(Circulation. 1999;99:1156-1160.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia
An Effect Reversible With Vitamin C Therapy
From the National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, UK (J.C.C., J.S.K.); the Department of Cardiology, Ealing Hospital, Middlesex, UK (A.M., J.J.-M.); and the Department of Human Nutrition, St Bartholomew's and the Royal London School of Medicine & Dentistry, Queen Mary and Westfield College, London, UK (O.A.O.).
Correspondence to Dr J. S. Kooner, MD, FRCP, Senior Lecturer and Consultant Cardiologist, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail jkooner{at}rpms.ac.uk
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Abstract |
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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 µmol/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 µmol/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.
Key Words: endothelium • arteriosclerosis • antoxidants • nitric oxide • blood flow
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hyperhomocysteinemia is a major and independent risk factor for vascular disease,1 2 3 and venous thrombosis.4 Homocysteine concentrations are elevated in up to 30% of patients with atherosclerosis,1 and levels only 12% above the upper limit of normal (15 µmol/L, mild hyperhomocysteinemia), are associated with a 3-fold increase in the risk of acute myocardial infarction.3
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 hyperhomocysteinemia. The mechanisms by which hyperhomocysteinemia promotes atherosclerosis are not fully understood. High homocysteine levels may cause endothelial damage,5 6 affect platelet function and coagulation factors,7 8 and promote LDL oxidation.9 Increasing evidence suggests that homocysteine may exert these effects through an action on the endothelium. In children with severe hyperhomocysteinemia10 and in adults with moderate hyperhomocysteinemia,11 12 chronically elevated homocysteine concentrations are associated with impaired flow-mediated endothelium-dependent vasodilatation. However, these studies have been unable to clarify whether endothelial dysfunction is caused by elevated homocysteine or occult atherosclerotic disease.10 11 To separate these effects, we studied the vascular endothelial responses to acutely elevated homocysteine concentrations in healthy human subjects. To investigate if homocysteine impairs endothelial function through increased oxidative stress, we have studied the effects of homocysteine on vascular endothelial responses before and after treatment with vitamin C.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Subjects
Seventeen healthy volunteers (10 male and 7 female) mean age 33 (range 21 to 59) years were recruited from hospital staff. All were normotensive with normal serum cholesterol and had no previous history of diabetes or vascular disease. Eight of the 17 subjects were cigarette smokers. All subjects abstained from smoking on the day of the study. None were taking medications. All subjects gave informed and written consent. The study was approved by the local ethics committee.
Methods
Studies were performed on 3 separate days, in random order, and
at least 2 weeks apart. Brachial artery diameter responses to
hyperemic flow (endothelium dependent) and
glyceryltrinitrate (GTN, endothelium independent) were
measured at 0 hours (fasting), 2 hours, and 4 hours after (1) oral
methionine (L-methionine 100 mg/kg, the metabolic precursor
of homocysteine), (2) oral methionine preceded by vitamin C
(1g/day orally for 1 week), and (3) placebo (methionine-free
fruit juice). L-methionine (Scientific Hospital Supplies) was
administered in diluted, chilled fruit juice (25 mg methionine per mL
orange juice) to mask its flavor.
Brachial Artery Diameter
Studies were performed after an overnight fast with subjects
supine and at rest. Room temperature ranged from 21°C to 24°C.
Brachial artery flow-mediated dilatation was measured with a 7.0 MHz
linear array transducer, an Acuson 128XP/10 system, and a high
resolution ultrasonic vessel wall tracking system (Vadirec, Ingenious
Systems) as described by Celermajer et al.13 The brachial
artery was scanned longitudinally and a stereotactic clamp
was used to hold the transducer in the same position throughout the
procedure. The transmit (focus) zone was set to the depth of the near
wall of the artery. Depth and gain settings were set to optimize images
of the lumen-arterial wall interface. The images were
magnified by a resolution box function and measurements were taken from
the anterior to posterior "m" line at end diastole by
the use of the R wave on the ECG. Brachial artery diameter was measured
by identifying a clear section of the vessel on B-mode. The M-mode
cursor was then placed over this point at right angles to the vessel
wall. A 5-second segment of the A-mode signal was then routed to the
wall tracking system designed to track vessel wall movement on a beat
to beat basis. The minimal arterial diameter was calculated
from the distance between opposite lumen-arterial
interfaces, as identified by manual selection of the maximal change in
recorded radio frequency amplitude.
