ORIGINAL RESEARCH ARTICLE
 
High-sensitivity C-reactive protein onseverity and prognosis of symptomic middle cerebral artery atherosclerotic stenosis
Cao JX¹, Jiang JD¹,Liu L¹,Liu H¹,Zhuang AX¹, Geng DQ^2
 
1Department of Neurology,Lianyungang City Second People’s Hospital,Jiangsu, People’s Republic of China
²Department of Neurology,Affiliated Hospital of Xuzhou Medical College, Jiangsu, People’s Republic of China
 
Abstract:Objective: To investigate the relationship between high-sensitivity CRP(hs-CRP) and poor outcome (modified Rankin Scale score>2) or endpoint events at 3 months inpatients with symptomatic middle cerebral artery atherosclerotic stenosis(SMCAAS). Methods: One hundred and twenty-three consecutive patients with SMCAAS were admitted within 72 hours of symptom onset. hs-CRP and NIH stroke scale (NIHSS) were measured at the time of admission. Patients were followed-up for up to 3 months for short-term functional outcome measured by modified Rankin scale (mRS) and endpoint events. Logistic regression model was applied to adjust for confounding variables. Results: Patients with hs-CRP levels >3 mg/L had high NIHSS (P< 0.001)and poor short-term functional outcomes or endpoint events (P=0.01; P =0.03). After adjusting for confounding variables, high hs-CRP remained to be associated with high end point events (P=0.033)at 3 months only.Conclusion: hs-CRP concentration is an independent predictor of endpoint events at 3 months when measured within 72 hours after onset of SMCAAS.
Keywords:C-reactive protein;symptomatic middle cerebral artery atherosclerotic stenosis; MR angiography; prognosis
Citation:Cao JX et al, High-sensitivity C-reactive protein onseverity and prognosis of symptomic middle cerebral artery atherosclerotic stenosis, J Gen Neuro 2016; 1(1):
 
*Correspondence to:
Received:            Accepted:           Published Online:
Introduction
Atherosclerotic intracranial artery stenosis is themain cause of ischemic cerebral apoplexy in China, mainly happening in the middle cerebral artery (MCA), with a high rate of relapse ^[1,2].Curative effectsare unsatisfactory even with regular treatment of atherosclerosis intracranial artery lesions^[1,2].Disease severity and prognosis related serological indicator has important practical significance. C-reactive protein (CRP) is an indicator which has been extensively researchedas atherosclerosis and cardiovascular disease risk factors in recent years, and it is one of the indicationof vascular disease prognosis and future vascular events^[3].Inflammation also occurs in intracranial atherosclerotic stenosis^[4]. Not much research has been done on the relationship of disease severity and prognosis of CRP and symptomatic intracranial artery stenosisdue to the high recurrence of symptomatic intracranial artery stenosisin the early phase^[5–7].This study aimed to investigate the predictive valueof condition judgment and short-term prognosis of high sensitivity C-reactive protein(hs-CRP) in symptomatic middle cerebral artery stenosis.
 
Materials and Methods
One hundred and twenty-threecases of symptomatic middle cerebral artery atherosclerotic stenosisconfirmed by transcranial Doppler (TCD) and MRA clinical diagnosis were selectedfrom September 2008 to March 2011.All patients had an attack within 72 hours.There were 76 male and 47 female cases, 40 to 87 years old,with an average of 69.3 ±11.2 years old.At the same time, diffusion weighted imaging (DWI) examinations confirmed new infarctions of 40 or higher in narrow MCA blood vessels.Patients’ clinical data and main risk factors of stroke were recorded, including afamily history of stroke, hypertension, diabetes mellitus (DM), coronary heart disease, high cholesterol, tobacco use, alcoholism, and carotid plaques. All of the patients were examined based on the National Institute of Health Stroke Scale Score (NIHSS) and followed-up with amodified Rankin Scale (mRS) score 3 months after treatment (mRS> 2 is categorized in the poor prognosis index) and endpoint events incidence.Endpoint events include the primary endpoint (TIA) and cerebral infarction, while secondary events wereacute angina and myocardial infarction, and death.
 
Determination of hs-CRP Serum
Venous blood serum (3 mL) was extracted from patients before any food intakethe next morning.The serum was centrifugedand analyzedusing an automated special protein analyzer[AR1] (Beckman Coulter,USA).hs-CRP kit [AR2] (Beckman Coulter, USA) using immune scattering turbidimetric method was used for quantitative determination. Tests were conducted as per the kit’s instructionsand were classified as normal (0–3 mg/L) and above average (greater than 3 mg/L).hs-CRP≥ 9.5 mg/L was consideredpotentiallyinfectious and were not included in the analysis.
 
MRI analysis
Using Siemens 1.5T superconducting magnetic resonance system, all patients were screened by MRI (conventional MRI DWI) and three-dimensional time leap method of magnetic resonance angiography (3D TOF MRA) examination within 5 d after having an attack, androutine MRI including T₁ weighted and T₂ weighted FLAIR sequence line transverse, sagittal scans, and MRA examinations including intracranial vascular were conducted. Two consecutive high intensity DWI signals can be regarded as acute cerebral infarction.
 
MCA Stenosis Criterion
Standard of MRA in the diagnosis of MCA stenosis:The degree of tube cavity stenosis and signal loss was based upon MRA display according to Gao etal.to evaluate the degree of vascular stenosis^[8].More than 50% of cerebral artery stenosis was defined as meaningful narrow lesions in this study andpatients with extracranial stenosis of 50% or higher were excluded. The blood flow velocity ofMCA stenosis was diagnosed by TCDwith the following conditions:all patients had been accepted for TCD examination within 5 d after an attack;the peak systolic blood flow velocity ≥140 cm/sand the mean flow velocity (MFV) ≥l00 cm/s with spectrum disorders and/or vortex noise suggested that there may be MCA stenosis; the existence of MCA stenosis must be confirmed with TCD and MRA examinations for all patients, and other intracranial artery stenosis were recorded.
 
Statistical analysis
Statistical analyses were done using SPSS 13.0 statistical software. Normal distribution variables, such as the t-test and non-normal distribution variables adopting the median and interquartile range description, such as the non-parametric test were conducted. Data countsusing χ² test, small sample Fisher’s inspection, Spearman’s correlation analysis method, multiple factors Logistic regression analysis were done withP values < 0.05 were all statistically significant.
 
Results
Five hundred and eighty-nine cases of hospitalized patients diagnosed with cerebral infarction were selected. The eligible patients with symptomatic MCA stenosis were 123 cases, with 108 cases of cerebral infarction(87.8%) and 15casesof transient ischemic attack (TIA)(12.2%).The risk factors of symptomatic MCA stenosis apoplexy were: 87 cases of hypertension(70.7%), 41 cases of diabetes(33.3%), 68 cases of hyperlipidemia(55.3%), 25 cases of coronary heart disease(20.3%), 58 cases of tobacco use(47.2%), 32 cases of alcoholism(26.0%), and 31 cases with a family history of stroke(25.2%). hs-CRP were abnormallydistributed, within the range of 0.14–8.84 mg/L, with a median of 2.17 mg/L, and the interquartile range of 1.06–4.54 mg/L. Patients were divided into the normal hs-CRP group (hs-CRP≤3 mg/L) and increased hs-CRP group(hs-CRP > 3 mg/L); thetwo groups were compared.There were 44 cases in the hs-CRP increased group(35.8%), and their stroke risk factors such asDM and tobacco usewere higher than the normal hs-CRP group (Table 1).
 
 
The relationship betweenhs-CRP and illness severity of SMCAAS
The SMCAAS illness severity through NIHSS expression scoreswere abnormal distribution, range of 0 to 6, with a median of 3 and the interquartile range of 2–4. NIHSS score of the hs-CRP increased group was higher than that of normal hs-CRP group (P< 0.001; rank-sum test, see Table 1). Correlation analysis results showed that the hs-CRP levels and NIHSS scores were positively correlated (r = 0.454, P< 0.001; Spearman’s correlation).
 
The relationship between hs-CRP and short-term prognosis of SMCAAS
Three months after treatment, the degree of functional recovery in patients (mRS score)wereof abnormal distribution, ranging from0 to 5, with a median of 2, and the interquartile range of 1–3. NIHSS score of the hs-CRP increased group was higher than that of normal hs-CRP group (P = 0.001; rank-sum test), and the incidence of poor prognosis was significantly higher than the normal hs-CRP group (63.6%,30.4%;P = 0.001; OR4.01,95% CI1.84–8.74). In the logistic regression analysis, hs-CRP > 3 mg/L was not an independent risk factor for poor prognosis (P = 0.69). There were 17 cases of outcome events(13.8%),12 cases recurrent of stroke (9.8%), 5 patients died (4.1%) and in the3 months follow-up, 4 cases of vascular factors, 2 cases of cerebral infarction recurrences, 1 case of myocardial infarction, 1 case of lower limb arterial thrombosis, 1 case of vascular factors and 3 cases pulmonary infections. The endpoint events of the hs-CRP increased group was significantly higher than that of normal hs-CRP group(25.0%,7.6%;P=0.007, 0R4.06,95%CI1.38–11.89). In the logistic regression analysis, control other confounding factors such as gender, age, hypertension, diabetes, hyperlipidemia, coronary heart disease, tobacco use, alcohol consumption, family history of stroke, NIHSS score, etc.,hs-CRP > 3 mg/L (OR3.98;95% CI1.12–14.23;P=0.033) was an independent risk factor for SMCAAS endpoint events.
 
Discussion
The NIHSS score of the hs-CRP increased group wassignificantly higher than that of normal hs-CRP group in patients with symptomatic middle cerebral artery atherosclerotic stenosis(SMCAAS) at admission.According to the results of this study andthe mRS score, poor prognosis, recurrence of ischemic vascular lesions and the risk of death weresignificantly higher than the normal groupafter 3 months follow-up.Theseresults corrected other cerebrovascular disease risk factors after the acute phase of hs-CRP increaseand is still closely related to the endpoint event for the independent risk factors;the hs-CRP increased group had 3.98 times risk of endpoint events occurring than the normal group(P=0.033). These results suggested that acute hs-CRP levels are closely related to SMCAAS condition and short-term prognosis risk predictors.
 
As an acute inflammatory reaction protein,CRP is minimally availablein the serum or plasmaunder normal circumstances. Serum CRP concentration can be quickly elevated into one hundred times if there is an acute inflammation in the body. Numerous studies have found that atherosclerosis is a chronic inflammation and it would continuously increaseserum CRP levelsfrom 3 to 10 mg/L.Conventional CRP detection methods would be unable to detect such an increase (lower limit detection of 8–10 mg/L) thus the hs-CRP detection (detection range of 0.01–10.00 mg/L) can improve the sensitivity of CRP determination. Past studies have shown that the increase of serum CRP concentration is one of the independent risk factors for cardiovascular diseases withthe reason beingthe hardening of intracranial and extracranialarteries;coronary atherosclerosis have certain differences^[3–10]. The relationship studiesbetween hs-CRPand intracranial atherosclerosis especially with SMCAAS areless, and the detection time and follow-up timesare also inconsistent^[4–6]. Arenillaset al. found that CRP levels after 3 months was related to prognosis risk of 1-year symptomatic intracranial artery stenosis follow-up and found that elevated levels of CRP wasindependentlyassociated with intracranial atherosclerosis progression^[4,6]. Intracranial atherosclerosis has a dynamic evolutionary process, and intracranial atherosclerosis progression was closely related with the recurrence of ischemic vascular lesions and the risk of death supported the results^[4–11].
 
The hs-CRP levels of acute SMCAAS disease severity of short-term prognosis related mechanism is not clear.It could be that serum hs-CRP in the acute phase of SMCAAS reflects the degree of brain tissue damage and individual levels of inflammation;increase in hs-CRP during the acute phase of brain tissue damagehas strong inflammatory reaction sothe risk of cardiovascular disease and future recurrence would be also increased^[3–9].hs-CRP increased by inflammatory mechanisms promotes vascular endothelial injury and intracranial atherosclerosis progress, and is closely related to the recurrence of ischemic vascular disease and mortality risk^[9–14]. It canalso directly damage the blood-brain barrier, promotingbrain tissue damage ^[15].
 
Intracranial atherosclerosis is the major cause of stroke in Asian populations, especially brain artery stenosis or occlusion, and there is still lack of ideal treatments. Effective evaluation and screening of high-risk patients with SMCAAS would predict its prognosis withimportant theoretical values and practical significance. The results showedthe risk of ischemic vascular lesions and death for SMCAAS patientswith increasedhs-CRP levelswere significantly higher than that of normal hs-CRP within 3 months. These results suggestedthat acute hs-CRP levels wereclosely related to SMCAAS conditions and are short-term prognosis risk predictors.These results have important significance in the treatment and secondary prevention of SMCAAS in the future. More attention should be doneto detect the levels of hs-CRP and for intervention in the early phase for SMCAAS treatment. The instability of intracranial atherosclerosis plaque using anti-inflammatory intervention therapy according to hs-CRP levels might improve the prognosis of SMCAAS;more research should be done^[15].
 
References
1.      Komotar RJ, Kellner CP, Raper DM, Strozyk D, Higashida RT, et al. Update on the natural history of intracranial atherosclerotic disease: a critical review.World J Radiol 2010;2(5):166–171.doi: 10.4329/wjr.v2.i5.166.
2.      Samaniego EA, Hetzel S, Thirunarayanan S, Aagaard-Kienitz B, Turk AS, et al. Outcome of symptomatic intracranial atherosclerotic disease.Stroke2009;40(9):2983–2987.doi: 10.1161/STROKEAHA.109.549972.
3.      Schlager O, Exner M, Mlekusch W, Sabeti S, Amighi J, et al.C-reactive protein predicts future cardiovascular events in patients with carotid stenosis.Stroke2007;38(4):1263–1268.doi: 10.1161/01.STR.0000259890.18354.d2.
4.      Arenillas JF, Álvarez-Sabín J, Molina CA, Chacón P, Fernández-Cadenas I, et al. Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis.Stroke2008;39(5):1456–1463.doi: 10.1161/STROKEAHA.107.498600.
5.      Arenillas JF, Massot A, Álvarez-Sabín J, Fernandez-Cadenas I, del Rio-Espinola A, et al. C-reactive protein gene C1444T polymorphism and risk of recurrent ischemic events in patients with symptomatic intracranial atherostenoses. Cerebrovasc Dis2009;28(1):95–102.doi: 10.1159/000222660.
6.      Arenillas JF, Álvarez-Sabín J, Molina CA, Chacón P, Montaner J, et al. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease.Stroke2003;34(10):2463–2468.doi: 10.1161/01.STR.0000089920.93927.A7.
7.      Ovbiagele B, Cruz-Flores S, Lynn MJ, Chimowitz MI, Warfarin-Asparin Symptomatic Intracranial Disease (WASID) Study Group. Early stroke risk after transient ischemic attack among individuals with symptomatic intracranial artery stenosis.Arch Neurol2008;65(6):733–737.doi:10.1001/archneur.65.6.733.
8.      Gao S, Wong KS, Huang YN, Li SW. (Chinese) [Diagnosis and epidemiology of large intracranial artery stenosis].ZhongguoYiXueKeXue Yuan XueBao2003; 25(1):96–100.
9.      Elkind MS, Luna JM, Moon YP, Liu KM, Spitalnik SL, et al.High-sensitivity C-reactive protein predicts mortality but not stroke: the Northern Manhattan Study. Neurology2009;73(16):1300–1307.doi: 10.​1212/​WNL.​0b013e3181bd10bc.
10.  Man BL, Fu YP, Chan YY, Lam W, Hui ACF, et al. Lesion patterns and stroke mechanisms in concurrent atherosclerosis of intracranial and extracranial vessels.Stroke2009;40(10):3211–3215.doi: 10.1161/STROKEAHA.109.557041.
11.  Arenillas JF, Molina CA, Montaner J, Abilleira S, González-Sánchez MA, et al. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study.Stroke2001;32(12):2898–2904.doi: 10.1161/hs1201.099652.
12.  Youn CS, Choi SP, Kim SH, Oh SH, Jeong WJ, et al. Serum highly selective C-reactive protein concentration is associated with the volume of ischemic tissue in acute ischemic stroke. Am J Emerg Med 2010; 30(1): 124–128.doi: 10.1016/j.ajem.2010.11.006.
13.  Purroy F, Montaner J, Molina CA, Delgado P, Arenillas JF, et al. C-reactive protein predicts further ischemic events in transient ischemic attack patients.ActaNeurolScand2007;115(1):60–66.doi: 10.1111/j.1600-0404.2006.00715.x.
14.  Kuhlmann CR, Librizzi L, Closhen D, Pflanzner T, Lessmann V, et al. Mechanisms of C-reactiveprotein-induced blood-brain barrier disruption. Stroke2009;40(4):1458–1466.doi: 10.1161/STROKEAHA.108.535930.
15.  Chan YH, Lau KK, Yiu KH, Li SW, Chan HT, et al.Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke. Eur Heart J2008;29(22):2800–2807.doi: 10.1093/eurheartj/ehn409.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 The basic information of symptomatic MCA stenosis patients

	Normal hs-CRP group (79 cases)	Increasedhs-CRP group (44 cases)	P value
Age mean (SD) Gender(male) Diabetes; n (%) Blood pressure; n (%) Hyperlipidemia; n (%) Tobacco use; n (%) Alcohol consumption; n (%) Coronary heart disease (CHD); n (%) Family history of stroke; n (%) NIHSS, mean (SD) mRS> 2; n (%) Recurrent stroke; n (%) Death; n (%) Endpoint events	65.39(9.83) 47 (32) 20(25.3%) 54(68.4%) 41(51.9%) 31(39.2%) 19(24.1%) 12(15.2%) 19(24.1%) 2.33(1.56) 24(30.4%) 4(5.1%) 2(2.5%) 6(7.6%)	66.77(9.69) 29 (15)            21(47.7%) 33(75.0%) 27(61.4%) 27(61.4%) 13(29.5%) 13(29.5%) 12(27.3%) 3.46(1.19) 28(63.6%) 8(18.2%) 3(6.8%) 11(25.0%)	0.45 0.48 0.01 0.44 0.31 0.02 0.51 0.06 0.69 0.001 0.001 0.027 0.348 0.007