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Background: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress., Methods: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture., Results: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture., Conclusions: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage., Competing Interests: Disclosures None.

Objective: The aim of this study was to carry out a systematic review of the literature with meta-analysis to evaluate the effect of using oral contraceptive and hormone replacement therapy as a protective factor in the formation of intracranial aneurysms and subarachnoid hemorrhage., Methods: This is a systematic review of the literature with meta-analysis, using PubMed and Embase as databases and the PRISMA method. Case-control and cohort studies published until December 2022 were included in this review., Results: Four studies were included in this review; three of which were eligible for meta-analysis. Regarding the use of oral contraceptive and the development of subarachnoid hemorrhage, there was a lower risk of aneurysm rupture with an odds ratio 0.65 (confidence interval 0.5-0.85). In the analysis of patients using hormone replacement therapy and developing subarachnoid hemorrhage, there was also a lower risk of aneurysm rupture with an OR 0.54 (CI 0.39-0.74). Only one article analyzed the formation of intracranial aneurysm and the use of hormone replacement therapy and oral contraceptive, and there was a protective effect with the use of these medications. oral contraceptive: OR 2.1 (CI 1.2-3.8) and hormone replacement therapy: OR 3.1 (CI 1.5-6.2)., Conclusion: The use of hormone replacement therapy and oral contraceptive has a protective effect in intracranial aneurysm rupture and formation.

Background: Alzheimer's disease (AD) is a form of dementia that strikes elderly people more frequently than it does younger people. The cognitive skills and memory of Alzheimer's sufferers continue to deteriorate over time. Recent studies have shown that patients with AD have greater amounts of inflammatory markers in their bodies, which suggests that inflammation occurs early on in the progression of the disease. There is a possibility that Aß oligomers and fibrils can be recognised by TLRs, in addition to the microglial receptors CD14, CD36, and CD47. When Aß binds to either CD36 or TLR4, it sets off a chain reaction of inflammatory chemokines and cytokines that ultimately results in neurodegeneration. Diabetes and Alzheimer's disease have both been recently related to TLR4. The activation of TLR4 has been connected to a variety of clinical difficulties that are associated with diabetes, in addition to the internal environment of the body and the microenvironment of the brain. TLR4 inhibitors have been shown in clinical investigations to not only lessen the likelihood of getting sick but also to increase the average longevity., Result: In this work we used molecular docking and molecular dynamics modelling to investigate the effectiveness of FDA-approved antidiabetic plant derived drugs in combating the TLR4 receptor. Molecular docking experiments were used to make a prediction regarding the most important interactions involving 2-Bromoergocryptine Mesylate. With a binding affinity of -8.26 kcal/mol, it stood out from the other candidates as the one with the greatest potential. To verify the interaction pattern that takes place between 2-Bromoergocryptine Mesylate and the TLR4 receptor, a molecular dynamic simulation was run at a time scale of 150 nanoseconds. Because of this, 2-Bromoergocryptine Mesylate was able to make substantial contact with the active site, which led to increased structural stability during the process of the complex's dynamic development., Conclusion: As a result of this, the results of our research may be relevant for future research into the efficacy of 2-bromoergocryptine mesylate as a potential lead treatment for TLR4 receptors in intracranial aneurysm rupture in AD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Debnath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2-PGE2-NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients., Methods: The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses., Results: De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level., Conclusion: For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition., (© 2022 European Academy of Neurology.)

