Skip to main content
NCBI home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2006 Dec 5;26(12):563–568. doi: 10.1002/clc.4960261204

The association of homocysteine and coronary artery disease

Gregory M Gauthier 1,✉, Jon G Keevil 2, Patrick E McBride 3
PMCID: PMC6654122  PMID: 14677809

Abstract

Hyperhomocysteinemia has been associated with increased risk of atherosclerosis and myocardial infarction by a number of prospective case‐control studies. A variety of genetic mutations, nutritional deficiencies, disease states, and drugs can elevate homocysteine concentrations. Treatment with folic acid with or without B‐complex vitamins effectively lowers homocysteine levels. Whether therapy corresponds with decreased risk of coronary events is unknown, but may be promising. This article reviews the biochemistry of homocysteine metabolism, pathogeneisis, and etiology of hyperhomocysteinemia, along with its association with coronary artery disease, screening, and treatment.

Keywords: homocysteine, coronary artery disease

Full Text

The Full Text of this article is available as a PDF (55.9 KB).

References

  • 1. McCully KS: Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis. Am J Path 1969; 56: 111–128 [PMC free article] [PubMed] [Google Scholar]
  • 2. Larkin M, Kilmer McCully: Pioneer of the homocysteine theory. Lancet 1998; 352: 1364–1367 [DOI] [PubMed] [Google Scholar]
  • 3. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG: Prospective study of serum total homocysteine concentration and risk of stroke in middle‐aged British men. Lancet 1995; 346: 1395–1398 [DOI] [PubMed] [Google Scholar]
  • 4. Stampher MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH: A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J Am Med Assoc 1992; 268: 877–881 [PubMed] [Google Scholar]
  • 5. Tayler LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM: Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg 1999; 29: 8–19 [DOI] [PubMed] [Google Scholar]
  • 6. den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM: Hyperhomocysteinemia and venous thrombosis: A meta‐analysis. Thromb Hemostasis 1998; 80: 874–877 [PubMed] [Google Scholar]
  • 7. Hankey GJ, Eikelboom JW: Homocysteine and vascular disease. Lancet 1999; 354: 407–U3 [DOI] [PubMed] [Google Scholar]
  • 8. Selhub J: Homocysteine metabolism. Ann Rev Nutr 1999; 19: 217–246 [DOI] [PubMed] [Google Scholar]
  • 9. Stein JH, McBride PE: Hyperhomocysteinemia and atherosclerotic vascular disease. Arch Intern Med 1998; 158: 1301–1306 [DOI] [PubMed] [Google Scholar]
  • 10. Fowler B: Disorders of homocysteine metabolism. J Inher Metabolism 1997; 20: 270–285 [DOI] [PubMed] [Google Scholar]
  • 11. Goyette P, Sumner JS, Milos R, Duncan AMV, Rosenblatt DS, Matthews RG, Rozen R: Human methylenetetrahdyrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Gen 1994; 7: 195–200 [DOI] [PubMed] [Google Scholar]
  • 12. Mudd HS, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GHJ, Bronberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L: The natural history of homocysteinuria due to cystathionine beta‐synthase. deficiency Am J Med Genet 1989; 34: 427–34 [PMC free article] [PubMed] [Google Scholar]
  • 13. Watkins D, Rosenblatt DS: Functional methionine synthase deficiency (cblE and cblG): Clinical and biochemical heterogeneity. Am J Med Genet 1989; 34: 427–34 [DOI] [PubMed] [Google Scholar]
  • 14. Rozen R: Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inher Metab Dis 1996; 19: 589–594 [DOI] [PubMed] [Google Scholar]
  • 15. Jacobsen DW: Homocysteine and vitamins in cardiovascular disease. Clin Chem 1998; 44: 8(B) 1833–1843 [PubMed] [Google Scholar]
  • 16. Tonstad S, Refsum H, Ose L, Ueland PM: The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine. J Pediatr 1998; 132: 365–368 [DOI] [PubMed] [Google Scholar]
  • 17. Refsum H, Ueland PM, Kvinnsland S: Acute and long‐term effects of highdose methotrexate treatment on homocysteine in plasma and urine. Cancer Res 1986; 46: 5385–5391 [PubMed] [Google Scholar]
  • 18. Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter‐Sack I: Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999; 40: 345–350 [DOI] [PubMed] [Google Scholar]
  • 19. James GK, Jones MW, Pudek MR: Homocyst(e)ine levels in patients on phenytoin therapy. Clin Bio chem 1997; 30: 6447–6449 [DOI] [PubMed] [Google Scholar]
