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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

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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

	Introduction

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Although atherosclerosis is clearly multifactorial, it is now universally recognized that inflammation within the lesions contributes importantly to their initiation and progression,¹ whereas histopathological and immunocytochemical observations suggest that active inflammatory processes may destabilize the fibrous cap tissue, thus triggering plaque rupture and enhancing the risk of coronary thrombosis.² On the other hand, prospective epidemiological studies have shown a strong and consistent association between clinical manifestations of atherothrombotic disease and systemic markers of inflammation, including white blood cell count,³ and various hemostatic proteins that are also acute-phase reactants such as fibrinogen,⁴ plasminogen-activator inhibitor type-1,⁵ and von Willebrand factor.⁶ A potentially important role of inflammation in the onset of acute ischemic syndromes is indicated by neutrophil activation⁷ and elevated levels of various acute-phase proteins^{8 9 10} in unstable angina and the notable temporal relationship between acute or chronic infections and coronary events.^{11 12 13}

C-reactive protein (CRP), the classic acute-phase protein, is not directly involved in the coagulation process but is an exquisitely sensitive objective marker of inflammation, tissue damage, and infection.¹⁴ Its plasma half-life (19 hours) is rapid but identical under all conditions, in contrast to the coagulation proteins and virtually all other major acute-phase reactants, so the synthesis rate of CRP is the sole determinant of its plasma concentration.¹⁵ Excellent anti-CRP antibodies and a well-established World Health Organization (WHO) international reference standard for CRP¹⁶ are available, so precise, sensitive, and robust clinical serum/plasma assays can be readily undertaken.^{17 18} CRP measurement thus has many advantages in the detection and monitoring of the acute-phase response in general and the relation to atheroma and its complications in particular. Indeed, the recent use of sensitive CRP assays in a large prospective study in patients with angina pectoris¹⁹ and in 3 nested case-control studies in initially healthy subjects^{20 21 22} showed a consistent positive association between baseline CRP levels and cardiovascular end points. Subjects from 2 of these studies were drawn from participants in clinical trials,^{20 21} raising the question of their representativeness, and 1 study²² included only elderly subjects. Thus, to confirm the reported association between CRP levels and coronary heart disease (CHD) risk in large, unselected populations, we have measured serum CRP in 936 initially healthy men (age, 45 to 64 years) drawn from a random sample of the general population who took part in the first MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg survey in 1984 to 1985. On the basis of an 8-year follow-up, we report here the prognostic significance of CRP values for the occurrence of a first major coronary event in these men.

	Methods

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MONICA Project, Augsburg Center
The objectives and design of the MONICA project have been described elsewhere.^{23 24} The first cross-sectional study of the MONICA Augsburg (Germany) center was carried out in 1984 to 1985. The study population and data collection procedures have also been reported previously.^{25 26} Briefly, 4022 of the 5069 eligible individuals 25 to 64 years of age initially sampled at random from a study population of 282 279 inhabitants of a mixed urban/rural area participated in the study (response rate, 79.3%). The present report is based on all men (age, 45 to 64 years) who participated in the first survey (n=1074). Of these subjects, 43 were not included in the analyses because of previous myocardial infarction. Eight were excluded because their medical histories suggested disease other than CHD, possibly associated with an acute-phase reaction. In the remaining 1023 men, measurements of CRP were missing from 74 (7.2%); in 13 other men, at least 1 control variable could not be obtained. Thus, a total of 936 men 45 to 64 years of age had data on all variables studied.

Survey Methods
Participants completed a standardized questionnaire, including medical history, lifestyle, and drug history.²⁶ Blood pressure, body height (m), body weight (kg), body mass index (BMI, m/kg²), smoking behavior, and alcohol consumption (g/d) were determined as described elsewhere.^{26 27 28} Leisure-time physical activity (LTPA) was assessed on a 4-level graded scale for winter and summer time (0, <1, 1 to 2, and >2 h/wk).²⁹ The number of education years was calculated on the basis of the highest level of formal education completed.

