Abstract 561: A Novel Integrin Modulating Arg-Gly-Asp(RGD)-Peptide-Coated Stent Reduces Neoatherosclerosis in a Rabbit Model

Abstract

Objective: While drug-eluting stents have dramatically reduced restenosis, they are often associated with increased risk of late stent thrombosis and neointimal atherosclerosis (“neoatherosclerosis”). In-stent neoatherosclerosis represents a further accelerated and possibly more unstable manifestation of atherosclerotic progression in nascent neointimal tissue after stent implantation. We hypothesized that poor arterial re-endothelialization accompanied by leaky endothelial junctions is a primary mechanism contributing to neoatherosclerosis. In the present study, we tested the ability of a RGD-peptidomimetic-coating of bare metal stents to reduce the formation of in-stent neoatherosclerosis by promoting integrin-mediated adhesion of endothelial cells, and improving their functional integrity. Approach and Results: Established iliofemoral plaques were created in male New Zealand white rabbits (n=10) by balloon injury and feeding a high cholesterol (1.0%) diet for 5 wks, which was then switched to a low cholesterol diet (0.025%) for the remainder of the study. At 3 wks after diet switch, an RGD-coated stent was implanted together with a drug-eluting stent in the contralateral iliac artery, and animals were continued on the low cholesterol diet for 7 wks (serum cholesterol between 400-1,000 mg/dl). Endothelial permeability was assessed by FITC-dextran (250/500 kDa, approx. LDL radius) injected intravenously 1 h before termination. Oil red O and Filipin staining demonstrated neutral lipid and free cholesterol accumulation in the developing neointimal of stented arteries. En face confocal microscopy of the luminal surface following immunostaining against endothelial markers followed by scanning electron microscopy showed greater endothelial coverage of luminal surfaces for RGD-coated stents. Stents were further quantified by histomorphometric analysis for vascular healing, thrombus formation and inflammation. Conclusion: A rabbit neoatherosclerosis model was established to study the formation and progression of this novel disease manifestation. RGD-coated stents showed reduced formation of neoatherosclerosis in association with improved vessel healing and re-endothelialization compared to drug-eluting stents.