Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective Studies

Background and Objectives:Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. Still, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. Here, we set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population.Methods:Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias.Results:We identified 11 studies (n=27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were females. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7 to 9). In meta-analyses, 1-standard deviation increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.Discussion:Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

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Circulating interleukin-6 levels and incident ischemic stroke: a systematic review and meta-analysis of population-based cohort studies

10.1101/2021.03.27.21254451 ◽

2021 ◽

Author(s):

Andreas Papadopoulos ◽

Konstantinos Palaiopanos ◽

Harry Björkbacka ◽

Annette Peters ◽

James A. de Lemos ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Cohort Studies ◽

Stroke Risk ◽

Meta Analysis ◽

Population Based ◽

Risk Of Bias ◽

Vascular Risk ◽

Ischemic Stroke Risk ◽

Meta Analyses

ABSTRACTObjectiveTo determine the association between circulating interleukin-6 (IL-6) levels and risk of incident ischemic stroke in the general population.MethodsFollowing the PRISMA guidelines, we systematically searched the literature for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effect meta-analyses and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS).ResultsWe identified 11 studies (n=27,411 individuals; 2,669 incident stroke cases) meeting our eligibility criteria. Overall, quality of the included studies was high (median 8 out of 9 NOS points). In meta-analyses, 1-standard deviation increment in circulating IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.ConclusionsHigher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

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Association of NOTCH3 Gene Polymorphisms with Ischemic Stroke and its Subtypes: A Meta-Analysis

Medicina ◽

10.3390/medicina55070351 ◽

2019 ◽

Vol 55 (7) ◽

pp. 351 ◽

Cited By ~ 1

Author(s):

Keat Wei ◽

Griffiths ◽

Irene ◽

Kooi

Keyword(s):

Ischemic Stroke ◽

Gene Polymorphisms ◽

Stroke Risk ◽

Autosomal Dominant ◽

Meta Analysis ◽

Lacunar Stroke ◽

Notch3 Gene ◽

Ischemic Stroke Risk ◽

Review Manager

Background and objectives: NOTCH3 gene variations play a significant role in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, the role of NOTCH3 gene polymorphisms in the risk of ischemic stroke, and its subtypes such as atherothrombotic or lacunar strokes, remains unclear. Aims: Hence, we carried out a meta-analysis to examine whether the NOTCH3 rs1043994, rs1044009 and rs3815188 polymorphisms are associated with ischemic stroke and its major subtypes. Materials and Methods: All relevant studies were systematically screened and meta-analyzed using Review Manager (Revman) version 5.3. The strength of the association between NOTCH3 polymorphisms and ischemic stroke risk and its subtypes were measured as odds ratios and 95% confidence intervals, under different genetic models. Results: A total of ten studies were identified, five of which considered NOTCH3 rs1043994 (2077 cases/2147 controls), five of which considered NOTCH3 rs1044009 (2315 cases/3053 controls), and nine of which considered NOTCH3 rs3815188 (2819 cases/2769 controls). These studies were meta-analyzed for their association with ischemic stroke risk. Four studies (874 cases/2002 controls) of the NOTCH3 rs3815188 polymorphism and three studies of the NOTCH3 rs1043994 (643 cases/1552 controls) polymorphism were meta-analyzed for lacunar stroke risk. Three studies (1013 cases/1972 controls) of the NOTCH3 rs3815188 polymorphism were meta-analyzed for atherothrombotic stroke risk. The meta-analysis results showed a lack of association between all of the studied polymorphisms and the risk of ischemic stroke and its major subtypes (i.e., atherothrombotic and lacunar). Conclusions: NOTCH3 polymorphisms are not significantly associated with the risk of ischemic stroke and its subtypes (p < 0.05).