Laboratory Procedures
Nonfasting blood samples were taken from all subjects at baseline in 1984 to 1985 and stored at -70°C. Serum concentrations of CRP were measured in a sensitive immunoradiometric assay with monospecific polyclonal and monoclonal antibodies produced by immunization with highly purified CRP.¹⁵ Briefly, 96-well microtiter plates (Costar Co) activated with N-oxysuccinimide were coated with the IgG fraction of polyclonal goat anti-human CRP antiserum offered at 100 µg/mL. Serum samples, 100 µL at 1:100 dilution, were added to each well and incubated at 37°C for 4 hours and at 4°C overnight. The plates were then washed, and bound CRP was detected by incubation with ¹²⁵I-radiolabeled monoclonal anti-human CRP antibody, followed by rinsing and counting of retained radioactivity in each well. CRP concentrations were determined by use of a 5-point standard curve calibrated with the WHO international reference standard for CRP immunoassay, standard 85/506, produced at the Immunological Medicine Unit, Royal Postgraduate Medical School (London, UK). Recovery of pure CRP¹⁵ spiked into serum was 100%, and the assay range was 0.05 to 10 mg/L, with coefficients of variation within assays of 4% and between-assay coefficients of 12% across the whole range. Samples with values >10 mg/L were remeasured at appropriately higher dilutions. All samples were measured in triplicate, and values were averaged for analysis. Total and HDL cholesterol levels were measured by enzymatic methods.

Follow-Up Procedure
Within the population-based Augsburg Coronary Event Register, all death certificates of residents of the study area who were 25 to 74 years of age were screened in the 3 health departments for suspected cases of acute myocardial infarction (AMI) occurring since October 1, 1984. Additional information was gained from standardized questionnaires sent from the health departments to the last attending physician and/or coroner. On the basis of both the information from the death certificate and the questionnaire, the register team decided whether a case fulfilled the MONICA algorithm for fatal CHD. Data on cases of fatal and nonfatal AMI occurring in hospital were actively collected by register nurses. No information could be obtained on nonfatal events in patients outside hospital (<1% of AMI patients) or on patients with silent AMI. Detailed information on the case-finding procedure and on data-quality aspects has been published elsewhere.³⁰

An incident was defined as a first fatal or nonfatal AMI, including sudden cardiac death. According to the MONICA manual,^{27 31} diagnosis of a major CHD event was based on symptoms, cardiac enzymes (creatine kinase, aspartate aminotransferase, and lactate dehydrogenase), and serial changes from 12-lead ECGs evaluated by Minnesota coding,³² necropsy results, and history of CHD in fatal cases.

Addresses of all participants in the first survey (1984 to 1985) were checked at 2-year intervals, and information on survival was collected. If a subject had died, information on the cause of death was obtained. The results reported here comprise the 8-year follow-up of participants in the first survey (as of December 31, 1992).

Statistical Analysis
The number of events was rather small relative to the number of variables considered (10 to 20 events per regression term should be available for a reliable analysis). We therefore used variables in their simplest form if warranted, used a forward stepping procedure to discard unneeded variables, and did not investigate interactions.

CRP was used as a continuous variable, transformed to natural logarithms for greater symmetry of the distribution (ln mg/L). Covariables controlled for possible confounding effects were age (years), BMI (ln kg/m²), total cholesterol (ln mg/dL), HDL cholesterol (square root mg/dL), smoking status (never smoked, ex-smoker, current smoker), alcohol consumption (square root g/d), systolic and diastolic blood pressures (ln mm Hg), education (ln years), winter and summer LTPA (0, <1, 1 to 2, and >2 h/wk), and diabetes by history (no, yes). The categorical variables, recognizing their ordinal character, were used as continuous variables, transformed to orthogonal polynomial coefficients if necessary.

Cox proportional hazards regression³³ was used to model time to event in the presence of censoring. An individual was considered censored when he died from another cause or left the study area or when the observation period ended. The crude relation of CHD and CRP was checked for departures from linearity, poorly fitted observations, overly influential observations, and validity of the proportional hazards assumption by use of residual plots and nonparametric smoothing functions.

To investigate possible nonlinear transformations of the covariables for adjusting the crude relation, we compared the hazard rate ratio (HRR) for CRP from the model including the covariable in its simplest form with HRR from models including more complex forms (polynomials, splines). Model validity was assessed in a fashion analogous to the crude analysis. The resulting variables were then added to the crude model in a forward stepping manner, at each step adding the variable that changed the absolute value of HRR the most when added to the variable terms already in the model. Age was forced into the model from the beginning. As a stepping criterion, we used 5% change, although some authors recommend 10%.³⁴

All computations and graphics were performed on a personal computer under Windows NT 4 with SAS software, version 6.12,³⁵ and S-PLUS, version 4.0.³⁶

	Results

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The empirical cumulative distribution of log-CRP values in our study sample of 936 men 45 to 64 years of age was remarkably smooth and symmetrical (coefficient of skewness, 0.13; SE=0.08) (Figure 1), and the coefficient of kurtosis was also close to zero (0.09; SE=0.16), indicating that CRP levels in this population approximated a log-normal distribution. The minimal CRP value was 0.05 mg/L, the maximal value was 90.8 mg/L, and the antilogs of the mean (geometric mean) and SD were 1.623 and 3.132 mg/L, respectively.

