Published online before print October 2, 2006, doi: 10.1161/CIRCULATIONAHA.106.619833
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(Circulation. 2006;114:1591-1598.)
© 2006 American Heart Association, Inc.
Stroke |
High Serum C-Reactive Protein Level Is Not an Independent Predictor for Stroke
The Rotterdam Study
From the Departments of Epidemiology and Biostatistics (M.J.B., M.A.S., J.C.M.W., A.H., M.M.B.B.) and Neurology (M.J.B., P.J.K.), Erasmus Medical Center, Rotterdam, the Netherlands.
Reprint requests to Prof Dr M.M.B. Breteler, Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail m.breteler{at}erasmusmc.nl
Received February 9, 2006; revision received July 7, 2006; accepted July 14, 2006.
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Abstract |
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Background— Current guidelines recommend the assessment of C-reactive protein (CRP) levels with a high-sensitivity assay in cardiovascular risk prediction. Recent studies have put forward that although elevated CRP is a risk factor for cardiovascular disease, it is not helpful in the prediction of cardiovascular disease risk. We studied the importance of CRP as a risk factor and as a risk predictor of future stroke.
Methods and Results— The present study was based on 6430 participants of the Rotterdam Study who at baseline (1990–1993) were 
55 years of age, were stroke free, and had blood taken. Strokes were classified as hemorrhagic, ischemic, or unspecified. Ischemic strokes were further subclassified. Whether stroke risk varied with baseline CRP serum levels was assessed with Cox proportional hazards models. Whether CRP was helpful in the prediction of individual stroke risk was assessed with receiver operating characteristic curves and by comparing the distribution of strokes between predicted risk strata. During an average of 8.2 years of follow-up, 498 first-ever strokes occurred. High CRP levels were significantly associated with risk of any stroke (age- and sex-adjusted hazard ratio per SD, 1.14; 95% confidence interval, 1.04 to 1.24) and risk of ischemic stroke (age- and sex-adjusted hazard ratio per SD, 1.17; 95% confidence interval, 1.04 to 1.32). Taking CRP levels into account did not improve the individual stroke risk prediction, however, regardless of whether it was based on the Framingham stroke risk score or on age and sex only.
Conclusions— Although CRP levels are associated with stroke risk, their use in the assessment of individual stroke risk seems limited.
Key Words: C-reactive protein • cerebral infarction • inflammation • risk factors • stroke
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Introduction |
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Small persistent increases in systemic inflammatory activity, commonly referred to as low-grade inflammation, are associated with an increased risk of cardiovascular disease. Elevated levels of acute-phase proteins may mark this low-grade inflammation when transient fluctuations during acute inflammation are ignored.1–3 The acute-phase protein that is most strongly associated with cardiovascular disease appears to be C-reactive protein (CRP)3,4; indeed, an association between CRP measured with a high-sensitivity assay and coronary heart disease has been shown by many studies.5 The January 2003 statement from the Centers for Disease Control and Prevention and the American Heart Association therefore recommends using CRP to assess cardiovascular risk.6 These recommendations are inspired by the strong associations that have been found between CRP levels and the risk of cardiovascular disease. However, a large meta-analysis and more recent findings suggested that CRP is a weaker risk factor than initially thought.3,7 More important, what has often been overlooked is the difference between risk factors and clinically useful risk predictors: Even when a strong association exists between a risk factor and the occurrence of a disease, additional statistical methods are required to determine whether that risk factor adds to the accuracy of disease risk prediction.8–10 The number of studies that assessed the predictive value of CRP with appropriate statistical methods is quite small, but they seem to suggest that the predictive value of CRP for cardiovascular disease is limited.11–13 Several studies suggest that the strength of the association between CRP and stroke is similar to that between CRP and coronary heart disease,14–17 but no studies thus far have examined the role of CRP as a risk predictor for stroke as a unique end point.
