Morphometry of cerebral arterial bifurcations harbouring aneurysms: a case-control study.

BACKGROUND: Conclusions from studies evaluating vessel dimensions and their deviations from values resulting from the principle of minimum work (PMW) on the formation of intracranial aneurysms (IAs) are still inconclusive. Our study aimed to perform a morphometric analysis of cerebral arterial bifurcations harbouring aneurysms. METHODS: The study comprised 147 patients with basilar artery (BA) and middle cerebral artery (MCA) aneurysms and 106 patients constituting the control group. The following morphometric parameters were evaluated: the radii of vessels forming the bifurcation, the junction exponent, the values of the bifurcation angles (Φ1 and Φ2 angles between the parent vessel trunk axis and the larger or smaller branches, respectively; α angle, the total bifurcation angle) and the difference between the predicted optimal and observed branch angles. RESULTS: The analysed parameters for internal carotid artery (ICA) bifurcations were not significantly different among the groups. The MCA and BA bifurcation angles and the radii of the parent MCA and BA vessels with aneurysms were significantly higher than those of the control group. The differences between the predicted optimal and observed branch angles were significantly higher for BA and MCA bifurcations with aneurysms compared to the control group. The mean junction exponent for bifurcations in the circle of Willis (i.e., ICA and BA bifurcations, respectively) and MCA bifurcations with aneurysms was significantly lower than the theoretical optimum and did not significantly differ among the groups. In a multilevel multivariate logistic regression analysis, the branch angles and the radius from the parent vessel were significant independent predictors of the presence of an IA. The ROC analysis indicated that the α angle was the best performer in discriminating between aneurysmal and nonaneurysmal bifurcations. CONCLUSIONS: The dimensions of the arteries forming the circle of Willis do not follow the PMW. Deviation from the energetically optimum geometry for bifurcations beyond the circle of Willis (particularly, a larger radius of the parent artery and a wider total bifurcation angle) may lead to the formation of IAs. Further studies are warranted to investigate the significance of vessel dimensions and the bifurcation angle on the magnitude of shear stress in the walls of arterial bifurcations.

Wall shear stress gradient is independently associated with middle cerebral artery aneurysm development: a case-control CFD patient-specific study based on 77 patients.

BACKGROUND: Previously published computational fluid dynamics (CFD) studies regarding intracranial aneurysm (IA) formation present conflicting results. Our study analysed the involvement of the combination of high wall shear stress (WSS) and a positive WSS gradient (WSSG) in IA formation. METHODS: We designed a case-control study with a selection of 38 patients with an unruptured middle cerebral artery (MCA) aneurysm and 39 non-aneurysmal controls to determine the involvement of WSS, oscillatory shear index (OSI), the WSSG and its absolute value (absWSSG) in aneurysm formation based on patient-specific CFD simulations using velocity profiles obtained from transcranial colour-coded sonography. RESULTS: Among the analysed parameters, only the WSSG had significantly higher values compared to the controls (11.05 vs - 14.76 [Pa/mm], P = 0.020). The WSS, absWSSG and OSI values were not significantly different between the analysed groups. Logistic regression analysis identified WSS and WSSG as significant co-predictors for MCA aneurysm formation, but only the WSSG turned out to be a significant independent prognosticator (OR: 1.009; 95% CI: 1.001-1.017; P = 0.025). Significantly more patients (23/38) in the case group had haemodynamic regions of high WSS combined with a positive WSSG near the bifurcation apex, while in the control group, high WSS was usually accompanied by a negative WSSG (14/39). From the analysis of the ROC curve for WSSG, the area under the curve (AUC) was 0.654, with the optimal cut-off value -0.37 Pa/mm. The largest AUC was recognised for combined WSS and WSSG (AUC = 0.671). Our data confirmed that aneurysms tend to form near the bifurcation apices in regions of high WSS values accompanied by positive WSSG. CONCLUSIONS: The development of IAs is determined by an independent effect of haemodynamic factors. High WSS impacts MCA aneurysm formation, while a positive WSSG mainly promotes this process.

The rupture of an anterior communicating artery aneurysm does not associate with an asymmetry in the A1 or A2 arteries: a retrospective study of radiological features.

