Aneurysm Formation, Growth, and Rupture: The Biology and Physics of Cerebral Aneurysms.

Cerebral aneurysms (CAs) are characterized by a pathological wall structure with internal elastic lamina and media disruption, which leads to focal weakened pouches of the arterial wall. The prevalence of unruptured CAs has been estimated to be 2%-5% in the general population. During the past few decades, the pathophysiological mechanisms behind the formation, growth, and rupture of CAs have been the focus of numerous research studies. In the present review, we have summarized the inflammatory pathways, genetics, and risk factors for the formation, growth, and rupture of CAs. In addition, we have discussed the concepts of geometric indexes, flow patterns, and fluid dynamics that govern CA development

Endothelial Cell Thrombin Receptors and PAR-2 TWO PROTEASE-ACTIVATED RECEPTORS LOCATED IN A SINGLE CELLULAR ENVIRONMENT

Human endothelial cells express thrombin receptors and PAR-2, the two known members of the family of protease-activated G protein-coupled receptors. Because previous studies have shown that the biology of the human thrombin receptor varies according to the cell in which it is expressed, we have taken advantage of the presence of both receptors in endothelial cells to examine the enabling and disabling interactions with candidate proteases likely to be encountered in and around the vascular space to compare the responses elicited by the two receptors when they are present in the same cell and to compare the mechanisms of thrombin receptor and PAR-2 clearance and replacement in a common cellular environment. Of the proteases that were tested, only trypsin activated both receptors. Cathepsin G, which disables thrombin receptors, had no effect on PAR-2, while urokinase, kallikrein, and coagulation factors IXa, Xa, XIa, and XIIa neither substantially activated nor noticeably disabled either receptor. Like thrombin receptors, activation of PAR-2 caused pertussis toxin-sensitive phospholipase C activation as well as activation of phospholipase A2, leading to the release of PGI2. Concurrent activation of both receptors caused a greater response than activation of either alone. It also abolished a subsequent response to the PAR-2 agonist peptide, SLIGRL, while only partially inhibiting the response to the agonist peptide, SFLLRN, which activates both receptors. After proteolytic or nonproteolytic activation, PAR-2, like thrombin receptors, was cleared from the endothelial cell surface and then rapidly replaced with new receptors by a process that does not require protein synthesis. Selective activation of either receptor had no effect on the clearance of the other. These results suggest that the expression of both thrombin receptors and PAR-2 on endothelial cells serves more to extend the range of proteases to which the cells can respond than it does to extend the range of potential responses. The results also show that proteases that can disable these receptors can distinguish between them, just as do most of the proteases that activate them. Finally, the residual response to SFLLRN after activation of thrombin receptors and PAR-2 raises the possibility that a third, as yet unidentified member of this family is expressed on endothelial cells, one that is activated by neither thrombin nor trypsin

Bottleneck Factor and Height-Width Ratio: Association With Ruptured Aneurysms in Patients With Multiple Cerebral Aneurysms

Abstract OBJECTIVE Determining factors predictive of the natural risk of rupture of cerebral aneurysms is difficult because of the need to control for confounding variables. We studied factors associated with rupture in a study model of patients with multiple cerebral aneurysms, one aneurysm that had ruptured and one or more that had not, in which each patient served as their own internal control. METHODS We collected aneurysm location, one-dimensional measurements, and two-dimensional indices from the computed tomographic angiograms of patients in the proposed study model and compared ruptured versus unruptured aneurysms. Bivariate statistics were supplemented with multivariable logistic regression analysis to model ruptured status. A total of 40 candidate models were evaluated for predictive power and fit with Wald scoring, Cox and Snell R2, Hosmer and Lemeshow tests, case classification counting, and residual analysis to determine which of the computed tomographic angiographic measurements or indices were jointly associated with and predictive of aneurysm rupture. RESULTS Thirty patients with 67 aneurysms (30 ruptured, 37 unruptured) were studied. Maximum diameter, height, maximum width, bulge height, parent artery diameter, aspect ratio, bottleneck factor, and aneurysm/parent artery ratio were significantly (P < 0.05) associated with ruptured aneurysms on bivariate analysis. When best subsets and stepwise multivariable logistic regression was performed, bottleneck factor (odds ratio = 1.25, confidence interval = 1.11–1.41 for every 0.1 increase) and height-width ratio (odds ratio = 1.23, confidence interval = 1.03–1.47 for every 0.1 increase) were the only measures that were significantly predictive of rupture. CONCLUSION In a case-control study of patients with multiple cerebral aneurysms, increased bottleneck factor and height-width ratio were consistently associated with rupture

Pivotal Trial of the Neuroform Atlas Stent for Treatment of Anterior Circulation Aneurysms: One-Year Outcomes.

