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August 19, 1992, Vol 268, No. 7 >
ARTICLE | August 19, 1992

A Prospective Study of Plasma Homocyst(e)ine and Risk of Myocardial Infarction in US Physicians FREE

Meir J. Stampfer, MD; M. Rene Malinow, MD; Walter C. Willett, MD; Laura M. Newcomer; Barbara Upson; Daniel Ullmann, MPH; Peter V. Tishler, MD; Charles H. Hennekens, MD
[+] Author Affiliations

Presented in part at the 57th Meeting of the European Arteriosclerosis Society in Lisbon, Portugal, May 25, 1991.

Reprint requests to The Channing Laboratory, 180 Longwood Ave, Boston, MA 02115 (Dr Stampfer).


JAMA. 1992;268(7):877-881. doi:10.1001/jama.1992.03490070059042
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References

Objective.  —To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine.

Design.  —Nested case-control study using prospectively collected blood samples.

Setting.  —Participants in the Physicians' Health Study.

Participants.  —A total of 14916 male physicians, aged 40 to 84 years, with no prior myocardial infarction (Ml) or stroke provided plasma samples at baseline and were followed up for 5 years. Samples from 271 men who subsequently developed Ml were analyzed for homocyst(e)ine levels together with paired controls, matched by age and smoking.

Main Outcome Measure.  —Acute Ml or death due to coronary disease.

Results.  —Levels of homocyst(e)ine were higher in cases than in controls (11.1±4.0 [SD] vs 10.5±2.8 nmol/mL; P=.03). The difference was attributable to an excess of high values among men who later had MIs. The relative risk for the highest 5% vs the bottom 90% of homocyst(e)ine levels was 3.1 (95% confidence interval, 1.4 to 6.9; P=.005). After additional adjustment for diabetes, hypertension, aspirin assignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4 (95% confidence interval, 1.3 to 8.8) (P=.01). Thirteen controls and 31 cases (11%) had values above the 95th percentile of the controls.

Conclusions.  —Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of Ml independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable risk factor.(JAMA. 1992;268:877-881)

