In Vivo Three-Dimensional Surface Geometry of Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a local, progressive dilation of the distal aorta that risks rupture until treated. Using the law of Laplace, in vivo assessment of AAA surface geometry could identify regions of high wall tensions as well as provide critical dimensional and shape data for customized endoluminal stent grafts. In this study, six patients with AAA underwent spiral computed tomography imaging and the inner wall of each AAA was identified, digitized, and reconstructed. A biquadric surface patch technique was used to compute the local principal curvatures, which required no assumptions regarding axisymmetry or other shape characteristics of the AAA surface. The spatial distribution of AAA principal curvatures demonstrated substantial axial asymmetry, and included adjacent elliptical and hyperbolic regions. To determine how much the curvature spatial distributions were dependent on tortuosity versus bulging, the effects of AAA tortuosity were removed from the three-dimensional (3D) reconstructions by aligning the centroids of each digitized contour to the z axis. The spatial distribution of principal curvatures of the modified 3D reconstructions were found to be largely axisymmetric, suggesting that much of the surface geometric asymmetry is due to AAA bending. On average, AAA surface area increased by 56% and abdominal aortic length increased by 27% over those for the normal aorta. Our results indicate that AAA surface geometry is highly complex and cannot be simulated by simple axisymmetric models, and suggests an equally complex wall stress distribution. © 1999 Biomedical Engineering Society. PAC99: 8719Rr, 8759Fm, 8757Gg     

Quantification of Hemodynamics in Abdominal Aortic Aneurysms During Rest and Exercise Using Magnetic Resonance Imaging and Computational Fluid Dynamics

Abdominal aortic aneurysms (AAAs) affect 5–7% of older Americans. We hypothesize that exercise may slow AAA growth by decreasing inflammatory burden, peripheral resistance, and adverse hemodynamic conditions such as low, oscillatory shear stress. In this study, we use magnetic resonance imaging and computational fluid dynamics to describe hemodynamics in eight AAAs during rest and exercise using patient-specific geometric models, flow waveforms, and pressures as well as appropriately resolved finite-element meshes. We report mean wall shear stress (MWSS) and oscillatory shear index (OSI) at four aortic locations (supraceliac, infrarenal, mid-aneurysm, and suprabifurcation) and turbulent kinetic energy over the entire computational domain on meshes containing more than an order of magnitude more elements than previously reported results (mean: 9.0-million elements; SD: 2.3 M; range: 5.7–12.0 M). MWSS was lowest in the aneurysm during rest 2.5 dyn/cm² (SD: 2.1; range: 0.9–6.5), and MWSS increased and OSI decreased at all four locations during exercise. Mild turbulence existed at rest, while moderate aneurysmal turbulence was present during exercise. During both rest and exercise, aortic turbulence was virtually zero superior to the AAA for seven out of eight patients. We postulate that the increased MWSS, decreased OSI, and moderate turbulence present during exercise may attenuate AAA growth.     

