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Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

Aneurysmal subarachnoid hemorrhage is diagnosed by computed tomography of the head and by CT angiography, catheter angiography, or both. Randomized trials suggest that aneurysms treatable by either open surgery or endovascular intervention are usually better treated by the latter.

Patient-specific cerebral aneurysms exhibit complex hemodynamics insights that influence thrombus formation, wall remodeling, and therapeutic delivery. The article presents a high-fidelity, multi-parametric CFD analysis of nine distinct aneurysm cases using 3-D model-resolved meshes, non-Newtonian Casson rheology, and steady-state flow conditions. Further, the Lagrangian particle tracking was employed to assess drug transport and hemodynamic metrics such as WSS and normalized residence time (NRT) were evaluated, along with vortex dynamics, indicators including helicity ( H ) and Q criterion to characterize rotational flow structures. Results reveal that narrowed neck models (m 1 , m 2 , m 5 , m 8 ) exhibit weak vortex structures and dominant axial washout (velocity magnitude < 0.10 m/s; NRT < 0.2), while sac-expanded geometries (m 3 , m 4 , m 6 , m 9 ) support robust helical vortices ( H  > 40 m²/s², Q  > 0) and elevated residence times. Regions of low WSS (τ w  < 0.5 Pa) spatially co-localize with high NRT and potential thrombogenicity, whereas high WSS (τ w  > 2.5 Pa) associates with jet impingement zones and possible endothelial damage. Notably, sharp WSS gradients are identified as destabilizing hemodynamic factors. Rheological analysis reveals a critical threshold at γ̇ ≈ 415 s⁻¹ ( µ  ≈ 6.4 mPa·s), distinguishing thrombosis-prone regions (low γ̇, high µ) from stable zones (high γ̇, low µ). Particle transport studies show that effective drug retention occurs in high-helicity, wide neck models for Stokes number (St = 0.1–1), while laminar-dominant aneurysmal flows demonstrate poor drug deposition due to axial convection. Overall, the findings underscore that aneurysm stability and therapeutic outcomes are governed by the interplay of aneurysm induced flow structures, WSS heterogeneity, non-Newtonian rheology, and vortex coherence are refining rupture risk assessments and optimizing endovascular drug delivery strategies.

The initiation, growth, and rupture of cerebral aneurysms are directly associated with Hemodynamic factors. This report tries to disclose effects of endovascular technique (coiling and stenting) on the quantitative intra-aneurysmal hemodynamic and the rupture of cerebral aneurysms. In this paper, Computational Fluid Dynamic are done to investigate and compare blood hemodynamic inside aneurysm under effects of deformation (due to stent) and coiling of aneurysm. The blood stream inside the sac of aneurysm as well as pressure and OSI distribution on the aneurysm wall are compared in nine cases and results of two distinctive cases are compared and reported. Obtained results specifies that the mean WSS is reduced up to 20% via coiling of the aneurysm while the deformation of the aneurysm (applying stent) could reduce the mean WSS up to 71%. In addition, comparison of the blood hemodynamic shows that the blood bifurcation occurs in the dome of aneurysm when endovascular technique for the treatment is not applied. It is found that the bifurcation occurs at ostium section when ICA aneurysm is deformed by the application of stent. The impacts of coiling are mainly limited since the blood flow entrance is not limited in this technique and WSS is not reduced substantial. However, usage of stent deforms the aneurysm angle with the orientation of parent vessel and this reduces blood velocity at entrance of the ostium and consequently, WSS is decreased when deformation of the aneurysm fully occurs. These qualitative procedures provide a preliminary idea for more profound quantitative examination intended for assigning aneurysm risk of upcoming rupture.

Introduction Delayed aneurysm rupture and delayed intraparenchymal hemorrhages (DIPH) are poorly understood and often fatal complications of flow diversion (FD) for intracranial aneurysms. The purpose of this study was to identify risk factors for these complications. Methods We performed a systematic review on post-FD delayed aneurysm rupture and DIPH. For each reported case, we collected the following information: aneurysm location, size and rupture status, type of flow diverter used, timing of the hemorrhage, and neurological outcome. We reported descriptive statistics of patients suffering DIPH and delayed aneurysm rupture to determine if there were any characteristics consistently present among patients with these complications. Results We identified 81 delayed aneurysm ruptures and 101 DIPH. Of the delayed ruptures, 76.6 % (45/58) occurred within 1 month. The prognosis of delayed ruptures was poor, with 81.3 % (61/75) experiencing death or poor neurological outcome. Giant aneurysms accounted for 46.3 % of ruptures (31/67). Of these aneurysms, 80.9 % (55/68) were initially unruptured. Of the delayed ruptured aneurysms, 17.8 % (13/73) had prior or concomitant coiling. DIPHs were ipsilateral to the treated aneurysm in 82.2 % (60/73) of cases. Of the DIPH, 86.0 % (43/50) occurred within 1 month after FDS. Combined morbidity/mortality rate was 68.5 % (50/73) following DIPH. Of DIPHs, 23.0 % (14/61) occurred in patients with giant aneurysms. Conclusions Our study demonstrates that giant aneurysms represent almost 50 % of delayed aneurysm ruptures in the flow diverter literature. About 20 % of delayed ruptures occurred despite associated coiling. A substantial proportion of DIPHs occur early following FDS treatment of giant aneurysms.

