on August 11, 2003
Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000085067.55901.89
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Submitted on November 12, 2002
From the University Clinic of Innsbruck (M.C.S., O.P.), Innsbruck, Austria; Stanford University School of Medicine (M.C.S., O.K., A.S., J.P.C.), Calif; University of California (R.K.O.), Los Angeles; Oregon National Primate Research Center (E.E.G., B.M.U., M.R.M.), Beaverton; and University Clinic of Graz (I.S., T.C.W.), Graz, Austria. * To whom correspondence should be addressed. E-mail: John.Cooke{at}Stanford.edu.
Background--Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans. Methods and Results--We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64±3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65±1 years), and 5 young control subjects (younger adults; 5 men; age, 31±1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P<0.001). Plasma ADMA levels rose in all subjects, from 0.9±0.2 to 1.6±0.2 µmol/L in younger adults, from 1.5±0.2 to 3.0±0.4 µmol/L in older adults, and from 1.8±0.1 to 3.9±0.3 µmol/L in peripheral arterial disease patients (all, P<0.001). Flow-mediated vasodilatation was reduced from 13±2% to 10±1% in younger adults, from 6±1% to 5±1% in older adults, and from 7±1% to 3±1% in peripheral arterial disease patients (all, P<0.001). Furthermore, we found positive correlations between plasma Hcy and ADMA concentrations (P=0.03, r=0.450), as well as ADMA and flow-mediated vasodilatation (P=0.002, r=0.623). Conclusions--Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.
Revised on May 15, 2003
Accepted on June 3, 2003
Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia. Role of Asymmetric Dimethylarginine
Markus C. Stühlinger MD,
Key words: endothelium • dimethylarginine • atherosclerosis • nitric oxide • peripheral arterial disease
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