Skip to main content
SpringerLink
Log in

Homocysteine as a Risk Factor for Coronary Artery Disease

  • Chapter
Homocysteine and Vascular Disease

Part of the book series: Developments in Cardiovascular Medicine ((DICM,volume 230))

Summary

Hyperhomocysteinemia is an important addition to the growing list of potentially reversible risk factors for coronary heart disease (CHD). A compelling case can be made for performing screening measurements of plasma homocysteine concentrations in most if not all patients with myocardial infarction or a high risk of coronary artery disease. The genetic basis for regulation of plasma homocysteine levels suggests that approximately 50% of first-degree relatives of patients with hyperhomocysteinemia also may be hyperhomocysteinemic. Appropriate intervention includes correction of secondary causes of elevated homocysteine levels and treatment with folic acid, possibly in combination with vitamins B6 and B12. This intervention can effectively reduce plasma homocysteine concentrations in most patients and is predicted to prevent cardiovascular complications. Aggressive treatment of traditional CHD risk factors also is indicated, particularly among patients known to have atherosclerotic vascular disease. Verification of the clinical benefit and safety of homocysteine-lowering will require the completion during the next 5 to 10 years of 10 ongoing large scale prospective randomized clinical intervention trials involving more than 61,000 subjects.

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 219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ross R: Atherosclerosis–and inflammatory disease. N Engl J Med 1999; 340: 115–126.

    Article  PubMed  CAS  Google Scholar 

  2. Ross R: Cell biology of atherosclerosis. Ann Rev Physiol 1995; 57: 791–804.

    Article  CAS  Google Scholar 

  3. Bierman EL: Atherogenesis in diabetes. Arterioscler Thromb 1992; 12: 647–656.

    Article  PubMed  CAS  Google Scholar 

  4. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA 1993; 269: 3015–3023.

    Article  Google Scholar 

  5. Welch GN, Loscalzo J: Homocysteine and atherothrombosis N Engl J Med 1998; 338: 1042–1050.

    Article  CAS  Google Scholar 

  6. Duell PB, Malinow MR: Homocyst(e)inemia and risk of atherosclerosis: a clinical approach to evaluation and management. The Endocrinologist 1998; 8: 170–177.

    Article  Google Scholar 

  7. Scanu AM, Lawn RM, Berg K: Lipoprotein (a) and atherosclerosis. Ann Int Med 1991; 115: 209–218.

    PubMed  CAS  Google Scholar 

  8. Sniderman AD, Wolfson C, Teng B, Franklin FA, Bachorik PS, Kwiterovich PO Jr: Association of hyperapobetalipoproteinemia with endogenous hypertriglyceridemia and atherosclerosis. Ann Int Med 1982; 97: 833–839.

    PubMed  CAS  Google Scholar 

  9. Austin MA: Triacylglycerol and coronary heart disease. Proc Nutr Soc 1997; 56: 667–670.

    Article  PubMed  CAS  Google Scholar 

  10. Krauss RM: Triglycerides and atherogenic lipoproteins: rationale for lipid management. Am J Med 1998; 105: 58S - 62S.

    Article  PubMed  CAS  Google Scholar 

  11. Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J: Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54–59.

    Article  PubMed  CAS  Google Scholar 

  12. Steinberg D: Oxidative modification of LDL and atherogenesis. Circulation 1997; 95: 1062–1071.

    Article  PubMed  CAS  Google Scholar 

  13. Steinberg D: Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997; 272: 20963–20966.

    Article  PubMed  CAS  Google Scholar 

  14. O’Malley JP, Maslen CL, Illingworth DR: Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation 1998; 97: 1780–1783.

    Article  PubMed  Google Scholar 

  15. Clemetson KJ, Clemetson JM: Integrins and cardiovascular disease. Cell Mol Life Sci 1998; 54: 502–513.

    Article  PubMed  CAS  Google Scholar 

  16. Mackness MI, Mackness B, Durrington PN, Fogelman AM, Berliner J, et al: Paraoxonase and coronary heart disease. Curr Opin Lipidology 1998; 9: 319–324.

    Article  CAS  Google Scholar 

  17. Gibbs RG, Carey N, Davies AH: Chlamydia pneumoniae and vascular disease. British J Surg 1998; 85: 1191–1197.

    Article  CAS  Google Scholar 

  18. Cook PJ, Lip GY: Infectious agents and atherosclerotic vascular disease. QJM 1996; 89: 727–735.

    Article  PubMed  CAS  Google Scholar 

  19. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR, et al: Relation of serum lipoprotein (a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 1990; 322: 1494–1499.