Background: Aneurysm wall degeneration is linked to growth and rupture. To address the effect of aspirin (ASA) on aneurysm formation under various wall conditions, this issue was analyzed in a novel rabbit bifurcation model., Methods: Bifurcation aneurysms created in 45 New Zealand White rabbits were randomized to vital (n=15), decellularized (n=13), or elastase-degraded (n=17) wall groups; each group was assigned to a study arm with or without ASA. At follow-up 28 days later, aneurysms were evaluated for patency, growth, and wall inflammation at macroscopic and histological levels., Results: 36 rabbits survived to follow-up at the end of the trial. None of the aneurysms had ruptured. Patency was visualized in all aneurysms by intraoperative fluorescence angiography and confirmed in 33 (92%) of 36 aneurysms by MRI/MRA. Aneurysm size was significantly increased in the vital (without ASA) and elastase-degraded (with and without ASA) groups. Aneurysm thrombosis was considered complete in three (50%) of six decellularized aneurysms without ASA by MRI/MRA. Locoregional inflammation of the aneurysm complex was significantly reduced in histological analysis among all groups treated with ASA., Conclusion: ASA intake prevented inflammation of both the periadventitial tissue and aneurysm wall, irrespective of initial wall condition. Although ASA prevented significant growth in aneurysms with vital walls, this preventive effect did not have an important role in elastase-degraded pouches. In possible translation to the clinical situation, ASA might exert a potential preventive effect during early phases of aneurysm formation in patients with healthy vessels but not in those with highly degenerative aneurysm walls., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To study the effect of pharmacological inhibition of epidermal growth factor receptor (EGFR) on intracranial aneurysm (IA) initiation., Methods: Human IA samples were analyzed for the expression of p-EGFR and alpha smooth muscle actin (α-SMA) by immunofluorescence (IF). Rat models of IA were established to evaluate the ability of the EGFR inhibitor, erlotinib, to attenuate the incidence of IA. We analyzed anterior cerebral artery tissues by pathological and proteomic detection for the expression of p-EGFR and relevant proteins, and vessel casting was used to evaluate the incidence of aneurysms in each group. Rat vascular smooth muscle cells (VSMCs) and endothelial cells were extracted and used to establish an in vitro co-culture model in a flow chamber with or without erlotinib treatment. We determined p-EGFR and relevant protein expression in VSMCs by immunoblotting analysis., Results: Epidermal growth factor receptor activation was found in human IA vessel walls and rat anterior cerebral artery walls. Treatment with erlotinib markedly attenuated the incidence of IA by inhibiting vascular remodeling and pro-inflammatory transformation of VSMC in rat IA vessel walls. Activation of EGFR in rat VSMCs and phenotypic modulation of rat VSMCs were correlated with the strength of shear stress in vitro, and treatment with erlotinib reduced phenotypic modulation of rat VSMCs. In vitro experiments also revealed that EGFR activation could be induced by TNF-α in human brain VSMCs., Conclusions: These results suggest that EGFR plays a critical role in the initiation of IA and that the EGFR inhibitor erlotinib protects rats from IA initiation by regulating phenotypic modulation of VSMCs., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objectives: Aspirin has been suggested as a potential therapeutic strategy to prevent the growth and rupture of unruptured intracranial aneurysms (UIAs), but there is still controversy. The aim of this systematic review and meta-analysis is to determine the association between aspirin use and growth, rupture of UIAs., Methods: We performed a systematic literature search of electronic databases to identify cohort and case-control studies investigating the relationship between aspirin use and growth or rupture of UIAs. Pooled odds ratio (OR) with corresponding 95% confidence interval (CI) were calculated using a random effects model. Heterogeneity among studies was quantified using the I 2 statistic, and potential publication bias was assessed using funnel plots. Sensitivity analysis was performed to verify the robustness of the intention-to-treat results. Subgroup analysis was conducted according to the frequency of aspirin use., Results: We identified 8 studies comprising 10,518 participants. The risk of bias was low to moderate. The pooled estimate showed that aspirin use was associated with a lower likelihood of growth of UIAs (OR = 0.25, 95% CI = 0.11-0.55; p = 0.0005) without statistical heterogeneity (p for Cochran Q statistic = 0.62, I 2 = 0%). Likewise, aspirin intake also significant decreased 58% risk of intracranial aneurysms rupture (OR = 0.42, 95% CI = 0.29-0.60; p < 0.00001) with moderate heterogeneity (p for Cochran Q statistic = 0.005, I 2 = 66%). Similar results were observed in the sensitivity analysis. Pooled OR of aspirin frequency subgroup analysis for less than or equal to 2 times per week was 0.82 (95%CI = 0.40-1.72; I 2 = 0%), for at least 3 times per week to daily was 0.25 (95%CI = 0.12-053; I 2 = 0%), for daily was 0.59 (95%CI: 0.47-0.74; I 2 = 0%), and for unknown was 0.26 (95%CI: 0.15-0.45; I 2 = 51%)., Conclusions: The results of this systematic review and meta-analysis indicates a beneficial effect of aspirin on growth and rupture of UIAs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Endothelial dysfunction triggers early pathological changes in artery, leading to the formation of intracranial aneurysm (ICA). Increase in plasma homocysteine (Hcy) impairs endothelium and endothelial progenitor cells (EPCs) are critical in repairing damaged endothelium. The aim of this study was to assess the impact of simvastatin on ICA formation in rats with hyperhomocysteinemia (HHcy)., Methods: ICAs were induced in Male Sprague-Dawley rats after surgical induction in the presence of HHcy induced by a high L-methionine diet with or without oral simvastatin treatment. The size and media thickness of ICAs were evaluated 2 months after aneurysm induction. EPCs and serum vascular endothelial grow factor (VEGF) were measured be flow cytometry and ELISA respectively. Plasma Hcy levels and expression of VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysmal walls were examined and correlated with ICA formation., Results: HHcy accelerates ICA formation and rats treated with simvastatin exhibited a significant increase in media thickness and a reduction in aneurysmal size. Simvastatin increased levels of circulating EPCs and decreased iNOS, MMP-2, MMP-9 and VEGF mRNA levels, while increased eNOS mRNA in aneurysmal tissue., Conclusion: In a rat model, HHcy reduces circulating EPCs and accelerates ICA formation. Simvastatin treatment increases circulating EPCs and inhabits the formation of ICA. We have shown a close association among circulating EPCs, biochemical markers related to vascular remodeling and the formation of ICA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state., Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice., Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis., Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Background and Purpose: Establishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for preventive treatment of IA rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials., Materials and Methods: We performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019 at our institution. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. We also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status., Results: In total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38-0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30-0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48-0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71-6.13)., Conclusions: The present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: The role of aspirin in unruptured intracranial aneurysm (UIA) growth remains largely unknown. We aim to identify whether aspirin is associated with a lower rate of UIA growth in patients with UIA <7 mm., Methods: This prospective cohort study consecutively enrolled patients with UIAs <7 mm with ischemic cerebrovascular disease between January 2016 and December 2019. Baseline and follow-up patient information, including the use of aspirin and blood pressure level, were recorded. Patients were considered aspirin users if they took aspirin, including standard- and low-dose aspirin, ≥3× per week. The primary end point was aneurysm growth in any direction or an indisputable change in aneurysm shape., Results: Among the 315 enrolled patients, 272 patients (86.3%) underwent imaging examinations during follow-up (mean follow-up time, 19.6±12.7 months). A total of 113 patients were continuously treated with aspirin. UIA growth occurred in 31 (11.4%) patients. In the multivariate Cox analysis, specific aneurysm locations (anterior communicating artery, posterior communicating artery, or middle cerebral artery; hazard ratio, 2.89 [95% CI, 1.22-6.88]; P =0.016) and a UIA size of 5 to <7 mm (hazard ratio, 7.61 [95% CI, 3.02-19.22]; P <0.001) were associated with a high risk of UIA growth, whereas aspirin and well-controlled blood pressure were associated with a low risk of UIA growth (hazard ratio, 0.29 [95% CI, 0.11-0.77]; P =0.013 and hazard ratio, 0.25 [95% CI, 0.10-0.66]; P =0.005, respectively). The cumulative annual growth rates were as high as 40.0 and 53.3 per 100 person-years in the high-risk patients (>1 risk factor) with and without aspirin, respectively., Conclusions: Aspirin therapy and well-controlled blood pressure are associated with a low risk of UIA growth; the incidence of UIA growth in high-risk patients in the first year is high, warranting intensive surveillance in this patient group. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02846259.

