scholarly journals Circulating Exosomal miRNAs as Novel Biomarkers Perform Superior Diagnostic Efficiency Compared With Plasma miRNAs for Large-Artery Atherosclerosis Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengying Niu ◽  
Hong Li ◽  
Xu Li ◽  
Xiaoqian Yan ◽  
Aijun Ma ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
High Throughput Sequencing ◽  
Area Under The Curve ◽  
Large Artery ◽  
Diagnostic Efficiency ◽  
Validation Phase ◽  
Discovery Phase ◽  
Exosomal Mirnas ◽  
Small Artery Occlusion ◽  
Plasma Mirnas

Recently, exosomal miRNAs have been reported to be associated with some diseases, and these miRNAs can be used for diagnosis and treatment. However, diagnostic biomarkers of exosomal miRNAs for ischemic stroke have rarely been studied. In the present study, we aimed to identify exosomal miRNAs that are associated with large-artery atherosclerosis (LAA) stroke, the most common subtype of ischemic stroke; to further verify their diagnostic efficiency; and to obtain promising biomarkers. High-throughput sequencing was performed on samples from 10 subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on exosomes and plasma in the discovery phase (66 subjects in total) and the validation phase (520 subjects in total). We identified 5 candidate differentially expressed miRNAs (miR-369-3p, miR-493-3p, miR-379-5p, miR-1296-5p, and miR-1277-5p) in the discovery phase according to their biological functions, 4 of which (miR-369-3p, miR-493-3p, miR-379-5p, and miR-1296-5p) were confirmed in the validation phase. These four exosomal miRNAs could be used to distinguish LAA samples from small artery occlusion (SAO) samples, LAA samples from atherosclerosis (AS) samples, and LAA samples from control samples and were superior to plasma miRNAs. In addition, composite biomarkers achieved higher area under the curve (AUC) values than single biomarkers. According to our analysis, the expression levels of exosomal miR-493-3p and miR-1296-5p were negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score. The four identified exosomal miRNAs are promising biomarkers for the diagnosis of LAA stroke, and their diagnostic efficiency is superior to that of their counterparts in plasma.

Abstract T P153: Women and Men with Ischemic Stroke in SiGN Have Different Subtype Distributions and Risk Factors

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Kathryn M Rexrode ◽  
Braxton D Mitchell ◽  
Kathleen A Ryan ◽  
Steven J Kittner ◽  
Hakan Ay ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Stroke Risk ◽  
Cardioembolic Stroke ◽  
Relative Distribution ◽  
Large Artery ◽  
Stroke Risk Factors ◽  
Stroke Subtypes ◽  
Small Artery Occlusion ◽  
Ischemic Stroke Risk

Introduction: The relative distribution of stroke risk factors, as well as ischemic stroke subtypes, in women compared with men is not well described. Hypothesis: We hypothesized that the distribution of ischemic stroke risk factors and subtypes would differ by sex, with a later onset in women and greater proportion of comorbidities. Methods: The NINDS Stroke Genetics Network (SiGN) consortium was established to evaluate genetic risk factors for ischemic stroke. A total of 23 separate studies performed Causative Classification of Stroke (CCS) typing using standardized criteria on ischemic stroke cases and contributed data on risk factors. We compared the distribution of ischemic stroke risk factors and CCS phenotypes between men and women with ischemic stroke. Results: Of the 16,228 ischemic strokes in SiGN, 8005 (49.3%) occurred in women. Median age at stroke was older in female than male stroke cases (73 vs. 66 years) (p=<0.0001). Among stroke cases, women were more likely than men cases to have hypertension or atrial fibrillation and less likely to have diabetes or coronary artery disease, or to smoke (p <0.003 for all). The distribution of stroke subtypes also differed by sex, with women less likely than men to have large artery infarction and small artery occlusion, and more likely to have cardioembolic stroke and undetermined stroke due to incomplete work-up (p values all <0.0001; see Table). Results were similar when the distribution of stroke subtypes was examined for those <70 years and ≥70 years, except for cardioembolic stroke remaining more common only among women ≥70. Conclusions: In this large group of carefully phenotyped ischemic strokes, the distribution of ischemic stroke subtypes and risk factor profiles differ significantly by sex. Evaluation of the causes of these differences may highlight areas for improved prevention and risk reduction in both genders.

