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C-reactive protein in ischemic stroke and its etiologic subtypes
C-Reactive Protein in Ischemic Stroke and its Etiologic Subtypes John W. Eikelboom, MBBS,*,‡ Graeme J. Hankey, MBBS,†,‡ Ross I. Baker, Andrew McQuillan, MBBS,* Jim Thom, BSc,* Janelle Staton, PhD,* Vanessa Cole, BSc,* and Qilong Yi, PhD§
MBBS,*,‡
The possible role of C-reactive protein (CRP) in the etiology and prognosis of ischemic stroke remains to be clearly defined. The purpose of this study was to determine whether CRP levels are elevated in patients with stroke, whether they remain persistently elevated, and whether CRP levels are higher in patients with etiologic subtypes of stroke caused by large or small artery disease (“atherogenic hypothesis”) or whether they may be higher in patients with more extensive cerebral infarction caused by large artery or cardiogenic embolism (“inflammatory hypothesis”). We conducted a case-control study of 199 hospital cases with a first-ever ischemic stroke and 202 randomly selected community controls. Cases of stroke were classified by etiologic subtype and the prevalence of conventional vascular risk factors and CRP levels were determined in cases and controls. Blood levels of CRP measured within 7 days of acute stroke were significantly higher in cases compared with controls (8.50 vs. 2.18 mg/L, P ⬍ .0001) and remained elevated in stroke survivors at 3 to 6 months of follow-up (3.35 vs. 2.18 mg/L, P ⫽ .003) although levels were significantly lower compared with the first 7 days (3.35 vs. 8.50 mg/L, P ⬍ .001-.003). Compared with the lowest quartile of CRP, the upper 3 quartiles were associated with an adjusted odds ratio (OR) of ischemic stroke of 1.9 (95% CI: 1.0-3.8) for the second quartile, 5.8 (95% CI: 2.9-11.4) for the third quartile, and 16.9 (95% CI: 7.9-36.1) for the fourth quartile (P for trend ⬍ .0001). Comparing the upper with the lower quartile, the strongest association was with etiologic stroke subtypes caused by large artery disease (OR 52.5; 95% CI: 13.4-205) and embolism from the heart (OR 56.1; 95% CI: 11.3-278), with a much weaker association with small artery disease (OR 2.4; 95% CI: 0.8-6.0). The mean Oxford Handicap Scale score was lowest in small artery, intermediate in large artery and highest in cardioembolic stroke (2.8 vs. 3.1 vs. 3.6, respectively; P ⫽ .001) while the mean Barthel Index was highest in small artery, intermediate in large artery, and lowest in cardioembolic stroke (13.5 vs. 11.5 vs. 8.6, respectively; P ⫽ .002). Furthermore, there was a significant correlation between CRP levels during the first 7 days and stroke severity, as measured by the Oxford Handicap Scale score (P ⫽ .03) and Barthel index (P ⫽ .001). We conclude that there is a strong, independent relationship between elevated blood levels of CRP and ischemic stroke, particularly because of more severe strokes caused by large artery disease and embolism from the heart, which remains evident over the long term. These results are consistent
From the *Thrombosis and Hemophilia Unit and the †Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia, the ‡Department of Medicine, University of Western Australia, and the §Department of Biostatistics, Princess Margaret Hospital, Toronto, Canada. Supported by grants from the Royal Perth Hospital Medical Research Foundation and the National Heart Foundation of Australia.
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Received November 4, 2002; accepted January 14, 2003. Address reprint requests to John W. Eikelboom, Department of Hematology, Royal Perth Hospital, Box X2213 GPO, Perth WA 6897, Australia. E-mail: [email protected]. Copyright © 2003 by National Stroke Association 1052-3057/03/1202-0001$30.00/0 doi:10.1053/jscd.2003.16
Journal of Stroke and Cerebrovascular Diseases, Vol. 12, No. 2 (March-April), 2003: pp 74-81
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with the inflammatory marker hypothesis of CRP as a marker of the extent of ischemic cerebral injury and its complications. Key Words: Cerebral infarction— C-reactive protein—ischemic stroke—pathophysiology—stroke—subtypes. Copyright © 2003 by National Stroke Association
Elevated blood levels of C-reactive protein (CRP) are associated with an increased risk of atherosclerotic vascular disease,1 including stroke.2 However, the role of CRP in the etiology and prognosis of ischemic stroke remains to be clearly defined.3-5 One hypothesis is that CRP plays a direct causal role in the pathogenesis of atherosclerosis by promoting endothelial cell adhesion molecule expression,6 monocyte recruitment,7 or complement activation,8 or by mediating low-density lipoprotein cholesterol uptake by macrophages.9 This “atherogenic hypothesis” is consistent with prospective observational studies of apparently healthy individuals as well as patients with established vascular disease,10 including stroke,11-15 which have shown that elevated blood concentrations of CRP are a significant predictor of future cardiovascular events, independent of conventional vascular risk factors. Another hypothesis is that CRP is a sensitive blood marker of inflammation (response to injury)16 and that the elevated blood concentrations of CRP, which have been reported during the first few days after the ischemic stroke event, primarily reflect the extent of cerebral ischemic injury and its complications.11,17 This “inflammatory marker hypothesis” would also explain why elevated CRP is associated with a poor outcome after stroke.11 We sought to further explore these hypotheses by conducting a case-control study of consecutive hospitalized patients with first-ever ischemic stroke and randomly selected community controls. Our specific objectives were to determine: (1) whether blood concentrations of CRP are elevated during the first 7 days after acute ischemic stroke; (2) whether any such association between CRP and ischemic stroke is still evident during long-term follow-up; (3) whether blood concentrations of CRP are higher in patients with stroke caused by large or small artery atherosclerosis than in patients with cardioembolic and other types of stroke, thus supporting the atherogenic hypothesis, or whether they are higher in stroke caused by large artery or cardiogenic embolism (which tend to cause larger infarcts18 and worse outcomes19) than small artery atherosclerosis (which causes small infarcts), thus supporting the inflammatory marker hypothesis; and (4) whether blood concentrations of CRP are higher in patients with more severe stroke caused by large artery disease and cardiogenic embolism, as measured by the Oxford Handicap Scale20 and Barthel index.21
Materials and Methods The Institutional Review Board of Royal Perth Hospital approved this study and each study participant provided informed consent.