B2 Cells Suppress Experimental Abdominal Aortic Aneurysms

Recent reports of rupture in patients with abdominal aortic aneurysm (AAA) receiving B-cell depletion therapy highlight the importance of understanding the role of B cells (B1 and B2 subsets) in the development of AAA. We hypothesized that B2 cells aggravate experimental aneurysm formation. The IHC staining revealed infiltration of B cells in the aorta of wild-type (C57BL/6) mice at day 7 after elastase perfusion and persisted through day 21. Quantification of immune cell types using flow cytometry at day 14 showed significantly greater infiltration of mononuclear cells, including B cells (B2: 93% of total B cells) and T cells in elastase-perfused aortas compared with saline-perfused or normal aortas. muMT (mature B-cell deficient) mice were prone to AAA formation similar to wild-type mice in two different experimental AAA models. Contradicting our hypothesis, adoptive transfer of B2 cells suppressed AAA formation (102.0% ± 7.3% versus 75.2% ± 5.5%; P < 0.05) with concomitant increase in the splenic regulatory T cell (0.24% ± 0.03% versus 0.92% ± 0.23%; P < 0.05) and decrease in aortic infiltration of mononuclear cells. Our data suggest that B2 cells constitute the largest population of B cells in experimental AAA. Furthermore, B2 cells, in the absence of other B-cell subsets, increase splenic regulatory T-cell population and suppress AAA formation.Abdominal aortic aneurysms (AAAs) remain a life-threatening disease. Rupture of AAAs causes acute hemorrhage leading to shock and death. Moreover, recent reports indicate AAA rupture in patients receiving rituximab (a commercially available anti-CD20 antibody) for the treatment of various autoimmune diseases and B-cell lymphomas.^1–3 With no available nonsurgical therapies to treat AAAs, there is a pressing need to understand the mechanisms of AAA growth and rupture. During AAA formation, aortic medial and adventitial layers undergo major pathological changes, such as degradation of extracellular matrix and marked infiltration of inflammatory cells, such as T cells, B cells, macrophages, mast cells, neutrophils, natural killer cells, and dendritic cells.^4–10 Therefore, understanding the role of the inflammatory cells is crucial to develop a therapy to suppress aneurysm growth.B cells have long been known to be present in human AAA. By immunohistochemistry (IHC), an estimated 60% to 80% of the inflammatory infiltrate in the adventitia is classified as B cells (CD20⁺). By using flow cytometry, nearly 20% to 41.1% of total mononuclear hematopoietic cells (CD45⁺) are considered B cells (CD19⁺).^4,8 Flow cytometry analysis of lymphocytes⁴ in human AAA wall identified activated memory B cells with homing properties and expressing activation markers. The presence of B-cell–bound immunoglobulins, such as IgM and IgG, in human AAA tissue has also been well documented.^4,7,8,11 B cells are known to form lymphoid follicles called vascular-associated lymphoid tissue^12,13 with T cells, which are prominent in AAA. B cells are also detected in AAA of apolipoprotein E–deficient mice after 14 days of angiotensin II infusion.¹⁴Similar to AAA, atherosclerosis is characterized by a chronic inflammatory cell infiltrate, including B and T cells.¹⁵ Genetically B-cell–deficient mice, muMT, develop atherosclerosis.¹⁶ Doran et al¹⁷ have reported adoptive transfer of total B-cell population to muMT mice protected mice against atherosclerosis with significant decrease in macrophage content in aortas. Specific roles for B-cell subsets B1a, B1b, and B2 in the pathogenesis and progression of atherosclerosis have also been identified.^16–26 Specifically, B1a cells appear to be protective in atherosclerosis via production of natural antibodies IgM, whereas B2 cells are proatherogenic via activation/proliferation of T cells. As far as role of T cells is concerned, CD4⁺ T cells are atherogenic,²⁷ whereas T-regulatory cells (Tregs; CD4⁺CD25⁺Foxp3⁺) are atheroprotective.^28,29Although the role of T cells in AAA formation has been widely investigated,^30–35 the role of B cells or B-cell subsets in AAA remains elusive. We hypothesized that B cells were necessary for AAA formation, and the largest constituent of B cells in AAA would be B2 cells. We further hypothesized that adoptive transfer of B2 cells to a B-cell–deficient mouse would exacerbate AAA formation. We have previously detected neutrophils, macrophages, and T cells in the murine aorta at day 3 using a well-established model of aortic elastase perfusion.³⁶ Because B cells have never been fully characterized in experimental AAA, we first examined if B cells are present in murine AAA and, subsequently, developed a flow cytometry method to methodically phenotype and quantify B-cell subsets in AAA. To understand the role of B2 cells, we adoptively transferred isolated B2 cells to muMT mice and examined AAA formation. Our study addresses a putative protective role of B2 cells in experimental AAA.     

