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Nappo F, De Rosa N, Marfella R, et al. Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins. JAMA. 1999;281(22):2113–2118. doi:10.1001/jama.281.22.2113
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.
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.
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