A potential role for skeletal myoblast transplantation (cellular cardiomyoplasty) in augmenting myocardial performance in disease states is established. Yet, a number of factors continue to limit myoblast engraftment and thus performance. For example, reduced substrate delivery and toxin removal may limit myoblast therapy. Data also support the role of therapeutic angiogenesis (increased vascular density) in augmenting some aspects of myocardial performance. However, increasing vascular density in the absence of viable target tissue is likely to yield less than optimal benefit. Combining CCM and therapeutic angiogenesis may allow optimal benefit from both regimens, beyond a simple additive effect. The investigators hypothesize that relative ischemia, in the setting of myocardial infarction, limits transplanted skeletal myoblast growth and endgraftment within damaged heart. Therefore, increasing vascular density and blood flow in injured myocardium may augment myoblast engraftment and thereby improve myocardial performance. Timing of this increase in blood flow relative to myoblast injection is likely to be critical. Although increased vascular density and blood flow alone may increase myocardial compliance, a greater impact (especially on systolic performance or myocardial contractility) is likely to derive from combined treatment with myoblast transplantation.
The aims designed to test this hypothesis are to: 1) Increase vascular density within damaged myocardium 7 - 10 days prior to skeletal myoblast transplantation and determine the effect on vascularity (in vivo blood flow, regional capillary density, VEGF, FGF protein expression), and scar histology (scar size, cardiocyte or myoblast apoptosis, myoblast proliferation and percent myoblast engraftment). 2) increase vascular density within damaged myocardium shortly after myoblast delivery (by injecting myoblasts that over-express secretable VEGF or bFGF) and ascertaining the effect on vascularity (blood flow, regional capillary density, VEGF or FGF protein expression); and scar histology (scar size, cardiocyte or myoblast apoptosis, myoblast proliferation and percent myoblast engraftment). 3) Increase vascular density within damaged myocardium (by delivery of angiogenic molecules in the presence or absence of skeletal myoblast transplantation) and compare the effect on myocardial performance. Accomplishing these specific aims should enable them to develop and evaluate novel methods for treating end stage heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063703-01A1
Application #
6196665
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
2000-09-20
Project End
2004-07-31
Budget Start
2000-09-20
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$325,623
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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McCue, Jonathan D; Swingen, Cory; Feldberg, Tanya et al. (2008) The real estate of myoblast cardiac transplantation: negative remodeling is associated with location. J Heart Lung Transplant 27:116-23
Davis, Bryce H; Schroeder, Thies; Yarmolenko, Pavel S et al. (2007) An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy. Ann Biomed Eng 35:1414-24
Ott, Harald C; Brechtken, Johannes; Swingen, Cory et al. (2006) Robotic minimally invasive cell transplantation for heart failure. J Thorac Cardiovasc Surg 132:170-3
Ott, H C; McCue, J; Taylor, D A (2005) Cell-based cardiovascular repair--the hurdles and the opportunities. Basic Res Cardiol 100:504-17
van den Bos, Ewout J; Thompson, Richard B; Wagner, Anja et al. (2005) Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging. Eur J Heart Fail 7:435-43
van den Bos, Ewout J; Davis, Bryce H; Taylor, Doris A (2004) Transplantation of skeletal myoblasts for cardiac repair. J Heart Lung Transplant 23:1217-27
Thompson, Richard B; Parsa, Cyrus J; van den Bos, Ewout J et al. (2004) Video-assisted thoracoscopic transplantation of myoblasts into the heart. Ann Thorac Surg 78:303-7
Baklanov, Dmitri V; Peters, Kevin G; Seidel, Amy L et al. (2003) Neovascularization in intimal hyperplasia is associated with vein graft failure after coronary artery bypass surgery. Vasc Med 8:163-7
Rauscher, Frederick M; Goldschmidt-Clermont, Pascal J; Davis, Bryce H et al. (2003) Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 108:457-63

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