Impact of qualifying artery on the efficacy of stenting plus medical therapy versus medical therapy alone in patients with symptomatic intracranial stenosis: a post-hoc analysis of the CASSISS trial.

BACKGROUND: A recent trial failed to show any benefit of stenting plus medical therapy over medical therapy alone in patients with symptomatic intracranial stenosis. We aimed to examine whether the symptomatic qualifying artery modifies the effect of stenting plus medical therapy. METHODS: This is a post-hoc analysis of the CASSISS trial that included patients with symptomatic intracranial stenosis, randomly assigned to undergo stenting plus medical therapy or medical therapy alone; 358/380 patients were included. Multivariable logistic regression analysis was used with an interaction term to estimate the altered treatment effect by the qualifying artery. The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The five secondary outcomes included stroke or death related to the qualifying artery territory at 2 and 3 years. RESULTS: No significant treatment allocation-by-stenosis site interaction was observed (Pinteraction=0.435). Compared with medical therapy alone, the adjusted ORs for stenting plus medical therapy were 2.73 (95% CI 0.42 to 17.65) for internal carotid artery stenosis, 1.20 (95% CI 0.29 to 4.99) for M1 stenosis, 0.23 (95% CI 0.02 to 2.31) for vertebral artery stenosis, and 1.33 (95% CI 0.34 to 5.28) for basilar artery stenosis. Of the five secondary outcomes, none showed a significant treatment allocation-by-stenosis site interaction including stroke in the qualifying artery territory at 2 years (Pinteraction=0.659) and 3 years (Pinteraction=0.493). CONCLUSIONS: Among patients with transient ischemic attacks or ischemic stroke due to severe intracranial atherosclerotic stenosis, there was no evidence that the symptomatic qualifying artery could determine the addition of stenting to medical therapy.

Deliberately Staged Combined Endovascular Embolization and Subsequent Microsurgery Resection for the Treatment of Cerebral Arteriovenous Malformations.

OBJECTIVE: Complex cerebral arteriovenous malformations (AVMs) require a combined therapy of endovascular embolization and microsurgical resection to eliminate the lesion and maximize neurological protection, while a deliberate time interval might contribute to optimal clinical outcomes. The present study aimed to explore the feasibility of this paradigm. METHODS: All patients who underwent deliberately planned presurgery embolization and microsurgery resection between 2015 and 2023 were reviewed, with baseline data, postoperative complications, and follow-up outcomes recorded. The modified Rankin scale (mRS) was used to evaluate clinical outcomes, with mRS 0-2 defined as good. RESULTS: A total of 30 patients were included in the study (15 were ruptured AVMs). The median Spetzler-Martin grade of baseline AVMs was 3 (interquartile range: 2-3). The median interval between the last embolization and microsurgery was 5 days (interquartile range: 2.25-7). The complete removal rate was 100%, and the overall permanent complication rate was 16.67%. At the last follow-up, 26 patients achieved mRS 0-2, while 28 had improved or unaltered mRS. The last follow-up mRS significantly improved from baseline and discharge (P = 0.0006 and P = 0.006). The last follow-up mRS decreased by 0.65 for each additional day of time interval before the 4.4-day inflection point (ß = -0.65, P = 0.02) in the AVM ruptured cohort. CONCLUSIONS: The deliberately staged combined procedure of embolization and microsurgery might be a safe and efficacious strategy for Spetzler-Martin grade 2-5 AVMs, 4-5 days might be an appropriate staged time interval for ruptured AVMs, although further studies are needed to substantiate these findings.

Low-profile visualized intraluminal support-within-Enterprise overlapping-stent technique versus flow diversion in the treatment of intracranial vertebrobasilar trunk dissecting aneurysms.

Background: It is necessary to explore the safety and efficacy of various endovascular treatment techniques in the treatment of patients with intracranial vertebrobasilar trunk dissecting aneurysms (VBTDAs). This study sought to compare the clinical and angiographic outcomes of patients with intracranial VBTDAs following low-profile visualized intraluminal support (LVIS)-within-Enterprise overlapping-stent technique with those of flow diversion (FD). Methods: This was a retrospective, observational, cohort study. Between January 2014 and March 2022, 9,147 patients with intracranial aneurysms were screened, and 91 patients with 95 VBTDAs who underwent LVIS-within-Enterprise overlapping-stent assisted-coiling technique or FD were included in the analysis. The primary outcome was the complete occlusion rate at the last angiographic follow-up. The secondary outcomes included adequate aneurysm occlusion, in-stent stenosis/thrombosis, general neurological complications, neurological complications within 30 days after the procedure, the mortality rate, and unfavorable outcomes. Results: Among the 91 included patients, 55 were treated with LVIS-within-Enterprise overlapping-stent technique (the LE group) and 36 were treated with FD (the FD group). The angiography results at the median follow-up time of 8 months showed complete occlusion rates of 90.0% and 60.9% for the LE and FD groups, respectively, with an adjusted odds ratio of 5.79 (95% CI: 1.35-24.85; P=0.01). Adequate aneurysm occlusion (P=0.98), in-stent stenosis/thrombosis (P=0.46), general neurological complications (P=0.22), neurological complications within 30 days after the procedure (P=0.63), mortality rate (P=0.31), and unfavorable outcomes (P=0.07) at the last clinical follow-up did not differ significantly between the 2 groups. Conclusions: A significantly higher complete occlusion rate for VBTDAs was found following LVIS-within-Enterprise overlapping-stent technique as compared with FD. The 2 treatment modalities have comparable adequate occlusion rates and safety profiles.

Endovascular Treatment of Acute Ischemic Stroke Due to Isolated Proximal Posterior Artery Occlusion.

Background: Acute ischemic stroke (AIS) due to isolated proximal posterior cerebral artery (PPCA) occlusion is rare but associated with high morbidity and mortality rates. However, the optimal treatment strategy for patients with AIS caused by PPCA remains unclear. We discuss our single-center experience with endovascular treatment (EVT) in patients with PPCA. Methods: Data from patients with AIS due to PPCA occlusion were retrospectively analyzed. We analyzed procedural details, the degree of reperfusion, functional outcomes, and complications. Functional outcomes were determined using the modified Rankin Scale (mRS) at 90 days, and good outcome was defined as mRS 0-2 at 90 days. Successful reperfusion was defined as modified treatment in cerebral ischemia (mTICI) 2b-3 after endovascular therapy. Safety variables included symptomatic hemorrhage (defined as an increase of four or more points in the National Institute of Health Stroke Scale score), vessel perforation or dissection, and new ischemic stroke in different territories. Results: Seven patients were included in this study. The mean age of the patients was 64 ± 12.4 years. Successful reperfusion was achieved in all seven patients (100%). Good outcomes were achieved at 90 days in 2 patients (28.6%), and favorable outcomes were observed in five patients (71.4%). One patient underwent angioplasty as rescue therapy after three attempts. One patient died because of severe gastrointestinal bleeding 24 h after EVT, which was probably a complication of intravenous alteplase. One patient had an embolism in the basilar artery and achieved complete reperfusion after rescue thrombectomy. Another patient had a complication of vessel dissection in the PPCA and underwent stent implantation as rescue therapy. We observed no recurrence of ischemic stroke or any intracranial hemorrhage on non-contrast computed tomography 24 h after the procedure. Conclusion: EVT may represent an alternative treatment strategy for patients with acute ischemic stroke caused by PPCA.

Time correlation of success recanalization for endovascular recanalization of medically refractory non-acute intracranial arterial occlusions.

Background and purpose: The management of patients with symptomatic non-acute atherosclerotic intracranial artery occlusion (sNAA-ICAO), which is a special subset with high morbidity and a high probability of recurrent serious ischemic events despite standard medical therapy, has been clinically challenging. A number of small-sample clinical studies have discussed endovascular recanalization for sNAA-ICAO and the lack of a uniform standard of operation time. The purpose of this study was to investigate the time correlation of successful recanalization. Methods: From January 2013 to August 2021, 69 consecutive patients who underwent endovascular recanalization for sNAA-ICAO were analyzed retrospectively in the First Affiliated Hospital of Harbin Medical University. The technical success rate, periprocedural complications, and rate of TIA/ischemic stroke during follow-up were evaluated. Results: The overall technical success rate was 73.91% (51/69), and the rate of perioperative complications was 37.68% (26/69). The percentage of patients with perioperative symptoms was 27.53% (19/69). The rate of serious symptomatic perioperative complications was 8.70% (6/69). After adjusting for age, sex, and BMI, the effect of the time from the last symptom to operation on successful recanalization was 0.42 (IQR, 0.20, 0.88, P = 0.021), before the inflection point (51 days). Conclusions: Endovascular recanalization for sNAA-ICAO is technically feasible in reasonably selected patients. The perioperative safety is within the acceptable range. Before 51 days, the last symptoms to operation time, for every 10 days of delay, the probability of successful recanalization is reduced by 57%.

Development and external validation of a dynamic nomogram for delayed cerebral ischaemia after aneurysmal subarachnoid hemorrhage: a study protocol for a multicentre retrospective cohort study.

INTRODUCTION: Delayed cerebral ischaemia (DCI) caused by aneurysmal subarachnoid haemorrhage (aSAH) is the most frequent complication and typically contributes to poor neurological outcome or deterioration of patients' condition. Therefore, early accurate and effective prediction of DCI is urgently needed. This study aims to construct a dynamic nomogram for precisely calculating the risk of DCI in patients with aSAH. Internal validation of this tool is conducted using the training cohort, and independent external validation is completed by using other medical centre datasets. METHODS AND ANALYSIS: This study is a multicentre, retrospective, observational cohort study using data from patients with aSAH. The participants include all adult patients who received surgical treatment in neurosurgery of multiple medical centres from 1 September 2019 to 1 April 2021, including Renmin Hospital of Wuhan University, Huzhou Central Hospital, First Affiliated Hospital of Harbin Medical University, General Hospital of Northern Theatre Command and Affiliated Hospital of Panzhihua University. Clinical information is collected via the electronic medical record system, including demographic data, clinical state on admission and serum laboratory tests. Modified Fisher grade at admission, admission subarachnoid clot and cerebral oedema density, and residual postoperative subarachnoid clot density are determined using the electronic imagine record software. The primary outcome is DCI. ETHICS AND DISSEMINATION: This study protocol was reviewed and approved by the Medical Ethics Committee of Renmin Hospital of Wuhan University, which is the principal affiliation of this study (approval number: WDRM2021-K022). The other Ethics Committees, including Huzhou Central Hospital (approval number: 202108005-01), First Affiliated Hospital of Harbin Medical University (approval number: H202156), General Hospital of Northern Theater Command (approval number: Y2021060) and Affiliated Hospital of Panzhihua University (approval number: 202105002), also approved the protocol. The results of this research will be published in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: ChiCTR2100044448.

T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin-1-Like Protein Pathway.

METHODS: Subarachnoid hemorrhage (SAH) models of Sprague-Dawley rats were established with perforation method. T0901317 was injected intraperitoneally 1-hour post-SAH. GSK2033, an inhibitor of LXRs, and interferon regulatory factor (IRF-1) CRISPR activation were injected intracerebroventricularly to evaluate potential signaling pathway. The severity of SAH, neurobehavior test in both short- and long-term and apoptosis was measured with Western blot and immunofluorescence staining. RESULTS: Expression of LXR-α and IRF-1 increased and peaked at 24 h post-SAH, while LXR-ß remained unaffected in SAH+vehicle group compared with Sham group. Post-SAH T0901317 treatment attenuated neuronal impairments in both short- and long-term and decreased neuronal apoptosis, the expression of IRF-1, P53 upregulated modulator of apoptosis (PUMA), dynamin-1-like protein (Drp1), Bcl-2-associated X protein (Bax) and cleaved caspase-3, and increasing B-cell lymphoma 2 (Bcl-2) at 24 h from modeling. GSK2033 inhibited LXRs and reversed T0901317's neuroprotective effects. IRF-1 CRISPR activation upregulated the expression of IRF-1 and abolished the treatment effects of T0901317. CONCLUSION: T0901317 attenuated neuronal apoptosis via LXRs/IRF-1/PUMA/Drp1 pathway in SAH rats.

miR-137 boosts the neuroprotective effect of endothelial progenitor cell-derived exosomes in oxyhemoglobin-treated SH-SY5Y cells partially via COX2/PGE2 pathway.

BACKGROUND: We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured SH-SY5Y cells. METHODS: The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs, and neurons. The uptake mechanisms of EPC-EXs in SH-SY5Y cells were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002, and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression. RESULTS: The present work showed (1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; (2) miR-137 was decreased in neurons after oxyHb treatment, and EXsmiR-137 could restore the miR-137 levels; (3) EXsmiR-137 worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; (4) EXsmiR-137 are more effective in improving the cellular MMP, ROS, and ATP level; (5) EXsmiR-137, but not EXs, protected oxyHb-treated SH-SY5Y cells against lipid peroxidation, iron overload, degradation of glutathione, and glutathione peroxidase 4; and (6) EXsmiR-137 suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXsmiR-137. CONCLUSION: miR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated SH-SY5Y cells. Furthermore, EXsmiR-137 rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.

Apelin-13 attenuates early brain injury following subarachnoid hemorrhage via suppressing neuronal apoptosis through the GLP-1R/PI3K/Akt signaling.

