Objective-To test the hypothesis that abnormalities of endothelial function are present in Indian Asians and may contribute to their increased coronary heart disease risk.Setting-Single centre in west London.Patients-26 Indian Asian and 18 European white healthy male subjects, aged 35 to 61 years recruited from general practice lists.Design-Brachial artery diameter responses to reactive hyperaemia and sublingual glyceryl trinitrate were compared using high resolution ultrasound.Results-Mean (SEM) flow mediated, endothelium dependent dilatation was reduced in Indian Asians compared with European whites, at 3.2 (0.8)% v 5.9 (1.0)%, p = 0.03. In contrast, there were no significant differences in baseline brachial arterial diameter (4.6 (0.1) v 4.6 (0.1) mm, p = 0.65) or glyceryl trinitrate induced dilatation (18.8 (1.5)% v 18.5 (1.7)%, p = 0.90) between Indian Asians and European whites, respectively. Univariate analysis showed that Indian Asian race was significantly associated with impaired flow mediated dilatation (regression coefficient = -2.8 (1.3)%, p = 0.03), and in multivariate analysis, this relation was independent of both conventional coronary heart disease risk factors and markers of insulin resistance.Conclusions-Endothelial function is impaired in healthy UK Indian Asians compared with European whites, and the defect is not accounted for by major coronary heart disease risk factors. Endothelial function may be modulated by novel risk factors in Indian Asians.

BACKGROUND:Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations 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 hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/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 flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect 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 micromol/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 endothelium independent brachial artery dilatation was not affected after methionine 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 can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.

Hyperhomocysteinaemia is a major and independent risk factor for vascular disease, 1 Clarke R Daly L Robinson K et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991; 324: 1149-1155 Crossref PubMed Scopus (2039) Google Scholar , 2 Nygard O Nordrehaug JE Refsum H Ueland PM Farstad M Vollset SE Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997; 337: 230-236 Crossref PubMed Scopus (1646) Google Scholar and venous thrombosis. High concentrations of homocysteine are found in up to 30% of patients with atherosclerosis, and concentrations only 12% above the upper limit of normal (15 μmol/L, mild hyperhomocysteinaemia) are associated with a three-fold increase in the risk of acute myocardial infarction. Homocysteine concentrations are determined by genetic and nutritional factors; mutations in the genes for enzymes involved in homocysteine metabolism and deficiencies of vitamins B6, B12, and folic acid are associated with hyperhomocysteinaemia. The mechanisms by which hyperhomocysteinaemia promote atherosclerosis are not fully understood. We have measured flow-mediated dilatation during an oral methionine load to test whether an acute increase in homocysteine concentration is associated with endothelial dysfunction in healthy volunteers.