    Article  PubMed  CAS  Google Scholar 

  20. Maher VM, Brown BG, Marcovina SM, Hillger LA, Zhao XQ, Albers JJ: Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995; 274: 1771–1774.

    Article  PubMed  CAS  Google Scholar 

  21. Foody JM, Robinson K, Jacobsen DW, Milberg JA, Sprecher DL: Homocysteine and lipoprotein (a) interaction: enhanced prediction of CAD in women. Circulation 1998; 98: 1602 (abstract).

    Google Scholar 

  22. Hirano K, Ogihara T, Miki M, et al: Homocysteine induces iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by a-tocopherol. Free Rad Res 1994; 21: 267–276.

    Article  CAS  Google Scholar 

  23. Blom HJ, Kleinveld HA, Boers GH, et al: Lipid peroxidation and susceptibility of low density lipoprotein to in vitro oxidation in hyperhomocysteinemia. Eur J Clin Invest 1995; 25: 149–154.

    Article  PubMed  CAS  Google Scholar 

  24. Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, et al: Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641–644.

    Article  PubMed  CAS  Google Scholar 

  25. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE: Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998; 98: 204–210.

    Article  PubMed  CAS  Google Scholar 

  26. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P, Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I: Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation 1998; 97: 437–443.

    Article  PubMed  CAS  Google Scholar 

  27. Malinow MR: Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. Clin Chem 1995; 41: 173–176.

    PubMed  CAS  Google Scholar 

  28. Kang SS, Wong PWK, Malinow MR: Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 1992; 12: 279–298.

    Article  CAS  Google Scholar 

  29. Malinow MR: Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases. J Nutr 1996; 126: 12385–12435.

    Google Scholar 

  30. Mudd SH, Levy HL, Skovby F: Disorders in transsulfuration. In: The Metabolic and Molecular Basis of Metabolic Disease, Scriver CR, Beaudet AL, Sly WS, Valle D, eds. McGraw Hill: New York, 1995: 1279–1327.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Wilcken DEL, Wilcken B: The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 1976; 57: 1079–1082.

    Article  PubMed  CAS  Google Scholar 

  33. Refsum H, Ueland PM: Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opin Lipidology 1998; 9: 533–539.

    Article  CAS  Google Scholar 

  34. Refsum H, Deland PM, Nygard O, Vollset SE: Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 31–61.

    Article  PubMed  CAS  Google Scholar 

  35. Malinow MR. Homocyst(e)ine and arterial occlusive diseases. J Intern Med 1994; 236: 603–617.

    Article  PubMed  CAS  Google Scholar 

  36. Boushey CJ, Beresford SA, Omen GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 1995; 274: 1049–1057.

    Article  PubMed  CAS  Google Scholar 

  37. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham 1: Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149–1155.

    Article  PubMed  CAS  Google Scholar 

  38. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337: 230–236.

    Article  PubMed  CAS  Google Scholar 

  39. Mayer EL, Jacobsen DW, Robinson KR: Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996; 27: 517–527.

    Article  PubMed  CAS  Google Scholar 

  40. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett WC: Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996; 143: 845–859.

    Article  PubMed  CAS  Google Scholar 

  41. Kang SS, Wong PWK, Cook HY, Norusis M, Messer JV: Protein-bound homocyst(e)ine. A possible risk factor for coronary artery disease. J Clin Invest 1986; 77: 1482–1486.

    Article  PubMed  CAS  Google Scholar 

  42. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR: The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and the methylenetetrahydrofolate reductase genotype. Arteriosclerosis and Thrombosis 1997; 17: 1157–1162.

    Article  CAS  Google Scholar 

  43. Wilcken DEL, Reddy SG, Gupta VJ: Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism 1983; 32: 363–370.

    Article  PubMed  CAS  Google Scholar 

  44. Murphy-Chutorian DR, Wexman MP, Grieco AJ, Heininger JA, Glassman E, Gaull GE, Ng SK, Feit F, Wexman K, Fox AC: Methionine intolerance: a possible risk factor for coronary artery disease. J Am Coll Cardiol 1985; 6: 725–730.

