(Circulation. 1998;98:1848-1852.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults
From the Cardiovascular Sciences Research Group and Department of Medical Computing and Statistics (R.G.N.), University of Wales College of Medicine, Heath Park, Cardiff, UK.
Correspondence to Professor Malcolm J. Lewis, Department of Pharmacology, Therapeutics, and Toxicology, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, UK. E-mail longem{at}cf.ac.uk
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Abstract |
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Background—Elevated plasma homocysteine is a risk factor for arteriosclerosis, but a cause-and-effect relationship remains to be fully established. Endothelial dysfunction, an early event in the atherogenic process, has been shown to be associated with hyperhomocysteinemia in experimental and human studies. To further establish a direct relationship between changes in plasma homocysteine and endothelial dysfunction, we investigated whether moderate hyperhomocysteinemia induced by an oral methionine load would acutely impair flow-mediated endothelium-dependent vasodilatation in healthy adults.
Methods and Results—Twenty-four healthy volunteers completed a randomized crossover study in which an oral methionine load (0.1 g/kg) was administered on 1 of 2 study days, 7 days apart. At each visit, plasma homocysteine and brachial artery endothelium-dependent and -independent dilatation were measured at baseline and at 4 hours. To further elucidate the temporal relationship between methionine, homocysteine, and endothelial function, an oral methionine load was administered in 10 subjects on a separate visit, and the time courses of plasma methionine, homocysteine, and flow-mediated brachial artery dilatation were measured at baseline and after 1, 2, 3, 4, and 8 hours. After oral methionine, plasma homocysteine increased from 7.9±2.0 µmol/L at baseline to 23.1±5.4 µmol/L at 4 hours (P<0.0001, n=24) and was associated with a decrease in flow-mediated brachial artery dilatation from 0.12±0.09 to 0.06±0.09 mm (P<0.05). The time course of the impairment of flow-mediated vasodilatation mirrored the time course of the increase in homocysteine concentration.
Conclusions—Oral methionine loading raises plasma homocysteine and impairs flow-mediated endothelium-dependent vasodilatation. This supports the view that homocysteine may promote vascular disease by inducing endothelial dysfunction.
Key Words: homocysteine • endothelium • methionine • vasodilation
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Introduction |
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Homocysteine is a sulfur-containing amino acid that is derived from dietary methionine. An elevated plasma homocysteine level is associated with an increased risk of arteriosclerosis (coronary, cerebral, and peripheral) independent of other risk factors,1 but a causal role has not yet been fully established.
In homocystinuria, which is a rare inherited disorder (most often due to cystathionine ß-synthase deficiency, 1 in 200 000), plasma homocysteine levels are markedly elevated (>50 µmol/L; normal range, 5 to 15 µmol/L), and patients have severe, widespread vascular disease.2 In the general population, mild to moderate elevations in plasma homocysteine (15 to 35 µmol/L) are common and may be due to inherited enzyme variants3 and/or a relative deficiency of folate, vitamin B12, or vitamin B6, which are required for the normal metabolism of homocysteine.4 Methionine taken orally is converted to homocysteine by demethylation, and the effect of an oral load can be used as a diagnostic test to identify individuals with enzyme defects who show an exaggerated rise in homocysteine levels.5
Endothelial injury appears to be an early event in the promotion of atherogenesis6 and may be one mechanism whereby homocysteine leads to an increased risk of both arterial and venous disease. Studies in vitro have demonstrated that homocysteine may injure endothelium,7 8 but the mechanism for such an effect is not yet known. Dietary modification to increase homocysteine levels in monkeys, including augmenting methionine intake, impairs vascular function.9 In humans, endothelial dysfunction has been demonstrated in homocystinuria10 and in association with less markedly elevated plasma homocysteine levels more relevant to the general population.11 12 13
We therefore hypothesized that moderate elevations of plasma homocysteine would be acutely injurious to endothelium. The objectives of the present study were to investigate the effect of an oral methionine load on plasma homocysteine and flow-mediated endothelial function in healthy subjects and to observe the time course of any such effects.
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Methods |
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Subjects
Crossover Study
Twenty-eight members of the hospital staff were invited to enter the study, but 3 volunteers later declined to participate after randomization. One subject developed a severe headache after sublingual nitroglycerin (NTG) and withdrew after completing the first visit. Twenty-four subjects (mean age, 32 years; range, 21 to 46 years; 14 men) completed the protocol.