巨噬细胞在腹主动脉瘤中作用的研究进展

主动脉瘤（AAA）是因动脉中层结构破坏,动脉壁不能承受血流冲击的压力所致永久性局部或广泛血管扩张。相关研究证实,在主动脉瘤中被鉴定出来的先天性和获得性免疫细胞,包括嗜中性粒细胞、巨噬细胞、肥大细胞等可促进主动脉瘤的发展。形成AAA的主要危险因素有吸烟和家族史,然而在组织学层面上,AAA的发病特征包括炎症、平滑肌细胞凋亡,细胞外基质降解,氧化应激等。炎症反应在AAA中起着至关重要的作用,且主要影响主动脉壁重塑的决定性因素。本综述关注于主动脉瘤中的巨噬细胞的起源及巨噬细胞在AAA发展过程中的作用,充分描述巨噬细胞的潜在应用。     

Micromechanical Characterization of Intra-luminal Thrombus Tissue from Abdominal Aortic Aneurysms

The reliable assessment of Abdominal Aortic Aneurysm rupture risk is critically important in reducing related mortality without unnecessarily increasing the rate of elective repair. Intra-luminal thrombus (ILT) has multiple biomechanical and biochemical impacts on the underlying aneurysm wall and thrombus failure might be linked to aneurysm rupture. Histological slices from 7 ILTs were analyzed using a sequence of automatic image processing and feature analyzing steps. Derived microstructural data was used to define Representative Volume Elements (RVE), which in turn allowed the estimation of microscopic material properties using the non-linear Finite Element Method. ILT tissue exhibited complex microstructural arrangement with larger pores in the abluminal layer than in the luminal layer. The microstructure was isotropic in the abluminal layer, whereas pores started to orient along the circumferential direction towards the luminal site. ILT’s macroscopic (reversible) deformability was supported by large pores in the microstructure and the inhomogeneous structure explains in part the radially changing macroscopic constitutive properties of ILT. Its microscopic properties decreased just slightly from the luminal to the abluminal layer. The present study provided novel microstructural and micromechanical data of ILT tissue, which is critically important to further explore the role of the ILT in aneurysm rupture. Data provided in this study allow an integration of structural information from medical imaging for example, to estimate ILT’s macroscopic mechanical properties.     

Development of a Simulator for Endovascular Repair of Abdominal Aortic Aneurysms

The design and development of a simulator for endovascular repair of abdominal aortic aneurysm (AAA) is described. The simulator consists of an interchangeable model of a human AAA based on computed tomography data and is produced by means of computer-aided design and manufacture (CAD/CAM) techniques. The model has renal, iliac, and femoral arteries, and is perfused with a temperature controlled blood–analog fluid under simulated physiological flow conditions. Fluoroscopic imaging is simulated by a computerized imaging system that uses visible light. A movable video camera relays images in the antero–posterior and lateral planes of the AAA to a monitor. The imaging system allows arteriography and road-mapping to be performed so as to facilitate accurate deployment of endovascular stent-grafts. The system has been used for teaching and demonstrating endovascular techniques to clinicians, as well as the evaluation of new stent-graft devices. Its successful incorporation into endovascular workshops has demonstrated its role in the training of clinicians in endovascular repair of AAA. © 1998 Biomedical Engineering Society. PAC98: 0150-i, 8745Hw, 8759Fm     

Diagnosis of Ovarian Cancer Using Decision Tree Classification of Mass Spectral Data

Recent reports from our laboratory and others support the SELDI ProteinChip technology as a potential clinical diagnostic tool when combined with $n$ -dimensional analyses algorithms. The objective of this study was to determine if the commercially available classification algorithm biomarker patterns software (BPS), which is based on a classification and regression tree (CART), would be effective in discriminating ovarian cancer from benign diseases and healthy controls. Serum protein mass spectrum profiles from 139 patients with either ovarian cancer, benign pelvic diseases, or healthy women were analyzed using the BPS software. A decision tree, using five protein peaks resulted in an accuracy of 81.5% in the cross-validation analysis and 80%in a blinded set of samples in differentiating the ovarian cancer from the control groups. The potential, advantages, and drawbacks of the BPS system as a bioinformatic tool for the analysis of the SELDI high-dimensional proteomic data are discussed.     

Three Dimensional Active Contours for the Reconstruction of Abdominal Aortic Aneurysms

An aneurysm is a gradual and progressive ballooning of a blood vessel due to wall degeneration. Rupture of abdominal aortic aneurysm (AAA) constitutes a significant portion of deaths in the US. In this study, we describe a technique to reconstruct AAA geometry from CT images in an inexpensive and streamlined fashion. A 3D reconstruction technique was implemented with a GUI interface in MATLAB using the active contours technique. The lumen and the thrombus of the AAA were segmented individually in two separate protocols and were then joined together into a hybrid surface. This surface was then used to obtain the aortic wall. This method can deal with very poor contrast images where the aortic wall is indistinguishable from the surrounding features. Data obtained from the segmentation of image sets were smoothed in 3D using a Support Vector Machine technique. The segmentation method presented in this paper is inexpensive and has minimal user-dependency in reconstructing AAA geometry (lumen and wall) from patient image sets. The AAA model generated using this segmentation algorithm can be used to study a variety of biomechanical issues remaining in AAA biomechanics including stress estimation, endovascular stent-graft performance, and local drug delivery studies.     

Surface Curvature as a Classifier of Abdominal Aortic Aneurysms: A Comparative Analysis

An abdominal aortic aneurysm (AAA) carries one of the highest mortality rates among vascular diseases when it ruptures. To predict the role of surface curvature in rupture risk assessment, a discriminatory analysis of aneurysm geometry characterization was conducted. Data was obtained from 205 patient-specific computed tomography image sets corresponding to three AAA population subgroups: patients under surveillance, those that underwent elective repair of the aneurysm, and those with an emergent repair. Each AAA was reconstructed and their surface curvatures estimated using the biquintic Hermite finite element method. Local surface curvatures were processed into ten global curvature indices. Statistical analysis of the data revealed that the L2-norm of the Gaussian and Mean surface curvatures can be utilized as classifiers of the three AAA population subgroups. The application of statistical machine learning on the curvature features yielded 85.5% accuracy in classifying electively and emergent repaired AAAs, compared to a 68.9% accuracy obtained by using maximum aneurysm diameter alone. Such combination of non-invasive geometric quantification and statistical machine learning methods can be used in a clinical setting to assess the risk of rupture of aneurysms during regular patient follow-ups.     

The Effects of Anisotropy on the Stress Analyses of Patient-Specific Abdominal Aortic Aneurysms

The local dilation of the infrarenal abdominal aorta, termed an abdominal aortic aneurysm (AAA), is often times asymptomatic and may eventually result in rupture—an event associated with a significant mortality rate. The estimation of in-vivo stresses within AAAs has been proposed as a useful tool to predict the likelihood of rupture. For the current work, a previously-derived anisotropic relation for the AAA wall was implemented into patient-specific finite element simulations of AAA. There were 35 AAAs simulated in the current work which were broken up into three groups: elective repairs (n = 21), non-ruptured repairs (n = 5), and ruptured repairs (n = 9). Peak stresses and strains were compared using the anisotropic and isotropic constitutive relations. There were significant increases in peak stress when using the anisotropic relationship (p < 0.001), even in the absence of the ILT (p = 0.014). Rutpured AAAs resulted in elevated peak stresses as compared to non-ruptured AAAs when using both the isotropic and anisotropic simulations, however these comparisons did not reach significance (p _ani = 0.55, p _iso = 0.73). While neither the isotropic or anisotropic simulations were able to significantly discriminate ruptured vs. non-ruptured AAAs, the lower p-value when using the anisotropic model suggests including it into patient-specific AAAs may help better identify AAAs at high risk.     

