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Circulation. 1997;95:1119-1121

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(Circulation. 1997;95:1119-1121.)
© 1997 American Heart Association, Inc.


Articles

Hyperhomocyst(e)inemia Is Associated With Impaired Endothelium-Dependent Vasodilation in Humans

Ahmed Tawakol, MD; Torbjørn Omland, MD, PhD; Marie Gerhard, MD; James T. Wu, PhD; Mark A. Creager, MD

the Vascular Medicine and Atherosclerosis Unit (A.T., T.O., M.G., M.A.C.), Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, and Associated Regional and University Pathologists, Inc Laboratories (J.T.W.), Salt Lake City, Utah.

Correspondence to Mark A. Creager, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Background Hyperhomocyst(e)inemia is a risk factor for atherosclerosis and is prevalent in the elderly. The objective of this study was to determine whether hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.

Methods and Results High-resolution vascular ultrasonography was used to study endothelium-dependent and -independent vasodilation in a nonatherosclerotic peripheral conduit artery of 26 elderly hyperhomocyst(e)inemic subjects and 15 age- and sex-matched subjects with normal homocysteine levels. Flow-mediated, endothelium-dependent (nitric oxide–mediated) vasodilation was assessed by measuring the percent change in brachial artery diameter during reactive hyperemia. Endothelium-independent vasodilation was assessed after the administration of 0.4 mg sublingual nitroglycerin. Endothelium-dependent vasodilation was significantly impaired in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7±0.6% versus 8.1±1.2%; P=.004), whereas endothelium-independent vasodilation was not different between the two groups (10.1±1.6% versus 9.3±1.5%; P=NS). In a linear regression analysis with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation.

Conclusions These data indicate that hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans and suggest that the bioavailability of nitric oxide is decreased in hyperhomocyst(e)inemic humans. (. 1997;95:1119-1121.)


Key Words: endothelium • endothelium-derived factors • homocysteine • vasodilation




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D. Z. van Asselt, J. W. Pasman, H. J. van Lier, D. M. Vingerhoets, P. J. Poels, Y. Kuin, H. J. Blom, and W. H. Hoefnagels
Cobalamin Supplementation Improves Cognitive and Cerebral Function in Older, Cobalamin-Deficient Persons
J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2001; 56(12): M775 - 779.
[Abstract] [Full Text] [PDF]


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NEJMHome page
G. Schnyder, M. Roffi, R. Pin, Y. Flammer, H. Lange, F. R. Eberli, B. Meier, Z. G. Turi, and O. M. Hess
Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels
N. Engl. J. Med., November 29, 2001; 345(22): 1593 - 1600.
[Abstract] [Full Text] [PDF]


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CirculationHome page
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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Proc. Natl. Acad. Sci. USAHome page
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 12, 2001; (2001) 231428998.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
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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ChestHome page
L. Lavie, A. Perelman, and P. Lavie
Plasma Homocysteine Levels in Obstructive Sleep Apnea : Association With Cardiovascular Morbidity
Chest, September 1, 2001; 120(3): 900 - 908.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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Br J OphthalmolHome page
M. Weger, O. Stanger, H. Deutschmann, M. Simon, W. Renner, O. Schmut, J. Semmelrock, and A. Haas
Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy
Br J Ophthalmol, July 1, 2001; 85(7): 803 - 806.
[Abstract] [Full Text] [PDF]


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J CARDIOVASC PHARMACOL THERHome page
A. lannuzzi, G. Jannuzzo, C. Sapio, P. Pauciullo, D. Jorio, N. Spampinato, M. Mancini, and P. Rubba
L-Arginine Improves Post-Ischemic Vasodilation in Coronary Heart Disease Patients Taking Vasodilating Drugs
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2001; 6(2): 121 - 127.
[Abstract] [PDF]


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Clin. Chem.Home page
V. Cavalca, G. Cighetti, F. Bamonti, A. Loaldi, L. Bortone, C. Novembrino, M. De Franceschi, R. Belardinelli, and M. D. Guazzi
Oxidative Stress and Homocysteine in Coronary Artery Disease
Clin. Chem., May 1, 2001; 47(5): 887 - 892.
[Abstract] [Full Text] [PDF]


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Am. J. Clin. Nutr.Home page
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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HeartHome page
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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StrokeHome page
V. Gallai, V. Caso, M. Paciaroni, G. Cardaioli, E. Arning, T. Bottiglieri, and L. Parnetti
Mild Hyperhomocyst(e)inemia : A Possible Risk Factor for Cervical Artery Dissection
Stroke, March 1, 2001; 32(3): 714 - 718.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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JPEN J Parenter Enteral NutrHome page
C. W. Compher, B. P. Kinosian, N. Evans-Stoner, J. Huzinec, and G. P. Buzby
Hyperhomocysteinemia Is Associated with Venous Thrombosis in Patients with Short Bowel Syndrome
JPEN J Parenter Enteral Nutr, January 1, 2001; 25(1): 1 - 8.
[Abstract] [PDF]


