Value of Dual Arterial Access for Improved Angiographic Control for Double-Lumen Arterial Balloon Onyx Embolization of Multifeeder Complex Cranial Dural Arteriovenous Fistulas: A Technical Nuance.

BACKGROUND: Here we describe our experience managing intracranial dural arteriovenous fistulas (DAVFs) via endovascular embolization using a transarterial embolization (TAE) technique with liquid embolic agents. We illustrate the technical nuance of using dual arterial access for angiographic control runs in complex DAVFs supplied by multiple feeders from 2 distinct arterial systems. METHODS: Retrospective analysis of intracranial DAVF embolization as a single treatment technique at our institution from 2013 to 2023. RESULTS: Twenty-three patients with intracranial DAVF who underwent endovascular treatment as their initial treatment were included. All embolizations were approached transarterially with Onyx (n = 19), n-butyl cyanoacrylate (n = 2), or a combination (n = 2). Twenty-two patients (96%) had angiographic evidence of complete fistula obliteration after initial embolization. Six DAVF TAEs were performed with dual arterial access for simultaneous embolic delivery and angiographic control intraoperatively. Two patients recanalized twice postprocedure, 1 of whom was found to have incidental new DAVF at follow-up. Median patient follow-up was 12 months (interquartile range, 6-36 months), with a median modified Rankin Scale score on discharge of 1 and a Glasgow Outcome Scale score at 3 months of 5. CONCLUSIONS: In this initial series of patients with DAVF managed by endovascular embolization, dual arterial access was feasible, safe, and effective in achieving fistula obliteration. Dual-arterial access conveniently provides simultaneous access for control angiography and embosylate delivery intraoperatively.

CD14 Blockade Does Not Improve Outcomes of Deep Vein Thrombosis Following Inferior Vena Cava Stenosis in Mice.

Background: Neutrophil-mediated persistent inflammation and neutrophil extracellular trap formation (NETosis) promote deep vein thrombosis (DVT). CD14, a co-receptor for toll-like receptor 4 (TLR4), is actively synthesized by neutrophils, and the CD14/TLR4 signaling pathway has been implicated in proinflammatory cytokine overproduction and several aspects of thromboinflammation. The role of CD14 in the pathogenesis of DVT remains unclear. Objective: To determine whether CD14 blockade improves DVT outcomes. Methods: Bulk RNA sequencing and proteomic analyses were performed using isolated neutrophils following inferior vena cava (IVC) stenosis in mice. DVT outcomes (IVC thrombus weight and length, thrombosis incidence, neutrophil recruitment, and NETosis) were evaluated following IVC stenosis in mice treated with a specific anti-CD14 antibody, 4C1, or control antibody. Results: Mice with IVC stenosis exhibited increased plasma levels of granulocyte colony-stimulating factor (G-CSF) along with a higher neutrophil-to-lymphocyte ratio and increased plasma levels of cell-free DNA, elastase, and myeloperoxidase. Quantitative measurement of total neutrophil mRNA and protein expression revealed distinct profiles in mice with IVC stenosis compared to mice with sham surgery. Neutrophils of mice with IVC stenosis exhibited increased inflammatory transcriptional and proteomic responses, along with increased expression of CD14. Treatment with a specific anti-CD14 antibody, 4C1, did not result in any significant changes in the IVC thrombus weight, thrombosis incidence, or neutrophil recruitment to the thrombus. Conclusion: The results of the current study are important for understanding the role of CD14 in the regulation of DVT and suggest that CD14 lacks an essential role in the pathogenesis of DVT following IVC stenosis.

Interactions between integrin α9ß1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.