Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke:current evidence and future perspectives

Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Chinese Stroke Association guidelines for clinical management of ischaemic cerebrovascular diseases:executive summary and 2023 update

Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.

Somatic mutation contributing to clonal haematopoiesis is a risk factor of recurrent stroke in first-ever acute ischaemic stroke:a prospective cohort study

Background Somatic mutation contributes to clonal haematopoiesis of indeterminate potential(CHIP)is related to age and associated with a higher risk of stroke and atherosclerotic cardiovascular disease.Here,we investigated the prognostic significance of CHIP in a large first-ever acute ischaemic stroke(AIS)cohort and explored the underlying mechanisms.Methods We studied a prospective cohort of 6016 patients who had a first-ever AIS in China.Whole-genome sequencing was performed to identify CHIP.High-sensitivity C reactive protein(hs-CRP)levels above 3 mg/L at baseline were defined as hyperinflammation.Recurrent stroke during the 3-month follow-up was the primary outcome.Results Among the 6016 patients who had a first-ever AIS,with a median age was 62 years(IQR,54.0‒70.0),3.70%were identified as CHIP carriers.The most common mutations occurred in the DNMT3A(30.0%)and TET2(11.4%)genes.During a follow-up of 3 months,the presence of CHIP was associated with recurrent stroke(HR 1.62,95%CI 1.04 to 2.51,p=0.03),recurrent ischaemic stroke(HR 1.64,95%CI 1.04 to 2.58,p=0.03)and combined vascular events(HR 1.58,95%CI 1.02 to 2.44,p=0.04)after adjusting for hsCRP levels at baseline in patients who had a first-ever AIS.Subgroup analysis demonstrated that CHIP was only associated with recurrent stroke when patients under hyperinflammation(OR 3.10,95%CI 1.92 to 5.00,p<0.001)but not in those without hyperinflammation(OR 0.18,95%CI 0.03 to 1.04,p=0.06,Pinteraction=0.002).Conclusion Our results suggest that somatic mutations contributing to CHIP increase the risk of short-term recurrent stroke in patients who had a first-ever AIS.Hyperinflammation may be important in the relationship between CHIP and recurrent stroke.

Detailed phenotype of RNF213 p.R4810K variant identified by the Chinese patients with acute ischaemic stroke or transient ischaemic attack

Background and purpose The ring finger protein 213 gene(RNF213)p.R4810K variant increased the risk of acute ischaemic stroke(AIS)attributable to intracranial arterial stenosis(ICAS)in the Japanese and Korean populations.In this study,we aimed to examine the prevalence of the RNF213 p.R4810K variant in Chinese patients with AIS or transient ischaemic attack and identify the phenotype of the carriers.Methods We analysed data from the Third China National Stroke Registry.All included participants were divided into two groups by carrier status of the p.R4810K variant.The aetiological classification was conducted according to the Trial of Org 10172 in Acute Stroke Treatment(TOAST)criteria.The presence of ICAS and extracranial arterial stenosis(ECAS)was defined as 50%-99%stenosis or occlusion of any intracranial and extracranial artery.Logistic regression models and Cox regression models were used to evaluate the association of the p.R4810K variant with TOAST classification,stenosis phenotypes and clinical outcomes.Results A total of 10381 patients were enrolled,among which 56(0.5%)had the heterozygote GA genotype for p.R4810K.The variant carriers were younger(p=0.01),and more likely to suffer from peripheral vascular disease(p=0.04).The p.R4810K variant was associated with large-artery atherosclerosis(LAA)(adjusted OR=1.94,95%CI 1.13 to 3.33),anterior circulation stenosis(adjusted OR=2.12,95%CI 1.23 to 3.65)and ECAS(adjusted OR=2.29,95%CI 1.16 to 4.51).Nevertheless,the p.R4810K variant was not associated with recurrence,poor functional outcome and mortality at 3 months and 1 year.Conclusions The RNF213 p.R4810K variant was associated with LAA,anterior circulation stenosis and ECAS in Chinese patients.Given the low carrying rate and only 1-year follow-up information,caution should be taken to interpret our findings in no statistically significant association between the p.R4810K variant and stroke prognosis in Chinese patients.

Temporal trends and rural-urban disparities in cerebrovascular risk factors,in-hospital management and outcomes in ischaemic strokes in China from 2005 to 2015:a nationwide serial cross-sectional survey

Background Stroke is the leading cause of mortality in China,with limited evidence of in-hospital burden obtained from nationwide surveys.We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors,management and outcomes from 2005 to 2015.Methods We used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005,2010 and 2015.We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach.We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015.Results We analysed 28277 ischaemic stroke admissions from 189 participating hospitals.From 2005 to 2015,the estimated national hospital admission rate for ischaemic stroke per 100000 people increased(from 75.9 to 402.7,Ptrend<0.001),and the prevalence of risk factors,including hypertension,diabetes,dyslipidaemia and current smoking,increased.The composite score of diagnostic tests for stroke aetiology assessment(from 0.22 to 0.36,Ptrend<0.001)and secondary prevention treatments(from 0.46 to 0.70,Ptrend<0.001)were improved.A temporal decrease was found in discharge against medical advice(DAMA)(from 15.2%(95%CI 13.7%to 16.7%)to 8.6%(8.1%to 9.0%);adjusted Ptrend=0.046),and decreases in in-hospital mortality(0.7%in 2015 vs 1.8%in 2005;adjusted OR(aOR)0.52;95%CI 0.32 to 0.85)and the composite outcome of in-hospital mortality or DAMA(8.4%in 2015 vs 13.9%in 2005;aOR 0.65;95%CI 0.47 to 0.89)were observed.Disparities between rural and urban hospitals narrowed;however,disparities persisted in in-hospital management(brain MRI:rural-urban difference from−14.4%to−11.2%;cerebrovascular assessment:from−20.3%to−16.7%;clopidogrel:from−2.1%to−10.3%;anticoagulant for atrial fibrillation:from−10.9%to−8.2%)and in-hospital outcomes(DAMA:from 2.7%to 5.0%;composite outcome of in-hospital mortality or DAMA:from 2.4%to 4.6%).Conclusions From 2005 to 2015,improvements in hospital admission and in-hospital management for ischaemic stroke in China were found.A temporal improvement in DAMA and improvements in in-hospital mortality and the composite outcome of in-hospital mortality or DAMA were observed.Disparities between rural and urban hospitals generally narrowed but persisted.

Predictors of dysphagia screening and pneumonia among patients with acute ischaemic stroke in China:findings from the Chinese Stroke Center Alliance(CSCA)

Background and purpose Guidelines recommend dysphagia screening to identify those at high risk of pneumonia.However,little is known about the prevalence and predictors of dysphagia screening and pneumonia among patients with acute ischaemic stroke in China.Methods Using data from the Chinese Stroke Center Alliance,which is a multicentre,prospective,consecutive patient enrolment programme,univariate and multivariate analyses were conducted to identify patient and hospital characteristics associated with dysphagia screening and pneumonia during acute hospitalisation.Results Of 790811 patients admitted to 1476 hospitals,622718(78.7%)underwent dysphagia screening,and 64398(8.1%)developed pneumonia.Patients in stroke units were more likely to be screened for dysphagia than those not in stroke units(OR 1.50;95%CI 1.48 to 1.52),while patients with a past history of stroke were less likely to be screened(OR 0.87;95%CI 0.86 to 0.88).Dysphagia screening(OR 1.46;95%CI 1.30 to 1.65),dysphagia(OR 7.31;95%CI 7.15 to 7.46),and admission to stroke units(OR 1.17;95%CI 1.14 to 1.19)were significantly associated with a greater risk of pneumonia.Conclusions Dysphagia was a critical factor in the development of pneumonia.Nearly one in five patients with acute ischaemic stroke in the Chinese Stroke Center Alliance were not screened for dysphagia.Pneumonia prevention during acute hospitalisation is dependent not only on dysphagia screening but also on the effectiveness of subsequent dysphagia management interventions.Further studies are needed to elucidate the relationship between dysphagia screening,stroke unit care and pneumonia in patients with acute ischaemic stroke.

Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke

Acute ischemic stroke(AIS)is a major cause of disability and mortality worldwide.Non-cardioembolic ischemic stroke(NCIS),which constitutes the majority of AIS cases,is highly heterogeneous,thus requiring precision medicine treatments.This study aimed to investigate the molecular mechanisms underlying NCIS heterogeneity.We integrated data from the Third China National Stroke Registry,including clinical phenotypes,biomarkers,and whole-genome sequencing data for 7695 patients with NCIS.We identified 30 molecular clusters based on 63 biomarkers and explored the comprehensive landscape of biological heterogeneity and subpopulations in NCIS.Dimensionality reduction revealed fine-scale subpopulation structures associated with specific biomarkers.The subpopulations with biomarkers for inflammation,abnormal liver and kidney function,homocysteine metabolism,lipid metabolism,and gut microbiota metabolism were associated with a high risk of unfavorable clinical outcomes,including stroke recurrence,disability,and mortality.Several genes encoding potential drug targets were identified as putative causal genes that drive the clusters,such as CDK10,ERCC3,and CHEK2.We comprehensively characterized the genetic architecture of these subpopulations,identified their molecular signatures,and revealed the potential of the polybiomarkers and polygenic prediction for assessing clinical outcomes.Our study demonstrates the power of large-scale molecular biomarkers and genomics to understand the underlying biological mechanisms of and advance precision medicine for NCIS.

Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis(INSPIRES)

Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial.Eligible subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin therapy.The primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after randomisation.The primary safety endpoint is moderate to severe bleeding at 90 days.Conclusion The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.