Cases Consecutive patients presenting to Royal Perth Hospital between March 1996 and June 1998 with first-ever ischemic stroke were approached for consent to participate in our study. Stroke was defined as a clinical syndrome characterized by rapidly developing clinical symptoms and/or signs of focal, and at times global, loss of brain function, with symptoms lasting more than 24 hours or leading to earlier death, and with no apparent cause other than that of vascular origin.22 Ischemic stroke was defined as a stroke with either a normal computed tomography (CT) brain scan or evidence of a recent infarct in the clinically relevant area of the brain on a CT or magnetic resonance imaging (MRI) brain scan performed within 3 weeks of the event, or at autopsy. Patients with cerebral hemorrhage or cerebral venous thrombosis were not included. Baseline demographic data (age, sex), history of conventional vascular risk factors (hypertension, diabetes, hypercholesterolemia, current smoker), and history of previous vascular events (myocardial infarction, angina, claudication, amputation) was obtained. Stroke severity was assessed using the Oxford score and Barthel index. All patients underwent a CT brain scan. Echocardiography and extra-cranial duplex ultrasound were performed at the discretion of the clinician. Within 7 days of the acute stroke event, an overnight fasting blood sample was obtained for CRP measurement. Survivors were requested to return for review at 3 to 6 months after the acute event at which time a second blood sample was taken to measure CRP levels in the convalescent state. On the basis of clinical evaluation and results of imaging studies, the study neurologist (who remained blinded to the results of laboratory assays) classified all strokes into 4 major etiological subtypes according to the following pre-defined criteria23: (1) large artery disease: ischemic stroke with (a) evidence of extracranial or intracranial occlusive large artery disease (eg, doppler, angiographic), and (b) no major cardioembolic source (atrial fibrillation, recent myocardial infarction [in the last 6 weeks], endocarditis, prosthetic heart valve), and (c) clinical opinion that the most likely cause of brain infarc-
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tion was atherothrombosis involving the aortic arch, carotid arteries or major branches (main stem middle cerebral artery), or vertebral, basilar and posterior cerebral arteries; (2) small artery disease: ischemic stroke with (a) consciousness and higher cerebral function maintained; plus (b) one of the classical lacunar syndromes (ie, pure motor hemiparesis, pure hemisensory loss, pure hemisensori-motor loss, ataxic hemiparesis) or non-lacunar small artery clinical syndromes (eg, basilar branch artery syndromes); and (c) CT or MRI brain scan, performed within 3 weeks of symptom onset, that is either normal or shows a small deep infarct in the basal ganglia, internal capsule, or brainstem; (3) cardioembolic disease: ischemic stroke with (a) a major cardioembolic source; plus (b) no definite evidence of occlusive large artery disease, and (c) clinical opinion that the most likely cause of brain infarction was embolism from the heart; (4) other: ischemic stroke which did not meet the criteria for one of the categories outlined above (eg, peri-procedural, hypoperfusion, dissection, procoagulant state), or where there was more than one likely explanation (eg, concurrent large artery occlusive disease and major cardioembolic source). Stroke severity was classified according to the Oxford Handicap Scale20 and Barthel index,21 also blinded to the results of CRP concentrations.
Controls Control subjects were randomly selected from the Western Australian electoral roll, stratified by 5-year age group, sex, and postal code. A letter of invitation to participate, together with a stamped and self-addressed envelope, was sent to potential controls. Non-responders were contacted by telephone. Controls who agreed to participate in the study were required to fast for a minimum of 8 hours before their appointment, and were given the option of attending the hospital outpatient clinic or being visited at home by the study nurse. Baseline demographic data (age, sex), history of conventional vascular risk factors, and history of previous vascular events were obtained for each control. A fasting blood sample was obtained for CRP measurement.
Laboratory Analysis All samples were collected and processed using a standardized protocol. CRP levels were measured using a high-sensitivity assay (Dade Behring Diagnostics; Marburg, Germany) by laboratory personnel who were blinded to case or control status of the study participants.
and controls was tested using the Student t test for means and a 2 test for proportions. Because CRP levels were skewed, geometric means were calculated after log transformation of the raw data and the significance of any difference in geometric mean between cases and controls was tested using the Student t test. In cases of stroke, CRP concentrations measured during the first 7 days after the acute event and at 3 to 6 months of follow-up were compared using a paired Student t test. Follow-up levels also were compared with controls using an unpaired Student t test. The significance of any relationship between blood levels of CRP and the timing of blood sampling during long-term follow-up was examined by Pearson correlation co-efficient. Logistic regression was used to examine the association between CRP levels during the first 7 days after the acute event (independent variable) and ischemic stroke (dependent variable) after dividing the samples into quartiles defined by the distribution of the complete cohort. Adjusted estimates were obtained using a separate model that controlled for age, sex, individual vascular risk factors, and history of previous vascular events. Results are expressed as odds ratios (OR) together with their 95% confidence intervals (CI). Analysis of variance (ANOVA) was used to compare mean CRP levels among etiological subtypes of stroke and controls. If overall significance was confirmed, pairwise comparisons were performed using Tukey’s adjustment for multiple comparisons. Separate logistic regression models were used to examine the association between CRP and etiologic subtypes of ischemic stroke after adjusting for age, sex, conventional vascular risk factors, and history of previous vascular events. The association between CRP and stroke severity was examined using a Spearman rank approach. The difference in mean Oxford Handicap Scale scores and mean Barthel index scores among different etiologic subtypes of stroke were compared using a Kruskal-Wallis test. Statistical significance for all analyses was taken as a 2-sided P value of less than 0.05.
Results One hundred and ninety nine consecutive patients with ischemic stroke (128 males and 71 females; mean age 66.2 years [SD 12.4]), and 202 controls (129 males, 73 females, mean age 66.9 years [SD 11.8]) were included in our study.
Demographics and Baseline Vascular Risk Factors Statistical Methods Means or proportions for baseline demographics and vascular risk factors were calculated for cases and controls. The significance of any difference between cases
The age and gender distribution of cases and controls was similar. There was a significantly higher prevalence of conventional vascular risk factors, including hypertension, diabetes, current smoking, and previous history of
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Table 1. Baseline demographics, conventional vascular risk factors, and history of previous vascular events in stroke cases and controls
Age (y), mean ⫾ SD Male, N (%) Hypertension Diabetes Hypercholesterolemia Current smoker Previous vascular event
Cases (n ⫽ 199)
Controls (n ⫽ 202)
OR
95% CI
P
66.2 ⫾ 12.4 128 (64.3) 108 (54.3) 53 (26.6) 47 (23.6) 69 (34.7) 55 (27.6)
66.9 ⫾ 11.8 129 (63.9) 67 (33.2) 22 (10.9) 44 (21.8) 35 (17.5) 26 (12.9)
1.0 2.4 3.0 1.1 2.5 2.6
0.6-1.5 1.6-3.6 1.7-5.1 0.7-1.8 1.6-4.0 1.5-4.3
.58 .92 ⬍.0001 ⬍.0001 .66 .0001 .0002
*2 test for categorical data, unpaired Student t test for continuous data.
arterial vascular events, among cases compared with controls (Table 1).