Time-Course Study
Five of the 24 subjects who completed the crossover study
volunteered to attend on a second occasion, together with 5 additional
participants not studied in the first phase (see below).
All were nonsmokers, were normotensive (blood pressure
<150/90 mm Hg), had serum cholesterol <6.5
mmol/L, and were not taking vitamin supplements. Baseline
characteristics are shown in Table 1
. All
subjects gave informed, written consent, and the study protocol was
approved by the local Research Ethics Committee.
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Study Design
Randomized Crossover Study of an Oral Methionine Load
Twenty-four subjects attended after an overnight fast on 2
separate days, 1 week apart. Subjects were randomized to receive oral
L-methionine (0.1 g/kg, Scientific Hospital Supplies) on
either day 0 or day 7 as a crossover study. Randomization to methionine
on day 0 or day 7 was performed by a research nurse, who administered
the oral methionine load in a room separate from the vascular
laboratory to ensure that the investigators performing the vascular
measurements remained blinded throughout the study. Due to the
distinctive taste of methionine, subjects knew which day they had
received methionine but were specifically instructed not to inform the
ultrasound operators. At baseline, flow-mediated
(endothelium-dependent) and NTG-related
(endothelium-independent) brachial artery dilatation
was measured and venous blood was sampled for total plasma homocysteine
(with additional sampling for total cholesterol,
triglycerides, glucose, folate, and
B12 on the first visit). Subjects then received
oral methionine or no medication (control), and measurements were
repeated 4 hours later.
Time-Course Study
To further examine the relationship between changes in plasma
methionine, homocysteine, and flow-mediated brachial artery dilatation,
10 volunteers (mean age, 29 years; range, 21 to 40 years; 8 men)
received an oral methionine load (0.1 g/kg), and flow-mediated brachial
artery dilatation, plasma methionine, and total plasma homocysteine
were measured at baseline and at 1, 2, 3, 4, and 8 hours. This was an
open (nonblinded) study. In those subjects who had previously
participated in the crossover study (5 of the 10 subjects), these
measurements were performed on a separate visit at least 7 days
later.
Noninvasive Measurement of Flow-Mediated,
Endothelium-Dependent Vasodilatation
Endothelial function was assessed by comparing
endothelium-dependent vasodilatation in response to
flow with the endothelium-independent response to
sublingual NTG. The increase in brachial artery flow was induced by
release of a wrist cuff after a period of hand ischemia. This
technique thereby avoids ischemia of the brachial artery
itself.
Subjects lay supine in a temperature-controlled room (21°C to 23°C) with the left arm outstretched on a pneumatic cushion. As previously described,14 brachial artery end-diastolic diameter was measured by high-resolution vessel wall tracking (Vadirec, Medical Systems Arnhem, resolution ±3 µm), blood flow by continuous-wave Doppler ultrasound (SciMed Dopstation) derived from the mean velocity time integral corrected for Doppler angle and internal brachial artery diameter, and blood pressure and heart rate by finger photoplethysmography (Finapres, Ohmeda).
Measurements were made at baseline (after 15 minutes of supine rest), at 60 and 120 seconds of hand hyperemia (produced by releasing a pneumatic wrist cuff inflated for 5 minutes to suprasystolic pressure), and 3 minutes after 400 µg NTG. The maximum increase in end-diastolic brachial artery diameter from baseline was used as the measure of dilatation. All hemodynamic measurements were confirmed as having returned to baseline 15 minutes after each intervention.
Blood Samples and Assays
Venous blood was sampled into tubes containing EDTA (for
homocysteine), lithium-heparin (for methionine), SST (gel and clot
activator) (for lipids, B12, and
folate), and fluoride-oxalate (for glucose). Samples for
homocysteine were immediately placed on ice, and plasma was separated
within 30 minutes by centrifugation. Plasma for
methionine assay was deproteinized immediately with 10%
5-sulfosalicylic acid. Samples were stored at -70°C until
analysis. Total plasma homocysteine was measured by
high-performance liquid chromatography using
SBD-F (ammonium 7-fluoro-2-oxa-1,3-diazole-4-sulfonate) derivatization
(within-batch precision, 2.2%).15 Plasma
methionine was measured by ion-exchange amino acid
chromatography (Biotronik LC 5001).
