Progression Of Cerebral Aneurysms Research Articles

A matched-pair case control study identifying hemodynamic predictors of cerebral aneurysm growth using computational fluid dynamics.

Introduction: Initiation and progression of cerebral aneurysms is known to be driven by complex interactions between biological and hemodynamic factors, but the hemodynamic mechanism which drives aneurysm growth is unclear. We employed robust modeling and computational methods, including temporal and spatial convergence studies, to study hemodynamic characteristics of cerebral aneurysms and identify differences in these characteristics between growing and stable aneurysms. Methods: Eleven pairs of growing and non-growing cerebral aneurysms, matched in both size and location, were modeled from MRA and CTA images, then simulated using computational fluid dynamics (CFD). Key hemodynamic characteristics, including wall shear stress (WSS), oscillatory shear index (OSI), and portion of the aneurysm under low shear, were evaluated. Statistical analysis was then performed using paired Wilcoxon rank sum tests. Results: The portion of the aneurysm dome under 70% of the parent artery mean wall shear stress was higher in growing aneurysms than in stable aneurysms and had the highest significance among the tested metrics (p = 0.08). Other metrics of area under low shear had similar levels of significance. Discussion: These results align with previously observed hemodynamic trends in cerebral aneurysms, indicating a promising direction for future study of low shear area and aneurysm growth. We also found that mesh resolution significantly affected simulated WSS in cerebral aneurysms. This establishes that robust computational modeling methods are necessary for high fidelity results. Together, this work demonstrates that complex hemodynamics are at play within cerebral aneurysms, and robust modeling and simulation methods are needed to further study this topic.

Simvastatin suppresses cerebral aneurysm in rats through suppression of release of pro-inflammatory cytokines

Purpose: To investigate the protective effect of simvastatin (SA) against onset of cerebral aneurysmmediated inflammatory cytokine release and subsequent inflammation and degradation of the extracellular matrix of smooth muscle cells.Methods: Cerebral aneurysm was induced in male Wistar rats using elastase injection, and aneurysm growth was monitored for one month following SA treatment. Inhibition of aneurysm growth was determined along with the expression levels of chemokines and pro-inflammatory cytokines, including TNF-α, IL-8, IL-1β, IL-17, IL-6, macrophage chemoattractant protein-1 (MCP-1), and matrix metalloproteinases 2 and 9, using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR).Results: Aneurysm size decreased in rats treated with SA, relative to values obtained for control rats (p < 0.05). The corresponding expressions of inflammatory cytokines and chemokines were also reduced following pre-treatment with SA (p < 0.05). The results indicate a reduction in the aneurysm area in rats pre-treated with SA, when compared to the untreated animals (p < 0.05).Conclusion: SA treatment inhibits the progression of cerebral aneurysms via its protective effect against inflammation, indicating its potential for use in the prevention and treatment of cerebralaneurysms.

MicroRNA-124-5p delays the progression of cerebral aneurysm by regulating FoxO1.

Cerebral aneurysm (CA) is a common brain disease, and the development of cerebral aneurysm is driven by inflammation and hemodynamic stress. MicroRNA (miR)-124-5p is reported to be associated with inflammatory response in brain disease such as cerebral ischemia-reperfusion injury. However, the function and molecular mechanism of miR-124-5p in CA are not clear, thus, the effects of miR-124-5p on inflammatory response in CA were explored. Firstly, the expression of miR-124-5p in the peripheral blood of patients with CA and the control group was detected by reverse transcription-quantitative PCR. Then, the human umbilical vein endothelial cells (HUVECs) were used as an in vitro model system and stimulated with interleukin (IL)-1β to simulate the inflammatory environment of CA, and the expression of miR-124-5p was detected. Next, the effect of miR-124-5p on the migration and invasion of HUVECs was detected using Transwell assays. Meanwhile, the function of miR-124-5p on various inflammatory factors was determined by western blotting and enzyme-linked immunosorbent assay (ELISA). Next, the TargetScan website was used to predict FoxO1 as a target gene of miR-124-5p, and this target association was validated by double luciferase reporter assay and western blotting. Finally, the interaction of miR-124-5p with FoxO1 in CA was measured by Transwell western blotting and ELISA assays. The results showed that the expression level of miR-124-5p in the peripheral blood of patients with CA was lower compared with that of control group, and the miR-124-5p in HUVECs stimulated by IL-1β was less compared with that in normal HUVECs. Besides, miR-124-5p could inhibit the migration and invasion abilities of HUVECs and the release of inflammatory factors. Additionally, the overexpression of miR-124-5p was able to inhibit the expression of FoxO1. miR-124-5p-inhibitor promoted the migration and invasion of HUVECs, as well as inflammatory response, which was weakened following the introduction of FoxO1 small interfering RNA. Overall, the present study demonstrated that miR-124-5p could prevent the occurrence and development of cerebral aneurysm by downregulating the expression of FoxO1.

Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression

Cerebral aneurysm growth is characterized by vessel wall frailness, although the underlying cellular mechanisms are unclear. Here, we examined the relationship between inflammatory smooth muscle cells (SMCs) and endothelial cells (ECs) in cerebral aneurysms, including the mechanisms underlying inflammatory SMC-induced changes in ECs. Five saccular cerebral aneurysms were collected and five temporal artery samples were used as controls. Cells and cytokines were detected by immunohistochemistry and TUNEL (transferase dUTP nick end labeling) assays performed to evaluate apoptosis. Human umbilical vein endothelial cells (HUVECs) were seeded on collagen I, IV, and VI-coated plates for cell adhesion assays and inflammatory SMCs (iSMCs) were established by culture in flexible silicone chambers subjected to cyclic mechanical stretch. HUVECs were cultured in iSMC-conditioned medium, followed by evaluation of their viability, apoptosis, and function, and determination of VEGF (vascular endothelial growth factor) -A and integrin levels by western blotting. Aneurysm tissue contained fewer SMCs and lacked ECs. In aneurysm walls, more matrix metalloproteinase (MMP) -1, MMP-3, and apoptotic cells were detected, accompanied by decreased collagen IV and VI levels. Cell adhesion assays revealed that more HUVECs were attached in collagen IV and VI-coated plates compared with controls. iSMC-conditioned medium significantly reduced HUVEC viability and apoptosis showed an increased trend; however, the difference was not significant. iSMC medium also reduced tube formation and migration of HUVECs. Moreover, iSMC medium reduced HUVEC expression of VEGF-A, integrin α1, integrin α2, and integrin β. Our data demonstrate a lack of SMCs and ECs in aneurysm walls, accompanied by elevated MMP and decreased collagen levels. In vitro assays showed that iSMCs induced reduction in EC adhesion, and caused EC dysfunction. Understanding of the relationships among SMC, EC, and collagens during aneurysm progression provides an additional therapeutic option for prevention of cerebral aneurysm progression.

Abstract 205: Association of Statin Use With the Risk of Subarachnoid Hemorrhage in Medicare Patients With Unruptured Cerebral Aneurysms

Background: Animal studies have demonstrated that statins decrease cerebral aneurysm progression and the risk of subarachnoid hemorrhage (SAH). A protective effect has also been observed in human studies of abdominal aortic aneurysms. We investigated the association between statin use and SAH in Medicare beneficiaries. Methods: We used the 40% random sample Medicare denominator file and corresponding inpatient, outpatient (2003-2011) and prescription (2006-2011) claims to conduct a retrospective cohort study of patients diagnosed with unruptured cerebral aneurysms, between 2003 and 2011. We used propensity-adjusted logistic models to investigate the association of statin use with the risk of SAH, out-of-hospital death, and undergoing intervention more than 3 months after the diagnosis (as a marker of disease progression), as well as the composite outcome of all events. Results: We identified 27,574 patients with unruptured cerebral aneurysms (average age 72.3 years, 72.7% female); mean follow up was 29.8 months. Statins were used by 41.4%. Overall, 1,497 patients developed SAH and 725 underwent intervention (coiling or clipping) before aneurysm rupture. Current or recent statin use was not associated with decreased risk of SAH (OR 1.05, 95% CI 0.93 to 1.17), even after stratification on tobacco use/chronic pulmonary disease. Similarly, no association was observed between statin use and the likelihood for operative intervention (OR 0.89, 95% CI 0.75 to 1.10). The risk of the composite outcome was lower among ongoing statin users, compared to remote or no users (OR 0.72, 95% CI 0.68 to 0.77). Conclusions: Use of statins by patients with unruptured cerebral aneurysms was not associated with decreased risk of SAH. This underscores the differences in human physiology from the animal models used. The lack of the protective effect of statins seen in aortic aneurysms may be explained by the non-atherosclerotic nature of cerebral aneurysms. Funding: National Institute on Aging (PO1- AG19783).