Abstract 3884: Stroke Subtypes in Hispanic Patients in the NINDS Stroke Genetics Network (SiGN): A Comparison of Two Classification Systems

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Michael Katsnelson ◽  
Tatjana Rundek ◽  
Ralph Sacco ◽  
Hannah Gardener ◽  
Shaneela Malik ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Classification Systems ◽  
Blood Collection ◽  
Large Artery ◽  
Stroke Subtype ◽  
Reliable Determination ◽  
Stroke Treatment ◽  
Stroke Subtypes ◽  
Small Artery Occlusion

Objectives: Identification of gene variants of stroke subtypes is important for the development of tailored ischemic stroke therapies among various ethnic groups. Valid and reliable determination of ischemic stroke subtype is essential for achieving this goal and to standardize a classification scheme across multi-center studies and different populations. Causative Classification System for Ischemic Stroke (CCS) is a novel computerized subclassification tool developed to improve reliability and accuracy of classifying stroke types. The CCS algorithm relies on both phenotypic and causative stroke variables. A Hispanic subset of the SiGN, an important and distinct target population with greater risk of certain stroke subtypes, was evaluated with Trial of Org 10172 in Acute Stroke Treatment (TOAST) and CCS and the agreement between the two classification systems was analyzed. Methods: Over 6000 subjects at 15 sites across US and Europe were enrolled, with TOAST and CCS locally adjudicated. Blood collection and central data quality control (10% central readjudication) were performed on all participants. A subset of Hispanics was analyzed for the purpose of this study and the agreement between the TOAST and CCS were assessed by kappa statistic. Findings: Hispanics (n=595, 10.9%) compared to non-Hispanics (n=5457) were more likely to be younger (63.7 vs. 64.0), male (55% vs. 46%) and have fewer of the traditional stroke risk factors HTN (54% vs. 64%), Afib (11% vs. 14%), DM(23% vs. 25%), CAD(16% vs. 20%) and smoking(19% vs. 22%). While the TOAST showed no differences between stroke subtypes for Hispanic vs. non-Hispanics, in CCS, Hispanics were classified with more of large vessel (22% vs. 20%), cardioembolic (37% vs. 30%) and small vessel strokes (13% vs. 9%) and fewer with undetermined etiology (28% vs. 40%) as compared to non-Hispanics. TOAST and CCS offered moderate correlation across all stroke types in Hispanics: kappa of 0.66 for large artery atherosclerosis, 0.58 for cardioembolic, and 0.58 for small artery occlusion. Conclusion: CCS offers a more sensitive and accurate system for subphenotyping of strokes in Hispanics who tended to have relatively fewer risk factors and unclassified strokes. Further studies correlating the two classification systems and their relation to genotyping data are warranted.

scholarly journals Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

2019 ◽  
Vol 267 (3) ◽  
pp. 649-658 ◽  
Author(s):  
Petrea Frid ◽  
◽  
Mattias Drake ◽  
A. K. Giese ◽  
J. Wasselius ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Large Artery ◽  
Small Artery ◽  
Anterior Circulation ◽  
Lesion Location ◽  
Stroke Subtypes ◽  
Small Artery Occlusion ◽  
Male Sex

Abstract Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

scholarly journals Changes of Metabolites in Acute Ischemic Stroke and Its Subtypes

2021 ◽  
Vol 14 ◽  
Author(s):  
Xin Wang ◽  
Luyang Zhang ◽  
Wenxian Sun ◽  
Lu-lu Pei ◽  
Mengke Tian ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Acid Metabolism ◽  
Artery Occlusion ◽  
Large Artery ◽  
Serum Samples ◽  
Multivariate Statistical ◽  
Pathophysiological Mechanisms ◽  
Small Artery Occlusion ◽  
Potential Biomarkers

Existing techniques have many limitations in the diagnosis and classification of ischemic stroke (IS). Considering this, we used metabolomics to screen for potential biomarkers of IS and its subtypes and to explore the underlying related pathophysiological mechanisms. Serum samples from 99 patients with acute ischemic stroke (AIS) [the AIS subtypes included 49 patients with large artery atherosclerosis (LAA) and 50 patients with small artery occlusion (SAO)] and 50 matched healthy controls (HCs) were analyzed by non-targeted metabolomics based on liquid chromatography–mass spectrometry. A multivariate statistical analysis was performed to identify potential biomarkers. There were 18 significantly different metabolites, such as oleic acid, linoleic acid, arachidonic acid, L-glutamine, L-arginine, and L-proline, between patients with AIS and HCs. These different metabolites are closely related to many metabolic pathways, such as fatty acid metabolism and amino acid metabolism. There were also differences in metabolic profiling between the LAA and SAO groups. There were eight different metabolites, including L-pipecolic acid, 1-Methylhistidine, PE, LysoPE, and LysoPC, which affected glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, histidine metabolism, and lysine degradation. Our study effectively identified the metabolic profiles of IS and its subtypes. The different metabolites between LAA and SAO may be potential biomarkers in the context of clinical diagnosis. These results highlight the potential of metabolomics to reveal new pathways for IS subtypes and provide a new avenue to explore the pathophysiological mechanisms underlying IS and its subtypes.

scholarly journals Upregulation of LncRNAs THRIL and Malat1 in Peripheral Blood of Ischemic Stroke Patients with Large Artery Atherosclerotic and Small Vessel Disease

2021 ◽  
Author(s):  
Mahnaz Bayat ◽  
Najmeh Karimi ◽  
Moosa Rahimi ◽  
Reza Tabrizi ◽  
Tahereh Asadabadi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Small Vessel Disease ◽  
Area Under The Curve ◽  
Positive Association ◽  
Small Vessel ◽  
Main Role ◽  
Large Artery ◽  
Significant Positive Association ◽  
Vessel Disease ◽  
Potential Biomarker

Abstract Background Long non-coding RNA (lncRNA) has the main role in gene regulation and it might serve as a potential biomarker in clinical practice. Malat1 and THRIL LncRNAs have been demonstrated to play key roles in inflammation and atherosclerosis. It was hypothesized that the Malat1 and THRIL expression increase in patients with atherosclerotic ischemic stroke (IS) with significant diagnostic value for discriminating IS from controls. Methods We evaluated Malat1 and THRIL expression on days 1,3, and 5 after stroke in 59 IS cases with small-vessel disease (SVD) and large artery atherosclerosis (LAA), and 63 controls. A real-time polymerase chain reaction was used for the evaluation of lncRNA expression. Results In patients with SVD or LAA, Malat1 and THRIL expression significantly were higher than the controls and mix model analysis showed significantly higher expression of lncRNAs on days 5 relative to days 1 and 3 after stroke while the positive correlation was also detected between Malat1 expression and time after stroke (r = 0.27, p = 0.03). After logistic regression analysis, elevated Malat1 and THRIL showed a significant positive association with the risk of SVD and LAA. We found Malat1 could be used as a diagnostic marker with an area under the curve of 0.78 (p < 0.001). Conclusion This was the first study that demonstrated the significant upregulation of THRIL from 24 hours after IS until 5 days. This upregulation may serve as a biomarker for the diagnosis of IS. To reach a reliable conclusion we need a larger sample size.

scholarly journals Heart Failure and Ischemic Stroke: A Bidirectional and Multivariable Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Luyang Zhang ◽  
Weishi Liu ◽  
Wenxian Sun ◽  
Xin Wang ◽  
Mengke Tian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemic Stroke ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Link ◽  
Artery Occlusion ◽  
Causal Effects ◽  
Genome Wide Association Studies ◽  
Large Artery ◽  
Small Artery Occlusion

