Skip to main content
SpringerLink
Log in

Homocysteine: Role in Cardiovascular Disease

  • Chapter
  • First Online:
Modern Dietary Fat Intakes in Disease Promotion

Part of the book series: Nutrition and Health ((NH))

  • 1399 Accesses

Key Points

Elevated plasma levels of homocysteine are associated with atherosclerosis and cardiovascular ischemic events.

Hyperhomocysteinemia (HHcy) is an independent risk factor for ischemic heart disease, stroke, hypertension, arrhythmia, and peripheral vascular disease.

Some factors induce elevation of homocysteine concentration such as mutations in the enzymes responsible for homocysteine metabolism: cystathionine β-synthase (CβS) or 5,10-methylenetetrahydrofolate reductase, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism; vitamin B6 (pyridoxal phosphate), vitamin B12 (methylcobalamin), and folic acid.

Studies using animal models of genetic- and diet-induced HHcy have recently demonstrated a causal relationship between hyperhomocysteinemia, endothelial dysfunction, and accelerated atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. de Bree A, Monique Verschuren WM, Kromhout D, Kluijtmans LAJ, Blom HJ. Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev 2002; 54: 599–618.

    Article  PubMed  Google Scholar 

  2. Trabetti E. Homocysteine MTHFR gene polymorphisms, and cardiocerebrovascular risk. J Appl Genet 2008; 49(3): 267–282.

    Article  PubMed  Google Scholar 

  3. Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 2004; 11(1): S56–S64.

    Article  PubMed  CAS  Google Scholar 

  4. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. [See Comments]. Am J Clin Nutr 2000; 72: 324–332.

    PubMed  CAS  Google Scholar 

  5. McCully KS. Vascular pathology of homocysteinaemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56(1): 111–128.

    PubMed  CAS  Google Scholar 

  6. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy Over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000; 72(2): 324–332.

    PubMed  CAS  Google Scholar 

  7. Kaplan ED. Association between homocyst (e) ine levels and risk of vascular events. Drugs Today (Barc) 2003; 39(3): 175–192.

    Article  CAS  Google Scholar 

  8. 8.The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. Jama 2002; 288(16): 2015–2022.

    Article  Google Scholar 

  9. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst (e) ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case control studies and nested case-control studies. Int J Epidemiol 2002; 31(1): 59–70.

    Article  PubMed  Google Scholar 

  10. Bunout D, Hirsch S. Are we losing homocysteine as a cardiovascular risk factor? Nutrition 2005; 21(10): 1068–1069.

    Article  PubMed  Google Scholar 

  11. Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S. Hyperhomocysteinaemia: an independent risk factor or a simple marker of vascular disease? Epidemiological data. Pathol Biol. (Paris) 2003; 51(2): 111–121.

    Article  CAS  Google Scholar 

  12. Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S. Hyperhomocysteinaemia: an independent risk factor or a simple marker of vascular disease? 1. Basic data. Pathol Biol (Paris) 2003; 51(2): 101–110.

    Article  CAS  Google Scholar 

  13. Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 2005; 331(7524): 1053.

    Article  PubMed  CAS  Google Scholar 

  14. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990; 1: 228–237.

    Article  PubMed  CAS  Google Scholar 

  15. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over Homocysteine and cardiovascular risk. [See Comments]. Am J Clin Nutr 2001; 72: 324–332.

    Google Scholar 

  16. Blanco C, Caballería J, Deulofeu R, Lligoña A, Parés A,Lluis JM et al. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res 2005; 29: 1044–1048.

    Article  Google Scholar 

  17. van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med (Maywood) 2001; 226: 243–270.

    Google Scholar 

  18. Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power shortage: clinical trials testing the “homocysteine hypothesis” against a background of folic acid fortified cereal grain flour. Ann Intern Med 2001; 135: 133–137.

    PubMed  CAS  Google Scholar 

  19. Singal R, Ferdinand L, Das PM, Reis IM, Schlesselman JJ et al. Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk. Int J Oncol 2004; 25(1465): 1471.

    Google Scholar 

  20. Papa A, De Stefano V, Danese S, Chiusolo P, Persichilli S, Casorelli I et al. Hyperhomocysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease. Am J Gastroenterol 2001; 96: 2677–2682.

    Article  PubMed  CAS  Google Scholar 

  21. Sengul E, Cetinarslan B, Tarku I, Canturk Z, Turemen E. Homocysteine concentrations in subclinical hypothyroidism. Endocr Res 2004; 3: 351–359.

    Article  Google Scholar 

  22. Refsum H, Smith AD, Ueland PM et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50: 3–32.

    Article  PubMed  CAS  Google Scholar 

  23. Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, Weger M. DACH–LIGA Homocystein (German, Austrian and Swiss Homocysteine Society) Consensus Paper on the Rational Clinical Use of Homocysteine, Folic Acid and B-Vitamins in Cardiovascular and Thrombotic Diseases: Guidelines and Recommendations. Clin Chem Lab Med 1392; 41: 1403.