After the baseline resting scan, a pneumatic cuff, placed at the level of the wrist, was inflated to 300 mm Hg for 4.5 minutes. The second scan was performed 55 to 65 seconds after cuff deflation. Fifteen minutes were allowed for vessel recovery, after which the second baseline scan was performed. GTN (400 µg) was then administered and the fourth scan of the brachial artery was undertaken. The vessel diameter was measured by 2 independent observers unaware of the subjects' clinical details, the type, and stage of the study. Repeat measurements in individuals by the use of this technique are consistent and reproducible.14 Flow-mediated dilatation of conduit arteries is endothelium dependent and largely mediated by nitric oxide.15
Biochemical Measurements
Blood samples for glucose, total cholesterol,
HDL cholesterol, triglycerides, total plasma
homocysteine, red-cell folate, and serum B12 were
collected at 0 hours. Additional samples for plasma homocysteine were
collected at 2 hours and 4 hours during the study. Aliquots were placed
on ice, centrifuged within 1 hour, and the separated plasma
stored at -20°C before assays. Lipid profiles were determined by the
use of an Olympus AU800 multichannel analyzer, vitamin
B12 and red cell folate by MEIA (Abbott IMX
system), and total plasma homocysteine by high pressure liquid
chromatography.16
Data Processing and Statistical Analysis
Data were analyzed by the use of SPSS version 8.0
statistical package. Continuous data were expressed as mean±SEM.
Repeated measures ANOVA was used to examine the fixed effects of
administration of methionine, vitamin C, and time on flow-mediated
dilatation, GTN-induced dilatation, and plasma homocysteine. Linear
regression equations relating flow-mediated dilatation to plasma
homocysteine were calculated for each subject and were used to predict
the mean flow-mediated dilatation for any homocysteine level and its
95% CI for the study population. Statistical significance was inferred
at a P value of <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clinical and Biochemical Characteristics
Baseline clinical and biochemical measurements are summarized (Table 1
). All subjects had
normal blood pressure, fasting blood glucose, lipid profile, red cell
folate, and serum B12.
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Brachial Artery Flow-Mediated Dilatation and Methionine
Loading
Plasma homocysteine concentrations increased after oral methionine
compared with placebo (P<0.001, Table 2). Mean brachial artery flow-mediated
dilatation fell rapidly after oral methionine, but not placebo
(P<0.001, Figure 1, Table 2). Flow-mediated dilatation was strongly related to plasma
homocysteine (P<0.001) with no independent effect of time.
For each subject, a regression equation describing the relationship
between flow-mediated dilatation and plasma homocysteine was generated.
The fitted model predicting mean flow-mediated dilatation for the study
population was described by the equation: flow-mediated
dilatation=1.579- 0.245x(plasma homocysteine-20.86), where the
standard error of the intercept=0.638, standard error of the regression
slope=0.045, and residual SD=8.607. In contrast, GTN-induced brachial
artery dilatation after methionine and after placebo were not
significantly different. There were no significant differences in
baseline brachial artery diameter between the 2 sets of studies.
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The clinical correlates of fasting and postload homocysteine and of
flow-mediated dilatation are presented in Table 3. Fasting homocysteine was associated
with male sex and serum creatinine, and postload
homocysteine with body mass index (BMI), fasting
triglycerides, and diastolic blood pressure.