Objective: Women have been shown to have a higher risk of cerebral aneurysm formation, growth, and rupture than men. The authors present a review of the recently published neurosurgical literature that studies the role of pregnancy and female sex steroids, to provide a conceptual framework with which to understand the various risk factors associated with cerebral aneurysms in women at different stages in their lives., Methods: The PubMed database was searched for "("intracranial" OR "cerebral") AND "aneurysm" AND ("pregnancy" OR "estrogen" OR "progesterone")" between January 1980 and February 2019. A total of 392 articles were initially identified, and after applying inclusion and exclusion criteria, 20 papers were selected for review and analysis. These papers were then divided into two categories: 1) epidemiological studies about the formation, growth, rupture, and management of cerebral aneurysms in pregnancy; and 2) investigations on female sex steroids and cerebral aneurysms (animal studies and epidemiological studies)., Results: The 20 articles presented in this study include 7 epidemiological articles on pregnancy and cerebral aneurysms, 3 articles reporting case series of cerebral aneurysms treated by endovascular therapies in pregnancy, 3 epidemiological articles reporting the relationship between female sex steroids and cerebral aneurysms through retrospective case-control studies, and 7 experimental studies using animal and/or cell models to understand the relationship between female sex steroids and cerebral aneurysms. The studies in this review report similar risk of aneurysm rupture in pregnant women compared to the general population. Most ruptured aneurysms in pregnancy occur during the 3rd trimester, and most pregnant women who present with cerebral aneurysm have caesarean section deliveries. Endovascular treatment of cerebral aneurysms in pregnancy is shown to provide a new and safe form of therapy for these cases. Epidemiological studies of postmenopausal women show that estrogen hormone therapy and later age at menopause are associated with a lower risk of cerebral aneurysm than in matched controls. Experimental studies in animal models corroborate this epidemiological finding; estrogen deficiency causes endothelial dysfunction and inflammation, which may predispose to the formation and rupture of cerebral aneurysms, while exogenous estrogen treatment in this population may lower this risk., Conclusions: The aim of this work is to equip the neurosurgical and obstetrical/gynecological readership with the tools to better understand, critique, and apply findings from research on sex differences in cerebral aneurysms.

BACKGROUND Endothelial injury is the early pathological change of cerebral aneurysm (CA) formation. In addition to its lipid-lowering activity, atorvastatin (ATR) also reportedly promotes vascular repair via mobilizing endothelial progenitor cells (EPC). Here, we investigated the influence of ATR on vascular worsening after CA induction in rats. MATERIAL AND METHODS Adult male Sprague-Dawley rats were randomly assigned to 3 groups: a control (CTR) group, a CA group, and a CA+ATR treatment group. Circulating EPC level and hematological and lipid profiles were measured 3 months after CA induction. Verhoeff-Van Gieson staining and transmission electron microscopy were performed to assess pathological changes in the artery wall. RT-PCR was also performed to evaluate the expression of inflammation-related genes in the aneurysmal wall. RESULTS ATR significantly restored the impaired level of circulating EPC without changing hematological and lipid profiles 3 months after CA induction. ATR markedly inhibited endothelial injury, media thinning, and CA enlargement, accompanied by reduced vascular inflammation. CONCLUSIONS Our preliminary results demonstrate that the mobilization of EPC and improvement of endothelial function by ATR contribute to the prevention of cerebral aneurysm. Further studies are warranted to investigate the detailed mechanism.

Cerebral aneurysms (CAs) are dilations of the wall of an artery in the brain filled with blood. The prevalence of unrupted CA in general population is estimated at approximately 3%. Ruptured aneurysms are the cause of 85% of spontaneous subarachnoid hemorrhage (SAH) cases. The formation of cerebral aneurysms results from various factors, including chronic inflammation, hemodynamic stress and vascular wall remodeling. Reactive oxygen species may induce the endothelial dysfunction possibly through the activation of Nuclear Factor Kappa-B, which is a key regulator of the proinflammatory genes. Hypertension may additionally increase the hemodynamic stress and activate the local renin-angiotensin system. The aim of this review was to assess the role of selected diet-related factors in the formation and rupture of cerebral aneurysms. It appears that inadequate intake of dietary antioxidants, hyperhomocysteinemia, hypertension (including incidental elevated blood pressure) and alcohol consumption may increase the risk of intracranial aneurysms. Individuals at high risk of CA formation and/or rupture should consume adequate amounts of antioxidant vitamins (vitamin C, vitamin E and carotenoids), B vitamins (vitamin B6, vitamin B12 and folate), flavonoids and n-3 fatty acids, limit alcohol and caffeine consumption and regularly control their blood pressure. Vegetables, fruits, grains, pulses, nuts and fish, as well as herbs, spices and tea, should be the major components of the daily diet. Due to the synergistic effect of various dietary components on health, Mediterranean diet or Dietary Approach to Stop Hypertension (DASH) diet, as they meet abovementioned requirements and have high anti-inflammatory potential, are thus recommended for the prevention of cerebral aneurysm formation and rupture.

Optimizing outcomes after aneurysmal subarachnoid hemorrhage remains a challenge for neurosurgeons and neurointensivists alike. Although we have learned a lot about the pathophysiology of this disease, many clinical questions are still unanswered. In this review, the authors discuss some of these questions, including the current diagnostic value of lumbar puncture in patients with negative computed tomography scans, the treatment value of blood pressure reduction and antifibrinolytics for prevention of early rebleeding, the indication for antiseizure medications, the optimal management of hydrocephalus and intracranial pressure, the role of clipping, and the options for diagnosis and treatment of delayed cerebral ischemia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture., Approach and Results: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox -/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox -/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs., Conclusions: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies., (© 2018 American Heart Association, Inc.)

Aims and Objectives: To examine the roles of two modifiable factors-health-promoting behaviours and perceived stress-in predicting aneurysmal rupture., Background: Unruptured intracranial aneurysm detection produces significant stress and anxiety in patients because of the risk of rupture. Compared to nonmodifiable risk factors for rupture such as age, gender and aneurysm size/location, less attention has been given to modifiable risk factors. Two modifiable factors, health-promoting behaviours and perceived stress, have hardly been examined as potential predictors of rupture., Design: This study used a cross-sectional design., Methods: We assessed 155 patients with intracranial aneurysms-that is, subarachnoid haemorrhage (n = 77) or unruptured intracranial aneurysm (n = 78)-to examine (i) baseline characteristics (patient and aneurysmal factors), (ii) health-related factors (lifestyle habits and health-promoting behaviour) and (iii) perceived stress levels (psychological stress and physical stress). Patient records provided medical histories and aneurysmal factors; other data were collected using a structured questionnaire addressing lifestyle habits, the Health-Promoting Lifestyle Profile-II to measure health-promoting behaviour and the Perceived Stress Questionnaire to measure perceived-psychological stress and perceived-physical stress levels., Results: Bivariate analysis indicated that aneurysm rupture risk was associated with female gender, aneurysm size/location, defecation frequency, hyperlipidaemia, sedentary time, low Health-Promoting Lifestyle Profile-II mean scores and high perceived-psychological stress scores. After adjusting for known risk factors, the mean Health-Promoting Lifestyle Profile-II and perceived-psychological stress scores remained robust predictors of rupture. Furthermore, known risk factors combined with these scores had greater predictive power than known risk factors alone., Conclusion: Health-promoting behaviour and psychological stress are promising modifiable factors for reducing risk of aneurysmal rupture., Relevance to Clinical Practice: Our findings may stimulate greater understanding of mechanisms underlying aneurysmal rupture and suggest practical strategies for nurses to employ in optimising conservative management of rupture risk by teaching patients how to modify their risk. Both health-promoting behaviour and perceived stress should be addressed when designing preventive nursing interventions for patients with unruptured intracranial aneurysm., (© 2017 John Wiley & Sons Ltd.)