    Article  PubMed  CAS  Google Scholar 

  45. Dudman NPB, Wilcken DEL, Wang J, Lynch JF, Macey D, Lundberg P: Disordered methionine/homocysteine metabolism in premature vascular disease. Arterioscler Thromb 1993; 13: 1253–1260.

    Article  PubMed  CAS  Google Scholar 

  46. Pancharuniti N, Lewis CA, Sauberlich HE, Perkins LL, Go RC, Alvarez JO, Macaluso M, Acton RT, Copeland RB, Cousins AL, et al: Plasma homocysteine, folate, and vitamin B12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr 1994; 59: 940–948.

    PubMed  CAS  Google Scholar 

  47. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B: Homocyst(e)inemia in daily practice. Coron Artery Dis 1990; 1: 215–220.

    Article  Google Scholar 

  48. von Eckardstein A, Malinow MR, Upson B, Heinrich J, Schulte H, Schonfeld R, Kohler E, Assmann G: Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Atheroscler Thromb 1994; 14: 460–464.

    Article  CAS  Google Scholar 

  49. 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. JAMA 1992; 268: 877–881.

    Article  PubMed  CAS  Google Scholar 

  50. Ubbink JB, Vermaak WJH, Bennett JM, Becker PJ, van Staden DA, Bissbort S: The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary artery disease. Klin Wochenscr 1991; 69: 527–534.

    Article  CAS  Google Scholar 

  51. Genest JJ, McNamara JR, Salem DN, Wilson PWF, Schaefer EJ, Malinow MR: Plasma homocyst(e)ine levels in men with premature coronary artery disease. J Am Coll Cardiol 1990; 16: 1114–1119.

    Article  PubMed  Google Scholar 

  52. Wu LL, Wu J, Hunt SC, James BC, Vincent GM, Williams RR, Hopkins PN: Plasma homocysteine as a risk factor for early familial coronary artery disease. Clin Chem 1994; 40: 552–561.

    PubMed  CAS  Google Scholar 

  53. Israelsson B, Brattström LE, Hultberg BL: Homocysteine and myocardial infarction. Atherosclerosis 1988; 71: 227–233.

    Article  PubMed  CAS  Google Scholar 

  54. Graham I: Interactions between homocysteinemia and conventional risk factors in vascular disease. Eur Heart J 1994; I5 (suppl): 530 (abstract).

    Google Scholar 

  55. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaung JE: Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995; 24: 704–709.

    Article  PubMed  CAS  Google Scholar 

  56. Brattström LE, Harbebo JE, Hultberg BL: Moderate homocysteinemia. Stroke 1984; 15: 1012–1016.

    Article  PubMed  Google Scholar 

  57. Araki A, Sako Y, Fukushima Y, Matsumoto Asada T, Kita T: Plasma sulfhydrylcontaining amino acids in patients with cerebral infarction and in hypertensive subjects. Atherosclerosis 1989; 79: 139–146.

    Article  PubMed  CAS  Google Scholar 

  58. Coull B, Malinow MR, Beamer N, Sexton G, Nordt F, deGarmo P: Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 1990; 21: 572–576.

    Article  PubMed  CAS  Google Scholar 

  59. Brattström LE, Israelsson B, Norrving B, Bergqvist D, Thorne J, Hultberg B, Hamfelt A: Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Atherosclerosis 1990;8]:51–60.

    Google Scholar 

  60. Brattström LE, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B, Hamfelt A: Hyperhomocysteinemia in stroke. Eur J Clin Invest 1992; 22: 214–221.

    Article  PubMed  Google Scholar 

  61. Lindgren A, Brattstrom L, Norrving B, Hultberg B, Andersson A, Johansson BB: Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995; 26: 795–800

    Article  PubMed  CAS  Google Scholar 

  62. Bergmark C, Mansoor MA, Swedenborg J, deFaire U, Svardal AM, Ueland PM: Hyperhomocysteinemia in patients operated for lower extremity ischemia below the age of 50: effect of smoking and extent of disease. Eur J Vasc Surg 1993; 7: 391–396.

    Article  PubMed  CAS  Google Scholar 

  63. Molgaard J, Malinow MR, Lassvik C, Holm A-C, Upson B, Olsson AG: Hyperhomocyst(e)inemia: an independent risk factor for intermittent claudication: J Intern Med 1992; 231: 273–279.