BACKGROUND AND OBJECTIVES: Although the formation and rupture risk of an anterior communicating artery (ACoA) aneurysm has been the subject of many studies, no previous study has primarily searched for the relationship of the parent and daughter vessels and the impact of their size/diameter ratio on the potential rupture risk of an AcoA aneurysm. The objective of this study is to explore this link and to further analyse the surrounding vasculature of the anterior communicating artery aneurysm. MATERIALS AND METHODS: We conducted a retrospective analysis of 434 patients: 284 patients with an ACoA aneurysm (121 unruptured and 162 ruptured) and 150 control patients without an ΑCoA aneurysm. Radiological angiography investigations were used to assess the diameter ratios of the parent vessels in addition to ACoA aneurysm morphology parameters. RESULTS: When comparing the ruptured to the unruptured cases, we observed no significant difference in the parent or daughter vessel diameter ratios. Younger patient age (OR 0.96, p = 0.00) and a higher aneurysm size ratio (OR 1.10, p = 0.02) were of prognostic importance concerning the rupture risk of the aneurysm. The A1 diameter ratio and the A2 diameter were not statistically significant (OR 1.00, p = 0.99, and OR 3.38, p = 0.25 respectively). CONCLUSIONS: In our study, we focused on asymmetry in the parent and daughter vessels as well as traditional ACoA aneurysm morphological characteristics. We were able to label younger patient age and a greater size ratio as independent prognostic factors for ACoA aneurysm rupture. We were unable to label parent and daughter vessel asymmetry as prognostic factors. To validate our findings, parent and daughter vessel asymmetry should be subjected to future prospective studies.

Effect of Siphon Morphology on the Risk of C7 Segment Aneurysm Formation : A Case-control CFD Study.

PURPOSE: Tortuosity of the internal carotid artery (ICA) is associated with intracranial aneurysms (IAs). The siphon is the most curved segment of the ICA, but its morphology has controversial effects on IAs. This study aimed to explore the morphometric features of the siphon and the potential hemodynamic mechanisms that may affect C7 aneurysm formation. METHODS: In this study 32 patients with C7 aneurysms diagnosed at Xiangya Hospital between 2019 and 2021 and 32 control subjects were enrolled after propensity score matching. Computed tomography angiography (CTA) images were acquired to measure morphologic features, and then, by combining clinical data, simplified carotid siphon models were constructed, and computational fluid dynamics (CFD) analysis was performed. RESULTS: The presence of C7 aneurysms was associated with the height of the C4-C6 curved arteries (odds ratio [OR] 0.028, 95% confidence interval [CI] 0.003-0.201; P < 0.001). The heights of the C4-C6 curved arteries in the aneurysm group were significantly shorter than those in the control group. The CFD analysis revealed that shorter C4-C6 bends led to greater blood velocity and pressure in the C7 segment arteries. CONCLUSION: A shorter C4-C6 bend was associated with distal C7 aneurysm formation, and an elaborate hemodynamic mechanism may underlie this association.

Long-term observation of polycaprolactone small-diameter vascular grafts with thickened outer layer and heparinized inner layer in rabbit carotid arteries.

In our previous study, the pristine bilayer small-diameterin situtissue engineered vascular grafts (pTEVGs) were electrospun from a heparinized polycaprolactone (PCL45k) as an inner layer and a non-heparinized PCL80k as an outer layer in the thickness of about 131 µm and 202 µm, respectively. However, the hydrophilic enhancement of inner layer stemmed from the heparinization accelerated the degradation of grafts leading to the early formation of arterial aneurysms in a period of 3 months, severely hindering the perennial observation of the neo-tissue regeneration, host cell infiltration and graft remodeling in those implanted pTEVGs. Herein to address this drawback, the thickness of the outer layers was increased with PCL80k to around 268 µm, while the inner layer remained unchangeable. The thickened TEVGs named as tTEVGs were evaluated in six rabbits via a carotid artery interpositional model for a period of 9 months. All the animals kept alive and the grafts remained patent until explantation except for one whose one side of arterial blood vessels was occluded after an aneurysm occurred at 6 months. Although a significant degradation was observed in the implanted grafts at 9 month, the occurrence of aneurysms was obviously delayed compared to pTEVGs. The tissue stainings indicated that the endothelial cell remodeling was substantially completed by 3 months, while the regeneration of elastin and collagen remained smaller and unevenly distributed in comparison to autologous vessels. Additionally, the proliferation of macrophages and smooth muscle cells reached the maximum by 3 months. These tTEVGs possessing a heparinized inner layer and a thickened outer layer exhibited good patency and significantly delayed onset time of aneurysms.

Lymphocyte-C-reactive protein ratio combined with albumin upon admission predicts coronary artery dilation and aneurysm formation in pediatric patients with Kawasaki disease: a retrospective cohort study.

