Oral Heparin Prevents Neointimal Growth Following Vascular Injury: Implications for Potential Clinical Use

摘要

Heparin is the archetypical modulator of vascular repair following arterial injury in an mal models. In these models, heparin delivered either as a continuous intravenous infusion or via frequent subcutaneous dosing, inhibits neointimal hyperplasia after either balloon injury or stent implantation. However, use of subcutaneous heparin following human percutaneous intervention has failed to prevent restenosis. It may be that these failures arise from a need for more frequent dosing regimens in man. Recently, the drug delivery agent Sodium N-caprylate (SNAC) has been found to facilitate gastric absorption of heparin raising the possibility of convenient frequent dosing. Methods and Results: To investigate the effects of orally delivered heparin on neointimal hyperplasia following varying froms of arterial injury, New Zealand White rabbits underwent iliac artery balloon dilatation. In half of the animals, endovascular stents were implanted and heparin delivered though different methods. Arteries were harvested at 14 days and neointimal area was assessed using computer-aided morphometry. Following balloon injury, both intravenous (0.3 mg/kg/hr) and oral heparin (90 mg/kg BID) inhibited neointimal growth (0.11+-0.02 and 0.09+-0.07 mm~2 respectively vs. control 0.16+-0.06 mm~2, p<0.05). Following stent implantation, intravenous administration of heparin (0.3 mg/kg/hr) inhibited neointimal growth (0.35+-0.05 mm~2 vs. control 0.45+-0.09 mm~2, p<0.05), but oral heparin was not effective at either 90 mg/kg BID or 180 mg/kg BID (0.48+-0.04 and 0.49+-0.08 mm~2, p=NS vs. control). However, the same dose given more frequently (120 mg/kg TID) was effective (0.40+-0.10 mm~2, p<0.05 vs. control). Conclusions: Oral heparin effectively inhibits neointimal growth following vascular injury. Stented arteries require higher and more frequent dosing for efficacy than that required after simple balloon dilatation. These data indicate that oral heparin may be an effective method of suppressing restenosis, and that differences in type of vascular injury should be considered in the design of drug delivery.