    CAS  Google Scholar 

  64. Alfthan G, Pekkanen J, Jauhiainen M, et al: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994; 106: 9–19.

    Article  PubMed  CAS  Google Scholar 

  65. Genest JJ, McNamara JR, Upson B, Salem DN, Ordovaas JM, Schaefer EJ, Malinow MR: Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991;1 1:1 129–1 136.

    Google Scholar 

  66. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ: A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994; 25: 1924–1930.

    Article  PubMed  CAS  Google Scholar 

  67. Alfthan G, Aro A, Gey F: Plasma homocysteine and cardiovascular disease mortality. Lancet 1997; 349: 397 (letter).

    Google Scholar 

  68. van den Berg M, Stehouwer CDA, Bierdrager E, et al.. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vasc Biol 1996; 16: 165–71

    Article  PubMed  Google Scholar 

  69. Glueck CJ, Shaw P, Lang JE, et al.. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am. J. Cardiol. 1995; 75: 132–36

    Article  PubMed  CAS  Google Scholar 

  70. Bachmann J, Tepel M, Raidt H, et al.. Hyperhomocysteinernia and the risk for vascular disease in hemodialysis patients. J Am. Soc. Nephrol. 1995; 6: 121–25

    PubMed  CAS  Google Scholar 

  71. Currie IC, Wilson YG, Scott J, et al: Homocysteine: an independent risk factor for the failure of vascular intervention. Br J Surg 1996; 83: 1238–1241.

    Article  PubMed  CAS  Google Scholar 

  72. Tonstad S, Joakimsen O, Stenslandbugge E, et al.. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects. Arterioscler Thromb Vasc Biol 1996; 16: 984–91

    Article  PubMed  CAS  Google Scholar 

  73. Robinson K, Gupta A, Dennis V, et al: Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation 1996; 94: 2743–48

    Article  PubMed  CAS  Google Scholar 

  74. Herzlich BC, Lichstein E, Schulhoff N, et al: Relationship among homocysteine, vitamin B-12 and cardiac disease in the elderly: association between vitamin B-12 deficiency and decreased left ventricular ejection fraction. J Nutr 1996; 126: S1249–53

    Google Scholar 

  75. Tonstad S, Refsum H, Siversten M, et al: Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res 1996; 40: 4752.

    Article  Google Scholar 

  76. Tonstad S, Refsum H, Ueland PM: Association between total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia. Circulation 1997; 96

    Google Scholar 

  77. Munshi MN, Stone A, Fink L, Fonseca V: Hyperhomocysteinernia following a methionine load in patients with noninsulin-dependent diabetes mellitus and macrovascular disease. Metabolism 1996; 45: 133–135.

    Article  PubMed  CAS  Google Scholar 

  78. Simioni P, Prandoni P, Burlina A, et al: Hyperhomocysteinemia and deep vein thrombosis–a case-control study. Thromb. Haemost. 1996; 76: 883–886

    PubMed  CAS  Google Scholar 

  79. Bots ML, Laurier U, Lindemans J, et al. Homocysteine, atherosclerosis and prevalent cardiovascular disease in the elderly: The Rotterdam study. J Intern Med 1997.

    Google Scholar 

  80. Title LM, Dunn J, Cummings P, Zayed E, Dempsey GI, O’Neill BJ, Johnstone DE, Bata IR, Nassar BA: Relation between homocysteine, a mutation in methylenetetrahydrofolate reductase and extent of coronary artery disease. Circulation 1998;98:1–439–440 (abstract).

    Google Scholar 

  81. Konecky N, Malinow MR, Tunick PA, Freedberg RS, Rosenzweig BP, Katz ES, Hess DL, Upson B, Leung B, Perez J, Kronzon L: Correlation between plasma homocyst(e)ine and aortic atherosclerosis. Am Heart J 1997; 133: 534–540.

