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     

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     

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.     

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.     

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。     

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.     

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.     

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.     

Decision Tree Based Classification of Abdominal Aortic Aneurysms Using Geometry Quantification Measures

Abdominal aortic aneurysm (AAA) is an asymptomatic aortic disease with a survival rate of 20% after rupture. It is a vascular degenerative condition different from occlusive arterial diseases. The size of the aneurysm is the most important determining factor in its clinical management. However, other measures of the AAA geometry that are currently not used clinically may also influence its rupture risk. With this in mind, the objectives of this work are to develop an algorithm to calculate the AAA wall thickness and abdominal aortic diameter at planes orthogonal to the vessel centerline, and to quantify the effect of geometric indices derived from this algorithm on the overall classification accuracy of AAA based on whether they were electively or emergently repaired. Such quantification was performed based on a retrospective review of existing medical records of 150 AAA patients (75 electively repaired and 75 emergently repaired). Using an algorithm implemented within the MATLAB computing environment, 10 diameter- and wall thickness-related indices had a significant difference in their means when calculated relative to the AAA centerline compared to calculating them relative to the medial axis. Of these 10 indices, nine were wall thickness-related while the remaining one was the maximum diameter (D_max). D_max calculated with respect to the medial axis is over-estimated for both electively and emergently repaired AAA compared to its counterpart with respect to the centerline. C5.0 decision trees, a machine learning classification algorithm implemented in the R environment, were used to construct a statistical classifier. The decision trees were built by splitting the data into 70% for training and 30% for testing, and the properties of the classifier were estimated based on 1000 random combinations of the 70/30 data split. The ensuing model had average and maximum classification accuracies of 81.0 and 95.6%, respectively, and revealed that the three most significant indices in classifying AAA are, in order of importance: AAA centerline length, L2-norm of the Gaussian curvature, and AAA wall surface area. Therefore, we infer that the aforementioned three geometric indices could be used in a clinical setting to assess the risk of AAA rupture by means of a decision tree classifier. This work provides support for calculating cross-sectional diameters and wall thicknesses relative to the AAA centerline and using size and surface curvature based indices in classification studies of AAA.     

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.     

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.     

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.     

A Numerical Implementation to Predict Residual Strains from the Homogeneous Stress Hypothesis with Application to Abdominal Aortic Aneurysms

Wall stress analysis of abdominal aortic aneurysm (AAA) is a promising method of identifying AAAs at high risk of rupture. However, neglecting residual strains (RS) in the load-free configuration of patient-specific finite element analysis models is a sever limitation that strongly affects the computed wall stresses. Although several methods for including RS have been proposed, they cannot be directly applied to patient-specific AAA simulations. RS in the AAA wall are predicted through volumetric tissue growth that aims at satisfying the homogeneous stress hypothesis at mean arterial pressure load. Tissue growth is interpolated linearly across the wall thickness and aneurysm tissues are described by isotropic constitutive formulations. The total deformation is multiplicatively split into elastic and growth contributions, and a staggered schema is used to solve the field variables. The algorithm is validated qualitatively at a cylindrical artery model and then applied to patient-specific AAAs (n = 5). The induced RS state is fully three-dimensional and in qualitative agreement with experimental observations, i.e., wall strips that were excised from the load-free wall showed stress-releasing-deformations that are typically seen in laboratory experiments. Compared to RS-free simulations, the proposed algorithm reduced the von Mises stress gradient across the wall by a tenfold. Accounting for RS leads to homogenized wall stresses, which apart from reducing the peak wall stress (PWS) also shifted its location in some cases. The present study demonstrated that the homogeneous stress hypothesis can be effectively used to predict RS in the load-free configuration of the vascular wall. The proposed algorithm leads to a fast and robust prediction of RS, which is fully capable for a patient-specific AAA rupture risk assessment. Neglecting RS leads to non-realistic wall stress values that severely overestimate the PWS.     

A Framework for the Automatic Generation of Surface Topologies for Abdominal Aortic Aneurysm Models

Patient-specific abdominal aortic aneurysms (AAAs) are characterized by local curvature changes, which we assess using a feature-based approach on topologies representative of the AAA outer wall surface. The application of image segmentation methods yields 3D reconstructed surface polygons that contain low-quality elements, unrealistic sharp corners, and surface irregularities. To optimize the quality of the surface topology, an iterative algorithm was developed to perform interpolation of the AAA geometry, topology refinement, and smoothing. Triangular surface topologies are generated based on a Delaunay triangulation algorithm, which is adapted for AAA segmented masks. The boundary of the AAA wall is represented using a signed distance function prior to triangulation. The irregularities on the surface are minimized by an interpolation scheme and the initial coarse triangulation is refined by forcing nodes into equilibrium positions. A surface smoothing algorithm based on a low-pass filter is applied to remove sharp corners. The optimal number of iterations needed for polygon refinement and smoothing is determined by imposing a minimum average element quality index with no significant AAA sac volume change. This framework automatically generates high-quality triangular surface topologies that can be used to characterize local curvature changes of the AAA wall.     

腹主动脉瘤直型覆膜支架的生物力学分析

应用数值模拟分析方法,研究腹主动脉瘤直型覆膜支架在径向压握、自膨胀释放及植入后平衡状态3种工况下的稳定性及各项生物力学指标。建立覆膜支架、压握工具以及目标血管的有限元模型。对圆柱状压握工具沿R轴负方向施加大小为6.50 mm的位移载荷,压握覆膜支架至外径为7.00 mm;将压握工具恢复到原始尺寸,建立血管/覆膜支架接触关系;支架完全释放后平衡状态下,对其内表面均匀施加50～150 mmHg动脉压。分析支架部分在压握与平衡状态下的最大主应变(MPS)峰值及分析后形态、释放状态下变形血管以及覆膜的等效应力峰值(VMS)。在径向压握过程中,金属支架最大压握主应变峰值为5.73%;在自膨胀释放过程中,造成血管壁应力集中的峰值为0.371 MPa,覆膜应力峰值为0.388 MPa;在植入后平衡状态下,支架平均应变为0.0859%,振荡应变为0.0486%,覆膜应力峰值为2.09 MPa,安全因子为8.23。支架部分在各工况下应变处于镍钛合金屈服强度之内,在圆角弯折处应变最为集中;覆膜部分在各工况下应力值也满足e PTFE膜材料的屈服强度。该研究结果可以为覆膜支架的结构优化设计以及覆膜材料选择提供一种分析方法, 可以提高覆膜支架的生物力学性能,并给工程设计和临床操作提供参考。