Hypoxia Marker Carbonic Anhydrase IX Is Present in Abdominal Aortic Aneurysm Tissue and Plasma

Abdominal aortic aneurysms (AAA) are a significant cause of premature deaths worldwide. Since there is no specific treatment for reducing AAA progression, it is crucial to understand the pathogenesis leading to aneurysm wall weakening/remodeling and identify new proteins involved in this process which could subsequently serve as novel therapeutic targets. In this study, we analyzed the presence of the hypoxia-related proteins carbonic anhydrase IX (CA IX), hypoxia-inducible factor 1α (HIF-1α), and AKT as the key molecule in the phosphoinositide-3-kinase pathway in the AAA wall. Additionally, we used a blood-based assay to examine soluble CA IX (s-CA IX) levels in the plasma of AAA patients. Using western blotting, we detected CA IX protein in 12 out of 15 AAA tissue samples. Immunohistochemistry staining proved CA IX expression in the media of the aneurysmal wall. Evaluation of phosphorylated (p-AKT) and total AKT showed elevated levels of both forms in AAA compared to normal aorta. Using ELISA, we determined the concentration of s-CA IX >20 pg/mL in 13 out of 15 AAA patients. Results obtained from in silico analysis of CA9 and aneurysm-associated genes suggest a role for CA IX in aneurysmal wall remodeling. Our results prove the presence of hypoxia-related CA IX in AAA tissues and indicate a possible role of CA IX in hypoxia-associated cardiovascular diseases.

Effect of Pulsatility on the Transport of Thrombin in an Idealized Cerebral Aneurysm Geometry

Computational models of cerebral aneurysm thrombosis are designed for use in research and clinical applications. A steady flow assumption is applied in many of these models. To explore the accuracy of this assumption a pulsatile-flow thrombin-transport computational fluid dynamics (CFD) model, which uses a symmetrical idealized aneurysm geometry, was developed. First, a steady-flow computational model was developed and validated using data from an in vitro experiment, based on particle image velocimetry (PIV). The experimental data revealed an asymmetric flow pattern in the aneurysm. The validated computational model was subsequently altered to incorporate pulsatility, by applying a data-derived flow function at the inlet boundary. For both the steady and pulsatile computational models, a scalar function simulating thrombin generation was applied at the aneurysm wall. To determine the influence of pulsatility on thrombin transport, the outputs of the steady model were compared to the outputs of the pulsatile model. The comparison revealed that in the pulsatile case, an average of 10.2% less thrombin accumulates within the aneurysm than the steady case for any given time, due to periodic losses of a significant amount of thrombin-concentrated blood from the aneurysm into the parent vessel’s bloodstream. These findings demonstrate that pulsatility may change clotting outcomes in cerebral aneurysms.

Vessel wall imaging with advanced flow suppression in the characterization of intracranial aneurysms following flow diversion with Pipeline embolization device

BackgroundHigh-resolution vessel wall MRI (VWI) is increasingly used to characterize intramural disorders of the intracranial vasculature unseen by conventional arteriography.ObjectiveTo evaluate the use of VWI for surveillance of flow diverter (FD) treated aneurysms.Materials and methodsRetrospective study of 28 aneurysms (in 21 patients) treated with a FD (mean 57 years; 14 female). All examinations included VWI and a contemporaneously obtained digital subtraction angiogram. Multiplanar pre- and post-gadolinium 3D, variable flip-angle T1 black-blood VWI was obtained using delay alternating nutation for tailored excitation (DANTE) at 3T. 3D time-of-flight MR angiography (MRA) was also carried out. Images were assessed for in-stent stenosis, aneurysm occlusion, presence and pattern/distribution of aneurysmal or parent vessel gadolinium enhancement.ResultsThe VWI-MRI was performed on average at 361±259 days after the intervention. Follow-up DSA was performed at 338±254 days postintervention. Good or excellent black-blood angiographic quality was recorded in 22/28 (79%) pre-contrast and 21/28 (75%) post-contrast VWI, with no cases excluded for image quality. Aneurysm enhancement was noted in 24/28 (85.7%) aneurysms, including in 79% of angiographically occluded aneurysms and 100% of angiographically non-occluded aneurysms. Enhancement of the stented parent-vessel wall occurred significantly more often when aneurysm enhancement was present (92% vs 33%, p=0.049).ConclusionAdvanced VWI produces excellent depiction of FD-treated aneurysms, with robust evaluation of the parent vessel and aneurysm wall to an extent not achievable with conventional MRI/MRA. Gadolinium enhancement may, however, continue even after enduring catheter angiographic occlusion, confounding interpretation, and requiring cognizance of this potentially prolonged effect in such patients.

Analysis of Cerebral Aneurysm Wall Tension and Enhancement Using Finite Element Analysis and High-Resolution Vessel Wall Imaging

Biomechanical computational simulation of intracranial aneurysms has become a promising method for predicting features of instability leading to aneurysm growth and rupture. Hemodynamic analysis of aneurysm behavior has helped investigate the complex relationship between features of aneurysm shape, morphology, flow patterns, and the proliferation or degradation of the aneurysm wall. Finite element analysis paired with high-resolution vessel wall imaging can provide more insight into how exactly aneurysm morphology relates to wall behavior, and whether wall enhancement can describe this phenomenon. In a retrospective analysis of 23 unruptured aneurysms, finite element analysis was conducted using an isotropic, homogenous third order polynomial material model. Aneurysm wall enhancement was quantified on 2D multiplanar views, with 14 aneurysms classified as enhancing (CRstalk≥0.6) and nine classified as non-enhancing. Enhancing aneurysms had a significantly higher 95th percentile wall tension (μ = 0.77 N/cm) compared to non-enhancing aneurysms (μ = 0.42 N/cm, p < 0.001). Wall enhancement remained a significant predictor of wall tension while accounting for the effects of aneurysm size (p = 0.046). In a qualitative comparison, low wall tension areas concentrated around aneurysm blebs. Aneurysms with irregular morphologies may show increased areas of low wall tension. The biological implications of finite element analysis in intracranial aneurysms are still unclear but may provide further insights into the complex process of bleb formation and aneurysm rupture.