Statistical Analysis
Data are presented in the text, tables, and figures as
group mean±SD unless stated otherwise. Changes in
hemodynamic data, brachial artery flow-mediated
dilatation, and NTG-mediated dilatation from baseline to 4 hours during
the methionine period were compared with those occurring during the
control period by a paired analysis based on that of the
2-period crossover trial.16 Thus, the difference
between changes occurring in the first and second periods was compared
between the 2 treatment order groups by an unpaired t test,
which obviates confounding with period differences introduced by
unequal numbers in the 2 groups. In the time-course study, a
Wilcoxon paired test was used to compare changes in methionine,
homocysteine, and flow-mediated dilatation at each of the 5 time points
relative to baseline.
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Results |
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Fasting plasma total homocysteine and basal vascular measurements were similar on each of the 2 study days, and there was no evidence of an order effect. Administration of the oral methionine load increased total homocysteine from 7.9±2.0 µmol/L at baseline to 23.1±5.4 µmol/L at 4 hours (P<0.0001) (Table 2
). Flow-mediated brachial artery
dilatation decreased from 0.12±0.09 to 0.06±0.09 mm
(P=0.045), despite similar hyperemic blood flow
(67±66 versus 78±81 mL/min). NTG-induced dilatation was similar at
baseline and at 4 hours (0.48±0.17 versus 0.40±0.11 mm,
P=0.32) (Figure 1). There was
no significant correlation between change in flow-mediated dilatation
and basal, postload, or increase in plasma homocysteine. Five subjects
reported mild nausea after oral methionine, which was most pronounced
in the first hour after administration.
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In the group of 10 subjects who participated in the time-course study,
plasma methionine increased from 27±5 µmol/L at baseline to a
maximum of 714±155 µmol/L at 1 hour and declined thereafter but
remained above baseline in all subjects at 8 hours (P=0.002)
(Figure 2). Plasma total homocysteine
increased from 7.2±1.4 µmol/L at baseline to 23.5±5.2
µmol/L at 4 hours (P<0.001) and remained elevated at
25.9±7.0 µmol/L at 8 hours (P=0.002 versus
baseline). Flow-mediated brachial artery dilatation decreased in all
subjects (P=0.002) from 0.12±0.04 mm at baseline and
remained impaired up to 8 hours.
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Discussion |
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The principal finding of this study is that an oral methionine load, which produces an increase in plasma homocysteine, acutely impairs flow-mediated brachial artery dilatation in healthy subjects. These findings provide evidence to support the hypothesis that homocysteine is a risk factor for vascular disease by a mechanism that involves injury to the endothelium. However, these data do not exclude some other possible interpretation, such as a direct effect of methionine or an alteration in methylation reactions, which are dependent on methionine-homocysteine interconversion. Inspection of the time-course data is relevant to this point. The impairment of endothelial function from 0 to 4 hours mirrored in all subjects the increase in plasma homocysteine, which is consistent with a direct toxic effect of homocysteine. However, the tendency for flow-mediated responses to improve at 8 hours when methionine is falling but homocysteine continues to rise is more indicative of a direct methionine effect. Different experimental approaches will be necessary to distinguish these possibilities.
The absence of any carryover effect in those subjects who received
methionine on day 0 suggests that the effect on
endothelium-dependent dilatation is reversible within 7
days. This is consistent with the return of plasma homocysteine
to baseline at 
24 hours after an oral methionine
load.17 The effect of methionine loading was
repeatable. In the 5 subjects who received methionine twice, similar
increases in homocysteine were measured at 4 hours in association with
similar decreases in flow-mediated vasodilatation on both occasions.
A potential drawback of the study was that a matched placebo was not possible because of the distinctive taste of methionine. The study did, however, incorporate a randomized crossover design, and particular attention was paid to ensure that the observers performing vascular measurements were unaware of the order of methionine administration.
Flow-mediated brachial artery dilatation reflects endothelium-dependent vasodilatation. It can be largely blocked by inhibitors of nitric oxide synthase (eg, the nonmetabolized L-arginine analogue NG-monomethyl-L-arginine [L-NMMA]) and is therefore attributable predominantly to nitric oxide activity.18 In this study, flow-mediated dilatation of a conduit artery was measured in response to reactive hyperemia of the hand by an established method and further developed to higher resolution and precision by computer-aided "wall tracking" with validated reproducibility.14 Distal placement of the cuff avoids the confounding effects of brachial artery ischemia, which occurs if a proximal position is chosen above the antecubital fossa. These differences in methodology may account for differences in "normal" values for flow-mediated brachial artery dilatation compared with some previously published data11 19 20 but are consistent with results obtained by other investigators using the same technique.