View larger version (44K): [in this window] [in a new window]   Figure 1. Empirical distribution of CRP on logarithmic scale. Geometric mean (SD) is shown.

The cohort was followed up for a maximum of 8.2 years. During this time, 53 first major CHD events (5.7%) occurred, of which 26 were fatal and 27 were nonfatal. Of the 53 events, 48 occurred after 7.5 years, together with 72 censored observations that were fairly evenly distributed over the time period. The last event occurred after 7.9 years, at which point there was a total of 433 censored observations, and the estimated survival probability was 0.94. The average annual incidence rate was 7.64 per 1000 person-years (95% CI, 5.72 to 9.99).

Table 1 reports unadjusted associations of CRP levels with the covariables, computed as group means of categorized variables. The means are back-transformed to the original scale by taking antilogs, thus representing geometric means. The probability value is the significance level obtained for testing the simultaneous equality of all group means in a 1-way ANOVA. All tests are significant at the 5% level except that for HDL cholesterol, but the tests for alcohol consumption, education, and work activity are only very slightly significant. Of the other variables, total cholesterol shows a U-shaped relation; age, BMI, and smoking exhibit a graded positive association, and diabetes showed a positive association. Blood pressure also is positively related, with the first 2 categories having essentially the same CRP levels. The 2 LTPA variables show nonmonotonic behavior, perhaps with a slight downward linear trend.

View this table: [in this window] [in a new window]   Table 1. CRP Means and SEs (Antilogs) in Subgroups of Categorical Covariables, Including Probability Value for Testing the Simultaneous Equality of the Means: MONICA Augsburg Cohort Study, 1984–1992

Analysis
Modeling the crude association of CRP concentration and CHD by means of a Cox regression resulted in a linear relationship of log hazards and CRP. There was no indication of a nonlinear relation not accounted for by the linear CRP term; no observation showed unusual behavior in the model; and the proportional hazard assumption appeared to be tenable throughout the observation period. The procedure for prechecking the covariables for nonlinearities, as outlined in the Statistical Analysis section, did not indicate the need to abandon the linear terms. The variable selection procedure chosen, forcing age into the model, resulted in 1 variable, namely smoking, changing the HRR, ignoring the sign, by >5% (-5.4%). The next variable would have been BMI, entering with a change of 2.3%, then total cholesterol (1.9%), and eventually HDL cholesterol (-1.7%). The remaining variables produced changes <1%.

Table 2 presents selected regression statistics for the crude model, age-adjusted model, and 5%-change model, with adjustment for age and smoking. The table includes the regression coefficients of the linear log-transformed CRP variable and their 95% confidence limits. It also gives formulas for computing the HRRs for 2 arbitrary CRP values. For instance, for the 90th percentile of the CRP distribution (6.5 mg/L, read from Figure 1) and the 10th percentile (0.4 mg/L), the fully adjusted HRR was (6.5/0.4)^0.3557=2.69 [lower 95% confidence limit, (6.5/0.4)^0.1169=1.39; upper limit, (6.5/0.4)^0.5945=5.25].

View this table: [in this window] [in a new window]   Table 2. CRP Regression Coefficients From Cox Regressions of CHD Incidence on CRP in Various Degrees of Adjustment: MONICA Augsburg Cohort Study, 1984–1992

Table 3 presents HRRs for an increase in CRP concentration of 1 SD of the log-transformed values (1.142 ln mg/L) and corresponding 95% confidence limits for the fully adjusted model.

View this table: [in this window] [in a new window]   Table 3. HRRs for a 1-SD CRP Increase on the Log-Transformed Scale for the Models of Table 2: MONICA Augsburg Cohort Study, 1984–1992

Figure 2 shows a plot of HRRs for CRP quintiles relative to the first quintile. These HRRs were obtained by computing the median CRP value within each quintile and using the ratio of the 2 medians in the formula for HRR in Table 2. The unadjusted HRR, age-adjusted HRR, and fully adjusted HRR, together with 95% confidence limits for the fully adjusted HRR, are shown.

