Abdominal Aortic Aneurysm Wall Research Articles

Increasing abdominal aortic aneurysm curvature visibility using 3D dual probe bistatic ultrasound imaging combined with probe translation

High frame rate ultrasound (US) imaging techniques in 3D are promising tools for capturing abdominal aortic aneurysms (AAAs) over time, however, with the limited number of channel-to-element connections current footprints are small, which limits the field of view. Moreover, the maximal steering angle of the ultrasound beams in transmit and the maximal receptance angle in receive are insufficient for capturing the curvy shape of the AAA. Therefore, an approach is needed towards large arrays. In this study, high frame rate bistatic 3D US data (17 Hz) were acquired with two synchronized matrix arrays positioned at different locations (multi-aperture imaging) using a translation stage to simulate what a larger array with limited channel-to-element connections can potentially achieve. Acquisitions were performed along an AAA shaped phantom with different probe tilting angles (0 up to ± 30°). The performance of different multi-aperture configurations was quantified using the generalized contrast-to-noise ratio of the wall and lumen (gCNR). Furthermore, a parametric model of the multi-aperture system was used to estimate in which AAA wall regions the contrast is expected to be high. This was evaluated for AAAs with increasing diameters and curvature. With an eight-aperture 0° probe angle configuration a 69 % increase in field of view was measured in the longitudinal direction compared to the field of view of a single aperture configuration. When increasing the number of apertures from two to eight, the gCNR improved for the upper wall and lower wall by 35 % and 13 % (monostatic) and by 36 % and 13 % (bistatic). Contrast improvements up to 22 % (upper wall) and 12 % (lower wall) are achieved with tilted probe configurations compared to non-tilted configurations. Moreover, with bistatic imaging with tilted probe configurations gCNR improvements up to 4 % (upper wall) and 7 % (lower wall) are achieved compared to monostatic imaging. Furthermore, imaging with a larger inter-probe distance improved the gCNR for a ± 15° probe angle configuration. The gCNR has an expected pattern over time, where the contrast is lower when there is more wall motion (systole) and higher when motion is reduced (diastole). Furthermore, a higher frame rate (45 Hz) yields a lower gCNR, because fewer compound angles are used. The results of the parametric model suggest that a flat array is suitable for imaging AAA shapes with limited curvature, but that it is not suitable for imaging larger AAA shapes with more curvature. According to the model, tilted multi-aperture configurations combined with bistatic imaging can achieve a larger region with high contrast compared to non-tilted configurations. The findings of the model are in agreement with experimental findings. To conclude, this study demonstrates the vast improvements in field of view and AAA wall visibility that a large, sparsely populated 3D array can potentially achieve when imaging AAAs compared to single or dual aperture imaging. In the future, larger arrays, less thermal noise, more steering, and more channel-to-element connections combined with carefully chosen orientations of (sub-) apertures will likely advance 3D imaging of AAAs.

Computational Study of Abdominal Aortic Aneurysm Walls Accounting for Patient-Specific Non-Uniform Intraluminal Thrombus Thickness and Distinct Material Models: A Pre- and Post-Rupture Case.

An intraluminal thrombus (ILT) is present in the majority of abdominal aortic aneurysms, playing a crucial role in their growth and rupture. Although most computational studies do not include the ILT, in the present study, this is taken into account, laying out the whole simulation procedure, namely, from computed tomography scans to medical image segmentation, geometry reconstruction, mesh generation, biomaterial modeling, finite element analysis, and post-processing, all carried out in open software. By processing the tomography scans of a patient's aneurysm before and after rupture, digital twins are reconstructed assuming a uniform aortic wall thickness. The ILT and the aortic wall are assigned different biomaterial models; namely, the first is modeled as an isotropic linear elastic material, and the second is modeled as the Mooney-Rivlin hyperelastic material as well as the transversely isotropic hyperelastic Holzapfel-Gasser-Ogden nonlinear material. The implementation of the latter requires the designation of local Cartesian coordinate systems in the aortic wall, suitably oriented in space, for the proper orientation of the collagen fibers. The composite aneurysm geometries (ILT and aortic wall structures) are loaded with normal and hypertensive static intraluminal pressure. Based on the calculated stress and strain distributions, ILT seems to be protecting the aneurysm from a structural point of view, as the highest stresses appear in the thrombus-free areas of the aneurysmal wall.

Assessing trans-endothelial transport of nanoparticles for delivery to abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are localized, rupture-prone expansions of the abdominal aorta wall. In this condition, structural extracellular matrix (ECM) proteins of the aorta wall, elastic fibers and collagen fibers, that impart elasticity and stiffness respectively, are slowly degraded by overexpressed matrix metalloproteinases (MMPs) following an injury stimulus. We are seeking to deliver therapeutics to the AAA wall using polymer nanoparticles (NPs) that are capable of stimulating on-site matrix regeneration and repair. This study aimed to determine how NP shape and size impacts endocytosis and transmigration past the endothelial cell (EC) layer from circulation into the medial layer of the AAA wall. First, rod-shaped NPs were shown to be created based mechanical stretching of PLGA NPs while embedded in a PVA film with longer rod-shaped NPs created based of the degree in which the PVA films are stretched. Live/dead assay reveals that our PLGA NPs are safe and do not cause cell death. Immunofluorescence staining reveal cytokine activation causes endothelial dysfunction in ECs by increasing expression of inflammatory marker Integrin αVβ3 and decreasing expression of adhesion protein vascular endothelial (VE)-cadherin. We showed this disruption enable greater EC uptake and translocation of NPs. Fluorescence studies demonstrate high endothelial transmigration and endocytosis with rod-shaped NPs in cytokine activated ECs compared to healthy control cells, arguing for the benefits of using higher aspect ratio (AR) NPs for accumulation at the aneurysm site. We also demonstrated that the mechanisms of NP transmigration across an activated EC layer depend on NP AR. These results show the potential of using shape as a modality for enhancing permeation of NPs into the aneurysm wall. These studies are also significance to understanding the mechanisms that are likely engaged by NPs for penetrating the endothelial lining of aneurysmal wall segments.

Morphology of Abdominal Aortic Aneurysms and Correlation with Biomechanical Tests of Aneurysmal Wall Fragments

Evaluate how specific morphologic aspects of abdominal aortic aneurysms (AAAs), including asymmetries, curvatures, tortuosities, and angulations, among others can influence the intrinsic biomechanical properties of the AAA's wall. This study analyzed the correlation of geometric measurements (1-dimensional, 2-dimensional, and 3-dimensional) of preoperative tomographic images of AAA with uniaxial biomechanical tests of the arterial wall fragments of these AAA obtained in open surgical repair of aneurysms. It was a multicenter, experimental, and observational study, and initially 54 individuals were selected who underwent open surgical of AAA, with valid biomechanical tests of the anterior wall of the AAA. Seven individuals were excluded because they had poor preoperative quality computed tomography scans and/or artifacts that impeded image segmentation and extraction of AAA geometric indices. The aortic fragments were subjected to uniaxial biomechanical destructive tests to obtain the following data: maximum load, failure stress, failure tension, failure strain energy, strain, and fragment thickness. In the same patients, preoperative computed tomography scans were performed with the extraction of 26 geometric indices, subdivided into 9 1-dimensional indices, 6 2-dimensional indices, and 11 3-dimensional indices. Data were subjected to statistical analysis using SPSS version28. Comparing ruptured and unruptured AAA, no statistical difference was observed between the biomechanical and geometric parameters. The fragment thickness of the ruptured AAA was lower than that of the unruptured AAA (P<0.05). By comparing tomographic geometric indices and biomechanical parameters of the aortic fragments using Pearson's coefficient, positive and linear correlations (P<0.05) were observed between the geometric variable maximum diameter (Dmax) of the AAA with maximum load (r=0.408), failure tension (r=0.372), and failure stress (r=0.360). Positive and linear correlations were also observed between the variable diameter/height ratio (DHr) and the maximum load (r=0.360), failure tension (r=0.354), and failure stress (r=0.289). The geometric variable DHr was dependent and correlated with Dmax. Simple regression analysis showed that R2 varied between 8.3% and 16.7%, and all models were significant (P<0.05). Dmax and DHr were linearly and positively correlated with the resistance parameters (maximum load, failure tension, and failure stress) of the AAA fragments. The DHr variable is dependent and correlated with Dmax. There was no correlation between the other geometric indices and the biomechanical parameters of the AAA wall. The asymmetries did not globally influence the biomechanics of AAA wall; however, they may influence regionally. Larger AAAs were stronger than smaller ones. Therefore, such findings may point toward Dmax is still the main geometric parameter, which influences the anterior wall, and possibly globally in the AAA.

Intermediate pressure-normalized principal wall strain values are associated with increased abdominal aortic aneurysmal growth rates.