Spontaneous Internal Carotid Artery Occlusion and Rapid Cerebral Aneurysm Progression: Case Series and Literature Review

PurposeAn accurate determination of the natural history of a cerebral aneurysm has implications on management. Few risk factors other than female gender and cigarette smoking have been identified to be associated with cerebral aneurysm progression, particularly rapid progression.Materials and MethodsThis case series and literature review serves to illustrate a relationship between spontaneous carotid occlusion and rapid enlargement of cerebral aneurysms.ResultsIn our case series, we demonstrated that increased hemodynamic stress on collateral vessels caused by a spontaneous carotid occlusion may contribute to unusually rapid aneurysm growth and/or rupture.ConclusionSpontaneous carotid occlusive disease may be considered a risk factor for rapid cerebral aneurysm progression and/or rupture that may warrant more aggressive management options, including more frequent surveillance imaging in previously treated aneurysms.

Vascular Smooth Muscle Cells in Cerebral Aneurysm Pathogenesis

Vascular smooth muscle cells (SMC) maintain significant plasticity. Following environmental stimulation, SMC can alter their phenotype from one primarily concerned with contraction to a pro-inflammatory and matrix remodeling phenotype. This is a critical process behind peripheral vascular disease and atherosclerosis, a key element of cerebral aneurysm pathology. Evolving evidence demonstrates that SMCs and phenotypic modulation play a significant role in cerebral aneurysm formation and rupture. Pharmacological alteration of smooth muscle cell function and phenotypic modulation could provide a promising medical therapy to inhibit cerebral aneurysm progression. This study reviews vascular SMC function and its contribution to cerebral aneurysm pathophysiology.

Abstract TP79: Imbalance Between Activation Of Matrix Metalloprotease And Its Inhibition May Facilitate The Growth Of Cerebral Aneurysm In Female Rats

Introduction: Cerebral aneurysms are a major cause of subarachnoid hemorrhage . Despite the catastrophic consequences of their rupture, not all mechanisms underlying the formation, progression, and rupture of cerebral aneurysms are fully understood. Using our model of reproducible cerebral aneurysms in oophorectomized rats we have documented the pathogenesis of cerebral aneurysms. Methionine-induced hyperhomocysteinemia which participates in coronary disease or stroke, is also associated with cerebral aneurysm formation. Whether it facilitates the growth and rupture of cerebral aneurysms remains obscure. We explored the role of methionine in the growth and rupture of cerebral aneurysms. Methods: We subject 13 week-old female Sprague-Dawley rats fed an 8% high-salt diet to bilateral oophorectomy and ligation of the right common carotid artery. Four weeks later they underwent ligation of the bilateral posterior renal artery divided into 2 groups; one group did and the other did not receive 1g/kg/day methionine in the drinking water. The aneurysmal rupture rate and morphologic- and genomic changes in the 2 groups were compared at 12 weeks. Results: The incidence of cerebral aneurysm formation was the same in both groups. While the rate of rupture was not higher in the methionine group, their aneurysms were larger and oxidative stress-related NOX4, Rac1, and apoptosis-related Rac1 were up-regulated. Interestingly, the expression of MMP-9 was increased as was the ratio of MMP-9 to TIMP2 but not of MMP-9 to TIMP1, suggesting vascular degradation due to an imbalance between the activation and inhibition of extracellular matrix metalloprotease. Conclusion: Our findings suggest that excessive vascular degradation due to oxidative stress and apoptosis induced by methionine contribute to the progression of cerebral aneurysms in oophorectomized rats.

Erratum: Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells

Erratum: Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells

Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results

BackgroundM1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture.MethodsTen patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and immunostained with monoclonal antibodies for M1, M2, and mast cells.ResultsAll ten aneurysm tissues stained positive for M1, M2, and mast cells. M1 and M2 cells were present in equal proportions in unruptured aneurysms. This contrasted with a marked predominance of M1 over M2 cells in ruptured aneurysms (p = 0.045). Mast cells were also prominently upregulated in ruptured aneurysms (p = 0.001). Few M1 and M2 cells were present in STA samples.ConclusionsM1/M2 macrophages and mast cells are found in human cerebral aneurysms; however, M1 and mast cell expression seems to markedly increase in ruptured aneurysms. These findings suggest that macrophage M1/M2 imbalance and upregulation of mast cells may have a role in the progression of cerebral aneurysms to rupture.

The FLOWLENS: A Focus-and-Context Visualization Approach for Exploration of Blood Flow in Cerebral Aneurysms

Blood flow and derived data are essential to investigate the initiation and progression of cerebral aneurysms as well as their risk of rupture. An effective visual exploration of several hemodynamic attributes like the wall shear stress (WSS) and the inflow jet is necessary to understand the hemodynamics. Moreover, the correlation between focus-and-context attributes is of particular interest. An expressive visualization of these attributes and anatomic information requires appropriate visualization techniques to minimize visual clutter and occlusions. We present the FLOWLENS as a focus-and-context approach that addresses these requirements. We group relevant hemodynamic attributes to pairs of focus-and-context attributes and assign them to different anatomic scopes. For each scope, we propose several FLOWLENS visualization templates to provide a flexible visual filtering of the involved hemodynamic pairs. A template consists of the visualization of the focus attribute and the additional depiction of the context attribute inside the lens. Furthermore, the FLOWLENS supports local probing and the exploration of attribute changes over time. The FLOWLENS minimizes visual cluttering, occlusions, and provides a flexible exploration of a region of interest. We have applied our approach to seven representative datasets, including steady and unsteady flow data from CFD simulations and 4D PC-MRI measurements. Informal user interviews with three domain experts confirm the usefulness of our approach.

Effect of dietary β carotene on cerebral aneurysm and subarachnoid haemorrhage in the brain apo E−/− mice

Atherosclerosis will lead to stenosis/occlusion in the lumen of various arteries of living body. This can lead various conditions including myocardial infarction, cerebral infarction/aneurysm and peripheral artery disease. Ang II is believed to be an important regulatory peptide involved in maintaining cardiovascular homeostasis and pathogenesis of various cardiovascular diseases. Matrix metalloproteinase's (MMPs), adhesion molecules and plasminogen systems are involved in the inflammatory reaction of various blood vessels as well as pathogenesis of cerebro vasuclar disease in apo E(-/-) mice during angiotensin II injection. The present study analyses the role of ang II in development of cerebral aneurysm and also evaluated the mRNA levels of MMPs, adhesion molecules, plasminogen systems and peroxisome proliferators-associated receptors in the brain of apo E(-/-) mouse during the progression of cerebral aneurysm and ischemic conditions. Also, this study evaluates the role of dietary β carotene on cerebrovascular disease. Serum total cholesterol (TC), Low density lipoprotein (LDL) and triglyceride (TG) levels were significantly increased in angiotensin II treated animals and further β carotene supplementation reduces TC but does not affect the triglyceride and LDL levels. Circulating levels of macrophages were significantly increased in angiotensin treated animals and further beta carotene supplementation significantly reduced the circulating macrophages. Cerebro meningeous aneurysm, subarachnoid haemorrhage, multiple foci of infarction, necrosis and infiltration of inflammatory cells were observed in the cerebral hemispheres of ang II treated animals, however, infarction size were reduced and no aneurysm, inflammatory foci was observed in β carotene treated animals. Real time analysis showed down regulation of mRNA levels of MMP 2, uPA, PAI, PPAR-A, MCSF1 and up regulation of tPA and MCP-1 in the brain during the progression of cerebral aneurysm and β carotene supplementation to bring to normal expression levels of all the candidate genes for cerebrovascular diseases. Based on above results, Ang II may induced cerebral aneurysm, ischemia/infarction on brain through RAS system by down regulating the mRNA levels of MMP 2, uPA, PAI, PPAR-A, MCSF1 and up regulating tPA and MCP-1 and β carotene attenuates the disease condition and bring down to normal expression levels of above genes.

Erythropoietin increases circulating endothelial progenitor cells and reduces the formation and progression of cerebral aneurysm in rats

Endothelial dysfunction triggers early pathological changes in vessel walls, potentially leading to the formation of cerebral aneurysm (CA). Endothelial progenitor cells (EPCs) are critical in repairing damaged endothelium and could prevent or slow CA formation. We hypothesize that erythropoietin (EPO) stimulates EPCs mobilization, could alter the rate of CA formation and progression. The hypothesis was tested in a rat model of CA. CAs were induced in male Sprague-Dawley rats and treated with s.c. administration of EPO. Circulating EPCs and serum vascular endothelial grow factor (VEGF) were measured be flow cytometry and ELISA, respectively. mRNAs for inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysm tissue were quantified by Real-time PCR. The size, internal elastic lamina (IEL), and media thickness of CAs were evaluated 1 and 3 months after aneurysm induction. Circulating EPCs were significantly lower in CA rats as compared to non-surgical controls. EPO increased levels of circulating EPCs and VEGF. It also decreased iNOS, MMP-2, and MMP-9 mRNA levels, while increased eNOS mRNA in aneurysm tissue. The changes in EPCs and biochemical markers are associated with suppression of new CA formation and prevention of preexisting CA progression. We have shown a close association among circulating EPCs, biochemical markers related to vascular remodeling, and the rate of CA formation and progression. Changes in patterns of cerebral blood flow and hypertension induced by surgical ligations of selected arteries exert significant hemodynamic stress to weaken vessel walls, primarily at sites of basilar bifurcation. The surgical stress also reduced circulating EPCs and slowed vascular repairs. EPO mobilizes EPCs from the bone marrow and promotes their homing. These results suggest that EPCs may serve as a marker for CA progression and EPO a promising candidate for the clinical management of CA.

Role of Shear Stress in the Blister Formation of Cerebral Aneurysms

The development of cerebral aneurysms is related to hemodynamic stress. To elucidate the role of shear stress in the blister formation of cerebral aneurysms. Among 82 aneurysms detected during catheter-based 3D rotational angiography (3DRA), 4 aneurysms enlarged with blister formation during a mean follow-up period of 10.1 month. Three of these 4 aneurysms were analyzed in this study. The regions of blister formation were characterized by comparing 3DRA before and after blister formation, and computational fluid dynamic simulations were performed based on the aneurysm geometry before blister formation. The spatially averaged shear magnitude was lower in the aneurysm region (0.97 ± 0.39 Pa) than in the parent artery (2.75 ± 0.92 Pa). The spatially averaged shear magnitude of the blister-forming area was extremely low (0.48 ± 0.12 Pa), and the shear magnitude dropped precipitately to subphysiological levels, resulting in a high shear gradient near the border of the blister-forming area. These data suggest that low shear magnitude may trigger the progression of cerebral aneurysms and that blister formation is associated with high shear gradient in the large region of low shear magnitude on the aneurysm wall.

Numerical simulations of the discontinuous progression of cerebral aneurysms based on fluid-structure interactions study

Investigations into the characteristics of hemodynamics will provide a better understanding of the pathology of cerebral aneurysms for clinicians. In this work, a steady state discontinuous-growth model of the cerebral aneurysms was proposed. With the assumption of the fluid-structure interaction between the wall of blood vessel and blood, a fluid-structure coupling numerical simulation for this model was built using software ANSYS and CFX. The simulation results showed that as the aneurysm volume increased, a blood flow vortex came forth, the vortex region became asymptotically larger, and eddy density became gradually stronger in it. After the emergence of the vortex region, the blood flow in the vicinity of the downstream in the aneurysms volume turned into bifurcated flow, and the location of the flow bifurcated point was shifted with the aneurysm volume growing while directions of the shear stress applied to two sides of the bifurcated point were opposite. The Von Mises stress distribution along the wall of aneurysm volume decreased in the prior period and increased gradually in the later period. The maximum stress was in the neck of the volume and the minimum was on the distal end in the whole process of growth. It was shown that as the aneurysm increased the maximum deformation location of the aneurysm, vertical to the streamline, was transferred from the distal end of the aneurysm to its neck, then back to its distal end of the aneurysm again.

Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells

Cerebral aneurysm (CA) rupture is one of the leading causes of stroke death. Recent experimental studies suggest that the pathophysiology of CA is closely associated with inflammation. A transcription factor, Ets-1, has been shown to regulate vascular inflammation and remodeling in a physiological and pathological condition. The expression and role of Ets-1 in CA development has been investigated in this study. Ets-1 was expressed and activated mainly in vascular smooth muscle cells (VSMCs) in both experimentally induced rat CAs and human CA walls by immunohistochemistry, western blotting and enzyme-linked mobility shift assay. The downstream target of Ets-1 in CA development was identified by chromatin immunoprecipitation (CHIP) analysis. CHIP analysis revealed that Ets-1 transactivated monocyte chemoattractant protein-1 (MCP-1) expression in CA walls. Treatment with ets decoy oligodeoxynucleotides resulted in the prevention of CA enlargement, upregulation of MCP-1 expression and increase in macrophage accumulation in CA walls. In conclusion, Ets-1 mediates MCP-1 expression in VSMCs in CA walls, thus promoting the progression of CAs. Inhibition of DNA-binding activity of Ets-1 may lead to the prevention of human CA enlargement and rupture. Results of this study will provide us a clue to a novel therapeutic strategy for CAs.

