Pathogenesis Of Cerebral Aneurysms Research Articles

Role of IL6 induced inflammation in cerebral aneurysm pathogenesis

Role of IL6 induced inflammation in cerebral aneurysm pathogenesis

Reconstructive endovascular treatment of distal cerebral aneurysm associated with cardiac myxoma

Introduction. The etiology and pathogenesis of cerebral aneurysms are diverse. The rare cause of cerebral aneurysms occurrence is cardioembolism in cases of heart tumors, in particular in myxoma. Cardiac myxoma (from Latin muxa, mucus) is the most common (about 50 %) benign tumor of heart. With untimely diagnosis and absence of the disease treatment, embolisms in cerebral vessels may occur with typical symptoms of ischemic stroke as well as in some cases the myxomal aneurysms may develop. There are several theories of their origin. The myxomal aneurysms of cerebral vessels are more common in women and in the vast majority of cases they develop in carotid basins. In a quarter of cases, the disease onsets as intracranial hemorrhage caused by rupture of an oncotic (myxomal) aneurysm, that significantly exceeds the frequency of ruptures (1–3 % per year) in cases of “normal” bifurcation‑hemodynamic intracranial aneurysms. The mortality rate is 3.4 %. The majority (80 %) of ruptures were observed within 2 years after the diagnosis of cardiac myxoma, and in half (48.6 %) of cases clinically significant episodes of embolism were noted. Timely treatment can prevent the hemor rhagic type of course of these aneurysms. Various methods of treatment are described in the literature: different options for surgical eradication as well as the possibilities of chemotherapy and radiation exposure.Aim. To present a case of successful radical reconstructive endovascular treatment of patient with distal cerebral aneurysm associated with cardiac myxoma, combined with presence of multiple cavernous malformations and also to highlight issues of diagnosis, differential diagnosis and existing treatment options for these diseases.Clinical observation. The article presents a clinical observation of multiple aneurysms associated with myxoma of the heart in combination with multiple cavernous angiomas of the brain. The possibility of reconstructive eradication of distal aneurysm after its transformation from fusiform to saccular is demonstrated. The etiology and pathogenesis of occurrence, the nuances of differential diagnosis, possible methods and the algorithm for choosing a method for treating brain aneurysms associated with myxomas are reflected. The patient underwent reconstructive aneurysm shutdown by embolization with microspirals, which became possible due to the anatomical shape that favored this type of treatment. Conversion to destructive intervention was not required. Due to the natural course of the disease, the patient remains at risk of progression of a distal aneurysm in the basin of the same artery, and therefore it will be observed in dynamics.Conclusion. All patients with cardiac myxomas, both before and in dynamics after their removal, are recommended to perform noninvasive visualization of brain vessels for verification of such complication as metastatic (myxomal) aneurysms. The prognosis in most patients with multiple intracranial aneurysms associated with myxoma is favorable and most aneurysms associated with myxoma are stable. However, in cases with progressive or ruptured aneurysms, surgical treatment options should be considered including microsurgical or endovascular eradication. Radiation and chemotherapy methods may have a certain therapeutic value.

Endovascular Biopsy for Detection of Somatic Mosaicism in Human Fusiform Cerebral Aneurysms

Endovascular Biopsy for Detection of Somatic Mosaicism in Human Fusiform Cerebral Aneurysms

Computational Fluid Dynamics for Cerebral Aneurysms in Clinical Settings.

Hemodynamics is thought to play an important role in the pathogenesis of cerebral aneurysms and recent development of computer technology makes it possible to simulate blood flow using high-resolution 3D images within several hours. A lot of studies of computational fluid dynamics (CFD) for cerebral aneurysms were reported; therefore, application of CFD for cerebral aneurysms in clinical settings is reviewed in this article.CFD for cerebral aneurysms using a patient-specific geometry model was first reported in 2003 and it has been revealing that hemodynamics brings a certain contribution to understanding aneurysm pathology, including initiation, growth and rupture. Based on the knowledge of the state-of-the-art techniques, this review treats the decision-making process for using CFD in several clinical settings. We introduce our CFD procedure using digital imaging and communication in medicine (DICOM) datasets of 3D CT angiography or 3D rotational angiography. In addition, we review rupture status, hyperplastic remodeling of aneurysm wall, and recurrence of coiled aneurysms using the hemodynamic parameters such as wall shear stress (WSS), oscillatory shear index (OSI), aneurysmal inflow rate coefficient (AIRC), and residual flow volume (RFV).

Induction of large cerebral aneurysms by intraperitoneal administration of β-aminopropionitrile fumarate in male rats.

It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of β-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). Induction rate in the high-dose groups was significantly higher (P<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs. 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 μm, vs. 12 weeks; 181.7 μm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs. 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

In vivo cerebral aneurysm models

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.

Hemodynamic characteristics associated with cerebral aneurysm formation in patients with carotid occlusion.

The pathogenesis of cerebral aneurysms in patients with internal carotid artery (ICA) occlusion is hypothesized to be hemodynamic. For the first time, the authors quantify the hemodynamic characteristics associated with aneurysm formation in patients with ICA occlusion. Records of patients with unilateral ICA stenosis or occlusion ≥ 90% who underwent hemodynamic assessment before treatment using quantitative MR angiography were retrospectively reviewed. The patients were classified into 2 groups based on the presence or absence of aneurysms. The hemodynamic parameters of flow volume rate, flow velocity, and wall shear stress (WSS) were measured in each vessel supplying collateral flow-bilateral A1 segments and bilateral posterior communicating arteries-and then compared between the groups. A total of 36 patients were included (8 with and 28 without aneurysms). The mean flow (72.3 vs 48.9 ml/min, p = 0.10), flow velocity (21.1 vs 12.7 cm/sec, p = 0.006), and WSS (22.0 vs 12.3 dynes/cm2, p = 0.003) were higher in the A1 segment contralateral to the side of the patent ICA in patients with versus without aneurysms. All de novo or growing aneurysms in our cohort were located on the anterior communicating artery (ACoA) or P1 segment. Flow velocity and WSS are significantly higher across the ACoA in patients who harbor an aneurysm, and de novo or growing aneurysms are often located on collateral vessels. Thus, robust primary collaterals after ICA occlusion may be a contributing factor in cerebral aneurysm formation.

Abstract WMP32: Adaptive and Maladaptive Remodeling in Flow Loaded Rat Cerebral Arteries: Potential Significance to Pathogenesis of Cerebral Aneurysms

Background and purpose: In animal models, flow loading is a necessary and sufficient hemodynamic factor to express the cerebral aneurysm (CA) phenotype. Promotional biological factors may include variant forms of the adaptive response to flow loading. Using a rat model, this study characterizes molecular events that comprise cerebral arterial responses to flow loading and reveals their significance in relation to the CA phenotype. Methods: 32 rats underwent bilateral common carotid artery ligation (BCL) (n=16) or sham surgery (SS)(n=16). Nineteen days later, vertebrobasilar arteries were harvested, histologically examined and analyzed for mRNA and protein expression. Flow (shear) induced changes in mRNA expression, protein expression and histology were determined by comparing BCL to SS rats. Differences between aneurysm-prone (Long Evans, LE) and resistant (Brown Norway, BN) strains were evaluated. Results: Basilar artery medial thickness/luminal diameter ratio was significantly reduced in BCL rats, without significant differences between LE (2.02 fold) and BN (1.94 fold) rats. BCL significantly altered basilar artery expression of mRNA and proteins that modulate wall structure and function but had no effect on blood pressure. Eight genes showed similarly large flow induced expression changes in LE and BN rats (TyrRS, Mfge8, Galnt13, GABRP, Pp1r1a, Dpt_predicted, Cd34_predicted, ApoE). Twenty six shear responsive genes showed significant differences in shear induced expression between LE and BN rats. The Cthrc1, Gsta3, Tgfb3, Ldha, Myo1d, Ermn, PTHrp, Rgs16 and TRCCP genes showed the strongest shear responsive expression, and the largest difference in shear responsive expression between LE and BN rats. Conclusions: Our study reveals specific molecular biological responses involved in flow induced expansive remodeling of cerebral arteries. A group of 9 strongly shear responsive genes showed major differences in flow induced expression between LE and BN rats and are implicated as having important roles in maladaptive remodeling associated with the CA phenotype.

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

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. 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. 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.

Anaesthetic challenges in complicated labour: Unruptured intracranial aneurysm

Intracranial aneurysms are uncommon during pregnancy. Haemodynamic stress during pregnancy is a key factor in the multifactorial pathogenesis of cerebral aneurysm, contributing to the risk of aneurysm formation, progression and rupture. Successful management requires multidisciplinary care; anaesthetists require knowledge of obstetric anaesthesia, neuro-anaesthesia and critical care. The incidence of subarachnoid haemorrhage in pregnancy is 0.01%—0.05%, with a maternal mortality rate of 11% in treated cases and a foetal mortality rate of 5% in treated cases.[1] Definitive treatment involves either open neurosurgical clipping or endovascular therapy, maintaining stable transmural pressure in the aneurysm to prevent rupture. Very few cases have been reported in the literature, and guidelines for the management of intracranial aneurysm during pregnancy and evidence-based recommendations for obstetric anaesthesia in patients with unruptured intracranial aneurysm during labour do not exist. A review of the literature reveals varying results, differing on a case-by-case basis, for the treatment of intracranial aneurysms during pregnancy and labour. Reducing risks associated with intracranial aneurysm must focus on both mother and child. This review encourages the establishment of formal guidelines for an algorithmic approach to manage the intracranial aneurysm during pregnancy and labour.

Expression profile of long noncoding RNAs in human cerebral aneurysms: a microarray analysis.

OBJECTIVE The pathogenesis of cerebral aneurysms (CAs) remains largely unknown. Long noncoding RNAs (lncRNAs) were reported recently to play crucial roles in many physiological and biological processes. Here, the authors compared the gene-expression profiles of CAs and their control arteries to investigate the potential functions of lncRNAs in the formation of CAs. METHODS A prospective case-control study was designed to identify the changes in expression of lncRNAs and mRNAs between 12 saccular CA samples (case group) and 12 paired superficial temporal artery samples (control group). Microarray analysis was performed to investigate the expression of lncRNAs and messenger RNAs (mRNAs), and reverse-transcription quantitative polymerase chain reaction was used to validate the microarray analysis findings. Then, an lncRNA target-prediction program and gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to explore potential lncRNA functions. RESULTS A comparison between the case and control groups revealed that 1518 lncRNAs and 2545 mRNAs were expressed differentially. By using target-prediction program analysis, the authors constructed a complex network consisting of 2786 matched lncRNA-mRNA pairs, in which ine1 mRNA was potentially targeted by one to tens of lncRNAs, and vice versa. The results of further gene ontology and KEGG pathway analyses indicated that lncRNAs were involved mainly in regulating immune/inflammatory processes/pathways and vascular smooth muscle contraction, both of which are known to have crucial pathobiological relevance in terms of CA formation. CONCLUSIONS By comparing CAs with their control arteries, the authors created an expression profile of lncRNAs in CAs and propose here their possible roles in the pathogenesis of CAs. The results of this study provide novel insight into the mechanisms of CA pathogenesis and shed light on developing new therapeutic intervention for CAs in the future.

Abstract 10: Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice in vivo

Background and Purpose: Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. In this study, the role of PPARγ in aneurysm formation and rupture was tested. Methods: Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Results: Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P&lt;0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P&lt;0.05). Conclusions: Endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.

Bacterial DNA findings in ruptured and unruptured intracranial aneurysms

Objective Chronic inflammation has earlier been detected in ruptured intracranial aneurysms. A previous study detected both dental bacterial DNA and bacterial-driven inflammation in ruptured intracranial aneurysm walls. The aim of this study was to compare the presence of oral and pharyngeal bacterial DNA in ruptured and unruptured intracranial aneurysms. The hypothesis was that oral bacterial DNA findings would be more common and the amount of bacterial DNA would be higher in ruptured aneurysm walls than in unruptured aneurysm walls. Materials and methods A total of 70 ruptured (n = 42) and unruptured (n = 28) intracranial aneurysm specimens were obtained perioperatively in aneurysm clipping operations. Aneurysmal sac tissue was analysed using a real-time quantitative polymerase chain reaction to detect bacterial DNA from several oral species. Both histologically non-atherosclerotic healthy vessel wall obtained from cardiac by-pass operations (LITA) and arterial blood samples obtained from each aneurysm patient were used as control samples. Results Bacterial DNA was detected in 49/70 (70%) of the specimens. A total of 29/42 (69%) of the ruptured and 20/28 (71%) of the unruptured aneurysm samples contained bacterial DNA of oral origin. Both ruptured and unruptured aneurysm tissue samples contained significantly more bacterial DNA than the LITA control samples (p-values 0.003 and 0.001, respectively). There was no significant difference in the amount of bacterial DNA between the ruptured and unruptured samples. Conclusion Dental bacterial DNA can be found using a quantitative polymerase chain reaction in both ruptured and unruptured aneurysm walls, suggesting that bacterial DNA plays a role in the pathogenesis of cerebral aneurysms in general, rather than only in ruptured aneurysms.

Serum Levels of Monocyte Chemoattractant Protein-1 Correlate with Poor Clinical Grades in Cerebral Aneurysms.

