This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rost, N. S. Articles by Wilson, P. W.F. Search for Related Content PubMed PubMed Citation Articles by Rost, N. S. Articles by Wilson, P. W.F. Related Collections Risk Factors Acute Cerebral Infarction Primary and Secondary Stroke Prevention Risk Factors for Stroke

(Stroke. 2001;32:2575.)
© 2001 American Heart Association, Inc.

Original Contributions

Plasma Concentration of C-Reactive Protein and Risk of Ischemic Stroke and Transient Ischemic Attack

The Framingham Study

Natalia S. Rost, MA; Philip A. Wolf, MD; Carlos S. Kase, MD; Margaret Kelly-Hayes, EdD, RN; Halit Silbershatz, PhD; Joseph M. Massaro, PhD; Ralph B. D’Agostino, PhD; Carl Franzblau, PhD Peter W.F. Wilson, MD

From the National Heart, Lung, and Blood Institute’s Framingham Study (P.A.W., C.S.K., M.K.-H., P.W.F.W.), Framingham, Mass, and the Departments of Neurology (N.S.R., P.A.W., C.S.K., M.K.-H.), Mathematics and Statistics (H.S., R.B.D), Epidemiology and Biostatistics (J.M.M.), Biochemistry (C.F.), and Medicine (P.W.F.W.), Boston University School of Medicine, Boston, Mass.

Correspondence to Philip A. Wolf, MD, Neurological Epidemiology and Genetics, Boston University School of Medicine, 715 Albany St, B-608, Boston, MA 02118-2526. E-mail pawolf{at}bu.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background—— The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort.

Methods—— There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed.

Results—— During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (RR=2.0, P=0.027), and women had almost 3 times the risk (RR=2.7, P=0.0003) compared with those in the lowest quartile. Assessment of the trend in risk across quartiles showed unadjusted risk increase for men (RR=1.347, P=0.0025) and women (RR=1.441, P=0.0001). After adjustment for smoking, total/HDL cholesterol, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men (P=0.0365) and women (P=0.0084).

Conclusions—— Independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.

Key Words: atherosclerosis • C-reactive protein • inflammation • ischemic stroke • risk factors • TIA

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
An increasing body of evidence has linked inflammation with the pathogenesis of atherothrombotic stroke. Infections and inflammation may promote atherosclerosis and thrombosis by elevating serum levels of fibrinogen,¹ leukocytes,² clotting factors,³ and cytokines⁴ and by altering the metabolism and functions of endothelial cells and monocyte macrophages.⁵ Low-grade infections, reflected in elevated levels of various acute-phase proteins,⁶ may be partly responsible for the inflammatory processes observed in atherosclerotic lesions, which in turn may relate to the occurrence of ischemic symptoms.

C-reactive protein (CRP), an acute-phase reactant, is an indicator of underlying systemic inflammation and a novel plasma marker for atherothrombotic disease. The recent use of highly sensitive CRP assays, with international reference standards set by the World Health Organization (WHO),⁷ has enhanced the usefulness of CRP as a reliable predictor of cardiovascular events. A strong and consistent association between clinical manifestations of atherothrombotic disease and baseline CRP levels has been described in epidemiological studies of patients with acute myocardial ischemia⁸ or myocardial infarction,^9,10 stable and unstable angina pectoris,¹¹ and myocardial infarction or recurrent ischemia among those hospitalized with angina pectoris.^12,13 Large prospective studies in apparently healthy subjects confirmed the prognostic relevance of CRP to (1) the risk of cardiovascular disease in men,¹⁴ women,^15,16 and the elderly^17,18; (2) the risk of fatal coronary disease among smokers with multiple risk factors for atherosclerosis¹⁹; (3) the development of peripheral vascular disease²⁰; and (4) the risk of coronary heart disease (CHD) in a large cohort of initially healthy middle-aged men.²¹

Most researchers have used a case-control design,^8–13 have focused on selected subject populations,^14–21 and have largely investigated men,^8–14,20,21 with few studies of women.^15–17 Furthermore, limited availability of other pertinent risk factors in some of these studies has not permitted determination of the joint and net effect of CRP levels on the outcome. Last, the research findings linking CRP to atherosclerotic cardiovascular disease have mostly focused on CHD^{8–11,13–17,19,21} or have used cardiovascular "events" (encompassing fatal CHD, nonfatal myocardial infarction or stroke, and coronary revascularization procedures) instead of stroke as the specific outcome of interest,^15,16 and there have been only a few large-scale prospective epidemiological studies of stroke.¹⁴ To address the issue of baseline CRP levels and risk of subsequent stroke events, we measured the concentration of CRP in members of the Framingham Study original cohort who were free of stroke or transient ischemic attack (TIA) at the time of their 1980 to 1982 clinic examination and related the baseline plasma concentrations of CRP to incident first ischemic stroke or TIA in these subjects during a 12- to 14-year follow-up period.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects and Definition of Clinical Outcome
The Framingham Study was begun in 1948 to explore risk factors for and consequences of cardiovascular disease in a longitudinal community-based population sample. At entry, there were 5209 male and female participants who were aged 28 to 62 years. The subjects have been examined biennially with routine assessment of medical history, physical examination, blood tests, and 12-lead ECGs. The examination procedures were approved by the Institutional Review Board of Boston Medical Center, and all subjects gave informed consent. Study design, response rates, and completeness of follow-up have been reported elsewhere.²²

For the present study, we related CRP level at biennial examinations 16 and 17 (1980 to 1982) to ischemic stroke or TIA incidence during 12 to 14 years of follow-up at examination 23 (1994). Of the initial Framingham Study cohort, 2999 subjects were alive and stroke free on January 1, 1982. At the time of the clinic examinations from 1980 to 1982, nonfasting blood specimens were obtained from 591 men and 871 women of the original cohort who were free of stroke or TIA. This study population represented approximately 60% of living subjects who attended the clinic examination, and frozen specimens were available for almost all of these participants (an overall inclusion rate of 50% of the living subjects). Subjects were followed up over a 12- to 14-year period for the development of incident ischemic stroke, including atherothrombotic brain infarction, cerebral embolism, or TIA. Most subjects with stroke or suspected stroke had been hospitalized in the only general hospital in Framingham, where they were evaluated by a Framingham Study neurologist within a few days (often within hours) after onset. The criteria for stroke were met by the presence of a neurological deficit of sudden or rapid onset that persisted for 24 hours, and the events were adjudicated by a panel of 2 neurologists. CT scans and MRI studies of the brain and arteries were available to confirm the diagnosis; since 1982, 91.5% have had at least 1 CT or MRI scan of the brain and arteries, and many have undergone >1 study.²³

Assessment of the Risk Factors
Baseline covariables assessed for the present analysis included plasma CRP, age, sex, systolic blood pressure, cigarette smoking, total and HDL cholesterol levels, and diabetes. Nonfasting blood specimens were obtained from all subjects at biennial examinations 16 and 17, and the serum aliquots were stored at -20°C until mid-1997. Plasma concentrations of CRP were measured by use of a standardized commercial biochemical assay (Hemagen Diagnostics). Total and HDL cholesterol levels were assessed from fresh nonfasting plasma samples by standard Lipid Research Clinics techniques.²⁴ Diabetes was defined as use of insulin preparations or oral hypoglycemic agents or any recorded blood glucose level of 11.1 mmol/L (200 mg/dL). Persons reporting cigarette smoking during the past year were considered smokers. Systolic blood pressure was recorded with patients in the sitting position after at least 5 minutes of rest. On the basis of 2 consecutive measurements, elevated systolic blood pressure of 140 mm Hg and/or diastolic blood pressure of 90 mm Hg was defined as hypertension.