REFERENCES

1 +
Mudd SH, Levy HL, Skovby F.  Disorders of transulfuration.  In: Scriver CS, Beaudet AL, Sly WL, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:693-734.
2 +
Malinow MR.  Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation . 1990;;81:2004-2006.
3 +
Malinow MR.  Homocyst(e)ine and vascular occlusive disease. Nutr Metabol Cardiovasc Dis . 1992;; 1:166-169.
4 +
Clarke R, Daly L, Robinson K, et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med . 1991;;324:1149-1155.
5 +
Stampfer MJ, Buring JE, Willett W, Rosner B, Eberlein K, Hennekens CH.  The2×2factorial design: its application to a randomized trial of aspirin and carotene in US physicians. Stat Med . 1985;;4:111-116.
6 +
Steering Committee of the Physicians' Health Study Research Group.  Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med . 1989;;321:129-135.
7 +
IHD Registers: Report of the Fifth Working Group . Copenhagen, Denmark: World Health Organization; 1971;.
8 +
Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH.  A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med . 1991;;325:373-381.
9 +
Katrangi N, Kaplan LA, Stein EA.  Separation and quantitation of β-carotene and other carotenoids by high performance liquid chromatography. J Lipid Res . 1984;;25:400-406.
10 +
Polansky MM, Reynolds RD, Vanderslice JT.  Vitamin B6.  In: Augustine J, Klein BP, Becher DA, Venugopal PB, eds. Methods of Vitamin Assay . 4th ed. New York, NY: John Wiley & Sons Inc; 1985;: 417-445.
11 +
Smolin LA, Schneider JA.  Measurement of total plasma cysteamine using high-performance liquid chromatography with electrochemical detection. Anal Biochem . 1988;;168:374-379.
12 +
Malinow MR, Kang SS, Taylor LM, et al.  Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation . 1989;;79:1180-1188.
13 +
Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B.  Homocyst(e)ine in daily practice: levels in coronary artery disease. Coronary Artery Dis . 1990;;1:215-220.
14 +
Storer BE, Wacholder S, Breslow NE.  Maximum likelihood fitting of general risk models to stratified data. Appi Stat . 1983;;32:172-181.
15 +
Mereau-Richard C, Muller JP, Faivre E, Ardouin P, Rousseaux J.  Total plasma homocysteine determination in subjects with premature cerebral vascular disease. Clin Chem . 1991;;37:126.
16 +
Wilcken DEL, Wilcken B.  The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest . 1976;;57:1079-1082.
17 +
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.
18 +
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.
19 +
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.
20 +
Genest JJ Jr, McNamara JR, Upson B, et al.  Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterio Throm . 1991;;11:1129-1136.
21 +
Israelsson B, Brattstrom LE, Hultberg BL.  Homocysteine and myocardial infarction. Atherosclerosis . 1988;;71:227-233.
22 +
Williams RR, Malinow MR, Hunt SC, et al.  Hyperhomocyst(e)inemia in Utah siblings with early coronary disease. Coronary Artery Dis . 1990;;1:681-685.
23 +
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.
24 +
Wall RT, Harlan JM, Harker LA, Striker GE.  Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Throm Res . 1980;;18:113-121.
25 +
DeGroot PG, Willems C, Boers GH, Gonsalves MD, Van Aken WG, Van Mourik JA.  Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest . 1983;;13:405-410.
26 +
Starkebaum G, Harlan JM.  Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest . 1986;; 77:1370-1376.
27 +
Reed T, Malinow MR, Christian JC, Upson B.  Estimates of heritability for plasma homocyst(e)ine levels in aging adult male twins. Clin Genet . 1991;;39:425-428.
28 +
Rubba P, Faccenda F, Pauciullo P, et al.  Early signs of vascular disease in homocystinuria: a noninvasive study by ultrasound methods in eight families with cystathionine-beta synthase deficiency. Metabolism . 1990;;39:1191-1195.
29 +
Kang SS, 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;; 48:536-545.
30 +
Kang SS, Wong PWK, Norusis M.  Homocysteinemia due to folate deficiency. Metabolism . 1987;; 36:458-462.
31 +
Brattstrom L, Israelsson B, Lindgärde F, Hultberg B.  Higher total plasma homocysteine in vitamin B 12 deficiency than in heterozygosity for homocystinuria due to cystathionine β-synthase deficiency. Metabolism . 1988;;37:175-178.
32 +
Subar AF, Block G, James LD.  Folate intake and food sources in the US population. Am J Clin Nutr . 1989;;50:508-516.
33 +
Manore MM, Vaughan LA, Carroll SS, Leklem JE.  Plasma pyridoxal 5′phosphate concentration and dietary vitamin B6 intake in free-living, low-income elderly people. Am J Clin Nutr . 1989;;50: 339-345.
34 +
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.
35 +
Smolin LA, Benevenga NJ, Berlow S.  The use of betaine for the treatment of homocystinuria. J Pediatr . 1981;;99:467-472.
36 +
Wilcken DEL, Dudman NPB, Tyrrell PA.  Homocystinuria due to cystathionine βsynthase deficiency—the effects of betaine treatment in pyridoxine-responsive patients. Metabolism . 1985;; 34:1115-1121.

