Skip to main content

Link between Homocysteine and Cardiovascular Diseases

Abstract

Purpose of Review

Numerous studies have shown a positive correlation between serum Hcy level and various pathological conditions such as coronary, carotid, and peripheral vascular disease. Increased plasma Hcy levels are associated not only with an increased risk of arteriosclerosis but also with atherosclerosis and thrombosis. The aim of this review is to review biochemical mechanisms responsible for development and progression of cardiovascular diseases (CVD).

Recent Findings

A recent finding shows that cardiac tissue function improves in hyperhomocysteinemic (HHcy) patients after consumption of folic acid and cobalamin. Furthermore, in patients with HHcy plasma levels of nitric oxide (NO) and tetrahydrobiopterin were remarkably decreased compared with the normal individuals. Cardiac endothelial function and coronary flow velocity reserve were significantly disrupted in chronic HHcy patients compared with the control subjects.

Summary

Lowering elevated level of Hcy by supplementation with folic acid and B12 vitamin reduces plasma level of Hcy and substantially reduces the risk of CVD. The combination of consuming supplements of B12, B6, and folate on a daily basis reduces the progression of atherosclerosis, measured by the area of the carotid artery plaques and their administration, improve CVD and may slightly prevent the incidence of atherosclerotic vascular events. A correlation between Hcy and hypertension indicates that Hcy levels could be used as a potential marker for atherosclerosis progression.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

ADMA:

Asymmetric dimethylarginine

CHD:

Coronary heart disease

CAD:

Coronary artery; disease

CVD:

Cardiovascular diseases

eNOS:

Endothelial nitric oxide synthase

Hcy:

Homocysteine

HHcy:

Hyperhomocysteinemia

MS:

Methionine synthase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

VSMC:

Vascular smooth muscle cell

ROS:

Reactive oxygen species

GFR:

Glomerular filtration rate

ESRD:

End-stage renal disease

References

  1. Jakubowski H. Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease. J Biol Chem. 2002;277(34):30425–8. https://doi.org/10.1074/jbc.C200267200.

    CAS  Article  PubMed  Google Scholar 

  2. Fanapour PC, Yug B, Kochar MS. Hyperhomocysteinemia: an additional cardiovascular risk factor. Wmj. 1999;98(8):51–4.

    CAS  PubMed  Google Scholar 

  3. Stanger O, et al. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. Z Kardiol. 2004;93(6):439–53. https://doi.org/10.1007/s00392-004-0075-3.

    CAS  Article  PubMed  Google Scholar 

  4. Brattstrom L, et al. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Investig. 1992;22(3):214–21. https://doi.org/10.1111/j.1365-2362.1992.tb01829.x.

    CAS  Article  Google Scholar 

  5. Han L, et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke. 2015;46(7):1777–86. https://doi.org/10.1161/STROKEAHA.115.009111.

    CAS  Article  PubMed  Google Scholar 

  6. Ferechide D, Radulescu D. Hyperhomocysteinemia in renal diseases. J Med Life. 2009;2(1):53–9.

    PubMed  PubMed Central  Google Scholar 

  7. Cattaneo M. Hyperhomocysteinemia: a risk factor for arterial and venous thrombotic disease. Int J Clin Lab Res. 1997;27(3):139–44. https://doi.org/10.1007/BF02912449.

    CAS  Article  PubMed  Google Scholar 

  8. Blum A, et al. Homocysteine levels in patients with risk factors for atherosclerosis. Clin Cardiol. 2001;24(6):463–6. https://doi.org/10.1002/clc.4960240609.

    CAS  Article  PubMed  Google Scholar 

  9. Mercie P, et al. Homocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic features. Apoptosis. 2000;5(5):403–11. https://doi.org/10.1023/A:1009652011466.

    CAS  Article  PubMed  Google Scholar 

  10. Lai WK, Kan MY. Homocysteine-induced endothelial dysfunction. Ann Nutr Metab. 2015;67(1):1–12. https://doi.org/10.1159/000437098.

    CAS  Article  PubMed  Google Scholar 

  11. Toda N, Okamura T. Hyperhomocysteinemia impairs regional blood flow: involvements of endothelial and neuronal nitric oxide. Pflugers Arch. 2016;468(9):1517–25. https://doi.org/10.1007/s00424-016-1849-y.

    CAS  Article  PubMed  Google Scholar 

  12. McCully KS. Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci. 2009;39(3):219–32.

    CAS  PubMed  Google Scholar 

  13. Sanchez-Espinosa MP, Atienza M, Cantero JL. Sleep mediates the association between homocysteine and oxidative status in mild cognitive impairment. Sci Rep. 2017;7(1):017–08292.

    Article  Google Scholar 

  14. Zhang Z, et al. Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxidative Med Cell Longev. 2017;5736506(10):28.

    Google Scholar 

  15. Smith AD, Refsum H, Homocysteine B. Vitamins, and cognitive impairment. Annu Rev Nutr. 2016;36(1):211–39. https://doi.org/10.1146/annurev-nutr-071715-050947.

    CAS  Article  PubMed  Google Scholar 

  16. Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost. 1999;81(2):165–76.

    CAS  PubMed  Google Scholar 

  17. Dietrich-Muszalska A, et al. The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients. Neurochem Res. 2012;37(5):1057–62. https://doi.org/10.1007/s11064-012-0707-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Stanger O, et al. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother. 2009;9(9):1393–412. https://doi.org/10.1586/ern.09.75.

    CAS  Article  PubMed  Google Scholar 

  19. Pawlak R. Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am J Prev Med. 2015;48(6):009.

    Article  Google Scholar 

  20. Shiraishi M, et al. Relationship between plasma total homocysteine level and dietary caffeine and vitamin B6 intakes in pregnant women. Nurs Health Sci. 2014;16(2):164–70. https://doi.org/10.1111/nhs.12080.

    Article  PubMed  Google Scholar 

  21. Mangge H, et al. Antioxidants, inflammation and cardiovascular disease. World J Cardiol. 2014;6(6):462–77. https://doi.org/10.4330/wjc.v6.i6.462.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sun ZH, Rashmizal H, Xu L. Molecular imaging of plaques in coronary arteries with PET and SPECT. J Geriatr Cardiol. 2014;11(3):259–73. https://doi.org/10.11909/j.issn.1671-5411.2014.03.005.

    PubMed  PubMed Central  Google Scholar 

  23. Cunnane EM, et al. Mechanical properties and composition of carotid and femoral atherosclerotic plaques: a comparative study. J Biomech. 2016;49(15):3697–704. https://doi.org/10.1016/j.jbiomech.2016.09.036.

    Article  PubMed  Google Scholar 

  24. Shenoy V, et al. Correlation of serum homocysteine levels with the severity of coronary artery disease. Indian J Clin Biochem. 2014;29(3):339–44. https://doi.org/10.1007/s12291-013-0373-5.

    CAS  Article  PubMed  Google Scholar 

  25. Patel MR, et al. Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC). J Am Coll Cardiol. 2015;65(9):931–41. https://doi.org/10.1016/j.jacc.2014.12.036.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ochijewicz D, et al. Intravascular imaging of coronary artery disease: recent progress and future directions. J Cardiovasc Med. 2017;18(10):733–41. https://doi.org/10.2459/JCM.0000000000000552.

    Article  Google Scholar 

  27. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56(1):111–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. McCully KS. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev Clin Pharmacol. 2015;8(2):211–9. https://doi.org/10.1586/17512433.2015.1010516.

    CAS  Article  PubMed  Google Scholar 

  29. Roth GA, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1–25. https://doi.org/10.1016/j.jacc.2017.04.052.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Veeranna V, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol. 2011;58(10):1025–33. https://doi.org/10.1016/j.jacc.2011.05.028.

