Skip to main content
SpringerLink
Log in

Analytic Approaches for the Treatment of Hyperhomocysteinemia and Its Impact on Vascular Disease

  • REVIEW ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Homocysteine is an intermediary metabolite in the methionine cycle. Accumulation of homocysteine is caused either by mutation of relevant genes or by nutritional depletion of related vitamin(s). This review covers the historical background of hyperhomocysteinemia in which indispensable subjects in relation to underlying pathophysiological processes are discussed with the view of metabolism and genetics of folate and methionine cycles. This review emphasizes the unique role of homocysteine that is clearly distinct from other risk factors, particularly cholesterol in the development of vascular disease. The critical issue in understanding the role of homocysteine is the relation with plasma folic acid. The majority of subjects with homocysteine > 15 μmol/L exhibit plasma folate < 9 nmol/ L, indicating that depletion of folate is the main cause of hyperhomocysteinemia irrespective of the presence or absence of vascular disease. Furthermore, only the group of subjects with homocysteine levels > 15 μmol/L demonstrated a higher prevalence of vascular disease. Analytic approaches to treat hyperhomocysteinemia are discussed in which stepwise administration with nutritional doses of folic acid, 5-methyitetrahydrofolate (5-MTHF), and betaine is provided singly or by combined manner based on clinical and laboratory evaluations. Whether correction of hyperhomocysteinemia is able to prevent the development of homocysteine-associated vascular disease remains an unresolved issue. The review discussed a biochemical and mechanistic approach to resolve questions involved in the relation between homocysteine and the development of atherosclerotic vascular disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kang S-S, Wong PWK, Malinow MR. Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Ann Rev Nutr. 1992;12:279–98.

    Article  CAS  Google Scholar 

  2. Nehler MR, Taylor LM Jr, Porter JM. Homocysteinemia as a risk factor for atherosclerosis: a review. Cardiovasc Surg. 1997;5:559–67.

    Article  PubMed  CAS  Google Scholar 

  3. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Ann Rev Med. 1998;49:31–62.

    Article  PubMed  CAS  Google Scholar 

  4. Eikelboom JW, Lonn E, Genest J, Henkey Yusuf S. Homocysteine and cardiovascular disease: a critical review of epidemiologic evidence. Ann Intern Med. 1999;131:365–75.

    Article  Google Scholar 

  5. Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Ann Rev Med. 2009;60:39–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Rosenson RS, Kang DS. Overview of homocysteine. UpToDate. 2017.

  7. Kang S-S, Wong PWK, Becker N. Protein-bound homocysteine in normal subjects and in patients with homocystinuria. Pediatr Res. 1979;13:1141–3.

    Article  PubMed  CAS  Google Scholar 

  8. Kanwar YS, Manoligod JR, Wong PWK. Morphological studies in a patient with methylenetetrahydrofolate reductase deficiency. Pediatr Res. 1976;10:598–609.

    Article  PubMed  CAS  Google Scholar 

  9. Baumgartner ER, Wick H, Linnell JC, Gaul GE. Congenital defect in intracellular cobalamin metabolism resulting in homocysteine and methylmalonicaciduria. Helo Pediatr Acta. 1979;34:483–96.

    CAS  Google Scholar 

  10. McCully KS. Homocysteine theory of arteriosclerosis: development and current status. Atheiosclerosis Rev. 1983;11:157–246.

    CAS  Google Scholar 

  11. Mudd SH, Levy HL, Skovy F. Disorder of transsulfuration. In: Scriver CR, Beadel AL, Sly WS, Valle D (eds): The metabolic basis of inherited disease, 16th ed. McGraw-Hill 1989. P698.

  12. Kang S-S, Wong PWK, Norusis M, Zhou J, Sora J, Lessck M, et al. Thermolabile methylenetetrahydrofolate reductase in patients with coronary heart disease. Metabolism. 1987;37:611–3.

    Article  Google Scholar 

  13. Kang S-S, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991;48:536–45.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Goyette P, Christensen B, Rosenblatt DS, Rozen R. Severe and Mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene and description of five novel mutations in MTHFR. Am J Hum Genet. 1996;59:1268–75.

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Kang S-S, Wong PWK, Bidani A, Milanez S. Plasma protein-bound homocysteine in patients regulating chronic hemodialysis. Clin Sci. 1983;65:335–6.

    Article  PubMed  CAS  Google Scholar 

  16. Haltberg B, Agaidh E, Anderson A, et al. Increased levels of homocysteine are associated with nephropathy. Clin Lab Investig. 1991;51:277–82.

    Article  Google Scholar 

  17. Kang S-S, Wong PWK, Barnes LJ. Severe homocysteinemia in a non-homocystinuric subject. Unpublished Communication, 1984.