Laboratory Procedures
Serum concentrations of CRP were measured with an ultrasensitive enzyme immunoassay by using monospecific polyclonal and monoclonal antibodies produced by immunization with highly purified CRP. Briefly, the IgG fraction of polyclonal goat anti-human CRP antiserum was immobilized on the inner surface of microwell plates. One hundred microliters (at 1:100 dilution) of each serum sample was introduced into the test wells. The titer plates were incubated for 30 minutes at room temperature and then washed 4 times with rinsing solution. Aliquots (100 µL) of secondary rabbit anti-human CRP antibody conjugated to horseradish peroxidase were added to each well and incubated for 30 minutes at room temperature. At the end of the incubation, the plates were rinsed 4 times with rinsing solution. Horseradish peroxidase activity was determined by the addition of 100 µL of the substrate 3,3',5,5'-tetramethylbenzidine, followed by incubation for 30 minutes at room temperature. The enzymatic reaction was stopped by transferring 50 µL of 1N H₂SO₄. The optical density of the product was quantified in an enzyme immunoassay plate reader at a wavelength of 450 nm. A standard curve was generated by using known concentrations of human serum CRP as an internal control in each experiment. The concentration of CRP in the test samples was determined from the standard curve. To verify the accuracy of CRP results interpolated from the standard curve, the WHO standard preparation^7,25 was serially diluted in the working range of the kit. The response of the Hemagen CRP150 Kit was linear with a coefficient of determination (r²) >0.99 and colinear with the standard curve of the assay. On split specimens, the correlation coefficient was 0.86.

Statistical Analyses
Analyses were performed separately for men and women by using sex-specific quartiles (Q₁ to Q₄) of CRP (men: Q₁=0 to 1.08, Q₂=1.10 to 3.0, Q₃=3.03 to 6.80, and Q₄=6.90 to 48.30 µg/mL; women: Q₁=0 to 1.00, Q₂=1.02 to 3.19, Q₃=3.20 to 7.31, and Q₄=7.33 to 50.20 µg/mL).

Unadjusted, bivariate (adjusted for age), and multivariate (adjusted for age, smoking, total and HDL cholesterol, systolic blood pressure, and diabetes) risk ratio (RR) estimates (with 95% CIs) for plasma CRP quartiles were generated by Cox proportional hazards modeling by using CRP quartiles as the independent variable. These RRs were derived by using the lowest quartile (Q₁) as the referent group.

For each of the unadjusted, bivariate, and multivariate Cox regression analyses, a trend analysis was performed to determine whether the risk of first ischemic stroke/TIA increased as the CRP quartile increased.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study participant characteristics were recorded at biennial examinations 16 and 17 (Table 1). The cohort (n=1462) was followed for up to 14 years. During this time, 196 (13.4%) first cerebrovascular events (ischemic stroke or TIA) occurred; 82 (13.9%) occurred in men, and 114 (13.1%) occurred in women.

View this table: [in this window] [in a new window]   Table 1. Subject Characteristics at Exams 16 and 17

Unadjusted relative risk of first ischemic stroke or TIA increased significantly with each increasing quartile of baseline plasma CRP concentrations in both sexes (Table 2). Men with plasma CRP levels in the third quartile (3.03 µg/mL) had an unadjusted relative risk of first ischemic stroke/TIA almost 2 times greater than the relative risk for those in Q₁ (RR=1.9, P=0.037). A similar association was found for women in the third quartile of CRP (RR=1.8, P=0.033). Even greater relative risks were observed for men (RR=2.0, P=0.028) and women (RR=2.9, P=0.0001) in the highest sex-specific quartiles of CRP.

View this table: [in this window] [in a new window]   Table 2. Unadjusted Relative Risk of Incident Ischemic Stroke or TIA According to Plasma Concentration of CRP

Adjustment for age in Table 3 did not attenuate the response, and the top 2 CRP quartiles were consistently associated with an increased risk of first ischemic stroke/TIA in men and women.

View this table: [in this window] [in a new window]   Table 3. Adjusted Relative Risk of First Ischemic Stroke or TIA According to Plasma Concentration of CRP

After multivariate adjustment, the Q₄ plasma CRP levels were related to a 1.6-fold increase in risk of first ischemic stroke/TIA in men, a result that was no longer statistically significant (P=0.123). However, for women in the highest CRP quartile, the relative risk of first ischemic stroke or TIA remained significantly increased after multivariate adjustment (RR=2.1, P=0.008; Table 3).

In the series of trend analyses, the unadjusted relative risk of first ischemic stroke/TIA for an increase in CRP from one quartile to the next higher quartile was 1.347 in men (P=0.0025) and 1.441 in women (P=0.0001). Statistical significance of this trend was not altered by the age adjustment (men: RR=1.346, P=0.0027; women: RR=1.411, P=0.0002). Multivariate adjustment did not attenuate the response in men (RR=1.248, P=0.0365) or women (RR=1.288, P=0.0084) (Table 4).

View this table: [in this window] [in a new window]   Table 4. Trend in Risk of Ischemic Stroke/TIA Across CRP Quartiles in 1462 Framingham Study Participants

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
More than 700 000 strokes occur in the United States each year,²⁶ and it is paramount to identify new risk markers and preventive strategies for ischemic cerebrovascular disease.

Ischemic cerebrovascular disease accounts for a substantial proportion of all strokes.²⁷ Although the proximate cause of most brain infarcts is thrombus formation, atherosclerosis is the chief underlying cause.^28,29 The lesions of atherosclerosis represent a series of specific cellular and molecular responses that include lipoprotein, hematologic, mechanical, and inflammatory components.²⁹ CRP, one of the acute-phase reactants, is an indicator of underlying systemic inflammation³⁰ and a novel plasma marker of atherothrombotic disease.^31–33 It is likely that CRP has many pathophysiological roles in the inflammatory process, including binding of phosphocholine and recognition of foreign pathogens and phospholipid constituents of damaged cells.³⁰ A recent meta-analysis of several prospective studies of CRP and cardiovascular disease showed that the relative risk for CHD among individuals with CRP values in the top third compared with those in the bottom third was 1.7 (95% CI 1.4 to 2.1).³¹ However, few prospective epidemiological studies of stroke and markers of inflammation have been performed to date. Previous data on plasma CRP levels and ischemic stroke have suggested that this plasma marker is an independent predictor of the risk of future stroke.^14,15 Men with the highest baseline CRP values had twice the risk of ischemic stroke,¹⁴ and women with the highest CRP levels had a 5-fold increase in risk of any vascular event and a 7-fold increase in risk of the combined outcome of myocardial infarction or stroke.¹⁵

Our prospective data from a large community-based cohort of men and women free of stroke and TIA demonstrate a strong relationship between plasma CRP and incidence of first ischemic stroke or TIA in both sexes. This relationship is linear and consistent with the CRP quartile gradation in both men and women. These data demonstrate a graded increase in the incidence of ischemic stroke and TIA with increased levels of CRP, even when the values were within the normal range. Furthermore, in trend analyses, shown in Table 4, this relationship persisted after adjusting for a number of potential confounders, including smoking, systolic blood pressure, total and HDL cholesterol, and diabetes. Elevated serum levels of CRP are not disease specific but are sensitive markers produced in response to tissue injury, infectious agents, immunologic stimuli, and inflammation. Cytokines such as interleukin-6, interleukin-1, and tumor necrosis factor- are highly correlated with CRP levels and their function.³⁴