Baseline flow-mediated dilatation was correlated with age and
inversely correlated with baseline brachial artery diameter. Postload
flow-mediated dilatation was inversely correlated with age, male sex,
baseline brachial artery diameter, and creatinine, and
positively correlated with vitamin B12.
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Pretreatment with vitamin C did not significantly affect the increase
in homocysteine concentrations after oral methionine (Table 2
).
However, the fall in flow-mediated dilatation after methionine was
prevented by pretreatment with vitamin C (P<0.02, Figure 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The major findings of this study are that an acute elevation in homocysteine concentration is associated with rapid onset endothelial dysfunction, which can be prevented by pretreatment with vitamin C. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.
In this study, brachial artery flow-mediated dilatation was impaired within 2 hours of oral methionine. Previous studies indicate that brachial artery flow-mediated dilatation is endothelium dependent17 and is largely mediated by the release of nitric oxide.15 Our results therefore imply that endothelial nitric oxide activity may be impaired during acute hyperhomocysteinemia in normal human subjects. Regression analysis showed an inverse relationship between homocysteine concentration and flow-mediated dilatation. These findings are consistent with previous reports of a dose- and time-dependent effect of homocysteine on endothelial cellular function18 and may help to explain the incremental risk of vascular events with increasing homocysteine concentrations.3 19 In this study, endothelial dysfunction was detected at homocysteine concentrations similar to those associated with increased risk of myocardial infarction and stroke. Our results extend previous observations of impaired endothelial function in children with cystathionine ß-synthase deficiency10 and in elderly patients with low serum folate11 who have chronically elevated homocysteine concentrations. However, in both studies, it was not possible to distinguish whether endothelial dysfunction was caused by homocysteine or established atherosclerosis. Our findings of acute onset endothelial dysfunction after oral methionine support a role for homocysteine (and not structural arterial disease) in the observed vascular responses. Our results contrast with findings of preserved endothelial function in the obligate heterozygote parents of cystathionine ß-synthase–deficient children,10 although total plasma homocysteine concentrations were not assessed in the latter study.
The mechanisms by which hyperhomocysteinemia evokes endothelial dysfunction are not well understood. In vitro studies show that initial exposure of cultured endothelial cells to homocysteine leads to the formation and release of nitric oxide, S-nitrosothiols, and S-nitrosohomocysteine,18 substances with potent vasodilator and platelet-inhibitor properties. However, with continued exposure the oxidative effects of homocysteine predominate (with the resultant generation of superoxide anion radicals and hydrogen peroxide),18 20 leading to reduced production and/or inactivation of nitric oxide. Impaired availability of nitric oxide leaves the endothelium vulnerable to unopposed homocysteine-mediated oxidative damage.21 In the present study, pretreatment with vitamin C, an antioxidant that scavenges superoxide anion-radicals, prevented the decrease in flow-mediated dilatation after methionine. This finding suggests that oxidative stress mechanisms mediate endothelial dysfunction during hyperhomocysteinemia. Oxidative stress is a key factor in atherosclerosis. Generation of free-radical superoxide anions deactivates nitric oxide. Deactivation of nitric oxide, the major endothelium derived vasodilator, may lead to vasoconstriction, platelet aggregation, and monocyte adhesion, all of which promote atherosclerosis. Our study does not exclude a direct effect of methionine or its related metabolites on endothelial function in our subjects. However, metabolites such as cysteine, present in plasma at a 3- to 4-fold greater concentration than homocysteine and capable of generating superoxide, do not inhibit glutathione peroxidase,20 22 suggesting that homocysteine may have unique effects in mechanisms generating oxidative stress.
In summary, our results have shown that an elevation in homocysteine concentration is associated with an acute impairment of endothelial function that can be prevented by pretreatment with vitamin C. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.
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Acknowledgments |
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This work was supported by a grant from the British Heart Foundation (PG/96193). We are grateful to Caroline Doré for statistical analysis.
Received September 22, 1998; revision received November 4, 1998; accepted November 18, 1998.
