Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans

BACKGROUND: Hyperhomocyst(e)inemia is associated with premature peripheral vascular, cerebrovascular, and coronary artery disease. Because homocysteine has been found to be damaging to endothelial cells in animal and cell culture studies, we evaluated the association between hyperhomocysteinemia and arterial endothelial dysfunction (a marker of early atherosclerosis) in asymptomatic adult subjects. METHODS AND RESULTS: Using high-resolution ultrasound, we measured endothelium-dependent flow-mediated dilation (EDD) and endothelium-independent nitroglycerin-induced dilation (GTN) of the brachial artery in 14 prospectively defined hyperhomocysteinemic (mean plasma homocysteine, 34.8+/-8.5 micromol/L), nonsmoking, healthy subjects aged 53+/-9 years and 14 control subjects with low plasma homocysteine levels (9.9+/-3.2 micromol/L). The two groups were well matched for age; sex; body mass index; blood pressure, blood cholesterol, folate, and vitamin B12 levels; and vessel diameter. EDD was significantly lower in hyperhomocysteinemic subjects (6.5+/-1.7%) than in subjects with low homocysteine levels (10.8+/-1.7%) (P<.001). GTN responses were similar in the two subject groups (P=.90). Multivariate analysis confirmed homocysteine level as the strongest predictor for impaired EDD, independent of age, sex, body mass index, or blood pressure, folate, vitamin B12, and cholesterol levels. CONCLUSIONS: Hyperhomocysteinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.