(Circulation. 2000;102:1227.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease
From the Department of Medicine, Division of Cardiology, LDS Hospital, University of Utah, Salt Lake City.
Correspondence to Jeffrey L. Anderson, MD, Division of Cardiology, University of Utah School of Medicine, 50 North Medical Dr, Salt Lake City, UT 84132.
Background—Plasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (MTHFR) genotype.
Methods and Results—Blood samples were collected from 1412
patients with severe angiographically defined CAD (stenosis
70%). Plasma tHCY was measured by fluorescence polarization
immunoassay. The study cohort was evaluated for survival after a mean
of 3.0±1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years).
The average age of the patients was 65±11 years, 77% were males, and
166 died during follow-up. Mortality was greater in patients with tHCY
in tertile 3 than in tertiles 1 and 2 (mortality 15.7% versus 9.6%,
P=0.001 [log-rank test], hazard ratio [HR] 1.63).
The relative hazard increased 16% for each 5-µmol/L increase in tHCY
(P<0.001). In multivariate Cox
regression analysis, controlling for univariate
clinical and laboratory predictors, elevated tHCY remained predictive
of mortality (HR 1.64, P=0.009), together with age (HR
1.72 per 10-year increment, P<0.0001), ejection
fraction (HR 0.84 per 10% increment, P=0.0001),
diabetes (HR 1.98, P=0.001), CRP (HR 1.42 per tertile,
P=0.004), and hyperlipidemia.
Homozygosity for the MTHFR variant was weakly predictive
of tHCY levels but not mortality.
Conclusions—In patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.
Key Words: coronary disease • amino acids • genes • risk factors • inflammation
This article has been cited by other articles:
 |
|
 |
|
  M.-R. Taskinen, D. R. Sullivan, C. Ehnholm, M. Whiting, D. Zannino, R. J. Simes, A. C. Keech, P. J. Barter, and for the FIELD study investigators Relationships of HDL Cholesterol, ApoA-I, and ApoA-II With Homocysteine and Creatinine in Patients With Type 2 Diabetes Treated With Fenofibrate Arterioscler. Thromb. Vasc. Biol., June 1, 2009; 29(6): 950 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liao, H. Tan, R. Hui, Z. Li, X. Jiang, J. Gaubatz, F. Yang, W. Durante, L. Chan, A. I. Schafer, et al. Hyperhomocysteinemia Decreases Circulating High-Density Lipoprotein by Inhibiting Apolipoprotein A-I Protein Synthesis and Enhancing HDL Cholesterol Clearance Circ. Res., September 15, 2006; 99(6): 598 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Fraser, N. L. Tuite, A. Bhagwat, and C. P. O'Byrne Global effects of homocysteine on transcription in Escherichia coli: induction of the gene for the major cold-shock protein, CspA. Microbiology, August 1, 2006; 152(Pt 8): 2221 - 2231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Devlin and S. R. Lentz ApoA-I: A Missing Link Between Homocysteine and Lipid Metabolism? Circ. Res., March 3, 2006; 98(4): 431 - 433. [Full Text] [PDF]
|
|
|
|
 |
|
 K. W.J. Lee, J. S. Hill, K. R. Walley, and J. J. Frohlich Relative value of multiple plasma biomarkers as risk factors for coronary artery disease and death in an angiography cohort. Can. Med. Assoc. J., February 14, 2006; 174(4): 461 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-K. Kuo, F. A. Sorond, J.-H. Chen, A. Hashmi, W. P. Milberg, and L. A. Lipsitz The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2005; 60(9): 1190 - 1201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Williams, B. A Kingwell, K. Burke, J. McPherson, and A. M Dart Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype Am. J. Clinical Nutrition, July 1, 2005; 82(1): 26 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. Tuite, K. R. Fraser, and C. P. O'Byrne Homocysteine Toxicity in Escherichia coli Is Caused by a Perturbation of Branched-Chain Amino Acid Biosynthesis J. Bacteriol., July 1, 2005; 187(13): 4362 - 4371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chwatko and H. Jakubowski Urinary Excretion of Homocysteine-Thiolactone in Humans Clin. Chem., February 1, 2005; 51(2): 408 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C-K Wong, C J K Hammett, R The, J K French, W Gao, B J Webber, J M Elliott, A W Hamer, J A Ormiston, M W I Webster, et al. Lack of association between baseline plasma homocysteine concentrations and restenosis rates after a first elective percutaneous coronary intervention without stenting Heart, November 1, 2004; 90(11): 1299 - 1302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Vrentzos, J. A. Papadakis, N. Malliaraki, E. A. Zacharis, K. Katsogridakis, A. N. Margioris, P. E. Vardas, and E. S. Ganotakis Association of Serum Total Homocysteine with the Extent of Ischemic Heart Disease in a Mediterranean Cohort Angiology, September 1, 2004; 55(5): 517 - 524. [Abstract] [PDF]
|
|
|
|
 |
|
