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.
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| 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 |
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