Serum highly selective C-reactive protein concentration is associated with the volume of ischemic tissue in acute ischemic stroke
American Journal of Emergency Medicine (2012) 30, 124-128
Original Contribution
Serum highly selective C-reactive protein concentration is associated with the volume of ischemic tissue in acute ischemic stroke?,??
Chun Song Youn MD, Seung Pill Choi MD, Soo Hyun Kim MD, Sang Hoon Oh MD, Won Jung Jeong MD, Han Joon Kim MD, Kyu Nam Park MD?
Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
Received 6 August 2010; revised 1 November 2010; accepted 2 November 2010
Abstract
Background: There is growing evidence that inflammation plays an important role in atherogenesis. Previous studies have shown that the concentration of peripheral inflammatory markers, particularly C- reactive protein (CRP), strongly correlates with Stroke severity and independently predicts mortality and recurrent vascular events in patients with acute ischemic stroke. The aim of this study was to clarify the relationship between inflammatory markers and stroke severity by means of volumetric measurement of infarct size.
Methods: From March 1, 2008, to February 28, 2009, 96 patients who had laboratory investigations and magnetic resonance imaging scans were included retrospectively in this study. diffusion-weighted imaging (DWI) lesions were outlined using a semiautomatic threshold technique. Diffusion-weighted imaging Lesion volumes were measured with MIPAV software (Medical Image Processing, Analysis and Visualization, version 4.1.1; National Institutes of Health, Bethesda, MD). The relationship between highly selective CRP (hs-CRP) levels and DWI infarct volume quartiles was examined.
Results: The mean age of patients was 66.9 years, and 50 patients (51.2%) were male. There was a significant correlation between hs-CRP and DWI volumes (Spearman ? = 0.239, P = .010). The median hs-CRP values for successive volumes of DWI lesion quartiles (lowest to highest quartile) were as follows: 1.17, 1.14, 1.63, and 3.76 (P = .029).
Conclusions: Higher hs-CRP levels were associated with larger infarct volumes in patients with acute ischemic stroke. These results suggest that elevated hs-CRP levels, reflecting a large volume of infarct, may serve as a helpful serologic marker in the evaluation of severity of acute ischemic stroke.
(C) 2012
? There are no financial or other relations that might pose a conflict of interests.
?? This study was supported by a grant from the Korea Health 21
R&D Project (A070001), Ministry of Health & Welfare, Republic of Korea.
* Corresponding author. Department of Emergency Medicine, Seoul St Mary’s Hospital, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-701, Republic of Korea. Tel.: +82 2 2258 1987; fax: +82 2 2258 1997.
E-mail address: [email protected] (K.N. Park).
Introduction
Ischemic infarction is a potent stimulus for the acute phase response [1]. Inflammation plays a fundamental role in the development and progression of atherosclerosis as well as its thrombotic complications. This inflammation may contribute to ischemic tissue damage in the brain as well as in
0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2010.11.006
the heart, and anti-inflammatory therapies may be neuropro- tective [2].
C-reactive protein (CRP) is an acute phase reactant; therefore, it is used as a biochemical marker in studies demonstrating the relationship between inflammation and atherosclerosis in cerebrovascular disease [3-6]. Several studies have shown that CRP is a prognostic factor of functional outcome and an independent predictor of death and recurrent vascular events in patients with acute ischemic stroke [7-11]. A more sensitive CRP test, called a highly sensitive CRP (hs-CRP) assay, is available to determine cerebrovascular disease risk.
Verification of the role of CRP as a marker of disease severity after ischemic stroke may be of clinical importance, because it is an easily measured and readily available inflammatory marker. The aim of this study was to clarify the relationship between hs-CRP and stroke severity by means of volumetric measurement of infarct size.
Methods
This study was performed in the emergency department (ED) of a Tertiary EDucational hospital. Inclusion criteria were as follows: older than 18 years, diagnosis of acute ischemic stroke, multimodal magnetic resonance imaging (MRI) performed within 24 hours of admission, and hs-CRP performed on admission blood work. Patients who were clinically suspected acute ischemic stroke but had negative finding on diffusion-weighted MRI were excluded. Patients with clinical signs of infection on admission, known immunologic disease, known malignancy, and pregnancy were also excluded. This study was approved by the institutional review board of the Catholic University of Korea, Saint Mary’s Hospital.
