scholarly journals Potential Role of Aspirin in the Prevention of Aneurysmal Subarachnoid Hemorrhage

2015 ◽  
Vol 39 (5-6) ◽  
pp. 332-342 ◽  
Author(s):  
Robert M. Starke ◽  
Nohra Chalouhi ◽  
Dale Ding ◽  
David M. Hasan
Keyword(s):  
Cerebral Aneurysm ◽  
Peripheral Blood ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Aspirin Therapy ◽  
Blood Samples ◽  
Aneurysm Formation ◽  
Number Of Patients ◽  
Increased Risk ◽  
Cox 2

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.

scholarly journals Disruption of P2X4 purinoceptor and suppression of the inflammation associated with cerebral aneurysm formation

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Miyuki Fukuda ◽  
Shunichi Fukuda ◽  
Joji Ando ◽  
Kimiko Yamamoto ◽  
Naohiro Yonemoto ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cerebral Aneurysm ◽  
Arterial Wall ◽  
Quantitative Polymerase Chain Reaction ◽  
Cerebral Aneurysms ◽  
Artery Ligation ◽  
Hemodynamic Stress ◽  
Aneurysm Formation ◽  
Aneurysm Development ◽  
Cox 2

OBJECTIVEThere are no effective therapeutic drugs for cerebral aneurysms, partly because the pathogenesis remains unresolved. Chronic inflammation of the cerebral arterial wall plays an important role in aneurysm formation, but it is not clear what triggers the inflammation. The authors have observed that vascular endothelial P2X4 purinoceptor is involved in flow-sensitive mechanisms that regulate vascular remodeling. They have thus hypothesized that shear stress–associated hemodynamic stress on the endothelium causes the inflammatory process in the cerebral aneurysm development.METHODSTo test their hypothesis, the authors examined the role of P2X4 in cerebral aneurysm development by using P2X4−/− mice and rats that were treated with a P2X4 inhibitor, paroxetine, and subjected to aneurysm-inducing surgery. Cerebral aneurysms were induced by unilateral carotid artery ligation and renovascular hypertension.RESULTSThe frequency of aneurysm induction evaluated by light microscopy was significantly lower in the P2X4−/− mice (p = 0.0488) and in the paroxetine-treated male (p = 0.0253) and female (p = 0.0204) rats compared to control mice and rats, respectively. In addition, application of paroxetine from 2 weeks after surgery led to a significant reduction in aneurysm size in the rats euthanized 3 weeks after aneurysm-inducing surgery (p = 0.0145), indicating that paroxetine suppressed enlargement of formed aneurysms. The mRNA and protein expression levels of known inflammatory contributors to aneurysm formation (monocyte chemoattractant protein–1 [MCP-1], interleukin-1β [IL-1β], tumor necrosis factor–α [TNFα], inducible nitric oxide synthase [iNOS], and cyclooxygenase-2 [COX-2]) were all significantly elevated in the rats that underwent the aneurysm-inducing surgery compared to the nonsurgical group, and the values in the surgical group were all significantly decreased by paroxetine administration according to quantitative polymerase chain reaction techniques and Western blotting. Although immunolabeling densities for COX-2, iNOS, and MCP-1 were not readily observed in the nonsurgical mouse groups, such densities were clearly seen in the arterial wall of P2X4+/+ mice after aneurysm-inducing surgery. In contrast, in the P2X4−/− mice after the surgery, immunolabeling of COX-2 and iNOS was not observed in the arterial wall, whereas that of MCP-1 was readily observed in the adventitia, but not the intima.CONCLUSIONSThese data suggest that P2X4 is required for the inflammation that contributes to both cerebral aneurysm formation and growth. Enhanced shear stress–associated hemodynamic stress on the vascular endothelium may trigger cerebral aneurysm development. Paroxetine may have potential for the clinical treatment of cerebral aneurysms, given that this agent exhibits efficacy as a clinical antidepressant.

