CONSEQUENCES OF HYPERHOMOCYST(E)INEMIA ON VASCULAR FUNCTION IN ATHEROSCLEROTIC MONKEYS

Moderate elevation of plasma homocyst(e)ine is associated with increas ed risk for atherosclerotic vascular disease. In a previous study, we observed impaired vascular function in nonatherosclerotic monkeys with moderate hyperhomocyst(e)inemia. In this study, we tested the hypothe sis that dietary intervention to lower plasma homocyst(e)ine corrects vascular dysfunction in atherosclerotic monkeys. Cynomolgus monkeys we re fed an atherogenic diet that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. After 17 months, the atherogenic die t was supplemented with B vitamins (5 mg folic acid, 400 mu g vitamin B-12, and 20 mg vitamin B-6 daily) for 6 months. Total plasma homocyst (e)ine decreased from 12.8+/-2.8 to 3.5+/-0.3 mu mol/L (n=9; mean+/-SE ; P<.01) after vitamins were added to the diet, but plasma cholesterol remained elevated (522+/-63 versus 514+/-41 mg/dL; P>.05). In respons e to intra-arterial infusion of collagen, blood flow to the leg decrea sed by 30+/-3% and 38+/-5%, respectively, before and after vitamin sup plementation (P>.05). In vivo responses of resistance vessels to endot helium-dependent vasodilators (acetylcholine or ADP) were impaired at baseline and did not improve after vitamin supplementation. In carotid artery studied ex vivo, relaxation to low doses of acetylcholine impr oved after vitamin supplementation, but maximal relaxation remained im paired. Ex vivo thrombomodulin anticoagulant activity was threefold hi gher in monkeys fed the atherogenic diet (with or without B vitamins) than in normal monkeys (P<.05). We conclude that normalization of plas ma homocyst(e)ine is insufficient to restore normal vascular function in atherosclerotic monkeys with persistent hypercholesterolemia and th at atherosclerosis, with or without hyperhomocyst(e)inemia, is associa ted with elevated thrombomodulin activity.