Background: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model., Methods and Results: IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro., Conclusions: A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Activation of mast cells participates in the chronic inflammation associated with cerebral arteries in intracranial aneurysm formation and rupture. Several studies have shown that the anti-inflammatory effect of mesenchymal stem cells (MSCs) is beneficial for the treatment of aneurysms. However, some long-term safety concerns exist regarding stem cell-based therapy for clinical use. We investigated the therapeutic potential of microvesicles (MVs) derived from human MSCs, anuclear membrane bound fragments with reparative properties, in preventing the rupture of intracranial aneurysm in mice, particularly in the effect of MVs on mast cell activation. Intracranial aneurysm was induced in C57BL/6 mice by the combination of systemic hypertension and intrathecal elastase injection. Intravenous administration of MSC-derived MVs on day 6 and day 9 after aneurysm induction significantly reduced the aneurysmal rupture rate, which was associated with reduced number of activated mast cells in the brain. A23187-induced activation of both primary cultures of murine mast cells and a human mast cell line, LAD2, was suppressed by MVs treatment, leading to a decrease in cytokine release and tryptase and chymase activities. Upregulation of prostaglandin E2 (PGE2) production and E-prostanoid 4 (EP4) receptor expression were also observed on mast cells with MVs treatment. Administration of an EP4 antagonist with the MVs eliminated the protective effect of MVs against the aneurysmal rupture in vivo. Human MSC-derived MVs prevented the rupture of intracranial aneurysm, in part due to their anti-inflammatory effect on mast cells, which was mediated by PGE2 production and EP4 activation. Stem Cells 2016;34:2943-2955., Competing Interests: of Potential Conflicts of Interest None., (© 2016 AlphaMed Press.)

Most of cerebral aneurysms (CAs) are incidentally discovered without any neurological symptoms and the risk of rupture of CAs is relatively higher in Japanese population. The goal of treatments for patients with CAs is complete exclusion of the aneurysmal rupture risk for their lives. Since two currently available major treatments, microsurgical clipping and endovascular coiling, have inherent incompleteness to achieve cure of CAs with some considerable treatment risks, and there is no effective surgical or medical intervention to inhibit the formation of CAs in patients with ruptured and unruptured CAs, new treatment strategies with lower risk and higher efficacy should be developed to prevent the formation, growth, and rupture of CAs. Preemptive medicine for CAs should be designed to prevent or delay the onset of symptoms from CAs found in an asymptomatic state or inhibit the de novo formation of CAs, but we have no definite methods to distinguish rupture-prone aneurysms from rupture-resistant ones. Recent advancements in the research of CAs have provided us with some clues, and one of the new treatment strategies for CAs will be developed based on the findings that several inflammatory pathways may be involved in the formation, growth, and rupture of CAs. Preemptive medicine for CAs will be established with specific biomarkers and imaging modalities which can sensor the development of CAs., Competing Interests: The authors, who are members of the Japan Neurosurgical Society, have registered the online Self-reported COI Disclosure Statement Forms. T. A. is supported by the coordination fund from Japan Science and Technology Agency (JST) and Astellas Pharma Inc., Tokyo, Japan. K. N. has no conflicts of interest.

We previously found that aspirin decreases the risk of cerebral aneurysm rupture in humans. We aim to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin and confirm these observations in a mouse model of cerebral aneurysm. A nested case-control analysis from the International Study of Unruptured Intracranial Aneurysms was performed to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin. A series of experiments were subsequently performed in a mouse model of cerebral aneurysms. Aneurysms were induced with hypertension and elastase injection into mice basal cisterns. We found that aspirin decreased the risk of aneurysm rupture more significantly in men than in women in the International Study of Unruptured Intracranial Aneurysms. In mice, aspirin and cyclooxygenase-2 inhibitor did not affect cerebral aneurysm formation but significantly decreased the incidence of rupture. The incidence of rupture was significantly lower in male versus female mice on aspirin. Gene expression analysis from cerebral arteries showed higher 15-hydroxyprostaglandin dehydrogenase levels in male mice. The rate of cerebral aneurysm rupture was similar in male mice receiving aspirin and 15-hydroxyprostaglandin dehydrogenase inhibitor compared with females receiving aspirin and 15-hydroxyprostaglandin dehydrogenase agonist, signaling a reversal of the sex-differential response to aspirin. Aspirin decreases aneurysm rupture in human and mice, in part through cyclooxygenase-2 pathways. Evidence from animal and human studies suggests a consistent differential effect by sex. 15-Hydroxyprostaglandin dehydrogenase activation in females reduces the incidence of rupture and eliminates the sex-differential response to aspirin., (© 2016 American Heart Association, Inc.)

Recently multiple studies demonstrated the advantage of mechanical thrombectomy after thrombotic stroke onset in proximal intracranial arteries over i.v. thrombolysis. In experienced stroke centers, recanalization rates of up to 90% can be achieved. This article is dealing with various pitfalls which could face the interventionalist during endovascular therapy and can complicate or even make the procedure impossible.

Background and Purpose: Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation., Methods: Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm., Results: A PPARγ agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARγ. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate., Conclusions: Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture., (© 2015 American Heart Association, Inc.)

Aim: To address risk of first or recurrent cerebral haemorrhage in children with sickle-cell disease (SCD) who are being managed with modern stroke prevention strategies., Method: A systematically followed SCD paediatric cohort was retrospectively studied over a 9-year period. Haemorrhagic risk was defined as intracranial haemorrhage occurrence or intracranial aneurysm diagnosis during the study period. Ischaemic risk was defined as cerebrovascular ischaemic event occurrence or transcranial Doppler/magnetic resonance imaging hallmarks of ischaemic risk finding during the study period., Results: Among the 251 patients in the cohort, 36 patients were included in the ischaemic group. Seven patients were included in the haemorrhagic group, of which five also met the criteria for the ischaemic group. Age at first haemorrhagic symptom/hallmark of risk was older (10.4 vs 6.2 years old, p=0.036). Nine intracranial saccular aneurysms were found, mostly on the posterior circulation. Two patients had endovascular embolization., Interpretation: The ratio of ischaemic to haemorrhagic risk was not modified with modern management compared with historical series. Intracranial aneurysm in children with SCD had specific characteristics, close to intracranial aneurysms described in adults with SCD. Data favoured concurrent development of intracranial SCD-associated anterior stenosis and posterior dilation, suggesting common pathophysiology and management strategies., (© 2014 Mac Keith Press.)

Objective: To substantiate the reasonability and duration of angiographic follow-up of patients operated on for cerebral aneurysms to rule out de novo aneurysm formation., Material and Methods: The results of angiographic examination (cerebral angiography and SCT angiography) of 43 patients with cerebral aneurysms operated on at the Burdenko Neurosurgical Institute in 1995-2012 are analyzed. The follow-up duration varied from 1 to 14 years after surgery (mean duration, 5 years). Patients' age ranged from 14 to 56 years., Results: Control angiographic examination showed that de novo aneurysms were formed in 7 (16.2%) patients. A total of 8 de novo aneurysms were detected (in one case there were two aneurysms formed). All aneurysms, both the previously operated and the de novo ones, were located in the anterior part of the circle of Willis. De novo aneurysms were clipped in 5 cases; the cavity of the de novo aneurysm was occluded with spirals in one case. One patient with a small aneurysm of the middle cerebral artery refused surgery. Neither lethal nor unfavorable outcomes were recorded., Conclusions: The patient groups with the high risk of de novo aneurysm formation are as follows: 1) young smokers with hypertension; 2) patients who developed clinical signs of the disease when being young; 3) patients subjected to proximal exclusion of the main artery; and 4) patients with multiple and familial forms of the pathology. Dynamic angiographic follow-up (SCT angiography or magnetic resonance angiography) for 1-3 years is recommended for these patients.

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., (© 2015 S. Karger AG, Basel.)

Clinical observations suggest that postmenopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks of aneurysmal growth and subarachnoid hemorrhage in postmenopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. We used an intracranial aneurysm mouse model that recapitulates the key features of human intracranial aneurysms, including spontaneous rupture. Ten- to 12-week-old ovariectomized female mice received treatment with estrogen, nonselective estrogen receptor antagonist, estrogen receptor-α agonist, or estrogen receptor-β agonist starting 6 days after aneurysm induction so that the treatments affected the development of aneurysmal rupture without affecting aneurysmal formation. Estrogen significantly reduced the incidence of ruptured aneurysms and rupture rates in ovariectomized mice. Nonselective estrogen receptor antagonist abolished the protective effect of estrogen. Although estrogen receptor-α agonist did not affect the incidence of ruptured aneurysms or rupture rates, estrogen receptor-β agonist prevented aneurysmal rupture without affecting the formation of aneurysms. The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen seemed to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.

Background: Individuals with two or more first-degree relatives who have had aneurysmal subarachnoid haemorrhage (aSAH) have an increased risk of aneurysms and aSAH. We investigated the yield of long-term serial screening for intracranial aneurysms in these individuals., Methods: In a cohort study, we reviewed the results of screening of individuals with a positive family history of aSAH (two or more first-degree relatives who had had aSAH or unruptured intracranial aneurysms) done at the University Medical Centre Utrecht (Utrecht, Netherlands) between April 1, 1993, and April 1, 2013. Magnetic resonance angiography or CT angiography was done from age 16-18 years to 65-70 years. After a negative screen, we advised individuals to contact us after 5 years, but did not actively call them for repeated screening. We recorded familial history of ruptured and unruptured intracranial aneurysms, smoking history, hypertension, previous aneurysms, screening dates, and screening results. We identified risk factors for positive initial and follow-up screens with univariable and multivariable regression analysis., Findings: We identified aneurysms in 51 (11%, 95% CI 9-14) of 458 individuals at first screening, in 21 (8%, 5-12) of 261 at second screening, in seven (5%, 2-11) of 128 at third screening, and three (5%, 1-14) of 63 at fourth screening. Five (3%, 95% CI 1-6) of 188 individuals without a history of aneurysms and with two negative screens had a de-novo aneurysm in a follow-up screen. Smoking (odds ratio 2·7, 95% CI 1·2-5·9), history of previous aneurysms (3·9, 1·2-12·7), and familial history of aneurysms (3·5, 1·6-8·1) were significant risk factors for aneurysms at first screening in the multivariable analysis. History of previous aneurysms was the only significant risk factor for aneurysms at follow-up screening (hazard ratio 4·5, 1·1-18·7). Aneurysms were identified in six (5%, 95% CI 2-10) of 129 individuals who were screened before age 30 years. One patient developed a de-novo aneurysm that ruptured 3 years after the last negative screen., Interpretation: In individuals with a family history of aSAH, the yield of long-term screening is substantial even after more than 10 years of follow-up and two initial negative screens. We advocate long-term serial screening in these individuals, although the risk of aSAH within screening intervals is not eliminated., Funding: The Dutch Heart Foundation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Neurosurgery often requires skull immobilization with a Mayfield clamp, which often causes brief intense nociceptive stimulation, hypertension and tachycardia. Blunting this response may help prevent increased intracranial pressure, cerebral aneurysm or vascular malformation rupture, and/or myocardial stress. While various interventions have been described to blunt this response, no reports have compared administration of a propofol versus a remifentanil bolus., Methods: We retrospectively analyzed the hemodynamic response to Mayfield placement in over 800 patients who received a prior propofol or remifentanil bolus from 2004 to 2010., Results: Patients who received remifentanil experienced a 55% smaller increase in heart rate (p < 0.0001) and a 40% smaller increase in systolic blood pressure (p < 0.0001) after Mayfield placement than patients who received propofol. These data were retrospectively obtained from patients who were not randomized to receive remifentanil versus propofol, and hence these data could be subject to possible confounding. Nonetheless, these differences remained significant after multivariate analysis for possible confounding variables., Conclusions: Thus, a remifentanil bolus is more effective than a propofol bolus in blunting hemodynamic responses to Mayfield placement, and possibly for other short, intense nociceptive stimuli.

Arteriovenous malformation (AVM)-related aneurysms have been described in the literature. Their behavior varies based on their location in relation to and the activity of the shunting through the index AVM. The intuitive expectation supported by numerous reports is that these aneurysms should regress if the AVM is excluded from the circulation. We describe a case of 46-year-old man who presented with a posterior fossa AVM with an aneurysm on the posterior inferior cerebellar artery feeding the AVM. The nidus of the AVM was successfully excluded by glue embolization, with initial regression of the PICA aneurysm on serial imaging. Five years after the endovascular treatment, the aneurysm showed significant re-growth necessitating endovascular coiling. This case presents the re-growth of an AVM-related aneurysm and emphasizes the importance of long-term follow-up of such aneurysms even if the AVM is completely excluded.

A 48-year-old woman with no previous neurological diseases was transferred to our hospital because of sudden-onset unconsciousness. On arrival, she showed consciousness disturbance (E1V1M3 on the Glasgow Coma Scale), tetraplegia, right conjugate deviation and bilateral pathological reflexes. These symptoms resulted in a NIH stroke scale score of 32. Brain diffusion-weighted MR imaging (DWI) showed multiple hyper-intense lesions, and MR angiography revealed occlusions of the basilar artery (BA) and superior branch of the right middle cerebral artery (MCA). Transthoracic echocardiography disclosed a 51 × 24 mm myxoma in the left atrium. These findings led to diagnosis of acute ischemic stroke due to embolization from cardiac myxoma. Thrombolytic therapy with intravenous tissue plasminogen activator (IV tPA) was started 120 min after onset because there were no contraindications for this treatment. However, the symptoms did not resolve, and thus endovascular therapy was performed immediately after IV tPA. Angiography of the left vertebral artery initially showed BA occlusion, but a repeated angiogram resulted in spontaneous recanalization of the BA. However, the left posterior cerebral artery remained occluded by a residual embolus. Subsequently, occlusion found in the superior branch of the right MCA was treated by intra-arterial local thrombolysis using urokinase and thrombectomy with a foreign body retrieval device, but the MCA remained occluded. DWI after endovascular therapy showed new hyper-intense lesions in the bilateral medial thalamus and left occipital cortex. Clinically, neurological status did not improve, with a score of 5 on the modified Rankin Scale. IV tPA can be used for stroke due to cardiac myxoma, but development of brain aneurysms and metastases caused by myxoma is a concern. Given the difficulty of predicting an embolus composite from a thrombus or tumor particle, aspiration thrombectomy may be safer and more effective for stroke due to cardiac myxoma to avoid delayed formation of brain aneurysms and metastases.

Summary: Angiographic recurrence following endovascular therapy is an indirect measure of the potential for hemorrhage. Because patients and physicians consider recurrence to be a suboptimal outcome with some chance of future hemorrhage, much effort has been expended to reduce the incidence of recurrence. The literature regarding aneurysm recurrence following endovascular therapy, spanning 2 decades, is extensive. We will review and summarize the effort to reduce recurrence following endovascular treatment of cerebral aneurysms.

Intracranial aneurysms (IA) are a relatively frequent vascular abnormality. The prevailing opinion is that cerebral aneurysmal disease is related to hemodynamic and genetic factors, associated with structural weakness in the arterial wall which was acquired by a specific, often unknown, event. Possibly the trigger moment of aneurysm formation may depend on the dynamic arterial growth, which is closely related to aging/atherosclerosis. In most individuals, an endovascular/microsurgical approach is possible in order to obliterate the IA. However, in a number of patients with an unruptured IA (UIA), the neurosurgeon's decision is to just "sit back, observe, and wait", based on the favorable natural history of some of the UIAs. Furthermore, some individuals need to be kept under close observation since they have a higher chance of developing IA, especially those with at least two affected first-degree relatives with an IA, subjects with polycystic kidney disease, and patients who have undergone an aneurysm intervention. In these examples prophylactic strategies should be adopted, if it is at all possible. The main question is deciding the best option of clinical treatment for these cases, when surgical approach is contraindicated, or for those subjects who are more prone to develop an IA. In the present article, we hypothetically suggest a pharmacologic form of treatment with statins, beta-adrenergic blocker agents, and/or angiotensin-converting-enzyme inhibitor/angiotensin II receptor blockers to inhibit or slow down IA formation, taking into consideration some pathophysiological aspects related to aneurysmal development, such as: hemodynamic stress, arterial wall inflammation, nitric oxide formation, and atheromatous disease.

Incorrect implantation of a ventricular pacemaker (PM) lead into the left ventricle (LV) is a known problem associated with permanent pacing. The optimal management of such cases identified late has not been clearly established. Generally acceptable management options are: open-chest cardiac surgery using cardio-pulmonary bypass, chronic anticoagulation and antiplatelet-drugs therapy. Rarely, the problem is solved by percutaneous LV lead extraction. We present a case of a patient with DDD pacing and ventricular lead implanted incorrectly into the LV apex region via an atrial septal defect eight years ago. Chronic PM pocket infection developed after replacement of the device. Both leads were extracted percutaneously, and the embolic protection system (Filter-Wire EZ, Boston Scientific) was used to reduce cerebral circulation embolism. The hardest connective tissue adhesions affecting the lead and the anodal ring were found in the LV. Less dense surrounding fibrous tissue around the lead was present at all levels of the venous course of the lead and in the right atrium. Very small fragments of apparently connective tissue remnants were found in cerebral circulation protection filters, and had been removed after the procedure. We conclude that old, permanently implanted LV leads may be extracted percutaneously, especially when there is an increased risk of cardiac surgery, or where the patient's consent for surgical treatment is lacking. In order to perform the procedure it is recommended to establish a cerebral protection system and intraoperative transoesophageal echocardiography which are mandatory for successful lead removal.

