(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
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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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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 A. G. Bostom, I. H. Rosenberg, H. Silbershatz, P. F. Jacques, J. Selhub, R. B. D'Agostino, P. W.F. Wilson, and P. A. Wolf Nonfasting Plasma Total Homocysteine Levels and Stroke Incidence in Elderly Persons: The Framingham Study Ann Intern Med, September 7, 1999; 131(5): 352 - 355. [Abstract] [Full Text] [PDF]
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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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