    CAS  Article  PubMed  Google Scholar 

  31. Faeh D, Chiolero A, Paccaud F. Homocysteine as a risk factor for cardiovascular disease: should we (still) worry about? Swiss Med Wkly. 2006;136(47–48):745–56.

    CAS  PubMed  Google Scholar 

  32. Eikelboom JW, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131(5):363–75. https://doi.org/10.7326/0003-4819-131-5-199909070-00008.

    CAS  Article  PubMed  Google Scholar 

  33. Sengwayo D, Moraba M, Motaung S. Association of homocysteinaemia with hyperglycaemia, dyslipidaemia, hypertension and obesity. Cardiovasc J Afr. 2013;24(7):265–9. https://doi.org/10.5830/CVJA-2013-059.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hassan A, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127(Pt 1):212–9. https://doi.org/10.1093/brain/awh023.

    Article  PubMed  Google Scholar 

  35. Andras A, Stansby G, Hansrani M. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database Syst Rev. 2013;19(7) https://doi.org/10.1002/14651858.CD003285.pub2.

  36. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19(1):217–46. https://doi.org/10.1146/annurev.nutr.19.1.217.

    CAS  Article  PubMed  Google Scholar 

  37. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14(6):1475–2891.

    Google Scholar 

  38. Pang X, et al. Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-kappaB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 2014;236(1):73–81. https://doi.org/10.1016/j.atherosclerosis.2014.06.021.

    CAS  Article  PubMed  Google Scholar 

  39. Okura T, et al. Hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males. Sci Rep. 2014;4(5663)

  40. van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant. 2006 May;21(5):1161–6. https://doi.org/10.1093/ndt/gfl044.

    Article  PubMed  Google Scholar 

  41. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338(15):1042–50. https://doi.org/10.1056/NEJM199804093381507.

    CAS  Article  PubMed  Google Scholar 

  42. Woo CW, et al. Homocysteine stimulates inducible nitric oxide synthase expression in macrophages: antagonizing effect of ginkgolides and bilobalide. Mol Cell Biochem. 2003;243(1–2):37–47. https://doi.org/10.1023/A:1021601512058.

    CAS  Article  PubMed  Google Scholar 

  43. Topal G, et al. Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med. 2004;36(12):1532–41. https://doi.org/10.1016/j.freeradbiomed.2004.03.019.

    CAS  Article  PubMed  Google Scholar 

  44. Zhang S, et al. Association between serum homocysteine and arterial stiffness in elderly: a community-based study. J Geriatr Cardiol. 2014;11(1):32–8. https://doi.org/10.3969/j.issn.1671-5411.2014.01.007.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Eberhardt RT, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest. 2000;106(4):483–91. https://doi.org/10.1172/JCI8342.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Jiang X, et al. Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler Thromb Vasc Biol. 2005;25(12):2515–21. https://doi.org/10.1161/01.ATV.0000189559.87328.e4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Chen P, et al. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv Enzym Regul. 1999;39(1):93–109. https://doi.org/10.1016/S0065-2571(98)00029-6.

    CAS  Article  Google Scholar 

  48. Steed MM, Tyagi SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal. 2011;15(7):1927–43. https://doi.org/10.1089/ars.2010.3721.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Dionisio N, et al. Homocysteine, intracellular signaling and thrombotic disorders. Curr Med Chem. 2010;17(27):3109–19. https://doi.org/10.2174/092986710791959783.

    CAS  Article  PubMed  Google Scholar 

  50. Lacey B, et al. The role of emerging risk factors in cardiovascular outcomes. Curr Atheroscler Rep. 2017;19(6):017–0661.

    Article  Google Scholar 

  51. Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost. 2003;1(2):300–6. https://doi.org/10.1046/j.1538-7836.2003.00053.x.

    CAS  Article  PubMed  Google Scholar 

  52. Lanza GA, Careri G, Crea F. Mechanisms of coronary artery spasm. Circulation. 2011;124(16):1774–82. https://doi.org/10.1161/CIRCULATIONAHA.111.037283.

