Effect of macroscale formation of intraluminal thrombus on blood flow in abdominal aortic aneurysms

A mathematical approach of blood flow within an abdominal aortic aneurysm (AAA) with intraluminal thrombus (ILT) is presented. The macroscale formation of ILT is modeled as a growing porous medium with variable porosity and permeability according to values proposed in the literature. The model outlines the effect of a porous ILT on blood flow in AAAs. The numerical solution is obtained by employing a structured computational mesh of an idealized fusiform AAA geometry and applying the Galerkin weighted residual method in generalized curvilinear coordinates. Results on velocity and pressure fields of independent cases with and without ILT are presented and discussed. The vortices that develop within the aneurysmal cavity are studied and visualized as ILT becomes more condensed. From a mechanistic point of view, the reduction of bulge pressure, as ILT is thickening, supports the observation that ILT could protect the AAA from a possible rupture. The model also predicts a relocation of the maximum pressure region toward the zone proximal to the neck of the aneurysm. However, other mechanisms, such as the gradual wall weakening that usually accompany AAA and ILT formation, which are not included in this study, may offset this effect.     

Automated methodology for determination of stress distribution in human abdominal aortic aneurysm

Knowledge of impending abdominal aortic aneurysm (AAA) rupture can help in surgical planning. Typically, aneurysm diameter is used as the indicator of rupture, but recent studies have hypothesized that pressure-induced biomechanical stress may be a better predictor Verification of this hypothesis on a large study population with ruptured and unruptured AAA is vital if stress is to be reliably used as a clinical prognosticator for AAA rupture risk. We have developed an automated algorithm to calculate the peak stress in patient-specific AAA models. The algorithm contains a mesh refinement module, finite element analysis module, and a postprocessing visualization module. Several aspects of the methodology used are an improvement over past reported approaches. The entire analysis may be run from a single command and is completed in less than 1 h with the peak wall stress recorded for statistical analysis. We have used our algorithm for stress analysis of numerous ruptured and unruptured AAA models and report some of our results here. By current estimates, peak stress in the aortic wall appears to be a better predictor of rupture than AAA diameter. Further use of our algorithm is ongoing on larger study populations to convincingly verify these findings.     

Different Long-Term Outcomes of Abdominal Aortic Aneurysm and Intracranial Aneurysm Models: Hemodynamic Change may also Play an Essential Role in the Initiation and Progression of Abdominal Aortic Aneurysm in Rabbits

Self-healing phenomenon was found in the periarterial elastase-induced abdominal aortic aneurysm (AAA) in rabbit. This kind of aneurysm model does not progress and heals spontaneously in the long term, which is quite different from the performance of AAA disease in human. In order to better mimic human AAA and overcome this shortcoming of traditional AAA model in rabbit, we studied the pathogenesis of cerebral aneurysm (CA) model in small animal, which shows an excellent long-term patency and progressive enlargement. We found that hemodynamic conditions, such as turbulence flow, high blood flow, and shear stress, play an important role in the formation and progression of CA. So, we hypothesize that hemodynamic change may also play an essential role in the initiation and progression of rabbit AAA, and self-healing will be overcome if hemodynamic condition changes by coarctation of infra-renal aorta after elastase incubation.     

A New Murine Model of Endovascular Aortic Aneurysm Repair

Endovascular aneurysm exclusion is a validated technique to prevent aneurysm rupture. Long-term results highlight technique limitations and new aspects of Abdominal aortic aneurysm (AAA) pathophysiology. There is no abdominal aortic aneurysm endograft exclusion model cheap and reproducible, which would allow deep investigations of AAA before and after treatment. We hereby describe how to induce, and then to exclude with a covered coronary stentgraft an abdominal aortic aneurysm in a rat. The well known elastase induced AAA model was first reported in 1990¹ in a rat, then described in mice². Elastin degradation leads to dilation of the aorta with inflammatory infiltration of the abdominal wall and intra luminal thrombus, matching with human AAA. Endovascular exclusion with small covered stentgraft is then performed, excluding any interactions between circulating blood and the aneurysm thrombus. Appropriate exclusion and stentgraft patency is confirmed before euthanasia by an angiography thought the left carotid artery. Partial control of elastase diffusion makes aneurysm shape different for each animal. It is difficult to create an aneurysm, which will allow an appropriate length of aorta below the aneurysm for an easy stentgraft introduction, and with adequate proximal and distal neck to prevent endoleaks. Lots of failure can result to stentgraft introduction which sometimes lead to aorta tear with pain and troubles to stitch it, and endothelial damage with post op aorta thrombosis. Giving aspirin to rats before stentgraft implantation decreases failure rate without major hemorrhage. Clamping time activates neutrophils, endothelium and platelets, and may interfere with biological analysis.     