Inflammation is only one of multiple factors that can foster an increased risk of acute ischemic events. CRP levels are known to be greater in smokers,^35,36 obese individuals (body mass index >130% of the ideal), individuals with abnormal fibrinolytic activity (plasmin-antiplasmin complex), and individuals with subclinical atherosclerosis.^37,38 Overall, these data support the view that CRP, as a marker of low-level inflammation, predicts an increased risk of atherothrombotic events in otherwise healthy individuals. In addition, inflammation not only appears to be a response to the underlying atherosclerotic disease process but also may be an integral part of it.³⁶ This is consistent with the beneficial effects of anti-inflammatory agents, such as aspirin, in reducing the risk of cardiovascular events in men.¹⁴ The substantial reduction of risk of myocardial infarction in subjects with high baseline CRP levels who were treated with aspirin¹⁴ may suggest a beneficial anti-inflammatory effect of the drug that becomes detectable in low-risk patients. Unfortunately, we do not have adequate aspirin intake data in the present study to address this issue.

Our findings are based on the 1-time measurement of the plasma CRP levels, which may not completely and accurately reflect the status of the study participants over a prolonged follow-up period. However, this source of variability could not account for the relationship observed in the present study, because a random misclassification of such nature would tend to underestimate study findings and bias the results toward the null hypothesis. The nested prospective cohort design allows us to exclude the possibility that acute ischemia affected the levels of plasma CRP in the study participants. The data were obtained in an elderly cohort of men and women, and this may limit the applicability of the results to younger men and women.

We conclude that elevated plasma CRP levels significantly predict greater risk of ischemic stroke or TIA in elderly men and women. If the results of the present study are confirmed in other analyses of large population-based cohorts of men and women, the inclusion of CRP as a risk factor for ischemic stroke or TIA would have important implications. The addition of CRP levels in the highest quartile to the risk factor profile of the elderly may significantly increase the predictability of incident ischemic stroke or TIA. Thus, the use of CRP values may aid in identifying a potentially large number of men and women who are at risk for cerebrovascular events. This, in turn, may lead to the development of new treatment strategies for primary stroke prevention in those individuals identified as being at risk for developing cerebrovascular disease.

	Acknowledgments

 
This study was supported in part by a contract (NO1-HC-38038) with the National Heart, Lung, and Blood Institute and by a grant from the National Institute of Neurological Disorders and Stroke (5-RO1-NS-17950-19).