Effect of Aneurysm and Patient Characteristics on Intracranial Aneurysm Wall Thickness

Background: The circle of Willis is a network of arteries allowing blood supply to the brain. Bulging of these arteries leads to formation of intracranial aneurysm (IA). Subarachnoid hemorrhage (SAH) due to IA rupture is among the leading causes of disability in the western world. The formation and rupture of IAs is a complex pathological process not completely understood. In the present study, we have precisely measured aneurysmal wall thickness and its uniformity on histological sections and investigated for associations between IA wall thickness/uniformity and commonly admitted risk factors for IA rupture.Methods: Fifty-five aneurysm domes were obtained at the Geneva University Hospitals during microsurgery after clipping of the IA neck. Samples were embedded in paraffin, sectioned and stained with hematoxylin-eosin to measure IA wall thickness. The mean, minimum, and maximum wall thickness as well as thickness uniformity was measured for each IA. Clinical data related to IA characteristics (ruptured or unruptured, vascular location, maximum dome diameter, neck size, bottleneck factor, aspect and morphology), and patient characteristics [age, smoking, hypertension, sex, ethnicity, previous SAH, positive family history for IA/SAH, presence of multiple IAs and diagnosis of polycystic kidney disease (PKD)] were collected.Results: We found positive correlations between maximum dome diameter or neck size and IA wall thickness and thickness uniformity. PKD patients had thinner IA walls. No associations were found between smoking, hypertension, sex, IA multiplicity, rupture status or vascular location, and IA wall thickness. No correlation was found between patient age and IA wall thickness. The group of IAs with non-uniform wall thickness contained more ruptured IAs, women and patients harboring multiple IAs. Finally, PHASES and ELAPSS scores were positively correlated with higher IA wall heterogeneity.Conclusion: Among our patient and aneurysm characteristics of interest, maximum dome diameter, neck size and PKD were the three factors having the most significant impact on IA wall thickness and thickness uniformity. Moreover, wall thickness heterogeneity was more observed in ruptured IAs, in women and in patients with multiple IAs. Advanced medical imaging allowing in vivo measurement of IA wall thickness would certainly improve personalized management of the disease and patient care.

Lumen-oriented versus wall-oriented treatment strategies for intracranial aneurysms – A systematic review of suggested therapeutic concepts

The development of new treatment strategies for intracranial aneurysms (IAs) has been and continues to be a major interest in neurovascular research. Initial treatment concepts were mainly based on a physical-mechanistic disease understanding for IA occlusion (lumen-oriented therapies). However, a growing body of literature indicates the important role of aneurysm wall biology (wall-oriented therapies) for complete IA obliteration. This systematic literature review identified studies that explored endovascular treatment strategies for aneurysm treatment in a preclinical setting. Of 5278 publications screened, 641 studies were included, categorized, and screened for eventual translation in a clinical trial. Lumen-oriented strategies included (1) enhanced intraluminal thrombus organization, (2) enhanced intraluminal packing, (3) bridging of the intraluminal space, and (4) other, alternative concepts. Wall-oriented strategies included (1) stimulation of proliferative response, (2) prevention of aneurysm wall cell injury, (3) inhibition of inflammation and oxidative stress, and (4) inhibition of extracellular matrix degradation. Overall, lumen-oriented strategies numerically still dominate over wall-oriented strategies. Among the plethora of suggested preclinical treatment strategies, only a small minority were translated into clinically applicable concepts (36 of 400 lumen-oriented and 6 of 241 wall-oriented). This systematic review provides a comprehensive overview that may provide a starting point for the development of new treatment strategies.

Intracranial aneurysm wall (in)stability–current state of knowledge and clinical perspectives

Intracranial aneurysm (IA), a local outpouching of cerebral arteries, is present in 3 to 5% of the population. Once formed, an IA can remain stable, grow, or rupture. Determining the evolution of IAs is almost impossible. Rupture of an IA leads to subarachnoid hemorrhage and affects mostly young people with heavy consequences in terms of death, disabilities, and socioeconomic burden. Even if the large majority of IAs will never rupture, it is critical to determine which IA might be at risk of rupture. IA (in)stability is dependent on the composition of its wall and on its ability to repair. The biology of the IA wall is complex and not completely understood. Nowadays, the risk of rupture of an IA is estimated in clinics by using scores based on the characteristics of the IA itself and on the anamnesis of the patient. Classification and prediction using these scores are not satisfying and decisions whether a patient should be observed or treated need to be better informed by more reliable biomarkers. In the present review, the effects of known risk factors for rupture, as well as the effects of biomechanical forces on the IA wall composition, will be summarized. Moreover, recent advances in high-resolution vessel wall magnetic resonance imaging, which are promising tools to discriminate between stable and unstable IAs, will be described. Common data elements recently defined to improve IA disease knowledge and disease management will be presented. Finally, recent findings in genetics will be introduced and future directions in the field of IA will be exposed.