Editorial p 1557
Clinical Perspective p 1598
In the present study, we examined whether CRP is a risk factor for stroke and its subtypes. Moreover, we evaluated whether assessment of CRP levels contributes to the identification of patients at increased risk of stroke, in addition to both age and sex and the classic risk factors used in the 1991 Framingham Stroke Risk Function18 that performed reasonably well in our study population.19
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Methods |
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Population
The study is part of the Rotterdam Study, a population-based cohort study on chronic and disabling diseases in the elderly. All inhabitants of Ommoord, a district of Rotterdam,
55 years of age were invited. People living in homes for the elderly were included. Participation rate of those invited for the study was 78%; in total, 7983 subjects participated.20 The Medical Ethics Committee of Erasmus University Rotterdam approved the study. Written informed consent to retrieve information from treating physicians was obtained from all participants. Baseline measurements were obtained from 1990 through 1993 and consisted of a home interview and 2 visits to the research center for physical examination. At the baseline visit to the research center, we sampled blood and performed carotid duplex ultrasonography and electrocardiography. After exclusion of participants who had a stroke before baseline (n=261)21; who did not visit the research center due to death, refusal, or physical inability (n=844); for whom no blood was available for the CRP assay (n=413); or who had a very high serum CRP level (logarithm of CRP >3 SD above the mean; n=35), a total of 6430 persons were included in this study.
Assessment of Stroke
History of stroke or transient ischemic attack at baseline was assessed and verified as described previously.21 Once subjects enter the Rotterdam Study, they are monitored continuously for major events through automated linkage of the study database with files from general practitioners and the municipality. In addition, nursing home physicians’ files are scrutinized. For reported events, additional information (including brain images) is obtained from hospital records. Stroke research physicians reviewed information on all possible strokes and transient ischemic attacks; an experienced stroke neurologist (P.J.K.) verified all diagnoses while blinded for CRP status. Subarachnoid hemorrhages and retinal strokes were excluded. Follow-up was completed until January 1, 2002, for 97.1% of all potential person-years.22
Definitions of Stroke Subtypes
Ischemic strokes were diagnosed when a patient had typical symptoms and a CT or MRI within 4 weeks that ruled out other diagnoses or when indirect evidence (deficit limited to 1 limb or completely resolved within 72 hours, atrial fibrillation in the absence of anticoagulants) pointed to an ischemic nature of the stroke. Hemorrhagic stroke was diagnosed when a relevant hemorrhage was shown on CT or MRI scan or when the subject permanently lost consciousness or died within hours after onset of focal signs. If a stroke did not match these criteria, it was classified as unspecified.
Ischemic strokes were further subdivided into clinical syndromes. A hemispheric lacunar ischemic stroke syndrome was diagnosed when a patient suffered from a pure motor stroke, pure sensory stroke, ataxic hemiparesis, or dysarthria and a clumsy hand or arm in the absence of cortical symptoms or signs (dysphasia, hemineglect, apraxia, acalculia, dysgraphia, or visual field defects). A hemispheric cortical ischemic stroke syndrome was diagnosed when any cortical symptom or sign was present. Posterior fossa ischemic stroke syndromes were diagnosed when cerebellar or brainstem signs were the only clinical manifestation.
An alternative subdivision of hemispheric ischemic strokes was based on neuroimaging: Lacunar infarctions were subcortical infarctions <15 mm in diameter, and cortical infarctions were all infarctions in which the cerebral cortex was involved.
Measurement of CRP
At baseline, venipuncture was performed by applying minimal stasis with a 21-gauge Butterfly needle with tube (Surflo winged infusion set, Terumo, Tokyo, Japan). Nonfasting blood was collected, and all tubes were stored on ice before and after blood sampling. High-sensitivity CRP was determined in serum, which was stored at –20°C until CRP was measured in 2003 to 2004. CRP was measured with the Rate Near Infrared Particle Immunoassay (Immage Immunochemistry System, Beckman Coulter, Fullerton, Calif). This system measures concentrations from 0.2 to 1440 mg/L, with a within-run precision <5.0%, a total precision <7.5% and a reliability coefficient of 0.995.
