Local infusion of heparin reduces anastomotic neointimal hyperplasia in aortoiliac expanded polytetrafluoroethylene bypass grafts in baboons

Purpose: Recently, we designed and characterized a novel expanded polytetrafluoroethylene (ePTFE)-based local drug delivery approach that selectively concentrates infused pharmacologic agents specifically within those blood layers adjacent to the graft wall and at downstream anastomotic sites. In this study, we locally administrated standard heparin therapy and evaluated its effects on neointimal hyperplasia formation in a baboon model of aortoiliac bypass graft placement. Methods: Six adult male baboons underwent bilateral aortoiliac bypass grafting with ringed ePTFE (4 mm internal diameter x 5 cm length). In each animal, the distal anastomosis of one graft was continuously infused with heparin (50 U/h) and the distal anastomosis of the contralateral graft was infused with saline solution at the same rate (2.5 mu L/h), with osmotic pumps implanted for 4 weeks. Platelet counts and activated partial thromboplastin time measurements were performed weekly. The specimens were harvested at 4 weeks and were subjected to morphometric analysis. Cell proliferation was assessed with bromodeoxyuridine immunostaining. Results: All the harvested grafts were patent except for one control graft. There were no significant differences in platelet counts or activated partial thromboplastin time measurements taken before and during heparin infusion. As expected, there were no significant differences in graft neointimal hyperplasia and cell proliferation at the proximal anastomoses between the heparin-infused and control grafts. In contrast, at the treated distal anastomoses, heparin infusion significantly reduced the graft neointimal area by 65% and the cell proliferation index by 47% as compared with the untreated control distal anastomoses. Conclusion: These results show that local infusion of heparin significantly reduces distal anastomotic neointimal hyperplasia and cell proliferation without measurable systemic anticoagulation or other side effects. Thus, this approach may represent an attractive strategy for prolonging ePTFE bypass graft patency.