Received February 28, 2001; revision received July 14, 2001; accepted July 17, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Ernst E, Koenig W. Fibrinogen and cardiovascular risk. Vasc Med. 1997; 2: 115–125.[Medline] [Order article via Infotrieve]
2. Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA. Leukocytes and the risk of ischemic diseases. JAMA. 1987; 257: 2318–2324.[Abstract]
3. 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]
4. Dinerman JL, Mehta JL, Saldeen TG, Emerson 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]
5. Mattila KJ, Valtonen VV, Nieminen MS, Asikainen S. Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis. 1998; 26: 719–734.[Medline] [Order article via Infotrieve]
6. Mattila KJ. Viral and bacterial infections in patients with acute myocardial infarction. J Intern Med. 1989; 225: 293–296.[Medline] [Order article via Infotrieve]
7. WHO Expert Committee on Biological Standardization. WHO Technical Report Series 760. Geneva, Switzerland: World Health Organization; 1987.
8. 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]
9. deBeer FC, Hind CR, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial ischemia and infarction. Br Heart J. 1982; 47: 239–243.[Abstract/Free Full Text]
10. Pietila K, Harmoinen A, Hermens W, Simoons ML, van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J. 1993; 14: 915–919.[Abstract/Free Full Text]
11. 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]
12. 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]
13. 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]
14. 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]
15. Ridker PM, Buring JE, Shih H, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998; 98: 731–733.[Abstract/Free Full Text]
16. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.[Abstract/Free Full Text]
17. 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]
18. Gussekloo J, Schaap MCL, Frölich M, Blauw GJ, Westerdorp RGJ. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol. 2000; 20: 1047–1051.[Abstract/Free Full Text]
19. Kuller LH, Tracy RP, Shaten J, Meilahn EN. 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]
20. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998; 97: 425–428.[Abstract/Free Full Text]
21. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-reactive protein, a sensitive marker for 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) Augsberg Cohort Study, 1984 to 1992. Circulation. 1999; 99: 237–242.[Abstract/Free Full Text]
22. Cupples LA, D’Agostino RB. Some risk factors related to the annual incidence of cardiovascular disease and death using polled repeated biennial measurements.In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Bethesda, Md: National Heart, Lung, and Blood Institute; 1987. National Institutes of Health publication No. 87-2703.
23. Wolf PA, D’Agostino RB. Epidemiology of stroke.In: Barnett HJM, Mohr JP, Stein BM, Yatsu F, eds. Stroke: Pathophysiology, Diagnosis, and Management. 3rd ed. New York, NY: Churchill Livingstone; 1998: 6–7.
24. Kannel WB, Wolf PA, Garrison RJ. Section 34: some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study 30-Year Follow-Up.In: The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Springfield, Va: National Technical Information Service; 1987: 1–459.
25. WHO Expert Committee on Biological Standardization. 42nd Report, 1992. Potters Bar, UK: National Institute for Biological Standards and Control; 1992.
26. 2000 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1999.
27. Wolf PA, Kannel W, D’Agostino RB. Epidemiology of stroke.In: Ginsberg MD, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Malden, Mass: Blackwell Scientific Publications Inc; 1998; 2: 834–849.
28. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992; 326: 242–250.[Medline] [Order article via Infotrieve]
29. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.[Free Full Text]
30. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999; 340: 448–454.[Free Full Text]
31. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease. JAMA. 1998; 279: 1477–1482.[Abstract/Free Full Text]
32. Wilson PWF. Metabolic risk factors for coronary heart disease: current and future prospects. Curr Opin Cardiol. 1999; 14: 176–185.[Medline] [Order article via Infotrieve]
33. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med. 1999; 130: 933–937.[Abstract/Free Full Text]
34. Bauman H, Gauldie J. The acute phase response. Immunol Today. 1994; 25: 74–80.
35. Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta. 1985; 153: 9–13.[Medline] [Order article via Infotrieve]
36. Tracy RP. Inflammation in cardiovascular disease: cart, horse, or both? Circulation. 1998; 97: 2000–2002.[Free Full Text]
37. Tracy RP, Psaty BM, Macy E, Bovil EG, Cushman M, Cornell ES, Kuller LH. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997; 17: 2167–2176.[Abstract/Free Full Text]
38. Kuller LH, Tracy RP. The role of inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol. 2000; 20: 901.[Free Full Text]

This article has been cited by other articles:

				B. Mathew, L. Francis, A. Kayalar, and J. Cone Obesity: Effects on Cardiovascular Disease and its Diagnosis J Am Board Fam Med, November 1, 2008; 21(6): 562 - 568. [Abstract] [Full Text] [PDF]

				T. Tholstrup, M. Raff, E. M. Straarup, P. Lund, S. Basu, and J. M. Bruun An Oil Mixture with Trans-10, Cis-12 Conjugated Linoleic Acid Increases Markers of Inflammation and in Vivo Lipid Peroxidation Compared with Cis-9, Trans-11 Conjugated Linoleic Acid in Postmenopausal Women J. Nutr., August 1, 2008; 138(8): 1445 - 1451. [Abstract] [Full Text] [PDF]

				S. C. Larsson, S. Mannisto, M. J. Virtanen, J. Kontto, D. Albanes, and J. Virtamo Coffee and Tea Consumption and Risk of Stroke Subtypes in Male Smokers Stroke, June 1, 2008; 39(6): 1681 - 1687. [Abstract] [Full Text] [PDF]

				E. M. Matheson, M. S. Player, A. G. Mainous III, D. E. King, and C. J. Everett The Association Between Hay Fever and Stroke in a Cohort of Middle Aged and Elderly Adults J Am Board Fam Med, May 1, 2008; 21(3): 179 - 183. [Abstract] [Full Text] [PDF]

