Journal of Investigative Medicine最新文献

Background: Fibrinogenase for injection is an effective antithrombotic agent for eligible patients with acute ischaemic stroke (AIS), but evidence regarding its treatment effects remains limited. This study aimed to evaluate the efficacy and safety of fibrinogenase for injection in patients with AIS who did not receive reperfusion therapies.

Methods: A multicentre, randomised, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Inclusion criteria comprised patients aged 18-85 years with a diagnosis of AIS, an NIH Stroke Scale (NIHSS) score of 4 to 25 and within 72 hours of symptom onset. Eligible patients were randomly allocated in a 1:1 ratio to receive fibrinogenase for injection or placebo. The primary efficacy endpoint was the modified Rankin Scale (mRS) Score at 90 days after randomisation.

Results: Among 235 patients with AIS who were randomised, 233 were included in the intention-to-treat population (117 in the fibrinogenase for injection group and 116 in the placebo group). The mRS score at 90 days after randomisation was significantly lower in the fibrinogenase group (1 (0-2)) than in the placebo group (2 (1-3)), with a favourable shift in the distribution of mRS scores (OR 2.38, 95% CI 1.49 to 3.85; p<0.001). A significantly lower median NIHSS score at 90 days was observed in the fibrinogenase group (1 (0-2)) compared with the placebo group (2 (1-4)) (OR 1.95, 95% CI 1.23 to 3.10; p<0.001). The incidence of haemorrhagic events and mortality during treatment was comparable between the two groups.

Conclusions: In patients with AIS, treatment with fibrinogenase for injection was associated with improved 90-day functional outcomes compared with placebo. This clinical benefit was particularly evident among those who were randomised within 48 hours of symptom onset and in those with mild to moderate stroke due to large artery atherosclerosis or small artery occlusion.

Trial registration number: ChiCTR2100042526; Chinese Clinical Trial Registry.

Background: Hypertension stands as a major modifiable risk factor for cerebral small vessel disease (CSVD), driving pathological cerebrovascular rarefaction and blood-brain barrier (BBB) compromise through endothelial dysfunction and death. However, the mechanisms regulating cerebral endothelial cell death and endogenous vascular repair pathways remain incompletely characterised. While transforming growth factor-β-activated kinase 1 (TAK1) is recognised as a central regulator of cell survival and homeostasis across multiple tissues, its cerebrovascular-specific functions in hypertension-related CSVD pathogenesis have not been fully delineated.Methods Stroke-prone renovascular hypertensive rats (RHRSP) were used as a CSVD model. Cerebrovascular integrity, endothelial death patterns and TAK1 expression were comparatively analysed between RHRSP and sham-operated controls. Dual-route administration (intracerebroventricular and intravenous) of adeno-associated virus (AAV) vectors (AAV-siTAK1 or AAV-TAK1) was employed to achieve brain endothelial-specific TAK1 knockdown or overexpression. The underlying mechanism was validated in vitro.

Results: In RHRSP, chronic hypertension induces predominant necroptosis over apoptosis in cerebral cortical and hippocampal endothelial cells, accompanied by a marked reduction in TAK1 expression. Using genetic and pharmacological approaches, we found that TAK1 downregulation triggers a cascade of pathological events: endothelial necroptosis, tight junction protein degradation, irreversible microvascular rarefaction, BBB leakage and spatial memory deficits. Mechanistically, this cascade is centrally mediated by TAK1-dependent regulation of the receptor-interacting protein kinase 1 (RIPK1)-mixed lineage kinase domain-like (MLKL) axis.

Conclusions: Our results demonstrate that TAK1 downregulation in endothelial cells induces RIPK1-MLKL-mediated necroptosis and downregulation of tight junction protein expression. This coordinated mechanism orchestrates cerebrovascular integrity impairment and subsequent cognitive deterioration. This study positions TAK1 as a promising and potential therapeutic target for the prevention and treatment of hypertension-related CSVD.

Background and purpose: Controversy persists over the balance of benefits and harms of early intensive blood pressure (BP) lowering in thrombolysis-treated acute ischaemic stroke (AIS) patients. The BP-control arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) (n=2196) showed that compared with guideline-recommended management (systolic BP (SBP)<180 mm Hg), intensive BP lowering did not improve functional outcome despite reducing intracranial haemorrhage. We aimed to evaluate the relationship between the BP parameters and cerebral oedema in ENCHANTED BP-control arm participants.

Methods: ENCHANTED was an international, multicentre, open-label, blinded outcome assessed, randomised controlled trial in thrombolysed AIS patients. All baseline and follow-up brain images were centrally analysed using standardised techniques and planimetric software by expert readers blind to clinical details. The severity of cerebral oedema was measured on a 7-point scale that ranged from 0 (no oedema) to 6 (most severe oedema); the primary outcome of 'severe cerebral oedema' defined by scores 4-6.

Results: 1477 (67.3%) participants (mean age 67.7 years, 39.6% female) with available cerebral oedema data were included. Patients with a larger magnitude of SBP reduction in 1 hour had a lower odds of severe cerebral oedema (adjusted OR 0.72 per 10 mm Hg, 95% CI 0.53 to 0.98; p=0.04), whereas those with greater SBP variability between 1 hour and 24 hours had a shift towards worse cerebral oedema (adjusted OR 1.27 per 10 mm Hg, 95% CI 1.01 to 1.60; p=0.04).

Conclusion: Although the effect size is modest, achieving rapid lowering of SBP within 1 hour and then maintaining stable SBP over 24 hours appears to be associated with less cerebral oedema in thrombolysis-treated AIS patients.

Clinical trial registration: The trial is registered at ClinicalTrials.gov (NCT01422616).

Background: Aneurysmal subarachnoid haemorrhage (SAH) is a life-threatening condition with high morbidity. Delayed cerebral ischaemia (DCI) significantly contributes to secondary injury and poor outcomes. While perfusion CT (CTP) aids DCI detection, multimodal neuromonitoring-including brain tissue oxygenation (PtiO₂) and cerebral microdialysis-offers superior temporal resolution. Its value in guiding treatment remains underexplored.

Methods: This prospective cohort study included SAH patients monitored with multimodal neuromonitoring at RWTH Aachen University Hospital (2014-2020). DCI was diagnosed with neuromonitoring abnormalities and confirmed by CTP. First-line treatment involved induced hypertension, with endovascular rescue treatment for refractory cases. Physiological data were time-aligned to treatment onset and aggregated into hourly summaries. Binomial logistic regression identified predictors of favourable 1-year outcome (modified Rankin Scale 0-3).

Results: Of 56 patients with confirmed DCI, correctly placed probes and available outcome data, 22 (39.3%) achieved favourable outcome. These patients showed greater post-treatment reductions in pressure reactivity index (PRx) and lactate-to-pyruvate ratio (LPR). In multivariable analysis, greater PRx reduction was significantly associated with favourable outcome (OR 0.023, 95% CI 0.001 to 0.394, p=0.009), translating to a 46.5% increase in odds per 0.1-unit decrease. Greater LPR reductions were also predictive (OR 0.950, 95% CI 0.904 to 0.998, p=0.042), with a 5-unit drop linked to a 29.3% increase in odds. Although PtiO2_₂ improved post-treatment, it was not associated with outcome.

Conclusion: PRx and LPR reflect meaningful physiological responses to DCI treatment and are associated with 1-year outcomes. Multimodal neuromonitoring may support not only diagnosis but also treatment monitoring and decision-making in unconscious SAH patients.

Trial registration number: German Clinical Trial Registry (DRKS00030505).

Background: The optimal treatment approach for patients with severe atherosclerotic vertebral artery ostial stenosis (VAOS) is not yet supported by evidence from large-scale studies. Even with optimal medical treatment and effective risk factor management, substantial numbers of patients experience symptoms or recurrent strokes. Endovascular treatment is a potential solution, particularly when medicinal therapy alone is insufficient for symptom and stroke risk reduction. This study was aimed at assessing the safety and effectiveness of stent angioplasty in patients with VAOS.

