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) μmol/L at baseline to 27.1 (6.7) μmol/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] μmol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] μmol/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%l, 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