Rationale: Brain arteriovenous malformations (bAVMs) are abnormal entanglement of blood vessels in brain, with direct connections from arteries to veins, lacking functional capillary bed. Although several somatic mutations were reported, the molecular mechanism and genetic disposition of bAVM remain poorly understood. Objective: We aim to identify transcriptional anomalies and critical functional pathways in bAVM lesions and explore their association with key de novo germline and somatic variants in bAVM patients. Methods and Results: We established a comprehensive bAVM dataset from 269 patients, by performing single-cell sequencing of 17 bAVM lesions, whole-exome sequencing of germline DNA from 60 case-unaffected-parental trios, and genomic/transcriptomic sequencing of 231 bAVM lesions. We found abnormal expression of endothelial and mesenchymal markers in bAVM at both bulk and single-cell level, which was validated by flow cytometric analysis and immunofluorescence staining, suggesting an involvement of endothelial-to-mesenchymal transition (EndMT) process in AVM (arteriovenous-malformation). Using data from the 60 trios, we identified nonsynonymous de novo germline mutations affecting 46 genes, including EXPH5 (detected in 2 independent cases), and vessel-related genes, such as EPAS1 and ENG . Interestingly, knockdown of epas1 in zebrafish embryo showed AVM-like phenotype exclusively in brain. Subsequent computational and experimental analyses demonstrated that expression of genes affected by de novo germline mutations was enriched in vascular cell types and was involved in EndMT-relevant behaviors including cell migration, angiogenesis, and cell marker transition. Moreover, we detected somatic KRAS mutations in 129 of 179 (72%) cases and showed that KRAS mutations were associated with bleeding as the first symptom ( P =0.0072). Following experimental studies demonstrated that KRAS mutations independently regulated EndMT features, consolidating the involvement of EndMT in this disease. Lastly, we showed that lovastatin reversed EndMT features in vitro and ex vivo. Conclusions: Our results suggest the convergent role of de novo germline mutations and somatic mutations in regulating EndMT in bAVM and provided a potential therapeutic option.

The role of statins in unruptured intracranial aneurysm (UIA) growth and rupture remains ambiguous. This study sought to determine whether atorvastatin is associated with aneurysm growth and rupture in patients harboring UIA <7 mm. This prospective, multicenter cohort study consecutively enrolled patients with concurrent UIA <7 mm and ischemic cerebrovascular disease from four hospitals between 2016 and 2019. Baseline and follow-up patient information was recorded. Because of the strong anti-inflammatory effect of aspirin, patients using aspirin were excluded. Patients taking atorvastatin 20 mg daily were atorvastatin users. The primary and exploratory endpoints were aneurysm rupture and growth, respectively. Among the 1087 enrolled patients, 489 (45.0%) took atorvastatin, and 598 (55%) took no atorvastatin. After a mean follow-up duration of 33.0 ± 12.5 months, six (1.2%) and five (0.8%) aneurysms ruptured in atorvastatin and non-atorvastatin groups, respectively. In the adjusted multivariate Cox analysis, UIA sized 5 to <7 mm, current smoker, and uncontrolled hypertension were associated with aneurysm rupture, whereas atorvastatin [adjusted hazard ratio (HR) 1.495, 95% confidence interval (CI) 0.417–5.356, p = 0.537] was not. Of 159 patients who had follow-up imaging, 34 (21.4%) took atorvastatin and 125 (78.6%) took no atorvastatin. Aneurysm growth occurred in five (14.7%) and 21 (16.8%) patients in atorvastatin and non-atorvastatin groups (mean follow-up: 20.2 ± 12.9 months), respectively. In the adjusted multivariate Cox analysis, UIAs sized 5 to <7 mm and uncontrolled hypertension were associated with a high growth rate; atorvastatin (adjusted HR 0.151, 95% CI 0.031–0.729, p = 0.019) was associated with a reduced growth rate. We conclude atorvastatin use is associated with a reduced risk of UIA growth, whereas atorvastatin is not associated with UIA rupture.

Background There are limited data on new ischemic brain lesions after endovascular treatment for symptomatic intracranial atherosclerotic stenosis (ICAS). Purpose To investigate the (a) characteristics of new ischemic brain lesions at diffusion-weighted MRI (new diffusion abnormalities) after endovascular treatment, (b) characteristics between those treated with balloon angioplasty and stent placement procedures, and (c) predictors of new ischemic brain lesions. Materials and Methods Patients with symptomatic ICAS in whom maximum medical therapy failed were prospectively enrolled between April 2020 and July 2021 from a national stroke center and underwent endovascular treatment. All study participants underwent thin-section diffusion-weighted MRI (voxel size, 1.4 × 1.4 × 2 mm³ with no section gap) before and after treatment. The characteristics of new ischemic brain lesions were recorded. Multivariable logistic regression analysis was performed to determine potential predictors of new ischemic brain lesions. Results A total of 119 study participants (mean age, 59 years ± 11 [SD]; 81 men; 70 treated with balloon angioplasty and 49 with stent placement) were enrolled. Of the 119 participants, 77 (65%) had new ischemic brain lesions. Five of the 119 participants (4%) had symptomatic ischemic stroke. New ischemic brain lesions were located in (61%, 72 of 119) and/or beyond (35%, 41 of 119) the territory of the treated artery. Of the 77 participants with new ischemic brain lesions, 58 (75%) had lesions located in peripheral brain areas. There was no evidence of a difference in the frequency of new ischemic brain lesions between the balloon angioplasty and stent groups (60% vs 71%, P = .20). In adjusted models, cigarette smoking (odds ratio [OR], 3.6; 95% CI: 1.3, 9.7) and more than one operative attempt (OR, 2.9; 95% CI: 1.2, 7.0) were independent predictors of new ischemic brain lesions. Conclusion New ischemic brain lesions on diffusion-weighted MRI scans were common after endovascular treatment for symptomatic intracranial atherosclerotic stenosis, and occurrence may be associated with cigarette smoking and the number of operative attempts. Clinical trial registration no. ChiCTR2100052925 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Russell in this issue.

Background The time to maximum (Tmax) profile based on computed tomography perfusion (CTP) provides a quantitative assessment of cerebral hemodynamic compromise. We aimed to delineate the Tmax profile in stroke patients with symptomatic intracranial atherosclerotic stenosis (ICAS) and to investigate its predictive role in stroke recurrence after optimal medical treatment. Methods Consecutive patients with ischemic stroke within 30 days attributed to 50%–99% ICAS were prospectively enrolled. Baseline tissue volume at different perfusion parameter thresholds based on CTP was automatically calculated using the Rapid Processing of Perfusion and Diffusion (RAPID) software. All patients received optimal medical treatment. The primary outcome was a composite of stroke in the territory of qualifying artery or vascular death within 1 year. Results Among 204 patients with symptomatic ICAS, the median volume of Tmax >4 s, Tmax >6 s, and relative cerebral blood flow (rCBF) 4 s volume was significantly associated with the primary outcome (per 10 mL increase, adjusted hazard ratio (HR), 1.028 (1.008–1.049), P=0.005). The optimal cut-off value of Tmax >4 s volume for predicting the primary outcome was 83 mL. Patients with Tmax >4 s volume >83 mL had a higher risk of the 1 year primary outcome than those with Tmax >4 s volume ≤83 mL (adjusted HR, 7.346 (3.012–17.871), P4 s volume is a promising perfusion parameter to define hemodynamic compromise in patients with symptomatic ICAS. Patients with a larger volume of Tmax >4 s are likely to have a higher risk of stroke recurrence despite optimal medical treatment.

Brain arteriovenous malformations (bAVMs) are congenital anomalies of blood vessels that cause intracranial hemorrhage in children and young adults. Chromosomal rearrangements and fusion genes play an important role in tumor pathogenesis, though the role of fusion genes in bAVM pathophysiological processes is unclear. The aim of this study was to identify fusion transcripts in bAVMs and analyze their effects. To identify fusion transcripts associated with bAVM, RNA sequencing was performed on 73 samples, including 66 bAVM and 7 normal cerebrovascular samples, followed by STAR-Fusion analysis. Reverse transcription polymerase chain reaction and Sanger sequencing were applied to verify fusion transcripts. Functional pathway analysis was performed to identify potential effects of different fusion types. A total of 21 fusion transcripts were detected. Cathepsin C (CTSC)-Ras-Related Protein Rab-38 (RAB38) was the most common fusion and was detected in 10 of 66 (15%) bAVM samples. In CTSC-RAB38 fusion-positive samples, CTSC and RAB38 expression was significantly increased and activated immune/inflammatory signaling. Clinically, CTSC-RAB38 fusion bAVM cases had a higher hemorrhage rate than non-CTSC-RAB38 bAVM cases (p < 0.05). Our study identified recurrent CTSC-RAB38 fusion transcripts in bAVMs, which may be associated with bAVM hemorrhage by promoting immune/inflammatory signaling.