Current abdominal aortic aneurysm (AAA) assessment relies on analysis of AAA diameter and growth rate. However, evidence demonstrates that AAA pathology varies among patients and morphometric analysis alone is insufficient to precisely predict individual rupture risk. Biomechanical parameters, such as pressure-normalized AAA principal wall strain (/PP, %/mmHg), can provide useful information for AAA assessment. Therefore, this study utilized a previously validated ultrasound elastography (USE) technique to correlate /PP with the current AAA assessment methods of maximal diameter and growth rate. Our USE algorithm utilizes a finite element mesh, overlaid a 2D cross-sectional view of the user-defined AAA wall, at the location of maximum diameter, to track two-dimensional, frame-to-frame displacements over a full cardiac cycle, using a custom image registration algorithm to produce /PP. This metric was compared between patients with healthy aortas and AAAs (≥3 cm) and compared between small and large AAAs (≥5 cm). AAAs were then separated into terciles based on /PP values to further assess differences in our metric across maximal diameter and prospective growth rate. Non-parametric tests of hypotheses were used to assess statistical significance as appropriate. USE analysis was conducted on 129 patients, 16 healthy aortas and 113 AAAs, of which 86 were classified as small AAAs and 27 as large. Non-aneurysmal aortas showed higher /PP compared to AAAs (0.044 ± 0.015 vs. 0.034 ± 0.017%/mmHg, p = 0.01) indicating AAA walls to be stiffer. Small and large AAAs showed no difference in /PP. When divided into terciles based on /PP cutoffs of 0.0251 and 0.038%/mmHg, there was no difference in AAA diameter. There was a statistically significant difference in prospective growth rate between the intermediate tercile and the outer two terciles (1.46 ± 2.48 vs. 3.59 ± 3.83 vs. 1.78 ± 1.64 mm/yr, p = 0.014). There was no correlation between AAA diameter and /PP, indicating biomechanical markers of AAA pathology are likely independent of diameter. AAAs in the intermediate tercile of /PP values were found to have nearly double the growth rates than the highest or lowest tercile, indicating an intermediate range of /PP values for which patients are at risk for increased AAA expansion, likely necessitating more frequent imaging follow-up.

Optimization of nano-microparticle size and shape on wall-interaction: a human case study on an abdominal aortic aneurysm

Spherical nano-microcarriers generally perform targeted delivery of drugs to blood vessels with lesions. Recently, some studies have shown the importance of the non-spherical nature of nano-microcarriers in their movement toward the target wall inside blood arteries. Non-spherical particles tend to collide and adhere to the target wall due to their high interaction level with the artery wall. However, detailed kinematic studies have yet to be carried out to optimize nano-microcarriers’ shape based on their delivery rate to the target wall inside the artery. In addition, it is important to note that the flow of fluid in vessels can have diverse patterns that may affect the movement of drug carriers having different shapes. It is therefore necessary to study the impact of fluid flow patterns on drug carriers, refine their shapes and sizes to achieve the desired drug delivery rate, and reduce the risk of toxicity in blood vessels that have disorders. In the present study, we tried to provide optimal delivery of different forms of nano-microcarriers to the abdominal aortic aneurysm (AAA) wall, which is a common and dangerous lesion in the artery, based on the rate of particle impact on the inner wall of the AAA and the rate of their exit from the downstream of the aorta artery. The results showed that the non-spherical shape strongly depends on the interaction of the particles on the inner wall of the AAA and their departure rate from the aorta artery. Different shapes with different shape factors have optimal delivery conditions compared to the size of each nano-microcarrier in the drug delivery aimed at the wall.

3D-Ultrasound Based Mechanical and Geometrical Analysis of Abdominal Aortic Aneurysms and Relationship to Growth.

The heterogeneity of progression of abdominal aortic aneurysms (AAAs) is not well understood. This study investigates which geometrical and mechanical factors, determined using time-resolved 3D ultrasound (3D + t US), correlate with increased growth of the aneurysm. The AAA diameter, volume, wall curvature, distensibility, and compliance in the maximal diameter region were determined automatically from 3D + t echograms of 167 patients. Due to limitations in the field-of-view and visibility of aortic pulsation, measurements of the volume, compliance of a 60mm long region and the distensibility were possible for 78, 67, and 122 patients, respectively. Validation of the geometrical parameters with CT showed high similarity, with a median similarity index of 0.92 and root-mean-square error (RMSE) of diameters of 3.5mm. Investigation of Spearman correlation between parameters showed that the elasticity of the aneurysms decreases slightly with diameter (p = 0.034) and decreases significantly with mean arterial pressure (p < 0.0001). The growth of a AAA is significantly related to its diameter, volume, compliance, and surface curvature (p < 0.002). Investigation of a linear growth model showed that compliance is the best predictor for upcoming AAA growth (RMSE 1.70mm/year). To conclude, mechanical and geometrical parameters of the maximally dilated region of AAAs can automatically and accurately be determined from 3D + t echograms. With this, a prediction can be made about the upcoming AAA growth. This is a step towards more patient-specific characterization of AAAs, leading to better predictability of the progression of the disease and, eventually, improved clinical decision making about the treatment of AAAs.

