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Circulation. 1999;99:237-242

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(Circulation. 1999;99:237-242.)
© 1999 American Heart Association, Inc.


Clinical Investigation and Reports

C-Reactive Protein, a Sensitive Marker of Inflammation, Predicts Future Risk of Coronary Heart Disease in Initially Healthy Middle-Aged Men

Results From the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992

Wolfgang Koenig, MD; Malte Sund, MS; Margit Fröhlich, MD; Hans-Günther Fischer, MD, PhD; Hannelore Löwel, MD; Angela Döring, MD; Winston L. Hutchinson, PhD; Mark B. Pepys, MD

From the Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany (W.K., M.F., H.-G.F.); GSF, National Research Center for Environment and Health, MEDIS Institute (M.S.) and Institute of Epidemiology (H.L., A.D.), Neuherberg, Germany; and Immunological Medicine Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK (W.L.H., M.B.P.).

Correspondence to Wolfgang Koenig, MD, Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Robert-Koch Str 8, D-89081 Ulm, Germany. E-mail wolfgang.koenig{at}medizin.uni-ulm.de

Background—Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events.

Methods and Results—We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2.17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2.08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97).

Conclusions—These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.


Key Words: proteins • coronary disease • incidence • epidemiology




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W.H. L. Kao, W.-C. Hsueh, D. L. Rainwater, D. H. O'Leary, I. G. Imumorin, M. P. Stern, and B. D. Mitchell
Family History of Type 2 Diabetes Is Associated With Increased Carotid Artery Intimal-Medial Thickness in Mexican Americans
Diabetes Care, August 1, 2005; 28(8): 1882 - 1889.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. L. Sunehag, G. Toffolo, M. Campioni, D. M. Bier, and M. W. Haymond
Effects of Dietary Macronutrient Intake on Insulin Sensitivity and Secretion and Glucose and Lipid Metabolism in Healthy, Obese Adolescents
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4496 - 4502.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
C. Liu, S. Wang, A. Deb, K. A. Nath, Z. S. Katusic, J. P. McConnell, and N. M. Caplice
Proapoptotic, Antimigratory, Antiproliferative, and Antiangiogenic Effects of Commercial C-Reactive Protein on Various Human Endothelial Cell Types In Vitro: Implications of Contaminating Presence of Sodium Azide in Commercial Preparation
Circ. Res., July 22, 2005; 97(2): 135 - 143.
[Abstract] [Full Text] [PDF]


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CirculationHome page
L. R. Tannock, K. D. O'Brien, R. H. Knopp, B. Retzlaff, B. Fish, M. H. Wener, S. E. Kahn, and A. Chait
Cholesterol Feeding Increases C-Reactive Protein and Serum Amyloid A Levels in Lean Insulin-Sensitive Subjects
Circulation, June 14, 2005; 111(23): 3058 - 3062.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
G. M. Hirschfield, J. R. Gallimore, M. C. Kahan, W. L. Hutchinson, C. A. Sabin, G. M. Benson, A. P. Dhillon, G. A. Tennent, and M. B. Pepys
Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice
PNAS, June 7, 2005; 102(23): 8309 - 8314.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
M. B. Pepys
CRP or not CRP? That Is the Question
Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1091 - 1094.
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J Am Coll CardiolHome page
C. Kasapis and P. D. Thompson
The Effects of Physical Activity on Serum C-Reactive Protein and Inflammatory Markers: A Systematic Review
J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1563 - 1569.
[Abstract] [Full Text] [PDF]


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CirculationHome page
J.P. Empana, D.H. Sykes, G. Luc, I. Juhan-Vague, D. Arveiler, J. Ferrieres, P. Amouyel, A. Bingham, M. Montaye, J.B. Ruidavets, et al.
Contributions of Depressive Mood and Circulating Inflammatory Markers to Coronary Heart Disease in Healthy European Men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME)
Circulation, May 10, 2005; 111(18): 2299 - 2305.
[Abstract] [Full Text] [PDF]


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CirculationHome page
M. Schillinger, M. Exner, W. Mlekusch, S. Sabeti, J. Amighi, R. Nikowitsch, E. Timmel, B. Kickinger, C. Minar, M. Pones, et al.
Inflammation and Carotid Artery--Risk for Atherosclerosis Study (ICARAS)
Circulation, May 3, 2005; 111(17): 2203 - 2209.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
S. B. Kritchevsky, M. Cesari, and M. Pahor
Inflammatory markers and cardiovascular health in older adults
Cardiovasc Res, May 1, 2005; 66(2): 265 - 275.
[Abstract] [Full Text] [PDF]


