American Heart Journal
Volume 148, Issue 1 , Pages 34-40 , July 2004

Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials

  • Adam Splaver, MD

      Affiliations

    • Division of Cardiology Research, Mount Sinai Medical Center, University of Miami School of Medicine Miami Beach, FlaUSA
    • ,
  • Gervasio A Lamas, MD

      Affiliations

    • Division of Cardiology Research, Mount Sinai Medical Center, University of Miami School of Medicine Miami Beach, FlaUSA
    • Department of Medicine, University of Miami School of Medicine, Miami, FlaUSA
    • ,
  • Charles H Hennekens, MD, DrPH

      Affiliations

    • Department of Medicine, University of Miami School of Medicine, Miami, FlaUSA
    • Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami, FlaUSA
    • Agatston Research Institute (ARI), Miami Beach, FlaUSA
    • Corresponding Author InformationReprint requests: Charles H. Hennekens, 2800 S Ocean Blvd, PH-A, Boca Raton, FL 33432, USA.

Received 14 August 2003 ,Accepted 10 January 2004.

References 

  1. Hennekens CH. Increasing global burden of cardiovascular disease (current knowledge and future directions for research on risk factors). Circulation. 1998;97:1095–1102
  2. Harker L, Slichter SJ, Scott R, et al.  Homocystinemia (vascular injury and arterial thrombosis). N Engl J Med. 1974;291:537–543
  3. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999;354:407–413
  4. Harjai KJ. Potential new cardiovascular risk factors (left ventricular hypertrophy, homocysteine, lipoprotein (a), triglycerides, oxidative stress, and fibrinogen). Ann Intern Med. 1999;131:376–386
  5. Domagala TB, Undas A, Libura M, et al.  Pathogenesis of vascular disease in hyperhomocysteinaemia. J Cardiovasc Risk. 1998;5:239–247
  6. Refsum H, Ueland PM, Nygård O, et al.  Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31–62
  7. Robinson K. Homocysteine, B vitamins, and risk of cardiovascular disease. Heart. 2000;83:127–130
  8. Welch G, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042–1050
  9. Upchurch GR, Welch GN, Fabian AJ, et al.  Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem. 1997;272:17012–17017
  10. Yamamoto M, Hara H, Adachi T. Effects of homocysteine on the binding of extracellular-superoxide dismutase to the endothelial cell surface. FEBS Lett. 2000;486:159–162
  11. Doshi S, McDowell I, Moat S, et al. Folate improves endothelial function in coronary artery disease; an effect mediated by reduction of intracellular superoxide. Arterioscler Thromb Vasc Biol 2001:1196–202
  12. Zhang F, Slungaard A, Vercellotti G, et al.  Superoxide-dependent cerebrovascular effects of homocysteine. Am J Physiol. 1998;274:R1704–1711
  13. Berman R, Martin W. Arterial endothelial barrier dysfunction (actions of homocysteine and the hypoxanthine-xanthine oxidase free radical generating system). Br J Pharmacol. 1993;108:920–926
  14. Clarke R, Naughten E, Chalane S, et al.  The role of free radicals as mediators of endothelial cell injury in hyperhomocystenemia. Ir J Med Sci. 1992;161:561–564
  15. Heinecke J. Biochemical evidence for a link between elevated levels of homocysteine and lipid peroxidation in vivo. Curr Atheroscler Rep. 1999;1:87–89
  16. Stangl V, Gunther C, Jarrin A, et al.  Homocysteine inhibits TNF-alpha induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. Biochem Biophys Res Commun. 2001;280:1093–1100
  17. Hossain GS, van Thienen JV, Wersuck GH, et al.  TDAG51 is induced by homocysteine, promotes detachment mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocyseinemia. J Biol Chem. 2003;278:30317–30327
  18. Wang H, Jiang XH, Yang F, et al.  Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. Blood. 2002;99:939–945
  19. Stujlinger M, Tsao P, Her J, et al.  Homocysteine impairs the nitric oxide synthase pathway (role of asymmetric dimethylarginine). Circulation. 2001;104:2569–2575