    Article  PubMed  Google Scholar 

  53. Bhatia P, Singh N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundam Clin Pharmacol. 2015;29(6):522–8. https://doi.org/10.1111/fcp.12145.

    CAS  Article  PubMed  Google Scholar 

  54. Golino P, et al. Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo. Thromboxane A2 and serotonin are possible mediators. Circulation. 1989;79(1):154–66. https://doi.org/10.1161/01.CIR.79.1.154.

    CAS  Article  PubMed  Google Scholar 

  55. An YM, et al. Homocysteine ameliorates the endothelium-independent hypoxic vasoconstriction via the suppression of phosphatidylinositol 3-kinase/Akt pathway in porcine coronary arteries. Biochem Biophys Res Commun. 2017;486(1):178–83. https://doi.org/10.1016/j.bbrc.2017.03.022.

    CAS  Article  PubMed  Google Scholar 

  56. Qipshidze N, et al. Folic acid improves acetylcholine-induced vasoconstriction of coronary vessels isolated from hyperhomocysteinemic mice: an implication to coronary vasospasm. J Cell Physiol. 2011;226(10):2712–20. https://doi.org/10.1002/jcp.22621.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Zylberstein DE, et al. Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in Gothenburg. Circulation. 2004;109(5):601–6. https://doi.org/10.1161/01.CIR.0000112581.96154.EA.

    CAS  Article  PubMed  Google Scholar 

  58. Tawakol A, et al. Homocysteine impairs coronary microvascular dilator function in humans. J Am Coll Cardiol. 2002;40(6):1051–8. https://doi.org/10.1016/S0735-1097(02)02069-7.

    CAS  Article  PubMed  Google Scholar 

  59. Graham IM, O’Callaghan P. The role of folic acid in the prevention of cardiovascular disease. Curr Opin Lipidol. 2000;11(6):577–87. https://doi.org/10.1097/00041433-200012000-00003.

    CAS  Article  PubMed  Google Scholar 

  60. Dinckal MH, et al. Effect of homocysteine-lowering therapy on vascular endothelial function and exercise performance in coronary patients with hyperhomocysteinaemia. Acta Cardiol. 2003;58(5):389–96. https://doi.org/10.2143/AC.58.5.2005302.

    Article  PubMed  Google Scholar 

  61. Willems FF, et al. Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. J Am Coll Cardiol. 2002;40(4):766–72. https://doi.org/10.1016/S0735-1097(02)02016-8.

    CAS  Article  PubMed  Google Scholar 

  62. Chen Z, et al. Relationship between endothelial dysfunction and serum homocysteine in patients with coronary lesions. Chin Med Sci J. 2005;20(1):63–6.

    CAS  PubMed  Google Scholar 

  63. Kietadisorn R, et al. Role of tetrahydrobiopterin (BH4) in hyperhomocysteinemia-induced endothelial dysfuction: new indication for this orphan-drug? Am J Physiol Endocrinol Metab. 2011;300(6):E1176; author reply E1177-8. https://doi.org/10.1152/ajpendo.00084.2011.

    CAS  Article  PubMed  Google Scholar 

  64. He L, et al. Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia. Am J Physiol Endocrinol Metab. 2010;299(6):21.

    Article  Google Scholar 

  65. Tsuda K and I Nishio. Serum homocysteine and endothelial dysfunction in circulatory disorders in women: Circulation. 2004 110(4):e37.

  66. Stuhlinger MC, et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001;104(21):2569–75. https://doi.org/10.1161/hc4601.098514.

    CAS  Article  PubMed  Google Scholar 

  67. Guinn DA, Gibbs RS, eds. Preterm labor and delivery. In: Scot RGR, Karlan B, editors. Danforth’s obstetrics and gynecology. Philadelphia: Lippincott Williams & Wilkins; 2003.

  68. Kolodziejczyk J, et al. Comparison of the effect of homocysteine and its thiolactone on the fibrinolytic system using human plasma and purified plasminogen. Mol Cell Biochem. 2010;344(1–2):217–20. https://doi.org/10.1007/s11010-010-0545-z.