Objective: Robust guidelines exist for the treatment of carotid stenosis and intracranial aneurysms independently, however, the management of tandem carotid stenosis and intracranial aneurysms remains uncertain. Although the prevalence of tandem pathologies is small (1.9%-3.2%), treating carotid stenosis can alter intracranial hemodynamics potentially predisposing to aneurysm rupture. In this review, our aim was to assess the safety of intervention in this cohort, by analyzing outcomes from the published literature., Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to conduct the review. Articles from 1947 to 2012 were searched using EMBASE Classic and EMBASE (November, 1947 -March, 2012) and Ovid MEDLINE(R) In-Process and other NonIndexed Citations and Ovid MEDLINE(R) on Ovid SP, http://ClinicalTrials.gov, http://controlled-trials.com and the Cochrane review database using a predefined search strategy., Results: One hundred forty-one patients from 27 articles were included. Interventions ranged from single (n=104, 74%), staged (n=26, 18%) to simultaneous procedures (n=11, 8%). The largest cohort of patients was treated by carotid endarterectomy alone (n=92, 66%). The majority of patients presented with a symptomatic carotid stenosis and an asymptomatic ipsilateral intracranial aneurysm (n=70, 50%). Five subarachnoid hemorrhages occurred (4% [5/140], three within 30 days of the procedure and two thereafter) of which two were fatal. All five occurred in patients who underwent carotid endarterectomy as a single procedure (5%). Two of the five patients presented with ruptured posterior communicating artery aneurysms., Conclusions: Published reports of perioperative aneurysm rupture are rare in individuals with tandem carotid stenosis and intracranial aneurysms. This is the first analysis of all published cases. However, it is limited by the small number of studies and the possible underreporting due to publication bias and underdiagnosis where angiography was not performed. Although we report a low incidence of subarachnoid hemorrhage, analysis of registry data with a larger cohort is warranted to confirm these findings., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

The incidence of cerebral aneurysms is higher in women than in men, especially postmenopause. Although hypertension is thought to be associated with a high incidence of stroke, not all patients with unruptured cerebral aneurysms are hypertensive. The possibility of water-free Na(+) storage associated with hypertension has been raised. However, whether the increase in the body Na(+)/water ratio that characterizes water-free Na(+) accumulation is associated with the formation of cerebral aneurysms remains obscure. To examine this relationship, Sprague-Dawley female rats subjected to carotid artery ligation were divided into 3 groups: a high-salt diet group (HSD) without and another with bilateral oophorectomy (HSD/OVX) and a third group that underwent additional renal artery ligation (HSD/OVX/RL). Compared with rats receiving a normal diet (shams), water retention was increased in HSD rats but not in HSD/OVX rats. Interestingly, compared with HSD rats, the incidence of cerebral aneurysms and the body Na(+)/water ratio were significantly higher in HSD/OVX and HSD/OVX/RL rats, independent of hypertension. In their aneurysmal wall, ATP1α2, a subtype of Na(+)/K(+)-ATPase, was downregulated, whereas inflammatory-related molecules were upregulated. Treatment with low-dose olmesartan that did not affect the blood pressure in hypertensive HSD/OVX/RL rats reduced the rate of cerebral aneurysm formation, body Na(+) retention, and the Na(+)/water ratio and upregulated ATP1α2. These results suggest that the increase in the Na(+)/water ratio and a reduction in ATP1α2 may be associated with cerebral aneurysm formation. We provide the new insight that the management of water-free Na(+) is important to prevent their development.

Object: Recent studies in rats have demonstrated that statins may have an inhibitory effect on intracranial aneurysm (IA) development. The purpose of this study was to assess whether long-term statin use is associated with a reduced risk of IA formation in humans., Methods: This was a single-center case-control study that included consecutive patients admitted to the authors' institution between January 1, 2005, and December 31, 2008. A case was defined as a patient with a cerebral angiography-confirmed diagnosis of IA. Three controls were matched to each case based on age, sex, and index year of hospital admission. The primary exposure of interest was cumulative statin use. Conditional logistic regression was used to assess the relationship between statin intake and incidence of IA., Results: In total, 1200 patients were included in the study. No overall association was found between statin use and incidence of IA formation (OR 1.08, 95% CI 0.69-1.69), nor when dichotomized into hydrophilic and lipophilic user, or between short (≤ 12-month) and long (≥ 36-month) duration of intake. Hypertension and smoking significantly increased the risk of IA development (OR 4.02, 95% CI 2.49-6.45, and OR 1.67, 95% CI 1.02-2.72, respectively)., Conclusions: In contrast to recent experimental reports of the association between statins and a reduction of IA formation, the authors' findings suggest that in humans statins may have no significant beneficial effect on IA suppression.

Background: Cerebral aneurysms (CAs) have a high prevalence in the general population and cause lethal subarachnoid hemorrhage. We recently demonstrated that chronic inflammation is an underlying pathogenesis of CA. However, we identified the negative involvement of angiotensin receptor signaling in the pathogenesis of CA., Objective: To elucidate the involvement of the renin-angiotensin system (RAS) by assessing the expression and activity of angiotensin-converting enzyme (ACE), a key enzyme of RAS, during CA formation and evaluating the effect of imidapril, an ACE inhibitor and a potent inhibitor of matrix metalloproteinase-9 (MMP-9), on CA formation., Methods: Surgically induced CA models of rats were used. Imidapril was given intraperitoneally to rats, and aneurysm size and medial thickness of CAs were examined 1 month after induction. Then, ACE and MMP-9 expression was assessed by immunostaining and Western blot analysis. The MMP-9 activity was evaluated by gelatin zymography, and ACE expression in human CA walls was assessed by immunostaining., Results: Imidapril significantly suppressed the size and medial thinning of induced CAs. The expression and activity of ACE were not induced in CA walls. Furthermore, imidapril treatment did not influence ACE expression and activity, suggesting that the inhibitory effect of imidapril was independent of an inhibition of the RAS. Imidapril inhibited MMP-9 activity upregulated in CA walls. In an in vitro study, imidapril suppressed MMP-9 activity in a dose-dependent manner. In human CA walls, as in the rat model, ACE expression was not upregulated., Conclusion: Angiotensin-converting enzyme is not involved in the pathogenesis of CA formation. Imidapril suppresses CA formation in an ACE-independent and MMP-9-dependent manner.