Laboratory data were obtained for all patients on admission at ED. Highly selective CRP was measured by the latex agglutination nephelometry method using the Toshiba 200FR Neo chemistry analyzer (Toshiba Medical Systems, Tokyo, Japan). The analytical sensitivity was 0.1 mg/L, and the intra-assay coefficient of variation was lower than 5%.
Magnetic resonance imagings were performed within 24 hours of admission using a 1.5-T MRI unit (Signa Excite; GE Medical Systems, Milwaukee, WI) with echoplanar imaging capabilities. The common MRI parameters for diffusion- weighted imaging (DWI) and T2-weighted images were a slice thickness of 5 mm, an interslice gap of 2 mm, and 22 axial slices. Diffusion-weighted imaging parameters includ- ed a field-of-view of 240 x 240 mm, a repetition time of 7000 milliseconds, an echo time of 85.3 milliseconds, a matrix number of 128 x 128, and 2 levels of diffusion sensitization (b = 0 and b = 1000 s/mm2).
Diffusion-weighted imaging lesion volumes were mea- sured using the MIPAV software (Medical Image Proces-
sing, Analysis and Visualization, version 3.0; National Institutes of Health Bethesda, MD). Diffusion-weighted imaging lesion volumes of all patients were evaluated by experienced neuroradiologist blinded to the patients’ clinical data. Acute diffusion lesions were defined on a slice-by-slice basis using a semiautomatic threshold approach. Lesion volumes were calculated by multiplying slice thickness by the total lesion area.
Diffusion-weighted imaging lesion volumes were col- lapsed into quartiles. Nonnormally distributed continuous variables were compared across quartiles according to median values and tested for statistical significance using the Kruskal-Wallis rank sum test. Differences in categorical variables were compared using the?2 test or Fisher exact test. The relationship between hs-CRP level and DWI infarct volume quartiles was examined using spearman correlation analysis. All statistical analyses were carried out using the SAS version 8.0, and P values less than or equal to.05 were considered significant.
Results
Between March 1, 2008, and February 28, 2009, 96 patients met the study criteria. Among the 96 patients, the mean (SD) age was 66.9 (12.9) years, and 50 (52.1%) patients were male. The median time of duration of symptom (ie, between the last well- known time and the admission time) was 12.0 hours (interquartile range [IQR], 3.0-33.1
Table 1 Baseline demographics and clinical characteristics among patients with acute ischemic stroke
|
Acute ischemic stroke (n = 96) |
|
Demographics
Age (y), mean +- SD 66.9 +- 12.9 Sex, male 50 (52.1) History, n (%) HTN 63 (65.6) DM 33 (34.4) CAD 11 (11.5) CVA 25 (26.0) Af 18 (18.8) Metabolic syndrome 53 (55.2) Smoking 41 (42.7) Duration of symptom (h), median (IQR) 12.0 (3.0-33.1) NIHSS, mean +- SD 5.18 +- 5.07 Stroke subtype, n (%) Large-artery atherosclerosis 51 (53.1) Cardioembolism 15 (15.6) Small-vessel occlusion 13 (13.5) Other determined etiology 11 (11.5) Undetermined etiology 6 (6.3) |
|
HTN indicates hypertension; DM, diabetes mellitus; CAD, coronary artery disease; CVA, cerebrovascular accident; Af, atrial fibrillation. |
hours; full range, 0.5-106.0 hours). The mean (SD) National Institutes of Health Stroke Scale score on admission was 5.18 (5.07). Stroke subtypes, classified using the modified TOAST criteria, included the following:
51 (53.1%) large vessel atherosclerosis, 15 (15.6%)
cardioembolic, 13 (13.5%) small-vessel disease, 11
(11.5%) other-determined etiology, and 6 (6.3%) undeter- mined etiology (Table 1). The median DWI volume measured with the MIPAV software was 3.91 mL (IQR,
Table 3 Association between hs-CRP levels and stroke subtypes
Fig. 1 Box plot showing mean hs-CRP levels (solid bar) and IQR (bar width) across diffusion quartiles.
0.80-20.44 mL; full range, 0.01-42.96 mL). The estimated DWI volume was divided into 4 groups.
Highly selective CRP and estimated DWI volumes showed a significant correlation (Spearman ? = 0.239, P = .010) (Table 2, Fig. 1). The median hs-CRP value for successive volumes of DWI lesion quartiles (lowest to highest quartile) were as follows: 1.17, 1.14, 1.63, and 3.76 mg/L.
There was a significant difference in hs-CRP between stroke subtypes (P = .010). Highly selective CRP levels were highest in the cardioembolic stroke subtype (Table 3).
Discussion
We found that in patients with acute ischemic stroke, elevated hs-CRP levels were associated with larger volumes of ischemic tissue as measured by DWI MRI. This finding
|
hs-CRP |
P |
|
|
Small-vessel occlusion
|
1.04 (0.14-18.90) |
.010 |
|
Large-artery atherosclerosis |
1.73 (0.32-157.97) |
|
|
Cardioembolism |
2.88 (0.26-22.18) |
|
|
Other determined etiology |
1.02 (0.19-7.26) |
|
|
Undetermined etiology |
1.75 (0.15-9.24) |
|
|
Parenthesis indicates range. |
||
well correlated with the previous notion of the Inflammatory process of stroke pathomechanism.
An hs-CRP, which is more sensitive than a CRP test, is a hepatically derived pentraxin that plays an important role in the human immune system [12,13]. An hs-CRP is regulated by cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor; among them, interleukin-6 is the primary circulating physiologic mediator. Induction of an hs-CRP is rapid, and in contrast with other acute phase components, the half-life is long enough for a steady time course [13,14]. These properties make plasma hs-CRP very useful for the diagnostic workup of Inflammatory and infectious diseases. Inflammatory processes play a central part in the pathogenesis of atherosclerosis and its thrombotic complica- tions. The physiologic role of hs-CRP is not well understood, but it potentially has anti-inflammatory properties as well as proinflammatory effects. C-reactive protein exacerbates inflammatory Ischemic injury through the following mech- anism: activation of the classical complement pathway, cytokine production, and complement-related inflammatory reaction [15,16]. These may contribute to the progression of atherothrombosis and the development of ischemic injury
associated with atherothrombotic complications.
Elevated serum CRP levels are associated with athero- sclerosis of carotid, coronary, and peripheral arteries. C- reactive protein is an independent indicator of future Cerebrovascular events [4-6]. Although the degree of risk conferred by elevated CRP levels is still controversial, assessment of CRP concentrations may provide a useful method to assess cerebrovascular risk. Thus, the Centers for Disease Control and Prevention and the American Heart Association recommended guidelines in 2003 for the use of hs-CRP in clinical practice [17].
In the acute phase of ischemic stroke, inflammation causes brain damage. One animal study revealed that human CRP increases cerebral infarct size after Middle cerebral artery occlusion [18]. In the clinical setting, several studies have demonstrated that CRP levels are positively associated with stroke severity and neurologic disability. In the acute phase of ischemic stroke, high concentrations of CRP may reflect the extent and severity of Cerebral injury [8,9]. Our study supports this hypothesis that has been presented by previous studies.
There is no specific therapy to reduce plasma CRP concentrations and to improve cerebrovascular risk or to improve the outcome after ischemic stroke. Whether lowering CRP concentrations represents a useful pharmaco- logic goal in itself is unclear. However, the use of biochemical markers to guide therapy might not be a controversial issue in the future. Statins lower the CRP levels independent of cholesterol parameters [19]. Future studies are needed to determine whether statins improve the clinical outcome among patients with acute ischemic stroke with elevated CRP levels.
There were some limitations in this study. First, the sample size is relatively smaller than the previous studies.
Hence, it was difficult to judge whether previous use of statin and antiplatelet had an influence on hs-CRP and diffusion volume. Second, we measured a single hs-CRP level without regular interval between stroke attack and measurement. Third, patients who had negative finding on diffusion- weighted MRI were excluded. Highly selective CRP level of these patients may provide important information. However, the aim of this study was to clarify the relationship between hs-CRP and stroke severity by means of volumetric measurement of infarct size. Therefore, excluding DWI- negative stroke patients from this study does not adversely affect the most important hypothesis of this study. Finally, initial DWI lesion volume was analyzed, not final T2- weighted lesion volume. However, previous studies have demonstrated that early DWI lesion volumes correlate well with final T2 lesion volumes [20,21].
Conclusion
Higher hs-CRP levels were associated with larger infarct volumes in acute ischemic stroke. These results suggest that elevated hs-CRP levels, reflecting a large infarct volume, may serve as a helpful serologic marker in the evaluation of the severity of acute ischemic stroke.
Acknowledgment
This study was advised by the Catholic Research Coordinating Center.
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