View larger version (25K): [in this window] [in a new window]   Figure 2. HRRs for CRP quintiles, relative to the first quintile, in various adjustments. HRRs were computed for quintile medians listed in graph by use of formulas given in footnote of Table 2.

	Discussion

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These prospective data from a large random sample of initially healthy middle-aged men demonstrate a strong relationship between CRP and the future risk of a fatal or nonfatal coronary event. This relationship is linear in the log hazards and independent of a variety of potential confounders. A 1-SD increase in the log-transformed value of CRP was associated with a remarkable 50% increase in coronary risk, and subjects in the highest quintile of the CRP distribution thus showed a 2.6-fold increase in their risk of a future coronary event. These data confirm a recent nested case-control study in middle-aged US male physicians.²¹ Case-control data from the Cardiovascular Health Study showed that CRP levels may be able to predict coronary risk in men and women >65 years of age with and without evidence of subclinical atherosclerotic disease,²² and another case-control study among participants in MRFIT related CRP values to CHD mortality in healthy but high-risk individuals.²⁰ The prospective ECAT study in patients with angina pectoris showed that CRP levels also predict coronary events in symptomatic subjects over a 2-year period.¹⁹ Interestingly, the distribution of CRP values was very similar in all these studies, with 55% to 80% of CRP values being <2 mg/L, which is well below the range seen in routine use of CRP measurement for monitoring acute or chronic active inflammatory, infective, or tissue-damaging disorders. The strength of the association between CRP and future coronary events was also remarkably consistent in these studies, with a relative risk of 2 to 3 in comparisons of the top and bottom quintiles or quartiles of the CRP distribution.

In our study, CRP was also related to several cardiovascular risk factors that had been reported earlier.³⁷ Particularly strong unadjusted positive associations were found with age, BMI, smoking, and history of diabetes. Current smokers had CRP concentrations twice as high as nonsmokers, but interestingly, subjects who had never smoked had values similar to ex-smokers. Obese subjects (BMI 30 kg/m²) also had CRP concentrations twice as high as those with BMI <25 kg/m². Despite these associations, multivariable analysis clearly showed an independent contribution of CRP in the prediction of future coronary events.

CRP is an extremely sensitive, nonspecific, acute-phase reactant produced in response to most forms of tissue injury, infection, and inflammation and regulated by cytokines, including interleukin-6, interleukin-1, and tumor necrosis factor-.³⁸ Although reportedly expressed by some mononuclear populations, these cells do not secrete CRP, and circulating CRP is exclusively produced by hepatocytes.^{39 40} The stimuli responsible for the generally modest elevations in plasma CRP predictively associated with coronary events are not known. They may arise in the atheromatous lesions themselves and reflect the extent of atherosclerosis and the local inflammation that predisposes to plaque instability, rupture, and occlusive thrombosis. On the other hand, increased CRP production may result from inflammation elsewhere in the body that is somehow proatherogenic and procoagulant. Chronic low-grade infections may be associated with increased risk of CHD,^{41 42} as is the chronic inflammation of rheumatoid arthritis.⁴³ Many coagulation proteins, including fibrinogen, are acute-phase reactants; elevation of fibrinogen is a well-recognized risk factor for coronary events,⁴ and increased CRP values may just be a signal of the acute-phase response in general.

However, there is substantial evidence that CRP may contribute directly to the pathogenesis of atherothrombosis. CRP is a ligand binding protein that binds to the plasma membranes of damaged cells.^{44 45} Aggregated but not soluble native CRP selectively binds LDL and VLDL from whole plasma and, as we have previously proposed, could thereby participate in their atherogenic accumulation.⁴⁶ Complexed CRP also activates complement and can be proinflammatory,⁴⁷ whereas CRP has recently been found to be a potent stimulator of tissue factor production by macrophages in vitro.⁴⁸ Tissue factor is the main initiator of coagulation in vivo, and its local concentration in the arterial wall is clearly related to coronary thrombotic events.^{49 50 51} There are conflicting reports about the presence of CRP in atheromatous lesions,^{52 53 54} and claims that CRP affects platelet function are also controversial.⁵⁵ However, the capacity of CRP to enhance tissue factor production suggests a possible causative link between increased CRP values and coronary events.