The Effect of Material Model Formulation in the Stress Analysis of Abdominal Aortic Aneurysms

A reliable estimation of wall stress in Abdominal Aortic Aneurysms (AAAs), requires performing an accurate three-dimensional reconstruction of the medical image-based native geometry and modeling an appropriate constitutive law for the aneurysmal tissue material characterization. A recent study on the biaxial mechanical behavior of human AAA tissue specimens demonstrates that aneurysmal tissue behaves mechanically anisotropic. Results shown in this communication show that the peak wall stress is highly sensitive to the anisotropic model used for the stress analysis. In addition, the present investigation indicates that structural parameters (e.g., collagen fiber orientation) should be determined independently and not by means of non-linear fitting to stress–strain test data. Fiber orientation identified in this manner could lead to overestimated peak wall stresses.     

Hemodynamic Changes Quantified in Abdominal Aortic Aneurysms with Increasing Exercise Intensity Using MR Exercise Imaging and Image-Based Computational Fluid Dynamics

Abdominal aortic aneurysm (AAA) is a vascular disease resulting in a permanent, localized enlargement of the abdominal aorta. We previously hypothesized that the progression of AAA may be slowed by altering the hemodynamics in the abdominal aorta through exercise [Dalman, R. L., M. M. Tedesco, J. Myers, and C. A. Taylor. Ann. N.Y. Acad. Sci. 1085:92–109, 2006]. To quantify the effect of exercise intensity on hemodynamic conditions in 10 AAA subjects at rest and during mild and moderate intensities of lower-limb exercise (defined as 33 ± 10% and 63 ± 18% increase above resting heart rate, respectively), we used magnetic resonance imaging and computational fluid dynamics techniques. Subject-specific models were constructed from magnetic resonance angiography data and physiologic boundary conditions were derived from measurements made during dynamic exercise. We measured the abdominal aortic blood flow at rest and during exercise, and quantified mean wall shear stress (MWSS), oscillatory shear index (OSI), and particle residence time (PRT). We observed that an increase in the level of activity correlated with an increase of MWSS and a decrease of OSI at three locations in the abdominal aorta, and these changes were most significant below the renal arteries. As the level of activity increased, PRT in the aneurysm was significantly decreased: 50% of particles were cleared out of AAAs within 1.36 ± 0.43, 0.34 ± 0.10, and 0.22 ± 0.06 s at rest, mild exercise, and moderate exercise levels, respectively. Most of the reduction of PRT occurred from rest to the mild exercise level, suggesting that mild exercise may be sufficient to reduce flow stasis in AAAs.     

Towards A Noninvasive Method for Determination of Patient-Specific Wall Strength Distribution in Abdominal Aortic Aneurysms

The spatial distributions of both wall stress and wall strength are required to accurately evaluate the rupture potential for an individual abdominal aortic aneurysm (AAA). The purpose of this study was to develop a statistical model to non-invasively estimate the distribution of AAA wall strength. Seven parameters–namely age, gender, family history of AAA, smoking status, AAA size, local diameter, and local intraluminal thrombus (ILT) thickness–were either directly measured or recorded from the patients hospital chart. Wall strength values corresponding to these predictor variables were calculated from the tensile testing of surgically procured AAA wall specimens. Backwards–stepwise regression techniques were used to identify and eliminate insignificant predictors for wall strength. Linear mixed-effects modeling was used to derive a final statistical model for AAA wall strength, from which 95% confidence intervals on the model parameters were formed. The final statistical model for AAA wall strength consisted of the following variables: sex, family history, ILT thickness, and normalized transverse diameter. Demonstrative application of the model revealed a unique, complex wall strength distribution, with strength values ranging from 56 N/cm² to 133 N/cm². A four-parameter statistical model for the noninvasive estimation of patient-specific AAA wall strength distribution has been successfully developed. The currently developed model represents a first attempt towards the noninvasive assessment of AAA wall strength. Coupling this model with our stress analysis technique may provide a more accurate means to estimate patient-specific rupture potential of AAA.     

