Serum levels of high-sensitivity C-reactive protein in acute ischemic stroke and its subtypes: a prospective case-control study
Davinder Singh Rana MD 1, Ish Anand1, Anuradha Batra1, Prahlad Kumar Sethi1, Seema Bhargava2
1 Department of Neurology, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Biochemistry, Sir Ganga Ram Hospital, New Delhi, India
|Date of Submission||16-Oct-2018|
|Date of Decision||22-Oct-2018|
|Date of Acceptance||24-Oct-2018|
|Date of Web Publication||19-Nov-2018|
Davinder Singh Rana
Department of Neurology, Sir Ganga Ram Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Background and objectives: Studies in different populations have shown that ischemic stroke can trigger an acute phase response resulting in a rise of plasma concentration of C-reactive protein (CRP) and high level of high-sensitivity CRP (hsCRP) is a risk factor for ischemic stroke. The objective of this study was to investigate the association of high hsCRP levels (≥ 1 mg/L) with ischemic stroke and its subtypes in Indian patients.
Methods: This prospective observational case-control study included 150 patients (96 males, 54 females; aged 24–81 years) with first acute ischemic stroke who were admitted within 72 hours after onset, and 150 age- and sex-matched healthy controls. The study was conducted from July 2016 to July 2017. The patients were classified according to Trial of ORG 10172 in Acute Stroke Treatment classification. hsCRP levels were assessed in all included stroke patients.
Results: The mean serum level of hsCRP was significantly higher in patients with first acute ischemic stroke than in healthy controls (P < 0.001). The mean serum level of hsCRP was higher in patients who had more severe stroke on admission. The prevalence of high serum level of hsCRP was highest in large-artery atherosclerosis (35.2%), followed by in cardioembolic (28.2%) stroke. The mean serum level of hsCRP was highest in large-artery atherosclerosis, followed by in stroke of undetermined etiology and cardioembolic subtype. High serum level of hsCRP was significantly associated with hypertension and age (P < 0.001 or P < 0.05). Multiple Logistic regression analysis revealed that high level of hsCRP was independently associated with acute ischemic stroke [odds ratio (OR) = 3.87, 95% confidence interval (CI): 2.39–6.27]. High hsCRP level was strongly associated with cardioembolic stroke (OR = 4.97, 95% CI: 2.5–9.65), large-artery atherosclerosis (OR = 4.75, 95% CI: 2.57–8.81), and stroke of undetermined etiology (OR = 3.36, 95% CI: 1.72–6.54).
Conclusion: High hsCRP level is strongly associated with acute ischemic stroke and its subtypes, and it is an independent predictor of acute ischemic stroke.
Ethics: The study was approved by the Sir Ganga Ram Hospital Ethics Committee (EC/07/14/701) on July 5, 2014.
Keywords: high-sensitivity C-reactive protein; acute ischemic stroke, stroke subtype; risk factor; case-control study
|How to cite this article:|
Rana DS, Anand I, Batra A, Sethi PK, Bhargava S. Serum levels of high-sensitivity C-reactive protein in acute ischemic stroke and its subtypes: a prospective case-control study. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:128-35
|How to cite this URL:|
Rana DS, Anand I, Batra A, Sethi PK, Bhargava S. Serum levels of high-sensitivity C-reactive protein in acute ischemic stroke and its subtypes: a prospective case-control study. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2021 Jun 15];3:128-35. Available from: https://www.actnjournal.com/text.asp?2018/3/4/128/245216
| Introduction|| |
Stroke can be defined as a clinical syndrome characterized by rapidly developing clinical symptoms and/or signs; focal and at times global loss of brain function, with symptoms lasting > 24 hours or leading to earlier death, and with no apparent cause other than vascular origin (Bonita, 1992). Stroke has high mortality and long term physical and mental disability. Inflammation plays a vital role in pathophysiology of atherosclerosis (Libby et al., 2002). Therefore, it might be hypothesized that a more severe stroke is associated with greater inflammatory response. High-sensitivity C-reactive protein (hsCRP) is a sensitive marker of inflammation and tissue injury in the arterial wall (Chaudhuri et al., 2013).
CRP is a phylogenetically highly conserved plasma protein, with homolog in vertebrates and many invertebrates, and it participates in the systemic response to inflammation (Rost et al., 2001). CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. CRP, an acute-phase protein synthesized by hepatocytes under the influence of cytokines, e.g., interleukin (IL)-6, tumor necrosis factor-alpha, is released in the blood stream in response to inflammation and tissue damage (Gabay and Kushner, 1999).