    Article  PubMed  CAS  Google Scholar 

  82. den Heijer M, Blom HJ, Gerrits WBJ, et al: Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345: 882–85

    Article  Google Scholar 

  83. Landgren F, Israelsson B, Lindgren A, et al: Plasma homocysteine in acute myocardial infarction: homocysteine lowering effect of folic acid. J Intern. Med 1995; 237: 381–388

    Article  PubMed  CAS  Google Scholar 

  84. Dalery K, Lussier-Cacan S, Selhub J, et al.. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B 12, B6, pyridoxal phosphate, and olate. Am. J Cardiol. 1995; 75: 1107–11

    Article  PubMed  CAS  Google Scholar 

  85. Hopkins PN, Wu LL, Wit J, et al.. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1995; 15: 1314–20

    Article  PubMed  CAS  Google Scholar 

  86. Fermo 1, Arcelloni C, Devecchi E, et al.. High-performance liquid chromatographic method with fluorescence detection for the determination of total homocysteine in plasma. J Chromatography 1992; 593: 171–76

    Article  CAS  Google Scholar 

  87. Amundsen T, Ueland PM, Waage A: Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1321–23.

    Article  PubMed  CAS  Google Scholar 

  88. Robinson K, Mayer EL, Miller DP, et al.. Hyperhomocysteinemia and low pyridoxal phosphate: common and independent reversible risk factors for coronary artery disease. Circulation 1995; 92: 2825–30

    Article  PubMed  CAS  Google Scholar 

  89. Mansoor MA, Bergmark C, Svardal AM, et al: Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Arterioscler Thromb Vasc Biol 1995; 15: 232–240.

    Article  PubMed  CAS  Google Scholar 

  90. Valentine RJ, Kaplan H S, Green R, et al.. Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: a prospective, controlled analysis, J. Vasc. Surg. 1996; 23: 53–63

    Article  PubMed  CAS  Google Scholar 

  91. den Heijer M, Koster T, Blom HJ, et al: Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759–62

    Article  Google Scholar 

  92. Loehrer FMT, Angst CP, Haefuli WE, et al: Low whole-blood s-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease. Arterioscler Thromb Vasc Biol 1996; 16: 727–33

    Article  PubMed  CAS  Google Scholar 

  93. Lolin YI, Sanderson JE. Cheng SK, et al.. Hyperhomocysteinemia and premature coronary artery disease in the Chinese. Heart 1996; 76: 117–22

    Article  PubMed  CAS  Google Scholar 

  94. Gallagher PM, Meleady R, Shields DC, et al.. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation 1996; 94: 2154 2158.

    Google Scholar 

  95. Stammler F, Diehm C, Hsu E, et al.. Prevalence of hyperhomocysteinaernia in thrombangiitis obliterans (Buerger’s disease): does homocysteine play a pathogenetic role? Dtsch. Med Wochenschr. 1996; 121: 1417–1423.

    Article  CAS  Google Scholar 

  96. Malinow MR, Ducimetiere P, Luc G, Evans AE, Arveiler D, Cambien F, Upson BM: Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease. Atherosclerosis 1996; 126: 2734.

    Google Scholar 

  97. Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ: Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35–41.

    PubMed  CAS  Google Scholar 

  98. Graham IM, Daley LE, Refsum HM, et al: Plasma homocysteine as a risk factor for vascular disease: the European concerted action project. JAMA 1997; 277: 1775–1781.

    Article  PubMed  CAS  Google Scholar 

  99. Christensen B, Frosst P, Lussier-Cacan S, et al: Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease. Arterioscler Thromb Vasc Biol 1997; 17: 569–73.

    Article  PubMed  CAS  Google Scholar 

  100. Verhoef P, Kok FJ, Kruyssen DACM, et al.. Plasma total homocysteine, B vitamins and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17: 989–995.

    Article  PubMed  CAS  Google Scholar 

  101. Schwartz SM, Siscovick DS, Malinow MR, Rosendaal FR, Beverly RK, Hess DL, Psaty BM, Longstreth WT Jr, Koepsell TD, Raghunathan TE, Reitsma PH: Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation 1997; 96: 412–417.

    Article  PubMed  CAS  Google Scholar 

  102. Chambers JC, Obeid O, Hooper J, Kemp M, Reilly P, Powell-Tuck J, Kooner JS: Hyperhomocysteinamia may account for the excess coronary heart disease risk in UK Indian Asians compared to European whites. Circulation 1998; 98: 1–169 (abstract).

    Article  Google Scholar 

  103. Perry IJ, Refsum H, Morris RW, et al: Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: 1395–1398.

    Article  PubMed  CAS  Google Scholar 

  104. Ridker PM, Hennekens CH, Selhub J, et al.. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95: 1777 1782.

    Google Scholar 

  105. Verhoef P, Hennekens CH, Allen RH, et al: Plasma total homocysteine and risk of angina pectoris with subsequent coronary artery bypass surgery. Am. J Cardiol. 1997; 79: 799–801.

    Article  PubMed  CAS  Google Scholar 

  106. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH: Homocysteine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arteriosclerosis, Thrombosis & Vascular Biology 1997; 17: 1947–1953.

    Article  CAS  Google Scholar 

  107. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM: Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Int Med 1998; 158: 862–867.

    Article  CAS  Google Scholar 

  108. Ridker PM, Buring JE, Manson JE: A Prospective Study of Total Plasma Homocysteine and the Risk of Future Cardiovascular Events Among Apparently Healthy Women. Circulation 1998; 98: 1–810 (abstract).

    Article  Google Scholar 

  109. Petri M, Roubenoff R, Dallal GE, et al: Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996; 348: 1120–1124.

    Article  PubMed  CAS  Google Scholar 

  110. Bostom AG, Shemin D, Verhoef P, Nadeau MR, Jacques PF, Selhub J, Dworkin L, Rosenberg 1H: Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study. Arterioscler Thromb Vase Biol 1997; 17: 2554–2558.

    Article  CAS  Google Scholar 

  111. Moustapha A, Naso A, Nahlawi M, Gupta A, Arheart KL, Jacobsen DW, Robinson K, Dennis VW: Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998; 97: 138–141.

    Article  PubMed  CAS  Google Scholar 

  112. Al-Obaidi MK, Stubbs PJ., Amersey R, Conroy R, Graham IM, Noble MI: Admission Plasma Homocysteine Predicts Long Term Mortality In Patients Presenting With Acute Coronary Syndromes. Circulation 1998; 98: 1–555 (abstract).

    Article  Google Scholar 

  113. Stamler JS, Osborne JA, Jaraki O, et al: Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993;91:308–3I8.

    Google Scholar 

  114. Van Den Berg M, Boers GH, Franken DG, Blom HJ, Van Kamp GJ, Jakobs C, Rauwerda JA, Kluft C, Stehouwert CD: Hyperhomocysteinemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1995; 25: 176181

    Google Scholar 

  115. Dudman NPB, Hicks C, Lynch JF, Wilcken DEL, Wang J: Homocysteine thiolactone disposal by human arterial endothelial cells and serum in vitro. Arterioscler Thromb 1991; 11: 663–670.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  117. Wall RT, Harlan JM, Harker LA, Striker GE: Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980; 18: 1 13–121.

    Article  Google Scholar 

  118. Harker LA, Slichter SJ, Scott CR, Ross R: Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 1974; 291: 537–543.

    Article  PubMed  CAS  Google Scholar 

  119. Harker LA, Ross R, Slichter SJ, Scott CR: Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58: 73 1741.

    Google Scholar 

  120. Harker LA, Harlan JM, Ross R: Effects of sulfinpyrazone on homocysteine-induced endothelial injury and atherosclerosis in baboons. Circ Res 1983; 53: 731–739.

    Article  PubMed  CAS  Google Scholar 

  121. Radomski MW, Salas E: Nitric oxide - biological mediator, modulator and factor of injury: its role in the pathogenesis of atherosclerosis. Atherosclerosis 1995; 118: S69 - S80.

    Article  PubMed  CAS  Google Scholar 

  122. Levine GN, Keaney JF, Jr, Vita JA: Medical progress: cholesterol reduction in cardiovascular disease–clinical benefits and possible mechanisms. N Engl J Med 1995; 332: 512–521.

    Article  PubMed  CAS  Google Scholar 

  123. Celermajer DS, Sorensen K, Ryalls M, et al: Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not their heterozygous parents. J Am Coll Cardiol 1993; 22: 854–858.

    Article  PubMed  CAS  Google Scholar 

  124. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD: Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996; 98: 24–29.

    Article  PubMed  CAS  Google Scholar 

  125. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA: Hyperhomocysteinemia is associated with impaired endothelium-dependent dysfunction in humans. Circulation 1997; 95: 1119–1121.

    Article  PubMed  CAS  Google Scholar 

  126. Duell PB, Malinow MR: Hyperhomocyst(e)inemia is associated with impaired flow-mediated arterial vasodilation. J Invest Med 1997; 45: 220A (abstract).

    Google Scholar 

  127. Tsai JC, Perella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, Lee ME: Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Nat Acad Sci USA 1994; 91: 6369–6373.

