Antioxidant therapy reverses impaired graft healing in hypercholesterolemic rabbits

Objective

Limited endothelial cell (EC) coverage and anastomotic intimal hyperplasia contribute to thrombosis and failure of prosthetic grafts. Lipid accumulation and lipid oxidation are associated with decreased EC migration and intimal hyperplasia. The goal of this study was to assess the ability of antioxidants to improve graft healing in hypercholesterolemic animals.

Methods

Rabbits were placed in one of four groups: chow plus N-acetylcysteine (NAC), chow plus probucol, chow with 1% cholesterol plus NAC, or chow with 1% cholesterol plus probucol. After 2 weeks, expanded polytetrafluoroethylene grafts (12 cm long × 4-mm internal diameter) were implanted in the abdominal aorta. Grafts were removed after 6 weeks and analyzed for cholesterol content, EC coverage, anastomotic intimal thickness, and the cellular composition of the neointima. Plasma samples were obtained to assess systemic oxidative stress. The data were compared with previously reported data from animals fed diets of chow and chow with 1% cholesterol.

Results

Prosthetic grafts from rabbits fed chow with 1% cholesterol had significantly greater anastomotic intimal thickening and lower EC coverage than grafts from rabbits fed a regular chow diet. In hypercholesterolemic rabbits, antioxidant therapy decreased global oxidative stress as evidenced by a 40% decrease in plasma thiobarbituric acid reactive substances. In rabbits fed the chow with 1% cholesterol diet, NAC decreased intimal hyperplasia at the proximal anastomosis by 29% and significantly increased graft EC coverage from 46% to 71% (P = .03). Following a similar pattern, probucol decreased intimal hyperplasia by 43% and increased graft EC coverage to 53% in hypercholesterolemic rabbits.

Conclusions

Global oxidative stress and anastomotic intimal hyperplasia are increased, and endothelialization of prosthetic grafts is significantly reduced in rabbits fed a high-cholesterol diet. Antioxidant treatment improves EC coverage and decreases intimal hyperplasia. Reducing oxidative stress may promote healing of prosthetic grafts.

Clinical Relevance

Hypercholesterolemia is associated with an increased inflammatory response, elevated oxidative stress, and increased intimal hyperplasia after stent or vein graft placement in animal models and in humans. Reduced endothelialization is seen after stent or graft placement in hypercholesterolemic animals, and reduced endothelial cell growth and patency of endothelial cell-seeded grafts is found in humans with elevated serum lipid levels. Our results suggest that antioxidants are effective in reducing this pathologic response and in improving graft healing.