  • 20. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezier R, Vermaak WJH: The effect of subnormal vitamin B‐6 status on homocysteine metabolism. J Clin Invest 1996; 98: 177–184 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Ermans AAM, Refsum H, Rupreht J, Spijkers JM, Guttormsen AB, Lindemans J, Ueland PM, Abels J: Monitoring cobalamine inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine. Clin Pharmacol Ther 1991; 49: 385–393 [DOI] [PubMed] [Google Scholar]
  • 22. Dierkes J, Westphal S, Luley C: Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219–220 [DOI] [PubMed] [Google Scholar]
  • 23. Blankenhorn DJ, Malinow MR, Mack WJ: Colestipol plus niacin therapy elevates plasma homocyst(e)ine levels. Cor Art Dis 1991; 2: 357–360 [Google Scholar]
  • 24. Nygard O, Refsum H, Ueland PM, Stensvold I, Nordrehaug JE, Kvale G, Vollset SE: Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am J Clin Nutr 1997; 65: 136–143 [DOI] [PubMed] [Google Scholar]
  • 25. Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordehaug JE, Ueland PM, Kvale G: Total plasma homocysteine and cardiovascular risk profile. J Am Med Assoc 1995; 274: 1526–1533 [DOI] [PubMed] [Google Scholar]
  • 26. Bostom AG, Lathrop L: Hyperhomocysteinemia in end stage renal disease: Prevalence, etiology, and potential relationship to atherosclerotic outcomes. Kidney Int 1997; 52: 10–20 [DOI] [PubMed] [Google Scholar]
  • 27. Refsum H, Helland S, Ueland PM: Fasting plasma homocysteine as a sensitive parameter of antifolate effect: A study of psoriasis patients receiving low‐dose methotrexate treatment. Clin Pharmacol Ther 1989; 46: 510–520 [DOI] [PubMed] [Google Scholar]
  • 28. Nedrebo BG, Ericsson UB, Nygard O, Refsum H, Ueland PM, Aakvaag A, Aanderud S, Lien EA: Plasma total homocysteine levels in hyperthyroid and hypothyroid patients. Metabolism 1998; 47: 89–93 [DOI] [PubMed] [Google Scholar]
  • 29. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH: Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996; 348: 1120–1124 [DOI] [PubMed] [Google Scholar]
  • 30. Allen RH, Stabler SP, Savage DG, Lindenbaum J: Diagnosis of cobalamine deficiency I: Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am JHematol 1990; 34: 90–98 [DOI] [PubMed] [Google Scholar]
  • 31. Gupta A, Moustapha A, Jacobsen DW, Goormastic M, Tuzcu EM, Hobbs R, Young J, James K, McCarthy P, van Lente F, Green R, Robinson K: High homocysteine, low folate, and low vitamin B6 concentrations: Prevalent risk factors for vascular disease in heart transplant recipients. Transplantation 1998; 65: 544–550 [DOI] [PubMed] [Google Scholar]
  • 32. Berger PB, Jones JD, Olson LJ, Edwards BS, Frantz RP, Rodeheffer RJ, Kottke BA, Daly RC, McGregor CGA: Increase in total plasma homocysteine concentration after cardiac transplantation. Mayo Clin Proc 1994; 70: 125–131 [DOI] [PubMed] [Google Scholar]
  • 33. Cook RC, Tupper JK, Parker S, Kingsbury K, Frohlich JJ, Abel JG, Gao M, Ignaszewski AP: Effect of immunosupressive therapy, serum creatinine, and time after transplant on plasma total homocysteine in patients following heart transplantation. J Heart Lung Transplant 1999; 18: 420–424 [DOI] [PubMed] [Google Scholar]
  • 34. Arnadottir M, Hultberg B, Wahlberg J, Fellstrom B, Dimeny E: Serum total homocysteine concentration before and after renal transplantation. Kidney Int 1998; 54: 1380–1384 [DOI] [PubMed] [Google Scholar]
  • 35. Ducloux D, Rudein C, Givey R, Vautrin P, BressonVautrin C, Rebibou JM, Chalopin JM: Prevalence, determinants, and clinical significance of hyperhomocyst(e)inaemia in renal transplant recipients. Nephrol Dial Transplant 1998; 13: 2890–2893 [DOI] [PubMed] [Google Scholar]
  • 36. Bostom AG, Gohh RY, Beaulieu AJ, Han H, Jacques PF, Selhub J, Dworkin L, Rosenberg IH: Determinants of fasting plasma total homocysteine levels among chronic stable renal transplant recipients. Transplantation 1999; 68: 257–261 [DOI] [PubMed] [Google Scholar]
  • 37. Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM: Serum total homocysteine and cardiovascular disease occurrence in chronic, stable, renal transplant recipients: A prospective study. J Am Soc Nephrol 2000; 11: 134–137 [DOI] [PubMed] [Google Scholar]
  • 38. Fernandez‐Miranda C, Gomez P, Diaz‐Rubio P, Estenoz J, Carrillo JL, Andres A, Morales JM: Plasma homocysteine levels in renal transplanted patients on cyclosporin or tracrolimus therapy: Effect of treatment with folic acid. Clin Transplantation 2000; 14: 110–114 [DOI] [PubMed] [Google Scholar]