    Google Scholar 

  24. Herrmann W. The importance hyperhomocysteinemia as a risk factor for diseases: an overview. Clin Chem Lab Med 2001; 39: 666–674.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. Lentz SR. Homocysteine and cardiovascular physiology. In: Carmel R, Jacobsen DW (eds.), Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press, 2001.

    Google Scholar 

  27. Herrmann M, Kindermann I, Muller S, Georg T, Kindermann M, Bohm M et al. Relationship of plasma homocysteine with the severity of chronic heart failure. Clin Chem 2005; 51: 1512–1515.

    Article  PubMed  CAS  Google Scholar 

  28. Cesari M, Zanchetta M, Burlina A et al. Hyperhomocysteinemia is inversely related with left ventricular ejection fraction and predicts cardiovascular mortality in high-risk coronary artery disease hypertensives. Arterioscler Thromb Vasc Biol 2005; 25: 115–121.

    PubMed  CAS  Google Scholar 

  29. Bokhari SW, Bokhari ZW, Zell JA, Lee DW, Faxon DP. Plasma homocysteine levels and the left ventricular systolic function in coronary artery disease patients. Coron Artery Dis 2005; 16: 153–161.

    Article  PubMed  Google Scholar 

  30. Sundstrom J, Sullivan L, Selhub J et al. Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study. Eur Heart J 2004; 25: 523–530.

    Article  PubMed  CAS  Google Scholar 

  31. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM et al. Plasma homocysteine as a risk factor for vascular disease. The EuropeanConcertedActionProject. JAMA 1997; 277: 1775–1781.

    Article  PubMed  CAS  Google Scholar 

  32. Olivieri O, Friso S, Trabetti E, Girelli D, Pizzolo F, Faccini G et al. Homocysteine and atheromatous renal artery stenosis. Clin Exp Med 2001; 1: 211–218.

    Article  PubMed  CAS  Google Scholar 

  33. Pizzolo F, Friso S, Olivieri O, Martinelli N, Bozzini C, Guarini P et al. Homocysteine, traditional risk factors and impaired renal function in coronary artery disease. Eur J Clin Invest 2006; 36: 698–704.

    Article  PubMed  CAS  Google Scholar 

  34. Malinow M, Nieto F, Szklo M, Chambless L, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst (e) ine in asymptomatic adults. Circulation 1993; 87: 1107–1113.

    Article  PubMed  CAS  Google Scholar 

  35. Voutilainen S, Lakka TA, Hamelahti P, Lehtimaki T, Poulsen HE, Salonen JT. 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.

    Article  PubMed  CAS  Google Scholar 

  36. Stampfer 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.

    Article  CAS  Google Scholar 

  37. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta­analysis. BMJ 2002; 325: 1202.

    Article  PubMed  Google Scholar 

  38. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, 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.

    Article  Google Scholar 

  39. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Tolliet M, Heyrick S, Stark R, Klings ES, Moldovan NI, Yaghoubi M, Goldschmidt-Clermont PJ, Farber HW, Cohen R, Loscalzo J. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 2000; 106(4): 483–491.

    Article  PubMed  CAS  Google Scholar 

  40. Ungvari Z, Csiszar A, Edwards JG, Kaminski PM, Wolin MS, Kaley G, Koller A. Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 2003; 23: 418–424.

    Article  PubMed  CAS  Google Scholar 

  41. Dayal S, Brown KL, Weydert CJ, Oberley LW, Arning E, Bottiglieri T, Faraci FM, Lentz SR. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscler Thromb Vasc Biol 2002; 22: 1996–2002.

    Article  PubMed  CAS  Google Scholar 

  42. Weiss N, Zhang YY, Heydrick S, Bierl C, Loscalzo J. Overexpression of cellular glutathione peroxidase rescues homocyst (e) ine induced endothelial dysfunction. Proc Natl Acad Sci USA 2001; 98: 12503–12508.

    Article  PubMed  CAS  Google Scholar 

  43. Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol 2002; 22: 34–41.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  45. Bo¨ger RH, Lentz SR, Bode-Bo¨ger SM, Knapp HR, Haynes WG. Elevation of asymmetric dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst (e) inemia in humans. Clin Sci 2001; 100: 161–167.

    Article  Google Scholar 

  46. Stuhlinger MC, Oka RK, Graf EE, Schmolzer I, Upson BM, Kapoor O, Szuba A, Malinow MR, Wascher TC, Pachinger O, Cooke JP. Endothelial Dysfunction induced by hyperhomocyst(e) inemia: role of asymmetric dimethylarginine. Circulation 2003; 108: 933–938.

    Article  PubMed  Google Scholar 

  47. Duan J, Murohara T, Ikeda H, Sasaki K, Shintani S, Akita T, Shimada T, Imaizumi T. Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia. Arterioscler Thromb Vasc Biol 2000; 20: 2579–25853.