Abstract 107: Early Change in Ferumoxytol-Enhanced Magnetic Resonance Imaging Signal Suggests Unstable Human Cerebral Aneurysm. A Pilot Study

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
David M Hasan ◽  
donald hesitad
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Resonance Imaging ◽  
Unruptured Aneurysms ◽  
Ruptured Aneurysms ◽  
Cyclooxygenase 1 ◽  
Signal Changes ◽  
Cox 2

Background: Imaging with magnetic resonance imaging (MRI) 72 hours after infusion of ferumoxytol demonstrated maximal uptake by macrophages in the wall of human cerebral aneurysms. The clinical significance of early (i.e. within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol which may indicate inflammation, suggests unstable cerebral aneurysm. Methods: 30 unruptured aneurysms in 22 patients were imaged with MRI 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from four patients with early MRI signal changes, five patients with late signal changes, and five other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal-prostaglandin-E2 synthase-1 (mPGES-1) and macrophages. Findings: In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining three aneurysms which were managed conservatively with observation, all ruptured within six months. In 89% (16/18) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Nine aneurysms were surgically clipped and nine were managed conservatively; none ruptured or increased in size in six months. With immunostaining, expression of COX-2, mPGES-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol than in aneurysms with late uptake. Interpretation: Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within six months, and may warrant intervention. Larger clinical studies are indicated to validate this preliminary observation.

Abstract TP78: Down-regulation Of Vascular Na+/k+ ATPase In Oophorectomized Rats Feeding A High Salt Diet Is Associated With The Cerebral Aneurysm Formation

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Nobuhisa Matsushita ◽  
Yoshiteru Tada ◽  
Kenji Yagi ◽  
Keiko T Kitazato ◽  
Kenji Shimada ◽  
...  
Keyword(s):  
Cerebral Aneurysm ◽  
Efflux Pump ◽  
Cerebral Aneurysms ◽  
The Body ◽  
High Salt ◽  
Artery Ligation ◽  
High Salt Diet ◽  
Salt Diet ◽  
Aneurysm Formation ◽  
Water Ratio

Background and Purpose— Hypertension is thought to be associated with a high incidence of stroke. However, not all patients with unruptured cerebral aneurysms are hypertensive. In the DOCA-salt rats the increase in body water-free Na+ storage associated with hypertension is suggested. We hypothesized that in oophorectomized rats fed a high salt diet, body water-free Na+ accumulation may be increased, leading to the formation of cerebral aneurysms. To address the relationship between the increase in the body Na+-to-water ratio that characterizes water-free Na+ accumulation and the formation of cerebral aneurysms, we focused on vascular Na efflux pump Na+/K+ ATPase. Methods— Thirteen-week old female Sprague-Dawley rats subjected to carotid artery ligation were fed a high-salt diet and divided into 3 groups; a group without- (HSD) and another with bilateral oophorectomy (HSD/OVX) and a 3rd group that underwent additional renal artery ligation (HSD/OVX/RL) to induce hypertension. Results— Compared to HSD rats, the incidence of cerebral aneurysms and the body Na+-to-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 were down-regulated and renin-angiotensin system- and inflammation related molecules were up-regulated. In HSD/OVX/RL rats treatment with low dose olmesartan up-regulated ATP1α2 without affecting blood pressure and reduced the body Na+-to-water ratio and the incidence of cerebral aneurysm formation. Conclusions— These results suggest that a reduction in the vascular Na efflux pump during excessive salt intake in oophorectomized rats may be associated with the increase in water-free Na+ accumulation directing to cerebral aneurysm formation.

scholarly journals In vivo cerebral aneurysm models

2019 ◽  
Vol 47 (1) ◽  
pp. E20 ◽  
Author(s):  
John W. Thompson ◽  
Omar Elwardany ◽  
David J. McCarthy ◽  
Dallas L. Sheinberg ◽  
Carlos M. Alvarez ◽  
...  
Keyword(s):  
Cerebral Aneurysm ◽  
Surgical Techniques ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Large Animal ◽  
Pharmacological Interventions ◽  
Large Animal Models ◽  
First Line Therapy ◽  
Endovascular Devices

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.

scholarly journals Association between Circle of Willis Configuration and Rupture of Cerebral Aneurysms

Medicina ◽  
2019 ◽  
Vol 55 (7) ◽  
pp. 338
Author(s):  
Stojanović ◽  
Kostić ◽  
Mitić ◽  
Berilažić ◽  
Radisavljević
Keyword(s):  
Cerebral Aneurysm ◽  
Intracranial Hemorrhage ◽  
Lower Incidence ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Circle Of Willis ◽  
Type B ◽  
Brain Aneurysms

Background and Objectives: Intracranial hemorrhage caused by the rupture of brain aneurysms occurs in almost 10 per 100,000 people whereas the incidence of such aneurysms is significantly higher, accounting for 4–9%.Linking certain factors to cerebral aneurysm rupture could help in explaining the significantly lower incidence of their rupture compared to their presence. The aim of this study is to determine the association between the corresponding circle of Willis configurations and rupture of cerebral aneurysms. Materials and Methods: A group of 114 patients treated operatively for aruptured cerebral aneurysm and a group of 56 autopsied subjects were involved in the study. Four basic types of the circle of Willis configurations were formed—two symmetric types A and C, and two asymmetric types B and D. Results: A statistically significantly higher presence of asymmetry of the circle of Willis was determined in the group of surgically-treated subjects (p = 0.001),witha significant presence of asymmetric Type B in this group (p < 0.001). The changeson the A1 segment in the group of surgically-treated subjects showed a statistically significant presence compared to the group of autopsied subjects (p = 0.001). Analyzing the presence of symmetry of the circle of Willis between the two groups, that is, the total presence of symmetric types A and C, indicated their statistically significant presence in the group of autopsied patients (p < 0.001). Conclusions: Changes such as hypoplasia or aplasia of A1 and the resulting asymmetry of the circle of Willis directly affect the possibility of the rupture of cerebral aneurysms. Detection of the corresponding types of the circle of Willis after diagnostic examination can be the basis for the development of a protocol for monitoring such patients.

Size is the Most Important Predictor of Aneurysm Rupture Among Multiple Cerebral Aneurysms: Post Hoc Subgroup Analysis of Unruptured Cerebral Aneurysm Study Japan

Neurosurgery ◽  
2017 ◽  
Vol 82 (6) ◽  
pp. 864-869 ◽  
Author(s):  
Masaaki Shojima ◽  
Akio Morita ◽  
Hirofumi Nakatomi ◽  
Shinjiro Tominari
Keyword(s):  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Ruptured Aneurysm ◽  
Clinical Value ◽  
Total Cohort ◽  
Unruptured Cerebral Aneurysm ◽  
Specific Factors ◽  
Unruptured Cerebral Aneurysms ◽  
Post Hoc

Abstract BACKGROUND Multiple cerebral aneurysms are encountered in approximately 15% to 35% of patients harboring unruptured cerebral aneurysms. It would be of clinical value to determine which of them is most likely to rupture. OBJECTIVE To characterize features of the ruptured aneurysm relative to other concomitant fellow aneurysms in patients with multiple cerebral aneurysms. METHODS From a total of 5720 patients who were prospectively registered in the Unruptured Cerebral Aneurysm Study in Japan, a subgroup of patients with multiple cerebral aneurysms who developed subarachnoid hemorrhage was extracted for this post hoc analysis. Intrapatient comparisons of each aneurysm were carried out using aneurysm-specific factors such as size, location, and shape to identify predictors of rupture among the fellow aneurysms in a patient with multiple cerebral aneurysms. RESULTS Twenty-five patients with 62 aneurysms were identified from the total cohort of 5720 patients. With the distinctiveness in size, which means the aneurysm was the single largest among the multiple aneurysms, the ruptured aneurysm in each case was discriminated from the other coexisting aneurysms with a sensitivity of 0.76 and specificity of 0.86. CONCLUSION Our results suggest that the largest aneurysm is likely to rupture among coexisting aneurysms in a patient with multiple cerebral aneurysms.

scholarly journals Predicting Cerebral Aneurysm Rupture by Gradient Boosting Decision Tree using Clinical, Hemodynamic, and Morphological Information

10.29007/jjwt ◽  
2020 ◽  
Author(s):  
Toshiyuki Haruhara ◽  
Hideto Ohgi ◽  
Masaaki Suzuki ◽  
Hiroyuki Takao ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Prediction Method ◽  
Preventive Treatment ◽  
Aneurysm Rupture ◽  
Gradient Boosting ◽  
Machine Learning Model ◽  
The Individual ◽  
Shape Data

Stroke is a serious cerebrovascular condition in which brain cells die due to an abrupt blockage of arteries supplying blood and oxygen or when a blood vessel bursts or ruptures and causes bleeding in the brain. Because the onset of stroke is very sudden in most people, prevention is often difficult. In Japan, stroke is one of the major causes of death and is associated with high medical costs; these problems are exacerbated by the aging population. Therefore, stroke prediction and treatment are important. The incidence of stroke may be avoided by preventive treatment based on the patient’s risk of stroke. However, since judging the risk of stroke onset is largely dependent upon the individual experience and skill of the doctor, a highly accurate prediction method that is independent of the doctor’s experience and skills is necessary. This study focuses on a predictive method for subarachnoid hemorrhage, which is a type of stroke. LightGBM was used to predict the rupture of cerebral aneurysms using a machine learning model that takes clinical, hemodynamic and morphological information into account. This model was used to analyze samples from 338 cerebral aneurysm cases (35 ruptured, 303 unruptured). Simulation of cerebral blood-flow was used to calculate the hemodynamic features while the surface curvature was extracted from the 3D blood-vessel-shape data as morphological features. This model yielded a sensitivity of 0.77 and a specificity of 0.83.

scholarly journals Role of diet-related factors in cerebral aneurysm formation and rupture

2019 ◽  
pp. 119-126
Author(s):  
Anna Czekajło
Keyword(s):  
Blood Pressure ◽  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Renin Angiotensin System ◽  
Vascular Wall ◽  
Caffeine Consumption ◽  
Related Factors ◽  
Hemodynamic Stress ◽  
Aneurysm Formation

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.

scholarly journals Πρότυπο μεθυλίωσης σε ασθενείς με ιδιοπαθή φλεγμονώδη νόσο του εντέρου

2014 ◽  
Author(s):  
Παντελής Καρατζάς
Keyword(s):  
Peripheral Blood ◽  
Statistical Tests ◽  
Methylation Status ◽  
Methylation Profile ◽  
Healthy Individuals ◽  
Intestinal Tissue ◽  
Tissue Samples ◽  
Blood Samples ◽  
Number Of Patients ◽  
Show Evidence

Objective This thesis aimed to investigate the methylation profile of 22 genes associated with thepathogenesis of IBD in patients with ulcerative colitis (UC) or Crohn’s Disease (CD) andcompare them with the methylation profile of the same genes in healthy controls. Anadditional purpose of the study was to investigate whether methylation profile of these genesbetween inflamed intestinal tissue and peripheral blood are in concordance, hoping to indicatea possible future use of methylation as biomarker.Materials & MethodsIsolated peripheral blood samples and inflamed intestinal tissue samples were collectedfrom 24 patients with IBD, 12 of them suffering from UC and 12 from CD. The control groupconsisted of 12 healthy subjects without any personal and family history of digestive diseases.The promoter methylation status of genes involved in inflammation and autoimmunity wasprofiled using the Human Inflammatory Response and Autoimmunity EpiTect Methyl IISignature PCR Array profiles. Methylation was considered to be hyper-methylated if >20%according to the instructions of the manufacturer. The microarrays were validated with Quantitative Real-time PCR.The statistical analysis was performed using non-parametricstatistical tests (non-parametric statistical tests).ResultsRegarding CD, the methylation status of IL10RA, IL13, IL13RA1 and IL17C inperipheral blood samples did not differ significantly from the methylation status of healthycontrols. Only three genes – ATF2, CXCL5 and IL12B showed higher methylation in CDcompared to controls, but they did not exceed the threshold of 20% for hypermethylation. Allother genes tested appear lower methylation than controls.Regarding UC, methylation status of CXCL6 and IL13RA1 in peripheral blood samplesdid not differ significantly from the methylation status of healthy individuals. Five genes(CXCL14, CXCL5, GATA3, IL17C and IL4R,) were found to be significantly hypermethylatedin UC patients compared to healthy individuals. Some genes show higher methylation thancontrols, but they do not exceed 20% methylation threshold for hypermethylation. All other genes show lower methylation in UC compared to controls.Active cases of both CD and UC could be promptly distinguished from healthycontrols based on the signatures provided by the methylation profiles in peripheral bloodsamples. Based on these results - despite the relatively limited number of patients - it waspossible to define distinct signatures for active CD vs. active UC. Specifically, CXCL14,CXCL5, GATA3, IL17C and IL4R genes were hyper-methylated in UC compared to CD. Inaddition, CXCL6 which did not differ significantly between UC and controls appeared hypermethylatedcompared to CD; in contrast, IL13 which did not differ significantly between CDand controls appeared hypermethylated in CD compared to UC. Moreover the real-timequantitative PCR conducted for seven genes (CCL25, IL13, IL17RA, IL17A, IL12B, CXCL5,and IL4R) confirmed the causal relationship between hyper-methylation and lower expressionof genes. Finally, it was confirmed that methylation profile in intestinal tissue and peripheralblood are in concordance. ConclusionsIn this study we have identified panels of genes that show evidence of differentialmethylation between UC and controls, as well as CD and UC. Moreover there is strongevidence that methylation level in intestinal tissue samples is well related to methylation levelin whole blood samples. Our findings suggest that these genes play an important role in IBDpathogenesis, as differential methylation status observed affects gene expression at the mRNAlevel. In conclusion, the different methylation levels between CD and UC could play a role inconfirming the diagnosis of IBD, determining the exact type of IBD (UC or CD) and possiblyestimating the activity of disease

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