Blood levels of homocysteine and increased risks of cardiovascular disease: Causal or casual?

Archives of Internal Medicine

Volumn 160, Issue 4, 2000, Pages 422-434

  Christen, William G ^a   Ajani, Umed A ^a   Glynn, Robert J ^a,b   Hennekens, Charles H ^c  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^c UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HOMOCYSTEINE; METHIONINE;

BLOOD LEVEL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREBROVASCULAR DISEASE; CONTROLLED STUDY; DISEASE ASSOCIATION; HOMOCYSTINURIA; HUMAN; PRIORITY JOURNAL; REVIEW;

EID: 0034723761     PISSN: 00039926     EISSN: None     Source Type: Journal    
DOI: 10.1001/archinte.160.4.422     Document Type: Review

References (102)

1. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. In: Francis RB, ed. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function. New York, NY Marcel Dekker Inc; 1992:183-236.
2. Malinow MR. Plasma homocyst(e)ine: a risk factor for arterial occlusive disease. J Nutr. 1996; 126(4 suppl):1238S-1243S.
3. Mudd SH, Levy HL, Skovby F. Disorders of transulfuration. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. Vol 1. 6th ed. New York: McGraw-Hill; 1989:693-734.
4. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989;114:473-501.
5. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56:111-128.
6. Harker LA, Ross H, Slichter SJ, Scott CR. Homocysteine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58:731-741.
7. Wall RT, Harlan JM, Harker LA, Stroker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. 1980;18:113-121.
8. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest. 1986;77:1370-1376.
9. DeGroot PG, Willems C, Boers GHJ, Gonsalves MD. Endothelial cell dysfunction in homocysteinuria. Eur J Clin Invest. 1986;13:405-410.
10. Parthasarathy S. Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochem Biophys Acta. 1987;917:337-340.
11. Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987;262:10098-10103.
12. Tsai J-C, Perrella MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A. 1994;91:6369-6373.
13. Graeber JE, Slott JH, Ulane RE, Schulman JD, Stuart MJ. Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism. Pediatr Res. 1982;16:490-493.
14. Rodgers GM, Kane WH. Activation of endogenous factor V by homocysteine-induced vascular endothelial cell activator. J Clin Invest. 1986; 77:1909-1916.
15. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood. 1990;75:895-901.
16. Kang SS, Wong PWK, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279-298.
17. Selhub J, Jacques 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.
18. Erbe RW. Inborn error of folate metabolism. In: Blakeley RL, Whitehead VM, eds. Folate and Pterine. Vol 3. New York, NY: John Wiley & Sons; 1986:413-465.
19. 12 metabolism. Annu Rev Nutr. 1987; 7:291-320.
20. Kang S-S, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987;36:458-462.
21. 12 deficiency than in heterozygosity for homocystinuria due to cystathionine b-synthase deficiency. Metabolism. 1988;37:175-178.
22. Kang S-S, Wong PWK, Zhou J, et al. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. 1988;37:611-613.
23. Malinow MR, Kang S-S, Taylor LM, et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation. 1989;79:1180-1188.
24. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.
25. Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int. 1997;52:10-20.
26. Mereau-Richard C, Muller JP, Faivre E, Ardouin P, Rousseaux J. Total plasma homocysteine determination in subjects with premature cerebral vascular disease [letter]. Clin Chem. 1991;37:126.
27. Olszewski AJ, Szostak WB. Homocysteine content of plasma proteins in ischemic heart disease. Atherosclerosis. 1988;69:109-113.
28. Williams RR, Malinow MR, Hunt SC, et al. Hyperhomocyst(e)inemia in Utah siblings with early coronary disease. Coron Artery Dis. 1990;1:681-685.
29. Clarke R, Fitzgerald D, O'Brien C, et al. Hyperhomocysteinaemia: a risk factor for extracranial carotid artery atherosclerosis. Jr J Med Sci. 1992;161:61-65.
30. Genest JJ Jr, 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.
31. Schwartz SM, Siscovick DS, Malinow MR, et al. 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.
32. Woolf B. On estimating the relationship between blood group and disease. Ann Hum Genet. 1955;19:251-253.
33. Breslow NE, Day NE. Statistical Methods in Cancer Research, Vol 1: The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer; 1980. IARC Scientific Publication No. 32.
34. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiological Research Principles and Quantitative Methods. Belmont, Calif: Lifetime Learning Publications; 1982.
35. Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest. 1976;57: 1079-1082.
36. Murphy-Chutorian DR, Wexman MP. Grieco AJ, et al. Methionine intolerance: a possible risk factor for coronary artery disease. J Am Coll Cardiol. 1985;6:725-730.
37. Kang S-S, Wong PW, Cook HY, et al. Proteinbound homocyst(e)ine: a possible risk factor for coronary artery disease. J Clin Invest. 1986;77: 1482-1486.
38. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B. Homocyst(e)ine in daily practice: levels in coronary artery disease. Coron Artery Dis. 1990;1:215-220.
39. Murphy-Chutorian D, Alderman EL. The case that hyperhomocysteinemia is a risk factor for coronary artery disease. Am J Cardiol. 1994;73:705-707.
40. Wilcken DEL, Reddy SG, Gupta VJ. Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism. 1983;32:363-370.
41. Boers G, Smals AGH, Trijbels FJM, et al. Heterozygosity for homocysteinuria in premature peripheral and cerebral occlusive arterial disease, N Engl J Med. 1985;313:709-715.
42. Israelsson B, Brattstrom LE, Hultberg BL. Homocysteine and myocardial infarction. Atherosclerosis. 1988;71:227-233.
43. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324:1149-1155.
44. Ubbink JB, Vermaak WJH, Bennett JM, Becker PI, van Staden DA, Bissbort S. The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary artery disease. Klin Wochenschr. 1991;69:527-534.
45. Dudman NPB, Wilcken DEL, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/ homocysteine metabolism in premature vascular disease. Arterioscler Thromb Vasc Biol. 1993; 13:1253-1260.
46. 12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr. 1994;59:940-948.
47. von Eckardstein A, Malinow MR, Upson B, et al. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb Vasc Biol. 1994;14:460-464.
48. Wu LL, Wu J, Hunt SC, et al. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem. 1994; 40:552-561.