A fluid–structure interaction-based numerical investigation on the evolution of stress,strength and rupture potential of an abdominal aortic aneurysm

An abdominal aortic aneurysm (AAA) is an irreversible dilation of the abdominal artery. Once an aneurysm is detected by doctors, clinical intervention is usually recommended. The interventions involve traditional open surgery repair and endovascular aneurysm repair with a stent graft. Both types of prophylactic procedures are expensive and not without any risk to the patient. It is very difficult to balance the risk of aneurysm repair and the chance of rupture. The reason lies in that the changing trend of characteristic physical quantities with the evolution of AAA and the mechanisms that give rise to it are still not completely clear. In this study, computational 3D patient-specific model for investigating AAA development was established based on computed tomography (CT) images. Results showed that as the aneurysm evolved, peak wall stress and time-averaged wall shear stress distribution patterns changed. The expansion of AAA wall resulted in the increment of peak stress. The AAA wall compliance not only showed different magnitudes at different cross-sections of the aneurismal body, but also changed with the development of the aneurysm. Furthermore, minimum wall strength and rupture potential index during the three stages of AAA evolution were also investigated in detail. This study might provide valuable information on how to further explore the mechanical basis and the rupture potential during AAA evolution, and that it may assist clinical diagnostic procedures and avoid the potential risk of unnecessary surgical intervention.     

Intraluminal thrombus and risk of rupture in patient specific abdominal aortic aneurysm - FSI modelling

Recent numerical studies of abdominal aortic aneurysm (AAA) suggest that intraluminal thrombus (ILT) may reduce the stress loading on the aneurysmal wall. Detailed fluid structure interaction (FSI) in the presence and absence of ILT may help predict AAA rupture risk better. Two patients, with varied AAA geometries and ILT structures, were studied and compared in detail. The patient specific 3D geometries were reconstructed from CT scans, and uncoupled FSI approach was applied. Complex flow trajectories within the AAA lumen indicated a viable mechanism for the formation and growth of the ILT. The resulting magnitude and location of the peak wall stresses was dependent on the shape of the AAA, and the ILT appeared to reduce wall stresses for both patients. Accordingly, the inclusion of ILT in stress analysis of AAA is of importance and would likely increase the accuracy of predicting AAA risk of rupture.     

Intraluminal thrombus and risk of rupture in patient specific abdominal aortic aneurysm – FSI modelling

Recent numerical studies of abdominal aortic aneurysm (AAA) suggest that intraluminal thrombus (ILT) may reduce the stress loading on the aneurysmal wall. Detailed fluid structure interaction (FSI) in the presence and absence of ILT may help predict AAA rupture risk better. Two patients, with varied AAA geometries and ILT structures, were studied and compared in detail. The patient specific 3D geometries were reconstructed from CT scans, and uncoupled FSI approach was applied. Complex flow trajectories within the AAA lumen indicated a viable mechanism for the formation and growth of the ILT. The resulting magnitude and location of the peak wall stresses was dependent on the shape of the AAA, and the ILT appeared to reduce wall stresses for both patients. Accordingly, the inclusion of ILT in stress analysis of AAA is of importance and would likely increase the accuracy of predicting AAA risk of rupture.     

Intraluminal thrombus thickness is not related to lower concentrations of trace elements in the wall of infrarenal abdominal aortic aneurysms

BackgroundIntraluminal thrombus (ILT) formation plays a significant role in the progression of infrarenal abdominal aortic aneurysms (AAA). Potentially, as ILT thickness increases the availability of trace elements in the aneurysm wall could decrease thereby leading to oxidative stress and intensifying pro-inflammatory cytokine generation.AimTo determine if thrombus thickness is related to the concentration of trace elements in the wall of infrarenal AAA.Patients and methodsThe concentrations of trace elements in the wall of the aneurysm sack and ILT obtained from 19 consecutive patients during surgery for infrarenal AAA were determined using emission spectrometry.ResultsThe concentrations of magnesium, zinc, manganese, and lead in the wall of AAA were significantly greater than in the ILT. Only the concentration of copper was lower in the AAA wall compared with the thrombus. The concentration of calcium, phosphorus, zinc, lead, copper, and magnesium increased with ILT thickness. The concentrations of no other trace elements in the wall of AAA were found to be related to the ILT thickness.ConclusionsIntraluminal thrombus thickness is not associated with a lower concentration of trace elements in the wall of the infrarenal AAA. Thus, the intraluminal thrombus participates in the progression of AAA by mechanisms independent of trace element supply to the wall of the aneurysm sack.     