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References |
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 K. K.W. Au-Yeung, C. W.H. Woo, F. L. Sung, J. C.W. Yip, Y. L. Siow, and K. O Hyperhomocysteinemia Activates Nuclear Factor-{kappa}B in Endothelial Cells via Oxidative Stress Circ. Res., January 9, 2004; 94(1): 28 - 36. [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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 F. Wotherspoon, D. W Laight, K. M Shaw, and M. H Cummings Review: Homocysteine, endothelial dysfunction and oxidative stress in type 1 diabetes mellitus The British Journal of Diabetes & Vascular Disease, September 1, 2003; 3(5): 334 - 340. [Abstract] [PDF]
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M. C. Stuhlinger, R. K. Oka, E. E. Graf, I. Schmolzer, B. M. Upson, O. Kapoor, A. Szuba, M. R. Malinow, T. C. Wascher, O. Pachinger, et al. Endothelial Dysfunction Induced by Hyperhomocyst(e)inemia: Role of Asymmetric Dimethylarginine Circulation, August 26, 2003; 108(8): 933 - 938. [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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 N. P. Riksen, G. A. Rongen, H. J. Blom, F. G.M. Russel, G. H.J. Boers, and P. Smits Potential role for adenosine in the pathogenesis of the vascular complications of hyperhomocysteinemia Cardiovasc Res, August 1, 2003; 59(2): 271 - 276. [Abstract] [Full Text] [PDF]
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D. Tanne, M. Haim, U. Goldbourt, V. Boyko, R. Doolman, Y. Adler, D. Brunner, S. Behar, and B.-A. Sela Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease Stroke, March 1, 2003; 34(3): 632 - 636. [Abstract] [Full Text] [PDF]
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 U. Lim and P. A. Cassano Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., December 15, 2002; 156(12): 1105 - 1113. [Abstract] [Full Text] [PDF]
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 W.S. Waring, S.R.J. Maxwell, and D.J. Webb Uric acid concentrations and the mechanisms of cardiovascular disease Eur. Heart J., December 1, 2002; 23(23): 1888 - 1889. [Full Text] [PDF]
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 A. De Bree, W. M. M. Verschuren, D. Kromhout, L. A. J. Kluijtmans, and H. J. Blom Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease Pharmacol. Rev., December 1, 2002; 54(4): 599 - 618. [Abstract] [Full Text] [PDF]
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S. Dayal, K. L. Brown, C. J. Weydert, L. W. Oberley, E. Arning, T. Bottiglieri, F. M. Faraci, and S. R. Lentz Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1996 - 2002. [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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 J. Y. Jeremy, N. Shukla, G. D. Angelini, A. Day, I. Y.P. Wan, S. P. Talpahewa, and R. Ascione Sustained increases of plasma homocysteine, copper, and serum ceruloplasmin after coronary artery bypass grafting Ann. Thorac. Surg., November 1, 2002; 74(5): 1553 - 1557. [Abstract] [Full Text] [PDF]
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 K Jensen-Urstad, E Svenungsson, U de Faire, A Silveira, J L Witztum, A Hamsten, and J Frostegard Cardiac valvular abnormalities are frequent in systemic lupus erythematosus patients with manifest arterial disease Lupus, November 1, 2002; 11(11): 744 - 752. [Abstract] [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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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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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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M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 6 - 13. [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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 N. H. Badner, D. Freeman, and J. D. Spence Preoperative Oral B Vitamins Prevent Nitrous Oxide-Induced Postoperative Plasma Homocysteine Increases Anesth. Analg., December 1, 2001; 93(6): 1507 - 1510. [Abstract] [Full Text] [PDF]
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M. C. Stuhlinger, P. S. Tsao, J.-H. Her, M. Kimoto, R. F. Balint, and J. P. Cooke Homocysteine Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine Circulation, November 20, 2001; 104(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
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A. Virdis, L. Ghiadoni, H. Cardinal, S. Favilla, P. Duranti, R. Birindelli, A. Magagna, G. Bernini, G. Salvetti, S. Taddei, et al. Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1106 - 1115. [Abstract] [Full Text] [PDF]