Abstract BACKGROUND The rupture risk assessment of unruptured intracranial aneurysms (IAs) is still challenging. Aneurysm wall enhancement (AWE) on vessel wall magnetic resonance imaging (VW-MRI) is suggested as a potential marker for wall inflammation, but its relationship with rupture risk of unruptured IAs has not been well described. OBJECTIVE To investigate the correlation between AWE and conventional rupture risk factor of unruptured IAs. METHODS Clinical data and VW-MRI images were retrospectively reviewed in patients with unruptured IAs from January 2015 to December 2016 in our center. One hundred ten patients harboring 140 unruptured IAs were included. The presence of AWE was determined by comparing the postcontrast VW-MRI images with the precontrast ones. The rupture risk based on the PHASES score was calculated for each case. Univariate and multivariate analysis were performed to investigate the association of AWE with rupture risk and other conventional risk factors. RESULTS AWE was present in 82 (58.6%) lesions. Unruptured IAs with AWE had significantly larger size (P < .001), more irregular shape (P = .003), and different distribution of locations (P = .023) comparing with aneurysms without AWE. The rupture risk score of AWE group was significantly higher than non-AWE group (P < .001). Aneurysm size (odds ratio = 1.536; 95% confidential interval 1.312-1.798; P < .001) and location (odds ratio = 1.592; 95% confidential interval 1.237-2.049; P < .001) were independently related with AWE in multivariate analysis. CONCLUSION The presence of AWE on VW-MRI was highly associated with conventional rupture-related characteristics, including aneurysmal size and location, and was detected more frequently in unruptured IAs with high rupture risk based on the PHASES score.

MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.

Background: Inflammation is a key element behind the pathophysiology of cerebral aneurysm formation and rupture. Aspirin is a potent inhibitor of cyclooxygenase-2 (COX), which plays a critical role in the expression of immune modulators known to contribute to cerebral aneurysm formation and rupture. Currently, there are no pharmacological therapies for patients with cerebral aneurysms. Both endovascular and microsurgical interventions may be associated with significant morbidity and mortality. Potentially, a medical alternative that prevents aneurysm progression and rupture may be a beneficial therapy for a significant number of patients. Summary: In animal models, treatment with aspirin and genetic inactivation of COX-2 decreases aneurysm formation and rupture. Selective inhibition of COX-1 did not decrease aneurysm rupture, suggesting that selection inhibition of COX-2 may be critical in thwarting aneurysm progression. Walls of ruptured human intracranial aneurysms have higher levels of COX-2 and microsomal prostaglandin E2 synthase 1 (mPGES-1), both of which are known to be inhibited by aspirin. In a pilot study, patients undergoing microsurgical clipping had attenuated expression of COX-2, mPGES-1, and macrophages in aneurysm walls after 3 months of aspirin therapy versus those that did not receive aspirin. Additionally, in patients undergoing endovascular therapy, local circulating expression of chemokines and COX-2 were increased in blood samples taken from within aneurysm domes as compared to peripheral blood sample controls. Treatment with aspirin also resulted in decreased expression of COX-2 within leukocytes within aneurysms as compared to peripheral blood samples. Novel molecular imaging with ferumoxytol-enhanced MRI may help in the identification of patients at increased risk for aneurysm rupture and assessment of a response to aspirin therapy. Key Messages: Aspirin has been found to be a safe in patients harboring cerebral aneurysms and clinical studies provide evidence that it may decrease the overall rate of rupture. Furthermore, aspirin is an accessible and inexpensive medicine for patients who may not have access to endovascular or microsurgical treatment or for patients who are deemed low risk of aneurysm rupture, high risk for intervention, or both. Future clinical trials are indicated to determine the overall effect of aspirin on aneurysm progression and rupture. This review provides an update on the potential mechanisms and benefits of aspirin in the treatment of cerebral aneurysms.

BackgroundCerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.MethodsWe performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.ResultsThrough the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.ConclusionsThis study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.