
McGarvey, Jeremy R; Kondo, Norihiro; Witschey, Walter R T et al. (2015) Injectable microsphere gel progressively improves global ventricular function, regional contractile strain, and mitral regurgitation after myocardial infarction. Ann Thorac Surg 99:597-603
McGarvey, Jeremy R; Pettaway, Sara; Shuman, James A et al. (2014) Targeted injection of a biocomposite material alters macrophage and fibroblast phenotype and function following myocardial infarction: relation to left ventricular remodeling. J Pharmacol Exp Ther 350:701-9
Lee, Chung-Hao; Amini, Rouzbeh; Gorman, Robert C et al. (2014) An inverse modeling approach for stress estimation in mitral valve anterior leaflet valvuloplasty for in-vivo valvular biomaterial assessment. J Biomech 47:2055-63
Zgheib, Carlos; Allukian, Myron W; Xu, Junwang et al. (2014) Mammalian fetal cardiac regeneration after myocardial infarction is associated with differential gene expression compared with the adult. Ann Thorac Surg 97:1643-50
Han, Yuchi; Liimatainen, Timo; Gorman, Robert C et al. (2014) Assessing Myocardial Disease Using T1? MRI. Curr Cardiovasc Imaging Rep 7:9248
Witschey, Walter R T; Contijoch, Francisco; McGarvey, Jeremy R et al. (2014) Real-time magnetic resonance imaging technique for determining left ventricle pressure-volume loops. Ann Thorac Surg 97:1597-603
McGarvey, Jeremy R; Shimaoka, Toru; Takebayashi, Satoshi et al. (2014) Minimally invasive delivery of a novel direct epicardial assist device in a porcine heart failure model. Innovations (Phila) 9:16-21
Jassar, Arminder S; Vergnat, Mathieu; Jackson, Benjamin M et al. (2014) Regional annular geometry in patients with mitral regurgitation: implications for annuloplasty ring selection. Ann Thorac Surg 97:64-70
Witschey, Walter R T; Pouch, Alison M; McGarvey, Jeremy R et al. (2014) Three-dimensional ultrasound-derived physical mitral valve modeling. Ann Thorac Surg 98:691-4

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