CRP Levels Blood levels of CRP taken during the first 7 days after the acute stroke event were significantly higher in cases compared with controls (Table 2; 8.50 vs. 2.18 mg/L, P ⬍ .0001). In the 92 survivors who returned for follow-up between 3 and 6 months, CRP levels had fallen significantly compared with baseline values (3.35 vs. 8.50 mg/L, P ⬍ .0001) but remained elevated compared with controls (P ⫽ .003). There was no correlation between CRP levels and the timing of the follow-up blood sample (50-99 days, 100-149 days, 150-199 days, or 200⫹ days) after the acute stroke event (P ⫽ .50).
Association Between CRP and Stroke There was a strong, graded, and independent association between blood levels of CRP during the first 7 days after the acute event and ischemic stroke. Compared with the lower quartile, the upper quartile of blood levels of CRP during the first 7 days was associated with an unadjusted OR of ischemic stroke of 17.3
(95% CI: 8.6-34.7) and, after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events, of 16.9 (95% CI: 7.9-36.1; Table 3, Figure 1). A graded and independent association remained evident during long-term follow up, although the association was less strong. Compared with the lower quartile, the upper quartile of CRP at 3 to 6 months was associated with a unadjusted OR of ischemic stroke of 2.4 (95% CI: 1.2-4.9) and, after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events, of 2.0 (95% CI: 0.9-4.4, Table 3, Figure 1).
CRP Levels in Etiological Subtypes of Ischemic Stroke and Controls Blood levels of CRP during the first 7 days were significantly higher in each etiologic subtype of ischemic stroke compared with controls (Table 4). The highest levels occurred in stroke caused by large artery disease (10.80 mg/L, 95% CI: 7.70-15.19 mg/L), embolism from the heart (mean 14.59 mg/L, 95% CI: 9.8821.35 mg/L), and other causes (12.18 mg/L, 95% CI: 7.06-21.20 mg/L), while levels in patients with stroke caused by small artery disease were significantly lower
Table 2. CRP during the first 7 days after the acute stroke event and at follow-up (3-6 months) in stroke cases and controls* Cases
CRP
First 7 days (n ⫽ 199)
Follow-up (n ⫽ 92)
Controls (n ⫽ 202)
Mean, mg/L (95% CI)
8.50 (7.04-10.35)
3.35 (2.66-4.19)
2.18 (1.87-2.55)
P† First 7 days vs. control; P ⬍ .0001† First 7 days vs. follow-up: P ⬍ .0001‡ Follow-up vs. control; P ⫽ .003†
*CRP levels are log-transformed and presented as geometric means. †Unpaired Student t test. ‡Paired Student t test; the mean baseline CRP level for the 92 patients who returned for follow-up at 3-6 months was 7.8 mg/L (95% CI: 5.7-10.6).
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Table 3. Association between quartiles of CRP measured at baseline, ischemic stroke, and etiologic subtypes of ischemic stroke
All stroke (n ⫽ 199)
Large artery (n ⫽ 63)
Small artery (n ⫽ 66)
Cardio-embolic (n ⫽ 45)
Quartile 1 (⬍1.6 mg/L)
Quartile 2 (1.6-3.9 mg/L)
Quartile 3 (4.0-9.5 mg/L)
Quartile 4 (⬎9.5 mg/L)
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
2.3 (1.2-4.4) 1.9 (1.0-3.8) 2.5 (0.7-8.8) 2.5 (0.6-9.3) 1.4 (0.7-3.2) 1.1 (0.5-2.6) 3.8 (0.7-19.4) 3.5 (0.7-18.4)
6.5 (3.4-12.3) 5.8 (2.9-11.4) 11.2 (3.6-34.8) 12.4 (3.5-43.7) 3.8 (1.8-8.1) 3.3 (1.4-7.4) 9.6 (2.0-46.6) 7.5 (11.3-38.8)
17.3 (8.6-34.7) 16.9 (7.9-36.1) 30.9 (9.7-98.4) 52.5 (13.4-205) 3.4 (1.3-8.5) 2.4 (0.8-6.9) 59.7 (13.1-273) 56.1 (11.3-278)
P† ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 .0004 .007 ⬍.0001 ⬍.0001
Results are presented as odds ratios and 95% confidence intervals (P-value is for trend of association). Reliable estimates of odds of ‘other’ stroke could not be obtained because of the small number of cases in this group (n ⫽ 25). †Adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
Figure 1. Association between quartiles of CRP measured during the first 7 days after the acute event and ischemic stroke (P value is for trend of association). *Unadjusted OR (gray bars) and adjusted OR (black bars) for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
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Table 4. Plasma CRP during the first 7 days after the acute stroke event and at follow-up (3-6 months) in etiologic subtypes of ischemic stroke*
Large artery Small artery Cardio-embolic (n ⫽ 63) (n ⫽ 66) (n ⫽ 45)
Other (n ⫽ 25)
Control (n ⫽ 202)
C-reactive protein 10.80 during the first (7.70-15.19) 7 days, mg/L
3.97 (3.06-5.14)
14.59 (9.88-21.35)
12.18 2.18 (7.06-21.20) (1.86-2.55)
2.94 C-reactive protein (1.87-4.66) during longterm follow-up, mg/L‡
3.13 (2.27-4.27)
6.42 (3.98-10.41)
1.86 (0.89-3.86)
2.18 (1.86-2.55)
Overall Significant pair-wise significance comparisons† (P) (P ⬍ .05) ⬍0.0001
NS
LA, SA, CE or other vs. control LA, CE, or Other vs. SA —
*CRP levels are log-transformed and presented as geometric means; overall significance and pair-wise comparisons adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events. †Tukey’s adjustment for multiple comparisons. ‡Data are from 92 stroke survivors (27 large artery, 36 small artery, 18 cardioembolic, 11 other) who returned for follow-up. Abbreviations: C, control; CE, cardioembolic; LA, large artery; SA, small artery.