Towards enabling a cardiovascular digital twin for human systemic circulation using inverse analysis

An exponential rise in patient data provides an excellent opportunity to improve the existing health care infrastructure. In the present work, a method to enable cardiovascular digital twin is proposed using inverse analysis. Conventionally, accurate analytical solutions for inverse analysis in linear problems have been proposed and used. However, these methods fail or are not efficient for nonlinear systems, such as blood flow in the cardiovascular system (systemic circulation) that involves high degree of nonlinearity. To address this, a methodology for inverse analysis using recurrent neural network for the cardiovascular system is proposed in this work, using a virtual patient database. Blood pressure waveforms in various vessels of the body are inversely calculated with the help of long short-term memory (LSTM) cells by inputting pressure waveforms from three non-invasively accessible blood vessels (carotid, femoral and brachial arteries). The inverse analysis system built this way is applied to the detection of abdominal aortic aneurysm (AAA) and its severity using neural networks.

     

Metabolites secreted by human atherothrombotic aneurysms revealed through a metabolomic approach

Abdominal aortic aneurysm (AAA) is perma-nent and localized dilation of the abdominal aorta. Intraluminal thrombus (ILT) is involved in evolution and rupture of AAA. Complex biological processes associated with AAA include oxidative stress, proteolysis, neovascularization, aortic inflammation, cell death, and extracellular matrix breakdown. Biomarkers of growth and AAA rupture could give a more nuanced indication for surgery, unveil novel pathogenic pathways, and open possibilities for pharmacological inhibition of growth. Differential analysis of metabolites released by normal and pathological arteries in culture may help to find molecules that have a high probability of later being found in plasma and start signaling processes or be useful diagnostic/prognostic markers. We used a LC-QTOF-MS metabolomic approach to analyze metabolites released by human ILT (divided into luminal and abluminal layers), aneurysm wall (AW), and healthy wall (HW). Statistical analysis was used to compare luminal with abluminal ILT layer, ILT with AW, and AW with HW to select the metabolites exchanged between tissue and external medium. Identified compounds are related to inflammation and oxidative stress and indicate the possible role of fatty acid amides in AAA. Some metabolites (e.g., hippuric acid) had not been previously associated to aneurysm, others (fatty acid amides) have arisen, indicating a very promising line of research.     

Toward a biomechanical tool to evaluate rupture potential of abdominal aortic aneurysm: identification of a finite strain constitutive model and evaluation of its applicability

Knowledge of the wall stresses in an abdominal aortic aneurysm (AAA) may be helpful in evaluating the need for surgical intervention to avoid rupture. This must be preceded by the development of a more suitable finite strain constitutive model for AAA, as none currently exists. Additionally, reliable stress analysis of in vivo AAA for the purposes of clinical diagnostics requires patient-specific values of the material parameters, which are difficult to determine noninvasively. The purpose of this work, therefore, was three-fold: (1) to develop a finite strain constitutive model for AAA; (2) to estimate the variation of model parameters within a sample population; and (3) to evaluate the sensitivity of computed stress distribution in AAA due to this biologic variation. We propose here a two parameter, hyperelastic, isotropic, incompressible material model and utilize experimental data from 69 freshly excised AAA specimens to both develop the functional form of the model and estimate its material parameters. Parametric analyses were performed via repeated finite element computations to determine the effect of varying each of the two model parameters on the stress distribution in a three-dimensional AAA model. The agreement between experimental data and the proposed functional form of the constitutive law was very good (R2 > 0.9). Our finite element simulations showed that the computed AAA wall stresses changed by only 4% or less when both the parameters were varied within the 95% confidence intervals for the patient population studied. This observation indicates that in lieu of the patient-specific material parameters, which are difficult to determine the use of population mean values is sufficiently accurate for the model to be reasonably employed in a clinical setting. We believe that this is an important advancement toward the development of a computational tool for the estimation of rupture potential for individual AAA, for which there is great clinical need.     

The association of wall mechanics and morphology: a case study of abdominal aortic aneurysm growth

The purpose of this study is to evaluate the potential correlation between peak wall stress (PWS) and abdominal aortic aneurysm (AAA) morphology and how it relates to aneurysm rupture potential. Using in-house segmentation and meshing software, six 3-dimensional (3D) AAA models from a single patient followed for 28 months were generated for finite element analysis. For the AAA wall, both isotropic and anisotropic materials were used, while an isotropic material was used for the intraluminal thrombus (ILT). These models were also used to calculate 36 geometric indices characteristic of the aneurysm morphology. Using least squares regression, seven significant geometric features (p?相似文献   

Bioluminescence and magnetic resonance imaging of macrophage homing to experimental abdominal aortic aneurysms

Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n = 32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n = 13) at day 14 demonstrated T?* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.     

