Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins

CONTEXT: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. OBJECTIVE: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. DESIGN AND SETTING: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. SUBJECTS: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. INTERVENTIONS: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. MAIN OUTCOME MEASURES: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. RESULTS: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) micromol/L at baseline to 27.1 (6.7) micromol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 4.0 to 22.7 7.8 micromol/L; P<.001) but no significant increase was observed with placebo (10.1 3.7 to 10.4 3.2 micromol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% 2.7%; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% 4.5%; P=.009) and blood viscosity (-3.0% 1.2%; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% 1.5%, 4.0% 3.0%, and 1.5% 1.0%, respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% 2.5%, -7.9% 3.5%, and -1.5% 1.0%, respectively; P=.24). CONCLUSION: Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.