Endothelial dysfunction, when present, tends to be generalized and therefore is likely to be of clinical significance when demonstrated in an artery that is usually spared of atheroma. Indeed, a close relation has been demonstrated between endothelial function in the human coronary and peripheral circulation,21 suggesting that even in the absence of overt atheroma, these findings have relevance to vascular beds that are more commonly affected by atherosclerosis.
A clear association now exists between mild to moderate increases in plasma homocysteine and arteriosclerotic vascular disease. Homocysteine could promote atheroma formation by various mechanisms, including endothelial dysfunction, smooth muscle cell proliferation,22 alteration of coagulation factors,23 and lipoprotein oxidation.24 At the molecular level, there is some evidence that homocysteine may promote oxidant stress,25 26 thereby decreasing nitric oxide bioavailability.
In vitro studies have shown evidence of cellular injury in the presence of homocysteine, but the effect is nonspecific at the high concentrations used.8 The effect of more clinically relevant levels of homocysteine on vascular reactivity has been reported in a primate model9 in which dietary modification with methionine feeding and folate restriction impaired relaxation to endothelium-dependent vasodilators. Responses to endothelium-independent dilators were also impaired, although to a lesser extent.
In human studies, impaired endothelium-dependent, flow-mediated dilatation of the brachial and femoral arteries has been demonstrated in young patients with homocystinuria,10 in whom homocysteine concentrations would be markedly elevated. Endothelial dysfunction has also been reported in association with mild hyperhomocysteinemia11 13 and in subjects with hyperhomocysteinemia secondary to low vitamin B12 concentrations.12 This study demonstrates a temporal relationship between a rise in homocysteine and changes in flow-related endothelial function, but a cause-and-effect relationship remains to be established.
In a typical western diet, postprandial increases in plasma methionine
and homocysteine are usually small, the latter on the order of 1 to
2 µmol/L, and therefore unlikely to have any effect on vascular
reactivity. However, the findings of this study may be relevant to the
general population, because mild to moderate elevations in plasma
homocysteine may commonly occur as a result of inherited enzyme
variants and/or suboptimal vitamin status or in association with
disease states such as renal failure.27 Subjects
homozygous for the thermolabile variant of methylene tetrahydrofolate
reductase, the frequency of which is 12% in healthy subjects in our
region (Z. Clark, BSc, written communication, March 1998), are prone to
develop raised homocysteine concentrations28 29
that may be similar to those achieved here after an oral methionine
load. Endothelial dysfunction arising from mild to
moderate hyperhomocysteinemia could thereby contribute to the
atherogenic process in these individuals and could potentially be
ameliorated by lowering plasma homocysteine with vitamin
supplementation, particularly folic acid.
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Acknowledgments |
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Drs Bellamy, Ramsey, and McDowell were supported by the British Heart Foundation. Grateful thanks are due to S. Gorman for her help with vascular measurements, Dr D. Bradley for methionine measurements, and S. Cale for homocysteine measurements.
Received February 10, 1998; revision received June 30, 1998; accepted July 2, 1998.
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S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, May 1, 2005; 10(2_suppl): S27 - S33. [Abstract] [PDF]
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 M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response Eur. Heart J., February 2, 2005; 26(4): 363 - 368. [Abstract] [Full Text] [PDF]
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S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]
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A. S. De Vriese, H. J. Blom, S. G. Heil, S. Mortier, L. A.J. Kluijtmans, J. Van de Voorde, and N. H. Lameire Endothelium-Derived Hyperpolarizing Factor-Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia Circulation, May 18, 2004; 109(19): 2331 - 2336. [Abstract] [Full Text] [PDF]
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K. Sydow, B. Hornig, N. Arakawa, S. M Bode-Boger, D. Tsikas, T. Munuzel, and R. H Boger Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA Vascular Medicine, May 1, 2004; 9(2): 93 - 101. [Abstract] [PDF]
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 K. L Tucker, B. Olson, P. Bakun, G. E Dallal, J. Selhub, and I. H Rosenberg Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial Am. J. Clinical Nutrition, May 1, 2004; 79(5): 805 - 811. [Abstract] [Full Text] [PDF]
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 A. M. Devlin, E. Arning, T. Bottiglieri, F. M. Faraci, R. Rozen, and S. R. Lentz Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice Blood, April 1, 2004; 103(7): 2624 - 2629. [Abstract] [Full Text] [PDF]
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Z. Bagi, C. Cseko, E. Toth, and A. Koller Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2277 - H2283. [Abstract] [Full Text] [PDF]
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A. Vychytil, M. Fodinger, J. Pleiner, M. Mullner, P. Konner, S. Skoupy, C. Rohrer, M. Wolzt, and G. Sunder-Plassmann Acute effect of amino acid peritoneal dialysis solution on vascular function Am. J. Clinical Nutrition, November 1, 2003; 78(5): 1039 - 1045. [Abstract] [Full Text] [PDF]
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K. Robert, J.-F. Chasse, D. Santiard-Baron, C. Vayssettes, A. Chabli, J. Aupetit, N. Maeda, P. Kamoun, J. London, and N. Janel Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia J. Biol. Chem., August 22, 2003; 278(34): 31504 - 31511. [Abstract] [Full Text] [PDF]
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A. Virdis, M. Iglarz, M. F. Neves, F. Amiri, R. M. Touyz, R. Rozen, and E. L. Schiffrin Effect of Hyperhomocystinemia and Hypertension on Endothelial Function in Methylenetetrahydrofolate Reductase-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1352 - 1357. [Abstract] [Full Text] [PDF]
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B. Rosengarten, S. Osthaus, D. Auch, and M. Kaps Effects of Acute Hyperhomocysteinemia on the Neurovascular Coupling Mechanism in Healthy Young Adults Stroke, February 1, 2003; 34(2): 446 - 451. [Abstract] [Full Text] [PDF]
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N. Haulrik, S. Toubro, J. Dyerberg, S. Stender, A. R Skov, and A. Astrup Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6-mo randomized controlled trial in overweight subjects Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1202 - 1206. [Abstract] [Full Text] [PDF]
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 A. N. Friedman, C. Ritter, J. C. F. Moreira, F. Dal-Pizzol, M. G. Ziegler, X. Bao, R. Matz, Y. Higashi, K. Chayama, and M. Yoshizumi Renovascular Hypertension, Endothelial Function, and Oxidative Stress N. Engl. J. Med., November 7, 2002; 347(19): 1528 - 1530. [Full Text] [PDF]
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 O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 158 - 162. [Abstract] [Full Text] [PDF]
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A. Tawakol, M. A. Forgione, M. Stuehlinger, N. M. Alpert, J. P. Cooke, J. Loscalzo, A. J. Fischman, M. A. Creager, and H. Gewirtz Homocysteine impairs coronary microvascular dilator function in humans J. Am. Coll. Cardiol., September 18, 2002; 40(6): 1051 - 1058. [Abstract] [Full Text] [PDF]
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 C.-H. Yen and Y.-T. Lau Vascular Responses in Male and Female Hypertensive Rats With Hyperhomocysteinemia Hypertension, September 1, 2002; 40(3): 322 - 328. [Abstract] [Full Text] [PDF]
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N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
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 Z. Ungvari, A. Csiszar, Z. Bagi, and A. Koller Impaired Nitric Oxide-Mediated Flow-Induced Coronary Dilation in Hyperhomocysteinemia : Morphological and Functional Evidence for Increased Peroxynitrite Formation Am. J. Pathol., July 1, 2002; 161(1): 145 - 153. [Abstract] [Full Text] [PDF]
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H. Zheng, C. Dimayuga, A. Hudaihed, and S. D. Katz Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): e15 - 18. [Abstract] [Full Text] [PDF]
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E.M. Cottington, C. LaMantia, S. P. Stabler, R. H. Allen, A. Tangerman, C. Wagner, S. H. Zeisel, and S. H. Mudd Adverse Event Associated With Methionine Loading Test: A Case Report Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1046 - 1050. [Abstract] [Full Text] [PDF]
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M. C. Corretti, T. J. Anderson, E. J. Benjamin, D. Celermajer, F. Charbonneau, M. A. Creager, J. Deanfield, H. Drexler, M. Gerhard-Herman, D. Herrington, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force J. Am. Coll. Cardiol., January 16, 2002; 39(2): 257 - 265. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
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N. Weiss, S. Heydrick, Y.-Y. Zhang, C. Bierl, A. Cap, and J. Loscalzo Cellular Redox State and Endothelial Dysfunction in Mildly Hyperhomocysteinemic Cystathionine {beta}-Synthase-Deficient Mice Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 34 - 41. [Abstract] [Full Text] [PDF]
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S. N. Doshi, I. F.W. McDowell, S. J. Moat, N. Payne, H. J. Durrant, M. J. Lewis, and J. Goodfellow Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering Circulation, January 1, 2002; 105(1): 22 - 26. [Abstract] [Full Text] [PDF]
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C. H. Pullin, P. A. L. Ashfield-Watt, M. L. Burr, Z. E. Clark, M. J. Lewis, S. J. Moat, R. G. Newcombe, H. J. Powers, J. M. Whiting, and I. F. W. McDowell Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1799 - 1805. [Abstract] [Full Text] [PDF]
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R. A.J.M. van Dijk, J. A. Rauwerda, M. Steyn, J. W.R. Twisk, and C. D.A. Stehouwer Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2072 - 2079. [Abstract] [Full Text] [PDF]
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S. R. Lentz Does Homocysteine Promote Atherosclerosis? Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1385 - 1386. [Full Text] [PDF]
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J. Zhou, J. Moller, C. C. Danielsen, J. Bentzon, H. B. Ravn, R. C. Austin, and E. Falk Dietary Supplementation With Methionine and Homocysteine Promotes Early Atherosclerosis but Not Plaque Rupture in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1470 - 1476. [Abstract] [Full Text] [PDF]
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S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF]
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J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1858 - 1863. [Abstract] [Full Text] [PDF]
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J.C. Chambers and J.S. Kooner Homocysteine -- an innocent bystander in vascular disease? Eur. Heart J., May 1, 2001; 22(9): 717 - 719. [PDF]
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A. A Brown and F. B Hu Dietary modulation of endothelial function: implications for cardiovascular disease Am. J. Clinical Nutrition, April 1, 2001; 73(4): 673 - 686. [Abstract] [Full Text] [PDF]
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C G Hanratty, L T McGrath, D F McAuley, I S Young, and G D Johnston The effects of oral methionine and homocysteine on endothelial function Heart, March 1, 2001; 85(3): 326 - 330. [Abstract] [Full Text]
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A. K. Nightingale, P. P. James, J. Morris-Thurgood, F. Harrold, R. Tong, S. K. Jackson, J. R. Cockcroft, and M. P. Frenneaux Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1334 - H1339. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, L. Szollar, and A. Koller Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A2 Mediation Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 233 - 237. [Abstract] [Full Text] [PDF]
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J. Duan, T. Murohara, H. Ikeda, K.-i. Sasaki, S. Shintani, T. Akita, T. Shimada, and T. Imaizumi Hyperhomocysteinemia Impairs Angiogenesis in Response to Hindlimb Ischemia Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2579 - 2585. [Abstract] [Full Text] [PDF]
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C.-L. Chao and Y.-T. Lee Impairment of Cerebrovascular Reactivity by Methionine-Induced Hyperhomocysteinemia and Amelioration by Quinapril Treatment Stroke, December 1, 2000; 31(12): 2907 - 2911. [Abstract] [Full Text] [PDF]
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J. C. Chambers, P. M. Ueland, O. A. Obeid, J. Wrigley, H. Refsum, and J. S. Kooner Improved Vascular Endothelial Function After Oral B Vitamins : An Effect Mediated Through Reduced Concentrations of Free Plasma Homocysteine Circulation, November 14, 2000; 102(20): 2479 - 2483. [Abstract] [Full Text] [PDF]
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M. K. Al-Obaidi, P. J. Stubbs, P. Collinson, R. Conroy, I. Graham, and M. I. M. Noble Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1217 - 1222. [Abstract] [Full Text] [PDF]
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J. L. Anderson, J. B. Muhlestein, B. D. Horne, J. F. Carlquist, T. L. Bair, T. E. Madsen, and R. R. Pearson Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease Circulation, September 12, 2000; 102(11): 1227 - 1232. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, J. J. Genest Jr, and B. A. Nassar Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease J. Am. Coll. Cardiol., September 1, 2000; 36(3): 758 - 765. [Abstract] [Full Text] [PDF]
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S. R. Lentz, R. A. Erger, S. Dayal, N. Maeda, M. R. Malinow, D. D. Heistad, and F. M. Faraci Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta -synthase-deficient mice Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H970 - H975. [Abstract] [Full Text] [PDF]
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P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset The controversy over homocysteine and cardiovascular risk Am. J. Clinical Nutrition, August 1, 2000; 72(2): 324 - 332. [Abstract] [Full Text] [PDF]
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A. Khajuria and D. S. Houston Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis Blood, August 1, 2000; 96(3): 966 - 972. [Abstract] [Full Text] [PDF]
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J Thambyrajah and J.N Townend Homocysteine and atherothrombosis--mechanisms for injury Eur. Heart J., June 2, 2000; 21(12): 967 - 974. [PDF]
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 A. Gottsater, I. Anwaar, K.-F. Eriksson, I. Mattiasson, F. Lindgarde, and A. Gottsater Homocysteine Is Related to Neopterin and Endothelin-1 in Plasma of Subjects with Disturbed Glucose Metabolism and Reference Subjects Angiology, June 1, 2000; 51(6): 489 - 497. [Abstract] [PDF]
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D. W. Jacobsen Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check? Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1182 - 1184. [Full Text] [PDF]
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Z. Ungvari, E. Sarkadi-Nagy, Z. Bagi, L. Szollar, and A. Koller Simultaneously Increased TxA2 Activity in Isolated Arterioles and Platelets of Rats With Hyperhomocysteinemia Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1203 - 1208. [Abstract] [Full Text] [PDF]
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E. K. Hoogeveen, P. J. Kostense, C. Jakobs, J. M. Dekker, G. Nijpels, R. J. Heine, L. M. Bouter, and C. D. A. Stehouwer Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes : 5-Year Follow-Up of the Hoorn Study Circulation, April 4, 2000; 101(13): 1506 - 1511. [Abstract] [Full Text] [PDF]
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C.-L. Chao, T.-L. Kuo, and Y.-T. Lee Effects of Methionine-Induced Hyperhomocysteinemia on Endothelium-Dependent Vasodilation and Oxidative Status in Healthy Adults Circulation, February 8, 2000; 101(5): 485 - 490. [Abstract] [Full Text] [PDF]
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D. Lang, M. B. Kredan, S. J. Moat, S. A. Hussain, C. A. Powell, M. F. Bellamy, H. J. Powers, and M. J. Lewis Homocysteine-Induced Inhibition of Endothelium-Dependent Relaxation in Rabbit Aorta : Role for Superoxide Anions Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 422 - 427. [Abstract] [Full Text] [PDF]
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I. F. W. McDowell and D. Lang Homocysteine and Endothelial Dysfunction: A Link with Cardiovascular Disease J. Nutr., February 1, 2000; 130(2): 369 - 369. [Abstract] [Full Text]
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J. C. Chambers, O. A. Obeid, and J. S. Kooner Physiological Increments in Plasma Homocysteine Induce Vascular Endothelial Dysfunction in Normal Human Subjects Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2922 - 2927. [Abstract] [Full Text] [PDF]
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E. B. Stamm and R. D. Reynolds Plasma Total Homocyst(e)ine May Not Be the Most Appropriate Index for Cardiovascular Disease Risk J. Nutr., October 1, 1999; 129(10): 1927 - 1930. [Full Text]
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 F. Nappo, N. De Rosa, R. Marfella, D. De Lucia, D. Ingrosso, A. F. Perna, B. Farzati, and D. Giugliano Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins JAMA, June 9, 1999; 281(22): 2113 - 2118. [Abstract] [Full Text] [PDF]
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 S. N. Doshi, J. Goodfellow, M. J. Lewis, and I. F.W. McDowell Homocysteine and endothelial function Cardiovasc Res, June 1, 1999; 42(3): 578 - 582. [Full Text] [PDF]
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N. Weiss, Y.-Y. Zhang, S. Heydrick, C. Bierl, and J. Loscalzo Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction PNAS, October 23, 2001; 98(22): 12503 - 12508. [Abstract] [Full Text] [PDF]
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 J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects Circ. Res., July 20, 2001; 89(2): 187 - 192. [Abstract] [Full Text] [PDF]
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