Fast strain mapping in abdominal aortic aneurysm wall reveals heterogeneous patterns.

Abdominal aortic aneurysm patients are regularly monitored to assess aneurysm development and risk of rupture. A preventive surgical procedure is recommended when the maximum aortic antero-posterior diameter, periodically assessed on two-dimensional abdominal ultrasound scans, reaches 5.5mm. Although the maximum diameter criterion has limited ability to predict aneurysm rupture, no clinically relevant tool that could complement the current guidelines has emerged so far. In vivo cyclic strains in the aneurysm wall are related to the wall response to blood pressure pulse, and therefore, they can be linked to wall mechanical properties, which in turn contribute to determining the risk of rupture. This work aimed to enable biomechanical estimations in the aneurysm wall by providing a fast and semi-automatic method to post-process dynamic clinical ultrasound sequences and by mapping the cross-sectional strains on the B-mode image. Specifically, the Sparse Demons algorithm was employed to track the wall motion throughout multiple cardiac cycles. Then, the cyclic strains were mapped by means of radial basis function interpolation and differentiation. We applied our method to two-dimensional sequences from eight patients. The automatic part of the analysis took under 1.5minper cardiac cycle. The tracking method was validated against simulated ultrasound sequences, and a maximum root mean square error of 0.22mm was found. The strain was calculated both with our method and with the established finite-element method, and a very good agreement was found, with mean differences of one order of magnitude smaller than the image spatial resolution. Most patients exhibited a strain pattern that suggests interaction with the spine. To conclude, our method is a promising tool for investigating abdominal aortic aneurysm wall biomechanics as it can provide a fast and accurate measurement of the cyclic wall strains from clinical ultrasound sequences.

Effect of Intraluminal Thrombus Burden on the Risk of Abdominal Aortic Aneurysm Rupture.

Abdominal aortic aneurysm (AAA) is a critical health disorder, where the abdominal aorta dilates more than 50% of its normal diameter. Enlargement in abdominal aorta alters the hemodynamics and flow-induced forces on the AAA wall. Depending on the flow conditions, the hemodynamic forces on the wall may result in excessive mechanical stresses that lead to AAA rupture. The risk of rupture can be predicted using advanced computational techniques such as computational fluid dynamics (CFD) and fluid-structure interaction (FSI). For a reliable rupture risk assessment, formation of intraluminal thrombus (ILT) and uncertainty in arterial material properties should be taken into account, mainly due to the patient-specific differences and unknowns in AAAs. In this study, AAA models are computationally investigated by performing CFD simulations combined with FSI analysis. Various levels of ILT burdens are artificially generated in a realistic AAA geometry, and the peak effective stresses are evaluated to elucidate the effect of material models and ILT formation. The results indicate that increasing the ILT burden leads to lowered effective stresses on the AAA wall. The material properties of the artery and ILT are also effective on the stresses; however, these effects are limited compared to the effect of ILT volume in the AAA sac.

First-in-Human Study to Evaluate the Safety and Early Efficacy of a Novel Drug and Delivery System for Stabilizing Small to Medium-Sized Infrarenal Abdominal Aortic Aneurysms

To establish that a one-time, local administration of a novel drug, 1,2,3,4,6-pentagalloyl glucose (PGG) to the abdominal aortic aneurysm (AAA) wall is safe and potentially effective in stabilizing or slowing the growth of small to medium-sized AAA in humans in a multicenter study with ≤3 years of follow-up. Patients with AAA of <5.5 cm diameter were recruited. Via transfemoral access, 25 mL of PGG solution were delivered to the aneurysm wall with a weeping balloon over 3 minutes after infrarenal occlusion. Patients were assessed with computed tomography angiography at 1, 6, 12, 24, and 36 months. Core laboratory values of aneurysm sac maximum diameter and sac volume measurements were used to determine growth. Primary endpoints were technical success and safety (major adverse events at 30 days). Secondary endpoint was growth stabilization defined as freedom from aneurysm sac enlargement (diameter >5 mm/year, or volume increase of >10% per year). Twenty-one patients (20 male), mean age 69, were treated at five centers from June 2019 to August 2022. Technical success was 100%. Four patients showed transient elevation of liver enzyme levels, which returned to normal by 30 days with no clinical symptoms. Follow-up computed tomography angiography data showed average AAA diameter change of 0.2 mm (n = 18), 1.1 mm (n = 7), 2.0 mm (n = 5), and 0.8 mm (n = 2) from baseline at 6, 12, 24, and 36 months. Average volume changes were 2.5%, 9.6%, 24.3%, and 11.6% respectively. At 12 months, none of the aneurysms showed growth >5.0 mm and three had volume growth >10%. Local delivery of PGG in small to medium-sized aneurysms is safe and early efficacy data are promising. The potential for PGG to stabilize or slow growth of small to medium-sized AAA merits further evaluation in a randomized, controlled clinical trial.