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The Role of Classic Risk Factors and Prothrombotic Factor Gene Mutations in Ischemic Stroke Risk Development in Young and Middle-Aged Individuals

Journal of Stroke and Cerebrovascular Diseases ◽

10.1016/j.jstrokecerebrovasdis.2013.09.025 ◽

2014 ◽

Vol 23 (3) ◽

pp. e171-e176 ◽

Cited By ~ 11

Author(s):

Visnja Supanc ◽

Zdenko Sonicki ◽

Ines Vukasovic ◽

Vesna V. Solter ◽

Iris Zavoreo ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Stroke Risk ◽

Gene Mutations ◽

Middle Aged ◽

Factor Gene ◽

Ischemic Stroke Risk

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C-reactive protein and ischemic stroke risk in general population: A dose–response meta-analysis of prospective studies

International Journal of Cardiology ◽

10.1016/j.ijcard.2015.04.176 ◽

2015 ◽

Vol 190 ◽

pp. 264-267 ◽

Cited By ~ 9

Author(s):

Tian Xu ◽

Kaifu Ke

Keyword(s):

Ischemic Stroke ◽

General Population ◽

Dose Response ◽

Prospective Studies ◽

Stroke Risk ◽

Meta Analysis ◽

C Reactive Protein ◽

Reactive Protein ◽

Ischemic Stroke Risk

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

Stroke ◽

10.1161/str.45.suppl_1.tp153 ◽

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.

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Correlations of ANP Genetic Polymorphisms and Serum Levels with Ischemic Stroke Risk: A Meta-Analysis

Genetic Testing and Molecular Biomarkers ◽

10.1089/gtmb.2013.0498 ◽

2014 ◽

Vol 18 (5) ◽

pp. 349-356 ◽

Cited By ~ 1

Author(s):

De-Guang Xing ◽

Dong-Yong Zhang ◽

Zhan-Fu Wang ◽

Da-Ling Ding ◽

Jun Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Polymorphisms ◽

Stroke Risk ◽

Meta Analysis ◽

Serum Levels ◽

Ischemic Stroke Risk

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Abstract TMP58: Determinants of White Matter Hyperintensity in Acute Ischemic Stroke Patients: The MRI-GENIE Study

Stroke ◽

10.1161/str.48.suppl_1.tmp58 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Anne-Katrin Giese ◽

Markus D Schirmer ◽

Adrian V Dalca ◽

Ramesh Sridharan ◽

Lisa Cloonan ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Ischemic Stroke ◽

White Matter ◽

Stroke Risk ◽

Smoking Status ◽

Vascular Risk Factors ◽

White Matter Hyperintensity ◽

Vascular Risk ◽

Prior Stroke

Introduction: White matter hyperintensity (WMH) is a highly heritable trait and a significant contributor to stroke risk and severity. Vascular risk factors contribute to WMH severity; however, knowledge of the determinants of WMH in acute ischemic stroke (AIS) is still limited. Hypothesis: WMH volume (WMHv) varies across AIS subtypes and is modified by vascular risk factors. Methods: We extracted WMHv from the clinical MRI scans of 2683 AIS subjects from the MRI-Genetics Interface Exploration (MRI-GENIE) study using a novel fully-automated, volumetric analysis pipeline. Demographic data, stroke risk factors and stroke subtyping for the Causative Classification of Stroke (CCS) were performed at each of the 12 international study sites. WMHv was natural log-transformed for linear regression analyses. Results: Median WMHv was 5.7cm 3 (interquartile range (IQR): 2.2-12.8cm 3 ). In univariable analysis, age (63.1 ± 14.7 years, β=0.04, SE=0.002), prior stroke (10.2%, β=0.66, SE=0.08), hypertension (65.4%, β=0.75, SE=0.05), diabetes mellitus (23.1%, β=0.35, SE=0.06), coronary artery disease (17.6%, β=0.04, SE=0.002), and atrial fibrillation (14.6%, β=0.48, SE=0.07) were significant predictors of WMHv (all p<0.0001), as well as smoking status (52.2%, β=0.15, SE=0.05, p=0.005), race (16.5% Non-Caucasian, β=0.25, SE=0.07) and ethnicity (8.2% Hispanic, β=0.30, SE=0.11) (all p<0.01). In multivariable analysis, age (β=0.04, SE=0.002), prior stroke (β=0.56, SE=0.08), hypertension (β=0.33, SE=0.05), smoking status (β=0.16, SE=0.05), race (β=0.42, SE=0.06), and ethnicity (β=0.34, SE=0.09) were independent predictors of WMHv (all p<0.0001), as well as diabetes mellitus (β=0.13, SE=0.06, p=0.02). WMHv differed significantly (p<0.0001, unadjusted) across CCS stroke subtypes: cardioembolic stroke (8.0cm 3 , IQR: 4.2-15.4cm 3 ), large-artery stroke (6.9cm 3 , IQR: 3.1-14.7cm 3 ), small-vessel stroke (5.8cm 3 , IQR: 2.5-13.5cm 3 ), stroke of undetermined (4.7cm 3 , IQR: 1.6-11.0cm 3 ) or other (2.55cm 3 , IQR: 0.9-8.8cm 3 ) causes. Conclusion: In this largest-to-date, multicenter hospital-based cohort of AIS patients with automated WMHv analysis, common vascular risk factors contribute significantly to WMH burden and WMHv varies by CCS subtype.

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Chapter 1. Transient Ischemic Attack, Traumatic Brain Injury, and Ischemic Stroke: Risk Factors and Treatments

Acute Brain Impairment - Drug Discovery ◽

10.1039/9781788012539-00001 ◽

2017 ◽

pp. 1-14

Author(s):

Philip V. Peplow ◽

Jacqueline J. T. Liaw

Keyword(s):

Risk Factors ◽

Traumatic Brain Injury ◽

Ischemic Stroke ◽

Brain Injury ◽

Transient Ischemic Attack ◽

Stroke Risk ◽

Stroke Risk Factors ◽

Ischemic Stroke Risk ◽

Ischemic Attack

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Abstract 140: Comparison of Major Complication of Oral Anticoagulants in Non-Valvular Atrial Fibrillation: Systematic Review and Meta-Analyses

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.140 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Hong Seok Lee

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Major Bleeding ◽

Oral Anticoagulant ◽

Stroke Risk ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Gi Bleeding ◽

Ischemic Stroke Risk ◽

Meta Analyses

Background: Oral anticoagulants known as a novel oral anticoagulant have been used for the management of non -valvular atrial fibrillation. There was no enough study regarding the efficacy and safety of three major new oral anticoagulants. We assessed major three oral anticoagulants in terms of major bleeding complication and stroke prevention by meta-analyses studies comparing those drugs. Method: Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2016). RevMan and ITC software were used for direct comparisons, respectively. Results: Apixaban (N=6020), versus dabigatran(N=12038), apixaban versus rivaroxaban(N=8503) and rivaroxaban versus dabigatran were analyzed directly. There was significantly higher major bleeding risks in apixaban compared to dabigatran (both 110mg and 150mg) after adjusting baseline bleeding risk (Relative risk 3.41, 95% confidence interval(2.61 to 4.47) in 110mg, (5.62, 4.83 to 6.54) in 150mg. Intracranial bleeding risk in apixaban was significantly higher than in dabigatran (10.5, 6.10 to18.01). However, apixaban had less GI bleeding risk compared to dabigatran (0.80 , 0.65 to 0.98) and also had less ischemic stroke risk (0.31,0.22 to 0.42). Rivaroxaban showed higher major bleeding risk than dabigatran 110mg (2.34 , 1.81 to 3.03), however, Rivaroxaban had less bleeding risk compared to dabigatran 150mg (0.41, 0.35 to 0.46). Dabigatran 110mg and 150mg had less GI bleeding risk compared to rivaroxaban (0.31 , 0.24 to 0.39) and (0.23,0.17 to 0.29) respectively. Ischemic stroke risk was also decreased in dabigatran110mg (0.46, 0.38 to 0.57). and 150mg (0.66 ,0.52 to 0.83). Conclusion: Observed oral anticoagulants were associated with various complications. Overall, apixaban had higher intracranial bleeding risk than dabigatran. The highest GI bleeding risk in rivaroxaban compared to apixaban and dabigatran. Ischemic stroke risk was the highest in dabigatran. In conclusion, we may use those oral anticoagulant based on risks rates, however, a larger study with longer follow-up is needed to corroborate findings.

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