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Is plasma homocysteine a modifiable risk factor for stroke?

Nature Clinical Practice Neurology volume 2, pages 26–33 (2006)Cite this article

Abstract

Increased levels of plasma total homocysteine (tHcy) can be caused by genetic mutations, vitamin deficiencies, renal and other diseases, and numerous drugs. Raised tHcy also correlate with increasing age, and are associated with laboratory evidence of atherogenesis (e.g. endothelial dysfunction) and thrombosis, and with epidemiological evidence of an increased risk of atherothrombotic vascular disease, including ischemic stroke. The association between raised tHcy and increased risk of ischemic stroke is independent of other known vascular risk factors and is biologically plausible; however, randomized controlled trials have not revealed a causal relationship. The recently published Vitamins In Stroke Prevention (VISP) trial identified no significant reduction in the relative risk of stroke by lowering tHcy with B-vitamin therapy among 3,680 patients with recent ischemic stroke. It did not, however, reliably exclude a modest but important reduction of up to 20% in relative risk of stroke. Currently, there is insufficient evidence to confirm that homocysteine is a modifiable causal risk factor for stroke, or to recommend routine screening for, or treatment of, raised tHcy concentrations with folic acid and other vitamins, to prevent ischemic stroke.

Key Points

  • The hypothesis that high levels of plasma total homocysteine (tHcy) might predispose people to atherothrombosis and ischemic stroke was based on the observation that patients with homocystinuria are particularly susceptible to vascular disease and premature death from myocardial infarction

  • Evidence from laboratory studies, epidemiology and clinical trials support a correlation between elevated tHcy and stroke, but there is limited evidence for a causal relationship

  • The homocysteine hypothesis is currently being tested by at least 12 large ongoing clinical trials, involving more than 50,000 patients

  • B-vitamin therapy has been shown to be effective at reducing tHcy levels, but there are insufficient reliable data from large randomized controlled trials to indicate that B-vitamin therapy is effective for preventing clinical vascular events

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Figure 1: Homocysteine metabolic pathways.

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References

  1. Mudd SH et al. (2000) Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol 20: 1704–1706

    Article  CAS  Google Scholar 

  2. D'Angelo A and Selhub J (1997) Homocysteine and thrombotic disease. Blood 90: 1–11

    CAS  PubMed  Google Scholar 

  3. Moat SJ et al. (2004) Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 15: 64–79

    Article  CAS  Google Scholar 

  4. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56: 111–128

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Refsum H et al. (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 50: 3–32

    Article  CAS  Google Scholar 

  6. Desouza C et al. (2002) Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs 62: 605–616

    Article  CAS  Google Scholar 

  7. Homocysteine Lowering Trialists' Collaboration (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316: 894–898

  8. Van Guldener C et al. (1999) Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients. J Intern Med 245: 175–183

    Article  CAS  Google Scholar 

  9. Toole JF et al. (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291: 565–575

    Article  CAS  Google Scholar 

  10. Hankey GJ et al. (2004) Is there really a power shortage in clinical trials testing the “homocysteine hypothesis”? Arterioscler Thromb Vasc Biol 24: e147

    Article  CAS  Google Scholar 

  11. Dusitanond P et al. (2005) Homocysteine-lowering treatment with folic acid, cobalamin and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomised substudy of the VITATOPS trial. Stroke 36: 144–146

    Article  CAS  Google Scholar 

  12. Symons JD et al. (2002) Hyperhomocysteinemia evoked by folate depletion: effects on coronary and carotid arterial function. Arterioscler Thromb Vasc Biol 22: 772–780

    Article  CAS  Google Scholar 

  13. Faraci FM (2003) Hyperhomocysteinemia: a million ways to lose control. Arterioscler Thromb Vasc Biol 23: 371–373

    Article  CAS  Google Scholar 

  14. Faraci FM and Lentz SR (2004) Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 35: 345–347

    Article  Google Scholar 

  15. Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288: 2015–2022

  16. Wald DS et al. (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325: 1202–1206

    Article  Google Scholar 

  17. Bazzano LA et al. (2002) Dietary intake of folate and risk of stroke in US men and women: NHAMES I Epidemiologic Follow-up Study. Stroke 33: 1183–1189