Background and purposeStent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented.MethodsATLAS IDE trial (Investigational Device Exemption) is a prospective, multicenter, single-arm, open-label study of wide-neck (neck ≥4 mm or dome-to-neck ratio &lt;2) intracranial aneurysms in the anterior circulation treated with the Neuroform Atlas Stent and approved coils. The primary efficacy end point was complete aneurysm occlusion (Raymond-Roy class 1) on 12-month angiography, in the absence of retreatment or parent artery stenosis (&gt;50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent Imaging Core Laboratory and the Clinical Events Committee.ResultsA total of 182 patients with wide-neck anterior circulation aneurysms at 25 US centers were enrolled. The mean age was 60.3±11.4 years, 73.1% (133/182) women, and 80.8% (147/182) white. Mean aneurysm size was 6.1±2.2 mm, mean neck width was 4.1±1.2 mm, and mean dome-to-neck ratio was 1.2±0.3. The most frequent aneurysm locations were the anterior communicating artery (64/182, 35.2%), internal carotid artery ophthalmic artery segment (29/182, 15.9%), and middle cerebral artery bifurcation (27/182, 14.8%). Stents were placed in the anticipated anatomic location in all patients. The study met both primary safety and efficacy end points. The composite primary efficacy end point of complete aneurysm occlusion (Raymond-Roy 1) without parent artery stenosis or aneurysm retreatment was achieved in 84.7% (95% CI, 78.6%-90.9%) of patients. Overall, 4.4% (8/182, 95% CI, 1.9%-8.5%) of patients experienced a primary safety end point of major ipsilateral stroke or neurological death.ConclusionsIn the ATLAS IDE anterior circulation aneurysm cohort premarket approval study, the Neuroform Atlas stent with adjunctive coiling met the primary end points and demonstrated high rates of long-term complete aneurysm occlusion at 12 months, with 100% technical success and &lt;5% morbidity. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02340585

Y‐Stent–Assisted Coiling of Wide‐Necked Intracranial Aneurysms With the Neuroform Atlas Stent System

Background Endovascular management of wide‐necked bifurcation aneurysms poses a therapeutic challenge, as coiling often requires the use of multiple adjunctive stent constructs to achieve successful embolization without compromising parent vessel integrity. The Neuroform Atlas Stent System is a novel low‐profile, intraluminal remodeling device. The study aims to investigate the safety and efficacy of Y‐stent–assisted coiling configuration constructs using the next generation stent for aneurysm coil embolization. Methods Subjects undergoing Y‐stent–assisted coiling in the ATLAS IDE (Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms with the Neuroform Atlas Stent System Investigational Device Exception) trial were identified for subgroup analysis. Enrollment in the trial was not stratified on the basis of the procedural stenting technique used. The primary efficacy end point was complete aneurysm occlusion (Raymond–Roy class 1) on 12‐month angiography, in the absence of re‐treatment or parent artery stenosis (>50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent imaging core laboratory and the clinical events committee. Results A total of 60 subjects were identified. The mean age was 59, and 28.3% were men. The median aneurysm size was 6.7 mm, with a median neck size of 4.3 mm. Frequently reported aneurysm locations included the basilar apex (56.7%), anterior communicating artery (20.0%), and middle cerebral artery bifurcation (11.7%). The composite primary efficacy end point was achieved in 81.1% of subjects. Overall, 1.7% of subjects experienced a primary safety endpoint of major ipsilateral stroke or neurological death. Conclusion In the ATLAS IDE aneurysm cohort premarket approval study, Y‐stent–assisted coiling with Neuroform demonstrated high rates of complete aneurysm occlusion at 12 months, with low rates of morbidity

Pivotal trial of the Neuroform Atlas stent for treatment of posterior circulation aneurysms: one-year outcomes.

BACKGROUND: Stent-assisted coiling of wide-necked intracranial aneurysms (IAs) using the Neuroform Atlas Stent System (Atlas) has shown promising results. OBJECTIVE: To present the primary efficacy and safety results of the ATLAS Investigational Device Exemption (IDE) trial in a cohort of patients with posterior circulation IAs. METHODS: The ATLAS trial is a prospective, multicenter, single-arm, open-label study of unruptured, wide-necked, IAs treated with the Atlas stent and adjunctive coiling. This study reports the results of patients with posterior circulation IAs. The primary efficacy endpoint was complete aneurysm occlusion (Raymond-Roy (RR) class I) on 12-month angiography, in the absence of re-treatment or parent artery stenosis &gt;50%. The primary safety endpoint was any major ipsilateral stroke or neurological death within 12 months. Adjudication of the primary endpoints was performed by an imaging core laboratory and a Clinical Events Committee. RESULTS: The ATLAS trial enrolled and treated 116 patients at 25 medical centers with unruptured, wide-necked, posterior circulation IAs (mean age 60.2±10.5 years, 81.0% (94/116) female). Stents were placed in all patients with 100% technical success rate. A total of 95/116 (81.9%) patients had complete angiographic follow-up at 12 months, of whom 81 (85.3%) had complete aneurysm occlusion (RR class I). The primary effectiveness outcome was achieved in 76.7% (95% CI 67.0% to 86.5%) of patients. Overall, major ipsilateral stroke and secondary persistent neurological deficit occurred in 4.3% (5/116) and 1.7% (2/116) of patients, respectively. CONCLUSIONS: In the ATLAS IDE posterior circulation cohort, the Neuroform Atlas Stent System with adjunctive coiling demonstrated high rates of technical and safety performance. Trial registration number https://clinicaltrials.gov/ct2/show/NCT02340585