Clinton T. Lloyd, Andrew H. Baker, Sarah J. George, Gianni D. Angelini

Bristol Heart Institute, Bristol Royal Infirmary,Bristol,BS2 8HW

Background: Vein graft failure following coronary bypass surgery remains a disincentive for its use. Complex mechanisms underlying the wall thickening limit the efficacy of pharmacological interventions to prevent this. Gene transfer provides an ideal investigative tool as well as a possible therapeutic approach for limiting neointimal formation. Methods: As an initial step in assessing the feasibility of gene transfer into human and porcine saphenous vein, we made use of the highly efficient adenoviral transduction system. First generation replicative-defective recombinant adenoviruses (RAd35) expressing the bacterial lacZ gene under control of the high output cytomegalovirus major immediate early promoter were used to infect human saphenous vein prior to organ culture and ex vivo into porcine saphenous vein prior to reimplantation in the carotid interposition graft model. Transduction efficiency was assessed by fixation and staining for b -galactosidase and counting positive cells en face and in serial sections.

Results: No b -galactosidase positivity was detected in control non-tranduced veins. High level transgene expression occurred throughout the 14 days of culture in both endothelial cell and smooth muscle cell of human saphenous vein. Additionally adenoviral mediated delivery to porcine saphenous vein was highly efficient after 7 days of in vivo implantation. Adenoviral infection and subsequent gene expression was limited to the luminal surface. Adventitial cells were not infected.

Conclusion: Localised adenoviral vector mediated gene transfection to vascular endothelial cells and smooth muscle cells in the vein graft is highly efficacious in both the animal and human model. Further studies will identify potential therapeutic gene targets to limit neointimal formation in bypass grafting