  • 39. Abrosi P, Garcon D, Riberi A, Habib G, Barlatier A, Kreitmann B, Rolland PH, Bouvenot G, Luccioni T, Metras D: Association of mild hyperhomocysteinemia with cardiac graft vascular disease. Atherosclerosis 1998; 138: 347–350 [DOI] [PubMed] [Google Scholar]
  • 40. Cole DEC, Ross HJ, Evrovski J, Langman LJ, Miner SES, Daly PA, Wong PY: Correlation between total homocysteine and cyclosporin concentrations in cardiac transplant recipients. Clin Chem 1998; 44: 2307–2312 [PubMed] [Google Scholar]
  • 41. Ducloux D, Fournier V, Rebibou JM, Bresson‐Vautrin C, Gibey R, Chalopin JM: Hyperhomocyst(e)inemia in renal transplant recipients with and without cyclosporine. ClinNephrol 1998; 49: 232–235 [PubMed] [Google Scholar]
  • 42. Andersson A, Brattstrom L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B: Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992; 22: 79–87 [DOI] [PubMed] [Google Scholar]
  • 43. Guttormsen AB, Schneede J, Finkerstrand T, Ueland PM, Refsum HM: Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy subjects. Clin ChimActa 1992; 207: 119–128 [DOI] [PubMed] [Google Scholar]
  • 44. Egerton W, Silberberg J, Crooks R, Ray C, Xie L, Dudman N: Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol 1996; 77: 759–761 [DOI] [PubMed] [Google Scholar]
  • 45. Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L: Plasma homocysteine in acute myocardial infarction: Homocysteine lowering effect of folic acid. J Int Med 1995; 237: 381–388 [DOI] [PubMed] [Google Scholar]
  • 46. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett WC: Homocysteine metabolism and risk of myocardial infarction: Relation with vitamins B6, B12, and folate. Am J Epidemiol 1996; 143: 845–859 [DOI] [PubMed] [Google Scholar]
  • 47. Al‐obaidi MK, Stubbs PJ, Amersey R, Noble MIM: Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes. Heart 2001; 85: 380–384 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Celermajer DS, Sorensen K, Ryalls M, Robinson J, Thomas O, Leonard JV, Deanfield JE: Impaired endothelial function occurs in systemic arteries of children with homozygous homocysteinuria but not in their heterozygous parents. J Am Coll Cardiol 1993; 22: 854–858 [DOI] [PubMed] [Google Scholar]
  • 49. Wall RT, Harlan JM, Harker LA Striker GE: Homocysteine‐induced endothelial cell injury in vitro: A model for the study of vascular injury. Thromb Res 1980; 18: 113–121 [DOI] [PubMed] [Google Scholar]
  • 50. Tsai JC, Perrella MA, Yoshizumi M, Hseih CM, Haber E, Schlegel R, Lee M: Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Proc Natl Acad Sci USA 1994; 91: 6369–6373 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Upchurch GR, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF, Loscalzo J: Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997; 272: 17012–17017 [DOI] [PubMed] [Google Scholar]
  • 52. Rodgers GM, Kane WH: Activation of endogenous factor V by a homocysteine‐induced vascular endothelial activator. J Clin Invest 1986; 77: 1909–1916 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Ratnoff OD: Activation of Hageman factor by L‐homocysteine. Science 1968; 162: 1007–1009 [DOI] [PubMed] [Google Scholar]
  • 54. Nishinaga M, Ozawa T, Shimada K: Homocysteine, a thrombogenic agent, suppresses anticoagulant heparin sulfate expression in cultured porcine aortic endothelial cell. J Clin Invest 1993; 92: 1381–1386 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Lentz SR, Sadler JE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88: 1906–1914 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Fryer RH Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM: Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993; 13: 1327–1333 [DOI] [PubMed] [Google Scholar]
  • 57. Graeber JE, Slott JH, Ulane RE, Schulman JD, Stuart MJ: Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res 1982; 16: 490–493 [DOI] [PubMed] [Google Scholar]
  • 58. Wang J, Dudman NPB, Wilcken DEL: Effects of homocysteine and related compounds on prostacyclin production by cultures of human vascular endothelial cells. ThrombHaem 1993; 70: 1047–1052 [PubMed] [Google Scholar]
  • 59. Wilcken DEL, Wilcken B: The pathogenesis of coronary artery disease. J Clin Invest 1976; 57: 1079–1082 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Arnesen E, Refsum H, Bonaa KH, Uleland PM, Forde OH, Nordrehaug JE: Serum total homocysteine and coronary artery disease. Int J Epidemiol 1995; 24: 704–709 [DOI] [PubMed] [Google Scholar]
