Current Cardiovascular Risk Reports

, Volume 2, Issue 2, pp 141–149 | Cite as

Is homocysteine a relevant cardiovascular risk factor?



Scientific research is searching constantly for new markers to help stage the progress and prognosis of cardiovascular disease. Over the past few decades, homocysteine has been suggested as a risk factor involved in the promotion of atherosclerosis and thrombotic vascular events. Several large observational studies have indicated a relationship between homocysteine and cardiovascular illness. However, more robust prospective trials reveal a weaker association between the two than do case-control and cross-sectional data. Recently, many randomized controlled trials have evaluated the impact of homocysteine-lowering therapy on vascular risk. The overall evidence suggests a null effect, thereby failing to validate the hypothesis that a reduction in homocysteine levels would result in clinical benefit. This review outlines the latest relevant data and illustrates why the use of homocysteine as a screening tool or a target of cardiovascular treatment cannot be recommended.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Khot UN, Khot MB, Bajzer CT, et al.: Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003, 290:898–904.PubMedCrossRefGoogle Scholar
  2. 2.
    Greenland P, Knoll MD, Stamler J, et al.: Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA 2003, 290:891–897.PubMedCrossRefGoogle Scholar
  3. 3.
    Von Eckardstein A: Is there a need for novel cardiovascular risk factors? Nephrol Dial Transplant 2004, 19:761–765.CrossRefGoogle Scholar
  4. 4.
    McCully KS: Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969, 56:111–128.PubMedGoogle Scholar
  5. 5.
    Wilcken DE, Wilcken B: The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest 1976, 57:1079–1082.PubMedCrossRefGoogle Scholar
  6. 6.
    Selhub J: Homocysteine metabolism. Annu Rev Nutr 1999, 19:217–246.PubMedCrossRefGoogle Scholar
  7. 7.
    Refsum H, Smith AD, Ueland PM, et al.: Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004, 50:3–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Mudd SH, Levy HL, Skovby F: Disorders of transsulfuration. In The Metabolic and Molecular Basis of Inherited Disease, vol 1, edn 7. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:1279–1327.Google Scholar
  9. 9.
    Klerk M, Verhoef P, Clarke R, et al.: MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002, 288:2023–2031.PubMedCrossRefGoogle Scholar
  10. 10.
    Selub J, Jacques PF, Wilson PW, et al.: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993, 270:2693–2698.CrossRefGoogle Scholar
  11. 11.
    Homocysteine Lowering Trialists’ Collaboration: Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998, 316:894–898.Google Scholar
  12. 12.
    Booth GL, Wang EE: Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. CMAJ 2000, 163:21–29.PubMedGoogle Scholar
  13. 13.
    Homocysteine Studies Collaboration: Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002, 288:2015–2022.CrossRefGoogle Scholar
  14. 14.
    Wald DS, Law M, Morris JK: Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002, 325:1202–1206.PubMedCrossRefGoogle Scholar
  15. 15.
    Lewis SJ, Ebrahim S, Davey-Smith G: Meta-analysis of the MTHFR C to T polymorphism and coronary heart disease; does the totality of evidence support a causal role for homocysteine and the preventive potential of folate? BMJ 2005, 331:1053–1056.PubMedCrossRefGoogle Scholar
  16. 16.
    Verhoef P, Hennekens CH, Malinow MR, et al.: A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994, 25:1924–1930.PubMedGoogle Scholar
  17. 17.
    Evans RW, Shaten BJ, Hempel JD, et al.: Homocysteine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997, 17:1947–1953.PubMedGoogle Scholar
  18. 18.
    Folsom AR, Nieto FJ, McGovern PG, et al.: 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 1998, 98:204–210.PubMedGoogle Scholar
  19. 19.
    Voutilainen S, Lakka TA, Hamelahti P, et al.: Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. J Intern Med 2000, 248:217–222.PubMedCrossRefGoogle Scholar
  20. 20.
    Nygård O, Nordrehaug JE, Refsum H, et al.: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997, 337:230–236.PubMedCrossRefGoogle Scholar
  21. 21.
    Dudman NP: An alternative view of homocysteine. Lancet 1999, 354:2072–2074.PubMedCrossRefGoogle Scholar
  22. 22.
    Marcucci R, Zanazzi M, Bertoni E, et al.: Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinemic renal-transplant recipients. Transplantation 2003, 75:1551–1555.PubMedCrossRefGoogle Scholar