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1 +
Mudd SH, Levy HL, Skovby F.  Disorders of transulfuration.  In: Scriver CS, Beaudet AL, Sly WL, Valle D, eds. The Metabolic Basis of Inherited Disease . 6th ed. New York, NY: McGraw-Hill International Book Co; 1989;:693-734.
2 +
Malinow MR.  Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation . 1990;;81:2004-2006.
3 +
Malinow MR.  Homocyst(e)ine and vascular occlusive disease. Nutr Metabol Cardiovasc Dis . 1992;; 1:166-169.
4 +
Clarke R, Daly L, Robinson K, et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med . 1991;;324:1149-1155.
5 +
Stampfer MJ, Buring JE, Willett W, Rosner B, Eberlein K, Hennekens CH.  The2×2factorial design: its application to a randomized trial of aspirin and carotene in US physicians. Stat Med . 1985;;4:111-116.
6 +
Steering Committee of the Physicians' Health Study Research Group.  Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med . 1989;;321:129-135.
7 +
IHD Registers: Report of the Fifth Working Group . Copenhagen, Denmark: World Health Organization; 1971;.
8 +
Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH.  A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med . 1991;;325:373-381.
9 +
Katrangi N, Kaplan LA, Stein EA.  Separation and quantitation of β-carotene and other carotenoids by high performance liquid chromatography. J Lipid Res . 1984;;25:400-406.
10 +
Polansky MM, Reynolds RD, Vanderslice JT.  Vitamin B6.  In: Augustine J, Klein BP, Becher DA, Venugopal PB, eds. Methods of Vitamin Assay . 4th ed. New York, NY: John Wiley & Sons Inc; 1985;: 417-445.
11 +
Smolin LA, Schneider JA.  Measurement of total plasma cysteamine using high-performance liquid chromatography with electrochemical detection. Anal Biochem . 1988;;168:374-379.
12 +
Malinow MR, Kang SS, Taylor LM, et al.  Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation . 1989;;79:1180-1188.
13 +
Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson B.  Homocyst(e)ine in daily practice: levels in coronary artery disease. Coronary Artery Dis . 1990;;1:215-220.
14 +
Storer BE, Wacholder S, Breslow NE.  Maximum likelihood fitting of general risk models to stratified data. Appi Stat . 1983;;32:172-181.
15 +
Mereau-Richard C, Muller JP, Faivre E, Ardouin P, Rousseaux J.  Total plasma homocysteine determination in subjects with premature cerebral vascular disease. Clin Chem . 1991;;37:126.
16 +
Wilcken DEL, Wilcken B.  The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest . 1976;;57:1079-1082.
17 +
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.
18 +
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.
19 +
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.
20 +
Genest JJ Jr, McNamara JR, Upson B, et al.  Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterio Throm . 1991;;11:1129-1136.
21 +
Israelsson B, Brattstrom LE, Hultberg BL.  Homocysteine and myocardial infarction. Atherosclerosis . 1988;;71:227-233.
22 +
Williams RR, Malinow MR, Hunt SC, et al.  Hyperhomocyst(e)inemia in Utah siblings with early coronary disease. Coronary Artery Dis . 1990;;1:681-685.
23 +
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.
24 +
Wall RT, Harlan JM, Harker LA, Striker GE.  Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Throm Res . 1980;;18:113-121.
25 +
DeGroot PG, Willems C, Boers GH, Gonsalves MD, Van Aken WG, Van Mourik JA.  Endothelial cell dysfunction in homocystinuria. Eur J Clin Invest . 1983;;13:405-410.
26 +
Starkebaum G, Harlan JM.  Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest . 1986;; 77:1370-1376.
27 +
Reed T, Malinow MR, Christian JC, Upson B.  Estimates of heritability for plasma homocyst(e)ine levels in aging adult male twins. Clin Genet . 1991;;39:425-428.
28 +
Rubba P, Faccenda F, Pauciullo P, et al.  Early signs of vascular disease in homocystinuria: a noninvasive study by ultrasound methods in eight families with cystathionine-beta synthase deficiency. Metabolism . 1990;;39:1191-1195.
29 +
Kang SS, 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;; 48:536-545.
30 +
Kang SS, Wong PWK, Norusis M.  Homocysteinemia due to folate deficiency. Metabolism . 1987;; 36:458-462.
31 +
Brattstrom L, Israelsson B, Lindgärde F, Hultberg B.  Higher total plasma homocysteine in vitamin B 12 deficiency than in heterozygosity for homocystinuria due to cystathionine β-synthase deficiency. Metabolism . 1988;;37:175-178.
32 +
Subar AF, Block G, James LD.  Folate intake and food sources in the US population. Am J Clin Nutr . 1989;;50:508-516.
33 +
Manore MM, Vaughan LA, Carroll SS, Leklem JE.  Plasma pyridoxal 5′phosphate concentration and dietary vitamin B6 intake in free-living, low-income elderly people. Am J Clin Nutr . 1989;;50: 339-345.
34 +
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.
35 +
Smolin LA, Benevenga NJ, Berlow S.  The use of betaine for the treatment of homocystinuria. J Pediatr . 1981;;99:467-472.
36 +
Wilcken DEL, Dudman NPB, Tyrrell PA.  Homocystinuria due to cystathionine βsynthase deficiency—the effects of betaine treatment in pyridoxine-responsive patients. Metabolism . 1985;; 34:1115-1121.

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