  20. Drunat S, Moatti N, Paul J, et al.  Homocysteine-induced decrease in endothelin-1 production is initiated at the extracellular level and involves oxidative products. Eur J Biochem. 2001;268:5287–5294
  21. Demuth K, Atger V, Borderie D, et al.  Homocysteine decreases endothelin-1 production by cultured human endothelial cells. Eur J Biochem. 1999;263:367–376
  22. Doshi S, Goodfellow J, Lewis M, et al.  Homocysteine and endothelial function. Cardiovasc Res. 1999;42:578–582
  23. Thambyraja J, Landray M, McGlynn F, et al.  A randomized double blinded placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease. J Am Coll Cardiol. 2001;27:1858–1863
  24. Tyagi S, Smiley L, Mujumdar V. Homocysteine impairs endocardial endothelial function. Can J Physiol Pharmacol. 1999;77:950–957
  25. Welch G, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042–1050
  26. Rodgers G, Kane W. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest. 1986;77:1909–1916
  27. Fryer R, Wilson B, Gubler D, et al.  Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb. 1993;13:1327–1333
  28. Lentz S, Sadler J. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest. 1991;88:1906–1914
  29. Dalton M, Gadson P, Wrenn R, et al.  Homocysteine signal cascade; production of phospholipids, activation of protein kinase C and the induction of c-fos and c-myb in smooth muscle cells. FASEB J. 1997;11:703–711
  30. Tang L, Mamotte C, Van Bockxmeer F, et al.  The effect of homocysteine on DNA synthesis on cultured human vascular smooth muscle. Atherosclerosis. 1998;136:169–173
  31. Taha S, Azzi A, Ozer N. Homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells by a hydrogen peroxide independent mechanism. Antiox Redux Sig. 1999;1:365–369
  32. Tsai J, Perrella M, Yoshizumi M, et al.  Promotion of vascular smooth muscle cell growth by homocysteine (a link to atherosclerosis). Proc Natl Acad Sci USA. 1994;91:6369–6373
  33. Sung F, Slow Y, Wang G, et al.  Homocysteine stimulates the expression of monocyte chemo attractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis. Mol Cell Biochem. 2001;216:121–128
  34. Wang G, O K. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals. Biochem J 2001;357:233–40
  35. Poddar R, Sivasubramanian N, DiBello P, et al.  Association between increased homocysteine levels and impaired fibrinolytic potential (potential mechanism for cardiovascular risk). Thromb Haemost. 2002;88:799–804
  36. Tofler GH, D'Agostino RB, Jaques PF, et al.  Association between increased homocysteine levels and impaired fibrinolytic potential (potential mechanism for cardiovascular risk). Thromb Haemost. 2002;88:799–804
  37. 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;70:123–129
  38. Lauricella AM, Quintana IL, Kordich LC. Effects of homocysteine thiol group and fibrin networks (another possible mechanism of harm). Thromb Res. 2002;107:75–79
  39. Kristensen B, Malm J, Nilsson TK, et al.  Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke. 1999;30:974–980
  40. Clarke R, Collins R, Lewington S, et al.  Homocysteine and risk of ischemic heart disease and stroke (a meta-analysis). JAMA. 2002;288:2015–2022
  41. Christen W, Ajani U, Glynn R, et al.  Blood levels of homocysteine and increased risks of cardiovascular disease (causal or casual?). Arch Intern Med. 2000;160:422–434
  42. Ridker P, Manson J, Buring J, et al.  Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA. 1999;281:1817–1821
  43. Giles W, Croft J, Greenlund K, et al.  Association between total homocysteine and the likelihood for a history of acute myocardial infarction by race and ethnicity (results form the third national health and nutrition examination survey). Am Heart J. 2000;139:446–453
  44. Omland T, Samuelsson A, Hartford M, et al.  Serum homocysteine concentration as an indicator of survival in patients with acute coronary syndromes. Arch Intern Med. 2000;160:1834–1840