    CAS  Article  PubMed  Google Scholar 

  69. Refsum H, et al. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49(1):31–62. https://doi.org/10.1146/annurev.med.49.1.31.

    CAS  Article  PubMed  Google Scholar 

  70. Lee SJ, et al. Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. J Biol Chem. 2005;280(7):5781–8. https://doi.org/10.1074/jbc.M411224200.

    CAS  Article  PubMed  Google Scholar 

  71. Harpel PC, Zhang X, Borth W. Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr. 1996;126(4 Suppl):1285S–9S.

    CAS  Article  PubMed  Google Scholar 

  72. Duan J, et al. Phytoestrogen alpha-zearalanol antagonizes homocysteine-induced imbalance of nitric oxide/endothelin-1 and apoptosis in human umbilical vein endothelial cells. Cell Biochem Biophys. 2006;45(2):137–45. https://doi.org/10.1385/CBB:45:2:137.

    CAS  Article  PubMed  Google Scholar 

  73. Dong F, et al. Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells. Cardiovasc Toxicol. 2005;5(1):9–20. https://doi.org/10.1385/CT:5:1:009.

    CAS  Article  PubMed  Google Scholar 

  74. Basu A, et al. Plasma total homocysteine and carotid intima-media thickness in type 1 diabetes: a prospective study. Atherosclerosis. 2014;236(1):188–95. https://doi.org/10.1016/j.atherosclerosis.2014.07.001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Mao S, et al. Association between homocysteine status and the risk of nephropathy in type 2 diabetes mellitus. Clin Chim Acta. 2014;431:206–10. https://doi.org/10.1016/j.cca.2014.02.007.

    CAS  Article  PubMed  Google Scholar 

  76. Bleich S, et al. Homocysteine and risk of open-angle glaucoma. J Neural Transm. 2002;109(12):1499–504. https://doi.org/10.1007/s007020200097.

    CAS  Article  PubMed  Google Scholar 

  77. Sachdev PS, et al. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology. 2002;58(10):1539–41. https://doi.org/10.1212/WNL.58.10.1539.

    CAS  Article  PubMed  Google Scholar 

  78. Brown AS, et al. Elevated prenatal homocysteine levels as a risk factor for schizophrenia. Arch Gen Psychiatry. 2007;64(1):31–9. https://doi.org/10.1001/archpsyc.64.1.31.

    CAS  Article  PubMed  Google Scholar 

  79. Song H, et al. Association between PNPO and schizophrenia in the Japanese population. Schizophr Res. 2007;97(1–3):264–70. https://doi.org/10.1016/j.schres.2007.08.004.

    Article  PubMed  Google Scholar 

  80. Bouaziz N, et al. Plasma homocysteine in schizophrenia: determinants and clinical correlations in Tunisian patients free from antipsychotics. Psychiatry Res. 2010;179(1):24–9. https://doi.org/10.1016/j.psychres.2010.04.008.

    CAS  Article  PubMed  Google Scholar 

  81. Dwyer BE, et al. Homocysteine and Alzheimer’s disease: a modifiable risk? Free Radic Biol Med. 2004;36(11):1471–5. https://doi.org/10.1016/j.freeradbiomed.2004.03.009.

    CAS  Article  PubMed  Google Scholar 

  82. McLean RR, et al. Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. J Clin Endocrinol Metab. 2008;93(6):2206–12. https://doi.org/10.1210/jc.2007-2710.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Green R, Datta Mitra A. Megaloblastic anemias: nutritional and other causes. Med Clin North Am. 2017;101(2):297–317. https://doi.org/10.1016/j.mcna.2016.09.013.

    Article  PubMed  Google Scholar 

  84. Ozkan Y, et al. Usefulness of homocysteine as a cancer marker: total thiol compounds and folate levels in untreated lung cancer patients. Anticancer Res. 2007;27(2):1185–9.

