Cardiovascular Drugs and Therapy

, Volume 32, Issue 2, pp 233–240 | Cite as

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

  • Soo-Sang Kang
  • Robert S. Rosenson


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.


Homocysteine Hyperhomocysteinemia Atherosclerotic cardiovascular disease Genetics 


  1. 1.
    Kang S-S, Wong PWK, Malinow MR. Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Ann Rev Nutr. 1992;12:279–98.CrossRefGoogle Scholar
  2. 2.
    Nehler MR, Taylor LM Jr, Porter JM. Homocysteinemia as a risk factor for atherosclerosis: a review. Cardiovasc Surg. 1997;5:559–67.CrossRefPubMedGoogle Scholar
  3. 3.
    Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Ann Rev Med. 1998;49:31–62.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 5.
    Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Ann Rev Med. 2009;60:39–54.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rosenson RS, Kang DS. Overview of homocysteine. UpToDate. 2017.Google Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 8.
    Kanwar YS, Manoligod JR, Wong PWK. Morphological studies in a patient with methylenetetrahydrofolate reductase deficiency. Pediatr Res. 1976;10:598–609.CrossRefPubMedGoogle Scholar
  9. 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.Google Scholar
  10. 10.
    McCully KS. Homocysteine theory of arteriosclerosis: development and current status. Atheiosclerosis Rev. 1983;11:157–246.Google Scholar
  11. 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.Google Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.PubMedPubMedCentralGoogle Scholar
  14. 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.PubMedPubMedCentralGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 16.
    Haltberg B, Agaidh E, Anderson A, et al. Increased levels of homocysteine are associated with nephropathy. Clin Lab Investig. 1991;51:277–82.CrossRefGoogle Scholar
  17. 17.
    Kang S-S, Wong PWK, Barnes LJ. Severe homocysteinemia in a non-homocystinuric subject. Unpublished Communication, 1984.Google Scholar
  18. 18.
    Kang S-S, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987;36:458–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Refsum H, Ueland PM. Clinical significance of pharmacological modulation of homocysteine metabolism. Trans Pharmacol Sci. 1990;11:411–6.CrossRefGoogle Scholar
  20. 20.
    Wilcken DEL, Dudman NPB, Tyrrell DA. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency. Metabolism. 1988;37:697–701.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 22.
    Maron BA, Loscalzo J. Should hyperhomocysteinemia be treated in patients with atherosclerotic disease? Curr Atheroscler Rep. 2007;9:375–83.CrossRefPubMedGoogle Scholar
  23. 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.Google Scholar
  24. 24.
    Kang S-S. Treatment of hyperhomocysteinemia: physiological basis. J Nut. 1996;126:1273S–5S.CrossRefGoogle Scholar
  25. 25.
    Weiss N, Keller C, Hoffman U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med. 2003;7:227–39.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 27.
    Holm E, Kjellman B, Ronge E. Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Childh. 1989;60:1061–4.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Singh RB, Meng SA, Xu Y-J, et al. Pathogenesis of arteriosclerosis: a multifactorial process. Exp Clin Cardiol. 2002;7:40–53.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Potente M, Makinen T. Vascular heterogeneity and specialization in development and disease. Nat Rev Mol Cell Biol. 2017;18:477–94.CrossRefPubMedGoogle Scholar
  33. 33.
    Thorin E, Shreeve SM. Heterogeneity of vascular endothelial cells in normal and disease states. Pharmacol Ther. 1988;78:155–66.CrossRefGoogle Scholar
  34. 34.
    Sprecher DL, Kruth HS, Piece JE, et al. A familial basis for the heterogeneity atherosclerotic disease. Atherosclerosis. 1987;65:167–72.CrossRefPubMedGoogle Scholar
  35. 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.Google Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Biomedical GeneticsRush University Medical CenterChicagoUSA
  2. 2.Cardiometabolics Unit, Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Hnery R Kravis Center for Cardiovascular Health, Mount Sinai HeartIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations