EFFICIENT ADENOVIRAL GENE-TRANSFER TO EARLY VENOUS BYPASS GRAFTS - COMPARISON WITH NATIVE VESSELS

Objectives: Gene therapy may provide new approaches to reduce vein gra ft failure following coronary or peripheral bypass surgery. The aim of this study was to investigate the relative efficacy of intraoperative adenoviral gene transfer to vein grafts, comparing transgene expressi on in vein grafts with that in matched native vessels in the same anim al. In addition, we assessed the impact of bypass grafting on the cell ular targets of gene transfer. Methods: New Zealand White rabbits unde rwent interposition bypass grafting of the carotid artery, using the i psilateral external jugular vein, which was infected with an adenoviru s expressing beta-galactosidase immediately prior to bypass grafting ( n = 16). The contralateral native jugular vein (n = 16) and carotid ar tery (n = 8) were infected concurrently with the same adenoviral prepa ration. After 3, 7 or 14 days, beta-galactosidase protein expression w as quantified by ELISA, and specific cell types expressing beta-galact osidase were identified by X-Gal staining and by immunohistochemistry. Results: After 3 days, endothelial cells were efficiently transduced in all vessels; medial smooth muscle cells were transduced infrequentl y. In contrast to jugular veins after gene transfer, endothelium in ve in grafts showed expression of VCAM-1 and ICAM-1, and intense inflamma tion with CD18(+) leukocytes. Transgene expression in vein grafts at d ay 3 was maintained at levels approximately 50% of that in ungrafted j ugular veins, but continued to decrease through day 7. Conclusions: Al though vascular injury in early Venous bypass grafts reduces gene tran sfer efficacy, significant transgene expression is maintained for at l east 7 days. These findings have important implications for intraopera tive gene transfer strategies in vein grafts. (C) 1997 Elsevier Scienc e B.V.