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JAMAHome page
C. Kistorp, I. Raymond, F. Pedersen, F. Gustafsson, J. Faber, and P. Hildebrandt
N-Terminal Pro-Brain Natriuretic Peptide, C-Reactive Protein, and Urinary Albumin Levels as Predictors of Mortality and Cardiovascular Events in Older Adults
JAMA, April 6, 2005; 293(13): 1609 - 1616.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
Q. Wang, X. Zhu, Q. Xu, X. Ding, Y. E. Chen, and Q. Song
Effect of C-reactive protein on gene expression in vascular endothelial cells
Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1539 - H1545.
[Abstract] [Full Text] [PDF]


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Nephrol Dial TransplantHome page
E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw
Biochemical risk markers: a novel area for better prediction of renal risk?
Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508.
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Occup. Environ. Med.Home page
J Y Kim, J-C Chen, P D Boyce, and D C Christiani
Exposure to welding fumes is associated with acute systemic inflammatory responses
Occup. Environ. Med., March 1, 2005; 62(3): 157 - 163.
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ChestHome page
H.-K. Yip, C.-L. Hang, C.-Y. Fang, Y.-K. Hsieh, C.-H. Yang, W.-C. Hung, and C.-J. Wu
Level of High-Sensitivity C-Reactive Protein Is Predictive of 30-Day Outcomes in Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention
Chest, March 1, 2005; 127(3): 803 - 808.
[Abstract] [Full Text] [PDF]


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Diabetes CareHome page
S. Malik, N. D. Wong, S. Franklin, J. Pio, C. Fairchild, and R. Chen
Cardiovascular Disease in U.S. Patients With Metabolic Syndrome, Diabetes, and Elevated C-Reactive Protein
Diabetes Care, March 1, 2005; 28(3): 690 - 693.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
M. Gola, S. Bonadonna, M. Doga, and A. Giustina
Growth Hormone and Cardiovascular Risk Factors
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1864 - 1870.
[Abstract] [Full Text] [PDF]


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Diabetes and Vascular Disease ResearchHome page
S. P Marso, J. W Murphy, J. A House, D. M Safley, and W. S Harris
Metabolic syndrome-mediated inflammation following elective percutaneous coronary intervention
Diabetes and Vascular Disease Research, February 1, 2005; 2(1): 31 - 36.
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Eur Heart JHome page
R. Schnabel, H. J. Rupprecht, K. J. Lackner, E. Lubos, C. Bickel, J. Meyer, T. Munzel, F. Cambien, L. Tiret, S. Blankenberg, et al.
Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study
Eur. Heart J., February 1, 2005; 26(3): 241 - 249.
[Abstract] [Full Text] [PDF]


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Arch Intern MedHome page
P. Bogaty, J. M. Brophy, L. Boyer, S. Simard, L. Joseph, F. Bertrand, and G. R. Dagenais
Fluctuating Inflammatory Markers in Patients With Stable Ischemic Heart Disease
Arch Intern Med, January 24, 2005; 165(2): 221 - 226.
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ANGIOLOGYHome page
G. K. Paschos, N. Yiannakouris, L. S. Rallidis, I. Davies, B. A. Griffin, D. B. Panagiotakos, F. N. Skopouli, V. Votteas, and A. Zampelas
Apolipoprotein E Genotype in Dyslipidemic Patients and Response of Blood Lipids and Inflammatory Markers to Alpha-Linolenic Acid
Angiology, January 1, 2005; 56(1): 49 - 60.
[Abstract] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. Ropponen, K. Aittomaki, M. J. Tikkanen, and O. Ylikorkala
Levels of Serum C-Reactive Protein during Oral and Transdermal Estradiol in Postmenopausal Women with and without a History of Intrahepatic Cholestasis of Pregnancy
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 142 - 146.
[Abstract] [Full Text] [PDF]


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CirculationHome page
G. L. Myers, N. Rifai, R. P. Tracy, W. L. Roberts, R. W. Alexander, L. M. Biasucci, J. D. Catravas, T. G. Cole, G. R. Cooper, B. V. Khan, et al.
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Laboratory Science Discussion Group
Circulation, December 21, 2004; 110(25): e545 - e549.
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CirculationHome page
S. C. Smith Jr, J. L. Anderson, R. O. Cannon III, Y. Y. Fadl, W. Koenig, P. Libby, S. E. Lipshultz, G. A. Mensah, P. M Ridker, and R. Rosenson
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Clinical Practice Discussion Group
Circulation, December 21, 2004; 110(25): e550 - e553.
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CirculationHome page
S. P. Fortmann, E. Ford, M. H. Criqui, A. R. Folsom, T. B. Harris, Y. Hong, T. A. Pearson, D. Siscovick, F. Vinicor, and P. F. Wilson
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Population Science Discussion Group
Circulation, December 21, 2004; 110(25): e554 - e559.
[Abstract] [Full Text] [PDF]