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Clinical Investigation
June 9, 1999

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

Author Affiliations

Author Affiliations: Departments of Geriatrics and Metabolic Diseases (Drs Nappo, De Rosa, Marfella, and Giugliano) and Immunology (Dr Farzati), Institute of General Pathology and Oncology (Dr De Lucia), and Institute of Biochemistry of Macromolecules (Drs Ingrosso and Perna), Second University of Naples, Naples, Italy.

JAMA. 1999;281(22):2113-2118. doi:10.1001/jama.281.22.2113

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%], 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.