				I. Protopsaltis, P. Korantzopoulos, H. J. Milionis, A. Koutsovasilis, G. K. Nikolopoulos, E. Dimou, S. Kokkoris, P. Brestas, M. S. Elisaf, and A. Melidonis Metabolic Syndrome and Its Components as Predictors of Ischemic Stroke in Type 2 Diabetic Patients Stroke, March 1, 2008; 39(3): 1036 - 1038. [Abstract] [Full Text] [PDF]

				S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, M. Szarek, D. D. Waters, P. Libby, P. Ganz, and for the Myocardial Ischemia Reduction with Aggress Inflammation, Statin Therapy, and Risk of Stroke After an Acute Coronary Syndrome in the MIRACL Study Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 142 - 147. [Abstract] [Full Text] [PDF]

				P. S. Mullenix, S. R. Steele, M. J. Martin, B. W. Starnes, and C. A. Andersen C-reactive Protein Level and Traditional Vascular Risk Factors in the Prediction of Carotid Stenosis Arch Surg, November 1, 2007; 142(11): 1066 - 1071. [Abstract] [Full Text] [PDF]

				K. Sander, C. Schulze Horn, C. Briesenick, and D. Sander High-Sensitivity C-Reactive Protein Is Independently Associated With Early Carotid Artery Progression in Women But Not in Men: The INVADE Study Stroke, November 1, 2007; 38(11): 2881 - 2886. [Abstract] [Full Text] [PDF]

				D. N. Patel, C. A. King, S. R. Bailey, J. W. Holt, K. Venkatachalam, A. Agrawal, A. J. Valente, and B. Chandrasekar Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-{kappa}B and C/EBPbeta Activation J. Biol. Chem., September 14, 2007; 282(37): 27229 - 27238. [Abstract] [Full Text] [PDF]

				D. Tousoulis, C. Antoniades, and C. Stefanadis Assessing inflammatory status in cardiovascular disease Heart, August 1, 2007; 93(8): 1001 - 1007. [Full Text] [PDF]

				P. M. Ridker C-Reactive Protein and the Prediction of Cardiovascular Events Among Those at Intermediate Risk: Moving an Inflammatory Hypothesis Toward Consensus J. Am. Coll. Cardiol., May 29, 2007; 49(21): 2129 - 2138. [Abstract] [Full Text] [PDF]

				Z. S. Tan, A. S. Beiser, R. S. Vasan, R. Roubenoff, C. A. Dinarello, T. B. Harris, E. J. Benjamin, R. Au, D. P. Kiel, P. A. Wolf, et al. Inflammatory markers and the risk of Alzheimer disease: The Framingham Study Neurology, May 29, 2007; 68(22): 1902 - 1908. [Abstract] [Full Text] [PDF]

				P. M Ridker and B. M. Everett Letter by Ridker and Everett Regarding Article, "The Inflammatory Hypothesis: Any Progress in Risk Stratification and Therapeutic Targets?" Circulation, May 22, 2007; 115(20): e475 - e475. [Full Text] [PDF]

				I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes Relative Value of Inflammatory, Hemostatic, and Rheological Factors for Incident Myocardial Infarction and Stroke: The Edinburgh Artery Study Circulation, April 24, 2007; 115(16): 2119 - 2127. [Abstract] [Full Text] [PDF]

				O. Schlager, M. Exner, W. Mlekusch, S. Sabeti, J. Amighi, P. Dick, O. Wagner, R. Koppensteiner, E. Minar, and M. Schillinger C-Reactive Protein Predicts Future Cardiovascular Events in Patients With Carotid Stenosis Stroke, April 1, 2007; 38(4): 1263 - 1268. [Abstract] [Full Text] [PDF]