CRP stimulates the endothelial cells to produce various adhesion molecules, such as intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin (Sabatine et al., 2007). These molecules allow migration of mononuclear cells and T lymphocytes into the vessel wall and play a key role in the formation of atherosclerotic plaque. CRP is also involved in the release of superoxide anion and stimulation of tissue factor activity (Devaraj et al., 2009). In addition, it induces plasminogen activator inhibitor-1 (PAI-1), a marker of disrupted fibrinolysis and atherothrombosis (Devaraj et al, 2003). Finally, CRP may increase the chance of endothelial cell lysis and plaque erosion, and can contribute to acute ischemic stroke or coronary syndrome. All these, thus, predispose to atherosclerosis in cerebral and cardiac circulation. Recent studies confirm and extend previous evidence that hsCRP plays a significant role in atherosclerosis and is one of the important risk factors of cardiovascular diseases. There exists a robust and specific relation between increased levels of hsCRP and risk of ischemic heart disease and atherosclerosis (Koenig et al., 1999). However, there is no reliable or consistent data regarding association of hsCRP levels with ischemic stroke.
The objective of our study was to investigate the association of high hsCRP serum levels (≥ 1 mg/L) with ischemic stroke and its subtypes in Indian patients.
| Participants and Methods|| |
Study design and setting
This prospective observational case-control study [Figure 1] was conducted in the Department of Neurology of Sir Ganga Ram Hospital, New Delhi which is a tertiary care center and a major referral center in north India. This study was conducted from July 2016 to July 2017.
|Figure 1: Study flowchart. |
Note: TOAST: Trial of Org 10172 in Acute Stroke Treatment.
Click here to view
All 150 patients with ischemic stroke who received treatment in the Sir Ganga Ram Hospital were included in this study according to the following eligibility criteria.
Patients presenting with all of the following conditions were included in this study: a) diagnosis of cerebral infarction was confirmed by medical history, clinical signs, symptoms, cerebral computerized tomography or magnetic resonance imaging; b) age of 24–81 years; c) either sex; d) suffering from a first ever acute ischemic stroke; e) admission to hospital within 72 hours after onset; f) no evidence of co-morbidities that could affect hsCRP status, for example, clinical symptoms and signs of active infection, using steroids or immunomodulatory drugs, or a history of prior inflammatory diseases.
Patients with any of the following condition were excluded from this study: a) hemorrhagic stroke; b) transient ischemic attack; c) recurrent stroke or second stroke; d) admission to hospital over 72 hours after onset of stroke; e) having clinical symptoms and signs of active infection including fever, cough and burning micturition; f) asymptomatic subjects with evidence of infection, e.g., leucocytosis on peripheral smear, pus cells in urine, infiltrates on chest X-ray; g) taking steroids or immunomodulatory drugs; h) a history of prior inflammatory diseases, e.g., systemic lupus erythematosus and rheumatoid arthritis; i) failure to obtain consent for the study.
150 age- and gender-matched healthy ambulatory community-dwelling volunteer controls were also enrolled. These healthy controls had no present or past history of transient ischemic attack, stroke, or cardiac diseases. Diagnosis of cerebral infarction was confirmed by medical history, neurological examination, and neuroimaging (cerebral computerized axial tomography or magnetic resonance imaging). Patient information was documented in a proforma including presenting complaints, age, sex, systolic blood pressure, smoking habits, h/o diabetes, family history, and body mass index. Detailed physical and neurological examination was done.
Severity of stroke was categorized according to National Institute of Health Stroke Scale (NIHSS) as mild (score < 4), moderate (4–15) and severe (score > 15) (Clark and Hourihane, 1997).
Stroke etiologic subtypes were identified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, which distinguishes five stroke categories (Adams et al., 1993):
- Large-artery atherosclerosis or atherothrombotic-cortical or cerebellar lesions and brain stem or subcortical hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI along with evidence by duplex imaging or arteriography of a stenosis of greater than 50% of an appropriate intracranial or extracranial artery.
- Cardioembolic lesion: This category will include patients with arterial occlusions presumably due to an embolus arising in the heart. Cardiac sources are divided into high-risk and medium-risk groups based on the evidence of their relative propensities for embolism. At least one cardiac source for an embolus must be identified for a possible or probable diagnosis of cardioembolic stroke. High-risk sources include mechanical prosthetic valve, mitral stenosis with atrial fibrillation, atrial fibrillation (other than lone atrial fibrillation), left atrial/atrial appendage thrombus, sick sinus syndrome, recent myocardial infarction (< 4 weeks), left ventricular thrombus, dilated cardiomyopathy, akinetic left ventricular segment, atrial myxoma, and infective endocarditis. Medium-risk sources include mitral valve prolapsed, mitral annulus calcification, mitral stenosis without atrial fibrillation, left atrial turbulence (smoke), atrial septal aneurysm, patent foramen ovale, atrial flutter, lone atrial fibrillation, bioprosthetic cardiac valve, nonbacterial thrombotic endocarditis, congestive heart failure, hypokinetic left ventricular segment and myocardial infarction (> 4 weeks, < 6 months ).
- Small-vessel occlusion or lacunar lesion: The patient should have one of the traditional clinical lacunar syndromes and should not have evidence of cerebral cortical dysfunction. The patient should also have a normal CT/MRI examination or a relevant brain stem or subcortical hemispheric lesion with a diameter of less than 1.5 cm.
- Undetermined or cryptogenic lesion: where no likely etiology is determined despite an extensive evaluation or patients with two or more potential causes of stroke are present, making it difficult to find one etiology.
- Other determined etiologies (rare causes of stroke): This category includes patients with rare causes of stroke, such as nonatherosclerotic vasculopathies, hypercoagulable states, or hematologic disorders.
To determine the TOAST category, all the information available from the hospital admission was taken into account, including the panel of tests performed during the hospital stay.
The study was undertaken after due approval of the Sir Ganga Ram Hospital Ethics Committee (EC/07/14/701) (Additional file 1 [Additional file 1]) on July 5, 2014. A written informed consent in the language the patient understood was obtained from all the subjects being enrolled for the study after explaining the objectives and benefits of the study to them (Additional files 2 and Additional File 3 [Additional file 2] [Additional file 3]).
Determination of hsCRP level
Serum samples for determination of hsCRP level were taken within 24 hours of hospital arrival. hsCRP level was measured using the highly sensitive near-infrared particle immunoassay method. This method was based on the principle that an anti-CRP antibody coated particle binds to CRP in the patient sample resulting in formation of insoluble aggregates causing turbidity. Tests were carried out in the Department of Biochemistry of the Sir Ganga Ram Hospital on fully automated random assess Beckman Coulter (DXC-800) clinical chemistry analyzer as per the instructions in the insert provided with the kit. The SYNCHRON System(s) automatically adds the appropriate sample and reagent volumes into a cuvette. The ratio used was one part sample to 50 parts reagent. The System monitors the change in absorbance at 600 nm. This change in absorbance was proportional to the concentration of CRP in the sample and was used by the System to calculate and express CRP concentration based upon a single point adjusted, predetermined calibration curve. We classified hsCRP levels in low risk ( < 1 mg/L), moderate risk (1–3 mg/L) and high risk (> 3 mg/L) groups according to American Heart Association and Centers for Disease Control and Prevention criteria (Pearson et al., 2003). In our study, we considered hsCRP level of ≥ 1 mg/L as high. Blood glucose measurement, liver function tests, renal function tests, lipid profile (triglycerides, total and high-density lipoprotein cholesterol) were performed by standard enzyme methods.
Statistical analysis was performed using SPSS 17.0 software (SPSS, Chicago, IL, USA). Continuous variables were presented as the mean ± SD, and categorical variables are presented as absolute numbers and percentage. Data were checked for normality before statistical analysis. Normally distributed continuous variables were compared using the unpaired t-test, whereas the Mann-Whitney U test was used for those variables that were not normally distributed. Categorical variables were analyzed using either the chi-square test or the Fisher’s exact test. Logistic regression analysis involving odds ratio (OR) and 95% confidence interval (CI) was used to predict the presence of high hsCRP level in TOAST ischemic stroke subtypes. For all statistical tests, a P-value less than 0.05 was considered statistically significant.
| Results|| |
The mean age was 59.67 ± 10.84 years and 57.19 ± 9.25 years in patients with first acute ischemic stroke and healthy controls, respectively. Females accounted for 36.0% of the total number of patients with first acute ischemic stroke and healthy controls. The age and gender distribution were comparable between patients with first acute ischemic stroke and healthy controls [Table 1].
|Table 1: Comparisons of demographic parameters and hsCRP levels between patients and controls|
Click here to view
Risk factor for ischemic stroke
Hypertension was the most common risk factor for ischemic stroke, which was observed in 68.7% of patients. The other risk factors observed in the decreasing order of frequency included dyslipidemia (60.7%), diabetes (49.3%), smoking (30.7%), hyperhomocysteinemia (29.3%), left ventricular dysfunction (22.0%), and atrial fibrillation (15.3%).
Subtypes of ischemic stroke
Among included patients, 32.7% of them had small-vessel occlusion, and 25.3% of them had large-artery atherosclerosis. The prevalence was 21.3%, 11.3%, and 9.4% respectively for cardio-embolic stroke, stroke of other determined etiology, and stroke of undetermined etiology, respectively. Most of included patients (86.0%) had anterior circulation stroke. Posterior circulation stroke was seen in 14.0% of patients. The most common NIHSS grade in patients on admission was moderate (58.0%), followed by mild (29.3%) and severe (12.7%).
Serum levels of hsCRP
The mean serum level of hsCRP was 2.12 ± 3.16 in patients with acute ischemic stroke and it was 0.34 ± 0.47 in the healthy controls. Serum hsCRP level was found to be high in 71 (47.3%) patients while it was high only in 12 (8.0%) healthy controls. There was significant difference in serum hsCRP level between patients with acute ischemic stroke and healthy controls [Table 1].
The percentage of patients with hypertension and older age was significantly higher in the high-level hsCRP group than in the low-level hsCRP group [Table 2].
|Table 2: Stroke risk factors in acute ischemic stroke patients with various serum levels of hsCRP|
Click here to view
According to NIHSS grade on admission, the mean value of serum hsCRP level was highest in severe grade (7.76 ± 4.83 mg/L), followed by in moderate grade (1.81 ± 1.87 mg/L), and in mild grade (0.29 ± 0.30 mg/L). Significant statistical difference was found in serum hsCRP level among the various NIHSS grades (P < 0.001).
High hsCRP levels were associated with all stroke subtypes. The prevalence of high hsCRP level was highest in large-artery atherosclerosis (35.2%), followed by in the cardioembolic stroke (28.2%), small-vessel occlusion (19.7%), stroke of undetermined etiology (9.9%), and lowest in stroke of other determined etiology (7.0%). There was statistically significant difference in the prevalence of high hsCRP level between TOAST stroke subtypes (P = 0.002) [Table 3].
|Table 3: TOAST ischemic stroke subtype in patients with various serum levels of hsCRP|
Click here to view
The mean serum hsCRP level was highest in the large-artery atherosclerosis subtype, followed by in the stroke of undetermined etiology, cardioembolic subtype, small-vessel occlusion, and stroke of other determined etiology subtype. Significant statistical difference was found in serum hsCRP level among the various TOAST ischemic stroke subtypes (P < 0.001; [Table 4]).
Association of serum high hsCRP with TOAST ischemic stroke subtypes
Multiple logistic regression analysis revealed that high-level hsCRP was independently associated with acute ischemic stroke (OR = 3.87, 95% CI: 2.39–6.27). The association was found in all ischemic stroke subtypes. Strongest association was found in cardioembolic stroke (OR = 4.97, 95% CI: 2.5–9.65), followed by in the large-artery atherosclerosis (OR = 4.76, 95% CI: 2.57–8.81) and stroke of undetermined etiology (OR = 3.35, 95% CI: 1.72–6.54) [Table 5].
|Table 5: Association between presence of high hsCRP level and TOAST ischemic stroke subtypes|
Click here to view
| Discussion|| |
Stroke risk factors
The most common risk factor observed in our study was hypertension which occurred in 68.7% of included patients, followed by dyslipidemia (60.7%), diabetes mellitus (49.3%), smoking (30.7%), hyperhomocysteinemia (29.3%), left ventricular dysfunction (22.0%) and atrial fibrillation (15.3%). Hypertension has been the most common and important treatable risk factor for stroke in most of the other epidemiology studies including ICASS and the INTERSTROKE study (Dalal, 2006; O’Donnell et al., 2010; Brondum-Jacobsen et al., 2013).
Nagaraja et al. (2009) performed an epidemiology study of stroke in India and found that the majority of the patients had hypertension (48%) followed by tobacco use (32.6%), alcohol use (25.1%), diabetes (23.1%), a previous history of stroke (13.1%) and atrial fibrillation (9.7%). Prasad et al. (2012) also found that the majority of patients had a history of hypertension (77.6%), followed by smoking (56.1%), coronary artery disease (29%), diabetes (28%), obstructive sleep apnea (4.7%) and a previous history of stroke (2.8%). Our observation regarding hypertension and dyslipidemia is also supported by the findings in a recent multiethnic study on Asian population in Singapore by Sharma et al. (2012).
Among our 150 patients with ischemic stroke, the most common TOAST class was small-vessel occlusion (32.7%) followed by large-artery atherosclerosis (25.3%), cardioembolic subtype (21.3%), stroke of other determined etiology (11.3%), and stroke of undetermined etiology (9.4%). Our findings are consistent with findings from a study by Sharma et al. (2012), who made the observation in their multiethnic study that lacunar stroke was the most frequent stroke subtype (47.9%). Dewan and Rana (2011) performed a study in 100 patients with Nepalese ischemic stroke and found that the highest number of patients had small artery subtype (45%) followed by large artery (36%) and cardioembolic subtype (19%). However, Kaul et al. (2002) performed a study, in which 392 patients with ischemic stroke, consisting of 282 men and 110 women, aged 54 (range 2–97 years) years were included. They found that 41%, 18%, 10%, 4% and 27% of patients had large-artery atherosclerosis, lacunae, cardioembolism, stroke of other determined etiology and stroke of undetermined etiology, respectively.
Among patients included in this study, most of them (86.0%) had anterior circulation stroke, 44.7% of them had left middle cerebral artery stroke, 34.7% of them had right middle cerebral artery stroke, 4.0% of them had anterior cerebral artery stroke, 2.6% had bilateral middle cerebral artery stroke, and 14.0% of patients had posterior circulation stroke. Sivanandy et al. (2011) found anterior circulation involvement in 73.9% of studied patients, posterior circulation in 4.3% of studied patients, and both in 12.9% of studied patients. Melakea et al. (2015) found anterior circulation involvement in 75% of studied patients, posterior circulation in 20% of studied patients, and both in 12.9% of studied patients.
According to the NIH stroke scale at admission, among 150 patients with first ever acute stroke included in this study, the majority of them had a moderate (58.0%) followed by minor stroke (29.3%) at admission. This could be due to the referral bias but we did see severe stroke in 12.7% of patients. This may be then explained by the fact that the majority of patients with severe stroke had one or more exclusion criteria especially the co-morbidities, or they had suffered from a recurrent stroke. Dewan and Rana (2011) in their study also found that the majority of patients had a moderate (53%) followed by mild (29%) and severe (18%) NIHSS grade at admission.
hsCRP in acute ischemic stroke patients and controls
In this prospective study, 71(47.3%) patients with acute ischemic stroke had high hsCRP (≥ 1 mg/L) levels compared to 12 (8%) healthy controls. Chaudhuri et al. (2013) in their study found that hsCRP level was significantly higher in stroke patients than in controls [130 (61.9%) vs. 10 (6.6%)]. Other studies have shown varying prevalence. Rajput et al. (2011) performed a study in stroke patients from Pakistan and found that 132 (88%) patients had elevated CRP level ( > 10 mg/L). In a study by Di Napoli et al. (2000) from Italy, 95 (74.2%) patients with acute ischemic stroke had high CRP levels (> 0.5 mg/dL) at admission. In a study by den Hertog et al. (2009) from the Netherlands, only 22% of stroke patients and 14% of myocardial infarction patients had high CRP (> 7 mg/L) levels. This variance may be explained partly by the different definitions of high CRP level in various studies.
In our current study, the mean serum hsCRP level was 2.12 ± 3.16 mg/L in patients with an interquartile range of 0.03–17.49 and it was 0.34 ± 0.47 mg/L in controls with an interquartile range of 0.02–3.22. There was statistically significant difference in serum hsXRP level between patients and controls (P < 0.001).
In a study by Chaudhuri et al. (2013) involving Indian patients, the mean hsCRP level was significantly higher in stroke patients (3.8 ± 2.5 mg/dl) than in controls (1.8 ± 1.5 mg/dl). Kocer et al. (2005) in their study found that the mean serum level of hsCRP was significantly higher in patients (3.12 ± 4.4 mg/dl) than in controls (0.39 ± 0.6 mg/dl).
Stroke risk factors and serum hsCRP level
In this study, we found that high serum hsCRP level was significantly associated with older age in our patients. A study by Rost et al. (2011) found that elevated CRP level was a significant predictor of future risk of ischemic cerebrovascular accident in the elderly.
In this study, serum hsCRP level was high in 59.2% of patients with dyslipidemia, 76.1% of patients with hypertension, 23.9% of smokers, 26.8% of patients with left ventricular dysfunction, 23.9% of patients with hyperhomocysteinemia, and 53.5% of patients with diabetes. Hypertension (P ≤ 0.001) and older age (P < 0.05) were significantly associated with high hsCRP levels, but there was no significant difference in other risk factors of stroke between high-level hsCRP and low-level hsCRP groups. Dewan and Rana (2011) found that CRP was positive in 79.2% of patients with dyslipidemia, 63.8% of patients with hypertension, 62.8% of alcohol consumers, 62.1% of smokers, 60% of patients with coronary artery disease, and 57.9% of diabetics. Chaudhuri et al. (2013) found that hsCRP was high in 46.2% of patients with hypercholesterolemia, 63.8% of patients with hypertension, 32.2% of smokers, 10.7% of patients with hyperhomocysteinemia, and 40.7% of patients with diabetics.
Brescacin et al. (2015) in their study involving 695 patients found that inflammation was associated with high blood pressure levels during the acute-phase and 1 month after an ischemic stroke; patients with higher hsCRP also had worse outcomes. Hart et al. (2000) performed a 20-year follow-up study in men and women in Scotland and reported an extremely significant association between hypertension and stroke risk (P < 0.0001).
Jiménez et al. (2015) reported that elevated hsCRP levels were associated with a great risk of total stroke, even after adjustment for potential confounders and cardiovascular risk factors and risk of total stroke was significantly higher in hypertensive men with elevated hsCRP level than in normotensive men with low hsCRP level. It is hypothesized that increasing levels of blood pressure may stimulate a pro-inflammatory response and that endothelial inflammation may also herald the changes in arterial wall that characterize the hypertensive state; inflammation and endothelial dysfunction could be the link between hypertension and post-stroke disability (Kara et al., 2014; Pandey et al., 2014; Tang et al., 2016; Zhou et al., 2016).
hsCRP and NIHSS grade
In our study, we found that serum hsCRP levels varied according to NIHSS grade on admission. The mean serum hsCRP level was the lowest in mild grade, followed by in moderate and severe grades. Significant statistical difference was found in serum hsCRP levels among the various NIHSS grades. Our findings were similar to that of a study done by Dewan and Rana (2011).
hsCRP in stroke subtypes
In this study, the prevalence of high hsCRP level was highest in large-artery atherosclerosis (35.2%), followed by in cardioembolic stroke (28.2%), small-vessel occlusion (19.7%), stroke of undetermined etiology (9.9%), and stroke of other determined etiology (7.0%). There was significant difference in the prevalence of high hsCRP level between TOAST stroke subtypes (P = 0.002). Moreover, mean serum hsCRP level was highest in large-artery atherosclerosis subtype, followed by in stroke of undetermined etiology, cardioembolic subtype, small-vessel occlusion subtype, and stroke of other determined etiology subtype.
In a study by Chaudhuri et al. (2013), the prevalence of high hsCRP level was highest in cardioembolic stroke followed by large-artery atherosclerosis and small artery disease. Dewan and Rana (2011) in their study found that hsCRP was highest in patients with lacunar stroke, followed by in large-artery atherosclerotic infarction and cardioembolic etiology.
In this study, high hsCRP levels were found in 35.2% of patients with large-artery atherosclerosis. Rajeshwar et al. (2012) found high CRP level in both intracranial (48.7%) and extracranial large-artery atherosclerosis (54.9%). In contrast, few studies reported a much lower percentage of high hsCRP levels. den Hertog et al. (2009) and Dewan and Rana (2011) reported that 15% and 14.9% of patients with large-artery atherosclerosis, respectively, had high CRP levels.
In this study, high hsCRP levels were found in 28.2% of patients with cardioembolic stroke. den Hertog et al. (2009) performed a study in a Dutch population and reported that 15% of patients with cardioembolic stroke had high CRP levels. Dewan and Rana (2011) performed a study in a Nepalese population and reported that 14.9% of patients with cardioembolic stroke had high CRP levels. Two other studies from India by Rajeshwar et al. (2012) and Chaudhri et al. (2013) reported that 58.3% and 83.3% of patients with cardioembolic stroke, respectively, had high CRP levels.
Small vessel disease
In this study, the prevalence of high hsCRP levels was lower in stroke patients due to small vessel disease than in large-artery atherosclerosis and cardioembolic stroke. We found 19.7% of our small vessel patients had high hsCRP levels. Muir et al. (1999) reported that 21.8% of acute ischemic patients with small vessel disease had elevated CRP level (> 10 mg/L) and 29.8% of lacunar patients from Nepal in a study by Dewan and Rana (2011) had high CRP levels. den Hertog et al. (2009) reported that 13% of patients with small vessel disease had high hsCRP level. Rajeshwar et al. (2012) reported a 12.6% prevalence of high hsCRP levels.
In this study, multiple logistic regression analysis revealed that high hsCRP level is independently associated with acute ischemic stroke (OR = 3.87, 95% CI: 2.39–6.27). The association was found in all ischemic stroke subtypes. Strongest association was found among the stroke subtypes of cardioembolic stroke (OR = 4.97, 95% CI: 2.5–9.65), large-artery atherosclerosis (OR = 4.76, 95% CI: 2.57–8.81) and stroke of undetermined etiology (OR = 3.35, 95% CI: 1.72–6.54). Chaudhri et al. (2013) found that high hsCRP level was independently associated with acute ischemic stroke (OR = 4.5; 95% CI: 2.5–12.2), especially cardioembolic stroke (OR = 3.4, 95% CI: 1.9–10.5) and large-artery atherosclerosis (OR = 2.1, 95% CI: 1.5–3.8).
Conclusion and recommendations
Based on our study’s findings and conclusions, we can make the following recommendations.
- Significantly high hsCRP prevalence among patients in our study suggests the important role of inflammation in ischemic stroke pathogenesis. It needs to be further evaluated whether some infectious agents trigger a proinflammatory response besides the conventional risk factors in patients with ischemic stroke. High hsCRP level may be a marker to initiate primary and secondary preventive strategies. Everett et al. (2010) did a large randomized, clinical trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Patients were eligible for enrollment if they had no evidence of cardiovascular disease, diabetes, or hyperlipidemia but had an hsCRP level ≥ 2.0 mg/L. They were randomized to undergo Rosuvastatin or Placebo. The study was stopped early because of evidence of benefit from rosuvastatin therapy, with a significant reduction in the incidence of major cardiovascular events, including stroke. There was a 48% relative reduction in risk of stroke among those taking rosuvastatin (Everett et al., 2010).
- hsCRP as a biomarker in acute ischemic stroke can be considered as a non-invasive tool which might add important information regarding etiology and outcome. High hsCRP levels in patients with acute ischemic stroke may suggest high probability of cardioembolic or large-artery atherosclerosis stroke subtypes. High hsCRP level on admission may suggest stroke severity based on NIHSS grade, and might help in predicting prognosis.
Studies over a longer period with adequate follow up duration and involving a larger number of patients are needed to estimate the role of hsCRP versus other risk factors to justify the recommendation and/or of routine measurement of hsCRP in ischemic stroke patients.
Additional file 1: Hospital Ethics Approval.
Additional file 2: Informed Consent Form.
Additional file 3: Information Sheet for the Patient.
All authors contributed to study design, data collection, statistical analysis, and manuscript writing, and approved the final manuscript.
Conflicts of interest
The authors declare no conflicts of interest in this study.
Institutional review board statement
This study protocol was approved by the Sir Ganga Ram Hospital Ethics Committee, India (approval number EC/07/14/701) on July 5, 2014 and was performed in accordance with the Declaration of Helsinki.
Declaration of participant consent
The authors certify that they have obtained all appropriate participant consent forms. In the form the participants have given their consent for their images and other clinical information to be reported in the journal. The participants understand that their names and initials will not be published and due efforts will be made to conceal their identity.
This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.
The statistical methods of this study were reviewed by the biostatistician of Sir Ganga Ram Hospital, India.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be available. Study protocol, informed consent form will be available immediately after publication. Data will be available for investigations whose proposed use of the data has been approved by an independent review committee identified for this purpose for individual participant data meta-analysis. Proposals should be directed to corresponding author ([email protected]).
Checked twice by iThenticate.
Externally peer reviewed.
| References|| |
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35-41.
Bonita R (1992) Epidemiology of stroke. Lancet 339:342-348.
Brescacin L, Alonzo C, Zurru MC, Luzzi A, Guido B, Camera L, Cristiano E, Waisman G (2015) High sensitive C-reactive protein and blood pressure in ischemic stroke. J Hypertens doi: 10.1097/01.hjh.0000468787.68139.79.
Brondum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M (2013) 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann Neurol 73:38-47.
Chaudhuri JR, Mridula KR, Umamahesh M, Swathi A, Balaraju B, Bandaru VC (2013) High sensitivity C-reactive protein levels in acute ischemic stroke and subtypes: A study from a tertiary care center. Iran J Neurol 12:92-97.
Clark WM, Hourihane JM (1997) Clinical Stroke Scales. In: Handbook of Neurologic Rating Scale (Harndon RM, ed). New York: Demos Vermande.
Dalal PM (2006) Burden of stroke: Indian perspective. Int J Stroke 1:164-166.
den Hertog HM, van Rossum JA, van der Worp HB, van Gemert HM, de Jonge R, Koudstaal PJ, Dippel DW; PAIS investigators (2009) C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death. J Neurol 256:2003-2008.
Devaraj S, Dasu MR, Singh U, Rao LV, Jialal I (2009) C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo. Atherosclerosis 203:67-74.
Devaraj S, Xu DY, Jialal I (2003) C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 107:398-404.
Dewan KR, Rana PV (2011) C-reactive protein and early mortality in acute ischemic stroke. Kathmandu Univ Med J (KUMJ) 9:252-255.
Di Napoli M, Gianfilippo G, Sollecito A, Bocola V (2000) C-reactive protein and outcome after first ever ischemic stroke. Stroke 31:238-239.
Everett BM, Glynn RJ, MacFadyen JG, Ridker PM (2010) Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circulation 121:143-150.
Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448-454.
Hart CL, Hole DJ, Smith GD (2000) Comparison of risk factors for stroke incidence and stroke mortality in 20 years of follow-up in men and women in the renfrew/paisley study in Scotland. Stroke 30:1893-1896.
Jiménez MC, Rexrode KM, Glynn RJ, Ridker PM, Gaziano JM, Sesso HD (2015) Association between high-densitivity C-reactive protein and total stroke by hypertensive status among men. J Am Heart Assoc 4:e002073.
Kara H, Akinci M, Degirmenci S, Bayir A, Ak A, Nayman A, Unlu A, Akyurek F, Sivri M (2014) High-sensitivity C-reactive protein, lipoprotein-related phospholipase A2, and acute ischemic stroke. Neuropsychiatr Dis Treat 10:1451-1457.
Kaul S, Sunitha P, Suvarna A, Meena AK, Uma M, Reddy JM (2002) Subtypes of ischemic stroke in a metropolitan city of South India (one year data from a hospital based stroke registry). Neurol India 50 (Suppl 1):8-14.
Kocer A, Canbulat C, Gozke E, Ilhan A (2005) C-reactive protein is an indicator of fatal outcomes in first time stroke patients. Med Sci Monit 11:540-544.
Koenig W, Sund M, Fröhlich M, Fischer HG, Löwel H, Döring A, Hutchinson WL, Pepys MB (1999) C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 99:237-242.
Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135-1143.
Melakea MS, El-Kabanya RA, Al-Emama AI, El-Shereefa AM, Okdaa M (2015) The role of D-dimer, fibrinogen and C-reactive protein as plasma biomarkers in acute ischemic stroke. Neurol Res 5:277-282.
Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR (1999) C-reactive protein and outcome after ischemic stroke. Stroke 30:981-985.
Nagaraja D, Gururaj G, Girish N, Panda S, Roy AK, Sarma GR, Srinivasa R (2009) Feasibility study of stroke surveillance: data from Bangalore, India. Indian J Med Res 130:396-403.
O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, et al. (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376:112-123.
Pandey A, Shrivastava AK, Saxena K (2014) Neuron specific enolase and C-reactive protein levels in stroke and its subtypes: correlation with degree of disability. Neurochem Res 39:1426-1432.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention; American Heart Association (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107:499-511.
Prasad K, Dash D, Kumar A (2012) Validation of the Hindi version of National Institute of Health Stroke Scale. Neurol India 2012;60:40-44.
Rajeshwar K, Kaul S, Al-Hazzani A, Babu MS, Balakrishna N, Sharma V, Jyothy A, Munshi A (2012) C-reactive protein and nitric oxide levels in ischemic stroke and its subtypes: correlation with clinical outcome. Inflammation 35:978-984.
Rajput MR, Lakhair MA, Shaikh MA, Rind MS, Zafarullah, Bano R (2011) C-reactive protein (CRP) and other risk factors in acute ischemic stroke patients. J Liaquat Uni Med Health Sci 10:131-133.
Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW (2001) Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack. Stroke 32:2575-2579.
Sabatine MS, Morrow DA, Jablonski KA, Rice MM, Warnica JW, Domanski MJ, Hsia J, Gersh BJ, Rifai N, Ridker PM, Pfeffer MA, Braunwald E; PEACE Investigators (2007) Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation 115:1528-1536.
Sharma VK, Tsivgoulis G, Teoh HL, Ong BK, Chan BP (2012) Stroke risk factors and outcomes among various Asian ethnic groups in Singapore. J Stroke Cerebrovasc Dis 21:299-304.
Sivanandy P, Thomas B, Krishnan V, Arunachalam S (2011) Safety and efficacy of thrombolytic therapy using rt-PA (Alteplase) in acute ischemic stroke. ISRN Neurol 2011:618624.
Tang CZ, Zhang YL, Wang WS, Li WG, Shi JP (2016) Serum levels of high-sensitivity C-reactive protein at admission are more strongly associated with post stroke depression in acute ischemic stroke than homocysteine levels. Mol Neurobiol 53:2152-2160.
Zhou Y, Han W, Gong D, Man C, Fan Y (2016) Hs-CRP in stroke: A meta-analysis. Clin Chim Acta 453:21-27.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||High Sensitivity C- Reactive Protein Level in Acute Cerebrovascular Accident (Stroke) at a Tertiary Care Centre
| ||Sunil Dhanraj Bhaisare,Aniruddha Sunildatta Jog,Anuradha Krishnaraj Rao,Hariom Uddhav Kolapkar |
| ||Journal of Evolution of Medical and Dental Sciences. 2020; 9(10): 764 |
|[Pubmed] | [DOI]|
||Ligustilide protects PC12 cells from oxygen-glucose deprivation/reoxygenation-induced apoptosis via the LKB1-AMPK-mTOR signaling pathway
| ||Dan-Yang Zhao,Dong-Dong Yu,Li Ren,Guo-Rong Bi |
| ||Neural Regeneration Research. 2020; 15(3): 473 |
|[Pubmed] | [DOI]|
||Blood-Based Biomarkers Are Associated with Different Ischemic Stroke Mechanisms and Enable Rapid Classification between Cardioembolic and Atherosclerosis Etiologies
| ||Dorin Harpaz,Raymond C. S. Seet,Robert S. Marks,Alfred I. Y. Tok |
| ||Diagnostics. 2020; 10(10): 804 |
|[Pubmed] | [DOI]|
||Neuroprotective mechanism of TMP269, a selective class IIA histone deacetylase inhibitor, after cerebral ischemia/reperfusion injury
| ||Lu Su,Dan Liang,Shen-Yi Kuang,Qiang Dong,Xiang Han,Zheng Wang |
| ||Neural Regeneration Research. 2020; 15(2): 277 |
|[Pubmed] | [DOI]|
||Neuronal autophagy aggravates microglial inflammatory injury by downregulating CX3CL1/fractalkine after ischemic stroke
| ||Hong-Yun He,Lu Ren,Tao Guo,Yi-Hao Deng |
| ||Neural Regeneration Research. 2019; 14(2): 280 |
|[Pubmed] | [DOI]|