Ibudilast Inhibits Cerebral Aneurysms by Down-Regulating Inflammation-Related Molecules in the Vascular Wall of Rats

Phosphodiesterase-4 (PDE-4) is a cyclic adenosine monophosphate-specific enzyme involved in various inflammatory diseases. We studied its role in and the effect of ibudilast, which predominantly blocks PDE-4, on rat cerebral aneurysms. Cerebral aneurysms were induced at the anterior cerebral artery-olfactory artery bifurcation of female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The effect of ibudilast (30 or 60 mg/kg/d for 3 months) on their cerebral aneurysms was studied by morphological and immunohistochemical assessment and quantitative real-time polymerase chain reaction assay. In our in vitro study, we grew endothelial cells stimulated by angiotensin II under estrogen-free conditions and examined the effect of ibudilast on PDE-4 activation and the cyclic adenosine monophosphate level. Morphological evaluation using vascular corrosion casts showed ibudilast significantly suppressed cerebral aneurysms in a dose-dependent manner. In rats with induced cerebral aneurysms, the gene and protein expression of PDE-4 was high, and endothelial leukocyte adhesion molecules (P-selectin, intracellular adhesion molecule 1, and vascular adhesion molecule 1), matrix metalloproteinase-9, and tumor necrosis alpha were expressed. Macrophage migration was also increased. Treatment with ibudilast down-regulated these molecules, suppressed macrophage migration into the aneurysm wall, and inhibited PDE-4 activation and the elevation of cyclic adenosine monophosphate in endothelial cells. These results suggest that blocking of PDE4 is associated with the reduction of inflammation-related molecules and macrophage migration, thereby reducing the progression of cerebral aneurysms. It may represent a new conservative therapy to treat patients with cerebral aneurysms.

Fasudil, a Rho-kinase inhibitor, attenuates induction and progression of cerebral aneurysms: Experimental study in rats using vascular corrosion casts

Fasudil (a Rho-kinase inhibitor) has been shown to attenuate abdominal aortic aneurysm development, but any preventive effect against development of cerebral aneurysms is unclear. The effect of fasudil on the development of cerebral aneurysms was investigated in 55 female Sprague-Dawley rats divided into 4 groups: Group 1 ( n = 10) was the control group without treatment. Groups 2–4 ( n = 15 each) were subjected to cerebral aneurysm induction procedures plus 1% NaCl in the drinking water. Groups 3 and 4 were also treated with 0.5 or 1.0 mg/mL of fasudil in the drinking water, respectively. Vascular corrosion casts of the cerebral arteries were prepared and examined using a scanning electron microscope after 2 months. No significant differences were observed in the degree of induced hypertension between Groups 2, 3 and 4. No aneurysms were found in Group 1. Examination of the left anterior cerebral–olfactory artery junction, which is the most susceptible site for aneurysm development, found significantly fewer aneurysmal lesions in Groups 3 (60%) and 4 (53%) compared to Group 2 (100%) ( P < 0.02). This study suggests that fasudil attenuated induction of cerebral aneurysms in the rat model.

Hemodynamics of Cerebral Aneurysms

The initiation and progression of cerebral aneurysms are degenerative processes of the arterial wall driven by a complex interaction of biological and hemodynamic factors. Endothelial cells on the artery wall respond physiologically to blood-flow patterns. In normal conditions, these responses are associated with nonpathological tissue remodeling and adaptation. The combination of abnormal blood patterns and genetics predisposition could lead to the pathological formation of aneurysms. Here, we review recent progress on the basic mechanisms of aneurysm formation and evolution, with a focus on the role of hemodynamic patterns.

Cathepsin Enzymes and Cystatin C: Do They Play a Role in Positive Arterial Remodeling?

To the Editor: We have read the impressive article recently published by Aoki et al1 evaluating the cathepsin enzyme system in cerebral aneurysm formation. By using quantitative RT-PCR and immunohistochemistry, the authors have demonstrated increased expression of cathepsin B, cathepsin K, and cathepsin S in arterial wall of the cerebral aneurysms, whereas the expression of cystatin C was found to be decreased. These findings suggest an imbalance between cysteine cathepsins and their inhibitor. This imbalance may cause the excessive breakdown of extracellular matrix in the arterial wall resulting in progressing arterial aneurysm formation. This conclusion was supported by the experimental use …