  23. 23.
    Schnyder G, Roffi M, Pin R, et al.: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001, 345:1593–1600.PubMedCrossRefGoogle Scholar
  24. 24.
    Lange H, Suryapranata H, De Luca G, et al.: Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004, 350:2673–2681.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaul S, Zadeh AA, Shah PK: Homocysteine hypothesis for atherothrombotic cardiovascular disease. J Am Coll Cardiol 2006, 48:914–923.PubMedCrossRefGoogle Scholar
  26. 26.
    Toole JF, Malinow MR, Chambless LE, et al.: 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 2004, 291:565–575.PubMedCrossRefGoogle Scholar
  27. 27.
    Spence JD, Bang H, Chambless LE, Stampfer MJ: Vitamin intervention for stroke prevention trial: an efficacy analysis. Stroke 2005 36:2404–2409.PubMedCrossRefGoogle Scholar
  28. 28.
    Bønaa KH, Njølstad I, Ueland PM, et al.: Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006, 354:1578–1588.PubMedCrossRefGoogle Scholar
  29. 29.
    Bor MV, Refsum H, Bisp MR, et al.: Plasma vitamin B6 vitamers before and after oral vitamin B6 treatment: a randomized placebo controlled study. Clin Chem 2003, 49:155–161.PubMedCrossRefGoogle Scholar
  30. 30.
    Matsubara K, Mori M, Matsuura Y, Kato N: Pyridoxal 5-phosphate and pyridoxal inhibit angiogenesis in serumfree rat aortic ring assay. Int J Mol Med 2001, 8:505–508.PubMedGoogle Scholar
  31. 31.
    Lonn E, Yusuf S, Arnold MJ, et al.: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006, 354:1567–1577.PubMedCrossRefGoogle Scholar
  32. 32.
    Bazzano LA, Reynolds K, Holder K, et al.: Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006, 296:2720–2726.PubMedCrossRefGoogle Scholar
  33. 33.
    Schnyder G, Roffi M, Flammer Y, et al.: 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 2002, 288:973–979.PubMedCrossRefGoogle Scholar
  34. 34.
    Liem AH, van Boven AJ, Veeger NJ, et al.: Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomized pilot trial. Int J Cardiol 2004, 93:175–179.PubMedCrossRefGoogle Scholar
  35. 35.
    Righetti M, Serbelloni P, Milani S, et al.: Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif 2006, 24:379–386.PubMedCrossRefGoogle Scholar
  36. 36.
    Zoungas S, McGrath BP, Branley P, et al.: Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized controlled trial. J Am Coll Cardiol 2006, 47:1108–1116.PubMedCrossRefGoogle Scholar
  37. 37.
    Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, et al.: Secondary prevention with folic acid: results of the Goes extension study. Heart 2005, 91:1213–1214.PubMedCrossRefGoogle Scholar
  38. 38.
    Wrone EM, Hornberger JM, Zehnder JL, et al.: Randomized trial of folic acid for prevention for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol 2004, 15:420–426.PubMedCrossRefGoogle Scholar
  39. 39.
    Righetti M, Ferrario GM, Milani S, et al.: Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit 2003, 9:9PI19–9PI24.Google Scholar
  40. 40.
    Baker F, Picton D, Blackwood S, et al.: Blinded comparison of folic acid and placebo in patients with ischemic heart disease: an outcome trial. Circulation 2002, 106(Suppl 2):741S.Google Scholar
  41. 41.
    Wang X, Qin X, Demirtas H, et al.: Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007, 369:1876–1882.PubMedCrossRefGoogle Scholar
  42. 42.
    Mark SD, Wang W, Fraumeni JF Jr, et al.: Lowered risks of hypertension and cerebrovascular disease after vitamin/mineral supplementation: the Linxian Nutrition Intervention. Am J Epidemiol 1996, 143:658–664.PubMedGoogle Scholar
  43. 43.
    Albert C: A randomized trial of folic acid and B-vitamins in the secondary prevention of cardiovascular events in women: Results from the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS). Presented at the American Heart Association 2006 Scientific Sessions. Chicago; November 13, 2006.Google Scholar
  44. 44.
    Ebbing M: Results from the Western Norway B-Vitamin Intervention Trial (WENBIT). Presented at the European Society of Cardiology 2007 World Congress. Vienna; September 4, 2007.Google Scholar
  45. 45.
    Malinow MR, Bostom AG, Krauss RM: Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999, 99:178–182.PubMedGoogle Scholar
  46. 46.
    Vogel JHK, Bolling SF, Costello RB, et al.: Integrating complementary medicine into cardiovascular medicine. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). J Am Coll Cardiol 2005, 46:184–221.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Division of CardiologyCedars-Sinai Medical CenterLos AngelesUSA

Personalised recommendations