Circulation. 2003;108:933-938
Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000085067.55901.89
Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000085067.55901.89
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(Circulation. 2003;108:933.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia
Role of Asymmetric Dimethylarginine
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.
Correspondence to John P. Cooke, MD, PhD, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail John.Cooke{at}Stanford.edu
Received November 12, 2002; revision received May 15, 2003; accepted June 3, 2003.
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.
Key Words: endothelium • dimethylarginine • atherosclerosis • nitric oxide • peripheral arterial disease
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|
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|
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|
|
|
|
|
|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
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|
|
|
|
|
|
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|
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|
|
|
|
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|
|
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