Intimal hyperplasia following carotid endarterectomy in an insulin-resistant rat model

Hyperhomocysteinemia, a known risk factor for cardiovascular disease, results in an elevation of intimal hyperplasia (IH) following a carotid endarterectomy (CEA) in a rat model. An exaggerated IH response following CEA has been observed in rats with dietary induced hyperhomocysteinemia. Type 2 diabetics often present with hyperhomocysteinemia and are at higher risk for developing vascular blockage following surgical procedures. To determine if insulin resistance increases IH risks following endarterectomy, the 3 goals of this study were: (1) to establish plasma homocysteine concentrations in dietary induced insulin-resistant rats and their controls, (2) to investigate whether a positive correlation of IH and plasma homocysteine response occurs following CEA in the insulin-resistant rat model, and (3) if so, to attempt to decrease IH by supplementation with folic acid, a known enzymatic cofactor in the homocysteine metabolic pathway. To achieve these aims, male rats (275 to 300 g) were fed 1 of 4 diets for a 4-month period: (1) high-fat sucrose (HFS), (2) low-fat complex carbohydrate (LFCC), (3) HFS + 25 mg/kg folic acid (HFS+F), or (4) LFCC + 25 mg/kg folic acid (LFCC+F). At the end of the 4-month period the rats underwent an open (non-balloon) unilateral CEA. Two weeks post-endarterectomy, blood, liver and carotid tissue were removed to measure plasma insulin, folic acid, and homocysteine, 2 key enzymes of homocysteine metabolism-methylenetetrahydrofolate reductase (MTHFR) and cystathionine P-synthase (CBS)-and percent lumenal stenosis (IH%). Computer-assisted morphometric analysis was used to measure the percentage of IH in the carotid artery. Plasma homocysteine was significantly higher in the HFS group when compared with the LFCC group (11.3 +/- 1.3 mumol/L v 7.4 +/- 0.6 mumol/L, P = .008) as was post-endarterectomy IH producing lumenal stenosis (30.7% +/- 4.2% v 14.0% +/- 4.3%, P = .008). Plasma insulin in the HFS group was higher than the LFCC (control) group and was significant (36.3 +/- 3.0 muU/mL v 21.1 +/- 0.8 muU/mL, P = .0004). Folic acid supplementation in the HFS group resulted in reductions of plasma homocysteine (HFS v HFS+F, 11.3 +/- 1.3 mumol/L v 7.95 +/- 1.0 mumol/L, P = .02) and post-endarterectomy IH (HFS v HFS+F, 30.7% +/- 4.2 % v 10.4% +/- 1.6%, P =.0001). The control or LFCC group was not statistically different from the HFS+F group in homocysteine or IH. Folate supplementation did not decrease insulin concentrations in the HFS+F group compared to the LFCC group. We conclude that the HFS diet produced an insulin-resistant state with an elevated plasma homocysteine and an exaggerated lH response following carotid endarterectomy in this rat model. Dietary folate supplementation reduced plasma homocysteine concentrations in the HFS diet, which implicates hyperhomocysteinemia as an etiologic factor in the development of post-CEA IH in this insulin-resistant rat model. (C) 2003 Elsevier Inc. All rights reserved.