    Article  PubMed  CAS  Google Scholar 

  128. McDonald L, Bray C, Field C, Love F, Davies B: Homocystinuria, thrombosis and the blood-platelets. Lancet 1964; 1: 745–746.

    Article  PubMed  CAS  Google Scholar 

  129. DiMinno G, Davi G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, Catalano I, Strisciuglio P, Andria G, Patrono C, et al: Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 1993; 92: 1400–1406.

    Article  CAS  Google Scholar 

  130. Uhlemann ER, TenPas JH, Lucky AW, Schulman JD, Mudd SH, Shulman NR: Platelet survival and morphology in homocystinuria due to cystathione synthase deficiency. N Engl J Med 1976; 295: 1283–1286.

    Article  PubMed  CAS  Google Scholar 

  131. Hill-Zobel RL, Pyeritz RE, Scheffel U, Malpica O, Engin S, Camargo EE, Abbott M, Guilarte TR, Hill J, McIntyre PA, Murphy EA, Tsan MF: Kinetics and distribution of “indium-labeled platelets in patients with homocystinuria. N Engl J Med 1982; 307: 78 1786.

    Google Scholar 

  132. Graeber JE, Slott JH, Ulane RE, Schulman JD, Stuart M: Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res 1982; 16: 490–493.

    Article  PubMed  CAS  Google Scholar 

  133. Kokame K, Kato H, Miyata T: Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. J Biol Chem 1996; 271: 29659–29665.

    Article  PubMed  CAS  Google Scholar 

  134. Giannini MJ, Coleman M, Innerfield I. Antithrombin activity in homocystinuria. Lancet 1975; 1: 1094 (letter).

    Google Scholar 

  135. Palareti G, Coccheri S: Lowered antithrombin III activity and other clotting changes in homocystinuria: effects of a pyridoxine-folate regimen. Haemostasis 1989;19 Suppl:2428.

    Google Scholar 

  136. Hilden M, Brandt NJ, Nilsson IM, Schonheyder F: Investigation of coagulation and fibrinolysis in homocystinuria. Acta Med Scand 1974; 195: 533–535.

    Article  PubMed  CAS  Google Scholar 

  137. Rodgers GM, Kane WH: Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986; 77: 1909–1916.

    Article  PubMed  CAS  Google Scholar 

  138. Rogers GM, Conn MT: Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990; 75: 895–901.

    Google Scholar 

  139. Hayashi T, Honda G, Suzuki K: An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 1992; 79: 2930–2936.

    PubMed  CAS  Google Scholar 

  140. Hajjar KA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91: 2873–2879.

    Article  PubMed  CAS  Google Scholar 

  141. Nishinaga M Ozawa T, Shimada K: Homocysteine, a thrombogenic agent, suppresses anticoagulant heparin sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92: 1381–1386.

    Article  PubMed  Google Scholar 

  142. Lentz SR, Sadler JE: Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 1993; 81: 683689.

    Google Scholar 

  143. Peterson JC and Spence JD: Vitamins and progression of atherosclerosis in hyperhomocysteinemia. Lancet 1998; 351: 263 (letter).

    Google Scholar 

  144. Nugent A, Hadden DR, Carson NAJ: Long-term survival of homocystinuria: the first case. Lancet 1998; 352: 624–625.

    Article  PubMed  CAS  Google Scholar 

  145. Malinow MR, Bostom AG, Krauss RM. AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases. A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association. Circulation 1999; 99: 178–182.

    Article  PubMed  CAS  Google Scholar 

  146. Malinow MR, Kang, SS, Taylor LM, Wong PW, Coull B, Inahara T, Mukerjee D, Sexton G, Upson B: Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989; 79: 1180–1188.

    Article  PubMed  CAS  Google Scholar 

  147. Duell PB, Malinow MR, Gregory JF, Connor WE: Reduction of fasting and postprandial plasma homocysteine concentrations by a semi-vegetarian very low-fat diet. Circulation 1998; 98: 1192 (abstract).

    Article  Google Scholar 

  148. Andersson A, Brattström L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B: Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992; 22: 79–87.

    Article  PubMed  CAS  Google Scholar 

  149. Bostom AG, Roubenoff R, Dellaripa P, et a1: Validation of abbreviated oral methionineloading test. Clin Chem 1995; 41: 948–949.

    PubMed  CAS  Google Scholar 

  150. The 4S Investigators: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389.

    Google Scholar 

  151. Garg R, Malinow MR, Pettinger M, Hunninghake D: Treatment with niacin increases plasma homocyst(e)ine levels. Circulation 1996; 94: 1–457 (abstract).