Computational analysis of type II endoleaks in a stented abdominal aortic aneurysm model

Insertion of a stent-graft into an aneurysm to form a new (synthetic) blood vessel and prevent the weakened artery wall from rupture is an attractive surgical intervention when compared to traditional open surgery. However, focusing on a stented abdominal aortic aneurysm (AAA), post-operative complications such as endoleaks may occur. An endoleak is the net influx of blood during the cardiac cycle into the cavity (or sac) formed by the stent-graft and the AAA wall. A natural endoleak source may stem from one or two secondary branches leading to and from the aneurysm, labeled types IIa and IIb endoleaks. Employing experimentally validated fluid-structure interaction solvers, the transient 3-D lumen and cavity blood flows, wall movements, pressure variations, maximum wall stresses and migration forces were computed for types IIa and IIb endoleaks. Simulation results indicate that the sac pressure caused by these endoleaks depends largely on the inlet branch pressure, where the branch inlet pressure increases, the sac pressure may reach the systemic level and AAA-rupture is possible. The maximum wall stress is typically located near the anterior-distal side in this model, while the maximum stent-graft stress occurs near the bifurcating point, in both cases, due to local stress concentrations. The time-varying leakage rate depends on the pressure difference between AAA sac and inlet branch. In contrast, the stent-graft migration force is reduced by type II endoleaks because it greatly depends on the pressure difference between the stent-graft and the aneurysm cavity.     

Neuropsychiatric symptoms in patients with aortic aneurysms

Background

Emerging evidence suggests that vascular disease confers vulnerability to a late-onset of depressive illness and the impairment of specific cognitive functions, most notably in the domains of memory storage and retrieval. Lower limb athero-thrombosis and abdominal aortic aneurysm (AAA) have both been previously associated with neuropsychiatric symptoms possibly due to associated intracerebral vascular disease or systemic inflammation, hence suggesting that these illnesses may be regarded as models to investigate the vascular genesis of neuropsychiatric symptoms. The aim of this study was to compare neuropsychiatric symptoms such as depression, anxiety and a variety of cognitive domains in patients who had symptoms of peripheral athero-thrombosis (intermittent claudication) and those who had an asymptomatic abdominal aortic aneurysm AAA.

Methodology/Principal Findings

In a cross-sectional study, 26 participants with either intermittent claudication or AAA were assessed using a detailed neuropsychiatric assessment battery for various cognitive domains and depression and anxiety symptoms (Hamilton Depression and Anxiety Scales). Student t test and linear regression analyses were applied to compare neuropsychiatric symptoms between patient groups. AAA participants showed greater levels of cognitive impairment in the domains of immediate and delayed memory as compared to patients who had intermittent claudication. Cognitive dysfunction was best predicted by increasing aortic diameter. CRP was positively related to AAA diameter, but not to cognitive function. AAA and aortic diameter in particular were associated with cognitive dysfunction in this study.

Conclusions/Significance

AAA patients are at a higher risk for cognitive impairment than intermittent claudication patients. Validation of this finding is required in a larger study, but if confirmed could suggest that systemic factors peculiar to AAA may impact on cognitive function.     

Allelic genes involved in artery compliance and susceptibility to sporadic abdominal aortic aneurysm

Vascular smooth muscle cells (VSMCs) synthesize elastin (ELN), major protein of aortic tunica media which confers strength and elasticity to aortic wall. Protein loss or distortion is typical in aneurysm tunica media. Transforming growth factor β1 (TGFβ1) inhibits growth and connective protein expression of abdominal VSMCs cultures. Also, in atherogenic studies, estrogen (but not estrogen plus progestin) treatments inhibit aortic collagen accumulation and elastic loss, risk factors to subsequent aortic enlargement. Therefore, polymorphisms of ELN, estrogen receptor (ER) and β (ERβ), progesterone receptor (PR) and TGFβ1 genes and their products may be involved in the abdominal aortic aneurysm (AAA) development. Using PCR-RFLP method, we analyzed ELN RmaI (exon 16), ER PvuII-XbaI (intron 1), ERβ AluI (exon 8), PR TaqI (intron 7) and TGFβ1 Bsu36I (−509 bp, promoter) polymorphisms in 324 Caucasian male subjects: 225 healthy controls (mean age 71.20 ± 6.85 years) and 99 unrelated AAA patients (mean age 69.8 ± 7.1 years). No difference in ELN, ER, PR and TGFβ1 allele frequencies was observed in AAA patients versus controls (P > 0.05). However, because possessing at least an ERβ AluI restriction site was statistically associated to AAA onset (χ² = 5.220; OR = 1.82, P < 0.05), ERβ polymorphism was proposed as genetic determinant in the AAA susceptibility.     