(3.97 mg/L, 95% CI: 3.06-5.14 mg/L; P ⬍ .05 for each comparison). However, at follow-up, the numbers of patients were much smaller and the difference between individual etiologic subtypes of stroke and controls was no longer statistically significant.
Association Between CRP and Etiologic Subtypes of Stroke There was a strong, graded, and independent association between blood levels of CRP during the first 7 days and etiologic subtypes of ischemic stroke (Table 3, Figure 2). Compared with the lowest quartile, the upper quartile of CRP at baseline was associated with a unadjusted OR of large artery stroke of 30.9 (95% CI: 9.7-98.4), cardioembolic stroke of 59.7 (95% CI: 13.1-273), and small artery stroke of 3.4 (95% CI: 1.3-8.5). The magnitude of the association with each of these etiologic subtypes was similar after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events (Table 3). Because of the small number of strokes caused by other causes (n ⫽ 35), stable estimates of the odds of stroke in the highest relative to the lowest quartile could not be obtained for this etiologic subgroup of stroke.
Association Between CRP and Stroke Severity The mean Oxford Handicap Scale score was lowest in small artery, intermediate in large artery. and highest in cardioembolic stroke (2.8 vs. 3.1 vs. 3.6, respectively; P ⫽ .001) while the mean Barthel index was highest in small artery, intermediate in large artery, and lowest in cardioembolic stroke (13.5 vs. 11.5 vs. 8.6, respectively; P ⫽ .002). Furthermore, there was a significant correlation between CRP levels during the first 7 days and stroke
severity, as measured by the Oxford Handicap Scale score (P ⫽ .03) and Barthel index (P ⫽ .001).
Discussion The results of our study indicate a strong, graded, and independent association between elevated blood levels of CRP during the first 7 days after ischemic stroke. CRP concentrations were significantly lower at points between 3 and 6 months in stroke survivors compared with levels during the first 7 days but remained significantly elevated. Furthermore, CRP levels were most markedly elevated in patients with stroke caused by large artery disease or embolism from the heart, which tend to cause larger infarcts and greater disability, and were significantly lower in patients with stroke caused by small artery disease, which causes small infarcts. Although differences in CRP levels between etiologic subtypes of stroke were no longer statistically significant at followup, this is most likely because of the small number of patients. These findings support the inflammatory marker hypothesis of CRP as a measure of the extent of cerebral injury or the complications thereof and do not provide support for the hypothesis that elevated CRP levels are primarily atherogenic. Previous studies have consistently demonstrated an association between CRP and stroke.2,11-15 Muir et al11 further reported that stroke patients with an elevated CRP were more likely to have cerebral infarction on a cranial CT scan than patients without an elevated CRP level, while Beamer et al17 found that blood levels of CRP were higher in patients with large established infarcts on CT and lowest in patients with lacunar stroke. These findings are consistent with the results of our study and
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Figure 2. Association between quartiles of CRP measured during the first 7 days after the acute event and etiologic subtypes of ischemic stroke (P value is for trend of association). Adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
further support the conclusion that elevated CRP in patients with stroke is primarily a marker of the extent of cerebral ischemic injury and the complications thereof (eg, aspiration pneumonia). Likewise, the results of epidemiologic studies demonstrating a non-specific association between elevated CRP and cardiovascular as well as non-cardiovascular mortality, including cancer,11,24 do not support a primary causal role for CRP in the pathogenesis of atherosclerotic vascular disease and stroke. However, we are unable to exclude the possibility that CRP also exerts a pro-atherogenic effect in patients at risk of future vascular events, including stroke. Our study has several potential limitations. First, although cases were classified prospectively and recruited consecutively, and controls were randomly selected from the community, the potential for confounding can never be eliminated in an observational study. In particular, we cannot exclude the effect of pre-existing subclinical cerebrovascular disease or vascular risk factors such as smoking or hypercholesterolemia, on the observed association between elevated blood levels of CRP and ischemic stroke. However, our findings of an independent association between elevated CRP and stroke are consistent with the results of the majority of retrospective and prospective studies that have examined this question.1,2,10
Second, the reliance on clinical criteria to classify etiologic subtypes of ischemic stroke may have led to their misclassification. However, the diagnosis of stroke, and etiological subtype of ischemic stroke was made by a single neurologist who specializes in stroke medicine, on the basis of pre-defined and established criteria. Meanwhile, the impact of any misclassification would tend to reduce differences among etiologic subtypes of ischemic stroke rather than account for differences. Third, etiologic subtype of ischemic stroke is an imprecise surrogate measure of cerebral infarct size. However, there is no reason to expect that it is a biased measure. Furthermore, an association between etiologic stroke subtype and both extent of cerebral infarction and outcome after stroke is has previously been documented18,19 and our data confirm that there is also an association between etiologic stroke subtype and stroke severity as measured by the Oxford score and Barthel index. Therefore, our use of etiologic stroke subtype are a valid albeit imprecise reflection of cerebral infarct size. Fourth, both lipid-lowering therapy and aspirin reduce blood levels of CRP,25,26 and it is possible that their widespread use in patients included in our study have contributed to lower levels of CRP levels at follow-up compared with during the first few days after stroke. However, CRP levels nevertheless remained significantly
C-REACTIVE PROTEIN AND ISCHEMIC STROKE
elevated at 3 to 6 months, which is consistent with previous reports of a persistent inflammatory response in stroke survivors.27 In conclusion, our study adds to the growing body of evidence demonstrating an independent relationship between elevated blood levels of CRP and arterial vascular disease and stroke. In addition, however, our study raises questions concerning the proposed causal role of CRP in atherosclerotic vascular disease and rather suggests that elevated blood levels of CRP in patients with stroke are primarily reflection of the extent of cerebral ischemic injury.