Ruptured cerebral aneurysms (ICAs) are the most common non-traumatic cause of subarachnoid hemorrhage (SAH) that is associated with life threatening complications such as Vasospasm, Infarction, and Hydrocephalus (HCP). The active participation of macrophage/monocyte-mediated inflammatory response in the pathogenesis of cerebral aneurysm as labeled with Monocyte Chemoattractant Protein-1 (MCP-1) is suggested. To measure the serum level of MCP-1 in ruptured CAs in different time intervals. We measured the serum levels of MCP-1 in SAH patients who had CAs and compared it with that of MCP-1 in two control groups: including patients with SAH without CAs, and the normal population of blood donors. We also measured the MCP-1 levels in patients with CAs one week afterward to evaluate the effect of treatment. Serum level of MCP-1 was measured by a commercial ELISA assay. Mean serum MCP-1 level in patients with SAH and CAs was 188.2168 Pg/ml and 331.3982 Pg/ml in the normal population. There was no statistically significant difference between serum levels of MCP-1 on the first (mean=188.2168 Pg/ml) and 7th days after SAH onset (mean=171.8450 Pg/ml) (p=0.739). Serum level of MCP-1 increased significantly as Glasgow Coma Scale decreased (p=0.078) and Hunt and Hess score increased (p=0.089). Our results did not show an increasing MCP-1 serum level in patients with aneurysmal SAH. There was a relationship between poor clinical grade and MCP-1 levels in patients with CAs. MCP-1 may be a local inflammatory marker for cerebral aneurysms without systemic manifestation.

Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo.

Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. We tested the role of PPARγ in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.

Abstract W P79: Hyperhomocysteinemia Is Associated With Vulnerability of the Cerebral Aneurysmal Wall to Rupture in Ovariectomized Rats

Introduction: The pathogenesis of cerebral aneurysms is multifactorial. Hyperhomocysteinemia (HHcy) leads to endothelial and platelet deterioration and may be associated with the formation of cerebral aneurysms. We tested the hypothesis that HHcy plays a role in the growth and/or rupture of cerebral aneurysms. Methods: We exposed 13-week-old female Sprague-Dawley rats fed a high-salt diet to estrogen deficiency, hemodynamic stress, and induced hypertension. To induce HHcy we added methionine to their drinking water. Results: In methionine induced rats the aneurysms the total rupture rate was higher than in rats not treated with methionine. One fourth of the aneurysms arising at the anterior communicating (Acom) artery, and half of the aneurysms at the posterior half of the circle of Willis, but no aneurysms at the anterior cerebral artery-olfactory artery (ACA-OA) bifurcation ruptured. Immunohistochemically, the infiltration of M1 macrophages was increased at the Acom artery in methionine induced rats and the messenger ribonucleic acid level of matrix metalloproteinase (MMP)-9, the ratio of MMP-9 to tissue inhibitor of metalloprotease (TIMP)2, and the interleukin-6 level were higher at the Acom artery than the ACA-OA bifurcation. Treatment with folic acid abolished the exacerbated effects due to HHcy, suggesting that the propensity of cerebral aneurysms at the Acom artery to rupture is attributable to disequilibrium between the degradation molecules and their inhibitors and to macrophage infiltration. Conclusion: HHcy may be associated with vulnerability of the cerebral aneurysmal wall to rupture in hypertensive ovariectomized rats.

Role of inflammatory responses in the pathogenesis of human cerebral aneurysm.

We aimed to detect expressional profiles of intracellular cell adhesion molecule-1 (ICAM-1), nuclear factor-kappa B (NF-κB), and monocyte chemoattractant protein-1 (MCP-1) in human cerebral aneurysm, in order to investigate the effect of chronic inflammation on the pathogenesis of cerebral aneurysm. Samples from 40 cases of human cerebral aneurysms diagnosed at our hospital were selected along with 20 normal cerebral artery samples. Western blotting and immunohistochemical (IHC) staining were used to reveal expressional profiles of ICAM-1 and NF-κB in the aneurysmal wall of patients and normal cerebral artery tissues. Reverse transcription (RT)-PCR was employed to detect changes in transcript levels of MCP-1 mRNA. Western blotting showed significantly higher expressions of ICAM-1 and NF-κB in patients with cerebral aneurysm compared to the normal group (P < 0.01), which was consistent with IHC staining results. RT-PCR revealed significantly higher MCP-1 transcripts in cerebral aneurysm tissues compared to the normal group (P < 0.01), in addition to a positive relationship between ICAM-1 and NF-κB expression levels. In conclusion, expression levels of ICAM-1, NF-κB, and MCP-1 in patients are significantly elevated, suggesting an enhanced chronic inflammatory response and a significant correlation between inflammatory factors/adhesion molecules and the pathogenesis of cerebral aneurysm.

