Abstract 3699: Skeletal Myoblasts Engineered to Overexpress Placental Growth Factor Improve Cardiac Function Following Transfer to the Failing Heart in Rats
Transplantation of skeletal myoblasts (MB) is an attractive alternative in treatment of ischemic heart failure, but the first prospective trial in humans was frustrating. Evidence exists that the majority of engrafted MB do not survive long term in ischemic myocardium. Therefore, we investigated whether transplantation of MB overexpressing placental growth factor (PlGF) enhances MB survival in a rat heart failure model. Three weeks following myocardial infarction, rats developed heart failure and received intramyocardial injections of Ringer’s solution (control, n=15), fluorescent autologous unmodified MB (MB, n=15) or MB transfected with a PlGF (MB-PlGF, n=15) expression plasmid. Cardiac function was assessed by echocardiography over time up to 86 days. Immunocytochemistry, fluorescence microscopy, and in vivo imaging were used to analyze vessel formation, MB survival, infarct wall thickness and infarct size. Western blotting was performed to measure myocardial protein expression of matrix metalloprotease (MMP)-2, MMP-9 and tissue inhibitors of MMP (TIMP)-1, -2, -3 and -4. Left ventricular function significantly improved over time and fractional shortening on day 86 was significantly enhanced in the MB-PlGF group compared to the control (p<0.01) and MB (p<0.05) groups. Vascular density (p<0.01) and MB (p<0.05) survival were enhanced in rats treated with MB-PlGF compared to the control or MB groups. The mean fraction of fibrotic scar tissue decreased in the MB and MB-PlGF group compared to controls on day 86 (p<0.05) and left ventricular wall thickness significantly increased in the MB-PlGF group compared to the control or MB groups (p<0.05). MMP-2 and 9 were significantly up-regulated in the MB-PlGF group compared to all other groups (p<0.05). In addition, a significant increase in TIMP-1 and -2 expression was seen in the MB-PlGF group compared to the control and MB groups (p<0.05). These data demonstrate that intramyocardial injection of autologous MB overexpressing PlGF improves cardiac function, attenuates adverse cardiac remodeling, induces angiogenesis and enhances the survival of grafted myoblasts. Future clinical trials are necessary to prove the benefit of PlGF overexpressing MB in treatment of ischemic heart failure.