Possible Confounders
Blood pressure was measured twice in subjects in the sitting position on the right arm with a random-zero sphygmomanometer. We used the average of these 2 measurements. Intima-media thickness was measured by longitudinal 2-dimensional ultrasound of the carotid artery. We calculated the mean common carotid artery intima-media thickness as the mean of 4 locations: the near and far walls of both the right and left common carotid arteries. Atrial fibrillation was considered present when ECG confirmed it during the visit to the center or when it was reported in medical records. We considered diabetes mellitus present if a random or postload glucose level was 11.1 mmol/L or if a person used antidiabetic medication. Cardiovascular history was diagnosed if a participant had a myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty that was confirmed by ECG or medical records. Left ventricular hypertrophy was assessed with a 12-lead resting ECG and the Modular ECG Analysis System (MEANS)23 implemented on an ACTA electrocardiograph (ESAOTE, Florence, Italy). Smoking status was assessed during the home interview and classified as current, former, or never.
Statistical Analysis
To examine the association between CRP and various stroke subtypes, we used the Cox proportional hazards models. No violations to the proportional hazards assumption were detected by inspection of log(-log) survival curves. We used only first-ever strokes. Lost subjects were censored at the date last known to be alive. We calculated hazard ratios with 95% confidence intervals (CIs), which were expressed per 1-SD increase in logarithmically transformed CRP level and in CRP quartiles (relative to the lowest quartile). Because extremely high CRP levels likely reflect an acute inflammation at the time of blood sampling, individuals in whom the logarithm of the CRP level was >3 SD above the mean were excluded from the study sample.
We corrected all hazard ratios for age and sex (model 1) and additionally for the variables of the Framingham Risk Score (age, systolic blood pressure, antihypertensive therapy, systolic blood pressure by antihypertensive therapy, diabetes mellitus, smoking, coronary heart disease, atrial fibrillation, left ventricular hypertrophy)18 (model 2) and for these Framingham risk factors plus intima-media thickness (model 3). Missing values in covariates were imputed through the use of a linear regression model based on age and sex. To examine interactions with sex or intima-media thickness,14 we stratified analyses according to sex and according to strata of carotid intima-media thickness. Also, we tested for interaction of the association between CRP and the risk of stroke by sex and by stroke risk factors by entering an interaction term into the models.
The area under the curve (AUC) of a receiver operating characteristic curve reflects the sensitivity and specificity and hence the overall accuracy of a model. To examine the accuracy of CRP in predicting stroke risk, we assessed whether adding CRP to a logistic prediction model increased the AUC.24 This was done for a model that used age and sex and for a model that used the variables of the Framingham Risk Score.18 Finally, to assess whether the predictive utility of CRP varied with background risk, we compared a prediction model that used age, sex, and CRP with a model that used age and sex alone in various strata of the Framingham Risk Score.13,25,26 To examine whether CRP improved identification of high-risk subjects, we studied whether the aforementioned prediction models better allocated actual stroke patients to a highest quartile, octile, or decile of predicted risk when CRP was included than when CRP was not included.
The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.
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Results |
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The total follow-up time until study end, death, or first-ever stroke was 52 781 person-years (on average, 8.2 years). During follow-up, 498 first-ever strokes occurred, of which 278 (56%) were subclassified as ischemic strokes, 51 (10%) as hemorrhagic strokes, and 169 (34%) as unspecified. Median CRP level was 1.86 mg/L; the interquartile range was 0.90 to 3.59 mg/L.
Table 1 describes baseline characteristics. The age- and sex-adjusted survival plot (Figure 1) shows that stroke-free survival decreased with increasing levels of CRP. The age- and sex-adjusted hazard ratio for the association between CRP and stroke calculated with a Cox proportional hazards model was 1.14 (95% CI, 1.04 to 1.24) per 1-SD increase in logarithmically transformed CRP; persons with CRP levels in the highest quartile had a 36% increased stroke risk (hazard ratio, 1.36; 95% CI, 1.05 to 1.76) compared with those with CRP levels in the lowest quartile (Table 2). The hazard ratios for ischemic and hemorrhagic strokes were similar, although the latter association was not statistically significant, probably because of limited power. Adding stroke risk factors into the models attenuated these associations, whereas adding intima-media thickness attenuated them slightly further (Table 2).