BACKGROUND: We aimed to explore simple and effective clinical parameters or combinations to predict coronary artery dilation and aneurysm formation in pediatric patients with Kawasaki disease (KD). DESIGN AND METHODS: This retrospective cohort study included pediatric patients with KD from January, 2013 to December, 2022. Multiple demographic and clinical data were collected, collated, and calculated from the medical records. Then they were divided into the coronary artery dilation and aneurysm formation group or the non-coronary artery dilation and aneurysm formation group. Lymphocyte-C-reactive protein ratio (LCR) was transformed into its natural logarithm and expressed as lnLCR. RESULTS: A total of 64 pediatric patients with KD were enrolled in this cohort study after 1:3 propensity score matching (PSM). For each unit increase in lnLCR, the possibility of coronary artery dilation and aneurysm formation decreased to 0.419 times the original value. The areas under the receiver operating characteristic (ROC) curves of lnLCR combined with albumin (ALB), ALB, and lnLCR to classify pediatric patients with KD into the coronary artery dilation and aneurysm formation group were 0.781, 0.692, and 0.743, respectively. CONCLUSION: LCR combined with ALB upon admission is a promising predictor of coronary artery dilation and aneurysm formation in pediatric patients with KD.

Neutrophils: Novel Contributors to Estrogen-Dependent Intracranial Aneurysm Rupture Via Neutrophil Extracellular Traps.

Background Intracranial aneurysms (IAs) are more prevalent in women than men, and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner. Methods and Results We compared neutrophil infiltration in C57BL/6 female mice that develop IAs to those with a normal circle of Willis. Next, we investigated the estrogen-dependent role of neutrophils in IA formation, rupture, and symptom-free survival using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. Mice that developed aneurysms had increased neutrophil infiltration compared with those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. Conclusions Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.

Investigation of paraclinoid aneurysm formation by comparing the combined influence of hemodynamic parameters between aneurysmal and non-aneurysmal arteries.

Numerous studies have evaluated the effects of hemodynamic parameters on aneurysm formation. However, the reasons why aneurysms do not initiate in intracranial arteries are still unclear. This study aimed to investigate the influence of hemodynamic parameters, wall shear stress (WSS) and strain, on aneurysm formation by comparing between aneurysmal and non-aneurysmal arteries. Fifty-eight patients with paraclinoid aneurysms on one side were enrolled. Based on magnetic resonance angiography, each patient's left and right internal carotid arteries (ICAs) were reconstructed. For a patient having an aneurysm on one side, the ICA with the paraclinoid aneurysm was defined as the aneurysmal artery after eliminating the aneurysm, whereas the opposite ICA without aneurysm was defined as the non-aneurysmal artery. Computational fluid dynamics and fluid-structure interaction analyses were then performed for both aneurysmal and non-aneurysmal arteries. Finally, the relationship between high hemodynamic parameters and aneurysm location was investigated. For aneurysmal arteries, high WSS and strain locations were well-matched with the aneurysm formation site. Also, considerable correlations between high WSS and strain locations were observed. However, there was no significant relationship between high hemodynamic parameters and aneurysm formation for non-aneurysmal arteries. The findings are helpful for understanding aneurysm formation mechanism and encouraging further relevant research.

Giant Right Coronary Artery Aneurysm in a Patient With Multiple Coronary Artery Aneurysmatic Dilatations.

One kind of coronary artery disease that is uncommon is coronary artery aneurysm (CAA). According to angiographic reports, the incidence of coronary artery aneurysms ranges from 1.5% to 4.9%, with a higher frequency in men. A patient with both coronary heart disease and an aneurysm in the right coronary artery (RCA) underwent a successful simultaneous coronary bypass together with an aneurysmal reconstruction procedure.

Neuroinflammation and subarachnoid hemorrhage: a revised look at the literature.

A key topic for aneurysmal subarachnoid hemorrhage is neuroinflammation. Neuroinflammation can predispose to aneurysm formation and rupture. Neuroinflammation can also result from the blood breakdown products after aneurysm rupture. Recent evidence has shown that perpetual neuroinflammation can contribute to vasospasm and hydrocephalus. Targeting neuroinflammation is a novel mechanism for preventing subsequent neurologic sequalae. In this review, we highlight the pathophysiology of aneurysm formation, the neuroinflammatory surge after rupture including the involved cytokines, and ultimately tie in the contributory clinical relevance. In the last sections, we look at the pre-clinical data and novel avenues for further discovery. This paper will be a useful resource to both the clinician and scientific investigator.

New aneurysm formation and regrowth associated with rebleeding of residual pediatric ruptured arteriovenous malformation: patient series.

BACKGROUND: If complete obliteration of ruptured pediatric arteriovenous malformation (AVM) cannot be achieved, the appropriate follow-up duration and predictors of rebleeding remain unknown. OBSERVATIONS: Pediatric patients with ruptured AVMs admitted to the authors' hospital within the past 30 years were evaluated. Rebleeding was confirmed in two patients. The first patient was a 5-year-old boy who experienced right thalamic hemorrhage. AVM was found in the bilateral thalamus and treated with stereotactic radiosurgery (SRS). New aneurysm formation and residual AVM regrowth were confirmed 21 years after the SRS. Eight months later, rebleeding occurred. The second patient was a 5-year-old boy who underwent removal of a left cerebellar hemorrhage and AVM. The residual AVM was treated with SRS. Residual AVM regrowth was detected at 6 years 7 months after SRS. Five months later, new aneurysm formation was confirmed. Two additional days later, rebleeding occurred. LESSONS: New aneurysm formation and residual AVM regrowth may predict rebleeding and can occur >20 years after the initial rupture and treatment. If AVM obliteration is not achieved, long-term follow-up is needed, even in adulthood, with attention to new aneurysm formation and residual AVM regrowth. Further treatment is recommended if these findings are confirmed.

A Ruptured Left Gastric Artery Aneurysm That Neoplasticized during the Course of Coronavirus Disease 2019: A Case Report.

Coronavirus disease 2019 (COVID-19) is an acute respiratory syndrome caused by SARS-CoV-2 and is known to cause respiratory and systemic symptoms. A SARS-CoV-2 infection is involved in aneurysm formation, enlargement, and rupture in medium-sized vessels, such as the cerebral and coronary arteries and the aorta. In contrast, its involvement in forming aneurysms in medium-sized vessels other than the cerebral and coronary arteries has not been reported. An 84-year-old Japanese man with COVID-19 was admitted to our hospital. The treatment course was favorable, and the COVID-19 treatment was completed by the 10th day. On day 14, pancreatic enzymes increased mildly. An abdominal computed tomography revealed a ruptured left gastric aneurysm after spontaneous hemostasis. Arterial embolization was performed. In this patient, a new left gastric aneurysm was suspected of having formed and ruptured during the course of the COVID-19 treatment. To the best of our knowledge, this is the first report of abdominal visceral aneurysm formation caused by COVID-19 in a medium-sized vessel, and it is necessary to remember that aneurysms can be formed at any site when treating this syndrome.

A Modification to a Murine Model for Intracranial Aneurysm Formation and Rupture.

Between 3.6% and 6.0% of the population has an intracranial aneurysm. The mechanisms underlying intracranial aneurysm formation and rupture are not fully known. Several rodent models have been developed to better understand intracranial aneurysm pathophysiology. Hypertension, hemodynamic changes, and vessel injury are all necessary for aneurysm induction; however, multiple invasive procedures may disrupt an animal's physiology. Therefore, we hypothesized that our method for inducing hypertension could be modified to create a simpler model. We previously developed a highly reproducible murine model of intracranial aneurysm formation and rupture that involves hemodynamic changes through ligation of the left common carotid artery, vessel wall degradation using elastase and a lysyl oxidase inhibitor, and hypertension through a high-salt diet, continuous angiotensin II infusion, and right renal artery ligation. In order to create a simpler model, we sought to eliminate renal artery ligation. We assessed aneurysm formation, aneurysm rupture, and blood pressure in two separate cohorts of C57BL/6 mice: one cohort underwent our model as above, while another cohort did not receive right renal artery ligation. Our results demonstrate that intracranial aneurysm formation and rupture rates did not differ between each group. Further, the blood pressures between cohorts did not differ at various timepoints in the model. Both cohorts, however, did have a significant increase in blood pressure from baseline, suggesting that renal artery ligation is not needed for inducing hypertension. These findings demonstrate that our murine model can be modified to eliminate right renal artery ligation. Thus, we propose this modification to our murine model for studying intracranial aneurysm pathophysiology.

False lumen enhancement characteristics on computed tomography angiography predict risk of aneurysm formation in acute type B aortic dissection.