  45. Genest J, McNamara J, Salem D, et al.  Plasma homocysteine levels in men with premature coronary artery disease. J Am Coll Cardiol. 1990;16:1114–1119
  46. Vollset S, Refsum H, Tverdal A, et al.  Plasma total homocysteine and cardiovascular and noncardiovascular mortality (the Hordaland homocysteine study). Am J Clin Nutr. 2001;74:130–136
  47. Voutilainen S, Lakka T, Hamelahti P, et al.  Plasma total homocysteine concentration and the risk of acute coronary events (the Kuopio ischeaemic heart disease risk factor study). J Intern Med. 2000;248:217–222
  48. Folsom A, Nieto F, McGovern P, et al.  Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and b vitamins. Circulation. 1998;98:204–210
  49. Nygård O, Vollset S, Refsum H, et al.  Total homocysteine and cardiovascular disease. J Intern Med. 1999;246:425–454
  50. Ridker P, Hennekens C, Buring J, et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Eng J Med. 2000;342:836–843
  51. Dalery K, Lussier-Cacan S, Selhub J, et al.  Homocysteine and coronary artery disease in French Canadian subjects (relation with vitamins B12, B6, pyridoxal phosphate, and folate). Am J Cardol. 1995;75:1107–1111
  52. Anderson J, Muhlestein J, Horne B, et al.  Plasma homocysteine predicts mortality independently of traditional risk factors and c-reactive in patients with angiographically defined coronary artery disease. Circulation. 2000;102:1227–1232
  53. Buring J, Hennekens C. Contributions of basic research, observational studies, and randomized clinical trials. In:  Hennekens C,  Buring J,  Ridker P,  Manson J editor. Clinical trials in coronary heart disease. Philadelphia: WB Saunders Co; 1999;p. 3–8
  54. 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
  55. 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. JAMA. 2002;288:973–979
  56. Schnyder G, Roffi M, Pin R, et al.  Decreased rate of coronary restenosis after lowering plasma homocysteine levels. N Engl J Med. 2001;345:1593–1600
  57. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, et al.  Secondry prevention with folic acid (effects on clinical outcomes). J Am Coll Cardio. 2003;41:2105–2113
  58. Vermeulen EGJ, Stehouwer CDA, Twisk JWR, et al.  Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis (a randomized, placebo-controlled trial). Lancet. 2000;355:517–522
  59. Hackam DG, Peterson JC, Spence JD. What level of plasma homocysteine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocysteine levels above and below 14μmol/L. Am J Hypertens. 2000;13:105–110
  60. Woo KS, Chook P, Lolin YI, et al.  Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999;34:2002–2006
  61. Title LM, Cummings PM, Giddens K, et al.  Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000;36:758–765
  62. Doshi SN, McDowell IFW, Moat SJ, et al.  Folate improves endothelial function in coronary artery disease (an effect mediated by reduction of intracellular superoxide?). Arterioscler Thromb Vasc Biol. 2001;21:1196–1202
  63. Toole JF. Vitamin intervention for stroke prevention. J Neurol Sci. 2002;203:121–124
  64. Bostom AG, Selhub J, Jaques PF, et al.  Power shortage (clinical trials testing the “homocysteine hypothesis” against the background of folic acid-fortified cereal grain flour). Ann Intern Med. 2001;135:133–137
  65. Rossouw JE, Anderson GL, Prentice RL, et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women (principal results From the Women's Health Initiative randomized controlled trial). JAMA. 2002;288:321–333
  66. Eidelman R, Hebert P, Hollar D, et al. The randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Int Med 2004 (in press)

PII: S0002-8703(04)00094-8

doi: 10.1016/j.ahj.2004.02.004

American Heart Journal
Volume 148, Issue 1 , Pages 34-40 , July 2004

Article Tools