Abstract
Aim: This study aimed to investigate the relationship between symptomatic or asymptomatic intracranial/extracranial artery stenosis and high-sensitivity C-reactive protein (hs-CRP) levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA).
Methods: This study included 10404 patients from the Third China National Stroke Registry. Patients were divided into four or six groups according to patterns of intracranial or extracranial artery stenosis and hs-CRP levels. The outcomes were recurrence of ischemic stroke, stroke, and combined vascular events (CVE) at 1 year. The associations between different combinations of hs-CRP levels and patterns of artery stenosis and recurrent events were analyzed by multivariable Cox regression models.
Results: Patients in Group III (hs-CRP ＜3＋symptomatic intracranial or extracranial artery stenosis) had higher risk of recurrent ischemic stroke (adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.20–2.48,p=0.003). Those in Group VI (hs-CRP ≥ 3＋symptomatic intracranial or extracranial artery stenosis) had the highest risk of recurrent ischemic stroke (HR 2.04, 95% CI 1.42–2.92,p=0.0001) within 1 year compared with Group I (hs-CRP ＜3＋no artery stenosis). Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels.
Conclusion: Symptomatic intracranial or extracranial artery stenosis was associated with increased risk of recurrent ischemic stroke, stroke, and CVE at 1 year in patients with AIS or TIA, especially in patients with elevated hs-CRP levels. Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels.
Keywords: Inflammation, Intracranial/extracranial artery stenosis, Ischemic stroke
Introduction
Intracranial arterial stenosis (ICAS) or extracranial arterial stenosis (ECAS) is an important cause of ischemic stroke 1 , 2) and an independent predictor for stroke recurrence, even in patients with aggressive medical therapy 3 - 5) . Previous studies revealed that symptomatic arterial stenosis appeared to have a higher risk of stroke recurrence 5 - 7) , but studies comparing the recurrence rate of ischemic events in different arterial stenosis patterns (no stenosis, asymptomatic, and symptomatic) directly were very limited. Subgroup analysis of the Oxford Vascular Study (OXVASC) 8) revealed that there was no difference between patients with asymptomatic intracranial stenosis vs. no intracranial stenosis in risk of recurrent ischemic stroke, but risk was increased significantly in patients with symptomatic intracranial stenosis. However, this study was based on patients with minor stroke or transient ischemic attack (TIA). Whether consistent results could be obtained in a wider acute ischemic stroke (AIS) or TIA population need further study.
Inflammation plays an important role in atherosclerosis and thrombosis. Several studies have confirmed that high levels of inflammation could increase the risk of stroke recurrence 9 - 11) . We hypothesized that it might be helpful to combine artery stenosis and inflammation indicators for risk stratification based on a previous study 12) . This study aimed to investigate the relationship between patterns of intracranial or extracranial artery stenosis and high-sensitivity C-reactive protein (hs-CRP) levels in patients with AIS or TIA based on a large, multicenter, national stroke registration study.
Methods
Study Population
The Third China National Stroke Registry (CNSR-III) is a nationwide prospective registry that included 15166 patients with AIS or TIA from 201 hospitals between 2015 and March 2018 in China. Participants were consecutively enrolled if they met the following criteria: (1) ＞18 years old; (2) diagnosis of ischemic stroke or TIA within 7 days; and (3) informed consent from participant or legally authorized representative. The study was approved by ethics committees, and written informed consents were obtained. The detailed design and main results of the CNSR-III trial have been described previously 13) .
Basic Data Collection
Baseline data were collected prospectively using an electronic data capture system by face-to-face interviews, including age, sex, body mass index (BMI), current smoking, medical history (hypertension, diabetes, dyslipidemia, ischemic stroke, TIA, coronary heart diseases, atrial fibrillation/flutter), previous medication, TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria, NIHSS (National Institutes of Health Stroke Scale score) at admission, and medication during hospitalization.
Sample Collection and Measurement of Blood Markers
Fasting blood samples were collected in serum-separation tubes and EDTA anticoagulation blood collection tube within 24 h of admission. All blood samples were frozen in cryotube at −80℃ refrigerator and transported through cold chain to the center laboratory in Beijing Tiantan Hospital. The median time of sampling was 55 (interquartile range (IQR) 27–96) h after index event onset. The concentrations of plasma hs-CRP and serum low-density lipoprotein (LDL-C) were measured on Roche Cobas C701 and C702 analyzers, respectively. Hs-CRP levels were stratified according to the relative risk category (low to medium risk, 0–3 mg/L; high risk, ＞3 mg/L) recommended by the Centers for Disease Control and Prevention and the American Heart Association 14) , which was recommended for the risk assessment of cardiovascular disease.
Image Analysis
All patients’ image data during hospitalization were collected and uploaded to the center laboratory of Beijing Tiantan Hospital for centralized interpretation. Evaluation of intracranial artery stenosis was based on magnetic resonance angiography (MRA, 88.1%), computerized tomography angiography (CTA, 11.5%), and digital subtraction angiography (DSA, 0.4%). Evaluation of extracranial artery stenosis was based on Doppler (82.5%), CTA (10.5%), contrast enhanced MRA (6.4%), and DSA (0.5%). The presence of ICAS or ECAS (summarized as AS) was defined as 50%–99% stenosis or occlusion, by the Warfarin-Aspirin Symptomatic Intracranial Disease trial 15) and the North American Symptomatic Carotid Endarterectomy Trial criteria 16) . No artery stenosis (n-AS) was defined as ＜50% stenosis. Relevance of ICAS/ECAS to the index stroke (symptomatic artery stenosis, s-AS) was determined according to clinical symptoms, brain magnetic resonance imaging, and vascular images. Asymptomatic artery stenosis (a-AS) was defined as 50%–99% stenosis or occlusion but not related to this ischemic event. Infarction patterns (no infarction/single infarction/multiple infarcts) were evaluated based on diffusion-weighted imaging. Trained assessors who were blind to clinical data of patients independently evaluated vascular stenosis and infarction patterns. All images were visually evaluated by two experienced readers, and discrepancies were resolved by a third reader.
Outcomes Assessment
Recurrent events included ischemic stroke, stroke (new ischemic stroke or hemorrhagic stroke), and combined vascular events (CVE, including ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death) at 1 year. Confirmations of events were sought from the treating hospital, and suspected events without hospitalization were judged by independent endpoint judgment committee. Each case fatality was confirmed on a death certificate from either the attended hospital or the local citizen registry.
Statistical Analysis
Continuous variables were described by median with IQR, and categorical variables were described by frequencies with percentages. The non-parametric Wilcoxon was used to compare group differences for continuous variables and chi-square test for categorical variables. Patients were divided into several groups according to different patterns of AS and hs-CRP levels (low to medium risk, ＜3 mg/L; high risk, ≥ 3 mg/L). The associations of each group and recurrent events at 1 year were assessed by multivariable Cox regression model. Unadjusted and adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated. All the potential confounding factors were adjusted in multivariable analyses, including age, sex, BMI, smoking, medical histories (hypertension, diabetes, dyslipidemia, atrial fibrillation, coronary heart disease, ischemic stroke or TIA), baseline NIHSS score, baseline LDL-C levels, TOAST subtypes, antiplatelet therapy, lipid-lowering drugs, and infarction patterns. The Kaplan–Meier product-limit method was used to estimate the incidence rates of recurrent stroke, ischemic stroke, and CVE during the follow-up period.
Overall, a two-sided p value of ＜0.05 was considered statistically significant. All analyses were performed with SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
Data Availability Policy
The data that support the findings of this study are available from the corresponding author.
Results
Baseline Characteristics
After excluding 1910 patients without qualified image data and 2852 patients without baseline hs-CRP levels, this study included a total of 10404 patients for analysis. Baseline characteristics of patients included vs. excluded is shown in Supplementary Table 1 . Among 10404 patients included, 7084 (68.1%) were male, and the median (IQR) age was 63 (54–70) years. The median (IQR) levels of hs-CRP in the n-AS group (without intracranial or extracranial AS) and the AS group (intracranial or extracranial artery stenosis) were 1.44 (0.73–3.69) and 2.18 (0.95–5.70) mg/L (p＜0.05), respectively. Patients were divided into four groups: Group Ⅰ (hs-CRP ＜3＋n-AS), Group II (hs-CRP ＜3＋AS), Group III (hs-CRP ≥ 3＋n-AS), and Group Ⅳ (hs-CRP ≥ 3＋AS). Age, sex, smoking, baseline NIHSS, history of hypertension, diabetes, ischemic stroke or TIA, coronary heart disease, atrial fibrillation, stroke type, TOAST subtype, and baseline low-density lipoprotein (LDL) levels differed among the four groups ( Table 1 ) .
Supplementary Table 1. Baseline Characteristics of Patients Included and Excluded.
| Variables | Included (n= 10404) | Excluded (n= 4762) | P value |
|---|---|---|---|
| Age, median (IQR), y | 63 (54–70) | 62 (54–70) | 0.07 |
| Male (n, %) | 7084 (68.1) | 3280 (68.9) | 0.34 |
| BMI, median (IQR), kg/m2 | 24.5 (22.5–26.6) | 24.5 (22.8–26.5) | 0.06 |
| SBP, median (IQR), mmHg | 149 (135–164) | 148 (135–162) | 0.10 |
| DBP, median (IQR), mmHg | 87 (79–95) | 86 (80–95) | 0.90 |
| NIHSS, median (IQR) | 3 (1–6) | 3 (1–6) | 0.08 |
| Current smoker (n, %) | 3256 (31.3) | 1496 (31.4) | 0.90 |
| Medical history (n, %) | |||
| Hypertension | 6529 (62.8) | 2965 (62.3) | 0.56 |
| Diabetes | 2464 (23.7) | 1046 (22.0) | 0.021 |
| Dyslipidemia | 869 (8.35) | 322 (6.8) | 0.0007 |
| Ischemic stroke or TIA | 2399 (23.1) | 1074 (22.6) | 0.51 |
| Coronary heart diseases | 1092 (10.5) | 516 (10.8) | 0.53 |
| Atrial fibrillation/flutter | 710 (6.8) | 309 (6.5) | 0.46 |
| Stroke type (n, %) | 0.15 | ||
| Ischemic stroke | 9725 (93.5) | 4421 (92.8) | |
| TIA | 679 (6.5) | 341 (7.2) | |
| TOAST subtypes (n,%) | ＜0.0001 | ||
| Large-artery atherosclerosis | 2872 (27.6) | 984 (20.7) | |
| Cardioembolism | 614 (5.9) | 303 (6.4) | |
| Small-vessel occlusion | 2286 (22.0) | 879 (18.5) | |
| Other determined etiology | 121 (1.2) | 61 (1.3) | |
| Undetermined etiology | 4511 (43.4) | 2535 (53.2) |
Abbreviations: IQR, interquartile range; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; LDL, low-density lipoprotein.
Table 1. Baseline Characteristics according to hs-CRP and Intracranial and Extracranial Artery Stenosis.
| Variables |
Overall (n = 10404) |
Group 1 (hs-CRP ＜3＋ n-AS) (n = 3382) |
Group 2 (hs-CRP ＜3＋AS) (n = 3254) |
Group 3 (hs-CRP ≥ 3＋n-AS) (n = 1477) |
Group 4 (hs-CRP ≥ 3＋AS) (n = 2291) |
P value |
|---|---|---|---|---|---|---|
| Age, median (IQR), y | 63 (54-70) | 60 (52-68) | 63 (55-70) | 63 (54-71) | 65 (58-74) | ＜0.0001 |
| Male (n, %) | 7084 (68.1) | 2364 (69.9) | 2231 (68.6) | 991 (67.1) | 1498 (65.4) | 0.003 |
| BMI, median (IQR), kg/m2 | 24.5 (22.5-26.6) | 24.3 (22.5-26.4) | 24.5 (22.6-26.6) | 24.6 (22.6-26.8) | 24.4 (22.5-26.6) | 0.16 |
| NIHSS, median (IQR) | 3 (1-6) | 2 (1-5) | 3 (1-6) | 3 (2-6) | 5 (2-8) | ＜0.0001 |
| Current smoker (n, %) | 3256 (31.3) | 1135 (33.6) | 1007 (31.0) | 453 (30.7) | 661 (28.9) | 0.002 |
| Medical history (n, %) | ||||||
| Hypertension | 6529 (62.8) | 1973 (58.3) | 2091 (64.3) | 904 (61.2) | 1561 (68.1) | ＜0.0001 |
| Diabetes | 2464 (23.7) | 664 (19.6) | 838 (25.8) | 326 (22.1) | 636 (27.8) | ＜0.0001 |
| Dyslipidemia | 869 (8.4) | 272 (8.0) | 275 (8.5) | 145 (9.8) | 177 (7.7) | 0.12 |
| Ischemic stroke or TIA | 2399 (23.1) | 642 (19.0) | 848 (26.1) | 288 (19.5) | 621 (27.1) | ＜0.0001 |
| Coronary heart diseases | 1092 (10.5) | 282 (8.3) | 327 (10.1) | 160 (10.8) | 323 (14.1) | ＜0.0001 |
| Atrial fibrillation/flutter | 710 (6.82) | 142 (4.2) | 189 (5.8) | 129 (8.7) | 250 (10.9) | ＜0.0001 |
| Stroke type (n, %) | ＜0.0001 | |||||
| Ischemic stroke | 9725 (93.5) | 3073 (90.9) | 3061 (94.1) | 1386 (93.8) | 2205 (96.3) | |
| TIA | 679 (6.5) | 309 (9.1) | 193 (5.9) | 91 (6.2) | 86 (3.8) | |
| TOAST subtype (n, %) | ＜0.0001 | |||||
| Large-artery atherosclerosis | 2872 (27.6) | 33 (0.98) | 1595 (49.0) | 16 (1.1) | 1228 (53.6) | |
| Cardioembolism | 614 (5.9) | 213 (6.3) | 104 (3.2) | 180 (12.2) | 117 (5.1) | |
| Small-vessel occlusion | 2286 (22.0) | 1176 (34.8) | 486 (14.9) | 407 (27.6) | 217 (9.5) | |
| Other determined etiology | 121 (1.2) | 31 (0.9) | 46 (1.4) | 17 (1.2) | 27 (1.2) | |
| Undetermined etiology | 4511 (43.4) | 1929 (57.0) | 1023 (31.4) | 857 (58.0) | 702 (30.6) | |
| LDL, median (IQR), mmol/L | 2.36 (1.76-3.02) | 2.28 (1.70-2.95) | 2.37 (1.79-3.01) | 2.38 (1.80-3.05) | 2.43 (1.84-3.12) | ＜0.0001 |
| Medication during hospitalization antiplatelet therapy | ＜0.001 | |||||
| None | 381 (3.7) | 91 (2.7) | 116 (3.6) | 67 (4.5) | 107 (4.7) | |
| monoclonal antiplatelet | 4236 (40.7) | 1353 (40.1) | 1261 (38.8) | 637 (43.1) | 985 (43.0) | |
| dual antiplatelet | 5787 (55.6) | 1938 (57.3) | 1877 (57.7) | 773 (52.3) | 1199 (52.3) | |
| lipid-lowering drugs | 10027 (97.2) | 3279 (97.6) | 3143 (97.4) | 1407 (96.4) | 2198 (96.7) | 0.056 |
| Medication at 3-month follow-up | ||||||
| antiplatelet therapy | 8953 (87.8) | 2961 (88.4) | 2853 (89.2) | 1238 (85.3) | 1901 (86.5) | 0.003 |
| lipid-lowering drugs | 8430 (82.7) | 2729 (81.5) | 2688 (84.1) | 1150 (79.3) | 1863 (84.8) | 0.001 |
| Medication at 1-year follow-up | ||||||
| antiplatelet therapy | 8129 (82.1) | 2695 (82.1) | 2592 (83.0) | 1109 (78.7) | 1733 (82.8) | 0.003 |
| lipid-lowering drugs | 7323 (73.94) | 2401 (73.2) | 2343 (75.1) | 990 (70.2) | 1589 (76.0) | 0.001 |
| Carotid stenting during follow-up | 46 (0.44) | 3 (0.09) | 17 (0.52) | 2 (0.14) | 24 (1.05) | 0.001 |
| CEA during follow-up | 14 (0.13) | 3 (0.09) | 7 (0.22) | 1 (0.07) | 3 (0.13) | 0.001 |
Abbreviations: hs-CRP, high-sensitivity C-reactive protein; n-AS, without intracranial or extracranial artery stenosis; AS, intracranial or extracranial artery stenosis; IQR, interquartile range; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; LDL, low-density lipoprotein, CEA, carotid endarterectomy.
Association of hs-CRP levels and AS with Recurrent Events
As shown in Table 2 , 227 (6.7%), 315 (9.7%), 97 (6.6%), and 278 (12.1%) patients had recurrent ischemic stroke in Group Ⅰ (hs-CRP ＜3＋n-AS), Group II (hs-CRP ＜3＋AS), Group III (hs-CRP ≥ 3＋n-AS), and Group Ⅳ (hs-CRP ≥ 3＋AS), respectively. Compared with Group Ⅰ (hs-CRP ＜3＋n-AS), Group Ⅳ (hs-CRP ≥ 3＋AS) was associated with an increased risk of recurrent ischemic stroke within 1 year (HR 1.38, 95% CI 1.10–1.72, p=0.005), after adjustment for age, sex, BMI, smoking, medical histories (hypertension, diabetes, dyslipidemia, atrial fibrillation, coronary heart disease, ischemic stroke or TIA), baseline NIHSS score, baseline LDL-C levels, TOAST subtypes, infarction patterns, antiplatelet therapy and lipid-lowering drugs (during hospitalization, at 3-month and 1-year follow-up), and carotid stenting and carotid endarterectomy during follow-up. The Kaplan–Meier curves showed the cumulative hazard of recurrent ischemic stroke in Group Ⅰ–Ⅳ ( Supplementary Fig.1 ) . Similar results were found when taking stroke recurrence and CVE for outcomes ( Table 2 ) .
Table 2. HRs for Recurrent Events at 1 Year by the Status of hs-CRP and Arterial Stenosis.
| Outcomes | Events (n, %) | Unadjusted HR (95% CI) | P Value | ＊Adjusted HR (95% CI) | P Value |
|---|---|---|---|---|---|
| Ischemic stroke recurrence | |||||
| Group 1 (hs-CRP ＜3＋n-AS) | 227 (6.7) | Reference | / | Reference | / |
| Group 2 (hs-CRP ＜3＋AS) | 315 (9.7) | 1.47 (1.24-1.74) | ＜0.0001 | 1.17 (0.95-1.44) | 0.13 |
| Group 3 (hs-CRP ≥ 3＋n-AS) | 97 (6.6) | 0.98 (0.78-1.25) | 0.89 | 0.88 (0.68-1.13) | 0.32 |
| Group 4 (hs-CRP ≥ 3＋AS) | 278 (12.1) | 1.90 (1.59-2.26) | ＜0.0001 | 1.38 (1.10-1.72) | 0.005 |
| Stroke recurrence | |||||
| Group 1 (hs-CRP ＜3＋n-AS) | 256 (7.6) | Reference | / | Reference | / |
| Group 2 (hs-CRP ＜3＋AS) | 336 (10.3) | 1.39 (1.18-1.64) | ＜0.0001 | 1.12 (0.92-1.37) | 0.24 |
| Group 3 (hs-CRP ≥ 3＋n-AS) | 111 (7.5) | 1.00 (0.80-1.25) | 0.99 | 0.89 (0.70-1.13) | 0.32 |
| Group 4 (hs-CRP ≥ 3＋AS) | 295 (12.9) | 1.79 (1.51-2.11) | ＜0.0001 | 1.31 (1.05-1.62) | 0.01 |
| CVE, Combined vascular events | |||||
| Group 1 (hs-CRP ＜3＋n-AS) | 268 (7.9) | Reference | / | Reference | / |
| Group 2 (hs-CRP ＜3＋AS) | 348 (10.7) | 1.38 (1.17-1.61) | ＜0.0001 | 1.13 (0.93-1.37) | 0.22 |
| Group 3 (hs-CRP ≥ 3＋n-AS) | 119 (8.1) | 1.02 (0.82-1.27) | 0.89 | 0.91 (0.72-1.16) | 0.45 |
| Group 4 (hs-CRP ≥ 3＋AS) | 318 (13.9) | 1.85 (1.57-2.17) | ＜0.0001 | 1.30 (1.06-1.61) | 0.01 |
＊adjusted for age, sex, body mass index, smoking, medical histories (hypertension, diabetes, dyslipidemia, atrial fibrillation, coronary heart disease, ischemic stroke or TIA), baseline NIHSS score, baseline LDL-C levels, TOAST subtypes, infarction patterns, antiplatelet therapy and lipid-lowering drugs during hospitalization and at 3-month and 1-year follow-up, carotid stenting and carotid endarterectomy during follow-up.
Abbreviations: n-AS, without intracranial or extracranial artery stenosis; AS, intracranial or extracranial artery stenosis.
Supplementary Fig.1.
Kaplan-Meier curves of CRP and artery stenosis for ischemic stroke recurrence at 1 year.
Group 1, hs-CRP＜3＋no intracranial or extracranial artery stenosis;
Group 2, hs-CRP＜3＋intracranial or extracranial artery stenosis;
Group 3, hs-CRP≥3＋no intracranial or extracranial artery stenosis;
Group 4, hs-CRP≥3＋intracranial or extracranial artery stenosis.
Association of hs-CRP levels and Symptomatic or Asymptomatic AS with Recurrent Events
There were six groups after dividing the intracranial or extracranial AS into s-AS and a-AS. Taking Group I (hs-CRP ＜3＋n-AS) as reference, Group III (hs-CRP ＜3＋sAS) had higher risk of recurrent ischemic stroke within 1 year (HR 1.73, 95% CI 1.20–2.48, p=0.003), and Group VI (hs-CRP ≥ 3＋sAS) had the highest risk of recurrent ischemic stroke (HR 2.04, 95% CI 1.42–2.92, p=0.0001) after adjusting for confounding factors. However, there was no significant statistical difference between patients with a-AS and n-AS regardless of hs-CRP levels ( Table 3 ) . The Kaplan–Meier curves showed the cumulative hazard of recurrent ischemic stroke in Group I–VI ( Fig.1 ) . Similar results were found when taking stroke recurrence and CVE for outcomes.
Table 3. HRs for Recurrent Events at 1 Year by the Status of hs-CRP and Symptomatic or Asymptomatic Arterial Stenosis.
| Outcomes | Events (n, %) | Unadjusted HR (95% CI) | P Value | ＊Adjusted HR (95% CI) | P Value |
|---|---|---|---|---|---|
| Ischemic stroke recurrence | |||||
| Group I (hs-CRP ＜3＋n-AS) | 227 (6.7) | Reference | / | Reference | / |
| Group II (hs-CRP ＜3＋a-AS) | 113 (7.9) | 1.18 (0.94-1.48) | 0.14 | 1.11 (0.88-1.40) | 0.39 |
| Group III (hs-CRP ＜3＋s-AS) | 202 (11.1) | 1.70 (1.41-2.05) | ＜0.0001 | 1.73 (1.20-2.48) | 0.003 |
| Group IV (hs-CRP ≥ 3＋n-AS) | 97 (6.6) | 0.98 (0.78-1.25) | 0.89 | 0.88 (0.68-1.14) | 0.33 |
| Group V (hs-CRP ≥ 3＋a-AS) | 72 (9.1) | 1.39 (1.07-1.81) | 0.02 | 1.25 (0.94-1.65) | 0.12 |
| Group VI (hs-CRP ≥ 3＋s-AS) | 206 (13.9) | 2.17 (1.80-2.63) | ＜0.0001 | 2.04 (1.42-2.92) | 0.0001 |
| Stroke recurrence | |||||
| Group I (hs-CRP ＜3＋n-AS) | 256 (7.6) | Reference | / | Reference | / |
| Group II (hs-CRP ＜3＋a-AS) | 121 (8.5) | 1.12 (0.90-1.39) | 0.30 | 1.04 (0.83-1.31) | 0.71 |
| Group III (hs-CRP ＜3＋s-AS) | 215 (11.8) | 1.61 (1.34-1.93) | ＜0.0001 | 1.67 (1.18-2.37) | 0.004 |
| Group IV (hs-CRP ≥ 3＋n-AS) | 111 (7.5) | 1.00 (0.80-1.25) | 0.99 | 0.89 (0.71-1.13) | 0.35 |
| Group V (hs-CRP ≥ 3＋a-AS) | 78 (9.9) | 1.34 (1.04-1.73) | 0.02 | 1.22 (0.94-1.60) | 0.14 |
| Group VI (hs-CRP ≥ 3＋s-AS) | 217 (14.5) | 2.03 (1.70-2.44) | ＜0.0001 | 1.89 (1.33-2.67) | 0.0004 |
| CVE, Combined vascular events | |||||
| Group I (hs-CRP ＜3＋n-AS) | 268 (7.9) | Reference | / | Reference | / |
| Group II (hs-CRP ＜3＋a-AS) | 126 (8.8) | 1.12 (0.90-1.38) | 0.31 | 1.04 (0.83-1.30) | 0.73 |
| Group III (hs-CRP ＜3＋s-AS) | 222 (12.2) | 1.59 (1.33-1.90) | ＜0.0001 | 1.73 (1.23-2.44) | 0.002 |
| Group IV (hs-CRP ≥ 3＋n-AS) | 119 (8.1) | 1.02 (0.82-1.27) | 0.84 | 0.92 (0.73-1.16) | 0.48 |
| Group V (hs-CRP ≥ 3＋a-AS) | 84 (10.7) | 1.38 (1.08-1.76) | 0.01 | 1.22 (0.94-1.58) | 0.14 |
| Group VI (hs-CRP ≥ 3＋s-AS) | 234 (15.6) | 2.10 (1.76-2.50) | ＜0.0001 | 1.93 (1.37-2.72) | 0.0002 |
＊adjusted for age, sex, body mass index, smoking, medical histories (hypertension, diabetes, dyslipidemia, atrial fibrillation, coronary heart disease, ischemic stroke or TIA), baseline NIHSS score, baseline LDL-C levels, TOAST subtypes, infarction patterns, antiplatelet therapy and lipid-lowering drugs during hospitalization and at 3-month and 1-year follow-up, carotid stenting and carotid endarterectomy during follow-up.
Abbreviations: n-AS, without intracranial or extracranial artery stenosis; a-AS, asymptomatic intracranial or extracranial artery stenosis; s-AS, symptomatic intracranial or extracranial artery stenosis.
Fig.1.
Kaplan–Meier curves of CRP and symptomatic or asymptomatic arterial stenosis for ischemic stroke recurrence at 1 year
Discussion
This study showed that intracranial or extracranial s-AS was associated with increased risk of recurrent ischemic stroke, stroke, and CVE at 1 year in patients with AIS or TIA, especially in patients with elevated hs-CRP levels. Intracranial or extracranial a-AS did not increase the risk of ischemic events compared with no intracranial or extracranial artery stenosis regardless of hs-CRP levels.
As an important cause of ischemic stroke, evaluation of ICAS or ECAS is of great concern, especially in patients with AIS or TIA. Many studies proved that ICAS or ECAS increased the risk of recurrent ischemic events 17 - 19) . The annual recurrence rate of stroke in intracranial or extracranial s-AS is approximately 10%–20% in various studies 5 - 7) . Several pathological reasons could account for the higher ischemic recurrence rate of intracranial or extracranial s-AS. First, patients with ICAS or ECAS have more risk factors of cerebrovascular disease such as old age, hypertension, diabetes, and dyslipidemia. Second, distal brain tissue supplied by stenotic arteries is prone to hypoperfusion compared with those without AS. Furthermore, s-AS usually reflects insufficient collateral circulation and more vulnerable plaques, leading to subsequent recurrence of ischemic stroke. Therefore, this study proved that symptomatic stenosis, instead of asymptomatic stenosis, significantly increased the 1-year risk of stroke recurrence compared with no AS. Several large clinical trials 20 - 23) had proven the advantages of aggressive medical treatment in reducing the risk of recurrent stroke compared to endovascular treatment. Although recent studies showed lower recurrent events after stent implantation 24 - 26) with the improvement of interventional materials or technology and highly selective patient enrollment, aggressive medical therapy is still the first choice for patients with symptomatic arterial stenosis, especially for intracranial stenosis 23) .
Intracranial or extracranial a-AS is common, not only in apparently healthy individuals but also in patients who suffered from AIS or TIA, but data were limited on the risk of stroke recurrence of these patients, especially in AIS or TIA. Subgroup analysis of the OXVASC 8) , a population-based study of predominantly white patients, showed that asymptomatic intracranial stenosis in patients with minor stroke or TIA had similar risk of recurrent ischemic stroke with no intracranial stenosis, but symptomatic intracranial stenosis had significantly higher risk of recurrence, which is consistent with the results in this study. In contrast, this study combined intracranial and extracranial stenosis for analysis based on a wider ischemic stroke population. Ultimately, ECAS also accounts for a certain percentage of ischemic strokes, and moderate to severe arterial stenosis is more likely to occur in patients with non-mild stroke. Asymptomatic arterial stenosis may temporarily be in a stable stage compared with symptomatic arterial stenosis, so it did not increase the risk of 1-year recurrent events compared with those without AS. However, this result did not mean that asymptomatic stenosis could be ignored in evaluating the risk of recurrence and making treatment strategies because patients with asymptomatic stenosis also had many risk factors of cerebrovascular disease, and stable atherosclerotic plaques could progress in the future.
Many studies have proven that inflammation is associated with the occurrence and prognosis of ischemic stroke. As a sensitive and traditional indicator of inflammation, elevated hs-CRP levels were associated with s-AS or a-AS 27 , 28) . Hs-CRP was also associated with instability of atherosclerotic plaques 29) and predicted recurrent stroke 9 , 30) in patients with ischemic stroke or TIA. Considering the important role of inflammation, adding inflammatory markers to imaging parameters might further contribute to risk stratification. Our previous study proved that increased neutrophil counts with the presence of ICAS were associated with the incidence of recurrent stroke in patients with minor stroke in CHANCE study 12) , which is similar to the results in Table 2 in this study. However, after dividing the arterial stenosis into symptomatic and asymptomatic, we found that symptomatic intracranial or extracranial artery stenosis increased approximately two times the risk of recurrent events in high inflammation status and a-AS did not increase the risk of ischemic events regardless of hs-CRP levels. This study suggested that anti-inflammatory treatment may be meaningful in patients with symptomatic arterial stenosis.
Our study had several strengths. First, this study is based on a large, multicenter registration study including patients with mild to severe ischemic stroke or TIA. Second, this study defined responsible arterial stenosis or occlusion to distinguish between symptomatic and asymptomatic stenosis. There were also some limitations. First, the follow-up time is 1 year in this study, and the difference of long-term recurrent ischemic events in different stenosis patterns needs further study.
Second, intracranial AS is evaluated mostly based on MRA assessment (88.7%), which may exaggerate the degree of stenosis. Additionally, the interpretation of the degree of arterial stenosis was divided into ＜50% and 50%–99%; thus, we could not perform a further analysis to see if the association varied on the level of stenosis, that is, 50%–70% vs. ＞70%. Whether a more refined degree of stenosis would alter the rate of stroke recurrence is a question worthy of further investigation. Third, the results in this study might only apply to Asian populations because of the regional differences in the distribution of intracranial and extracranial arteries 5 , 6 , 31 , 32) , although we combined intracranial and extracranial arteries for analysis.
Conclusion
Intracranial or extracranial s-AS was associated with increased risk of recurrent ischemic stroke, stroke, and CVE in patients with AIS or TIA, especially in patients with elevated hs-CRP levels. Intracranial or extracranial a-AS did not increase the risk of ischemic events compared with no intracranial or extracranial artery stenosis regardless of hs-CRP levels.
Acknowledgements
We thank all the participants in the study.
Contributorship Statement
Shiyu Li, first author, conducted this study, interpreted the data, and drafted the manuscript.
Jing Jing, author, interpreted the data and supervised this study.
Jiejie Li, author, interpreted the data.
Anxin Wang, author, conducted the statistical analysis and interpreted the data.
Xia Meng, author, interpreted the data and supervised this study.
Yongjun Wang, corresponding author, designed and supervised this study and revised the manuscript.
Conflicts of Interests
The authors declare no conflicts of interests.
Source of Funding
This work was supported by grants from the Capital’s Funds for Health Improvement and Research (2020-1-2041), the National Natural Science Foundation of China (81870905, U20A20358), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2019-I2M-5-029).
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author.