(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
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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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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 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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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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 B. Frei On the Role of Vitamin C and Other Antioxidants in Atherogenesis and Vascular Dysfunction Experimental Biology and Medicine, December 1, 1999; 222(3): 196 - 204. [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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 Vitamin C Reverses Acute Effects of Hyperhomocysteinemia Journal Watch (General), March 23, 1999; 1999(323): 7 - 7. [Full Text]
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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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