Apelin, an endogenous ligand for the orphan G-protein-coupled receptor APJ, possesses anti-apoptotic and neuroprotective properties. It has been shown to be a protective factor for different types of central nervous system insults, such as ischemia and traumatic brain injury. Here, we investigated the effects of apelin-13 on early brain injury (EBI) following subarachnoid hemorrhage (SAH), and the underlying molecular mechanisms involved. Apelin-13 was delivered to rats via intracerebroventricular administration. Neurological scores, brain water content and neuronal apoptosis were measured 24 h after SAH. The PI3K/Akt inhibitor LY294002 or GLP-1R siRNA were injected into the lateral cerebral ventricle before induction of SAH. Changes in the expression of p-Akt, GLP-1R and apoptosis-associated proteins (Bax, Bcl-2, cleaved caspase-3) were then investigated. Results showed that the levels of GLP-1R in neurons increased significantly, reaching a peak at 24 h after the induction of SAH. Treatment with apelin-13 improved neurological deficits, as well as alleviated brain edema and apoptotic cell death. Apelin-13 was also able to increase the levels of p-Akt, GLP-1R and Bcl-2, while inhibiting the expression levels of Bax and cleaved caspase-3. The anti-apoptotic and neuroprotective effects of apelin-13 were partially reversed by addition of LY294002 or GLP-1R siRNA. These results provide evidence that apelin-13 attenuates EBI following SAH via suppressing neuronal apoptosis, and that this effect may act partially via the activation of the GLP-1R/PI3K/Akt signaling pathway.

Changes in mitochondrial ultrastructure in SH-SY5Y cells during apoptosis induced by hemin.

Hemorrhagic stroke is associated with high morbidity and mortality. Hemin is a decomposition product of hemoglobin that is related to neuronal apoptosis after hemorrhage, although the molecular basis for this association remains unclear. To address this issue, the present study investigated hemin-induced changes in the apoptotic index and mitochondrial ultrastructure in SH-SY5Y cells. Cell viability was evaluated using Cell Counting Kit-8 and by terminal transferase dUTP nick-end labeling, western blotting, and flow cytometry. Changes in mitochondrial ultrastructure were examined by super-resolution three-dimensional structured illumination microscopy. We found that cleaved-caspase-3 expression and the number of apoptotic cells increased in a time-dependent manner upon hemin treatment, which was associated with mitochondrial fragmentation. Our data suggest that hemin induces apoptosis and mitochondrial fission in neuronal cells. Thus, therapeutic strategies that target hemin could mitigate the damage caused by hemorrhagic stroke.

Genetic variant near TERC influencing the risk of gliomas with older age at diagnosis in a Chinese population.

A recent genome-wide association study has identified an association between rs1920116 near TERC and high-grade glioma in populations of European ancestry. In order to evaluate the effect of the SNP rs1920116 near TERC in the Chinese population, we examined associations of this candidate SNP with glioma in a sample of 1970 Chinese Han individuals. SNP genotype data were available for 980 Chinese glioma patients and 990 healthy controls. Logistic regression analyses were performed to evaluate the association between rs1920116 and glioma risk adjusted for age, gender and stratified by tumor grade where appropriate. The allele G at TERC rs1920116 are risk factors for gliomas, and its association with glioma risk was consistent across tumor subgroups in the Chinese Han population (OR = 1.18-1.21). In order to assess variation in SNP effect size at different patient ages, glioma cases and controls were divided into 3 age strata, in years: <50, 50-59, and 60+. The results of multiple logistic regression analyses indicate that the SNP has age-specific effects on the risk of developing glioma. Our report confirmed the effects of rs1920116 near TERC on glioma occurring in older peoples in the Chinese Han population for the first time. As TERC is a candidate for inter-individual variation in telomere length, our study supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life.

Hyperperfusion Syndrome After Stenting for Intracranial Artery Stenosis.

Hyperperfusion syndrome (HPS) is a rare but potentially devastating postoperative complication developing after endarterectomy and carotid stenting. Limited information is available about this complication. The aim of this study was to assess the incidence of HPS and risk factors leading to its development. We retrospectively reviewed 178 consecutive cases of patients who underwent stenting of intracranial artery revascularization. We analyzed the association between HPS and patient's age, collateral vascular supply of the lesion, the interval between operation and the last occurrence of ischemic symptom, adequacy of blood pressure control after the operation, and other risk factors such as diabetes, smoking, hypertension, and gender. Of 178 included patients, we found HPS in six cases (3.4%). Failure to strictly control postoperative blood pressure, a less than 3-week long interval between operation and the last occurrence of ischemic symptom, and poor collateral circulation were significantly associated with the development of HPS. The aforementioned factors are predictors for HPS. We argue that nitroprusside should not be used to control blood pressure after the operation because its use permits considerable blood pressure fluctuations.