				J. Jose Diaz, J. Arguelles, I. Malaga, C. Perillan, A. Dieguez, M. Vijande, and S. Malaga C-reactive protein is elevated in the offspring of parents with essential hypertension Arch. Dis. Child., April 1, 2007; 92(4): 304 - 308. [Abstract] [Full Text] [PDF]

				P. M Ridker, J. E. Buring, N. Rifai, and N. R. Cook Development and Validation of Improved Algorithms for the Assessment of Global Cardiovascular Risk in Women: The Reynolds Risk Score JAMA, February 14, 2007; 297(6): 611 - 619. [Abstract] [Full Text] [PDF]

				E. R. Bates, C. J. D. Babb, D. E. Casey, C. U. Cates, G. R. Duckwiler, T. E. Feldman, W. A. Gray, K. Ouriel, E. D. Peterson, K. Rosenfield, et al. ACCF/SCAI/SVMB/SIR/ASITN 2007 Clinical Expert Consensus Document on Carotid Stenting: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ASITN Clinical Expert Consensus Document Committee on Carotid Stenting) Vascular Medicine, February 1, 2007; 12(1): 35 - 83. [PDF]

				L. Deutsch Evaluation of the Effect of Neptune Krill Oil on Chronic Inflammation and Arthritic Symptoms J. Am. Coll. Nutr., February 1, 2007; 26(1): 39 - 48. [Abstract] [Full Text] [PDF]

				American Society of Interventional & Therapeutic N, Society for Cardiovascular Angiography and Interve, Society for Vascular Medicine and Biology, Society of Interventional Radiology, E. R. Bates, J. D. Babb, D. E. Casey Jr, C. U. Cates, G. R. Duckwiler, T. E. Feldman, et al. ACCF/SCAI/SVMB/SIR/ASITN 2007 Clinical Expert Consensus Document on Carotid Stenting: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ASITN Clinical Expert Consensus Document Committee on Carotid Stenting) J. Am. Coll. Cardiol., January 2, 2007; 49(1): 126 - 170. [Full Text] [PDF]

				B. M. Everett, T. Kurth, J. E. Buring, and P. M. Ridker The Relative Strength of C-Reactive Protein and Lipid Levels as Determinants of Ischemic Stroke Compared With Coronary Heart Disease in Women J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2235 - 2242. [Abstract] [Full Text] [PDF]

				P. Libby and P. M. Ridker Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A33 - A46. [Abstract] [Full Text] [PDF]

				M. J. Bos, C. M. A. Schipper, P. J. Koudstaal, J. C.M. Witteman, A. Hofman, and M. M.B. Breteler High Serum C-Reactive Protein Level Is Not an Independent Predictor for Stroke: The Rotterdam Study Circulation, October 10, 2006; 114(15): 1591 - 1598. [Abstract] [Full Text] [PDF]

				S. Sato, H. Iso, H. Noda, A. Kitamura, H. Imano, M. Kiyama, T. Ohira, T. Okada, M. Yao, T. Tanigawa, et al. Plasma Fibrinogen Concentrations and Risk of Stroke and Its Subtypes Among Japanese Men and Women Stroke, October 1, 2006; 37(10): 2488 - 2492. [Abstract] [Full Text] [PDF]

				C. D. Bushnell, P. Hurn, C. Colton, V. M. Miller, G. del Zoppo, M. S.V. Elkind, B. Stern, D. Herrington, G. Ford-Lynch, P. Gorelick, et al. Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group Stroke, September 1, 2006; 37(9): 2387 - 2399. [Abstract] [Full Text] [PDF]

				T. Dziedzic Systemic inflammatory markers and risk of dementia. American Journal of Alzheimer's Disease and Other Dementias, August 1, 2006; 21(4): 258 - 262. [Abstract] [PDF]

				G. J. Hankey Potential New Risk Factors for Ischemic Stroke: What Is Their Potential? Stroke, August 1, 2006; 37(8): 2181 - 2188. [Abstract] [Full Text] [PDF]