    Article  Google Scholar 

  152. Blankenhorn DH, Malinow MR, Mack WJ: Colestipol plus niacin therapy elevates plasma homocyst(e)ine levels. Coronary Artery Disease 1991; 2: 357–360.

    Article  Google Scholar 

  153. Landgren F, Israelsson B, Lindgren A, et al: Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med 1995; 237: 381–388.

    Article  PubMed  CAS  Google Scholar 

  154. Malinow MR: Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990; 81: 2004–2006.

    Article  PubMed  CAS  Google Scholar 

  155. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg 1H: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270: 2693–2698.

    Article  PubMed  CAS  Google Scholar 

  156. Guttormsen AB,Ueland PM, Nesthus I, Nygard O, Schneede J, Vollset SE, Refsum H: Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter): the Hordaland homocysteine Study. J Clin Invest 1996; 98: 2174–83.

    Article  Google Scholar 

  157. Kang SS, Wong PWK, Norusis M: Homocysteinemia due to folate deficiency. Metabolism 1987; 36: 458–462.

    Article  PubMed  CAS  Google Scholar 

  158. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. Homocysteine trialists’ collaboration. BMJ 1998;316:894–898.

    Google Scholar 

  159. Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM: Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998; 338: 1009–1015.

    Article  PubMed  CAS  Google Scholar 

  160. Bostom AG, Shemin D, Lapane KL, et al: High dose B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int 1996; 49: 147–152.

    Article  PubMed  CAS  Google Scholar 

  161. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ, Delport R, Potgieter HC: Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994; 124: 1927–1933.

    PubMed  CAS  Google Scholar 

  162. Brattström L, Israelsson B, Lindgarde F, Hultberg B: Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathione ßsynthase deficiency. Metabolism 1988; 37: 175–178.

    Article  PubMed  Google Scholar 

  163. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, Allen RH: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318: 1720–1728.

    Article  PubMed  CAS  Google Scholar 

  164. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J: Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92: 1191–1198.

    PubMed  CAS  Google Scholar 

  165. Wilcken DE, Wilcken B, Dudman NP, Tyrell PA: Homocystinuria: the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983; 309: 448453.

    Google Scholar 

  166. Malinow MR, Ryan M: unpublished data.

    Google Scholar 

  167. Emmert JL, Garrow TA, Baker DH: Hepatic betaine-homocysteine methyltransferase activity in the chicken is influenced by dietaary intake of sulfur amino acids, choline and betaine. J Nutrition 1996; 126: 2050–2058.

    CAS  Google Scholar 

  168. Lobley GE, Connell A, Revell D: The importance of transmethylation reactions to methionine metabolism in sheep; effects of supplementation with creatine and choline. Brit J Nutr 1996; 75: 47–56.

    Article  PubMed  CAS  Google Scholar 

  169. Voutilainen S, morrow JD, Roberts LJ, Alfthan G, Alho H, Nyyssönen K, Salonen Jt: Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine leveld. Arterioscler Thromb Basc Biol 1999; 19: 1263–1266.

    Article  CAS  Google Scholar 

  170. Kittner SI, Malnow MR, Seipp MJ, Upson B, Hebel Jr: Stability of blood homocysteine under epidemiological field conditions. J Clin Lab Anal 1995; 9: 75–76.

    Article  PubMed  CAS  Google Scholar 

  171. Manilow MR, Axthelm MK, Meredith MJ, MacDonald NA, Upson BM: Synthesis and transsulfuration of homocysteine in blood. J Lab Clin med 1994; 123: 421–9.

    Google Scholar 

Download references

Authors
  1. P. Barton Duell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. René Malinow
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Cardiology, The Cleveland Clinic Foundation, Desk F15, 9500 Euclid Avenue, 44195, Cleveland, Ohio, USA

    Killian Robinson

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Duell, P.B., Malinow, M.R. (2000). Homocysteine as a Risk Factor for Coronary Artery Disease. In: Robinson, K. (eds) Homocysteine and Vascular Disease. Developments in Cardiovascular Medicine, vol 230. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-1789-2_11

Download citation

  • DOI: https://doi.org/10.1007/978-94-017-1789-2_11

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-90-481-5431-9

  • Online ISBN: 978-94-017-1789-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation