Homocyst(e)ine: An important risk factor for atherosclerotic vascular disease

Current Opinion in Lipidology

Volumn 8, Issue 1, 1997, Pages 28-34

  Duell, P Barton ^a,b   Malinow, M René ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYANOCOBALAMIN; ENZYME; FOLIC ACID; HOMOCYSTEINE; LOW DENSITY LIPOPROTEIN; METHIONINE; METHOTREXATE; NITROUS OXIDE; PYRIDOXINE;

AGING; AMINO ACID BLOOD LEVEL; AMINO ACID METABOLISM; ATHEROGENESIS; ATHEROSCLEROSIS; BLOOD CLOTTING; CELL PROLIFERATION; CEREBROVASCULAR DISEASE; CORONARY ARTERY ATHEROSCLEROSIS; CYTOTOXICITY; ENDOTHELIUM INJURY; HUMAN; HYPERHOMOCYSTEINEMIA; KIDNEY DISEASE; MORBIDITY; MORTALITY; OXIDATION; PERIPHERAL VASCULAR DISEASE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SMOOTH MUSCLE FIBER; THROMBOCYTE ACTIVATION; THROMBOSIS; VASCULAR ENDOTHELIUM;

EID: 0030888183     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-199702000-00007     Document Type: Review

References (86)