    CAS  PubMed  Google Scholar 

  85. Chiang PK, et al. S-adenosylmethionine and methylation. FASEB J. 1996;10(4):471–80.

    CAS  Article  PubMed  Google Scholar 

  86. Chambers JC, Obeid OA, Kooner JS. Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol. 1999;19(12):2922–7. https://doi.org/10.1161/01.ATV.19.12.2922.

    CAS  Article  PubMed  Google Scholar 

  87. Bonaa KH, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354(15):1578–88. https://doi.org/10.1056/NEJMoa055227.

    CAS  Article  PubMed  Google Scholar 

  88. Toole JF, 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(5):565–75. https://doi.org/10.1001/jama.291.5.565.

    CAS  Article  PubMed  Google Scholar 

  89. Ray JG, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med. 2007;146(11):761–7. https://doi.org/10.7326/0003-4819-146-11-200706050-00157.

    Article  PubMed  Google Scholar 

  90. Armitage JM, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303(24):2486–94. https://doi.org/10.1001/jama.2010.840.

    CAS  Article  PubMed  Google Scholar 

  91. Saposnik G, et al. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009;40(4):1365–72. https://doi.org/10.1161/STROKEAHA.108.529503.

    CAS  Article  PubMed  Google Scholar 

  92. Park JH, Lee J, Ovbiagele B. Association of optimal combination drug treatment with obesity status among recent ischemic stroke patients: results of the Vitamin Intervention for Stroke Prevention (VISP) Trial. J Stroke. 2017;19(2):213–21. https://doi.org/10.5853/jos.2016.01347.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Liebson PR. Women’s Health Initiative (WHI) Dietary Trial and Norwegian Vitamin Trial (NORVIT). Prev Cardiol. 2006;9(3):178–82. https://doi.org/10.1111/j.1520-037X.2006.04993.x.

    Article  PubMed  Google Scholar 

  94. Bowman L, et al. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J. 2007;154(5):815–23.

    CAS  Article  PubMed  Google Scholar 

  95. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998;316(7135):894–8.

    Article  Google Scholar 

  96. Loland KH, et al. Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol. 2010;105(11):1577–84. https://doi.org/10.1016/j.amjcard.2010.01.019.

    CAS  Article  PubMed  Google Scholar 

  97. Spence JD. Homocysteine: call off the funeral. Stroke. 2006 Feb;37(2):282–3. https://doi.org/10.1161/01.STR.0000199621.28234.e2.

    Article  PubMed  Google Scholar 

  98. Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art. Am J Med Sci. 2009;338(1):48–9. https://doi.org/10.1097/MAJ.0b013e3181aaefd6.

    Article  PubMed  Google Scholar 

  99. Clarke R, et al. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis. 2011;34(1):83–91. https://doi.org/10.1007/s10545-010-9235-y.

    CAS  Article  PubMed  Google Scholar 

  100. Meye C, et al. Effects of homocysteine on the levels of caveolin-1 and eNOS in caveolae of human coronary artery endothelial cells. Atherosclerosis. 2007;190(2):256–63. https://doi.org/10.1016/j.atherosclerosis.2006.03.009.

    CAS  Article  PubMed  Google Scholar 

  101. Zhang JG, et al. The pathogenic mechanism of homocysteine-induced endothelial nitric oxide synthase dysfunction and the antagonistic effects by folic acid. Fen Zi Xi Bao Sheng Wu Xue Bao. 2007;40(1):17–23.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work has been supported by grant 173033 (to E.R.I.) from the Ministry of Education, Science and Technological Development, Republic of Serbia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Esma R. Isenovic.

Ethics declarations

Conflict of Interest

The authors declare that there is no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Cardiovascular Pharmacology

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Obradovic, M., Zaric, B.L., Haidara, M.A. et al. Link between Homocysteine and Cardiovascular Diseases. Curr Pharmacol Rep 4, 1–9 (2018). https://doi.org/10.1007/s40495-017-0119-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-017-0119-9

Keywords

  • Homocysteine
  • Cardiovascular diseases
  • Atherosclerosis
  • Hyperhomocysteinemia