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.

Impact of Pre-eclampsia/eclampsia on Hemorrhagic and Ischemic Stroke Risk: A 17 years Follow-up Nationwide Cohort Study

Objective No study ever investigated the long-term risk of stroke in women with pre-eclampsia/eclampsia. The purpose of this study is to explore long-term stroke risks, differentiating subtypes and their time trends. Design Nationwide population-based cohort study Methods Between 2000 and 2017, 1,384,427 pregnant women were registered in the National Health Insurance Research Database in Taiwan. After excluding women with previous stroke history and exact matching with all confounders, 6,053 women with pre-eclampsia/eclampsia and 24,212 controls were recruited. Main Outcome Measures Hemorrhagic and ischemic strokes after child-birth Results Over the 17-year follow-up, the adjusted hazard ratio (aHR) for stroke in women with a history of pre-eclampsia/eclampsia was 2.05 (95% confidence interval, CI = 1.67-2.52, p<0.001). The 17 years overall risks of both ischemic and hemorrhagic stroke were 1.98 and 3.45, respectively (p<0.001). The stroke subtypes, hemorrhagic and ischemic, had different time trend risks, and hemorrhagic stroke risks kept higher than that of ischemic stroke. The ischemic stroke risk peaked during 1-3 years after childbirth (aHR=3.09). The hemorrhagic stroke risk peaked during 3-5 years (aHR=7.49). Conclusions Stroke risk persisted even after decades, for both ischemic and hemorrhagic subtypes. Women with pre-eclampsia/eclampsia history should be aware of the long-term risk of stroke. Tweetable abstract Both ischemic and hemorrhagic stroke risks persisted high even after decades, while their time trend risks were different. Keywords: pre-eclampsia/eclampsia; ischemic stroke; hemorrhagic stroke

Transesophageal Echocardiography in Ischemic Stroke With Atrial Fibrillation

Background To clarify differences in clinical significance of intracardiac thrombi in nonvalvular atrial fibrillation‐associated stroke as identified by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE). Methods and Results Using patient data on nonvalvular atrial fibrillation‐associated ischemic stroke between 2011 and 2014 from 15 South Korean stroke centers (n=4841) and 18 Japanese centers (n=1192), implementation rates of TEE/TTE, and detection rates of intracardiac thrombi at each center were correlated. The primary outcome was recurrent ischemic stroke at 1 year after the onset. A total of 5648 patients (median age, 75 years; 2650 women) were analyzed. Intracardiac thrombi were detected in 75 patients (1.3%) overall. Thrombi were detected in 7.8% of patients with TEE (either TEE alone or TEE+TTE: n=679) and in 0.6% of those with TTE alone (n=3572). Thrombus detection rates varied between 0% and 14.3% among centers. As TEE implementation rates at each center increased from 0% to 56.7%, thrombus detection rates increased linearly (detection rate [%]=0.11×TEE rate [%]+1.09 [linear regression], P <0.01). TTE implementation rates (32.3%–100%) were not associated with thrombus detection rates ( P =0.53). Intracardiac thrombi were associated with risk of recurrent ischemic stroke overall (adjusted hazard ratio [aHR] 2.35, 95% CI, 1.07–5.16). Thrombus‐associated ischemic stroke risk was high in patients with TEE (aHR, 3.13; 95% CI, 1.17–8.35), but not in those with TTE alone (aHR, 0.89; 95% CI, 0.12–6.51). Conclusions Our data suggest clinical relevance of TEE for accurate detection and risk stratification of intracardiac thrombi in nonvalvular atrial fibrillation‐associated stroke. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01581502.

Antiplatelet Use and Ischemic Stroke Risk in Minor Stroke or Transient Ischemic Attack: A Post Hoc Analysis of the POINT Trial

Background and Purpose: Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear. Methods: This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization. Results: We included 4881 patients of whom 41% belonged to the no pretreatment antiplatelet. Ischemic stroke occurred in 6% and 5% in the antiplatelet pretreatment and no antiplatelet pretreatment, respectively. Antiplatelet pretreatment was not associated with the risk of ischemic stroke (adjusted hazard ratio, 1.05 [95% CI, 0.81–137]) or risk of major hemorrhage (hazard ratio, 1.10 [95% CI, 0.55–2.21]; P =0.794). The effect of dual antiplatelet therapy on recurrent ischemic stroke risk was not different in patients who were on antiplatelet before randomization (adjusted hazard ratio, 0.69 [95% CI, 0.50–0.94]) as opposed to those who were not (adjusted hazard ratio, 0.75 [95% CI, 0.50–1.12]), P for interaction = 0.685. Conclusions: In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

Poly (Adenosine Diphosphate Ribose) Polymerase-1 Single Nucleotide Polymorphism In The 3'-Untranslated Region For Ischemic Stroke Risk Reduction

Objective: To determine the effect of PARP1 polymorphism on gene interactions. Methods: A total of 500 patients and 500 healthy controls were enrolled. Results: Analysis of clinical data showed that patients with stroke, diabetes, hypertension, and elevated serum triglyceride levels had higher levels of alcohol and smoking. The polymorphism of PARP1rs8679 was inversely associated with the risk of ischemic stroke. Patients with PARP1rs8679AG/GG genotypes had a lower incidence of an initial stroke. Compared with the wild genotype, mRNA levels of PARP1 were reduced. MiR-124-5p directly induced PARP1 inhibition through the gain binding ability of 3 'UTR binding. Conclusion: Single nucleotide polymorphism (SNP) rs8679 in PARP13ʹUTR can prevent ischemic stroke.

Atrial Fibrillation Detected by Single Timepoint Handheld ECG Screening and the Risk of Ischemic Stroke

ABSTRACT Objective: We evaluated stroke risk in patients with single timepoint screen-detected atrial fibrillation (AF) and the effect of oral anticoagulants (OAC). Methods: Consecutive patients aged ≥65 years attending medical outpatient clinics were prospectively enrolled for AF-screening using handheld single-lead ECG (AliveCor) from 12/2014 to 12/2017 (NCT02409654). Repeated screening was performed in patients with >1 visit during this period. Three cohorts were formed, screen-detected AF, clinically-diagnosed AF and no AF. Ischemic stroke risk was estimated using adjusted sub-distribution hazard ratios (aSHR) from multivariate regression and no AF as reference, and stratified according to OAC use. Results: Of 11,972 subjects enrolled, 2,238 (18.7%) had clinically-diagnosed AF at study enrollment. The yield of screen-detected AF on initial screening was 2.3% (n=223/9,734). AF was clinically-diagnosed during follow-up in 2.3% (n=216/9,440) and during subsequent screening in 71 initially screen-negative patients. Compared to no AF, patients with screen-detected AF without OAC treatment had the highest stroke risk (aSHR 2.63; 95% confidence interval 1.46-4.72), while aSHR for clinically-diagnosed AF without OAC use was 2.01 (1.54-2.62). Among screen-detected AF the risk of stroke was significantly less with OAC (no strokes in 196 person-years) compared with those not given OAC (12 strokes in 429 person-years), p=0.01. Conclusion: The prognosis of single timepoint ECG screen-detected AF is not benign. The risk of stroke is high enough to warrant OAC use, and reduced by OAC. Keywords: atrial fibrillation, screening, ischemic stroke