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J Am Coll CardiolHome page
M. Rubenfire, S. Rajagopalan, and L. Mosca
Carotid artery vasoreactivity in response to sympathetic stress correlates with coronary disease risk and is independent of wall thickness
J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2192 - 2197.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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CirculationHome page
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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J Am Coll CardiolHome page
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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Am. J. Clin. Nutr.Home page
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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Nephrol Dial TransplantHome page
S. T. W. Morris, J. J. V. McMurray, R. S. C. Rodger, and A. G. Jardine
Impaired endothelium-dependent vasodilatation in uraemia
Nephrol. Dial. Transplant., August 1, 2000; 15(8): 1194 - 1200.
[Abstract] [Full Text] [PDF]


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Arch Intern MedHome page
T. Omland, A. Samuelsson, M. Hartford, J. Herlitz, T. Karlsson, B. Christensen, and K. Caidahl
Serum Homocysteine Concentration as an Indicator of Survival in Patients With Acute Coronary Syndromes
Arch Intern Med, June 26, 2000; 160(12): 1834 - 1840.
[Abstract] [Full Text] [PDF]


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Eur Heart JHome page
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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Arterioscler. Thromb. Vasc. Bio.Home page
R. H. Boger, S. M. Bode-Boger, K. Sydow, D. D. Heistad, and S. R. Lentz
Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Monkeys With Hyperhomocyst(e)inemia or Hypercholesterolemia
Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1557 - 1564.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
D. W. Jacobsen
Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check?
Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1182 - 1184.
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Arterioscler. Thromb. Vasc. Bio.Home page
D. E. L. Wilcken, X. L. Wang, T. Adachi, H. Hara, N. Duarte, K. Green, and B. Wilcken
Relationship Between Homocysteine and Superoxide Dismutase in Homocystinuria : Possible Relevance to Cardiovascular Risk
Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1199 - 1202.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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CirculationHome page
K. S. Woo, J. E. Sanderson, Y. Y. Sun, P. Chook, A. S. P. Cheung, L. T. Chan, C. Metreweli, Y. I. Lolin, and D. S. Celermajer
Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans
Circulation, March 28, 2000; 101 (12): e116 - e116.
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CirculationHome page
S. E. Brett, J. M. Ritter, and P. J. Chowienczyk
Diastolic Blood Pressure Changes During Exercise Positively Correlate With Serum Cholesterol and Insulin Resistance
Circulation, February 15, 2000; 101(6): 611 - 615.
[Abstract] [Full Text] [PDF]


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CirculationHome page
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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J. Appl. Physiol.Home page
M. R. Rinder, R. J. Spina, and A. A. Ehsani
Enhanced endothelium-dependent vasodilation in older endurance-trained men
J Appl Physiol, February 1, 2000; 88(2): 761 - 766.
[Abstract] [Full Text] [PDF]


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HeartHome page
K. ROBINSON
Homocysteine, B vitamins, and risk of cardiovascular disease
Heart, February 1, 2000; 83(2): 127 - 130.
[Full Text]


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J Am Coll CardiolHome page
K. S. Woo, P. Chook, Y. I. Lolin, J. E. Sanderson, C. Metreweli, and D. S. Celermajer
Folic acid improves arterial endothelial function in adults with hyperhomocystinemia
J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2002 - 2006.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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CirculationHome page
V. Schachinger, M. B. Britten, M. Elsner, D. H. Walter, I. Scharrer, and A. M. Zeiher
A Positive Family History of Premature Coronary Artery Disease Is Associated With Impaired Endothelium-Dependent Coronary Blood Flow Regulation
Circulation, October 5, 1999; 100(14): 1502 - 1508.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
V. Fonseca, S. C. Guba, and L. M. Fink
Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis
Endocr. Rev., October 1, 1999; 20(5): 738 - 759.
[Abstract] [Full Text]


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ANGIOLOGYHome page
G. Lupattelli, S. Rufini, E. H. Locati, R. Lombardini, G. Ciuffetti, D. Siepi, E. Mannarino, and G. Lupattelli
Hyperhomocyst(e)inemia Is Associated with Carotid Atherosclerosis
Angiology, October 1, 1999; 50(10): 823 - 830.
[Abstract] [PDF]