Background: Heart failure (HF) is a potential cause of ischemic stroke (IS), and previous studies have reported an association between HF and IS. This study aimed to analyze the causal link between HF and IS using bidirectional and multivariable Mendelian randomization (MR) studies.Methods: Genetic variants significantly associated with HF and IS were selected in the MR analysis from two large genome-wide association studies. Bidirectional and multivariable MR analyses were performed to evaluate the effect of HF on IS or the effect of IS on HF.Results: Two-sample MR analysis showed causal effects of HF on IS of all causes [odds ratio (OR) = 1.555, 95% confidence interval (CI): 1.343–1.799, p = 3.35 × 10−9] and large artery atherosclerosis stroke (LAS) (OR = 1.678, 95% CI: 1.044–2.696, p = 3.03 × 10−5), while there was a suggestive effect of HF on cardioembolic stroke (CES) (OR = 3.355, 95% CI: 1.031–10.919, p = 0.044). Genetically predicted HF was not associated with small artery occlusion stroke. Bidirectional MR analysis showed causal effects of IS of all causes (OR = 1.211, 95% CI: 1.040–1.410, p = 0.014) and CES (OR = 1.277, 95% CI: 1.213–1.344, p = 6.73 × 10−21) on HF, while there were no causal effects of LAS on HF.Conclusion: This MR analysis provided evidence of the causal links between genetically predicted HF and IS. Subgroup analysis highlighted the causal or suggestive relationship between genetically predicted HF and LAS or CES. The potential causal links need further investigation with genetic information about other ancestries or etiologies of HF.

scholarly journals Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes

Hypertension ◽  
2021 ◽  
Vol 77 (4) ◽  
pp. 1391-1398
Author(s):  
Clinton B. Wright ◽  
Alexander P. Auchus ◽  
Alan Lerner ◽  
Walter T. Ambrosius ◽  
Hakan Ay ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Blood Pressure Control ◽  
Standard Treatment ◽  
Pressure Control ◽  
Intensive Treatment ◽  
Large Artery ◽  
Stroke Subtypes ◽  
Small Artery Occlusion ◽  
Blood Pressures

In the SPRINT (Systolic Blood Pressure Intervention Trial), the number of strokes did not differ significantly by treatment group. However, stroke subtypes have heterogeneous causes that could respond differently to intensive blood pressure control. SPRINT participants (N=9361) were randomized to target systolic blood pressures of <120 mm Hg (intensive treatment) compared with <140 mm Hg (standard treatment). We compared incident hemorrhage, cardiac embolism, large- and small-vessel infarctions across treatment arms. Participants randomized to the intensive arm had mean systolic blood pressures of 121.4 mm Hg in the intensive arm (N=4678) and 136.2 mm Hg in the standard arm (N=4683) at one year. Sixty-nine strokes occurred in the intensive arm and 78 in the standard arm when SPRINT was stopped. The breakdown of stroke subtypes across treatment arms included hemorrhagic (intensive treatment, n=6, standard treatment, n=7) and ischemic stroke subtypes (large artery atherosclerosis: intensive treatment n=11, standard treatment, n=13; cardiac embolism: intensive treatment n=11, standard treatment n=15; small artery occlusion: intensive treatment n=8, standard treatment n=8; other ischemic stroke: intensive treatment n=3, standard treatment n=1). Fewer strokes occurred among participants without prior cardiovascular disease in the intensive (n=43) than the standard arm (n=61), but the difference did not reach predefined statistical significance level of 0.05 ( P =0.09). The interaction between baseline cardiovascular risk factor status and treatment arm on stroke risk did not reach significance ( P =0.05). Similar numbers of stroke subtypes occurred in the intensive BP control and standard control arms of SPRINT.

Prognosis of young ischemic stroke in Taiwan: impact of prothrombotic genetic polymorphisms

2004 ◽  
Vol 92 (09) ◽  
pp. 583-589 ◽  
Author(s):  
Poh-Shiow Yeh ◽  
Huey-Juan Lin ◽  
Kao-Chang Lin ◽  
Tain-Junn Cheng ◽  
Chia-Yu Chang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Genetic Polymorphisms ◽  
Arterial Occlusion ◽  
Factor Vii ◽  
Platelet Glycoprotein ◽  
Large Artery ◽  
Composite Outcome ◽  
Cox Regression Analysis ◽  
Small Artery Occlusion ◽  
Young Ischemic Stroke

SummaryWe investigated the effects of genetic factors on the prognosis of cerebral infarction in young adults in Taiwan. Because ischemic stroke with arterial occlusion or undetermined etiology is more likely to be related to a genetic prothrombotic state, 231 patients younger than 50 years (mean age 44.6 years, range 25 to 49 years) with acute ischemic stroke due to large artery atherosclerosis (n=90), small artery occlusion (n=114) or undetermined cause (n=27) were recruited and prospectively followed up for pre-determined outcome. On each patient, we screened the PlA1/PlA2 polymorphism of the platelet glycoprotein IIIa gene, 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene, G10976A polymorphism of the factor VII gene, C677T polymorphism of the methylenetetrahydrofolate reductase gene, and 27 base-pair repeat polymorphism of the endothelial nitric oxide synthase gene. End points were the composite outcome events of stroke, myocardial infarction, and death from all causes. During a mean duration follow-up of 29 months, composite outcome events occurred in 33 patients. There was a higher annual incidence rate of composite outcome events during the first year (9.1%, 95% CI 5.9-13.9%) than in the subsequent 2 years (2.6%, 95% CI 1.2-5.6%, p=0.038). None of the genetic polymorphism was associated with the composite outcome events. Past history of coronary artery disease or cerebrovascular disease was the only independent predictor of the composite outcome events (HR 3.71, 95% CI 1.69-8.14, p=0.001) at the Cox regression analysis. Our data indicate that the prothrombotic genetic polymorphisms do not have a significant influence on the prognosis in young ischemic stroke due to arterial occlusion or undetermined causes in Taiwan.

Abstract WP176: Assessing Genome-wide Associations With Ischemic Stroke Using Alternate Definitions of Stroke Subtypes: The SiGN Study

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sara Pulit ◽  
Hakan Ay ◽  
Robert D Brown ◽  
Dale M Gamble ◽  
Steven J Kittner ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Sample Size ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Classification Systems ◽  
Large Artery ◽  
Genetic Associations ◽  
Stroke Subtype ◽  
Stroke Subtypes ◽  
Small Artery Occlusion

Stroke subtype classification, applying standard criteria to clinical data, can reduce the heterogeneity of ischemic stroke for genetics studies. To date, most of the replicated genetic loci for ischemic stroke appear subtype-specific. Increasing homogeneity of phenotype comes with a trade-off in sample size, which influences the potential for successful identification of new loci. We estimated genetic associations using the union and intersection of two widely used stroke subtyping systems to assess the influence of sample size and homogeneity on test statistics. Methods: The Stroke Genetics Network (SiGN) study used both the Causative Classification of Stroke (CCS) and the Trial of ORG10172 Acute Stroke Trial (TOAST) classification systems. The CCS generates both a causal and a phenotypic subtype. Using all available data from case-control strata from the a previously performed GWAS, we focused on three main stroke subtypes: cardioembolic (CE), large artery atherosclerosis (LAA), and small artery occlusion (SAO). We estimated genetic associations with the union of the two CCS outputs and TOAST ( eg called CE by at least one method) and the intersection ( eg called CE by all three methods). Our modelling approach included a fixed-effects meta-analysis, i.e. pooling stratum specific estimates from logistic regression models using 10 principle components to account for genetic ancestry responsible for population stratification. Results: The majority of confirmatory findings from SiGN ( PITX2 and ZFHX3 for CE and HDAC9 for LAA) were evident in both models and in both the union and intersection of the subtyping systems. Some findings ( TSPAN2 in LAA) showed up best in the intersection with stronger corresponding p-values and odds ratios whereas other findings (12q24 for SAO) appear stronger in all of the union analyses, but were also evident in intersection analyses. We identify 16 potential novel loci, 6 of which appear in numerous analyses. Conclusion: Both expanding and refining stroke subtypes may help in the identification of additional stroke genetic risk variants and should be considered as complementary to a single classification system. We are pursuing replication of the novel findings.

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