Nitric Oxide Induces the Progression of Abdominal Aortic Aneurysms through the Matrix Metalloproteinase Inducer EMMPRIN

Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.Abdominal aortic aneurysm (AAA) is an age-related multifactorial cardiovascular disease and is usually asymptomatic until rupture or diameter size requires medical intervention.^1,2AAA is characterized by local chronic inflammation, degradation of the medial elastin, and components of the extracellular matrix. Resistance to rupture depends on tensile strength by interstitial collagens, and therefore, collagen-degrading enzymes may play a pivotal effect.³Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes involved in the development and progression of AAA in humans and mice. The effect of collagenases MMP-8³ and MMP-13,⁴ gelatinases A and B,⁵ and membrane type MMPs⁶ have been extensively analyzed. In particular, collagenases are responsible of cleavage of type I and III collagens, which are involved in keeping the vessel tensile strength, and therefore, increased production of collagen-degrading enzymes may be determinant for the progression of AAA. However, the molecular mechanisms leading to MMP expression and activation are not fully understood.The expression of MMPs have been recently associated to cardiovascular disease through the activation of the extracellular MMP inducer (EMMPRIN; Basigin and CD147).⁷ EMMPRIN is an immunoglobulin, which induces the expression of MMP-2, MMP-9, and MT1-MMP.^{8,9,10,11,12,13} Acute and chronic inflammation induces the expression of EMMPRIN by immune cells and vascular endothelial cells, and its role on MMP expression was related to atherosclerosis.^14,15Here we show the association of EMMPRIN and MMP-13 in human AAA and during the NO-mediated AAA in mice, providing evidence about the effect of EMMPRIN on MMP-13 expression in vascular cells.     

Evaluation of Texture for Classification of Abdominal Aortic Aneurysm After Endovascular Repair

The use of the endovascular prostheses in abdominal aortic aneurysm has proven to be an effective technique to reduce the pressure and rupture risk of aneurysm. Nevertheless, in a long-term perspective, complications such as leaks inside the aneurysm sac (endoleaks) could appear causing a pressure elevation and increasing the danger of rupture consequently. At present, computed tomographic angiography (CTA) is the most common examination for medical surveillance. However, endoleak complications cannot always be detected by visual inspection on CTA scans. The investigation on new techniques to detect endoleaks and analyse their effects on treatment evolution is of great importance for endovascular aneurysm repair (EVAR) technique. The purpose of this work was to evaluate the capability of texture features obtained from the aneurysmatic thrombus CT images to discriminate different types of evolutions caused by endoleaks. The regions of interest (ROIs) from patients with different post-EVAR evolution were extracted by experienced radiologists. Three techniques were applied to each ROI to obtain texture parameters, namely the grey level co-occurrence matrix (GLCM), the grey level run length matrix (GLRLM) and the grey level difference method (GLDM). The results showed that GLCM, GLRLM and GLDM features presented a good discrimination ability to differentiate between favourable or unfavourable evolutions. GLCM was the most efficient in terms of classification accuracy (93.41% ± 0.024) followed by GLRLM (90.17% ± 0.077) and finally by GLDM (81.98% ± 0.045). According to the results, we can consider texture analysis as complementary information to classified abdominal aneurysm evolution after EVAR.     

Tissue Responses to Endovascular Stent Grafts for Saccular Abdominal Aortic Aneurysms in a Canine Model

We investigated tissue responses to endoskeleton stent grafts for saccular abdominal aortic aneurysms (AAAs) in canines. Saccular AAAs were made with Dacron patch in 8 dogs, and were excluded by endoskeleton stent grafts composed of nitinol stent and expanded polytetrafluoroethylene graft. Animals were sacrificed at 2 months (Group 1; n = 3) or 6 months (Group 2; n = 5) after the placement, respectively. The aortas embedding stent grafts were excised en bloc for gross inspection and sliced at 5 to 8 mm intervals for histopathologic evaluation. Stent grafts were patent in all except a dog showing a thrombotic occlusion in Group 2. In the 7 dogs with patent lumen, the graft overhanging the saccular aneurysm was covered by thick or thin thrombi with no endothelial layer, and the graft over the aortic wall was completely covered by neointima with an endothelial layer. Transgraft cell migration was less active at an aneurysm than at adjacent normal aorta. In conclusion, endoskeleton stent grafts over saccular aneurysms show no endothelial coverage and poor transgraft cell migration in a canine model.