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J. C CHAMBERS and J. S KOONER Homocysteine: a novel risk factor for coronary heart disease in UK Indian Asians Heart, August 1, 2001; 86(2): 121 - 122. [Full Text] [PDF]
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S. E. Vollset, H. Refsum, A. Tverdal, O. Nygard, J. E. Nordrehaug, G. S Tell, and P. M. Ueland Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study Am. J. Clinical Nutrition, July 1, 2001; 74(1): 130 - 136. [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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N. M. de Roos, M. L. Bots, and M. B. Katan Replacement of Dietary Saturated Fatty Acids by Trans Fatty Acids Lowers Serum HDL Cholesterol and Impairs Endothelial Function in Healthy Men and Women Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1233 - 1237. [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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G. Sesmilo, B. M. K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone (GH) Administration on Homocyst(e)ine Levels in Men with GH Deficiency: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1518 - 1524. [Abstract] [Full Text]
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E. Nurk, G. S. Tell, O. Nygård, H. Refsum, P. M. Ueland, and S. E. Vollset Plasma Total Homocysteine Is Influenced by Prandial Status in Humans: The Hordaland Homocysteine Study J. Nutr., April 1, 2001; 131(4): 1214 - 1216. [Abstract] [Full Text]
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J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [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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H. Morita, H. Kurihara, S. Yoshida, Y. Saito, T. Shindo, Y. Oh-hashi, Y. Kurihara, Y. Yazaki, and R. Nagai Diet-Induced Hyperhomocysteinemia Exacerbates Neointima Formation in Rat Carotid Arteries After Balloon Injury Circulation, January 2, 2001; 103(1): 133 - 139. [Abstract] [Full Text] [PDF]
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D. J. Meiklejohn, M. A. Vickers, R. Dijkhuisen, and M. Greaves Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke Stroke, January 1, 2001; 32(1): 57 - 62. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, and B. A. Nassar Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2185 - 2191. [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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N. H. Badner, W. S. Beattie, D. Freeman, and J. D. Spence Nitrous Oxide-Induced Increased Homocysteine Concentrations Are Associated with Increased Postoperative Myocardial Ischemia in Patients Undergoing Carotid Endarterectomy Anesth. Analg., November 1, 2000; 91(5): 1073 - 1079. [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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J. Thambyrajah, M. J. Landray, F. J. McGlynn, H. J. Jones, D. C. Wheeler, and J. N. Townend Does Folic Acid Decrease Plasma Homocysteine and Improve Endothelial Function in Patients With Predialysis Renal Failure? Circulation, August 22, 2000; 102(8): 871 - 875. [Abstract] [Full Text] [PDF]
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D. Tomasian, J. F. Keaney Jr., and J. A. Vita Antioxidants and the bioactivity of endothelium-derived nitric oxide Cardiovasc Res, August 18, 2000; 47(3): 426 - 435. [Full Text] [PDF]
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L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [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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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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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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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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K. ROBINSON Homocysteine, B vitamins, and risk of cardiovascular disease Heart, February 1, 2000; 83(2): 127 - 130. [Full Text]
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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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B. W. Walsh, S. Paul, R. A. Wild, R. A. Dean, R. P. Tracy, D. A. Cox, and P. W. Anderson The Effects of Hormone Replacement Therapy and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 214 - 218. [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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V. A. Tyurin, S.-X. Liu, Y. Y. Tyurina, N. B. Sussman, C. A. Hubel, J. M. Roberts, R. N. Taylor, and V. E. Kagan Elevated Levels of S-Nitrosoalbumin in Preeclampsia Plasma Circ. Res., June 8, 2001; 88(11): 1210 - 1215. [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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