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Objective-To assess a non-invasive test for endothelial dysfunction, an important early event in the atherogenic process. Methods-Using high resolution ultrasound, the accuracy of detecting small changes in vessel diameter was assessed using phantom "arteries", and the same equipment was then used to measure flow mediated dilatation in the brachial artery of 40 healthy adults aged 22-51 years, studied on four occasions; intervals between scans were 1-2 days, 1-2 weeks, and 2-4 months. Results-Differences between pairs of phantom "arteries" with diameters 0-1-0'2 mm apart were correctly estimated in 162 of 264 cases (61%); no measurement by any of four independent observers was > 041 mm in error, and the mean error was 0*04 mm. For in vivo scans, the overall coefficient of variation for flow mediated dilatation was 1-8% (1.6% for women, 1-9% for men, P = 0.18). In 34/40 subjects (85%), all values for flow mediated dilatation were within 2-5% of the overall mean for each subject. A nested analysis of variance showed the expected between patient variability, and also significant day to day variation, but little between weeks or months. Using these data to generate power function analyses, we calculated that for individuals, an improvement in flow mediated dilatation of 4-8% is significantly greater than natural variability. In clinical trials, a mean improvement in flow mediated dilatation of at least 2% would usually be required to detect a treatment benefit, with much larger subject numbers needed for a parallel group compared to a crossover trial design. Conclusions-Vascular responses to endothelium dependent and independent stimuli in systemic arteries can be studied non-invasively in man. Subjects should be studied on at least two occasions before and after any intervention, to optimise the chance of showing a significant effect from any potentially beneficial therapy. (Br Heart J 1995;74:247-253).

In hypercholesterolemic rabbits, oral L -arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29 Ϯ 5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238 Ϯ 43 mg/dl. Each subject was studied before and after 4 wk of L -arginine (7 grams ϫ 3/ day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L -arginine, plasma L -arginine levels rose from 115 Ϯ 103 to 231 Ϯ 125 mol/liter ( P Ͻ 0.001), and EDD improved from 1.7 Ϯ 1.3 to 5.6 Ϯ 3.0% ( P Ͻ 0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L -arginine and placebo.

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Endothelium-dependent pulmonary artery relaxation can be demonstrated in vivo and is impaired in young patients with increased pulmonary flow secondary to congenital heart disease. This impairment may be an important early event in the pathogenesis of pulmonary vascular disease.