Background: Concomitant intracranial and visceral artery aneurysms are a rare occurrence. We report the case of a patient who underwent surgical repair of a ruptured intracranial aneurysm but subsequently experienced a ruptured hepatic artery aneurysm in the immediate postoperative period., Methods: A 59-year-old woman presented with a ruptured posterior communicating artery aneurysm and was treated with coil occlusion. On postoperative day 3, she became hypotensive with a rigid abdomen and was found to have a ruptured hepatic artery aneurysm. Rapid transfusion of packed red blood cells was begun, and the patient was taken to the angiography suite where the hepatic artery aneurysm was identified and successfully occluded using detachable coils to prevent further hemorrhage., Results: Recovery was complicated by an ileus and mild pulmonary edema. Over several weeks, neurological status and third nerve paresis improved, with eventual discharge to a subacute rehabilitation center. Subsequent follow-up is notable for recurrence of the intracranial aneurysm, and multiple strictures of right intrahepatic arteries and hepatic ducts. The patient is currently being evaluated for liver transplant, but continues to improve neurologically., Conclusion: Prior to this report, there have only been 2 documented cases of concomitant intracranial and visceral artery aneurysms. These reports serve to remind the clinician that intracranial aneurysms may be only part of a systemic pathology, which should be taken into account when unexpected complications arise postoperatively.

Background and Purpose: Limited data exist to guide patient selection for preventive treatment of unruptured cerebral aneurysms. Cerebral aneurysms have been associated with circle of Willis anomalies but whether this association is also related to aneurysm rupture is not known. The occurrence of cerebral aneurysm rupture when a circle of Willis anomaly was present or absent was compared., Methods: Patients admitted over a 2 year period with a diagnosis of a cerebral aneurysm and an anterior communicating artery (ACoA) or posterior communicating artery (PCoA) aneurysm were included in the analysis. Brain vascular imaging was reviewed for aneurysm size, morphology and presence of circle of Willis anomaly. Relevant medical history and demographics were obtained from the medical records., Results: Of the 113 patients with ACoA or PCoA aneurysms, 85 (75.2%) cases were ruptured. There were 49 (43.4%) PCoA aneurysms and 64 (56.6%) ACoA aneurysms. Mean aneurysm size was 5.65 mm (SD 3.31). A circle of Willis anomaly was identified in 46 (40.7%) of all patients. Circle of Willis anomalies were present in 38 (46.9%) ruptured aneurysm cases and eight (29.6%) unruptured aneurysm cases. Multivariate analysis revealed a higher risk of aneurysm rupture when a circle of Willis anomaly was present (p=0.0245, OR 3.72 (CI 1.18 to 11.66))., Conclusions: This series shows that circle of Willis anomalies are more commonly found in ruptured as opposed to unruptured cerebral aneurysms of the anterior and posterior communicating arteries. The presence of a circle of Willis anomaly may be an important characteristic for selecting patients for preventive aneurysm treatment.

Stroke remains a major cause of death in the US and around the world. Despite major scientific advances in our understanding of stroke pathology, the only FDA-approved drug for ischemic stroke is tissue plasminogen activator (tPA). Moreover, the therapeutic window for tPA is confined to the acute phase of stroke, thereby greatly limiting its benefits to less than 3% of ischemic stroke patients. Many treatment strategies for stroke have targeted the subacute or chronic phase in an effort to abrogate the secondary cell death that ensues after the initial stroke insult. Here, we advance the hypothesis that blood vessel disruption, or aneurysm, in the brain is an exacerbating factor for stroke, especially in the evolution of the penumbra or peri-infarct area. A better understanding of aneurysm, specifically its dynamic onset and juxtaposition to the ischemic brain tissue should facilitate the development of novel strategies for attenuating the secondary cell death associated with stroke. To this end, we discuss the laboratory and clinical evidence implicating aneurysm formation in stroke and also provide insights on how stem cell therapy may prove efficacious in combating aneurysm and stroke.

Background: Evidence regarding the most appropriate management of aneurysm recurrences following coiling consists only of uncontrolled case series and the resulting expert opinions, which range from not following coiled patients at all to performing invasive angiography at regular intervals., Methods: We discuss several current attitudes toward how to manage post-coiling recurrences and outline an approach to finding concrete, practical answers to common clinical questions., Results: Although some maxims and general statements can be reluctantly offered, in the absence of evidence the best approach is to emphasize proper methods in order to one day find reliable answers. These can only come from randomized clinical trials. The multitude of research questions is an added difficulty. A program of necessary trials is proposed and centers are encouraged to work in a collaborative fashion in order to offer best possible care as well as progress., Conclusion: Common clinical questions, including how to follow coiled aneurysm patients, if and when to re-treat, and with which treatment modality, are best addressed with the sound scientific methodology of clinical trials.

Background and Purpose: Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm rupture., Methods: Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case-control study. Cases were subjects who subsequently had a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and multivariable analyses were performed using conditional logistic regression., Results: A trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who used aspirin 3× weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18-0.87); reference group, no use of aspirin), patients in the "< once a month" group had an OR of 0.80 (95% CI, 0.31-2.05), and patients in the "> once a month to 2×/week" group had an OR of 0.87 (95% CI, 0.27-2.81; P=0.025). In multivariable risk factor analyses, patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95% CI, 0.11-0.67; P=0.03) compared with those who never take aspirin., Conclusions: Frequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future investigation in animal models and clinical studies is needed.

The rupture of cerebral aneurysm (CA) and subsequent subarachnoid hemorrhage can cause fatal results. Recent experimental findings have suggested that the mechanism of CA formation is based on chronic inflammation in arterial walls by hemodynamic force. Endothelial nitric oxide synthase (eNOS) protects arterial walls from vascular inflammation by relieving hemodynamic force through nitric oxide (NO) production. Thus, the expression and protective role of eNOS in CA formation have been investigated in this study. In this study, experimental induced rodent CA models by carotid ligation and systemic hypertension were used. The expression of eNOS was examined in rat CA models and revealed that it was decreased at the site of CA formation. Next, CA was induced in eNOS(-/-) mice to clarify the role of eNOS in CA formation. In eNOS(-/-) mice, the incidence of CA formation was similar to that found in wild-type mice. In CA walls of eNOS(-/-) mice, the expression of neuronal nitric oxide synthase (nNOS) was upregulated compared with that in wild-type mice, suggesting the compensatory effect of nNOS. Hence, eNOS(-/-) nNOS(-/-) mice were generated, underwent CA induction and confirmed that eNOS(-/-) nNOS(-/-) mice exhibited an increased incidence of CA formation accompanied by accelerated macrophage infiltration. These results suggested that the deficiency of eNOS could be compensated by nNOS upregulation in cerebral arteries and that the eNOS and nNOS complementarily had the protective role in CA formation. The results of this study will provide us with new insight about the mechanisms of CA formation and the functional redundancy between eNOS and nNOS in cerebral arteries.