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81 11. Muir KW, Weir CJ, Alwan W, et al. C-reactive protein and outcome after ischaemic stroke. Stroke 1999;30:981985. 12. Gussekloo J, Schaap MC, Frolich M, et al. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol 2000;20:1047-1051. 13. Ford ES, Giles WH. Serum C-reactive protein and selfreported stroke. Findings from the Third National Health and Nutrition Examination Survey. Arterioscler Thromb Vasc Biol 2000;20:1052-1056. 14. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischaemic stroke. Stroke 2001;32:133-138. 15. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischaemic stroke: an independent prognostic factor. Stroke 2001;32:917-924. 16. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115-126. 17. Beamer NB, Coull BM, Clark WM, et al. Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 1995;37:800-805. 18. Murat Sumer M, Erturk O. Ischemic stroke subtypes: risk factors, functional outcome and recurrence. Neurol Sci 2002;22:449-454. 19. Petty GW, Brown RD, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of functional outcome, survival, and recurrence. Stroke 2000;31:10621068. 20. Bamford JM, Sandercock PAG, Warlow CP, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989;20:828. 21. Wade DT, Collin C. The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud 1988;10: 64-67. 22. Hatano S. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 1976;54: 541-553. 23. Warlow CP, Dennis MS, van Gijn J, et al. Stroke: A Practical Guide to Management. Blackwell Scientific Productions, Oxford, UK, 1996. 24. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999;106:506-512. 25. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979. 26. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentrations of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230-235. 27. Beamer NB, Coull BM, Clark WM, et al. Persistent inflammatory response in stroke survivors. Neurology 1998;50:1722-1728.
MBBS,*,‡
The possible role of C-reactive protein (CRP) in the etiology and prognosis of ischemic stroke remains to be clearly defined. The purpose of this study was to determine whether CRP levels are elevated in patients with stroke, whether they remain persistently elevated, and whether CRP levels are higher in patients with etiologic subtypes of stroke caused by large or small artery disease (“atherogenic hypothesis”) or whether they may be higher in patients with more extensive cerebral infarction caused by large artery or cardiogenic embolism (“inflammatory hypothesis”). We conducted a case-control study of 199 hospital cases with a first-ever ischemic stroke and 202 randomly selected community controls. Cases of stroke were classified by etiologic subtype and the prevalence of conventional vascular risk factors and CRP levels were determined in cases and controls. Blood levels of CRP measured within 7 days of acute stroke were significantly higher in cases compared with controls (8.50 vs. 2.18 mg/L, P ⬍ .0001) and remained elevated in stroke survivors at 3 to 6 months of follow-up (3.35 vs. 2.18 mg/L, P ⫽ .003) although levels were significantly lower compared with the first 7 days (3.35 vs. 8.50 mg/L, P ⬍ .001-.003). Compared with the lowest quartile of CRP, the upper 3 quartiles were associated with an adjusted odds ratio (OR) of ischemic stroke of 1.9 (95% CI: 1.0-3.8) for the second quartile, 5.8 (95% CI: 2.9-11.4) for the third quartile, and 16.9 (95% CI: 7.9-36.1) for the fourth quartile (P for trend ⬍ .0001). Comparing the upper with the lower quartile, the strongest association was with etiologic stroke subtypes caused by large artery disease (OR 52.5; 95% CI: 13.4-205) and embolism from the heart (OR 56.1; 95% CI: 11.3-278), with a much weaker association with small artery disease (OR 2.4; 95% CI: 0.8-6.0). The mean Oxford Handicap Scale score was lowest in small artery, intermediate in large artery and highest in cardioembolic stroke (2.8 vs. 3.1 vs. 3.6, respectively; P ⫽ .001) while the mean Barthel Index was highest in small artery, intermediate in large artery, and lowest in cardioembolic stroke (13.5 vs. 11.5 vs. 8.6, respectively; P ⫽ .002). Furthermore, there was a significant correlation between CRP levels during the first 7 days and stroke severity, as measured by the Oxford Handicap Scale score (P ⫽ .03) and Barthel index (P ⫽ .001). We conclude that there is a strong, independent relationship between elevated blood levels of CRP and ischemic stroke, particularly because of more severe strokes caused by large artery disease and embolism from the heart, which remains evident over the long term. These results are consistent
From the *Thrombosis and Hemophilia Unit and the †Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia, the ‡Department of Medicine, University of Western Australia, and the §Department of Biostatistics, Princess Margaret Hospital, Toronto, Canada. Supported by grants from the Royal Perth Hospital Medical Research Foundation and the National Heart Foundation of Australia.
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Received November 4, 2002; accepted January 14, 2003. Address reprint requests to John W. Eikelboom, Department of Hematology, Royal Perth Hospital, Box X2213 GPO, Perth WA 6897, Australia. E-mail: [email protected]. Copyright © 2003 by National Stroke Association 1052-3057/03/1202-0001$30.00/0 doi:10.1053/jscd.2003.16
Journal of Stroke and Cerebrovascular Diseases, Vol. 12, No. 2 (March-April), 2003: pp 74-81
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with the inflammatory marker hypothesis of CRP as a marker of the extent of ischemic cerebral injury and its complications. Key Words: Cerebral infarction— C-reactive protein—ischemic stroke—pathophysiology—stroke—subtypes. Copyright © 2003 by National Stroke Association
Elevated blood levels of C-reactive protein (CRP) are associated with an increased risk of atherosclerotic vascular disease,1 including stroke.2 However, the role of CRP in the etiology and prognosis of ischemic stroke remains to be clearly defined.3-5 One hypothesis is that CRP plays a direct causal role in the pathogenesis of atherosclerosis by promoting endothelial cell adhesion molecule expression,6 monocyte recruitment,7 or complement activation,8 or by mediating low-density lipoprotein cholesterol uptake by macrophages.9 This “atherogenic hypothesis” is consistent with prospective observational studies of apparently healthy individuals as well as patients with established vascular disease,10 including stroke,11-15 which have shown that elevated blood concentrations of CRP are a significant predictor of future cardiovascular events, independent of conventional vascular risk factors. Another hypothesis is that CRP is a sensitive blood marker of inflammation (response to injury)16 and that the elevated blood concentrations of CRP, which have been reported during the first few days after the ischemic stroke event, primarily reflect the extent of cerebral ischemic injury and its complications.11,17 This “inflammatory marker hypothesis” would also explain why elevated CRP is associated with a poor outcome after stroke.11 We sought to further explore these hypotheses by conducting a case-control study of consecutive hospitalized patients with first-ever ischemic stroke and randomly selected community controls. Our specific objectives were to determine: (1) whether blood concentrations of CRP are elevated during the first 7 days after acute ischemic stroke; (2) whether any such association between CRP and ischemic stroke is still evident during long-term follow-up; (3) whether blood concentrations of CRP are higher in patients with stroke caused by large or small artery atherosclerosis than in patients with cardioembolic and other types of stroke, thus supporting the atherogenic hypothesis, or whether they are higher in stroke caused by large artery or cardiogenic embolism (which tend to cause larger infarcts18 and worse outcomes19) than small artery atherosclerosis (which causes small infarcts), thus supporting the inflammatory marker hypothesis; and (4) whether blood concentrations of CRP are higher in patients with more severe stroke caused by large artery disease and cardiogenic embolism, as measured by the Oxford Handicap Scale20 and Barthel index.21
Materials and Methods The Institutional Review Board of Royal Perth Hospital approved this study and each study participant provided informed consent.