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Although associations seemed stronger in men than in women, the interaction was not significant (Pinteraction=0.07 for stroke, 0.57 for ischemic strokes, and 0.14 for hemorrhagic strokes; Table 3). Analyses in strata of intima-media thickness showed stronger associations between CRP and stroke in persons with intima-media thickness in the middle and the upper tertiles compared with the lower tertile of the population distribution, yet the continuous interaction term was not significant (Pinteraction=0.48). Age- and sex-adjusted hazard ratios for stroke were 0.86 (95% CI, 0.65 to 1.13) in the lower tertile, 1.14 (95% CI, 0.95 to 1.38) in the middle tertile, and 1.26 (95% CI, 1.07 to 1.46) in the upper tertile. For ischemic stroke, the numbers were very similar (corresponding age- and sex-adjusted hazard ratios: 0.90 [95% CI, 0.63 to 1.28], 1.15 [95% CI, 0.91 to 1.50], and 1.28 [95% CI, 1.05 to 1.56]; Pinteraction=0.34).
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We studied 3 clinical subtypes of ischemic stroke: hemispheric lacunar syndromes (n=70), hemispheric cortical syndromes (n=140), and posterior fossa syndromes (n=38). The age- and sex-adjusted hazard ratios per 1-SD increase in logarithmically transformed CRP were 1.20 (95% CI, 0.95 to 1.53) for hemispheric lacunar syndromes, 1.12 (95% CI, 0.95 to 1.33) for hemispheric cortical syndromes, and 1.36 (95% CI, 0.99 to 1.86) for posterior fossa syndromes. We also studied 2 radiological subtypes of hemispheric ischemic stroke: lacunar infarctions (n=37) and cortical infarctions (n=57). The age- and sex-adjusted hazard ratios were 1.35 (95% CI, 0.98 to 1.87) for lacunar infarctions and 1.27 (95% CI, 0.97 to 1.65) for cortical infarctions.
When we used only age and sex to predict 5-year stroke risk, the AUC was 0.700 (95% CI, 0.670 to 0.731; Figure 2). When CRP was added to this model, the AUC increased only marginally to 0.704 (95% CI, 0.674 to 0.734), which was not significantly different (P=0.18). In addition, for 2.5- and 7.5-year stroke risk, the AUC for the model with CRP was not significantly larger than for the model without CRP. Likewise, the addition of CRP to a model based on the Framingham stroke risk factors resulted in a nonsignificant increase in AUC for 5-year risk prediction from 0.741 (95% CI, 0.711 to 0.772) to 0.742 (95% CI, 0.712 to 0.772; Figure 2). Results were similar for women (Table 4) and men (Table 5). When we compared the age, sex, and CRP model with the age and sex model in various strata of the Framingham Risk Score, we found no statistically significant difference between the models (Table 6). The prediction models with CRP did not allocate substantially more actual stroke patients to the highest risk quartile, octile, or decile than the models without CRP. In women, the largest observed increase was only 2% (Table 4). In men, CRP increased the number of actual strokes within 2.5 years in the octile of highest estimated risk from 30% to 36%. However, with the Framingham Risk Score, this percentage was 40%, which was decreased again to 36% when CRP was added to the prediction model. Similar effects were seen in the quartile and decile of highest estimated risk (Table 5).