腹主动脉瘤生长过程的蠕变力学模型

基于增强对腹主动脉瘤生长过程的理解、为腹主动脉瘤临床手术提供参考的目的,本文根据腹主动脉瘤的生长物理机制,提出了以蠕变力学为基础模拟腹主动脉瘤生长过程的模型.建立了腹主动脉瘤简化模型,利用有限元方法进行模拟计算.结果显示蠕变模型能够有效模拟腹主动脉瘤生长过程中的形态变化.参数优化模型模拟结果符合临床统计数据所示的腹主动脉瘤生长过程.本文还讨论了腹主动脉材料力学参数对模型的影响.     

Predicting Abdominal Aortic Aneurysm Target Genes by Level-2 Protein-Protein Interaction

Abdominal aortic aneurysm (AAA) is frequently lethal and has no effective pharmaceutical treatment, posing a great threat to human health. Previous bioinformatics studies of the mechanisms underlying AAA relied largely on the detection of direct protein-protein interactions (level-1 PPI) between the products of reported AAA-related genes. Thus, some proteins not suspected to be directly linked to previously reported genes of pivotal importance to AAA might have been missed. In this study, we constructed an indirect protein-protein interaction (level-2 PPI) network based on common interacting proteins encoded by known AAA-related genes and successfully predicted previously unreported AAA-related genes using this network. We used four methods to test and verify the performance of this level-2 PPI network: cross validation, human AAA mRNA chip array comparison, literature mining, and verification in a mouse CaPO₄ AAA model. We confirmed that the new level-2 PPI network is superior to the original level-1 PPI network and proved that the top 100 candidate genes predicted by the level-2 PPI network shared similar GO functions and KEGG pathways compared with positive genes.     

Pravastatin increases the expression of the tissue inhibitor of matrix metalloproteinase-1 and the oncogene Bax in human aortic abdominal aneurysms

The effect of pravastatin on matrix metalloproteinase-9 (MMP-9) and the level of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 was studied in explants of human abdominal aortic aneurysm (AAA) obtained from 13 patients. The effect of pravastatin on the apoptotic status of human AAA explants was also examined. Total MMP-9 content did not differ in human AAA explants incubated in vitro in the presence or absence of pravastatin (10-6 mol/L) for 48 h. TIMP-1 levels were significantly increased in pravastatin-incubated AAA explants, but TIMP-2 production was not modified by pravastatin. Western blot experiments showed that, whereas Bax expression was increased in pravastatin-incubated AAA explants, the expression of Bcl-2 was not modified. On the other hand, the ratio of the expression of Bax to Bcl-2, an apoptotic index, was not modified by pravastatin. In the human AAA explants, the increase in Bax expression, but not the increase in TIMP-1 expression elicited by pravastatin, was reversed by L-mevalonate, a downstream HMG-CoA reductase metabolite, suggesting that the expression of Bax and TIMP-1 followed HMG-CoA reductase-dependent and -independent pathways, respectively. In conclusion, pravastatin increases both TIMP-1 and Bax expression in human AAA explants without changes in either MMP-9 activity or the apoptotic status.     

Differential expression of TRAIL and its receptors relative to calcification in AAA

Abdominal aortic aneurysm (AAA) is commonly associated with atherosclerosis. Human AAA tissue displays cells undergoing all stages of apoptosis. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumour cells but not in normal cells. It has death receptors and decoy receptors. An inhibitor of TRAIL, osteoprotegerin (OPG), is involved in osteogenesis and vascular calcification. We investigated TRAIL and its receptors in AAA compared within normal aorta (NA). Both qualitative and quantitative analyses of calcification in AAA walls were determined using Von Kossa staining and pre-operation computer tomography (CT) scans. There was a significant difference in calcification level at different locations in the AAA wall (p <0.05). Apoptosis was confirmed in AAA by TUNEL assay. A significant difference in TRAIL and its receptor expression was observed between normal aortae and AAA (p<0.05). Significant differences were also observed between tissues displaying different extents of calcification for TRAIL mRNA (p<0.05) by RT-PCR examination and OPG protein (p<0.01) by protein blotting examination. We propose that this pattern of expression of TRAIL and its receptors may contribute to AAA formation and calcification in the AAA wall.