OBJECTIVES: Differential luminal enhancement [between true lumen (TL) and false lumen (FL)] results from differential flow patterns, most likely due to outflow restriction in the FL. We aimed to assess the impact of differential luminal enhancement at baseline computed tomography angiography on the risk of adverse events in patients with acute type B aortic dissection (TBAD). METHODS: Baseline computed tomography angiographies of patients with acute TBAD between 2007 and 2016 (n = 48) were analysed using three-dimensional software at multiple sites along the descending thoraco-abdominal aorta. At each location, we measured contrast density in TL and FL [Houndsfield unit (HU)], maximal diameter (cm) and circumferential FL extent (°). Outcome data were collected via retrospective chart review. Multivariable logistic regression models were employed to determine the independent risk of TL-FL differential luminal enhancement on aneurysm formation (maximal diameter ≥55 mm) and medical treatment failure. RESULTS: Patients were predominately male (75%) and 52.8±12.9 years at diagnosis. The mean follow-up was 5.9±2.6 years, and 42% (n = 20/48) patients were diagnosed with thoraco-abdominal aortic aneurysm. The baseline absolute difference between FL and TL contrast density measured at 2 cm distal to primary entry tear (TL-FLabs-Tear) was significantly higher among patients who developed aneurysm (26 HU, IQR: 15-53 vs 13 HU, IQR: 4-24, P = 0.001). Aneurysm development during follow-up was predicted by TL-FLabs-Tear (odds ratio 1.07, P = 0.012) and baseline maximal aortic diameter (odds ratio 1.90, P < 0.001). High (≥18 HU) differential luminal enhancement was associated with lower rates of aneurysm-free survival and higher rates of medical treatment failure. CONCLUSIONS: Differential luminal enhancement may be a novel predictor of aneurysm formation among patients with acute TBAD.

Repeated Retching and Vomiting in the Pathophysiology of Isolated Spinal Aneurysms.

BACKGROUND: Rupture of spinal aneurysms is a rare cause of subarachnoid hemorrhage. These aneurysms are often associated with a variety of vascular malformations that increase blood flow in the spinal circulation or with disorders that compromise the vessel wall. However, spinal aneurysms may be isolated, not associated with any known predisposing condition. The objective of this study is to explore the possible mechanisms associated with the formation and rupture of isolated spinal aneurysms (ISAs). METHODS: We conducted a retrospective review of a series of consecutive patients admitted for a ruptured ISA. In all cases, spinal angiography confirmed the presence of a spinal aneurysm responsible for the bleeding. Particular attention was paid to medical history and symptoms before bleeding, for potential factors predisposing to their formation and rupture. RESULTS: Between 2008 and 2020, ten cases of spinal aneurysms were seen at our institution including 4 cases of ISA. All patients with ISA were female, and in 3 cases the aneurysm involved the territory of the posterior spinal artery. In 3 of these 4 (75%) ISA cases, there was a strikingly similar history of retching and vomiting preceding the thunderclap headache. In 1 patient, the aneurysm was surgically resected; pathologic analysis revealed a fusiform dissecting aneurysm. All 4 patients had a favorable outcome. CONCLUSIONS: We suggest that the straining during prolonged retching and vomiting plays a role in the formation and rupture of some ISAs, possibly because of pressure spikes, increased transmural arterial pressure, and increased wall shear stress during straining.

Proximal Parent Vessel Tapering is Associated With Aneurysm at the Middle Cerebral Artery Bifurcation.

BACKGROUND: Cerebral aneurysm initiation and evolution have been linked to hemodynamic and morphological factors. Stenotic morphology upstream to a bifurcation can alter hemodynamic patterns and lead to destructive vessel wall remodeling and aneurysm initiation. The effect of more subtle proximal variations in vessel diameter on bifurcation aneurysm development has not been evaluated. OBJECTIVE: To investigate whether vessel tapering is associated with aneurysmal presence at the middle cerebral artery (MCA) bifurcation. METHODS: Bilateral catheter three-dimensional rotational angiographic datasets from 33 patients with unilateral unruptured MCA aneurysms and 44 datasets from healthy patients were analyzed. Equidistant cross-sectional cuts were generated along the MCA M1 segment with cross-sectional area measurement using edge-detection filtering. Relative tapering of the M1 segment was evaluated as the TaperingRatio. Computational fluid dynamics (CFD) simulations were performed on bilateral patient models and parametric MCAs of constant and tapered inflow vessel. RESULTS: MCA leading to aneurysms had significantly lower TaperingRatio (0.88 ± 0.15) compared to contralateral (1.00 ± 0.16, P = .002) and healthy MCAs (1.00 ± 0.15, P > .001, area under the curve = 0.73), which showed little to no tapering. CFD simulations showed that vessel tapering leads to flow acceleration with higher wall shear stress (WSS) and WSS gradients at the bifurcation apex. CONCLUSION: Aneurysmal but not contralateral or control MCA M1 segments demonstrate a previously undescribed progressive distal tapering phenomenon. This upstream vessel narrowing leads to flow acceleration that accentuates WSS and spatial gradients at the bifurcation apex, a pattern previously shown to favor aneurysm initiation and progression.

