Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion.

BACKGROUND: Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited. METHODS: We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications. RESULTS: Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P<0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation. CONCLUSIONS: In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

Thrombectomy improves functional independence in severe basilar artery occlusion with favorable collateral circulation.

BACKGROUND AND PURPOSE: This study aimed to investigate the effect of collateral circulation on the outcomes of thrombectomy versus medical management alone in basilar artery occlusion (BAO) patients with varying stroke severities. METHODS: Data from the ATTENTION cohort were used to perform a post-hoc analysis comparing the outcomes of thrombectomy with medical management in BAO patients with varying degrees of collateral circulation and stroke severity. Basilar Artery on Computed Tomography Angiography (BATMAN) scores were used to quantify the collateral circulation, and the effect was estimated through a primary outcome of 90-day functional independence (modified Rankin Scale score, mRS ≤2). Favorable versus unfavorable BATMAN scores were analyzed as both continuous and categorical variables, and an adjusted multivariate regression model was applied. RESULTS: Among 221 BAO patients, thrombectomy significantly improved functional independence compared to medical management in patients with favorable BATMAN scores (aOR 7.75, 95% CI 2.78-26.1), but not in those with unfavorable BATMAN scores (aOR 1.33, 95% CI 0.28-6.92; pinteraction = 0.028). When treated as a continuous variable, increased BATMAN score was found to be associated with a higher likelihood of functional independence in the thrombectomy group (aOR 1.97, 95% CI 1.44-2.81; pinteraction = 0.053). In severe stroke patients with higher BATMAN scores (National Institutes of Health Stroke Scale (NIHSS) ≥21), we identified a significant interaction for treatment effect with thrombectomy compared to medical management (pinteraction = 0.042). CONCLUSION: An increased BATMAN score was significantly associated with a higher probability of functional independence after thrombectomy than after medical management, particularly in patients with severe BAO.

Endovascular Treatment Versus Best Medical Management in Acute Basilar Artery Occlusion Strokes: Results From the ATTENTION Multicenter Registry.

BACKGROUND: The authors compare the effectiveness and safety of endovascular treatment (EVT) versus best medical management (BMM) in strokes attributable to acute basilar artery occlusion (BAO). METHODS: The present analysis was based on the ongoing, prospective, multicenter ATTENTION (Endovascular Treatment for Acute Basilar Artery Occlusion) trial registry in China. Our analytic sample comprised 2134 patients recruited at 48 sites between 2017 and 2021 and included 462 patients who received BMM and 1672 patients who received EVT. We performed an inversed probability of treatment weighting analysis. Qualifying patients had to present within 24 hours of estimated BAO. The primary clinical outcome was favorable functional outcome (modified Rankin Scale score, 0-3) at 90 days. We also performed a sensitivity analysis with the propensity score matching-based and the instrumental variable-based analysis. RESULTS: In our primary analysis using the inversed probability of treatment weighting-based analysis, there was a significantly higher rate of favorable outcome at 90 days among EVT patients compared with BMM-treated patients (adjusted relative risk, 1.42 [95% CI, 1.19-1.65]; absolute risk difference, 11.8% [95% CI, 6.9-16.7]). The mortality was significantly lower (adjusted relative risk, 0.78 [95% CI, 0.69-0.88]; absolute risk difference, -10.3% [95% CI, -15.8 to -4.9]) in patients undergoing EVT. Results were generally consistent across the secondary end points. Similar associations were seen in the propensity score matching-based and instrumental variable-based analysis. CONCLUSIONS: In this real-world study, EVT was associated with significantly better functional outcomes and survival at 90 days. Well-designed randomized studies comparing EVT with BMM in the acute BAO are needed. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2000041117.

TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage.

