Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia - An effect reversible with vitamin C therapy

Background-Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atheroscler osis are not well understood. We hypothesized that elevated homocysteine co ncentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C, Methods and Results-We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hype remic flow (endothelium dependent), and glyceryltrinitrate (GTN, endotheliu m independent) were measured with high resolution ultrasound at 0 hours (fa sting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg /kg), (2) oral methionine preceded by vitamin C (1 g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine incr eased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31.2+/-3.1 mu mol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and f low-mediated dilatation (P<0.001), Pretreatment with vitamin C did not affe ct the rise in homocysteine concentrations after methionine (0 hours, 13.6/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 mu mol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4.0+/-1. 0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02), GTN-induced endothe lium independent brachial artery dilatation was not affected after methioni ne or methionine preceded by vitamin C. Conclusions-We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that c an be prevented by pretreatment with vitamin C in healthy subjects. Our res ults support the hypothesis that the adverse effects of homocysteine on vas cular endothelial cells are mediated through oxidative stress mechanisms.