The effect of homocysteine reduction by B-vitamin supplementation on markers of endothelial dysfunction

Anita C.T. M. Peeters; Els F. van der Molen; Henk J. Blom; Martin den Heijer

doi:10.1160/TH04-05-0284

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(05): 1086-1091
DOI: 10.1160/TH04-05-0284

Endothelium and Vascular Development

Schattauer GmbH

The effect of homocysteine reduction by B-vitamin supplementation on markers of endothelial dysfunction

Anita C.T. M. Peeters

¹Department of Endocrinology, University Medical Centre Nijmegen,The Netherlands

,

Els F. van der Molen

²Department of Paediatrics, University Medical Centre Nijmegen,The Netherlands

,

Henk J. Blom

²Department of Paediatrics, University Medical Centre Nijmegen,The Netherlands

,

Martin den Heijer

¹Department of Endocrinology, University Medical Centre Nijmegen,The Netherlands

³Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen,The Netherlands

› Author Affiliations

Abstract

Summary

Hyperhomocysteinemia is a risk factor for arterial vascular disease and venous thrombosis. The pathophysiology of this relation is unclear, but several studies suggest that hyperhomocysteinemia impairs endothelial function. We examined the effect of homocysteine lowering by B-vitamin supplementation on tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI) and von Willebrand factor (vWf) markers of endothelial dysfunction in hyperhomocysteinemic and normohomocysteinemic volunteers. A total of 123 healthy volunteers were randomized to placebo or B-vitamins (5 mg folic acid, 0.4 mg hydroxycobalamin and 50 mg pyridoxine) daily for 8 weeks. Before and after the intervention period, blood samples were taken for measurements of homocysteine, tPA, PAI and vWf.There was no evident association between homocysteine concentration and concentrations of markers of endothelial dysfunction at baseline.The mean reduction of homocysteine concentration was 31% (95%CI 22.7 to 39.1) in the B-vitamin group compared to 3% reduction in the placebo group. Concentrations of tPA, PAI and vWf did not change after supplementation of B-vitamins. In conclusion, the results of our study show that homocysteine reduction by B-vitamin supplementation has no effect on markers of endothelial dysfunction in healthy volunteers.

Keywords

Endothelial dysfunction - hyperhomocysteinemia - plasminogen activator inhibitor type 1 - tissue plasminogen activator and von Willebrand factor

Full Text

References

References
1 Homocysteine studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288: 2015-22.
2 den Heijer M, Rosendaal FR, Blom HJ. et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874-7.
3 Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect?. Am J Clin Nutr 2000; 72: 315-23.
4 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202.
5 Klerk M, Verhoef P, Clarke R. et al. MTHFR 677C—>T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002; 288: 2023-31.
6 Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042-50.
7 Lentz SR. Homocysteine and vascular dysfunction. Life Sci 1997; 61: 1205-15.
8 Lentz SR, Sobey CG, Piegors DJ. et al. Vascular dysfunction in monkeys with dietinduced hyperhomocyst(e)inemia. J Clin Invest 1996; 98: 24-9.
9 Lawrence de Koning AB, Werstuck GH, Zhou J. et al. Hyperhomocysteinemia and its role in the development of atherosclerosis. Clin Biochem 2003; 36: 431-41.
10 Nappo F, De Rosa N, Marfella R. et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113-18.
11 Thambyrajah J, Townend JN. Homocysteine and atherothrombosis—mechanisms for injury. Eur Heart J 2000; 21: 967-74.
12 Widlansky ME, Gokce N, Keaney JF. et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-60.
13 Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 2002; 22: 6-13.
14 Verhaar MC, Rabelink TJ. The endothelium: a gynecological and obstetric point of view. Eur J Obstet Gynecol Reprod Biol 2001; 94: 180-85.
15 Tawakol A, Omland T, Gerhard M. et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: 1119-21.
16 Lambert J, van den Berg M, Steyn M. et al. Familial hyperhomocysteinaemia and endothelium-dependent vasodilatation and arterial distensibility of large arteries. Cardiovasc Res 1999; 42: 743-51.
17 Schreiner PJ, Wu KK, Malinow MR. et al. Hyperhomocyst(e)inemia and hemostatic factors: the atherosclerosis risk in communities study. Ann Epidemiol 2002; 12: 228-36.
18 Bienvenu T, Ankri A, Chadefaux B. et al. Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic parameters. Thromb Res 1993; 70: 123-29.
19 den Heijer M, Brouwer IA, Bos GM. et al. Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol 1998; 18: 356-61.
20 den Heijer M, Keijzer MB. Hyperhomocysteinemia as a risk factor for venous thrombosis. Clin Chem Lab Med 2001; 39: 710-13.
21 Ingerslev J. A sensitive ELISA for von Willebrand factor (vWf:Ag). Scand J Clin Lab Invest 1987; 47: 143-49.
22 Bozic M, Stegnar M, Fermo I. et al. Mild hyperhomocysteinemia and fibrinolytic factors in patients with history of venous thromboembolism. Thromb Res 2000; 100: 271-8.
23 Tofler GH, D’Agostino RB, Jacques PF. et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost 2002; 88: 799-04.
24 van den Berg M, Boers GH, Franken DG. et al. Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995; 25: 176-81.
25 Freyburger G, Labrouche S, Sassoust G. et al. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular diseases. Thromb Haemost 1997; 77: 466-71.
26 de Jong SC, Stehouwer CD, van den BM. et al. Endothelial marker proteins in hyper-homocysteinemia. Thromb Haemost 1997; 78: 1332-37.
27 Kuch B, Bobak M, Fobker M. et al. Associations between homocysteine and coagulation factors—a cross-sectional study in two populations of central Europe. Thromb Res 2001; 103: 265-73.
28 Yarnell JW, Sweetnam PM, Rumley A. et al. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
29 Vermeulen EG, Rauwerda JA, van den BM. et al. Homocysteine-lowering treatment with folic acid plus vitamin B6 lowers urinary albumin excretion but not plasma markers of endothelial function or C-reactive protein: further analysis of secondary end-points of a randomized clinical trial. Eur J Clin Invest 2003; 33: 209-15.
30 Gerdes VE, Hovinga HA, ten Cate H. et al. Homocysteine and markers of coagulation and endothelial cell activation. J Thromb Haemost 2004; 02: 445-51.
31 Klerk M, Verhoef P, Verbruggen B, Schouten EG. et al. Effect of homocysteine reduction by B-vitamin supplementation on markers of clotting activation. Thromb Haemost 2002; 88: 230-5.