BACKGROUND: Innate immunity can facilitate early brain injury (EBI) following subarachnoid hemorrhage (SAH). Numerous studies suggest that pyroptosis could exacerbate extracellular immune responses by promoting secretion of inflammatory cytokines. Transforming growth factor-ß-activated kinase 1 (TAK1) is a quintessential kinase that positively regulates inflammation through NF-κB and MAPK signaling cascades. However, the effects of TAK1 on neuroinflammation in EBI following SAH are largely unknown. METHODS: Two hundred and forty-six male C57BL/6J mice were subjected to the endovascular perforation model of SAH. A selective TAK1 inhibitor, 5Z-7-oxozeaenol (OZ) was administered by intracerebroventricular (i.c.v) injection at 30 min after SAH induction. To genetic knockdown of TAK1, small interfering RNA (siRNA) was i.c.v injected at 48 h before SAH induction. SAH grade, brain water content, BBB permeability, neurological score, western blot, real-time PCR, ELISA, transmission electron microscope, and immunofluorescence staining were performed. Long-term behavioral sequelae were evaluated by the rotarod and Morris water maze tests. Furthermore, OZ was added to the culture medium with oxyhemoglobin (OxyHb) to mimic SAH in vitro. The reactive oxygen species level was detected by DCFH-DA staining. Lysosomal integrity was assessed by Lyso-Tracker Red staining and Acridine Orange staining. RESULTS: The neuronal phosphorylated TAK1 expression was upregulated following SAH. Pharmacologic inhibition of TAK1 with OZ could alleviate neurological deficits, brain edema, and brain-blood barrier (BBB) disruption at 24 h after SAH. In addition, OZ administration restored long-term neurobehavioral function. Furthermore, blockade of TAK1 dampened neuronal pyroptosis by downregulating the N-terminal fragment of GSDMD (GSDMD-N) expression and IL-1ß/IL-18 production. Mechanistically, both in vivo and in vitro, we demonstrated that TAK1 can induce neuronal pyroptosis through promoting nuclear translocation of NF-κB p65 and activating nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. TAK1 siRNA treatment mitigated SAH-induced neurobehavioral deficits and restrained phosphorylated NF-κB p65 expression and NLRP3 inflammasome activation. TAK1 blockade also ameliorated reactive oxygen species (ROS) production and prevented lysosomal cathepsin B releasing into the cytoplasm. CONCLUSIONS: Our findings demonstrate that TAK1 modulates NLRP3-mediated neuronal pyroptosis in EBI following SAH. Inhibition of TAK1 may serve as a potential candidate to relieve neuroinflammatory responses triggered by SAH.

Stressful life events can predict post-stroke fatigue in patients with ischemic stroke.

OBJECTIVE: To investigate whether stressful life events (SLEs) can predict post-stroke fatigue (PSF) in patients with acute ischemic stroke (AIS). METHODS: This prospective cohort study included data from patients with AIS who were followed up to 2-year interview. PSF was assessed at admission and at 6 (n = 916), 12 (n = 880), and 24 (n = 857) months with the fatigue severity scale (FSS). SLEs were measured with the Social Readjustment Rating Scale questionnaire at 6, 12 and 24 months' interview. RESULTS: A significant dose-response association was found between SLEs and FSS score across all examined time-points: compared with those did not experience SLEs, FSS score was higher for those experiencing SLEs ≥3 at 6 months (ß 0.53, 95% CI 0.28-0.78), 12 months (ß 0.54, 95% CI 0.30-0.78) and 24 months (ß 0.48, 95% CI 0.29-0.68). Longitudinal analyses indicated a significantly positive relationship between the number of SLEs and FSS score (SLEs: ≥3 vs. 0, ß 0.14, 95% CI 0.09-0.19). Moreover, a distinct interaction of follow-up time and SLE numbers on FSS score was observed (p < 0.05), which means elevated exposure to SLEs during follow-up was associated with a lower rate of fatigue decline. A similar association was found in SLE load analysis. CONCLUSION: Patients with severe fatigue were more likely to report increased number of SLEs in the previous 6 months, which could suggest that a non-specific stressful event leads to an extra burden to an already vulnerable psychological system.

Association between tirofiban monotherapy and efficacy and safety in acute ischemic stroke.

BACKGROUND: Studies have suggested that glycoprotein IIb/IIIa antagonists such as tirofiban are beneficial for patients with acute coronary syndromes. However, it is still uncertain about the efficacy and safety of tirofiban in patients with acute ischemic stroke (AIS). METHODS: In this prospective non-randomized study, 255 AIS patients were recruited from 4 comprehensive stroke centers in China between January, 2017 and May, 2018. Among them,169 patients were treated with aspirin plus clopidogrel and 86 patients were treated with tirofiban. The primary functional outcome was the distribution of the 90 days' modified Rankin Scale (mRS). The safety outcomes included the incidence of intracranial hemorrhage (ICH) at discharge and mortality at 3 months. RESULTS: In the propensity score matched cohort, tirofiban alone was noninferior to the dual antiplatelet with regard to the primary outcome (adjusted common odds ratio, 0.97; 95% confidence interval, 0.46 to 2.04; P = 0.93). Mortality at 90 days was 10% in the dual antiplatelet group and 8% in the tirofiban group (adjusted odds ratio 0.75; 95% CI 0.08 to 7.40, p = 0.81). There was no difference of the ICH rate between two groups (adjusted odds ratio 0.44; 95% CI 0.13 to 1.48, p = 0.18). In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar differences were found for functional and safety outcomes. CONCLUSIONS: Our study suggested that tirofiban use appears to be safe as monotherapy in AIS treatment compared with common dual antiplatelet therapy, however, no improvement in functional outcomes was found. TRIAL REGISTRATION: Chinese clinical trial registry, ChiCTR2000034443 , 05/07/2020. Retrospectively registered.

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

BACKGROUND: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. METHODS: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. RESULTS: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10-23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10-17). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10-265). CONCLUSIONS: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.

Elabela ameliorates neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling in ischemic stroke.

Pyroptosis signifies a significant form of programmed neuronal demise subsequent to ischemic stroke. In our prior investigations, we demonstrated that the Elabela (ELA)-Apelin receptor (APJ) axis alleviated neuronal death by improving collateral circulation and mitigating ferroptosis in a murine model of middle cerebral artery occlusion (MCAO). However, the connection between ELA and neuronal pyroptosis remains further elucidation. Here, we observed an upregulation of ELA and APJ expression in both murine brain specimens and cultured HT-22 hippocampal neurons exposed to experimental ischemic stroke. ELA administration markedly diminished the infarct size in comparison to controls. ELA treatment ameliorated neurological deficits and anxiety-like symptoms in mice with stroke, concurrently inhibiting pyroptosis and mitochondria fission in neurons. Conversely, ELA knockdown yielded the opposite effects. Utilizing RNA-sequencing analysis, we identified a candidate for pyroptosis priming, Z-DNA-binding protein 1 (ZBP1), which was suppressed in ELA-treated HT-22 neurons during oxygen-glucose deprivation/reperfusion (OGD/R). Subsequent co-immunoprecipitation analyses demonstrated the binding between APJ and ZBP1. Specifically, APJ suppressed ZBP1 to inhibit NLRP3 inflammasome activation and dynamin-related protein 1-mediated mitochondrial fission in neurons. In summary, our findings suggest that ELA functions as a stroke-induced signal limiting neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling, thereby underscoring ELA as a potential therapeutic target for ischemic stroke treatment.

Incidence, predictors, and outcomes of malignant cerebral edema in acute basilar artery occlusion after endovascular treatment: a secondary analysis of the ATTENTION trial.

OBJECTIVE: Malignant cerebral edema (MCE) is a life-threatening complication of ischemic stroke. Few studies have evaluated MCE in patients with acute basilar artery occlusion (BAO) receiving endovascular treatment (EVT). Therefore, the authors investigated the incidence, predictors, and functional outcomes of MCE in BAO patients undergoing EVT. METHODS: This was a post hoc analysis of the Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION) trial, a prospective, randomized, multicenter clinical trial that compared endovascular treatment with conventional care of patients with BAO at 36 centers in China. Brain edema was retrospectively assessed using the Jauss score for all available follow-up scans, and patients with a Jauss score ≥ 4 were classified as having MCE. Clinical functional independence was defined as a modified Rankin Scale (mRS) score of 0-2, and a good outcome was defined as an mRS score of 0-3 at the 90-day follow-up. Univariate and multivariate analyses were used to explore the predictors of MCE and the impact of MCE on prognosis. RESULTS: A total of 189 patients were analyzed, and 13.2% of patients developed MCE. Multivariate analysis showed that the baseline Glasgow Coma Scale (GCS) score (OR 0.722, 95% CI 0.548-0.950; p = 0.020) and the number of procedures (OR 1.594, 95% CI 1.051-2.419; p = 0.028) were significantly associated with MCE. After adjusting for confounding factors, the presence of MCE was significantly associated with a lower rate of functional independence (OR 0.115, 95% CI 0.023-0.563; p = 0.008), a lower rate of good outcome (OR 0.092, 95% CI 0.023-0.360; p = 0.001), and a higher rate of mortality (OR 5.373, 95% CI 2.055-14.052; p = 0.001) at the 90-day follow-up. CONCLUSIONS: MCE is not uncommon in BAO patients undergoing EVT and is associated with poor outcomes. Baseline GCS score and the number of procedures were predictors of MCE. In clinical practice, it is crucial that physicians identifying MCE after EVT in patients with BAO and identification of MCE will help in the selection of an appropriate pharmacological treatment strategy and close monitoring.

The Role of Hyperdense Basilar Artery Sign in Predicting Outcome of Acute Basilar Artery Occlusion within Twelve Hours of Onset.

BACKGROUND: The correlation between hyperdense basilar artery sign (HDBAS) and outcome after acute basilar artery occlusion (ABAO) is debated. Our objective was to determine the usefulness of HDBAS in predicting the outcomes of patients with ABAO after endovascular treatment (EVT), intravenous thrombolysis (IVT), and best medical treatment (BMT). METHODS: The study participants were selected from the ATTENTION trial. The primary outcome of the study was a 90-day modified Rankin Scale (mRS) score, and the secondary outcome was the recanalization rate, any intracranial hemorrhage, and 90-day mortality. RESULTS: The study comprised 276 participants, with cohorts for EVT (n = 188), IVT (n = 82), and BMT (n = 88). In the EVT cohort, HDBAS was not associated with 90-day mRS score (adjusted odds ratio [OR], 0.87; 95% confidence interval [CI], 0.51-1.48; P = 0.6029), the recanalization after 24 hours of onset (adjusted OR, 0.76; 95% CI, 0.30-3.61; P = 0.9422), and 90-day mortality (adjusted OR, 0.77; 95% CI, 0.41-1.46; P = 0.4238). In the IVT cohort, HDBAS was not associated with a 90-day mRS score (adjusted OR, 0.69; 95% CI, 0.31-1.56; P = 0.3742), the recanalization after 24 hours of onset (adjusted OR, 2.24; 95% CI, 0.47-10.78; P = 0.3132), and 90-day mortality (adjusted OR, 0.64; 95% CI, 0.26-1.57; P = 0.3264). Similarly, in the BMT cohort, HDBAS was not associated with 90-day mRS score (adjusted OR, 1.11; 95% CI, 0.47-2.63; P = 0.8152), the recanalization after 24 hours of onset (adjusted OR, 1.27; 95% CI, 0.40-4.02; P = 0.6874), and 90-day mortality (adjusted OR, 1.17; 95% CI, 0.46-2.96; P = 0.748). CONCLUSIONS: HDBAS may not be a reliable predictor of outcomes for patients with ABAO, regardless of whether they received EVT, IVT, or BMT.

Predictors of good outcomes and mortality after thrombectomy for basilar artery occlusion within 12 hours of onset.

BACKGROUND: Patients with acute basilar artery occlusion (ABAO) who undergo combined standard medical treatment (SMT) and endovascular thrombectomy (EVT) may still have unsatisfactory outcomes. This study was conducted to identify the factors that may impact their outcomes. METHODS: We retrospectively reviewed the data of all patients with ABAO combined with SMT and EVT in the endovascular treatment for acute basilar artery occlusion (ATTENTION) trial. A good outcome is defined as a modified Rankin Scale (mRS) score of 0-3, a poor outcome as mRS score of 4-6, and mortality as death at 90-day follow-up. The study analyzed various factors influencing the patients' good outcomes and mortality. RESULTS: The study included 221 patients (148 men and 73 women). Among these patients, 45.7% achieved an mRS score of 0-3, while the overall mortality rate was 37.1% (82/221). A good outcome was significantly associated with younger age (adjusted OR 0.96; 95% CI 0.93 to 0.99; P=0.019), a baseline posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) of 8-10 (adjusted OR 2.34; 95% CI 1.07 to 5.12; P=0.034), and post-procedure pc-ASPECTS of 8-10 (adjusted OR 1.40; 95% CI 1.07 to 1.84; P=0.013). Additionally, time from puncture to reperfusion (adjusted OR 2.02; 95% CI 1.2 to 3.41; P=0.008) and intracranial hemorrhage (adjusted OR 3.59; 95% CI 1.09 to 11.8; P=0.035) were associated with 90-day mortality. CONCLUSIONS: Younger age, baseline pc-ASPECTS of 8-10, and higher post-procedure pc-ASPECTS could effectively predict good outcomes for patients with ABAO undergoing EVT. Additionally, a prolonged time from puncture to reperfusion and intracranial hemorrhage can independently predict mortality. TRIAL REGISTRATION NUMBER: NCT04751708.

Effects of admission hyperglycemia and intravenous thrombolysis allocation in acute basilar artery occlusion after endovascular treatment: Analysis of the ATTENTION registry.

This study was to investigate the admission hyperglycemia and modified effect of intravenous thrombolysis (IVT) on clinical outcomes in acute basilar artery occlusion (BAO) patients receiving endovascular treatment (EVT). We prospectively recruited acute BAO patients from 48 stroke centers across 22 Chinese provinces in the ATTENTION registry from 2017 to 2021. Hyperglycemia on admission was defined as glucose ≥7.8 â€‹mmol/L. We performed multivariable logistic regression analysis to evaluate the correlation of hyperglycemia on admission with the primary outcome defined as a modified Rankin scale (mRS) score of <4 â€‹at 90 days, and the secondary outcomes defined as successful recanalization, mRS 0-1 and 0-2 â€‹at 90 days. Safety outcomes were symptomatic intracranial hemorrhage (sICH) and mortality within 90 days. There were 1195 patients with acute BAO treated with EVT of whom 519 had hyperglycemia on admission. Hyperglycemia on admission was inversely associated with favorable neurological outcomes (mRS 0-3: adjusted odd ratio [aOR] 0.69, 95 â€‹% confidence intervals [CI] 0.54-0.89, P â€‹= â€‹0.004; mRS 0-1: aOR 0.67, 95 â€‹% CI 0.50-0.90, P â€‹= â€‹0.008; mRS 0-2: aOR 0.73, 95 â€‹% CI 0.56-0.95; P â€‹= â€‹0.02). Hyperglycemia on admission was not correlated to sICH nor successful recanalization. In the subgroup of BAO patients treated with direct EVT, those with hyperglycemia on admission had a higher mortality rate, and overall worse clinical outcomes at 90 days than patients without hyperglycemia. A significant interaction was observed between IVT and hyperglycemia on admission (Pinteraction â€‹= â€‹0.017). In patients with acute BAO treated with EVT, hyperglycemia on admission was associated with worse functional outcomes at 90 days but was not correlated with sICH nor successful recanalization. The effect of admission hyperglycemia appears to be modified by IVT allocation. Unique identifier: ChiCTR2000041117.

Intraarterial thrombolytics as an adjunct to mechanical thrombectomy in patients with basilar artery occlusion.

BACKGROUND AND PURPOSE: There are limited data regarding safety and effectiveness of concurrent intraarterial thrombolytics as adjunct to mechanical thrombectomy in acute ischemic stroke patients with basilar artery occlusion. METHODS: We analyzed data from a prospective multicenter registry to assess the independent effect of intraarterial thrombolysis on (1) favorable outcome (modified Rankin Scale 0-3) at 90 days; (2) symptomatic intracranial hemorrhage (sICH) within 72 hours; and (3) death within 90 days post-enrollment after adjustment for potential confounders. RESULTS: There was no difference in the adjusted odds of achieving favorable outcome at 90 days (odds ratio [OR] = 1.1, 95% confidence interval [CI]: 0.73-1.68) in patients who received intraarterial thrombolysis (n = 126) compared with those who did not receive intraarterial thrombolysis (n = 1546) despite significantly higher use in patients with postprocedure modified Thrombolysis in Cerebral Infarction (mTICI) grade <3. There were no differences in adjusted odds of sICH within 72 hours (OR = 0.8, 95% CI: 0.31-2.08) or death within 90 days (OR = 0.91, 95% CI: 0.60-1.37). In subgroup analyses, intraarterial thrombolysis was associated with (nonsignificantly) higher odds of achieving a favorable outcome at 90 days among patients aged between 65 and 80 years, those with National Institutes of Health Stroke Scale score <10, and those with postprocedure mTICI grade 2b. CONCLUSIONS: Our analysis supported the safety of intraarterial thrombolysis as adjunct to mechanical thrombectomy in acute ischemic stroke patients with basilar artery occlusion. Identification of patient subgroups in whom intraarterial thrombolytics appeared to be more beneficial may assist in future clinical trial designs.

Basilar artery occlusion location and clinical outcome: data from the ATTENTION multicenter registry.

BACKGROUND: Acute basilar artery occlusion is a disabling and life-threatening condition. The purpose of this study was to evaluate the impact of occluded vessel location on the prognostic outcomes of patients who underwent endovascular treatment for acute basilar artery occlusion. METHODS: Patient data for this study were obtained from the ATTENTION registry. Baseline data of the patients were described and compared across different occlusion locations. Univariable and multivariable regression analyses were performed to assess the effect of occluded vessel location on associated prognostic outcomes. RESULTS: A total of 1672 patients were included in the analysis, with 583 having distal occlusion, 540 having middle occlusion, and 549 having proximal occlusion. Unlike distal occlusion, both proximal and middle occlusions were significantly and negatively associated with favorable clinical outcomes (for modified Rankin Scale score 0-3: adjusted odds ratio (aOR) 0.634, 95% confidence interval (95% CI) 0.493 to 0.816, P<0.001 in middle occlusion, and aOR 0.620, 95% CI 0.479 to 0.802, P<0.001 in proximal occlusion). Mortality was higher in patients with proximal and middle occlusions (aOR 1.461, 95% CI 1.123 to 1.902, P=0.005 in middle occlusion, and aOR 1.648, 95% CI 1.265 to 2.147, P<0.001 in proximal occlusion). The occluded vessel location was not associated with symptomatic intracranial hemorrhage. CONCLUSIONS: Proximal and middle basilar artery occlusions were predominantly associated with poor clinical outcomes and increased risk of death following endovascular treatment.

TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2.

Objective: Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Materials and Methods: Mice were fed with 0.12% TMAO for 16 weeks. Then, mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in ischemic stroke, microglia of MCAO/R mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Results: TMAO promoted the release of inflammatory cytokines in the brain of MCAO/R mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating ischemic stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3. TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. Conclusion: Our results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. These findings explained the molecular mechanism of TMAO aggravating ischemic stroke in detail and provided molecular mechanism for clinical treatment.

Endovascular treatment of acute basilar artery occlusion in patients with and without atrial fibrillation: results from the ATTENTION registry.

Background: Previous studies have shown a potential beneficial effect of endovascular therapy (EVT) in patients with acute basilar artery occlusion (BAO). It was unclear that whether atrial fibrillation (AF) can affect the clinical outcomes for BAO patients treated with EVT. Objectives: To investigate the association between AF and clinical outcomes, and whether AF can modify the efficacy and safety of EVT in patients with BAO. Design: We conducted a multicenter, nationwide, retrospective analysis to investigate how the presence of AF affects treatment allocation for BAO patients. Methods: The endovascular treatment for acute basilar artery occlusion (ATTENTION) registry was a multicenter, prospective study in China that included acute BAO patients who underwent EVT or received best medical management (BMM) between 2017 and 2021. The outcomes include the distribution of 3-month modified Rankin scale (mRS) score, functional independence (defined as mRS 0-3), symptomatic intracerebral hemorrhage, and mortality. Results: 2134 patients were included in the study, of which 619 had AF and 1515 did not have AF. The median age was 65 (interquartile range [IQR]: 56-73) years, and 689 (32.3%) patients were female. Multivariate regression analysis indicated no significant association existed between AF and the distribution of mRS (adjusted common odds ratio, 1.05 [95% CI: 0.88, 1.25]; p = 0.564) at 90 days. Similarly, AF was not found to have a significant association with and other measured outcomes, or with the effects of EVT in AF subgroups for at 90 days as measured by ordinal mRS (p for heterogeneity = 0.247). Finally, no significant differences were found for symptomatic intracerebral hemorrhage and mortality within 90 days between the EVT and BMM groups across AF subgroups. Conclusions: Our results illustrated that the effect of EVT did not differ statistically in acute ischemic stroke patients with and without AF. Moreover, no significant association between AF and functional or safety outcomes could be detected at 90 days.

Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis.

Ferroptosis is a form of non-apoptotic cell death caused by iron-dependent peroxidation of lipids. It contributes to ischemic stroke-induced neuronal damage. Elabela (ELA), a novel endogenous ligand for Apelin receptor (APJ), regulates oxidative stress and exerts a protective role in cardiovascular disease. However, the effect of ELA-APJ axis on cellular ferroptosis in cerebral ischemia/reperfusion (I/R) remains elusive. The present study showed that ELA and APJ were expressed on neurons and increased after cerebral I/R injury. The I/R insult triggered typical molecular and morphological features of neuronal ferroptosis, including iron and MDA accumulation, mitochondrial shrink and membrane rupture, upregulation of positive ferroptosis regulators and downregulation of negative regulators. ELA-32 treatment reduced brain infarction and ameliorated neurobehavioral deficits and cognitive dysfunction. Moreover, ELA-32 administration alleviated neuronal ferroptosis, accompanied by reduced iron deposition, decreased mitochondrial damage, relived lipid peroxidation and glutathione reduction. Such effects of ELA-32 were abolished by AAV-APJ-RNAi or nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor ML385. Mechanistically, ELA was shown to bind to APJ and activate NRF2/ARE anti-oxidative signaling pathway via Gα13. Together, these findings suggested that ELA-APJ axis mitigates neuronal ferroptosis after ischemic stroke and that the ELA-32 peptide may be a putative therapeutic avenue for ischemic stroke.

Effect of routine inflammatory markers on clinical outcomes in acute basilar artery occlusion after endovascular thrombectomy: Results from ATTENTION registry.

BACKGROUND: To investigate the relationship between clinical routine inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), white blood cell count (WBC), neutrophils, lymphocytes, and platelets with clinical outcomes in acute basilar artery occlusion (BAO) patients receiving endovascular treatment (EVT). METHODS: We recruited 2134 acute BAO patients from 48 stroke centers across 22 Chinese provinces in the ATTENTION registry from 2017 to 2021. Blood samples were drawn at admission. An unfavorable functional outcome was defined using a modified Rankin Scale (mRS) of 4-6 at 90 days. Safety outcomes included mortality within 90 days and symptomatic intracerebral hemorrhage within 3 days. RESULTS: A total of 1044 patients were included in the final study. After adjusting for confounding factors, the upper quartiles of WBC and NLR were related to 90-day unfavorable functional outcome (mRS = 4-6) compared with those in the lowest quartile (WBC: quartile 4, odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.22-2.80; NLR: quartile 4, OR = 2.02, 95% CI = 1.34-3.06). The higher quartiles of WBC and NLR were also related to the increased risk of mortality at 90 days. Restricted cubic spline regression analysis showed an incremental trend between NLR and 90-day unfavorable functional outcome (Pnonlinearity = 0.055). In subgroup analysis, a significant interaction was found between NLR and bridging therapy for predicting unfavorable functional outcome (P = 0.006). CONCLUSION: Higher WBC and NLR on admission are significantly related to unfavorable functional outcome and mortality at 90 days in acute BAO patients receiving EVT. Significant interaction was found between increased NLR and bridging therapy on these outcome measures.

