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F7. Enhanced Angiogenesis and LV Function with Multimodal Cell-Based Gene Therapy
Terrence M Yau, Guangming Li, Yaoguang Zhang, Richard D Weisel, Ren-ke Li; Toronto, ON, Canada

Objective: Transplantation of VEGF-expressing cells into infarcted hearts increases the angiogenic response to cell transplantation but does not normalize function. Expression of a single proangiogenic gene in transplanted cells may be an inadequate stimulus either for the complex process of angiogenesis or for optimal return of function. We evaluated the synergism of transient VEGF and bFGF overexpression on angiogenesis and LV function after bone marrow cell (BMC) transplantation, to determine the potential of multimodal cell-based gene therapy for myocardial repair.
Methods: Female Lewis rats underwent LAD ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+V), bFGF (BMC+B), VEGF and bFGF (BMC+VB), or medium without cells (Ctrl, N=3 each group at each of 4 timepoints, N=60 total). Three days, 1, 2 and 4 weeks after transplantation, VEGF and bFGF expression were quantitated by realtime PCR, angiogenesis by fluorescent microspheres and quantitative histology (in the scar, border zone and normal myocardium), and LV function by echocardiography.
Results: Transgene expression: VEGF and bFGF were expressed transiently over the 4 week period after transplantation. One week after transplantation, VEGF expression in the scar and border zone was greatest in BMC+V and BMC+VB hearts (p<0.05), while bFGF expression in the scar was greatest in BMC+B and BMC+VB rats (p<0.05).
Angiogenesis: Regional perfusion by microspheres, and vascular densities in the scar (Figure, left) were lowest in Ctrl, intermediate in BMC, BMC+V, BMC+B, and greatest in BMC+VB (both microspheres and vascular densities p<0.05).
LV Function: LVEF 4 weeks after transplantation was lowest in Ctrl, intermediate in BMC, BMC+V and BMC+B, and greatest in BMC+VB (p<0.05) (Figure, right).
Conclusions: VEGF and bFGF transgenes were expressed transiently and exerted a powerful synergism on angiogenesis and restoration of LV function after cell transplantation, but did not normalize perfusion or function. Single-agent therapies such as cell therapy, gene therapy or even cell-based VEGF therapy are inadequate to treat a complex, multifactorial disease process. The future of myocardial cell transplantation strategies may lie in multimodal cell-based gene therapy, in combination with scar pretreatment and other novel therapies.

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