Methods: This single-centre retrospective analysis included 564 procedures in 525 patients (symptomatic n=265, without recent symptoms n=260; 72.2% male; median age: 70 years; stenosis >75% n=371) who underwent stenting for atherosclerotic VAOS between 2008 and 2022. Vertebrobasilar tandem lesions and dissections were excluded. Digital subtraction angiography was performed in all patients during the follow-up. Patients' characteristics, periprocedural and postprocedural neurological events, and follow-up data were evaluated.

Results: Stenting was successfully performed in all cases. The in-hospital stroke rate was 0.6% (disabling n=2; non-disabling n=1). No ipsilateral stroke or treatment-associated deaths occurred during a mean follow-up period of 56 months (min.-max., 9-183 months). In-stent restenosis >50% was found in 89 (15.8%) implanted stents, with the majority (70 out of 89) diagnosed within the first year, at a median time of 7 months.

Conclusions: Stent angioplasty was demonstrated to be a safe and feasible option for patients with VAOS, with a low risk of periprocedural stroke and symptom recurrence, and favourable stent patency rates at mid-term and long-term follow-up.

Background: Contact aspiration (CA) and stent retriever (SR) thrombectomy are two equally recommended first-line endovascular techniques for treating acute ischaemic stroke due to large vessel occlusion. Whether CA is more effective in achieving complete reperfusion compared with SR in patients with acute basilar artery occlusion (ABAO) remains unclear.

Aim: This study aims to compare the efficacy and safety of CA versus SR as the first-line strategy during endovascular treatment in improving the rates of first-pass effect (FPE) for patients with ABAO.

Methods and design: The ANGEL-COAST study is a prospective, multicentre, randomised controlled, open-label, blinded-endpoint (PROBE) clinical trial. Patients with acute ischaemic stroke due to ABAO within 24 hours from symptom onset will be recruited. Participants will be randomly assigned in a 1:1 ratio to either the CA or SR group. If the assigned treatment fails after three attempts, investigators may opt for alternative treatment strategies based on their clinical judgement.

Study outcomes: The primary endpoint is the FPE rate, defined as eTICI (Extended Thrombolysis in Cerebral Infarction) 2C/3 recanalisation after the first thrombectomy attempt without any rescue strategy. Key secondary endpoints include rates of modified FPE (eTICI ≥2b50), successful recanalisation (eTICI ≥2b50, eTICI ≥2b67, eTICI3) within ≤3 passes with the assigned device on conclusion of the procedure, procedural duration, use of rescue techniques and functional outcomes at 90 days, including modified Rankin Scale (mRS) 0-2 and mRS ordinal shift analysis. Safety outcomes include the rates of symptomatic intracerebral haemorrhage (sICH) at 36±12 hours, all-cause 90-day mortality and procedure-related serious adverse events.

Discussion: This is a head-to-head randomised trial to directly compare CA and SR in ABAO. The findings will help establish the optimal first-line endovascular treatment strategy for ABAO, potentially improving clinical outcomes in this high-risk group.

Trial registration number: https://www.

Clinicaltrials: gov; Unique identifier: NCT05615038.

Background: Most current studies on Onyx are limited by small sample sizes and often involve its use in combination with other embolic materials, with few investigations specifically evaluating Onyx as a sole embolic agent.

Methods: Using the Dural Arteriovenous Fistula Research and Management in China (DREAM-INI) database, we identified patients who underwent primary treatment for dural arteriovenous fistula (DAVF) with Onyx-only embolisation. Data collected included patient demographics, comorbidities, clinical manifestations, DAVF location, arterial supply, Borden and Cognard classifications, endovascular modalities, angiographic results, complications, and both clinical and angiographic follow-up. Multivariate logistic regression analyses were conducted to identify predictors of immediate complete obliteration, complications and poor clinical outcomes.

Results: A total of 471 patients with DAVFs underwent primary embolisation using Onyx. The median duration of clinical follow-up was 35.0 months (IQR 10.0-75.3), while the median angiographic follow-up was 24.0 months (IQR 8.0-63.0). Immediate complete obliteration was achieved in 417 patients (88.5%). Procedure-related complications occurred in 31 cases (6.6%). At the final follow-up, 90.6% of patients demonstrated good clinical outcomes. Borden type III DAVFs were positively associated with immediate complete obliteration, whereas the presence of occipital and pial artery feeders was negatively associated. Tentorial location correlated with a higher risk of complications, and age above 65 years emerged as a significant predictor of poor clinical outcome.

Conclusions: In this large single-centre study based on the DREAM-INI database, we report satisfactory obliteration rates, a low incidence of complications and favourable outcomes following Onyx-based single-agent primary embolisation for single DAVFs.

Background and purpose: There is a scarcity of evidence of tenecteplase administered within the 24-hour window of acute ischaemic stroke due to basilar artery occlusion (BAO). We sought to assess whether intravenous tenecteplase within 24 hours of stroke onset, with or without endovascular treatment (EVT), leads to superior outcomes compared with standard care in acute BAO.

Methods and design: Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-5 (TRACE-5), using a prospective, randomised, open-label, blinded-endpoint design, will enrol patients with acute ischaemic stroke due to BAO within 24 hours of the time they were last known well. Patients will be randomised to either intravenous tenecteplase (0.25 mg/kg, maximum 25 mg) or standard care. EVT is allowed in both groups.

Study outcomes: Modified Rankin Scale (mRS) of 0-1 or return to baseline mRS at 90 days is the primary outcome. Secondary outcomes include mRS 0-2 or return to baseline, mRS 0-3 and mRS distribution at 90 days, early neurological improvement within 72 hours and substantial reperfusion at initial angiogram. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, death within 90 days and mRS 5-6 at 90 days.

Discussion: The TRACE-5 trial will address whether extended-time window thrombolysis with a potentially more effective thrombolytic agent tenecteplase±EVT is superior to standard care in BAO.

Trial registration number: NCT06196320.

Background: While endovascular therapy (EVT) remains the primary treatment for acute ischaemic stroke (AIS) management, persistent functional deficits in patients with successful recanalisation underscore the necessity for complementary neuroprotective strategies.

Aim: To investigate the safety and efficacy of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) as a potential adjunctive neuroprotective intervention following EVT in AIS patients.

Design: The Low-Frequency REpetitive TRanscranial Magnetic Stimulation Combined with Endovascular Treatment in ACute Ischaemic StrokE (RETRACE-II) trial is a phase II, multicentre, prospective, randomised, double-blind, sham-controlled pilot study. 60 successfully recanalised AIS patients with anterior circulation occlusion were equally randomised (1:1) to active LF-rTMS or sham intervention. The intervention involved administration of 1200-pulse 1-Hz LF-rTMS sessions (two times per day for 3 consecutive days) targeting the ipsilesional primary motor cortex (M1), initiated within 24 hours of symptom onset. Sham procedures maintained equivalent positioning with deactivated magnetic output. Standardised protocol assessments were conducted at 3-day (postintervention), 7-day and 90-day follow-ups.

Study outcomes: The primary efficacy endpoint was the proportion of early neurological recovery (defined as a reduction of ≥4 points on the National Institutes of Health Stroke Scale (NIHSS) or achieving a score of 0-1) at 3 days. Secondary outcomes included ischaemic penumbral salvage volume ratio, final infarct volume measured by brain MRI at 7 days, and modified Rankin Scale score at 90 days. Safety outcomes encompassed symptomatic intracranial haemorrhage, neurological deterioration (≥4-point increase in NIHSS score) and all-cause mortality through 90-day follow-up.

Discussion: RETRACE-II establishes methodological rigour for evaluating neuromodulation therapies during the hyperacute stroke phase, with findings expected to inform future trials and advance combination therapy paradigms in cerebrovascular neuroprotection.

Trial registration number: NCT06064747.