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(Circulation. 1997;96:2542-2544.)
© 1997 American Heart Association, Inc.

Articles

Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans

K.S. Woo, MD, FRACP; P. Chook, MD; Y.I. Lolin, PhD, MD; A.S.P. Cheung, BN; L.T. Chan, RN; Y.Y. Sun, MD; J.E. Sanderson, MD, FRCP; C. Metreweli, MD, FRCP; ; D.S. Celermajer, PhD, FRACP

From the Department of Medicine, The Chinese University of Hong Kong (K.S.W., P.C., A.S.P.C., L.T.C., Y.Y.S., J.E.S.), the Department of Chemical Pathology (Y.I.L.), and the Department of Diagnostic Radiology and Organ Imaging (C.M.), Prince of Wales Hospital, Hong Kong; and the Department of Cardiology, Royal Prince Alfred Hospital (D.S.C.), Sydney, Australia.

Correspondence to Prof K.S. Woo, Department of Medicine, Prince of Wales Hospital, Shatin, Hong Kong.

Background Hyperhomocyst(e)inemia is associated with premature peripheral vascular, cerebrovascular, and coronary artery disease. Because homocysteine has been found to be damaging to endothelial cells in animal and cell culture studies, we evaluated the association between hyperhomocysteinemia and arterial endothelial dysfunction (a marker of early atherosclerosis) in asymptomatic adult subjects.

Methods and Results Using high-resolution ultrasound, we measured endothelium-dependent flow-mediated dilation (EDD) and endothelium-independent nitroglycerin-induced dilation (GTN) of the brachial artery in 14 prospectively defined hyperhomocysteinemic (mean plasma homocysteine, 34.8±8.5 µmol/L), nonsmoking, healthy subjects aged 53±9 years and 14 control subjects with low plasma homocysteine levels (9.9±3.2 µmol/L). The two groups were well matched for age; sex; body mass index; blood pressure, blood cholesterol, folate, and vitamin B₁₂ levels; and vessel diameter. EDD was significantly lower in hyperhomocysteinemic subjects (6.5±1.7%) than in subjects with low homocysteine levels (10.8±1.7%) (P<.001). GTN responses were similar in the two subject groups (P=.90). Multivariate analysis confirmed homocysteine level as the strongest predictor for impaired EDD, independent of age, sex, body mass index, or blood pressure, folate, vitamin B₁₂, and cholesterol levels.

Conclusions Hyperhomocysteinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.

Key Words: risk factors • atherosclerosis • ultrasonics • endothelium-derived factors • hyperhomocysteinemia

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				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]

				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]

				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]

				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. [Full Text] [PDF]

				F. H. de Man, A. W. E. Weverling-Rijnsburger, A. van der Laarse, A. H. M. Smelt, J. W. Jukema, and G. J. Blauw Not Acute but Chronic Hypertriglyceridemia Is Associated With Impaired Endothelium-Dependent Vasodilation : Reversal After Lipid-Lowering Therapy by Atorvastatin Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 744 - 750. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				K. J. Harjai Potential New Cardiovascular Risk Factors: Left Ventricular Hypertrophy, Homocysteine, Lipoprotein(a), Triglycerides, Oxidative Stress, and Fibrinogen Ann Intern Med, September 7, 1999; 131(5): 376 - 386. [Abstract] [Full Text] [PDF]

				G. W. de Valk-de Roo, C. D.A. Stehouwer, J. Lambert, C. G. Schalkwijk, M. J. van der Mooren, C. Kluft, and C. Netelenbos Plasma Homocysteine Is Weakly Correlated with Plasma Endothelin and von Willebrand Factor but not with Endothelium-dependent Vasodilatation in Healthy Postmenopausal Women Clin. Chem., August 1, 1999; 45(8): 1200 - 1205. [Abstract] [Full Text] [PDF]

				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]

				B. Kristensen, J. Malm, T. K. Nilsson, J. Hultdin, B. Carlberg, G. Dahlen, and T. Olsson Hyperhomocysteinemia and Hypofibrinolysis in Young Adults With Ischemic Stroke Stroke, May 1, 1999; 30(5): 974 - 980. [Abstract] [Full Text] [PDF]

				J. C. Chambers, A. McGregor, J. Jean-Marie, O. A. Obeid, and J. S. Kooner Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia : An Effect Reversible With Vitamin C Therapy Circulation, March 9, 1999; 99(9): 1156 - 1160. [Abstract] [Full Text] [PDF]

				D. E. Gutstein and V. Fuster Pathophysiology and clinical significance of atherosclerotic plaque rupture Cardiovasc Res, February 1, 1999; 41(2): 323 - 333. [Abstract] [Full Text] [PDF]

				M.F. Bellamy, I.F.W. McDowell, M.W. Ramsey, M. Brownlee, C. Bones, R.G. Newcombe, and M.J. Lewis Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults Circulation, November 3, 1998; 98(18): 1848 - 1852. [Abstract] [Full Text] [PDF]

				D. W. Jacobsen Homocysteine and vitamins in cardiovascular disease Clin. Chem., August 1, 1998; 44(8): 1833 - 1843. [Abstract] [Full Text] [PDF]

				A. R. Folsom, F. J. Nieto, P. G. McGovern, M. Y. Tsai, M. R. Malinow, J. H. Eckfeldt, D. L. Hess, and C. E. Davis Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins : The Atherosclerosis Risk in Communities (ARIC) Study Circulation, July 21, 1998; 98(3): 204 - 210. [Abstract] [Full Text] [PDF]

				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]