49. 6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;75: 1107-1111.
50. Landgren F, Israelsson B, Lindgren A, Hultberg B, Anderson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med. 1995;237:381-388.
51. 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;92:2825-2830.
52. 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.
53. 12, and folate. Am J Epidemiol. 1996;143:845-859.
54. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA. 1997;277:1775-1781.
55. Verhoef P, Kok FJ, Kruyssen ACM, et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17:989-995.
56. 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.
57. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24:704-709.
58. 6 and risk of myocardial infarction in US physicians J Am Coll Nutr. 1996;15:136-143.
59. Verhoef P, Hennekens CH, Allen RH, Stabler SP, Willett WC, Stampfer MJ. Plasma total homocysteine and risk of angina pectoris with subsequent coronary artery bypass surgery. Am J Cardiol. 1997;79:799-801.
60. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH, for the MRFIT Research Group. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997;17: 1947-1953.
61. 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.
62. 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 Intern Med. 1998;158:862-867.
63. Folsom AR, Nieto J, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210.
64. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-291.
65. Brattstrom LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia: a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984;15:1012-1016.
66. Araki A, Sako Y, Fukushima Y, Matsumoto M, Asada T, Kita T. Plasma sulfhydryl-containing amino acids in patients with cerebral infarction and in hypertensive subjects. Atherosclerosis. 1989;79:139-146.
67. Brattstrom L, Israelsson B, Norrving B, et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease: effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990;81:51-60.
68. Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, deGarmo P. Elevated plasma homocyst(e)ine concentrations as a possible risk factor for stroke. Stroke. 1990;21:572-576.
69. Brattstrom LE, Lindgren A, Israelsson B, et al. Hyperhomocysteinemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest. 1992;22: 214-221.
70. Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults: the Atherosclerosis Risk in Communities Study. Circulation. 1993;87:1107-1113.
71. 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.
72. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHB, et al. 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.
73. 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.
74. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet. 1995;346:1395-1398.
75. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-1124.
76. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881.
77. Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little Brown & Co; 1987.
78. Egerton W, Silberberg J, Crooks R, Ray C, Xie L, Dudman N. Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol. 1996;77:759-761.
79. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Lab Invest. 1996;56:41-46.
80. Norlund L, Grubb A, Fex G, et al. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med. 1998;36:175-178.
81. Verhoef P, Stampfer MJ. Prospective studies of homocysteine and cardiovascular disease. Nutr Rev. 1995;53:283-288.
82. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527.
83. Kuller LH, Eichner JE, Orchard TJ, Grandits GA, McCallum L, Tracy RP, for the Multiple Risk Factor Intervention Trial. The relation between serum albumin levels and risk of coronary heart disease in the Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1991;134:1266-1277.
84. Kuller LH, Tracy RP, Shaten J, Meilahn EN, for the MRFIT Research Group. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. 1996;144:537-547.
85. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA. 1995;274:1526-1533.
86. Israelsson B, Brattstrom L, Refsum H. Homocysteine in frozen plasma samples: a short cut to establish hyperhomocysteinaemia as a risk factor for arteriosclerosis? Scand J Clin Lab Invest. 1993;53:465-469.
87. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease: B vitamins and homocysteine. Circulation. 1998;97:421-424.
88. Kuller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease. Circulation. 1998; 98:196-199.
89. Wilcken DEL, Wilcken B, Dudman NPB, Tyrrell PA. Homocystinuria: the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983;309:448-453.
90. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6 and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993;57:47-53.
91. Franken DG, Boers GHJ, Blom HJ, Trijbels FJM, Kloopenborg PWC. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb. 1994;14:465-470.
92. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ, Delport R, Potgeiter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994;124:1927-1933.
93. Ubbink JB, van der Merwe A, Vermaak WJH, Delport R. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Invest. 1993;71:993-998.
94. Franken DG, Boers GHJ, Blom HJ, Trijbels FJM. Effect of various regimens of vitamin B6 and folic acid on mild hyperhomocysteinemia in vascular patients. J Inherit Metab Dis. 1994;17:159-162.
95. Nilsson K, Gustafson L, Faldt R, Andersson A, Hultberg B. Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriatric population. Eur J Clin Invest. 1994;24: 600-606.
96. van den Berg M, Franken DG, Boers GHJ, et al. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vasc Surg. 1994;20:933-940.
97. Brattstrom LE, Hultberg BL, Hardebo JE. Folic acid responsive postmenopausal homocysteinemia. Metabolism. 1985;34:1073-1077.
98. Brattstrom LE, Israelsson B, Jeppsson J-O, Hultberg BL. Folic acid: an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest. 1988;48:215-221.
99. Jacob RA, Wu M, Henning SM, Swendseid ME. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J Nutr. 1994;124:1072-1080.
100. Ubbink JB, Becker PJ, Vermaak WJH, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41: 1033-1037.
101. O'Keefe CA, Bailey LB, Thomas EA, et al. Controlled dietary folate affects folate status in non-pregnant women. J Nutr. 1995;125:2717-2725.
102. Manson JE, Gaziano JM, Spelsberg A, et al, for the WACS Research Group. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: rationale, design, and methods. Ann Epidemiol. 1995;5:261-269.