Cases Consecutive patients presenting to Royal Perth Hospital between March 1996 and June 1998 with first-ever ischemic stroke were approached for consent to participate in our study. Stroke was defined as a clinical syndrome characterized by rapidly developing clinical symptoms and/or signs of focal, and at times global, loss of brain function, with symptoms lasting more than 24 hours or leading to earlier death, and with no apparent cause other than that of vascular origin.22 Ischemic stroke was defined as a stroke with either a normal computed tomography (CT) brain scan or evidence of a recent infarct in the clinically relevant area of the brain on a CT or magnetic resonance imaging (MRI) brain scan performed within 3 weeks of the event, or at autopsy. Patients with cerebral hemorrhage or cerebral venous thrombosis were not included. Baseline demographic data (age, sex), history of conventional vascular risk factors (hypertension, diabetes, hypercholesterolemia, current smoker), and history of previous vascular events (myocardial infarction, angina, claudication, amputation) was obtained. Stroke severity was assessed using the Oxford score and Barthel index. All patients underwent a CT brain scan. Echocardiography and extra-cranial duplex ultrasound were performed at the discretion of the clinician. Within 7 days of the acute stroke event, an overnight fasting blood sample was obtained for CRP measurement. Survivors were requested to return for review at 3 to 6 months after the acute event at which time a second blood sample was taken to measure CRP levels in the convalescent state. On the basis of clinical evaluation and results of imaging studies, the study neurologist (who remained blinded to the results of laboratory assays) classified all strokes into 4 major etiological subtypes according to the following pre-defined criteria23: (1) large artery disease: ischemic stroke with (a) evidence of extracranial or intracranial occlusive large artery disease (eg, doppler, angiographic), and (b) no major cardioembolic source (atrial fibrillation, recent myocardial infarction [in the last 6 weeks], endocarditis, prosthetic heart valve), and (c) clinical opinion that the most likely cause of brain infarc-
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tion was atherothrombosis involving the aortic arch, carotid arteries or major branches (main stem middle cerebral artery), or vertebral, basilar and posterior cerebral arteries; (2) small artery disease: ischemic stroke with (a) consciousness and higher cerebral function maintained; plus (b) one of the classical lacunar syndromes (ie, pure motor hemiparesis, pure hemisensory loss, pure hemisensori-motor loss, ataxic hemiparesis) or non-lacunar small artery clinical syndromes (eg, basilar branch artery syndromes); and (c) CT or MRI brain scan, performed within 3 weeks of symptom onset, that is either normal or shows a small deep infarct in the basal ganglia, internal capsule, or brainstem; (3) cardioembolic disease: ischemic stroke with (a) a major cardioembolic source; plus (b) no definite evidence of occlusive large artery disease, and (c) clinical opinion that the most likely cause of brain infarction was embolism from the heart; (4) other: ischemic stroke which did not meet the criteria for one of the categories outlined above (eg, peri-procedural, hypoperfusion, dissection, procoagulant state), or where there was more than one likely explanation (eg, concurrent large artery occlusive disease and major cardioembolic source). Stroke severity was classified according to the Oxford Handicap Scale20 and Barthel index,21 also blinded to the results of CRP concentrations.
Controls Control subjects were randomly selected from the Western Australian electoral roll, stratified by 5-year age group, sex, and postal code. A letter of invitation to participate, together with a stamped and self-addressed envelope, was sent to potential controls. Non-responders were contacted by telephone. Controls who agreed to participate in the study were required to fast for a minimum of 8 hours before their appointment, and were given the option of attending the hospital outpatient clinic or being visited at home by the study nurse. Baseline demographic data (age, sex), history of conventional vascular risk factors, and history of previous vascular events were obtained for each control. A fasting blood sample was obtained for CRP measurement.
Laboratory Analysis All samples were collected and processed using a standardized protocol. CRP levels were measured using a high-sensitivity assay (Dade Behring Diagnostics; Marburg, Germany) by laboratory personnel who were blinded to case or control status of the study participants.
and controls was tested using the Student t test for means and a 2 test for proportions. Because CRP levels were skewed, geometric means were calculated after log transformation of the raw data and the significance of any difference in geometric mean between cases and controls was tested using the Student t test. In cases of stroke, CRP concentrations measured during the first 7 days after the acute event and at 3 to 6 months of follow-up were compared using a paired Student t test. Follow-up levels also were compared with controls using an unpaired Student t test. The significance of any relationship between blood levels of CRP and the timing of blood sampling during long-term follow-up was examined by Pearson correlation co-efficient. Logistic regression was used to examine the association between CRP levels during the first 7 days after the acute event (independent variable) and ischemic stroke (dependent variable) after dividing the samples into quartiles defined by the distribution of the complete cohort. Adjusted estimates were obtained using a separate model that controlled for age, sex, individual vascular risk factors, and history of previous vascular events. Results are expressed as odds ratios (OR) together with their 95% confidence intervals (CI). Analysis of variance (ANOVA) was used to compare mean CRP levels among etiological subtypes of stroke and controls. If overall significance was confirmed, pairwise comparisons were performed using Tukey’s adjustment for multiple comparisons. Separate logistic regression models were used to examine the association between CRP and etiologic subtypes of ischemic stroke after adjusting for age, sex, conventional vascular risk factors, and history of previous vascular events. The association between CRP and stroke severity was examined using a Spearman rank approach. The difference in mean Oxford Handicap Scale scores and mean Barthel index scores among different etiologic subtypes of stroke were compared using a Kruskal-Wallis test. Statistical significance for all analyses was taken as a 2-sided P value of less than 0.05.
Results One hundred and ninety nine consecutive patients with ischemic stroke (128 males and 71 females; mean age 66.2 years [SD 12.4]), and 202 controls (129 males, 73 females, mean age 66.9 years [SD 11.8]) were included in our study.