Intermediate Pressure-Normalized Strain Values Are Associated With Increased Abdominal Aortic Aneurysmal Growth Rates

Current abdominal aortic aneurysm (AAA) assessment methods rely on simple morphometric analysis of the AAA diameter and growth rate. However, evidence has shown that AAA pathology varies among patients, and morphometric analysis alone is insufficient to predict individual risk of growth. Biomechanical parameters, such as pressure-normalized aortic wall strain (εp+/PP), can provide a surrogate to vessel wall stiffness. We aimed to use our novel ultrasound elastography (USE) technique to measure ερ+/PP and correlate ερ+/PP with maximal AAA diameter and growth rate in the largest clinical trial to date. Our USE algorithm uses a finite element mesh overlayed on a 2D axial view of the user-defined AAA wall at the point of maximum diameter to track frame-to-frame displacements over a full cardiac cycle to measure ερ+/PP. ερ+/PP and growth rate were assessed between small and large AAAs based on a diameter of ≥5 cm. Patients with AAA were then separated into terciles based on ερ+/PP values of 0.0251 and 0.038 to assess differences in the AAA diameter and growth rate. Mann-Whitney U and Kruskal-Wallis tests were used to assess differences as appropriate. USE analysis was conducted on 127 patients, 16 normal aortas and 111 AAAs. A total of 79 patients had at least one follow-up clinical scan used to calculate growth rate. Of the 111 aortas, 85 were classified as small and 26 as large. AAAs showed lower ερ+/PP (stiffer) compared with nonaneurysmal aortas (0.034 ± 0.017 vs 0.044 ± 0.015 %/kPa; P = .006). There was no difference in ερ+/PP or growth rate between small and large AAAs. When divided into terciles based on ερ+/PP, there was no difference in the AAA diameter. There was a statistically significant difference in growth rate between the intermediate tercile and the outer terciles (1.46 ± 2.48 vs 3.59 ± 3.83 vs 1.78 ± 1.64 mm/y; P = .014) (Fig). Our validated USE algorithm shows that AAAs are stiffer than nonaneurysmal aortas, similar to previous reports. There was no correlation between AAA diameter and ερ+/PP, indicating that AAA stiffness is independent of diameter, and diameter thresholds alone may not accurately assess future risk of growth. AAAs in the intermediate tercile of ερ+/PP values were found to have greater growth rates than the outer tercile, indicating that an intermediate range of ερ+/PP values, regardless of diameter, place patients at increased risk for AAA growth. These findings also suggest that AAA growth may be related to a failure of collagen remodeling and may be the underlying event that leads to AAA rupture.

Histopathological Characterization of Abdominal Aortic Aneurysms from Patients with Multiple Aneurysms Compared to Patients with a Single Abdominal Aortic Aneurysm.

The aim of this study was to investigate histopathological differences in abdominal aortic aneurysms (AAAs) between patients with multiple and single arterial aneurysms, as we suspect that there are different underlying mechanisms in aneurysm formation. Analysis was based on a previous retrospective study on patients with multiple arterial aneurysms (mult-AA; defined as at least four, n = 143) and a single AAA (sing-AAA, n = 972) who were admitted to our hospital for treatment between 2006 and 2016. Available paraffin-embedded AAA wall specimens were derived from the Vascular Biomaterial Bank Heidelberg (mult-AA, n = 12 vs. sing-AAA, n = 19). Sections were analyzed regarding structural damage of the fibrous connective tissue and inflammatory cell infiltration. Alterations to the collagen and elastin constitution were assessed by Masson-Goldner trichrome and Elastica van Gieson staining. Inflammatory cell infiltration, response and transformation were assessed by CD45 and IL-1β immunohistochemistry and von Kossa staining. The extent of aneurysmal wall alterations was assessed by semiquantitative gradings and was compared between the groups using Fisher's exact test. IL-1β was significantly more present in the tunica media in mult-AA compared to sing-AAA (p = 0.022). The increased expression of IL-1β in mult-AA compared to sing-AAA indicates inflammatory processes play a role in aneurysm formation in patients with multiple arterial aneurysms.

Surface-Functionalized Stem Cell-Derived Extracellular Vesicles for Vascular Elastic Matrix Regenerative Repair.

Extracellular vesicles (EVs) are nanosized vesicles that carry cell-specific biomolecular information. Our previous studies showed that adult human bone marrow mesenchymal stem cell (BM-MSC)-derived EVs provide antiproteolytic and proregenerative effects in cultures of smooth muscle cells (SMCs) derived from an elastase-infused rat abdominal aortic aneurysm (AAA) model, and this is promising toward their use as a therapeutic platform for naturally irreversible elastic matrix aberrations in the aortic wall. Since systemically administered EVs poorly home into sites of tissue injury, disease strategies to improve their affinity toward target tissues are of great significance for EV-based treatment strategies. Toward this goal, in this work, we developed a postisolation surface modification strategy to target MSC-derived EVs to the AAA wall. The EVs were surface-conjugated with a short, synthetic, azide-modified peptide sequence for targeted binding to cathepsin K (CatK), a cysteine protease overexpressed in the AAA wall. Conjugation was performed using a copper-free click chemistry method. We determined that such conjugation improved EV uptake into cultured aneurysmal SMCs in culture and their binding to the wall of matrix injured vessels ex vivo. The proregenerative and antiproteolytic effects of MSC-EVs on cultured rat aneurysmal SMCs were also unaffected following peptide conjugation. From this study, it appears that modification with short synthetic peptide sequences seems to be an effective strategy for improving the cell-specific uptake of EVs and may be effective in facilitating AAA-targeted therapy.

The study on the impact of AAA wall motion on the hemodynamics based on 4D CT image data.

Purpose: To analyze the effect of the physiological deformation of the vessel wall on the hemodynamics in the abdominal aortic aneurysm (AAA), this paper compared the hemodynamics in AAA based on the moving boundary (MB) simulation and the rigid wall (RW) simulation. Method: Patient-specific models were reconstructed to generate mesh based on four-dimensional computed tomography angiography (4D CT) data. The dynamic mesh technique was used to achieve deformation of the vessel wall, surface mesh and volume mesh of the fluid domain were successively remeshed at each time step. Besides, another rigid wall simulation was performed. Hemodynamics obtained from these two simulations were compared. Results: Flow field and wall shear stress (WSS) distribution are similar. When using the moving boundary method (MBM), mean time-averaged wall shear stress (TAWSS) is lower, mean oscillatory shear index (OSI) and mean relative residence time (RRT) are higher. When using the 10th and 20th percentile values for TAWSS and 80th and 90th percentile values for RRT, the ratios of areas with low TAWSS, high OSI and high RRT to the entire vessel wall are higher than those assuming the vessel as rigid. In addition, one overlapping region of low TAWSS, high OSI and high RRT by using the MBM is consistent with the location of thrombus obtained from the follow-up imaging data. Conclusion: The hemodynamics results by using the MBM reflect a higher blood retention effect. This paper presents a potential tool to assess the risk of intraluminal thrombus (ILT) formation based on the MBM.

Automatic Segmentation and Mechanical Characterisation of the Intraluminal Thrombus and Arterial Wall of Abdominal Aortic Aneurysms Using Time Resolved 3D Ultrasound Images

This study proposes a method for semi-automatic segmentation of abdominal aortic aneurysms (AAAs) and their intraluminal thrombus (ILT), based on time resolved 3D ultrasound (US), and validates results with computed tomography (CT). Moreover, mechanical properties of both wall and ILT are determined, and possible correlations with ILT size and blood pressure are investigated. A semi-automatic segmentation algorithm was developed combining a star-Kalman approach with a 3D snake algorithm. The segmented geometries of both lumen and inner vessel wall were validated with both manual US based segmentations and CT based segmentations. Finally, the lumen and vessel wall distensibility and ILT compressibility were estimated, and correlated to ILT size and blood pressure. For the vessel wall and lumen, the median Similarity Index (SI) was 92% (IQR 90, 94%) and 83% (IQR 75, 87%), respectively. The distensibility of the vessel wall could be determined in 37 out of 40 cases, and had a median value of 0.28 10-5 Pa-1 (IQR 0.18, 0.51⋅10-5). The median systolic-diastolic volume change of the ILT was determined successfully in 21 out of 40 patients, and was -0.57% (IQR -1.1, 1.2%). The vessel and lumen distensibility showed a strong correlation with the systolic pressure (p < .010), rather than with the diastolic pressure. Besides, the lumen distensibility was strongly correlated with the ILT thickness (p = .023). The performance of the semi-automatic segmentation algorithm was shown to be as good as the manual segmentations and highly dependent on the visibility of the ILT (limited contrast in seven patients and clutter in nine patients). This study shows promising results for mechanical characterisation of the vessel, and ILT, including a correlation between distensibility, ILT size, and blood pressure. For future work, inclusion rate needs to be increased by improving the image contrast with novel US techniques.

Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells.

The chronic overexpression of matrix metalloproteases leading to consequent degradation and loss of the elastic matrix with the reduction in tissue elasticity is central to the pathophysiology of proteolytic disorders, such as abdominal aortic aneurysms (AAAs), which are localized rupture-prone aortic expansions. Effecting tissue repair to alleviate this condition is contingent on restoring elastic matrix homeostasis in the aortic wall. This is naturally irreversible due to the poor elastogenicity of adult and diseased vascular cells, and the impaired ability to assemble mature elastic fibers, more so in the context of phenotypic changes to medial smooth muscle cells (SMCs) owing to the loss of nitric oxide (NO) signaling in the AAA wall tissue. In this study, we report the benefits of the exposure of primary human aneurysmal SMCs (aHASMCs) to NO donor drug, sodium nitroprusside (SNP), in improving extracellular matrix homeostasis, particularly aspects of elastic fiber assembly, and inhibition of proteolytic degradation. SNP treatment (100 nM) upregulated elastic matrix regeneration at both gene (p < 0.05) and protein levels (p < 0.01) without affecting cell proliferation, improved gene, and protein expression of crosslinking enzyme, lysyl oxidase (p < 0.05), inhibited the expression of MMP2 (matrix metalloprotease 2) significantly (p < 0.05) and promoted contractile SMC phenotypes in aHASMC culture. In addition, SNP also attenuated the expression of mitogen-activated protein kinases, a significant player in AAA formation and progression. Our results indicate the promise of SNP for therapeutic augmentation of elastic matrix regeneration, with prospects for wall repair in AAAs. Impact Statement Chronic and naturally irreversible enzymatic degradation and loss of elastic fibers are centric to proteolytic disorders such as abdominal aortic aneurysms (AAAs). This is linked to poor elastogenicity of adult and diseased vascular cells, compromising their ability to assemble mature elastic fibers. Toward addressing this, we demonstrate the phenotype-modulatory properties of a nitric oxide donor drug, sodium nitroprusside on aneurysmal smooth muscle cells, and its dose-specific proelastogenic and antiproteolytic properties for restoring elastic matrix homeostasis. Combined with the development of vehicles for site-localized, controlled drug delivery, this can potentially lead to a new nonsurgical approach for AAA wall repair in the future.

Targeting Epidermal Growth Factor Receptor to Stimulate Elastic Matrix Regenerative Repair.

Abdominal aortic aneurysms (AAAs) represent a multifactorial, proteolytic disorder involving disintegration of the matrix structure within the AAA wall. Intrinsic deficiency of adult vascular cells to regenerate and repair the wall elastic matrix, which contributes to vessel stretch and recoil, is a major clinical challenge to therapeutic reversal of AAA growth. In this study, we investigate the involvement of epidermal growth factor receptor-mitogen activated protein kinase (EGFR-MAPK) pathway in the activation of aneurysmal smooth muscle cells (SMCs) by neutrophil elastase, and how EGFR can be targeted for elastic matrix regeneration. We have demonstrated that neutrophil elastase activates EGFR and downregulates expression level of key elastin homeostasis genes (elastin, crosslinking enzyme-lysyl oxidase, and fibulin4) between a dose range of 1-10 μg/mL (p < 0.05). It also incites downstream proteolytic outcomes by upregulating p-extracellular signal-regulated kinase (ERK)1/2 (p < 0.0001) and matrix metalloprotease 2 (MMP2) at a protein level, which is significantly downregulated upon EGFR-specific inhibition by tyrosine kinase inhibitor AG1478 (p-ERK1/2 and MMP2 [p < 0.05]). Moreover, we have shown that EGFR inhibition suppresses collagen amounts in aneurysmal SMCs (p < 0.05) and promotes robust formation of elastic fibers by enhancing its deposition in the extracellular space. Hence, the EGFR-MAPK pathway in aneurysmal cells can be targeted to provide therapeutic effects toward stimulating vascular matrix regeneration. Impact statement Proteolytic disorders such as aortal expansions, called abdominal aortic aneurysms (AAAs), are characterized by naturally irreversible enzymatic breakdown and loss of elastic fibers, a problem that has not yet been surmounted by existing tissue engineering approaches. In this work, we show, for the first time, how epidermal growth factor receptor (EGFR) inhibition provides downstream benefits in elastic fiber assembly and deposition in aneurysmal smooth muscle cell cultures. This work can open future possibilities for development of EGFR-targeted drug-based therapies not only for vessel wall repair in AAAs but also other proteolytically compromised elastic tissues.