1. Mudd SH, Levy HL, Skovby F: Disorders in transsulfuration. In The metabolic and molecular basis of metabolic disease. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw Hill; 1995:1279-1327.
2. Wilcken DEL, Wilcken B: The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 1976, 57:1079-1082.
3. Malinow MR: Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. Clin Chem 1995, 41:173-176.
4. Malinow MR: Homocyst(e)ine and arterial occlusive diseases. J Intern Med 1994, 236:603-617.
5. 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. An excellent overview and meta-analysis.
6. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I: Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991, 324:1149-1155.
7. Malinow MR: Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases. J Nutr 1996, 126(suppl):1238S-1243S.
8. Mayer EL, Jacobsen DW, Robinson KR: Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996, 27:517-527. A well written overview.
9. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J: Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectroscopy. J Clin Invest 1988, 81:466-474.
10. Cahsan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ: A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996, 15:136-143. A large prospective study.
11. 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. An important epidemiological study.
12. Selhub J, Jaques PF, Wilson PWF, Rush D, Rosenberg IH: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993, 270:2693-2698.
13. Brattström L, Israelsson B, Lindgarde F, Hultberg B: Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathione β-synthase deficiency. Metabolism 1988, 37:175-178.
14. Kang SS, Wong PWK, Norusis M: Homocysteinemia due to folate deficiency. Metabolism 1987, 36:458-462.
15. Kang SS, Passen EL, Ruggie N, Wong PW, Sora H: Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1993, 88:1463-1469.
16. 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.
17. Goyette P, Summer JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R: Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genet 1994, 7:196-200.
18. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, Van den Heuven LP et al.: A candidate genetic risk-factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995, 10:111-113. An important study of the genetics of MTHFR.
19. Kluijmans LAJ, Lambert PWJ, van den Heuvel WJ, 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. Another important study of the genetics of MTHFR.
20. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D et al.: The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and the methylenetetrahydrofolate reductase genotype. Arterioscler Thromb 1997, (In press).
21. Cooper BA, Rosenblatt DS: Inherited defects of vitamin B12 metabolism. Annu Rev Nutr 1987, 7:291-320.
22. Goyette P, Frosst P, Rosenblatt DS, Rozen R: Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 1991, 48:536-545.
23. Andersson A, Brattström L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B: Plasma homocysteine before and after methlonine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992, 22:79-87.
24. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM, Taylor LMJr: Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994, 40:873-881.
25. Boers GH, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg PW: Unique efficacy of methionine metabollsm in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest 1983, 72:1971-1976.
26. Refsum H, Wesenbδerg F, Ueland PM: Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer Res 1991, 51:828-835.
27. Wilcken DEL, Gupta VJ: Sulfur-containing amino acids in chronic renal failure with particular reference to homocystine and cysteinehomocysteine mixed disulfide. Eur J Clin Invest 1979, 9:301-307.
28. Chaveau P, Bernadette C, Coudé M, Aupetit J, Hannedouche T, Kamoun P, Jungers P: Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 1993, 43(suppl):S72-S77.
29. Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J: Adverse vascular effects of homocysteine are modulated by endothellum-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993, 91:308-318.
30. Van Den Berg M, Boers GHJ, Franken DG, Blom HJ, Van Kamp GJ, Jokobs C, Rauwerda JA, Kluft C, Stehouwert CD: Hyperhomocysteinemia and endothellal dysfunction in young patients with peripheral arterial occlusive disease. Eur J Clin Invest 1996, 25:176-181.
31. 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.
32. Starkebaum G, Marlan JM: Endothelial cell injury due to coppercatalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986, 77:1370-1376.
33. 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, 18:113-121.
34. Harker LA, Slichter SJ, Scott CR, Ross R: Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 1974, 291:537-543.
35. 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, 58:731-741.
36. Harker LA, Harlan JM, Ross R: Effects of sulfinpyrazone on homocysteine-Induced endothelial injury and atherosclerosis in baboons. Circ Res 1983, 53:731-739.
37. Radomski MW, Salas E: Nitric oxide - biological mediator, modulator and factor of injury: its role in the pathogenesis of atherosclerosis. Atherosclerosis 1995, 118[suppl]:S69-S80.
38. 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. An excellent overview with a discussion of the role of endothelial dysfunction.
39. 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.
40. 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. The first study to demonstrate impaired endothelium-dependent vasoreactivity in association with moderate hyperhomocyst(e)inemia.
41. 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.
42. Hirano K, Ogihara T, Miki M, Yasuda H, Tamai H, Kawamura N, Mino M: Homocysteine induces Iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by α-tocopherol. Free Rad Res 1994, 21:267-276.
43. Blom HJ, Kleinveld HA, Boers GH, Demacker PN, Hak-Lemmers HL, Te Poele-Pothoff MT, Trijbels JM: Lipid peroxidation and susceptibility of low density lipoprotein to in vitro oxidation in hyperhomocysteinemia. Eur J Clin Invest 1995, 25:149-154.
44. Witztum JL, Steinberg D: Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991, 88:1785-1792.
45. Duell PB The role of dietary antioxldants in prevention of atherosclerosis. Endocrinologist 1995, 5:347-356.
46. McDonald L, Bray C, Field C, Love F, Davies B: Homocystinuria, thrombosis and the blood-platelets. Lancet 1964, 1:745-746.
47. DiMinno G, Davi G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, Catalano I, Strisciuglio P, Andria G, Patrono C: Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 1993, 92:1400-1406.
48. 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.
49. 111Indium-labeled platelets in patients with homocystinuria. N Engl J Med 1982, 307:781-786.
50. 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.
51. Giannini MJ, Coleman M, Innerfield I. Antithrombin activity in homocystinuria [letter]. Lancet 1975, i:1094.
52. Palareti G, Coccheri S: Lowered antithrombin III activity and other clotting changes in homocystinuria: effects of a pyridoxine-folate regimen. Haemostasis 1989, 19(Suppl):24-28.
53. Hilden M, Brandt NJ, Nilsson IM, Schonheyder F: Investigation of coagulation and fibrinolysis in homocystinuria. Acta Med Scand 1974, 195:533-535.
54. Rogers GM, Conn MT: Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990, 75:895-901.
55. 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.
56. Hajjar KA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993, 91:2873-2879.
57. Rodgers GM, Kane WH: Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986, 77:1909-1916.
58. 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.
59. Lentz SR, Sadler JE: Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 1993, 81:683-689.
60. 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, 126:27-34. Demonstrates the graded risk for myocardial infarction associated with elevated levels of homocyst(e)ine.
61. Wilcken DEL, Reddy SG, Gupta VJ: Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism 1983, 32:363-370.
62. Murphy-Chutorian DR, Wexman MP, Grieco AJ, Heininger JA, Glassman E, Gaull GE, Ng SK, Feit F, Wexman K, Fox AC: Methionine intolerance. J Am Coll Cardiol 1985, 6:725-730.
63. Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvonen M, Tuomilehto J, Salonen JT, Ehnhoim C: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994, 106:9-19.
64. Pancharuniti N, Lewis CA, Sauberlich HE, Perkins LL, Go RC, Alvarez JO, Macaluso M, Acton RT, Copeland RB, Cousins AL: Plasma homocyst(e)ine, folate, and vitamin B12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr 1994, 59:940-948.
65. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B: Homocyst(e)inemia in daily practice. Coronary Artery Dis 1990, 1:215-220.
66. 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.
67. 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.
68. 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.
69. 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.
70. Wu LL, Wu J, Hunt SC, James BC, Vincent GM, Williams RR, Hopkins PN: Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem 1994, 40:552-561.
71. Israelsson B, Brattstrom LE, Hultberg BL: Homocysteine and myocardial infarction. Atherosclerosis 1988, 71:227-233.
72. Graham I: Interactions between homocysteinaemia and conventional risk factors in vascular disease [Abstract]. Eur Heart J 1994, 15(Suppl):530.
73. 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.
74. Brattstrom LE, Harbebo JE, Hultberg BL: Moderate homocysteinemia. Stroke 1984, 15:1012-1016.
75. 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.
76. Araki A, Sako Y, Fukushima Y, Matsumoto Asada T, Kita T: Plasma sulfhydryl-containing amino acids in patients with cerebral infarction and in hypertensive subjects. Atherosclerosis 1989, 79:139-146.
77. 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.
78. Brattstrom 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, 81:51-60.
79. Brattstrom LE, Lindgren A, Israelsson B, Brattstrom L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B, Hamfelt A: Hyperhomocysteinemia in stroke. Eur J Clin Invest 1992, 22:214-221.
80. 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.
81. Molgaard J, Malinow MR, Lassvik C, Holm A-C, Upson B, Olsson AG: Hyperhomocyst(e)inemia. J Intern Med 1992, 231:273-279.
82. Bergmark C, Manssor MA, Swedenborg J, deFaire U, Svardal AM, Ueland PM: Hyperhomocysteinemia in patients operated for lower extremity ischaemia below the age of 50: effect of smoking and extent of disease. Eur J Vasc Surg 1993, 7:391-396.
83. 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, 11:1129-1136.
84. Malinow MR, Kang, SS, Taylor LM, Malinow MR, Kang SS, Taylor LM, Wong PW, Coull B, Inahara T, Mukerjee K, Sexton G: Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989, 79:1180-1188.
85. Landgren F, Israelsson B, Lindgren A, Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L: Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med 1995, 237:381-388.
86. Malinow MR: Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990, 81:2004-2006.