Intra-arterial tenecteplase following endovascular therapy in patients with acute posterior circulation arterial occlusion: study protocol and rationale.

BACKGROUND: Recently, a randomized controlled trial showed a beneficial effect of intra-arterial thrombolysis following successful endovascular thrombectomy (EVT) in patients with acute ischemic stroke due to large vessel occlusion in the anterior circulation. Due to differences in response to thrombolytics in occlusion of the posterior circulation, the purpose of ATTENTION IA is to explore the adjunct benefit of intra-arterial thrombolysis after successful recanalization in patients presenting with large and medium vessel occlusion of the posterior circulation. METHODS: ATTENTION-IA is an investigator-initiated, multicenter, prospective, randomized clinical trial with open-label treatment and blinded endpoint assessment (PROBE). After achieving successful recanalization (expanded Thrombolysis In Cerebral Infarction (eTICI) 2b-3) of an occlusion of the vertebral, basilar, or posterior cerebral artery, patients will be randomized 1:1 to receive intra-arterial tenecteplase or standard of care. The primary effect parameter is a modified Rankin Score of 0-1 at day 90. RESULTS: The trial recently completed enrollment, and data collection/verification is ongoing. The final results will be made available on completion of enrollment and follow-up. CONCLUSIONS: ATTENTION-IA will provide definitive evidence for the efficacy and safety of adjunct intra-arterial tenecteplase after successful EVT in patients with an acute posterior circulation arterial occlusion stroke presenting within 24 hours of symptom onset. TRIAL REGISTRATION: ClinicalTrials.gov NCT05684172.

Anesthetic Management and Outcomes of Endovascular Treatment of Basilar Artery Occlusion: Results From the ATTENTION Registry.

BACKGROUND AND PURPOSE: To examine the clinical and safety outcomes after endovascular treatment (EVT) for acute basilar artery occlusion (BAO) with different anesthetic modalities. METHODS: This was a retrospective analysis using data from the Endovascular Treatment for Acute Basilar Artery Occlusion (ATTENTION) registry. Patients were divided into two groups defined by anesthetic modality performed during EVT: general anesthesia (GA) or non-general anesthesia (non-GA). The association between anesthetic management and clinical outcomes was evaluated in a propensity score matched (PSM) cohort and an inverse probability of treatment weighting (IPTW) cohort to adjust for imbalances between the two groups. RESULTS: Our analytic sample included 1,672 patients from 48 centers. The anesthetic modality was GA in 769 (46.0%) and non-GA in 903 (54.0%) patients. In our primary analysis with the PSM-based cohort, non-GA was comparable to GA concerning the primary outcome (adjusted common odds ratio [acOR], 1.01; 95% confidence interval [CI], 0.82 to 1.25; P=0.91). Mortality at 90 days was 38.4% in the GA group and 35.8% in the non-GA group (adjusted risk ratio, 0.95; 95% CI, 0.83 to 1.08; P=0.44). In our secondary analysis with the IPTW-based cohort, the anesthetic modality was significantly associated with the distribution of modified Rankin Scale at 90 days (acOR: 1.45 [95% CI: 1.20 to 1.75]). CONCLUSION: In this nationally-representative observational study, acute ischemic stroke patients due to BAO undergoing EVT without GA had similar clinical and safety outcomes compared with patients treated with GA. These findings provide the basis for large-scale randomized controlled trials to test whether anesthetic management provides meaningful clinical effects for patients undergoing EVT.