 Z. T. Bloomgarden Consequences of Diabetes: Cardiovascular disease Diabetes Care, July 1, 2004; 27(7): 1825 - 1831. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Undas, J. Perla, M. Lacinski, W. Trzeciak, R. Kazmierski, and H. Jakubowski Autoantibodies Against N-Homocysteinylated Proteins in Humans: Implications for Atherosclerosis Stroke, June 1, 2004; 35(6): 1299 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Glowacki and H. Jakubowski Cross-talk between Cys34 and Lysine Residues in Human Serum Albumin Revealed by N-Homocysteinylation J. Biol. Chem., March 19, 2004; 279(12): 10864 - 10871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matetzky, D. Freimark, S. Ben-Ami, I. Goldenberg, J. Leor, R. Doolman, I. Novikov, M. Eldar, and H. Hod Association of Elevated Homocysteine Levels With a Higher Risk of Recurrent Coronary Events and Mortality in Patients With Acute Myocardial Infarction Arch Intern Med, September 8, 2003; 163(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Liem, G. H. Reynierse-Buitenwerf, A. H. Zwinderman, J. W. Jukema, and D. J. van Veldhuisen Secondary prevention with folic acid: effects on clinical outcomes J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2105 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Bazzano, J. He, P. Muntner, S. Vupputuri, and P. K. Whelton Relationship between Cigarette Smoking and Novel Risk Factors for Cardiovascular Disease in the United States Ann Intern Med, June 3, 2003; 138(11): 891 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Anderson, J. F. Carlquist, B. D. Home, and J. B. Muhlestein Cardiovascular Pharmacogenomics: Current Status, Future Prospects Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 71 - 83. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Chandalia, N. Abate, A. V. Cabo-Chan Jr., S. Devaraj, I. Jialal, and S. M. Grundy Hyperhomocysteinemia in Asian Indians Living in the United States J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1089 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tanne, M. Haim, U. Goldbourt, V. Boyko, R. Doolman, Y. Adler, D. Brunner, S. Behar, and B.-A. Sela Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease Stroke, March 1, 2003; 34(3): 632 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 158 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Q. Hanson, J. H. Eckfeldt, K. Schwichtenberg, O. Aras, and M. Y. Tsai Interlaboratory Variation of Plasma Total Homocysteine Measurements: Results of Three Successive Homocysteine Proficiency Testing Surveys Clin. Chem., September 1, 2002; 48(9): 1539 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jakubowski Homocysteine Is a Protein Amino Acid in Humans. IMPLICATIONS FOR HOMOCYSTEINE-LINKED DISEASE J. Biol. Chem., August 16, 2002; 277(34): 30425 - 30428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
|
|
|
|
|
|
A. K. Majors, S. Sengupta, B. Willard, M. T. Kinter, R. E. Pyeritz, and D. W. Jacobsen Homocysteine Binds to Human Plasma Fibronectin and Inhibits Its Interaction With Fibrin Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1354 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.J. Blake and P.M. Ridker C-reactive protein and prognosis after percutaneous coronary intervention Eur. Heart J., June 2, 2002; 23(12): 923 - 925. [Full Text] [PDF]
|
|
|
|
|
|
R.J. de Winter, G.S. Heyde, K.T. Koch, J. Fischer, J.P. van Straalen, M. Bax, C.E. Schotborgh, K.J. Mulder, G.T. Sanders, J.J. Piek, et al. The prognostic value of pre-procedural plasma C-reactive protein in patients undergoing elective coronary angioplasty Eur. Heart J., June 2, 2002; 23(12): 960 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Acevedo, G. L. Pearce, K. Kottke-Marchant, and D. L. Sprecher Elevated Fibrinogen and Homocysteine Levels Enhance the Risk of Mortality in Patients From a High-Risk Preventive Cardiology Clinic Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 1042 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Doshi, I. F.W. McDowell, S. J. Moat, N. Payne, H. J. Durrant, M. J. Lewis, and J. Goodfellow Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering Circulation, January 1, 2002; 105(1): 22 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Auer, R. Berent, B. Eber, S. Friso, P. F. Jacques, I. H. Rosenberg, J. Selhub, and P. W.F. Wilson Lack of Association of Increased C-Reactive Protein and Total Plasma Homocysteine Response Circulation, December 18, 2001; 104 (25): e164 - e164. [Full Text] [PDF]
|
|
|
|
|
|
C. Fernandez-Miranda, M. Sanz, A. de la Calle, C. Loinaz, P. Gomez, P. Diaz-Rubio, A. G. de la Camara, and E. Moreno Determinants of Increased Plasma Homocysteine in 221 Stable Liver Transplant Patients Clin. Chem., November 1, 2001; 47(11): 2037 - 2040. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lavie, A. Perelman, and P. Lavie Plasma Homocysteine Levels in Obstructive Sleep Apnea : Association With Cardiovascular Morbidity Chest, September 1, 2001; 120(3): 900 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Friso, P. F. Jacques, P. W.F. Wilson, I. H. Rosenberg, and J. Selhub Low Circulating Vitamin B6 Is Associated With Elevation of the Inflammation Marker C-Reactive Protein Independently of Plasma Homocysteine Levels Circulation, June 12, 2001; 103(23): 2788 - 2791. [Abstract] [Full Text] [PDF]
|
|