Although the number of cases was relatively small, results of the present prospective study of a large cohort of initially healthy middle-aged men indicate that modest elevations in serum CRP concentration significantly predict future coronary events. These observations strengthen the association between low-grade inflammation and the progression and complications of atherosclerosis. Further work is required to clarify the underlying pathophysiological mechanisms, but modulation of the acute-phase response generally and/or the functions of specific acute-phase proteins specifically, especially CRP, already constitutes novel potential therapeutic targets in CHD.

	Acknowledgments

 
This work was supported in part by MRC program grant G790051 to Dr Pepys.

Received April 2, 1998; revision received September 30, 1998; accepted October 5, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:802–809.
   
2. Van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44.[Abstract/Free Full Text]
   
3. Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987;257:2318–2324.[Abstract]
   
4. Ernst E, Koenig W. Fibrinogen and cardiovascular risk. Vascular Med. 1997;2:115–125.
   
5. Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation. 1996;94:2057–2063.[Abstract/Free Full Text]
   
6. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.[Abstract/Free Full Text]
   
7. Dinerman JL, Mehta JL, Saldeen TGP, Eerson S, Wallin R, Davda R, Davidson A. Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction. J Am Coll Cardiol. 1990;15:1559–1563.[Abstract]
   
8. Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med. 1987;317:1361–1365.[Abstract]
   
9. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease. Am J Cardiol. 1990;65:168–172.[Medline] [Order article via Infotrieve]
   
10. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424.[Abstract/Free Full Text]
    
11. Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol. 1984;53:13–23.
    
12. Mattila KJ. Viral and bacterial infections in patients with acute myocardial infarction. J Int Med. 1989;225:293–296.[Medline] [Order article via Infotrieve]
    
13. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet. 1996;348:567–572.[Medline] [Order article via Infotrieve]
    
14. Pepys MB. The acute phase response and C-reactive protein. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine. 2nd ed. Oxford, UK: Oxford University Press; 1995:1527–1533.
    
15. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest. 1993;91:1351–1357.
    
16. WHO Expert Committee on Biological Standardization. WHO Technical Report Series 760. Geneva, Switzerland; 1987.
    
17. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem. 1997;43:52–58.[Abstract/Free Full Text]
    
18. Wilkins J, Gallimore JR, Moore E, Pepys MB. Rapid automated high sensitivity enzyme immunoassay of C-reactive protein. Clin Chem. 1998;44:1358–1361.[Free Full Text]
    
19. Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet. 1997;349:462–466.[Medline] [Order article via Infotrieve]
    
20. 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.[Abstract/Free Full Text]
    
21. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.[Abstract/Free Full Text]
    
22. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17:1121–1127.[Abstract/Free Full Text]
    
23. WHO-MONICA-Project Principal Investigators. The World Health Organization Monica Project (Monitoring Trends and Determinants in Cardiovascular Disease): a major international collaboration. J Clin Epidemiol. 1988;41:105–114.[Medline] [Order article via Infotrieve]
    
24. WHO MONICA Project. WHO MONICA project: objectives and design. Int J Epidemiol. 1989;18(suppl 1):29–37.
    
25. Keil U, Stieber J, Döring A, Chambless L, Härtel U, Filipiak B, Hense HW, Tietze M, Gostomzyk JG. The cardiovascular risk factor profile in the study area Augsburg: results from the first MONICA survey 1984/1985. Acta Med Scand. 1988;728(suppl):119–128.
    
26. Keil U, Cairns V, Döring A, Härtel U, Jorcik J, Perz S, Stieber J. MONICA-Project Region Augsburg. Manual of Operations, Survey. München, Germany: Gesellschaft für Strahlen und Umweltforschung; 1985. GSF report 20/85.
    
27. World Health Organization. MONICA Manual: CVD/MNC. Geneva, Switzerland: WHO; 1990.
    
28. Bray GA. Definition, measurement and classification of the syndromes of obesity. Int J Obesitiy. 1978;2:99–112.
    
29. Koenig W, Sund M, Döring A, Ernst E. Leisure-time physical activity but not work-related physical activity is associated with decreased plasma viscosity: results from a large population sample. Circulation. 1997;95:335–341.[Abstract/Free Full Text]
    
30. Löwel H, Lewis M, Hörmann A, Keil U. Case finding, data quality aspects and comparability of myocardial infarction registers: results of a south German register study. J Clin Epidemiol. 1991;44:249–260.[Medline] [Order article via Infotrieve]
    
31. WHO MONICA Project. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project: registration procedures, event rates, and case fatality rates in 38 populations from 21 countries in four continents. Circulation. 1994;90:583–612.[Abstract/Free Full Text]
    
32. Prineas RJ, Crow RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings: Standards and Procedures for Measurement and Classification. Boston, Mass; Wright; 1982.
    