  • 61. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma‐Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Luis AC, Parrot‐Rouland FM, Tan KS, Higgins I, Garcon D, Andria G: Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. J Am Med Assoc 1997; 277: 1775–1781 [DOI] [PubMed] [Google Scholar]
  • 62. Knekt P, Reunanen A, Alfthan G, Heliovaara M, Rissanen H, Marniemi J, Aromaa A: Hyperhomocysteinemia: A risk factor or consequence of coronary heart disease. Arch Intern Med 2001; 161: 1589–1594 [DOI] [PubMed] [Google Scholar]
  • 63. Chasen‐Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tischler PV, Willett W, Hennekens CH, Stamfer JM: A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996; 15: 136–143 [DOI] [PubMed] [Google Scholar]
  • 64. Alfthan G, Pekkanen J, Jauhianen, Pitkaniemi J, Karvonen M, Toumilehoto J, Salonen IT, Ehnholn C: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based Study Atherosclerosis 1994; 106: 9–19 [DOI] [PubMed] [Google Scholar]
  • 65. Evans RW, Shaten BJ, Hempel JD, Culter JA, Kuller LH: Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscl Thromb Vasc Bio 1997; 17: 1947–1953 [DOI] [PubMed] [Google Scholar]
  • 66. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE: Prospective study of coronary artery disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: The Atherosclerosis Risk In Communities Study. Circulation 1998; 98: 204–210 [DOI] [PubMed] [Google Scholar]
  • 67. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. J Am Med Assoc 1995; 274: 1049–1057 [DOI] [PubMed] [Google Scholar]
  • 68. Homocysteine Lowering Trialists' Collaboration : Lowering blood homocysteine with folic acid based supplements: Meta‐analysis of randomised trials. Br Med J 1998; 316: 894–898 [PMC free article] [PubMed] [Google Scholar]
  • 69. Woodside JV, Yarnell JWG, McMaster D, Young IS, Harmon DL, McCrum EE, Patterson CC, Gey KF, Whitehead AS, Evans A: Effect of B‐group vitamins and antioxidant vitamins on hyperhomocysteinemia: A double blind, randomized, factorial‐design, controlled trial. Am J Clin Nutr 1998; 67: 858–866 [DOI] [PubMed] [Google Scholar]
  • 70. Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM: Reduction of plasma homo‐cyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary artery disease. N Engl J Med 1998; 338: 1009–1015 [DOI] [PubMed] [Google Scholar]
  • 71. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli F, Meier B, Turi ZG, Hess OM: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2002; 345: 1593–1600 [DOI] [PubMed] [Google Scholar]
  • 72. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM: Effect of homocysteine‐lowering therapy with folic acid, vitamin B12, and Vitamin B6 on clinical outcome after percutaneous intervention. J Am Med Assoc 2002; 288: 973–979 [DOI] [PubMed] [Google Scholar]
  • 73. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337: 230–236 [DOI] [PubMed] [Google Scholar]
  • 74. Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TE, Pearson RR: Plasma homocysteine predicts mortality independently of traditional risk factors and C‐reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000; 102: 1227–1232 [DOI] [PubMed] [Google Scholar]
  • 75. Knekt P, Alfthan G, Aromaa A, Heliovaara M, Marniemi J, Rissanen H, Reunanen A: Homocysteine and major coronary events: A prospective study among women. J Int Med 2001; 249: 461–65 [DOI] [PubMed] [Google Scholar]
  • 76. Omland T, Samuelsson A, Hartford M, Herlitz J, Karlsson T, Christensen B, Caidahl K: Serum homocysteine concentration as an indicator of survival in patients with acute coronary syndromes. Arch Intern Med 2000; 160: 1834–1840 [DOI] [PubMed] [Google Scholar]
  • 77. Stubbs PJ, Al‐Obaidi MK, Conroy RM, Collinson PO, Graham IM, Noble MIM: Effect of plasma homocysteine concentration on early and late events in patients with acute coronary syndromes. Circulation 2000; 102: 605–610 [DOI] [PubMed] [Google Scholar]
  • 78. Liem A, Reynierse‐Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ: Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 2003; 41: 2105–2113 [DOI] [PubMed] [Google Scholar]
  • 79. van Guldener C, Janssen MJ, de Meer K, Donker AJ, Stehouwer CD: Effect of folic acid and betaine on fasting and postmethionine‐loading plasma homocysteine and methionine levels in chronic hemodialysis patients. J Intern Med 1999; 245: 175–183 [DOI] [PubMed] [Google Scholar]
  • 80. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA: Homocysteinuria‐the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983; 309: 448–453 [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES