Large Artery Atherosclerosis Subtype Research Articles

Dual Antiplatelet Therapy and Outcomes in Acute Mild to Moderate Stroke With Versus Without Large-Artery Atherosclerosis Post Hoc Analysis of ATAMIS.

We conducted a post hoc analysis of the ATAMIS (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) trial to investigate whether the priority of clopidogrel plus aspirin to aspirin alone was consistent between patients with and without stroke pathogenesis of large-artery atherosclerosis (LAA). Patients with stroke classification randomized to a clopidogrel-plus-aspirin group and aspirin-alone group in a modified intention-to-treat analysis set of ATAMIS were classified into LAA and non-LAA subtypes. The primary outcome was early neurologic deterioration at 7 days, defined as a >2-point increase in National Institutes of Health Stroke Scale score compared with baseline, and safety outcomes were bleeding events and intracranial hemorrhage. We compared treatment effects in each stroke subtype and investigated the interaction. Among 2910 patients, 225 were assigned into the LAA subtype (119 in the clopidogrel-plus-aspirin group and 106 in the aspirin-alone group) and 2685 into the non-LAA subtype (1380 in the clopidogrel-plus-aspirin group and 1305 in the aspirin-alone group). Median age was 66 years, and 35% were women. A lower proportion of early neurologic deterioration was found to be associated with dual antiplatelet therapy in the LAA subtype (adjusted risk difference, -10.4% [95% CI, -16.2% to -4.7%]; P=0.001) but not in the non-LAA subtype (adjusted risk difference, -1.4% [95% CI, -2.6% to 0.1%]; P=0.06). No significant interaction was found (P=0.11). Compared with the non-LAA subtype, patients with stroke of the LAA subtype may get more benefit from dual antiplatelet therapy with clopidogrel plus aspirin with respect to early neurologic deterioration at 7 days. URL: clinicaltrials.gov; UnIque identifier: NCT02869009.

Effectiveness of statin treatment for recurrent stroke according to stroke subtypes

Understanding the effectiveness of statin treatment is essential for developing tailored stroke prevention strategies. We aimed to evaluate the efficacy of statin treatment in preventing recurrent stroke among patients with various ischemic stroke subtypes. Using data from the Clinical Research Collaboration for Stroke-Korea-National Institute for Health (CRCS-K-NIH) registry, we included patients with acute ischemic stroke admitted between January 2011 and July 2020. To evaluate the differential effects of statin treatment based on the ischemic stroke subtype, we analyzed patients with large artery atherosclerosis (LAA), cardio-embolism (CE), and small vessel occlusion (SVO). The primary outcomes were recurrent ischemic stroke and recurrent stroke events. The hazard ratio for outcomes between statin users and nonusers was compared using a Cox proportional hazards model adjusted for covariates. A total of 46,630 patients who met the inclusion criteria were analyzed. Statins were prescribed to 92%, 93%, and 78% of patients with LAA, SVO, and CE subtypes, respectively. The hazards of recurrent ischemic stroke and recurrent stroke in statin users were reduced to 0.79 (95% confidence interval [CI], 0.63-0.99) and 0.77 (95% CI, 0.62-0.95) in the LAA subtype and 0.63 (95% CI, 0.52-0.76) and 0.63 (95% CI, 0.53-0.75) in CE subtype compared to nonusers. However, the hazards of these outcomes did not significantly decrease in the SVO subtype. The effectiveness of statin treatment in reducing the risk of recurrent stroke in patients with LAA and CE subtypes has been suggested. Nonetheless, no significant effect was observed in the SVO subtype, suggesting a differential effect of statins on different stroke subtypes.

Seasonal variability of lesions distribution in acute ischemic stroke: A retrospective study

Seasonal variability could have an impact on the incidence and outcome of stroke. However, little is known about the correlation between seasonal variability and location of acute cerebral infarction. This study aimed to explore the relationship between onset season and the lesions distribution of acute ischemic stroke (AIS). We retrospectively analysis data from 1488 AIS patients admitted to the Second Hospital of Tianjin Medical University from 2018 to 2022. All subjects completed head magnetic resonance imaging examination (MRI) and were divided into four groups according to the onset seasons. The lesions distribution of AIS was evaluated for anterior/posterior/double circulation infarction (DCI), unilateral/bilateral infarctions, and single/multiple cerebral infarctions based on MRI. Logistic regression models were employed to assess the association of season with lesions distribution of AIS. Subgroup analysis was performed in different stroke subtypes. Of 1488 patients, 387 (26.0%) AIS occurred in spring, 425 (28.6%) in summer, 331 (22.2%) in autumn and 345 (23.2%) in winter. Multivariate logistic regression demonstrated that the winter group had 2.15 times (95% CI:1.44–3.21) risk of multiple infarctions, 2.69 times (95% CI:1.80–4.02) of bilateral infarctions and 1.54 times (95% CI:1.05–2.26) of DCI compared with summer group, respectively. Subgroup analysis showed an increased risk of multiple (p < 0.01) or bilateral infarctions (p < 0.01) in small-artery occlusion (SAO) subtype, and higher risk of bilateral infarctions (p < 0.01) or DCI (p < 0.05) in large artery atherosclerosis (LAA) subtype during winter. No significant associations of season with lesions distribution in cardioembolism subtype. Our study highlighted a prominent seasonal variability in the lesions distribution of AIS, particularly in LAA and SAO subtypes. The findings could help to formulating meteorological risk warning strategies for different subtypes.

Residual inflammatory risk and vulnerable plaque in the carotid artery in patients with ischemic stroke.

Inflammation is a central driver of atherogenesis and eventual plaque rupture. This study aimed to evaluate the association between residual inflammatory risk (RIR) and vulnerable plaques in the carotid artery in patients with ischemic stroke. Patients with acute ischemic stroke were enrolled from January 2021 to July 2022. They were divided into four groups: RIR only (LDL-C <2.6 mmol/L and hsCRP ≥2 mg/L), residual cholesterol risk (RCR) only (LDL-C ≥2.6 mmol/L and hsCRP <2 mg/L), both risk or residual cholesterol and inflammatory risk (RCIR) (LDL-C ≥2.6 mmol/L and hsCRP ≥2 mg/L), and neither risk (LDL-C <2.6 mmol/L and hsCRP <2 mg/L). Vulnerable plaques were determined if it had a low attenuated plaque CT value of <35 Hounsfield Units (HU) and a remodeling index of >1.1, which indicated a positive remodeling. Out of the 468 enrolled patients, 157 (33.5%) were detected to have vulnerable plaques. The proportion of patients with neither risk, RIR, RCR, and RCIR were 32.9%, 28.6%, 18.8%, and 19.7%, respectively. Patients with vulnerable plaques exhibited a higher prevalence of hyperlipidemia (P = 0.026), higher proportion of RIR (P = 0.015), a higher ratio of stroke subtypes of large artery atherosclerosis (P = 0.012), and high leukocyte counts (P < 0.001). The logistic regression analysis detected that RIR was associated with vulnerable plaques after adjusted for major confounding factors (OR 1.98, 95% CI 1.13-3.45, P = 0.016), especially in the large artery atherosclerosis subtype (OR 2.71, 95% CI 1.08-6.77, P = 0.034). In patients with ischemic stroke, RIR is associated with the vulnerability of carotid plaques, especially for those with the large artery atherosclerosis subtype. Therefore, further studies investigating the interventions to modulate inflammation in these patients may be warranted.

Arterial transit artifact as a short-term prognostic indicator in acute ischemic stroke

BackgroundArterial transit artifact (ATA) observed on arterial spin labeling (ASL) was recently suggested to be associated with improved functional outcomes following acute ischemic stroke (AIS). AIS is a heterogeneous disease with diverse pathogenic mechanisms depending on the stroke subtype. This study aimed to investigate the association between ATA and 3-month functional outcomes in AIS patients according to etiology subtypes.MethodsConsecutive patients with AIS were included. All patients underwent ASL MRI with postlabeling delay (PLD) of 1.5 and 2.5 s. ATA was assessed from the ASL images of both PLDs. Stroke etiologic subtypes were determined according to the modified TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Short-term functional outcomes were evaluated using the 3-month modified Rankin scale (mRS). Log-binomial regression was applied to analyze the association between ATA and functional outcomes at 3 months after stroke.ResultsNinety-eight AIS patients (62.73 ± 13.05 years; 68 men) were finally included. ATA was detected in forty-six patients and most frequently seen in the large-artery atherosclerosis (LAA) subtype (35/46). The ATA group exhibited a lower percentage of patients with mRS > 2 compared to the group without ATA (36.5% vs. 19.6%; P < 0.001). ATA was independently associated with better 3-month clinical outcomes (adjusted risk ratio, 0.35[95% CI, 0.16—0.74]) in the multivariate log-binomial regression model. After stratification by TOAST subtypes, a significant association was found between ATA and better outcomes in the LAA subtype (adjusted risk ratio, 0.20[ 95% CI, 0.05—0.72]) but not in cardioembolism and small artery occlusion (SVO) subtype.ConclusionATA is associated with better outcomes at 3 months in patients with AIS, especially in the LAA subtype, but this association attenuated in the cardioembolism and SVO subtypes.

The Untargeted Metabolomics Reveals Differences in Energy Metabolism in Patients with Different Subtypes of Ischemic Stroke.

Ischemic stroke (IS) is the most common subtype of stroke. The risk factors and pathogenesis of IS are complex and varied due to different subtypes. Therefore, we used metabolomics technology to investigate the biomarkers and potential pathophysiological mechanisms of different subtypes of IS. We included 126 IS patients and divided them into two groups based on the TOAST classification: large-artery atherosclerosis (LAA) group (n = 87) and small-vessel occlusion (SVO) group (n = 39). Plasma metabolomics analysis was performed using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to identify metabolic profiles in LAA and SVO subtype IS patients and to determine metabolic differences between patients with the two subtypes of IS. We identified 26 differential metabolites between LAA and SVO subtype IS. A multiple prediction model based on the plasm metabolites had good predictive ability for IS subtyping (AUC = 0.822, accuracy = 77.8%), with 12,13-DHOME being the most important differential metabolite in the model. The differential metabolic pathways between the two subtypes of IS patients included tricarboxylic acid (TCA) cycle, alanine, aspartate and glutamate metabolism, and pyruvate metabolism, mainly focused on energy metabolism. 12,13-DHOME emerged as the primary discriminatory metabolite between LAA and SVO subtypes of IS. In LAA subtype IS patients, energy metabolism, encompassing pyruvate metabolism and the TCA cycle, exhibited lower activity levels when compared to patients with the SVO subtype IS. The utilization of targeted metabolomics holds the potential to improve diagnostic accuracy for distinguishing stroke subtypes.

Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Plasma D-dimer as a biomarker for the early classification of common acute ischemic stroke subtypes in Indonesia

BackgroundD-dimer is a well-known marker for abnormal hemostasis in acute ischemic stroke (AIS), indicating the presence of fibrin degradation due to thrombus formation and lysis. The diagnostic performance of D-dimer for different AIS types in the Indonesian population has not been established. The aim of this study is to compare the plasma D-dimer levels in three of the most common AIS subtypes in Indonesia; the cardioembolic, large artery atherosclerosis (LAA), and small-vessel occlusion (SVO), and to determine its most optimal diagnostic performance.ResultsIn this cross-sectional study, 64 subjects with confirmed AIS diagnosis at the Wahidin Sudirohusodo General Hospital Makassar between June and October 2019 were recruited. Plasma D-dimer levels were measured and grouped according to the subtype of acute ischemic stroke based on the TOAST classification. A significant difference was observed between the D-dimer levels across the three AIS subtypes, with an average D-dimer of 2.93 ± 1.7, 1.27 ± 0.81, and 0.56 ± 0.46 µg/ml in the cardioembolic, LAA, and SVO subtypes, respectively. As a marker of cardioembolic stroke, an optimal cut-off was determined to be 1.52 µg/ml, yielding a sensitivity of 84.44% (CI 71.22–92.25% and specificity of 84.21% (CI 62.43–94.48%).ConclusionPlasma D-dimer levels varied significantly between the cardioembolic, LAA, and SVO subtypes of AIS, with the highest D-dimer level in the cardioembolic subtypes. As a marker of cardioembolic stroke, an optimal cut-off was determined to be 1.52 µg/mL, yielding a sensitivity and specificity of 84.44% and 84.21%, respectively.

Texture analysis of apparent diffusion coefficient maps in predicting the clinical functional outcomes of acute ischemic stroke.

To investigate texture analysis (TA) based on apparent diffusion coefficient (ADC) map in predicting acute ischemic stroke (AIS) prognosis and discriminating TA features in stroke subtypes. This retrospective study included patients with AIS between January 2018 and April 2021. The patients were assigned to the favorable [modified Rankin Scale (mRS) score ≤ 2] and unfavorable (mRS score > 2) outcome groups. All patients underwent stroke subtyping according to the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification. The TA features were extracted from infarction lesions on the ADC map. The demographic characteristics, clinical characteristics, and texture features were used to construct prediction models with recurrent neural network (RNN). The receiver operating characteristic (ROC) curves were implemented to evaluate the performance of the predictive models. A total of 1,003 patients (682 male; mean age 65.90 ± 12.44) with AIS having documented the 90-day mRS score were identified, including 840 with favorable outcomes. In the validation set, the area under the curve (AUC) of the predictive model using only clinical characteristics achieved an AUC of 0.56, texture model 0.77, the model combining both clinical and texture features showed better with an AUC of 0.78. The texture feature profiles differed between large artery atherosclerosis (LAA) and small artery occlusion (SAO) subtypes (all p < 0.05). The AUC of combined prediction models for LAA and SAO subtypes was 0.80 and 0.81. Texture analysis based on ADC map could be useful as an adjunctive tool for predicting ischemic stroke prognosis.

Predictive Role of hsCRP in Recurrent Stroke Differed According to Severity of Cerebrovascular Disease: Analysis from a Prospective Cohort Study

Elevated levels of high-sensitivity C-reactive protein (hsCRP) were associated with an increased risk of recurrent stroke. However, it is still unknown whether the predictive value of hsCRP differed according to the severity of cerebrovascular disease. We used the cohort of the prospective multicenter cohort study of the Third China National Stroke Registry (CNSR-III), in which 10,765 consecutive patients with acute ischemic stroke or transient ischemic attack (TIA) had hsCRP levels measured. Patients were classified into minor stroke, or TIA, and non-minor stroke. The primary outcome was a new stroke within 1 year. Cox proportional hazards models were used to assess the association of hsCRP and its outcome. Elevated levels of hsCRP were associated with an increased risk of recurrent stroke in minor stroke or TIA patients, irrespective of using a National Institutes of Health Stroke Scale (NIHSS) score of ≤3 (the highest quartile vs. the lowest quartile: adjusted hazard ratio, 1.48; 95% CI, 1.12-1.97; p = 0.007) or ≤5 (the highest quartile vs. the lowest quartile: adjusted hazard ratio, 1.45; 95% CI, 1.15-1.84; p = 0.002) to define minor stroke. Such association was more apparent in the large-artery atherosclerosis subtype. However, for the patients with non-minor stroke, the association of hsCRP with recurrent stroke disappeared.

Abstract WP174: Elevated Homocysteine Intensify The Effect Of Lipoprotein(a) On Stroke Recurrence

Introduction: Lipoprotein(a) [Lp(a)] and homocysteine (tHcy) are risk factors for ischemic stroke. tHcy show great impact on Lp(a) binding to fibrin and interaction between Lp(a) and Mac-1 integrin, which might intensify the atherogenic and thrombotic pathway mediated by Lp(a). The study aims to explore the effect of Lp(a) on stroke recurrence within 1 year in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA), based on different tHcy level. Method: A total of 10068 patients with AIS or TIA from the third China National Stroke Registry cohort were included. Since Lp(a) levels vary strongly between ethnicities, the cut-off value was set at the 80 th percentile based on National Lipid Association recommendation. The association between Lp(a) and stroke recurrence was evaluated using Cox proportional hazards model. Patients were further categorized to five different subtypes according to the TOAST criteria. The interaction between Lp(a) and tHcy was tested in different subtypes. Result: 8054 patients were classified into the ≤80 th group, 2014 patients were classified into the &gt;80 th group. No significant differences were found between the two groups in terms of age, sex, and traditional risk factors (P&gt;0.05). 999 patients experienced recurrent stroke in 1 year follow-up. Patients with Lp(a)&gt;80 th patients had a higher risk of stroke recurrence (11.57% vs 9.51%). Patients were further stratified by tHcy (&gt;15 and ≤15 μmol/L). Among all patients, the highest recurrence rate (12.8%) was observed in the patients with elevated both Lp(a) and tHcy (aHR 1.41; 95%CI 1.14-1.74), the interaction between Lp(a) and tHcy was observed (P=0.03). We also found significant interaction among large-artery atherosclerosis (LAA) subtype (P&lt;0.01). Conclusion: The finding indicated elevated tHcy might intensify Lp(a)-associated stroke recurrence. Elevated Lp(a) should receive more attention in AIS/TIA patients with elevated tHcy, especially in the LAA subtype.

Polymorphisms of the Matrix Metalloproteinase Genes are Associated with Acute Ischemic Stroke in Chinese Han Population.

Studies have shown that matrix metalloproteinase (MMP-2,3,9) plays an important role in the pathologic process of ischemic stroke (IS). The aim of this study was to investigate the relationship between C1306T, 1612-5A/6A, C-1562T polymorphisms of MMP-2,3,9 genes and IS in Chinese Han population. The polymorphisms of MMP-2(C1306T), -3(1612-5A/6A), -9(C-1562T) gene were detected by PCR-RFLP and SNaPshot sequencing. Then, stratified analysis was used to study the relationship between IS subtypes and MMP-2,3,9 polymorphisms. For the MMP-2 gene C1306T polymorphism, TT genotype and T allele were significantly associated with a reduced risk of IS (P = 0.015, P = 0.003, respectively). T allele was significantly associated with a reduced risk of small artery occlusion (SAO) subtype compared with the control group (P = 0.012, OR = 0.550, 95% CI = 0.065-1.291). For the MMP-3 gene-1612 (5A/6A) polymorphism, 5A/5A genotype was significantly increased in the IS group (P = 0.011, OR = 0.370, 95% CI = 0.168-0.814), especially in the large-artery atherosclerosis (LAA) subtype (P = 0.001, OR = 2.345) as compared to the control group. Our study suggested that the T allele of MMP-2 may be a protective factor of IS, especially in SAO subtype, while the 5A/5A gene of MMP-3 may increase the risk of IS, especially in LAA subtype in Chinese Han population.

Mediation of Systemic Inflammation on Insulin Resistance and Prognosis of Nondiabetic Patients With Ischemic Stroke.

Insulin resistance is associated with stroke recurrence and poor functional outcomes of nondiabetic patients with ischemic stroke. The study aimed to investigate whether the association between insulin resistance and the prognosis of nondiabetic patients with ischemic stroke was mediated by systematic inflammation. Patients with ischemic stroke but without a history of diabetes who were enrolled in CNSR-III (Third China National Stroke Registry) were included in the study and followed up for 1 year after stroke onset. Insulin resistance was determined by using the homeostasis model assessment for insulin resistance (HOMA-IR) method. hs-CRP (high-sensitivity C-reactive protein) and Lp-PLA2 (lipoprotein-associated phospholipase A2) activity were measured at baseline. The primary outcome was stroke recurrence, and other outcomes included composite vascular events, mortality, and poor functional outcome (modified Rankin Scale score, 3-6). Multivariable Cox or logistic regression analyses were performed to estimate the association between HOMA-IR and the study outcomes. A mediation analysis was performed to examine the relationship between insulin resistance and the study outcomes mediated by systemic inflammation. Among a total of 3808 nondiabetic patients with ischemic stroke who were included in the study, the median HOMA-IR was 1.79 (interquartile range, 1.05-2.97). After adjustments for potential confounders, higher HOMA-IR quartiles were associated with higher risks of stroke recurrence, ischemic stroke, and composite vascular events, especially in the large artery atherosclerosis subtype. hs-CRP partially mediated the association between the HOMA-IR index and the prognosis of ischemic stroke (mediation proportion, 5.9% for stroke recurrence and 7.5% for composite vascular events). No evidence of Lp-PLA2 activity mediating the association of insulin resistance with stroke outcomes was observed. Our study found that insulin resistance was associated with poor clinical outcomes in nondiabetic patients with ischemic stroke, which was partially mediated by hs-CRP with a modest amount.

Association of time to groin puncture with patient outcome after endovascular therapy stratified by etiology

BackgroundRandomized clinical trials and large stroke registries have demonstrated a time-dependent benefit of endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). The aim of this study was to investigate whether this could be applied to different stroke subtypes in a real-world single-center cohort.Materials and methodsConsecutive ischemic stroke patients with LVOs presenting within 24 h after symptom onset were prospectively registered and retrospectively assessed. Baseline multimodal imaging was conducted before EVT. Independent predictors of functional independence [90-day modified Rankin scale (mRS), 0–2] and any incidence of intracranial hemorrhage (ICH) were explored using a stepwise logistic regression model in the entire cohort and in stroke subtypes.ResultsFrom 2015 to 2020, 140 eligible patients received EVT, of whom 59 (42%) were classified as large artery atherosclerosis (LAA)-related. Time from last known normal to groin puncture was identified as an independent predictor for functional independence in patients of cardioembolic (CE) subtype [odds ratio (OR) 0.90 per 10 min; 95% CI 0.82–0.98; P = 0.013] but not in the LAA subtype and the whole cohort. Groin puncture within 6 h after the time of last known normal was associated with a lower risk of any ICH in the whole cohort (OR 0.36, 95% CI 0.17–0.75, P = 0.007). Sensitivity analysis of patients with complete imaging profiles also confirmed the above findings. Besides, compared with patients of the CE subtype, the LAA subtype had a smaller baseline ischemic core volume, a better collateral status, a slower core growth rate, and a numerically smaller final infarct volume.ConclusionFaster groin puncture has a more pronounced effect on the functional outcome in patients of CE subtype than those of LAA subtype. Reducing time to groin puncture is of great importance in improving the prognosis of patients after EVT, especially those of CE subtype, and reducing the incidence of any ICH in all patients.

Association of modifiable risk factors with ischaemic stroke subtypes in Asian versus Caucasian populations: A systematic review and meta-analysis.

Ischaemic stroke (IS) is associated with various modifiable risk factors but the association of these risk factors based on TOAST classification, which characterises IS into five subtypes: large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolic disease (CE), other determined aetiology (ODE) and undetermined aetiology (UDE), is unknown. We aimed to summarise the published evidence for the association of modifiable risk factors with IS subtypes based on TOAST classification, specifically focussing on the Asian versus Caucasian population. A comprehensive search for all the published articles was performed in electronic databases including PubMed, EMBASE, Cochrane Library, and Google Scholar from 01st January 1950 to 10th April 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratio (OR) with 95% confidence interval (CIs) along with random-effect models was used to calculate summary estimates. In our meta-analysis, 32 studies with a total of 23,404 IS (14,364 in Asian vs. 9040 in Caucasian population), 7121 LAA (5219 in Asian vs. 1902 in Caucasian), 5532 SVO (3604 in Asian vs. 1928 in Caucasian), 3498 CE (1634 in Asian vs. 1864 in Caucasian), 1131 ODE (546 in Asian vs. 585 in Caucasian) and 4519 UDE (2076 in Asian vs. 2443 in Caucasian) were included. Our findings suggest a significant association between LAA and hypertension (OR=1.07, 95% CI=1.02-1.12), smoking (OR=1.11, 95% CI=1.04-1.17), dyslipidemia (OR=1.13, 95% CI=1.06-1.21), diabetes mellitus (OR=1.18, 95% CI=1.11-1.25) and atrial fibrillation (OR=0.55, 95% CI=0.40-0.75). Significantly strong association of hypertension, smoking, dyslipidemia, diabetes mellitus and atrial fibrillation was observed with SVO and CE stroke subtypes. Subgroup analysis based on ethnicity revealed a significant association for dyslipidemia, diabetes mellitus and atrial fibrillation in LAA for both Asians and Caucasians. Hypertension was significantly associated with SVO and ODE subtypes in both Asians and Caucasians; however, only Asian population showed significant association of hypertension in LAA and CE subtypes. The other risk factors did not show any statistical difference between the ethnic groups for the different stroke subtypes. The majority of the risk factors depicted positive association with LAA and SVO, negative with CE and neutral with ODE and UDE. Our findings suggest strong association of smoking, dyslipidemia and diabetes mellitus with LAA and SVO subtypes in the Caucasian population. However, only diabetes mellitus showed significant association with both LAA and SVO subtypes in Asian population as well. Thus, a majority of the traditional modifiable risk factors had a positive association in LAA and SVO, while a negative protective association was observed in CE subtype, among both the Asian and the Caucasian subgroups.

Genetic association of ANRIL with susceptibility to Ischemic stroke: A comprehensive meta-analysis.