Relationship between abnormal NOS expression and the pathogenesis of cerebral aneurysm.

We sought to investigate the relationship between abnormal expression of nitric oxide synthase (NOS) and pathogenesis of cerebral aneurysm. Brain tissues were collected from 36 patients with cerebral aneurysm confirmed by computer tomography with angiography or neurosurgical therapy. The control group consisted of 25 patients of similar age who had no vascular diseases, as confirmed by magnetic resonance imaging. Samples of cortical arterioles were collected. The structure of the aneurysms was detected by hematoxylin and eosin staining, and the expression of inducible NOS was detected by immunohistochemistry. NOS expression was significantly higher in the patient group than in the control group (patients: 30/36 strongly positive; control: 0/25 strongly positive; P < 0.05). In conclusion, the pathogenesis underlying cerebral aneurysm may be due to abnormal expression of NOS, degradation of the extracellular matrix, aggravation of a pro-inflammatory reaction, or a deficiency in arterial elasticity layer synthesis. These changes may result in a deficiency in vascular remodeling.

Inflammation mediates the pathogenesis of cerebral aneurysm and becomes therapeutic target

The treatment of cerebral aneurysms (CAs) is of social importance, because poor outcomes result in subarachnoid hemorrhages after rupture. However, there is currently no medical treatment available to prevent the progression and rupture of CAs, which results in a large number of patients without receiving treatment. Recent studies using human samples have revealed the presence of inflammatory responses in lesions and also the possible correlation of inflammation with CA progression or rupture. Furthermore, experimental studies using animal models of CAs have supported the notion from human studies and have clarified the crucial contribution of inflammation to the pathogenesis. In this process, a vicious cycle/positive feedback loop includes the nuclear factor-kappa B (NF-kB) activation, which plays a role in amplifying inflammatory responses to the point of chronicity. In addition, the infiltration of macrophages via NF-kB-mediated monocyte chemotactic protein 1 induction expands inflammation in whole arterial walls and contributes to the degeneration of media by producing various cytokines and tissue-destructive proteases. These series of studies have provided an important insight - antiinflammatory drugs can be therapeutically significant in the treatment of CAs. Indeed, in animal models, some drugs with an antiinflammatory effect effectively suppressed CA formation and progression, which supports this hypothesis. In addition, in human cases, some case-control studies have reported the preventive effect of statins and nonsteroidal antiinflammatory drugs on CA rupture. Therefore, the development of novel medical treatment for preventing the progression and rupture of CAs is needed in the near future. In this literature review, articles were selected by performing a PubMed search using the key words cerebral aneurysm and inflammation.

Arterial stiffness as a risk factor for cerebral aneurysm.

A low ankle-brachial index (ABI) is associated with increased mortality and risk of myocardial infarction and stroke in the general population. Arterial stiffness can be assessed non-invasively by the measurement of brachial-ankle pulse wave velocity (PWV), a simple and reproducible method. Because the importance of ABI and baPWV in the pathogenesis of cerebral aneurysms remains uncertain, we aimed to measure ABI and baPWV in patients with intracranial saccular and dissecting aneurysms to clarify whether these aneurysms are associated with arterial stiffness and atherosclerosis. We prospectively investigated 78 patients diagnosed with intracranial saccular (n = 66) and dissecting (n = 12) aneurysms. The control group consisted of an age- and gender-matched normal population. We compared the clinical characteristics in patients with intracranial saccular aneurysms and controls, those with intracranial dissecting aneurysms and controls, and those who had cerebral aneurysms with and without subarachnoid hemorrhage. We also compared ABI and baPWV among saccular aneurysm locations and evaluated the correlation between the number of saccular aneurysms and ABI and baPWV. Multivariate logistic regression analysis shows that hypertension and higher baPWV (>1400 cm/s) are significantly associated with saccular aneurysms. Simple regression analysis revealed no correlation between the number of saccular aneurysms and ABI (r = -0.064, P = 0.611), and baPWV (r = 0.007, P = 0.956). The baPWV was associated with intracranial saccular aneurysms even after adjustment of hypertension and smoking. Assessment of the baPWV may aid the evaluation of the intracranial saccular aneurysm and the development of strategies for screening patients with intracranial saccular aneurysms.