Natural Cerebral Aneurysm and Spontaneous Subarachnoid Hemorrhage in Mammals Other Than Man: Is There a Scope for Comparative Medicine?

BACKGROUND: Concepts that showed substantial efficacy in animal models of subarachnoid hemorrhage (SAH) often failed to improve outcome in humans with aneurysmal SAH. The concept of "comparative medicine," an open-minded comparison across species, might offer an alternative to the "constructed" animal models' approach. Naturally occurring diseases in animals might bear more similarity to human diseases than models. In this context, the question arises whether spontaneous intracranial aneurysms exist in animals or not, and whether they cause SAH or not. METHODS: A systematic literature search was performed. Only articles dealing with natural aneurysms and/or SAH of mammals other than man were included. All articles dealing with induced aneurysms and/or SAH were removed. RESULTS: Of 2812 screened articles, 9 articles describing natural intracranial aneurysms and/or SAH were found. In total 1979 individual animals of 29 species were examined. Natural intracranial aneurysms were described in 7 individual animals of 6 species. Spontaneous SAH was described in 3 species. In 1 chimpanzee, a ruptured intracranial aneurysm caused an SAH. Histological descriptions of the aneurysms were strikingly similar to those of humans. CONCLUSIONS: Although interesting and innovative, the concept of "comparative medicine" seems to be impracticable due to the seemingly ultralow incidence of natural aneurysmal SAH in mammals other than man. The answer to the question "why intracranial aneurysms are less common in animals despite the strong histological similarity of cerebral arteries" might be a key issue. Last but not least, primates likely matter in SAH-related research, as aneurysmal SAH occurs in primates.

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

OBJECTIVE: There 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. METHODS: To 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. RESULTS: The 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-1ß [IL-1ß], 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. CONCLUSIONS: These 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.

Proximal Stenosis Is Associated with Rupture Status in Middle Cerebral Artery Aneurysms.

BACKGROUND: Hemodynamic factors impact cerebral aneurysm development and progression. Parent vessel architectural features, such as caliber, curvature, and angle, can affect downstream pressure and shear stress. OBJECTIVE: To investigate the association between proximal parent vessel stenosis and aneurysm rupture status at the middle cerebral artery (MCA) bifurcation. METHODS: Catheter 3-dimensional rotational angiographic datasets from 69 Japanese patients with MCA aneurysms (58 unruptured/11 ruptured) were analyzed. The narrowest cross-sectional area of the M1 segment was evaluated through equidistant cross-sectional plane cuts along the M1 length. The degree of stenosis relative to M1 size (StenosisIndex) and the distance from stenosis to the aneurysm neck (StenosisAnDist) were statistically evaluated. The effects of StenosisIndex and StenosisAnDist were determined in parametric aneurysm models with/without stenosis using computational fluid dynamic and fluid-structure interaction simulations. RESULTS: MCA harboring ruptured aneurysms had significantly greater StenosisIndex (0.31 ± 0.21 vs. 0.17 ± 0.14, P = 0.01), indicative of greater narrowing, and shorter StenosisAnDist (4.26 ± 1.91 vs. 6.94 ± 4.06 mm, P = 0.02) compared with unruptured aneurysms. Multivariate analysis combining StenosisIndex and StenosisAnDist resulted in P = 0.003, area under the curve = 0.81 (80% sensitivity, 74% specificity). Computational fluid dynamic and fluid-structure interaction simulations identified a synergetic effect of high stenosis and short StenosisAnDist in inducing greater aneurysm inflow velocity and deeper jet penetration, greater dome pressure, and greater tensile stress in the aneurysm wall. CONCLUSIONS: Ruptured status in bifurcation MCA aneurysms was associated with severity of proximal M1 stenosis and its proximity to the aneurysm neck, a novel risk factor, which acts by increasing aneurysm dome wall tension, and should be considered in investigations of rupture risk stratification.