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BackgroundPipeline embolization device (PED) deployment combined with coil therapy for large complex intracranial aneurysms is effective and considered superior to PED deployment alone. However, the optimal strategy for use of coils remains unclear. We used patient-specific aneurysm models and finite element analysis to determine the ideal packing density of coils after PED placement.MethodsFinite element analysis was used to provide a higher-fidelity model for accurate post-treatment computational fluid dynamics analysis to simulate the real therapeutic process of PED and all coils. We then calculated and analyzed the reduction ratio of velocity to identify the hemodynamic change during PED deployment and each coil embolization.ResultsSixteen consecutive patients underwent PED plus coil procedures to treat internal carotid artery intracranial aneurysms. After PED deployment, the intra-aneurysmal flow velocity significantly decreased (15.3 vs 10.0 cm/s; p<0.001). When the first coil was inserted, the flow velocity in the aneurysm further decreased and the reduction was significant (10.0 vs 5.3 cm/s; p<0.001). Analysis of covariance showed that the effect of the reduction ratio of velocity of the second coil was significantly lower than that of the first coil (p<0.001)—that is, when the packing density increased to 7.06%, the addition of coils produced no further hemodynamic effect.ConclusionAdjunct coiling could improve the post-PED hemodynamic environment in treated intracranial aneurysms. However, dense packing is not necessary because the intra-aneurysmal hemodynamics tend to stabilize as the packing density reaches an average of 7.06% or after insertion of the second coil.

BackgroundBrain arteriovenous malformation (BAVM) is a main cause of cerebral hemorrhage and hemorrhagic stroke in adolescents. Morphologically, a BAVM is an abnormal connection between cerebrovascular arteries and veins. The genetic etiology of BAVMs has not been fully elucidated. In this study, we aim to investigate potential recessive genetic variants in BAVMs by interrogation of rare compound heterozygous variants.MethodsWe performed whole exome sequencing (WES) on 112 BAVM trios and analyzed the data for rare and deleterious compound heterozygous mutations associated with the disease.ResultsWe identified 16 genes with compound heterozygous variants that were recurrent in more than one trio. Two genes (LRP2, MUC5B) were recurrently mutated in three trios. LRP2has been previously associated with BAVM pathogenesis. Fourteen genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2, DNAH14, DNAH5, FCGBP, HERC2, HMCN1, MYH1, NHSL1, PLEC, RP1L1) were recurrently mutated in two trios, and five of these genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2) have been reported to play a role in angiogenesis or vascular diseases. Additionally, abnormal expression of the MYLK protein is related to spinal arteriovenous malformations.ConclusionOur study indicates that rare recessive compound heterozygous variants may underlie cases of BAVM. These findings improve our understanding of BAVM pathology and indicate genes for functional validation.

BackgroundGenetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown.ObjectiveTo investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs.MethodExome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype.ResultsBased on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family—that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain.ConclusionNFX1c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.