    Article  PubMed  CAS  Google Scholar 

  48. Dayal S, Brown KL, Weydert CJ, Oberley LW, Arning E, Bottiglieri T, Faraci FM, Lentz SR. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscler Thromb Vasc Biol 2002; 22: 1996–2002.

    Article  PubMed  CAS  Google Scholar 

  49. Chwatko G, Boers GHJ, Strauss KA, Shih DM, Jakubowski H. Mutations in methylenetetrahydrofolate reductase or Cystathionine B synthase gene or a high-methionine diet, increase homocysteine thiolactone levels in Humans and mice. FASEB J 2007. doi: 10.1096/ fj.06-7435com.

    Google Scholar 

  50. Poddar R, Sivasubramanian N, Dibello PM, Robinson K, Jacobsen DW. Homocysteine induces expression secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation 2001; 103: 2717–2723.

    Article  PubMed  CAS  Google Scholar 

  51. Zhang C, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, Kitajama S. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 2001; 276: 35867–35874.

    Article  PubMed  CAS  Google Scholar 

  52. Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death and Differ 2004; 11: S56–S64.

    Article  CAS  Google Scholar 

  53. Di Simone N, Maggiano N, Caliandro D, Riccardi P, Evangelista A, Carducci B, Caruso A. Homocysteine induces trophoblast cell death with apoptotic features. Biol Reprod 2003; 69: 1129–1134.

    Article  PubMed  CAS  Google Scholar 

  54. Mujumdar VS, Aru GM, Tyagi SC. Induction of oxidative stress by homocyst (e) ine impair endothelial function. J Cell Biochem 2001; 82: 491–500.

    Article  PubMed  CAS  Google Scholar 

  55. Hunt MJ, Aru GM, Hayden MR, Moore CK, Hoit BD, Tyagi SC. Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure. Am J Physiol 2002; 283: L239–L245.

    CAS  Google Scholar 

  56. Starkekbaum G, Harlan J. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370–1376.

    Article  Google Scholar 

  57. Visioli F, Smith A, Zhang W, Keaney JF Jr, Hagen T, Frei B et al. Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status. Redox Rep 2002; 7: 223–227.

    Article  PubMed  CAS  Google Scholar 

  58. McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis 1975; 22: 215–227.

    Article  PubMed  CAS  Google Scholar 

  59. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72(2): 324–332.

    PubMed  CAS  Google Scholar 

  60. 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(9): 759–761.

    Article  PubMed  CAS  Google Scholar 

  61. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996; 143(9): 845–859.

    Article  PubMed  CAS  Google Scholar 

  62. Hirsch S, Ronco AM, Vasquez M, de la Maza MP, Garrido A, Barrera G et al. Hyperhomocysteinaemia in healthy young men and elderly men with normal serum folate concentration is not associated with poor vascular reactivity or oxidative stress. J Nutr 2004; 134(7): 1832–1835.

    PubMed  CAS  Google Scholar 

  63. Hirsch S, de la Maza P, Mendoza L, Petermann M, Glasinovic A, Paulinelli P et al. Endothelial function in healthy younger and older hyperhomocysteinemic subjects. J Am Geriatr Soc 2002; 50(6): 1019–1023.

    Article  PubMed  Google Scholar 

  64. 64.Blacher J, Demuth K, Guerin AP et al. Association between plasma homocysteine concentrations and cardiac hypertrophy in end-stage renal disease. J Nephrol 1999; 12: 248–255.

    PubMed  CAS  Google Scholar 

  65. Sundstrom J, Sullivan L, Selhub J et al. Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study. Eur Heart J 2004; 25: 523–530.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ, 85724, USA

    Arash Sabetisoofyani, Douglas F. Larson & Ronald Ross Watson

  2. College of Public Health, The University of Arizona, Tucson, AZ, 85724, USA

    Ronald Ross Watson

Authors
  1. Arash Sabetisoofyani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas F. Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald Ross Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald Ross Watson .

Editor information

Editors and Affiliations

  1. Managing Director, DMF Ltd Company, Luxembourg Str 46, Marche/Famenne, 6900, Belgium

    Fabien De Meester

  2. Mel & Enid Zuckerman College of, Public Health, University of Arizona, Tucson, 85724-5163, Arizona, USA

    Sherma Zibadi

  3. Arizona Health Science Center, Mel and Enid Zuckerman College of Public, University of Arizona, 1501 N. Campbell Ave. Room 4335, Tucson, 85724-5155, Arizona, USA

    Ronald Ross Watson

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Sabetisoofyani, A., Larson, D.F., Watson, R.R. (2010). Homocysteine: Role in Cardiovascular Disease. In: De Meester, F., Zibadi, S., Watson, R. (eds) Modern Dietary Fat Intakes in Disease Promotion. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-571-2_26

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-571-2_26

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-570-5

  • Online ISBN: 978-1-60327-571-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation