eCLIPs bifurcation remodeling system for treatment of wide-neck bifurcation aneurysms: A systematic review and meta-analysis of safety and efficacy.

BACKGROUND: Wide neck bifurcation aneurysms (WNBAs) are a subtype of aneurysms that are especially complex to treat. We aim to conduct a systematic review and meta-analysis to synthesize the available literature on the safety and efficacy of employing endovascular clip system (eCLIPs) in the treatment of WNBAs. METHODS: We report this study in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. PubMed, Embase, Web of Science, and Scopus were queried for this review. Screening and extraction were performed by at least two authors to ensure accuracy and completeness, and a senior author arbitrated any discrepancies. All data were analyzed using R software version 4.3.0. and random-effects model. RESULTS: Four studies were finally included, of which three were prospective and one was retrospective. Successful adjunctive coiling occurred in 91.38% (95% CI = 70.71-97.9) of cases and overall technical success was achieved in 88.61% (95 CI = 75.54-95.15) of cases. The pooled complete occlusion (Raymond-Roy Class I) was 50.65% (95% CI = 39.63-61.60) and adequate occlusion (Raymond-Roy Class I/II) was 84.42% (95% CI = 74.53-90.93). Thrombo-embolic complication had a pooled rate of 1.22% (95% CI = 0.17-8.15), retreatment rate was 6.10% (95% CI = 2.56-13.83), and mortality reported in 3.66% (95% CI = 1.18-10.74) of patients. CONCLUSION: The use of eCLIPs may be a safe and efficacious treatment for WNBAs. Future randomized controlled trials are needed for further validation of the findings.

The Impact of Preprocedural Platelet Function Testing on Periprocedural Complication Rates Associated With Pipeline Flow Diversion: An International Multicenter Study.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel. METHODS: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant. RESULTS: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9). CONCLUSION: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.

Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study.

INTRODUCTION: Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR). METHODS: Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method. RESULTS: Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95% CI 0.99-1.04, p = 0.39), cardioembolic stroke (OR 1.04, 95% CI 0.97-1.12, p = 0.28), large-artery stroke (OR 1.02, 95% CI 0.95-1.09, p = 0.62), and small-vessel stroke (OR 0.98, 95% CI 0.91-1.04, p = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy. CONCLUSIONS: This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

CT Perfusion Derived rCBV < 42% Lesion Volume Is Independently Associated with Followup FLAIR Infarct Volume in Anterior Circulation Large Vessel Occlusion.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman's rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = -0.214, p < 0.01), mTICI (beta = -0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

Transcranial Doppler cerebrovascular reactivity: Thresholds for clinical significance in cerebrovascular disease.

BACKGROUND AND PURPOSE: Thresholds for abnormal transcranial Doppler cerebrovascular reactivity (CVR) studies are poorly understood, especially for patients with cerebrovascular disease. Using a real-world cohort with cerebral arterial stenosis, we sought to describe a clinically significant threshold for carbon dioxide reactivity (CO2R) and vasomotor range (VMR). METHODS: CVR studies were performed during conditions of breathing room air normally, breathing 8% carbon dioxide air mixture, and hyperventilation. The mean and standard deviation (SD) of CO2R and VMR were calculated for the unaffected side in patients with unilateral stenosis; a deviation of 2 SDs below the mean was chosen as the threshold for abnormal. Receiver operating characteristic (ROC) curves for both sides for patients with unilateral and bilateral stenosis were evaluated for sensitivity (Sn) and specificity (Sp). RESULTS: A total of 133 consecutive CVR studies were performed on 62 patients with stenosis with mean±SD age 55±16 years. Comorbidities included hypertension (60%), diabetes (15%), stroke (40%), and smoking (35%). In patients with unilateral stenosis, mean±SD CO2R for the unaffected side was 1.86±0.53%, defining abnormal CO2R as <0.80%. Mean±SD CO2R for the affected side was 1.27±0.90%. The CO2R threshold predicted abnormal acetazolamide single-photon emission computed tomography (SPECT) (Sn = .73, Sp = .79), CT/MRI perfusion abnormality (Sn = .42, Sp = .77), infarction on MRI (Sn = .45, Sp = .76), and pressure-dependent exam (Sn = .50, Sp = .76). For the unaffected side, mean±SD VMR was 39.5±15.8%, defining abnormal VMR as <7.9%. For the affected side, mean±SD VMR was 26.5±17.8%. The VMR threshold predicted abnormal acetazolamide SPECT (Sn = .46, Sp = .94), infarction on MRI (Sn = .27, Sp = .94), and pressure-dependent exam (Sn = .31, Sp = .90). CONCLUSIONS: In patients with multiple vascular risk factors, a reasonable threshold for clinically significant abnormal CO2R is <0.80% and VMR is <7.9%. Noninvasive CVR may aid in diagnosing and risk stratifying patients with stenosis.

Follow-up infarct volume on fluid attenuated inversion recovery (FLAIR) imaging in distal medium vessel occlusions: the role of cerebral blood volume index.

BACKGROUND: Distal medium vessel occlusions (DMVOs) contribute substantially to the incidence of acute ischemic strokes (AIS) and pose distinct challenges in clinical management and prognosis. Neuroimaging techniques, such as Fluid Attenuation Inversion Recovery (FLAIR) imaging and cerebral blood volume (CBV) index derived from perfusion imaging, have significantly improved our ability to assess the impact of strokes and predict their outcomes. The primary objective of this study was to investigate relationship between follow-up infarct volume (FIV) as assessed by FLAIR imaging in patients with DMVOs. METHODS: This prospectively collected, retrospective reviewed cohort study included patients from two comprehensive stroke centers within the Johns Hopkins Medical Enterprise, spanning August 2018-October 2022. The cohort consisted of adults with AIS attributable to DMVO. Detailed imaging analyses were conducted, encompassing non-contrast CT, CT angiography (CTA), CT perfusion (CTP), and FLAIR imaging. Univariable and multivariable linear regression models were employed to assess the association between different factors and FIV. RESULTS: The study included 79 patients with DMVO stroke with a median age of 69 years (IQR, 62-77 years), and 57% (n = 45) were female. There was a negative correlation between the CBV index and FIV in a univariable linear regression analysis (Beta = - 16; 95% CI, - 23 to - 8.3; p < 0.001) and a multivariable linear regression model (Beta = - 9.1 per 0.1 change; 95% CI, - 15 to - 2.7; p = 0.006). Diabetes was independently associated with larger FIV (Beta = 46; 95% CI, 16 to 75; p = 0.003). Additionally, a higher baseline ASPECTS was associated with lower FIV (Beta = - 30; 95% CI, - 41 to - 20; p < 0.001). CONCLUSION: Our findings underscore the CBV index as an independent association with FIV in DMVOs, which highlights the critical role of collateral circulation in determining stroke outcomes in this patient population. In addition, our study confirms a negative association of ASPECTS with FLAIR FIV and identifies diabetes as independent factor associated with larger FIV. These insights pave the way for further large-scale, prospective studies to corroborate these findings, thereby refining the strategies for stroke prognostication and management.

Endovascular vs surgical treatment of sigmoid sinus diverticulum causing pulsatile tinnitus: A systematic review.

INTRODUCTION: Sigmoid sinus diverticulum (SSD) has been increasingly reported as a cause of pulsatile tinnitus (PT). While both endovascular and surgical treatments have been used, there is a lack of consensus on the treatment modality to treat SSD. We conducted a systematic review of the available literature to compare the clinical outcomes and safety of endovascular versus surgical approaches for treating SSD. METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses to identify studies encompassing the management of SSD. Studies reporting the clinical outcomes and safety of endovascular or surgical treatments for SSD between January 2000 and January 2023 were included. Results were characterized using descriptive statistics. RESULTS: Endovascular treatment (EVT) was reported by 17 articles, yielding 26 patients with 27 diverticula. Surgical treatment was reported by 20 articles, yielding 105 patients with 107 diverticula. EVT led to complete or near-complete resolution in all patients with SSD and PT. Complications occurred in 3.7% (1/27) with a return to baseline after 2 months. There were no permanent complications from EVT. Surgical treatment resulted in complete resolution in 77.6% (83/107) of cases, incomplete resolution in 11.2% (12/107), and no resolution in 11.2% (12/107). Significant complications occurred in 9.3% (10/107) of the surgical-treated patients. CONCLUSION: EVT in patients with PT and venous diverticulum appears more effective and safer than surgical treatment, but large studies are lacking. Studies directly comparing endovascular and surgical treatment are needed.

Deconstructive repair of a direct carotid-cavernous fistula via a posterior circulation retrograde approach.

We report a case of a 24-year-old patient who presented after a head trauma with a traumatic occlusion of his left internal carotid artery. He underwent diagnostic cerebral angiogram and was found to have a direct left carotid-cavernous fistula (CCF) with retrograde filling from the posterior circulation across the posterior communicating artery. Because of the severe injury to the left internal carotid artery (ICA), reconstructive repair of the ICA was not possible. The patient underwent deconstructive repair of the CCF by coil embolization using a posterior retrograde approach. Coils were successfully placed in the cavernous sinus and back into the left ICA with complete cure of the CCF and restoration of cerebral perfusion distal to the treated CCF. We review the types of CCFs, their clinical presentation, and their endovascular treatments. Retrograde access of a direct CCF is rarely reported in the literature, and we believe this approach offers a viable alternative in appropriately selected patients.

Prolonged venous transit on perfusion imaging is associated with higher odds of mortality in successfully reperfused patients with large vessel occlusion stroke.

BACKGROUND: Poor venous outflow (VO) profiles are associated with unfavorable outcomes in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO), despite achieving successful reperfusion. The objective of this study is to assess the association between mortality and prolonged venous transit (PVT), a novel visual qualitative VO marker on CT perfusion (CTP) time to maximum (Tmax) maps. METHODS: We performed a retrospective analysis of prospectively collected data from consecutive adult patients with AIS-LVO with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b/2c/3). PVT+ was defined as Tmax ≥10 s timing on CTP Tmax maps in at least one of the following: superior sagittal sinus (proximal venous drainage) and/or torcula (deep venous drainage). PVT- was defined as lacking this in both regions. The primary outcome was mortality at 90 days. In a 1:1 propensity score-matched cohort, regressions were performed to determine the effect of PVT on 90-day mortality. RESULTS: In 127 patients of median (IQR) age 71 (64-81) years, mortality occurred in a significantly greater proportion of PVT+ patients than PVT- patients (32.5% vs 12.6%, P=0.01). This significant difference persisted after matching (P=0.03). PVT+ was associated with a significantly increased likelihood of 90-day mortality (OR 1.22 (95% CI 1.02 to 1.46), P=0.03) in the matched cohort. CONCLUSIONS: PVT+ was significantly associated with 90-day mortality despite successful reperfusion therapy in patients with AIS-LVO. PVT is a simple VO profile marker with potential as an adjunctive metric during acute evaluation of AIS-LVO patients. Future studies will expand our understanding of using PVT in the evaluation of patients with AIS-LVO.

The feasibility of mechanical thrombectomy versus medical management for acute stroke with a large ischemic territory.

BACKGROUND: Mechanical thrombectomy (MT) for acute ischemic stroke is generally avoided when the expected infarction is large (defined as an Alberta Stroke Program Early CT Score of <6). OBJECTIVE: To perform a meta-analysis of recent trials comparing MT with best medical management (BMM) for treatment of acute ischemic stroke with large infarction territory, and then to determine the cost-effectiveness associated with those treatments. METHODS: A meta-analysis of the RESCUE-Japan, SELECT2, and ANGEL-ASPECT trials was conducted using R Studio. Statistical analysis employed the weighted average normal method for calculating mean differences from medians in continuous variables and the risk ratio for categorical variables. TreeAge software was used to construct a cost-effectiveness analysis model comparing MT with BMM in the treatment of ischemic stroke with large infarction territory. RESULTS: The meta-analysis showed significantly better functional outcomes, with higher rates of patients achieving a modified Rankin Scale score of 0-3 at 90 days with MT as compared with BMM. In the base-case analysis using a lifetime horizon, MT led to a greater gain in quality-adjusted life-years (QALYs) of 3.46 at a lower cost of US$339 202 in comparison with BMM, which led to the gain of 2.41 QALYs at a cost of US$361 896. The incremental cost-effectiveness ratio was US$-21 660, indicating that MT was the dominant treatment at a willingness-to-pay of US$70 000. CONCLUSIONS: This study shows that, besides having a better functional outcome at 90-days' follow-up, MT was more cost-effective than BMM, when accounting for healthcare cost associated with treatment outcome.

The Relative Cerebral Blood Volume (rCBV) < 42% Is Independently Associated with Collateral Status in Anterior Circulation Large Vessel Occlusion.

Background: The pretreatment CT perfusion (CTP) marker the relative cerebral blood volume (rCBV) < 42% lesion volume has recently been shown to predict 90-day functional outcomes; however, studies assessing correlations of the rCBV < 42% lesion volume with other outcomes remain sparse. Here, we aim to assess the relationship between the rCBV < 42% lesion volume and the reference standard digital subtraction angiography (DSA)-derived American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) collateral score, hereby referred as the DSA CS. Methods: In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 1 September 2017 and 1 October 2023. Group differences were assessed using the Student's t test, Mann-Whitney U test and Chi-Square test. Spearman's rank correlation and logistic regression analyses were used to assess associations between rCBV < 42% and DSA CS. Results: In total, 222 patients (median age: 69 years, 56.3% female) met our inclusion criteria. In the multivariable logistic regression analysis, taking into account age, sex, race, hypertension, hyperlipidemia, diabetes, atrial fibrillation, prior stroke or transient ischemic attack, the admission National Institute of Health stroke scale, the premorbid modified Rankin score, the Alberta stroke program early CT score (ASPECTS), and segment occlusion, the rCBV < 42% lesion volume (adjusted OR: 0.98, p < 0.05) was independently associated with the DSA CS. Conclusion: The rCBV < 42% lesion volume is independently associated with the DSA CS.

Dual Layer vs Single Layer Woven EndoBridge Device in the Treatment of Intracranial Aneurysms: A Propensity Score-Matched Analysis.

BACKGROUND: The Woven EndoBridge (WEB) devices have been used for treating wide neck bifurcation aneurysms (WNBAs) with several generational enhancements to improve clinical outcomes. The original device dual-layer (WEB DL) was replaced by a single-layer (WEB SL) device in 2013. This study aimed to compare the effectiveness and safety of these devices in managing intracranial aneurysms. METHODS: A multicenter cohort study was conducted, and data from 1,289 patients with intracranial aneurysms treated with either the WEB SL or WEB DL devices were retrospectively analyzed. Propensity score matching was utilized to balance the baseline characteristics between the two groups. Outcomes assessed included immediate occlusion rate, complete occlusion at last follow-up, retreatment rate, device compaction, and aneurysmal rupture. RESULTS: Before propensity score matching, patients treated with the WEB SL had a significantly higher rate of complete occlusion at the last follow-up and a lower rate of retreatment. After matching, there was no significant difference in immediate occlusion rate, retreatment rate, or device compaction between the WEB SL and DL groups. However, the SL group maintained a higher rate of complete occlusion at the final follow-up. Regression analysis showed that SL was associated with higher rates of complete occlusion (OR: 0.19; CI: 0.04 to 0.8, p = 0.029) and lower rates of retreatment (OR: 0.12; CI: 0 to 4.12, p = 0.23). CONCLUSION: The WEB SL and DL devices demonstrated similar performances in immediate occlusion rates and retreatment requirements for intracranial aneurysms. The SL device showed a higher rate of complete occlusion at the final follow-up.

Intravenous Tenecteplase vs Alteplase Before Mechanical Thrombectomy in Patients with Large Vessel Occlusion Stroke. A Systematic Review & Meta-analysis.

BACKGROUND: The use of Alteplase (ALT) bridging to endovascular mechanical thrombectomy (MT) has become the standard approach in treating patients with large vessel stroke (LVO). Tenecteplase (TNK) has emerged as an equivalent fibrinolytic agent in treating ischemic stroke due to its remarkable pharmacological characteristics. This study aims to compare the use of intravenous TNK to ALT bridging to MT in patients with LVO. METHODS: We included observational and randomized controlled trials of patients with LVO who received bridging TNK vs ALT before undergoing MT. Efficacy outcomes included functional independence which is indicated by a modified Rankin Scale [mRS] score of 0-2 at 90 days. Radiological outcomes included the rate of successful recanalization post-MT (Modified Treatment in Cerebral Ischemia [mTICI] score of 2b/3), and the rate of pre-MT recanalization, indicated by an mTICI of 2b/3 at the first angiographic assessment. The all-cause mortality at 90 days (mRS of 6) was considered the primary safety outcome, while the symptomatic intracranial hemorrhage (sICH) rate was reported as an adverse event. RESULTS: We identified 5 comparative observational studies and 1 randomized controlled trial, totaling 4,186 patients with LVO. The crude odds ratio for post-MT recanalization in patients with LVO who received TNK was comparable to those who received ALT (OR = 1.14; 95% CI 0.57-2.27, I² = 54%). The rate of pre-MT recanalization was significantly higher in those given TNK as a bridging therapy to MT compared to those who received ALT (OR = 2.66; 95% CI 1.60-4.41, I² = 0%; P = <0.001). Functional independence at 90 days was not significantly different between patients with stroke who received TNK and those who were given ALT before MT (OR = 1.41; 95% CI 0.84-2.35; I² = 45%). The 90-day mortality was similar between patients with LVO who received TNK and those who were given ALT prior to undergoing MT (OR = 0.74; 95% CI 0.46-1.21; I² = 0%). CONCLUSIONS: Patients with LVO who received TNK as the primary fibrinolytic agent bridging to MT demonstrated higher rates of pre-MT recanalization, similar rates in post-MT recanalization, and equivalent functional independence outcomes at 90 days compared to those who received ALT. The administration of TNK before MT showed comparable results in the 90-day all-cause mortality rate compared to those who received ALT. These results warrant further trials for TNK to be used as a superior fibrinolytic agent to ALT in LVO-MT candidates.

PCSK9 increases vulnerability of carotid plaque by promoting mitochondrial dysfunction and apoptosis of vascular smooth muscle cells.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a novel lipid-lowing target. Recent clinical studies suggested the value of inhibiting PCSK9 in decreasing the vulnerability of coronary plaques. However, the evidence of PCSK9-regulated evolution of unstable carotid plaques is unclear, which has limited the use of PCSK9 inhibitor in carotid plaques. This study aimed to determine the effect and molecular mechanisms of PCSK9 on vulnerability of carotid plaques, to provide potential therapeutic targets for stabilizing carotid plaques. METHODS: The expression of PCSK9 in stable and unstable carotid plaques were examined in tissue and plasma. Human aortic vascular smooth muscle cells (VSMCs) and carotid VSMCs were employed to transfect lentivirus for overexpression and knockdown of PCSK9, respectively. Morphological and functional changes of mitochondria were observed by live-cell imaging. Cell apoptosis was evaluated by propidium iodide staining. RNA-sequencing and biological examinations were performed to explore and validate the underlying mechanisms. Truncated plasmids were employed to identify the functional domain of PCSK9 in regulation of VSMCs' mitochondrial morphology, function and apoptosis. RESULTS: Clinically, PCSK9 was closely related with vulnerability of human carotid plaques. Increased expression of PCSK9 in human VSMCs was accompanied by higher level of apoptosis. At subcellular level of VSMCs, the morphology of mitochondria was shifted toward the fission state, followed by mitochondrial dysfunction. Inhibition of p38 MAPK activation partially rescued the above morphological and behavioral changes caused by PCSK9. Furthermore, inhibiting of dynamin-related protein 1 (DRP1) attenuated PCSK9-related mitochondrial dysfunction and cell apoptosis. The 1-149aa domain of PCSK9 protein was essential to achieve functional regulation to VSMCs. CONCLUSION: Our findings demonstrated that PCSK9 induced morphology-related mitochondrial dysfunction and apoptosis of VSMCs, which may be related to increased vulnerability of carotid plaque.

First-in-human experience of sirolimus coated balloon for symptomatic intracranial artery stenosis.

BACKGROUND: The drug coated balloon is a promising endovascular therapy for intracranial atherosclerosis (ICAS), potentially combining the advantages of primary angioplasty and antiproliferative drugs. Previous studies have focused on the paclitaxel coated balloon, revealing promising outcomes in the treatment of ICAS, while concerns about the neurotoxicity of paclitaxel were reported. Sirolimus was shown to have less neurotoxicity in the canine cerebral vasculature. The feasibility and safety of a sirolimus coated balloon (SCB) for ICAS have never been evaluated in humans. We assessed the first-in-human feasibility and safety of SCBs for treating symptomatic patients with severe ICAS. METHODS: This prospective, open label, single arm cohort study was designed to enroll patients with transient ischemic attacks or non-disabling, non-perforator territory ischemic stroke caused by severe ICAS (70-99%) and following at least 3 weeks after the onset of ischemic symptoms. The primary outcome was stroke or death within 30 days. All patients were followed up to detect restenosis at 6 months. RESULTS: A total of 60 eligible patients were enrolled with an average age of 59.4±10.8 years. The technical success rate of SCBs for ICAS was 100%. Seven patients (11.7%) required stenting because of flow limited dissections or elastic retraction. Three patients (5.0%) had 30 day strokes, including two ischemic strokes and one hemorrhagic stroke. An additional three patients had recurrent stroke or death during follow-up. Ten patients had restenosis but only two had symptoms. CONCLUSIONS: SCBs may be feasible and safe in selected patients with symptomatic ICAS, with high grade stenosis (70-99%). Further studies are warranted.

Incidence and clinical outcomes of perforations during mechanical thrombectomy for medium vessel occlusion in acute ischemic stroke: A retrospective, multicenter, and multinational study.

BACKGROUND: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO. METHODS: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed. RESULTS: The incidence of vessel perforation was 4.8% (66/1373). Notably, our analysis indicates variations in perforation rates across different arterial segments: 8.9% in M3 segments, 4.3% in M2 segments, and 8.3% in A2 segments (p = 0.612). Patients with perforation had significantly worse outcomes, with lower rates of favorable angiographic outcomes (TICI 2c-3: 23% vs 58.9%, p < 0.001; TICI 2b-3: 56.5% vs 88.3%, p < 0.001). Functional outcomes were also worse in the perforation group (mRS 0-1 at 3 months: 22.7% vs 36.6%, p = 0.031; mRS 0-2 at 3 months: 28.8% vs 53.9%, p < 0.001). Mortality was higher in the perforation group (30.3% vs 16.8%, p = 0.008). CONCLUSION: This study reveals that while the occurrence of vessel perforation in MT for AIS due to MeVO is relatively rare, it is associated with poor functional outcomes and higher mortality. The findings highlight the need for increased caution and specialized training in performing MT for MeVO. Further prospective research is required for risk mitigation strategies.

Nonaneurysmal perimesencephalic subarachnoid hemorrhage on noncontrast head CT: An accuracy, inter-rater, and intra-rater reliability study.

BACKGROUND AND PURPOSE: To evaluate the reliability and accuracy of nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) on Noncontrast Head CT (NCCT) between numerous raters. MATERIALS AND METHODS: 45 NCCT of adult patients with SAH who also had a catheter angiography (CA) were independently evaluated by 48 diverse raters; 45 raters performed a second assessment one month later. For each case, raters were asked: 1) whether they judged the bleeding pattern to be perimesencephalic; 2) whether there was blood anterior to brainstem; 3) complete filling of the anterior interhemispheric fissure (AIF); 4) extension to the lateral part of the sylvian fissure (LSF); 5) frank intraventricular hemorrhage; 6) whether in the hypothetical presence of a negative CT angiogram they would still recommend CA. An automatic NAPSAH diagnosis was also generated by combining responses to questions 2-5. Reliability was estimated using Gwet's AC1 (κG), and the relationship between the NCCT diagnosis of NAPSAH and the recommendation to perform CA using Cramer's V test. Multi-rater accuracy of NCCT in predicting negative CA was explored. RESULTS: Inter-rater reliability for the presence of NAPSAH was moderate (κG = 0.58; 95%CI: 0.47, 0.69), but improved to substantial when automatically generated (κG = 0.70; 95%CI: 0.59, 0.81). The most reliable criteria were the absence of AIF filling (κG = 0.79) and extension to LSF (κG = 0.79). Mean intra-rater reliability was substantial (κG = 0.65). NAPSAH weakly correlated with CA decision (V = 0.50). Mean sensitivity and specificity were 58% (95%CI: 44%, 71%) and 83 % (95%CI: 72 %, 94%), respectively. CONCLUSION: NAPSAH remains a diagnosis of exclusion. The NCCT diagnosis was moderately reliable and its impact on clinical decisions modest.

Characterizing coma in large vessel occlusion stroke.

BACKGROUND: Coma is an unresponsive state of disordered consciousness characterized by impaired arousal and awareness. The epidemiology and pathophysiology of coma in ischemic stroke has been underexplored. We sought to characterize the incidence and clinical features of coma as a presentation of large vessel occlusion (LVO) stroke. METHODS: Individuals who presented with LVO were retrospectively identified from July 2018 to December 2020. Coma was defined as an unresponsive state of impaired arousal and awareness, operationalized as a score of 3 on NIHSS item 1a. RESULTS: 28/637 (4.4%) patients with LVO stroke were identified as presenting with coma. The median NIHSS was 32 (IQR 29-34) for those with coma versus 11 (5-18) for those without (p < 0.0001). In coma, occlusion locations included basilar (13), vertebral (2), internal carotid (5), and middle cerebral (9) arteries. 8/28 were treated with endovascular thrombectomy (EVT), and 20/28 died during the admission. 65% of patients not treated with EVT had delayed presentations or large established infarcts. In models accounting for pre-stroke mRS, basilar occlusion location, intravenous thrombolysis, and EVT, coma independently increased the odds of transitioning to comfort care during admission (aOR 6.75; 95% CI 2.87,15.84; p < 0.001) and decreased the odds of 90-day mRS 0-2 (aOR 0.12; 95% CI 0.03,0.55; p = 0.007). CONCLUSIONS: It is not uncommon for patients with LVO to present with coma, and delayed recognition of LVO can lead to poor outcomes, emphasizing the need for maintaining a high index of suspicion. While more commonly thought to result from posterior LVO, coma in our cohort was similarly likely to result from anterior LVO. Efforts to improve early diagnosis and care of patients with LVO presenting with coma are crucial.