    Article  CAS  Google Scholar 

  18. He K et al. (2004) Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 35: 169–174

    Article  CAS  Google Scholar 

  19. Klerk M et al. (2002) MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288: 2023–2031

    Article  CAS  Google Scholar 

  20. Casas JP et al. (2005) Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 365: 224–232

    Article  CAS  Google Scholar 

  21. Peterson JC and Spence JD (1998) Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia. Lancet 351: 263

    CAS  PubMed  Google Scholar 

  22. Hackam DG et al. (2000) What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14μM/l. Am J Hypertens 13: 105–110

    Article  CAS  Google Scholar 

  23. Marcucci R et al. (2003) Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinaemic renal-transplant recipients. Transplantation 75: 1551–1555

    Article  CAS  Google Scholar 

  24. Vermeulen EG et al. (2000) Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 355: 517–522

    Article  CAS  Google Scholar 

  25. Schnyder G et al. (2001) Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 345: 1593–1600

    Article  CAS  Google Scholar 

  26. Schnyder G et al. (2002) Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 288: 973–979

    Article  CAS  Google Scholar 

  27. Lange H et al. (2004) Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 350: 2673–2681

    Article  CAS  Google Scholar 

  28. Lawlor DA et al. (2004) Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 363: 1724–1727

    Article  Google Scholar 

  29. Dudman NP (1999) An alternative view of homocysteine. Lancet 354: 2072–2074

    Article  CAS  Google Scholar 

  30. Hankey GJ and Eikelboom JW (2005) Homocysteine and stroke. Lancet 365: 194–196

    Article  Google Scholar 

  31. Hankey GJ and Eikelboom JW (2004) Folic acid-based multivitamin therapy to prevent stroke: the jury is still out. Stroke 35: 1995–1998

    Article  CAS  Google Scholar 

  32. Jacques PF et al. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340: 1449–1454

    Article  CAS  Google Scholar 

  33. Bostom AG et al. (2001) Power shortage: clinical trials testing the “homocysteine hypothesis” against a background of folic acid-fortified cereal grain flour. Ann Intern Med 135: 133–137

    Article  CAS  Google Scholar 

  34. Hankey GJ et al. (2004) Sustained homocyteine-lowering effect over time of folic acid-based multivitamin therapy in stroke patients despite increasing folate status in the population. Cerebrovascular Dis 19: 110–116

    Article  Google Scholar 

  35. Quinlivan EP et al. (2002) Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 359: 227–228

    Article  CAS  Google Scholar 

  36. Robertson J et al. (2005) Vitamin B12, homocysteine and carotid plaque in the era of folate fortification of enriched cereal grain products. CMAJ 172: 1569–1573

    Article  Google Scholar 

  37. Clinical Trials Service Unit, Oxford, UK [http://www.ctsu.ox.ac.uk]

  38. B-vitamin Treatment Trialists' Collaboration: Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J, in press

  39. Morris CD and Carson S (2003) Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 139: 56–70

    Article  CAS  Google Scholar 

  40. Lucock M (2004) Is folic acid the ultimate functional food component for disease prevention? BMJ 328: 211–214

    Article  CAS  Google Scholar 

  41. Hankey GJ et al. (2004) Clinical usefulness of plasma homocysteine in vascular disease. Med J Aust 181: 314–318

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Consultant Neurologist and Head of the Stroke Unit at the Royal Perth Hospital, and a Clinical Professor in the School of Medicine and Pharmacology, University of Western Australia, WA, Australia

    Graeme J Hankey

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Correspondence to Graeme J Hankey.

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Competing interests

Graeme Hankey is the principal investigator of the Vitamins to Prevent Stroke (VITATOPS) Trial.

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Hankey, G. Is plasma homocysteine a modifiable risk factor for stroke?. Nat Rev Neurol 2, 26–33 (2006). https://doi.org/10.1038/ncpneuro0093

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