Ischemic stroke (IS) is a complex polygenic disease with a strong genetic background. The relationship between the ANRIL (antisense non-coding RNA in the INK4 locus) in chromosome 9p21 region and IS has been reported across populations worldwide; however, these studies have yielded inconsistent results. The aim of this study is to clarify the types of single-nucleotide polymorphisms on the ANRIL locus associated with susceptibility to IS using meta-analysis and comprehensively assess the strength of the association. Relevant studies were identified by comprehensive and systematic literature searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratios with corresponding 95% confidence intervals of combined analyses were calculated under three genetic models (allele frequency comparison, dominant model, and recessive model) using a random-effects or fixed-effects model. Heterogeneity was tested using the chi-square test based on the Cochran Q statistic and I2 metric, and subgroup analyses and a meta-regression model were used to explore sources of heterogeneity. The correction for multiple testing used the false discovery rate method proposed by Benjamini and Hochberg. The assessment of publication bias employed funnel plots and Egger's test. We identified 25 studies (15 SNPs, involving a total of 11,527 cases and 12,216 controls maximum) and performed a meta-analysis. Eight SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1333049, rs1537378, rs4977574, and rs1004638) in ANRIL were significantly associated with IS risk. Six of these SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1537378, and rs4977574) had a significant relationship to the large artery atherosclerosis subtype of IS. Two SNPs (rs2383206 and rs4977574) were associated with IS mainly in Asians, and three SNPs (rs10757274, rs1333040, and rs1333049) were associated with susceptibility to IS mainly in Caucasians. Sensitivity analyses confirmed the reliability of the original results. Ethnicity and individual studies may be the main sources of heterogeneity in ANRIL. Our results suggest that some single-nucleotide polymorphisms on the ANRIL locus may be associated with IS risk. Future studies with larger sample numbers are necessary to confirm this result. Additional functional analyses of causal effects of these polymorphisms on IS subtypes are also essential.

Endovascular treatment for acute basilar artery occlusion due to different stroke etiologies of large artery atherosclerosis and cardioembolism.

Stroke etiology may affect the prognosis of acute basilar artery occlusion (BAO). This study aimed to estimate the efficacy and safety of endovascular treatment (EVT) in BAO strokes due to the underlying stroke etiologies of large artery atherosclerosis (LAA) and cardioembolism (CE). Patients with LAA and CE subtypes from the registry EVT for Acute Basilar Artery Occlusion Study (BASILAR) were selected for this analysis. We estimated the EVT treatment effect relative to standard medical treatment (SMT) in these patients by using a propensity score approach with inverse probability of treatment weighted estimation. Outcomes included 90-day favorable functional outcomes (modified Rankin scale (mRS) 0-3), functional independence (mRS 0-2), all-cause mortality, and symptomatic intracranial hemorrhage (sICH). A total of 744 patients were included in the final analysis. After weighting with inverse probability of treatment estimation, the patients who, based on their characteristics, were treated with EVT rather than SMT, demonstrated higher rates of favorable functional outcomes in both the LAA (29.2% vs 11.7%, adjusted OR with 95% CI: 4.34 [2.15-8.78], p < 0.001) and the CE subtype (36.0% vs 8.1%, adjusted OR with 95% CI: 9.14 [1.96-42.55], p = 0.005). A similar finding was also observed for functional independence. EVT patients also demonstrated lower rates of mortality than SMT. Among EVT patients, no significant difference was observed in mortality or sICH between LAA and CE groups, but LAA patients had lower rates of favorable functional outcome and functional independence (29.2% vs 37% and 24.2% vs 32.9%, respectively), where the latter remained significant after adjustment for imbalances in baseline data (p = 0.04). In acute BAO strokes, both LAA and CE patients who, based on their characteristics, were treated with EVT rather than SMT, demonstrated better outcomes. Among EVT patients, LAA and CE subtypes displayed important baseline and treatment differences, and LAA patients were less likely to achieve functional independence at 3 months, but mortality and sICH were similar between LAA or CE subtypes. These results need to be confirmed in future clinical trials.

Essen score in the prediction of cerebrovascular events compared with cardiovascular events after ischaemic stroke or transient ischaemic attack: a nationwide registry analysis.

BACKGROUNDThe Essen risk score improves stratification of patients with acute ischemic stroke by early stroke recurrence. Recent study showed it could also predict myocardial infarction (MI). This study aimed to compare the Essen score’s ability to predict cerebrovascular events with compared cardiovascular events.METHODSWe included patients with acute ischaemic stroke or transient ischaemic attack within seven days from the Third China National Stroke Registry. One-year cumulative event rates of combined vascular events (a composite of MI, stroke recurrence or vascular death) and cardiac events (a composite of MI, heart failure or cardiac death) was estimated using the Kaplan-Meier method. The predictive value of the Essen score was assessed with C-statistics. In multivariate Cox regression analyses, we assessed whether Essen score, etiological subtype and imaging parameters were associated with outcomes.RESULTSOf 13,012 patients were included, the cumulative one-year event rates were 10.03% for combined vascular events and 0.77% for cardiac events, respectively. Compared with those with an Essen score < 3, patients with an Essen score ≥ 3 were more likely to have a subsequent combined vascular event [hazard ratio (HR) = 1.39, 95% CI: 1.24−1.55] and cardiac events (HR = 2.30, 95% CI: 1.53−3.44). The score tended to be more predictive of the risk of MI (C-statistic = 0.63, 95% CI: 0.55−0.71) and cardiac events (C-statistic = 0.62, 95% CI: 0.56−0.67) than stroke recurrence (C-statistic = 0.55, 95% CI: 0.54−0.57) and combined vascular events (C-statistic = 0.56, 95% CI: 0.54−0.57). In multivariable analysis after adjusted Essen score, patients with multiple acute infarctions or single acute infarctions and large artery atherosclerosis subtype were independently associated with an increased risk of combined vascular events. While the cardioembolism subtype was associated with an increased risk of cardiac events.CONCLUSIONSThe Essen score is potentially more suitable for risk stratification of cardiovascular events than cerebrovascular events. Moreover, future predictive tools should take brain imaging findings and cause of stroke into consideration.

Association of residual inflammatory risk with stroke recurrence in patients with acute ischaemic stroke or transient ischaemic attack.

The aim was to explore the association of residual inflammatory risk (RIR) with stroke recurrence after an index acute ischaemic stroke or transient ischaemic attack. This study was based on the Third China National Stroke Registry. A total of 5840 patients with two high sensitivity C-reactive protein (hsCRP) measurements at baseline and at 3 months were included in the analysis. High RIR was defined as an hsCRP ≥3mg/l. Patients were divided into four groups: persistent high RIR (first high then high hsCRP), attenuated RIR (first high then low hsCRP), increased RIR (first low then high hsCRP) and persistent low RIR (first low then low hsCRP). The primary outcome was new stroke onset during the 1-year follow-up. Secondary outcomes included composite vascular events, all-cause mortality and poor functional outcome (modified Rankin Scale score 3-6). During the 1-year follow-up, 523 (9.0%) patients had stroke recurrence. Patients with persistent high RIR had an increased risk of stroke recurrence (hazard ratio with 95% confidence interval 1.39, 1.08-1.78), compared with those with persistent low RIR. Similar results were found for the outcome of composite vascular events, mortality and poor functional outcome. An increased risk of stroke recurrence was further found in patients with persistent high RIR and intracranial artery stenosis or large-artery atherosclerosis stroke subtype. In patients with acute ischaemic stroke or transient ischaemic attack, persistent high RIR increased the risks of 1-year stroke recurrence, especially in those with intracranial artery stenosis or large-artery atherosclerosis subtype, composite vascular events, mortality and poor functional outcome.

Nontraditional Risk Factors for Residual Recurrence Risk in Patients with Ischemic Stroke of Different Etiologies

Background and Objective: With the popularization of guideline-based secondary prevention based on traditional risk factors, rates of stroke recurrence reduced greatly after ischemic stroke (IS) or transient ischemic attack (TIA), but the residual risk still exists. We aim to evaluate which IS subtype benefits the most from the current secondary prevention and to evaluate nontraditional risk factors for residual recurrence risk of different IS etiologies. Methods: The study included IS/TIA patients who participated in both biomarker substudy and imaging substudy of the Third China National Stroke Registry. We used 5 guideline-recommended interventions (antiplatelet, statins, anticoagulant, antihypertensive, and antidiabetic therapies) to document the performance of secondary prevention care. Residual risk was defined as the risk of stroke recurrence despite adherence to these 5 guideline-based secondary prevention strategies. Risk factors associated with stroke recurrence were analyzed by using Cox regression models. Results: In total, 9,733 patients were included in this study. At 3 months, 4,186 (43.0%) patients adhered to 5 secondary prevention strategies, and the residual risk of recurrence was 5.1%. According to Trial of Org 10172 in Acute Stroke Treatment subtypes, cardioembolism benefited the most from current secondary prevention (relative risk reduction: 65.2%), followed by large-artery atherosclerosis (LAA) (29.0%) and small-artery occlusion (SAO) (20.0%). Despite adhering to secondary prevention strategies, high sensitivity C-reactive protein, interleukin-6 (IL-6) levels, and impaired renal function were independent risk factors for the residual recurrence risk of LAA subtype, while IL-6 and trimethylamine N-oxide significantly contributed to the residual risk of SAO subtype. Conclusions: LAA and SAO subtypes own the specific nontraditional risk factors while inflammation is a common risk factor for residual recurrence risk of both.