  18. Kang S-S, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987;36:458–62.

    Article  PubMed  CAS  Google Scholar 

  19. Refsum H, Ueland PM. Clinical significance of pharmacological modulation of homocysteine metabolism. Trans Pharmacol Sci. 1990;11:411–6.

    Article  CAS  Google Scholar 

  20. Wilcken DEL, Dudman NPB, Tyrrell DA. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency. Metabolism. 1988;37:697–701.

    Article  PubMed  CAS  Google Scholar 

  21. Meleady R, Ueland PM, Blom H, Whitehead AS, Refsum H, Daly LE, et al. And the EC concerted action project: homocysteine and vascular disease. Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project. Am J Clin Nutr. 2003;77:63–70.

    Article  PubMed  CAS  Google Scholar 

  22. Maron BA, Loscalzo J. Should hyperhomocysteinemia be treated in patients with atherosclerotic disease? Curr Atheroscler Rep. 2007;9:375–83.

    Article  PubMed  CAS  Google Scholar 

  23. Kang S-S, Wong PWK, Bock HG, et al. Intermediate hyperhomocyteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutation. Am J Hum Gene. 1991;48:546–51.

    CAS  Google Scholar 

  24. Kang S-S. Treatment of hyperhomocysteinemia: physiological basis. J Nut. 1996;126:1273S–5S.

    Article  CAS  Google Scholar 

  25. Weiss N, Keller C, Hoffman U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med. 2003;7:227–39.

    Article  Google Scholar 

  26. Wendell U, Bremer HJ. Betaine in the treatment of homocystinuria due to 5,19-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr. 1984;142:147–50.

    Article  Google Scholar 

  27. Holm E, Kjellman B, Ronge E. Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Childh. 1989;60:1061–4.

    Article  Google Scholar 

  28. Van Guldner C, Janssen MJFM, Lambert J, et al. No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinemia in hemodialysis patients. Nephr Dialy Transp. 1998;13:106–12.

    Article  Google Scholar 

  29. Van Guldner C. Why is homocysteinemia elevated in renal failure and what can be expected from homocysteine lowering. Nephr Dialys Transp. 2006;21:1161–6.

    Article  Google Scholar 

  30. Rubba P, Mercuri M, Faccenda F, Iannuzzi A, Irace C, Strisciuglio P, et al. Premature carotid atherosclerosis: does it occur in both familial hypercholesterolemia and homocystinuria? Stroke. 1994;25:943–50.

    Article  PubMed  CAS  Google Scholar 

  31. Singh RB, Meng SA, Xu Y-J, et al. Pathogenesis of arteriosclerosis: a multifactorial process. Exp Clin Cardiol. 2002;7:40–53.

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Potente M, Makinen T. Vascular heterogeneity and specialization in development and disease. Nat Rev Mol Cell Biol. 2017;18:477–94.

    Article  PubMed  CAS  Google Scholar 

  33. Thorin E, Shreeve SM. Heterogeneity of vascular endothelial cells in normal and disease states. Pharmacol Ther. 1988;78:155–66.

    Article  Google Scholar 

  34. Sprecher DL, Kruth HS, Piece JE, et al. A familial basis for the heterogeneity atherosclerotic disease. Atherosclerosis. 1987;65:167–72.

    Article  PubMed  CAS  Google Scholar 

  35. Box LC, Angiolillo DJ, Suzuki N, Box LA, Jiang J, Guzman L, et al. Heterogeneity of atherosclerotic plaque characteristics in human coronary artery disease: a three dimensional intravascular ultrasound study. Catheter Cardiovasc Interv. 2007;70:349–56.

  36. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, 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;291:565–75.

    Article  PubMed  CAS  Google Scholar 

  37. Lonne E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567–77.

    Article  Google Scholar 

  38. Bonna KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578–88.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Biomedical Genetics, Rush University Medical Center, 1753 W. Congress Parkway, Chicago, IL, 60612, USA

    Soo-Sang Kang

  2. Cardiometabolics Unit, Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Hnery R Kravis Center for Cardiovascular Health, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, One. Gutave L. Levy Place, Hospital Box 1030, New York, NY, 10029, USA

    Robert S. Rosenson

Authors
  1. Soo-Sang Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert S. Rosenson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert S. Rosenson.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, SS., Rosenson, R.S. Analytic Approaches for the Treatment of Hyperhomocysteinemia and Its Impact on Vascular Disease. Cardiovasc Drugs Ther 32, 233–240 (2018). https://doi.org/10.1007/s10557-018-6790-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-018-6790-1

Keywords

Search

Navigation