33. Cox DR. Regression models and life-tables (with discussion). J Royal Stat Soc. 1972;34 (seriesB):187–220.
    
34. Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health. 1989;79:340–349.[Abstract/Free Full Text]
    
35. SAS/STAT Software: Changes and Enhancements for Release 6.12. Cary, NC: SAS Institute Inc; 1996.
    
36. S-PLUS User's Guide, Version 4.0. Seattle, Wass: MathSoft Inc; 1997.
    
37. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C-reactive protein and its relation to cardiovascular risk factors: a population based cross-sectional study. BMJ. 312;1996:1061–1065.
    
38. Baumann H, Gauldie J. The acute phase response. Immunol Today. 1994;25:74–80.
    
39. Dong Q, Wright JR. Expression of C-reactive protein by alveolar macrophages. J Immunol. 1995;156:4815–4820.[Abstract]
    
40. Murphy TM, Baum LL, Beaman KD. Extrahepatic transcription of human C-reactive protein. J Exp Med. 1991;173:495–498.[Abstract/Free Full Text]
    
41. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350:430–436.[Medline] [Order article via Infotrieve]
    
42. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol. 1996;67:1123–1137.[Medline] [Order article via Infotrieve]
    
43. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, Spitz PW, Haga M, Kleinheksel SM, Cathey MA. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994;37:481–494.[Medline] [Order article via Infotrieve]
    
44. Volanakis JE, Narkates AJ. Interaction of C-reactive protein with artificial phosphatidyl-choline bilayers and complement. J Immunol. 1981;126:1820–1825.[Abstract]
    
45. Li YP, Mold C, Du Clos TW. Sublytic complement attack exposes C-reactive protein binding sites on cell membranes. J Immunol. 1994;152:2995–3005.[Abstract]
    
46. Pepys MB, Rowe IF, Baltz ML. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol. 1985;27:83–111.[Medline] [Order article via Infotrieve]
    
47. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N Y Acad Sci. 1982;389:235–250.[Medline] [Order article via Infotrieve]
    
48. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82:513–520.[Abstract/Free Full Text]
    
49. Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernández-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenecity of human atherosclerotic plaques. Circulation. 1997;95:594–599.[Abstract/Free Full Text]
    
50. Kaikita K, Ogawa H, Yasue H, Takeya M, Takahashi K, Saito T, Hayasaki K, Horiuchi K, Takizawa A, Kamikubo Y, Nakamura S. Tissue factor expression on macrophages in coronary plaques in patients with unstable angina. Arterioscler Thromb Vasc Biol. 1997;17:2232–2237.[Abstract/Free Full Text]
    
51. Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue factor antigen and activity in human coronary atherosclerotic plaques. Lancet. 1997;349:769–771.[Medline] [Order article via Infotrieve]
    
52. Rowe IF, Walker LN, Bowyer DE, Soutar AK, Smith LC, Pepys MB. Immunohistochemical studies of C-reactive protein and apolipoprotein B in inflammatory and arterial lesions. J Pathol. 1985;145:241–249.[Medline] [Order article via Infotrieve]
    
53. Hatanaka K, Li X-A Masuda K, Yutoni C, Yamamoto A. Immunohistochemical localization of C-reactive protein binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method. Pathol Int. 1995;45:635–641.[Medline] [Order article via Infotrieve]
    
54. Torzewski J, Torzewski M, Boyer DE, Fröhlich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998;18:1386–1392.[Abstract/Free Full Text]
    
55. Fiedel BA, Simpson RM, Gewurz H. Effects of C-reactive protein (CRP) on platelet function. Ann N Y Acad Sci. 1982;263–273.Inflammation within plaques and elsewhere may contribute to thrombo-occlusive complications of atheroma. In a cohort of 936 randomly selected, initially healthy men 45 to 64 years of age, there was a positive, independent, statistically significant relationship between a single baseline measurement of serum C-reactive protein (CRP), a sensitive systemic marker of inflammation, and incidence of coronary heart disease (CHD) over the next 8 years. The adjusted hazard rate ratio for a first major CHD event associated with a 1-SD increase in log-CRP concentration was 1.50 (95% CI, 1.14 to 1.97). Thus, in apparently healthy subjects, low-grade inflammation is indeed associated with CHD.
    

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