Safety and Efficacy of Hybrid Surgery in Chronic Internal Carotid Artery Occlusion: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chronic internal carotid artery occlusion (CICAO) is a common cause of stroke and ischemia recurrence. An increasing number of reports have highlighted the potential of hybrid surgery for treating CICAO. There are few studies, specifically nonrandomized controlled trials, on the safety and effectiveness of hybrid surgery for the treatment of CICAO, so in this study, we hypothesized that hybrid surgery would be safe, have an acceptable complication rate and a high success rate. METHODS: MEDLINE, Embase, Cochrane Library, and Web of Science databases were searched for relevant studies published up to January 30, 2023. The primary endpoint was recanalization rates of occluded vessels, and the secondary endpoint was perioperative death and procedure-related complications. Subgroup analysis focused on the recanalization rates of endovascular intervention (EI) and hybrid surgery, as well as the rates of recanalization below the clinoid segment and at the clinoid segment and beyond. The follow-up visit was conducted at least 3 months after surgery, and stenosis or occlusion recurrence was confirmed by review of CTA or DSA scan. RESULTS: The databases were searched and 1,709 records were identified, of which 16 articles were used in the meta-analysis, and 464 CICAO patients with complete data who underwent hybrid surgery were enrolled. Hybrid surgery was associated with higher success rates (RD = 0.87, 95% CI [0.84-0.91], p < 0.00001) than EI (OR = 4.71, 95% CI [2.32-9.56], p < 0.0001). The procedural success rate in the below-clinoid segment group was significantly higher than that in the clinoid segment and beyond group (OR = 13.76, 95% CI [5.31-35.66], p < 0.00001). The total periprocedural complication rate was low (RD = 0.11, 95% CI [0.07-0.15], p < 0.00001 and RD = 0.04, 95% CI [0.00-0.07], p = 0.03). Target vessel restenosis or reocclusion occurred in 35 patients (8%) during the follow-up period (RD = 0.08, 95% CI [0.04-0.12], p < 0.0001). CONCLUSION: Hybrid surgery is the combination of the advantages of open surgery and EI, has a high success rate and a low risk of recurrence of stenosis and occlusion in the long term. Randomized controlled trials on hybrid surgery for internal carotid artery occlusion are necessary.

Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage.

BACKGROUND: Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms. METHODS: A total of 299 male Sprague-Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI. RESULTS: We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices. CONCLUSIONS: These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.

Thioredoxin-Interacting Protein Mediates Apoptosis in Early Brain Injury after Subarachnoid Haemorrhage.

Early brain injury (EBI) is considered to be the major factor associated with high morbidity and mortality after subarachnoid haemorrhage (SAH). Apoptosis is the major pathological mechanism of EBI, and its pathogenesis has not been fully clarified. Here, we report that thioredoxin-interacting protein (TXNIP), which is induced by protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), participates in EBI by promoting apoptosis. By using adult male Sprague-Dawley rats to establish SAH models, as well as Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, immunofluorescence, and western blot, we found that TXNIP expression significantly increased after SAH in comparison to the sham group and peaked at 48 h (up to 3.2-fold). Meanwhile, TXNIP was widely expressed in neurons and colocalized with TUNEL-positive cells in the hippocampus and cortex of SAH rats. After administration of TXNIP inhibitor-resveratrol (60 mg/kg), TXNIP small interfering RNA (siRNA) and the PERK inhibitor GSK2656157, TXNIP expression was significantly reduced, accompanied by an attenuation of apoptosis and prognostic indicators, including SAH grade, neurological deficits, brain water content, and blood-brain barrier (BBB) permeability. Collectively, these results suggest that TXNIP may participate in EBI after SAH by mediating apoptosis. The blockage of TXNIP induced by PERK could be a potential therapeutic strategy for SAH treatment.

Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats.

Early brain injury (EBI) is a major cause of mortality from subarachnoid hemorrhage (SAH). We aimed to study the pathophysiology of EBI and explore the role of hepcidin, a protein involved in iron homeostatic regulation, and its downstream proteins. One hundred and thirty-two male Sprague-Dawley rats were assigned into groups (n = 24/group): sham, SAH, SAH + hepcidin, SAH + hepcidin-targeting small interfering ribonucleic acid (siRNA), and SAH + scramble siRNA. Three hepcidin-targeting siRNAs and one scramble siRNA for hepcidin were injected 24 h before hemorrhage induction, and hepcidin protein was injected 30 min before induction. The rats were neurologically evaluated at 24 h and euthanized at 72 h. Hepcidin, ferroportin-1, and ceruloplasmin protein expression were measured by immunohistochemistry and Western blotting. Brain water content, blood-brain barrier (BBB) leakage, non-heme tissue iron and Garcia scale were evaluated. Hepcidin expression increased in the cerebral cortex and hippocampus after experimental SAH (P < 0.05 compared to sham), while ferroportin-1 and ceruloplasmin decreased (P < 0.05). Hepcidin injection lowered the expression of ferroportin-1 and ceruloplasmin further but siRNA reduced the levels of hepcidin (P < 0.05 compared to SAH) resulting in recovery of ferroportin-1 and ceruloplasmin levels. Apoptosis was increased in SAH rats compared to sham (P < 0.05) and increased slightly more by hepcidin, but decreased by siRNA (P < 0.05 compared to SAH). SAH rats had lower neurological scores, high brain water content, BBB permeability, and non-heme tissue iron (P < 0.05). In conclusion, downregulation of ferroportin-1 and ceruloplasmin caused by hepcidin enhanced iron-dependent oxidative damage and may be the potential mechanism of SAH.

[Enhanced expression of Toll-like receptor 3 in the basilar arteries and hippocampus of subarachnoid hemorrhage rats].

OBJECTIVE: To observe the dynamic expression and significance of Toll-like receptor 3 (TLR3) in subarachnoid hemorrhage (SAH) model. METHODS: SAH model was established using blood injection into the prechiasmatic cistern. Sixty SD rats were randomly divided into sham group and SAH groups (including SAH 1-, 3-, 7-day groups), each with 15 rats. The operation steps were the same in groups except the sham group that was injected with normal saline instead. At different time points after modeling, the basilar arteries and brain were obtained. The mRNA and protein expression of TLR3 was detected using reverse transcription PCR, Western blotting and immunohistochemistry, respectively. Meanwhile, the distribution of TLR3 was analyzed using the immunofluorescence double labeling technique. RESULTS: The mRNA and protein expression of TLR3 was weak in sham group and highly expressed in SAH groups, and the highest expression were found in SAH 3-day group. Immunohistochemistry showed that TLR3 was highly expressed in vascular endothelial and hippocampal neurons. The sham group showed a weak TLR3 expression in the cytoplasm, while the SHA group showed the strongly expressed TLR3 mainly in the nucleus and cytoplasm. The result of immunofluorescence double labeling also suggested TLR3 was co-localization with CD34 in the endothelial cells. CONCLUSION: The TLR3 expression was enhanced in the basilar arteries and hippocampus when the rats suffered from SAH, which suggested TLR3 might play a certain role in the pathogenesis of SAH.

Optimal hemoglobin concentration in patients with aneurysmal subarachnoid hemorrhage after surgical treatment to prevent symptomatic cerebral vasospasm.

Medical complications occur frequently after aneurismal subarachnoid hemorrhage (aSAH), such as cerebral vasospasm (CVS), anemia, etc. The relationship between hemoglobin (Hgb) concentration and the occurrence of CVS after aSAH remains largely elusive. A total of 218 patients with postoperative aSAH were recruited. Symptomatic cerebral vasospasm (SCVS) was initially diagnosed on the basis of their clinical signs and symptoms, and confirmed by imaging tests. The patients were then divided into four groups on the basis of the postoperative mean Hgb concentration (<11, 11-12, 12-13, and >13 g/dl). The possible influential factors that were statistically significant in the initial univariate analysis were subjected to a multivariable logistic regression analysis. Univariate analysis showed that Hunt and Hess neurological grade on admission, intraoperative aneurysm rupture, CT Fisher grade, and postoperative mean Hgb were associated significantly with SCVS in aSAH patients after surgical treatment (P<0.05). Subsequent multivariable analysis showed that postoperative mean Hgb remained significant after adjustment for Hunt and Hess neurological grade on admission and CT fisher grade. The incidence of SCVS in the group with an Hgb concentration 11-12 g/dl was found to be the lowest among all groups [odds ratio (OR), 3.29, 95% confidence interval (CI), 1.43-7.58, P=0.005; OR, 3.63, 95% CI, 1.41-9.34, P=0.007; OR, 5.34, 95% CI, 1.85-15.43, P=0.002]. Postoperative Hgb concentration is an independent risk factor for SCVS in aSAH patients following surgery, and maintaining the concentration at 11-12 g/dl may reduce the incidence of SCVS.