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Discussion |
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In this population-based follow-up study of 6430 subjects
55 years of age who were free of stroke at baseline, CRP serum levels were significantly associated with incident stroke and incident ischemic stroke. Adjustment for other cardiovascular risk factors attenuated these associations, however. Although CRP was a risk factor for stroke, it did not discriminate well between individuals at high and low stroke risk; it did not make stroke prediction more accurate when added to a model containing only age and sex or when added to a model based on the stroke risk predictors of the Framingham Risk Score. Before these results can be interpreted, some methodological issues need to be discussed. First, 1247 participants were excluded from the cohort at risk because they did not visit the research center owing to death, refusal, or physical inability or because we did not have baseline blood for them. Participants in this subgroup were more likely to be female (69%) and of older age (median age, 75.7 years) than the study population. However, this selection could have biased our results only if the associations between CRP levels and risk of subsequent stroke were different in those individuals compared with the remainder of the cohort included in the analyses, which we consider highly unlikely. More important for selection bias in a prospective study is the completeness of follow-up. Because we had follow-up for 97.1% of all potential person-years, we feel confident that selection bias did not play a major, if any, role in our study. Second, blood samples had been stored for almost 10 years at –20°C before the assays were carried out. We assessed the comparability of these CRP assays with assays in blood from the same participants that had been stored at –80°C (n=29). Although the median CRP was lower in –20°C blood, Spearman correlation coefficient for the association between CRP in –20°C blood and CRP in –80°C blood was highly significant (correlation coefficient, 0.99; P<0.001); therefore, the associations were unaffected. Third, CRP measurements were performed only once per participant. It has been recommended that these measurements be performed twice,6 but because CRP levels have been shown to be very constant over many years1 and given the size of our cohort, we do not think that lack of repetition can explain our results. Fourth, 35 participants were excluded because of extremely high CRP levels. Results did not change materially when these subjects were included in the analyses. Fifth, our stringent stroke monitoring procedures allowed us to include stroke patients who were not referred to a hospital. A restraint is that in these cases neuroimaging often was lacking (61% of our cases had neuroimaging) and examinations were not thorough enough to subclassify 36% of strokes. Finally, general strengths of our study are the large eligible population (n=6430), the intense stroke case finding, and the nearly complete follow-up (loss of potential person-years, 2.9%).22
Our finding that increased CRP serum levels are associated with stroke risk is in accordance with other population-based follow-up studies14–16 and with studies that reported significant associations between CRP and fatal stroke,27 CRP and stroke and transient ischemic attack,28 and CRP and stroke univariately.17 In previous studies, adjustment for other cardiovascular risk factors generally attenuated the association between CRP and stroke, although often the association remained significant.14,15 In our study, CRP was not an independent risk factor after adjustment for other vascular risk factors and risk markers.
This is the first study to report on subtypes of ischemic stroke. CRP appeared to be a risk factor for both large-artery hemispheric strokes and small-vessel lacunar strokes.
The mechanisms that may underlie the association between CRP and cardiovascular disease are not yet fully elucidated. Increased levels of CRP reflect inflammation—in this context, probably the inflammatory condition of the vascular wall. This is now generally accepted as the main mechanism underlying the relationship between CRP and cardiovascular disease. However, there are also indications that CRP is directly involved in the occurrence of cardiovascular events.29 Recent studies show that lower CRP levels on statin therapy go indeed hand in hand with a reduced risk of recurrent myocardial infarction and coronary artery disease, supporting a causal role of inflammation in cardiovascular disease.30,31
Although our results confirm a possible causal relationship between CRP and stroke, the receiver operating characteristic curve analyses imply that CRP measurement does not contribute to individual stroke risk estimation, similar to what has been found for coronary disease.3,12 In addition, in the subset of persons in the quartile, octile, or decile with the highest estimated risk, CRP assessment did not prove helpful. Our study underscores the importance of distinguishing between risk factors and risk predictors of disease. Association of a risk factor with the occurrence of disease may suggest important causal mechanisms, but that does not necessarily imply clinical utility of assessment of that same factor for risk prediction.10
It has been suggested recently that CRP might be less useful in the assessment of coronary disease risk than initially thought.3,12 Our study suggests that CRP measurement does not contribute much to the assessment of stroke risk either.
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Acknowledgments |
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Sources of Funding
The Rotterdam Study is supported by Erasmus Medical Center Rotterdam; the Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; and the Ministry of Health, Welfare and Sports. This study was supported by the Netherlands Organization for Scientific Research (NWO) grants 904-61-093 and 918-46-615.