Demographics and Baseline Vascular Risk Factors Statistical Methods Means or proportions for baseline demographics and vascular risk factors were calculated for cases and controls. The significance of any difference between cases
The age and gender distribution of cases and controls was similar. There was a significantly higher prevalence of conventional vascular risk factors, including hypertension, diabetes, current smoking, and previous history of
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Table 1. Baseline demographics, conventional vascular risk factors, and history of previous vascular events in stroke cases and controls
Age (y), mean ⫾ SD Male, N (%) Hypertension Diabetes Hypercholesterolemia Current smoker Previous vascular event
Cases (n ⫽ 199)
Controls (n ⫽ 202)
OR
95% CI
P
66.2 ⫾ 12.4 128 (64.3) 108 (54.3) 53 (26.6) 47 (23.6) 69 (34.7) 55 (27.6)
66.9 ⫾ 11.8 129 (63.9) 67 (33.2) 22 (10.9) 44 (21.8) 35 (17.5) 26 (12.9)
1.0 2.4 3.0 1.1 2.5 2.6
0.6-1.5 1.6-3.6 1.7-5.1 0.7-1.8 1.6-4.0 1.5-4.3
.58 .92 ⬍.0001 ⬍.0001 .66 .0001 .0002
*2 test for categorical data, unpaired Student t test for continuous data.
arterial vascular events, among cases compared with controls (Table 1).
CRP Levels Blood levels of CRP taken during the first 7 days after the acute stroke event were significantly higher in cases compared with controls (Table 2; 8.50 vs. 2.18 mg/L, P ⬍ .0001). In the 92 survivors who returned for follow-up between 3 and 6 months, CRP levels had fallen significantly compared with baseline values (3.35 vs. 8.50 mg/L, P ⬍ .0001) but remained elevated compared with controls (P ⫽ .003). There was no correlation between CRP levels and the timing of the follow-up blood sample (50-99 days, 100-149 days, 150-199 days, or 200⫹ days) after the acute stroke event (P ⫽ .50).
Association Between CRP and Stroke There was a strong, graded, and independent association between blood levels of CRP during the first 7 days after the acute event and ischemic stroke. Compared with the lower quartile, the upper quartile of blood levels of CRP during the first 7 days was associated with an unadjusted OR of ischemic stroke of 17.3
(95% CI: 8.6-34.7) and, after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events, of 16.9 (95% CI: 7.9-36.1; Table 3, Figure 1). A graded and independent association remained evident during long-term follow up, although the association was less strong. Compared with the lower quartile, the upper quartile of CRP at 3 to 6 months was associated with a unadjusted OR of ischemic stroke of 2.4 (95% CI: 1.2-4.9) and, after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events, of 2.0 (95% CI: 0.9-4.4, Table 3, Figure 1).
CRP Levels in Etiological Subtypes of Ischemic Stroke and Controls Blood levels of CRP during the first 7 days were significantly higher in each etiologic subtype of ischemic stroke compared with controls (Table 4). The highest levels occurred in stroke caused by large artery disease (10.80 mg/L, 95% CI: 7.70-15.19 mg/L), embolism from the heart (mean 14.59 mg/L, 95% CI: 9.8821.35 mg/L), and other causes (12.18 mg/L, 95% CI: 7.06-21.20 mg/L), while levels in patients with stroke caused by small artery disease were significantly lower
Table 2. CRP during the first 7 days after the acute stroke event and at follow-up (3-6 months) in stroke cases and controls* Cases
CRP
First 7 days (n ⫽ 199)
Follow-up (n ⫽ 92)
Controls (n ⫽ 202)
Mean, mg/L (95% CI)
8.50 (7.04-10.35)
3.35 (2.66-4.19)
2.18 (1.87-2.55)
P† First 7 days vs. control; P ⬍ .0001† First 7 days vs. follow-up: P ⬍ .0001‡ Follow-up vs. control; P ⫽ .003†
*CRP levels are log-transformed and presented as geometric means. †Unpaired Student t test. ‡Paired Student t test; the mean baseline CRP level for the 92 patients who returned for follow-up at 3-6 months was 7.8 mg/L (95% CI: 5.7-10.6).
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Table 3. Association between quartiles of CRP measured at baseline, ischemic stroke, and etiologic subtypes of ischemic stroke
All stroke (n ⫽ 199)
Large artery (n ⫽ 63)
Small artery (n ⫽ 66)
Cardio-embolic (n ⫽ 45)
Quartile 1 (⬍1.6 mg/L)
Quartile 2 (1.6-3.9 mg/L)
Quartile 3 (4.0-9.5 mg/L)
Quartile 4 (⬎9.5 mg/L)
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
Unadjusted
1.0
Adjusted
1.0
2.3 (1.2-4.4) 1.9 (1.0-3.8) 2.5 (0.7-8.8) 2.5 (0.6-9.3) 1.4 (0.7-3.2) 1.1 (0.5-2.6) 3.8 (0.7-19.4) 3.5 (0.7-18.4)
6.5 (3.4-12.3) 5.8 (2.9-11.4) 11.2 (3.6-34.8) 12.4 (3.5-43.7) 3.8 (1.8-8.1) 3.3 (1.4-7.4) 9.6 (2.0-46.6) 7.5 (11.3-38.8)
17.3 (8.6-34.7) 16.9 (7.9-36.1) 30.9 (9.7-98.4) 52.5 (13.4-205) 3.4 (1.3-8.5) 2.4 (0.8-6.9) 59.7 (13.1-273) 56.1 (11.3-278)
P† ⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001 .0004 .007 ⬍.0001 ⬍.0001
Results are presented as odds ratios and 95% confidence intervals (P-value is for trend of association). Reliable estimates of odds of ‘other’ stroke could not be obtained because of the small number of cases in this group (n ⫽ 25). †Adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
Figure 1. Association between quartiles of CRP measured during the first 7 days after the acute event and ischemic stroke (P value is for trend of association). *Unadjusted OR (gray bars) and adjusted OR (black bars) for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
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Table 4. Plasma CRP during the first 7 days after the acute stroke event and at follow-up (3-6 months) in etiologic subtypes of ischemic stroke*
Large artery Small artery Cardio-embolic (n ⫽ 63) (n ⫽ 66) (n ⫽ 45)
Other (n ⫽ 25)
Control (n ⫽ 202)
C-reactive protein 10.80 during the first (7.70-15.19) 7 days, mg/L
3.97 (3.06-5.14)
14.59 (9.88-21.35)
12.18 2.18 (7.06-21.20) (1.86-2.55)
2.94 C-reactive protein (1.87-4.66) during longterm follow-up, mg/L‡
3.13 (2.27-4.27)
6.42 (3.98-10.41)
1.86 (0.89-3.86)
2.18 (1.86-2.55)
Overall Significant pair-wise significance comparisons† (P) (P ⬍ .05) ⬍0.0001
NS
LA, SA, CE or other vs. control LA, CE, or Other vs. SA —
*CRP levels are log-transformed and presented as geometric means; overall significance and pair-wise comparisons adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events. †Tukey’s adjustment for multiple comparisons. ‡Data are from 92 stroke survivors (27 large artery, 36 small artery, 18 cardioembolic, 11 other) who returned for follow-up. Abbreviations: C, control; CE, cardioembolic; LA, large artery; SA, small artery.