Study of flow, Bioheat transfer and cardiac thermal pulse of aneurysm in the abdominal aortic

Abdominal aortic aneurysms (AAA) are serious and difficult to detect conditions that can be deadly if they rupture. Infrared thermography (IRT) is a promising imaging technique that can detect abdominal aortic aneurysms more quickly and less costly than other imaging techniques. A clinical biomarker of circular thermal elevation on the midriff skin surface of AAA patient at various scenarios was expected during diagnosis using IRT scanner. However, it is important to note that thermography is not a perfect technology, and it does have some limitations, such as lack of clinical trials. There is still work to be done to improve this imaging technique and make it a more viable and accurate method in detecting abdominal aortic aneurysms. Nevertheless, thermography is currently one of the most convenient technologies in imaging, and it has the potential to detect abdominal aortic aneurysms earlier than other techniques. Cardiac thermal pulse (CTP), on the other hand, was used to examine the thermal physics of AAA. AAA had a CTP that only responded to systolic phase at regular body temperature. Whereas the AAA wall would establish thermal homeostasis with blood temperature following a quasi-linear relationship as the body experienced fever or stage-2 hypothermia. In contrast, a healthy abdominal aorta displayed a CTP that responded to the full cardiac cycle, including diastolic phase at all simulated scenarios.

Tricaprin can prevent the development of AAA by attenuating aortic degeneration

Medical therapeutic options to prevent rupture of abdominal aortic aneurysm (AAA), a critical event, must be developed. Moreover, further understanding of the process of AAA development and rupture is crucial. Previous studies have revealed that aortic hypoperfusion can induce the development of AAA, and we successfully developed a hypoperfusion-induced AAA animal model. In this study, we examined the effects of medium-chain triglycerides (MCTs), tricaprylin (C8-TG) and tricaprin (C10-TG), on hypoperfusion-induced AAA rat model. We estimated the effects of MCTs on aortic pathologies, mechanical properties of the aorta, and development of AAA. C10-TG, but not C8-TG, significantly suppressed AAA development and completely prevented the rupture. We observed that C10-TG prevented the development and rupture of AAA, but not C8-TG. Additionally, regression of AAA diameter was observed in the C10-TG group. Pathological analysis revealed C10-TG improved the hypoperfusion-induced increase in hypoxia-inducible factor-1α levels, medial smooth muscle cells (SMCs) loss, degeneration of aortic elastin and collagen fibers, and loss of aortic wall elasticity. In addition, regression of the formed AAA was observed by administration of C10-TG after AAA formation. C10-TG administration after AAA formation improved degeneration of AAA wall including degradation of aortic elastin and collagen fibers, stenosis of vasa vasorum, and loss of medial SMCs. These data suggest C10-TG can prevent AAA by attenuating aortic hypoperfusion and degeneration. Considering the clinical safety of C10-TG, C10-TG can be a promising AAA drug candidate.

Mitochondrial Dysfunction and Increased DNA Damage in Vascular Smooth Muscle Cells of Abdominal Aortic Aneurysm (AAA-SMC).

There is increasing evidence for enhanced oxidative stress in the vascular wall of abdominal aortic aneurysms (AAA). Mitochondrial damage and dysfunction are hypothesized to be actors in altered production of reactive oxygen species (ROS) and oxidative stress. However, the role of mitochondria and oxidative stress in vascular remodelling and progression of AAA remains uncertain. We here addressed whether mitochondrial dysfunction is persistently increased in vascular smooth muscle cells (VSMCs) isolated from AAA compared to healthy VSMC. AAA-derived VSMC cultures (AAA-SMC, n = 10) and normal VSMC cultures derived from healthy donors (n = 7) were grown in vitro and analysed for four parameters, indicating mitochondrial dysfunction: (i) mitochondrial content and morphology, (ii) ROS production and antioxidative response, (iii) NADP+/NADPH content and ratio, and (iv) DNA damage, in the presence or absence of angiotensin II (AngII). AAA-SMC displayed increased mitochondrial circularity (rounded shape), reduced mitochondrial area, and reduced perimeter, indicating increased fragmentation and dysfunction compared to healthy controls. This was accompanied by significantly increased O2 - production, reduced NADP+/NADPH levels, a lower antioxidative response (indicated by antioxidative response element- (ARE-) driven luciferase reporter assays), more DNA damage (determined by percentage of γ-H2A.X-positive nuclei), and earlier growth arrest in AAA-SMC. Our data suggest that mitochondrial dysfunction and oxidative stress are persistently increased in AAA-SMC, emphasizing their implication in the pathophysiology of AAA.