Disclosures
None.
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  C. B. Wright, Y. Moon, M. C. Paik, T. R. Brown, L. Rabbani, M. Yoshita, C. DeCarli, R. Sacco, and M. S.V. Elkind Inflammatory Biomarkers of Vascular Risk as Correlates of Leukoariosis Stroke, November 1, 2009; 40(11): 3466 - 3471. [Abstract] [Full Text] [PDF]
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 K. Fatema, K. R. Bailey, G. W. Petty, I. Meissner, M. Osranek, A. A. Alsaileek, B. K. Khandheria, T. S. Tsang, and J. B. Seward Increased Left Atrial Volume Index: Potent Biomarker for First-Ever Ischemic Stroke Mayo Clin. Proc., October 1, 2008; 83(10): 1107 - 1114. [Abstract] [Full Text] [PDF]
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P. Welsh, G. D.O. Lowe, J. Chalmers, D. J. Campbell, A. Rumley, B. C. Neal, S. W. MacMahon, and M. Woodward Associations of Proinflammatory Cytokines With the Risk of Recurrent Stroke Stroke, August 1, 2008; 39(8): 2226 - 2230. [Abstract] [Full Text] [PDF]
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 M. D. M. Haag, M. J. Bos, A. Hofman, P. J. Koudstaal, M. M. B. Breteler, and B. H. C. Stricker Cyclooxygenase Selectivity of Nonsteroidal Anti-inflammatory Drugs and Risk of Stroke Arch Intern Med, June 9, 2008; 168(11): 1219 - 1224. [Abstract] [Full Text] [PDF]
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M. J. Bos, S. C.E. Schuit, P. J. Koudstaal, A. Hofman, A. G. Uitterlinden, and M. M.B. Breteler Variation in the Estrogen Receptor {alpha} Gene and Risk of Stroke: The Rotterdam Study Stroke, April 1, 2008; 39(4): 1324 - 1326. [Abstract] [Full Text] [PDF]
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 M. J. Bos, M. J. E. van Rijn, J. C. M. Witteman, A. Hofman, P. J. Koudstaal, and M. M. B. Breteler Incidence and Prognosis of Transient Neurological Attacks JAMA, December 26, 2007; 298(24): 2877 - 2885. [Abstract] [Full Text] [PDF]
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M. J. Bos, P. J. Koudstaal, A. Hofman, and M. M.B. Breteler Decreased Glomerular Filtration Rate Is a Risk Factor for Hemorrhagic But Not for Ischemic Stroke: The Rotterdam Study Stroke, December 1, 2007; 38(12): 3127 - 3132. [Abstract] [Full Text] [PDF]
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 J. J. Cao, A. M. Arnold, T. A. Manolio, J. F. Polak, B. M. Psaty, C. H. Hirsch, L. H. Kuller, and M. Cushman Association of Carotid Artery Intima-Media Thickness, Plaques, and C-Reactive Protein With Future Cardiovascular Disease and All-Cause Mortality: The Cardiovascular Health Study Circulation, July 3, 2007; 116(1): 32 - 38. [Abstract] [Full Text] [PDF]
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M. W. Lorenz, P. Karbstein, H. S. Markus, and M. Sitzer High-Sensitivity C-Reactive Protein Is Not Associated With Carotid Intima-Media Progression: The Carotid Atherosclerosis Progression Study Stroke, June 1, 2007; 38(6): 1774 - 1779. [Abstract] [Full Text] [PDF]
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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]
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S. Blankenberg and S. Yusuf Response to Letter Regarding Article, "The Inflammatory Hypothesis: Any Progress in Risk Stratification and Therapeutic Targets?" Circulation, May 22, 2007; 115(20): e476 - e476. [Full Text] [PDF]
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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]
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S. Blankenberg and S. Yusuf The Inflammatory Hypothesis: Any Progress in Risk Stratification and Therapeutic Targets? Circulation, October 10, 2006; 114(15): 1557 - 1560. [Full Text] [PDF]
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