(3.97 mg/L, 95% CI: 3.06-5.14 mg/L; P ⬍ .05 for each comparison). However, at follow-up, the numbers of patients were much smaller and the difference between individual etiologic subtypes of stroke and controls was no longer statistically significant.
Association Between CRP and Etiologic Subtypes of Stroke There was a strong, graded, and independent association between blood levels of CRP during the first 7 days and etiologic subtypes of ischemic stroke (Table 3, Figure 2). Compared with the lowest quartile, the upper quartile of CRP at baseline was associated with a unadjusted OR of large artery stroke of 30.9 (95% CI: 9.7-98.4), cardioembolic stroke of 59.7 (95% CI: 13.1-273), and small artery stroke of 3.4 (95% CI: 1.3-8.5). The magnitude of the association with each of these etiologic subtypes was similar after adjustment for age, sex, conventional vascular risk factors, and history of previous vascular events (Table 3). Because of the small number of strokes caused by other causes (n ⫽ 35), stable estimates of the odds of stroke in the highest relative to the lowest quartile could not be obtained for this etiologic subgroup of stroke.
Association Between CRP and Stroke Severity The mean Oxford Handicap Scale score was lowest in small artery, intermediate in large artery. and highest in cardioembolic stroke (2.8 vs. 3.1 vs. 3.6, respectively; P ⫽ .001) while the mean Barthel index was highest in small artery, intermediate in large artery, and lowest in cardioembolic stroke (13.5 vs. 11.5 vs. 8.6, respectively; P ⫽ .002). Furthermore, there was a significant correlation between CRP levels during the first 7 days and stroke
severity, as measured by the Oxford Handicap Scale score (P ⫽ .03) and Barthel index (P ⫽ .001).
Discussion The results of our study indicate a strong, graded, and independent association between elevated blood levels of CRP during the first 7 days after ischemic stroke. CRP concentrations were significantly lower at points between 3 and 6 months in stroke survivors compared with levels during the first 7 days but remained significantly elevated. Furthermore, CRP levels were most markedly elevated in patients with stroke caused by large artery disease or embolism from the heart, which tend to cause larger infarcts and greater disability, and were significantly lower in patients with stroke caused by small artery disease, which causes small infarcts. Although differences in CRP levels between etiologic subtypes of stroke were no longer statistically significant at followup, this is most likely because of the small number of patients. These findings support the inflammatory marker hypothesis of CRP as a measure of the extent of cerebral injury or the complications thereof and do not provide support for the hypothesis that elevated CRP levels are primarily atherogenic. Previous studies have consistently demonstrated an association between CRP and stroke.2,11-15 Muir et al11 further reported that stroke patients with an elevated CRP were more likely to have cerebral infarction on a cranial CT scan than patients without an elevated CRP level, while Beamer et al17 found that blood levels of CRP were higher in patients with large established infarcts on CT and lowest in patients with lacunar stroke. These findings are consistent with the results of our study and
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Figure 2. Association between quartiles of CRP measured during the first 7 days after the acute event and etiologic subtypes of ischemic stroke (P value is for trend of association). Adjusted for age, sex, individual conventional vascular risk factors, and history of arterial vascular events.
further support the conclusion that elevated CRP in patients with stroke is primarily a marker of the extent of cerebral ischemic injury and the complications thereof (eg, aspiration pneumonia). Likewise, the results of epidemiologic studies demonstrating a non-specific association between elevated CRP and cardiovascular as well as non-cardiovascular mortality, including cancer,11,24 do not support a primary causal role for CRP in the pathogenesis of atherosclerotic vascular disease and stroke. However, we are unable to exclude the possibility that CRP also exerts a pro-atherogenic effect in patients at risk of future vascular events, including stroke. Our study has several potential limitations. First, although cases were classified prospectively and recruited consecutively, and controls were randomly selected from the community, the potential for confounding can never be eliminated in an observational study. In particular, we cannot exclude the effect of pre-existing subclinical cerebrovascular disease or vascular risk factors such as smoking or hypercholesterolemia, on the observed association between elevated blood levels of CRP and ischemic stroke. However, our findings of an independent association between elevated CRP and stroke are consistent with the results of the majority of retrospective and prospective studies that have examined this question.1,2,10
Second, the reliance on clinical criteria to classify etiologic subtypes of ischemic stroke may have led to their misclassification. However, the diagnosis of stroke, and etiological subtype of ischemic stroke was made by a single neurologist who specializes in stroke medicine, on the basis of pre-defined and established criteria. Meanwhile, the impact of any misclassification would tend to reduce differences among etiologic subtypes of ischemic stroke rather than account for differences. Third, etiologic subtype of ischemic stroke is an imprecise surrogate measure of cerebral infarct size. However, there is no reason to expect that it is a biased measure. Furthermore, an association between etiologic stroke subtype and both extent of cerebral infarction and outcome after stroke is has previously been documented18,19 and our data confirm that there is also an association between etiologic stroke subtype and stroke severity as measured by the Oxford score and Barthel index. Therefore, our use of etiologic stroke subtype are a valid albeit imprecise reflection of cerebral infarct size. Fourth, both lipid-lowering therapy and aspirin reduce blood levels of CRP,25,26 and it is possible that their widespread use in patients included in our study have contributed to lower levels of CRP levels at follow-up compared with during the first few days after stroke. However, CRP levels nevertheless remained significantly
C-REACTIVE PROTEIN AND ISCHEMIC STROKE
elevated at 3 to 6 months, which is consistent with previous reports of a persistent inflammatory response in stroke survivors.27 In conclusion, our study adds to the growing body of evidence demonstrating an independent relationship between elevated blood levels of CRP and arterial vascular disease and stroke. In addition, however, our study raises questions concerning the proposed causal role of CRP in atherosclerotic vascular disease and rather suggests that elevated blood levels of CRP in patients with stroke are primarily reflection of the extent of cerebral ischemic injury.
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