Experimental investigation of steady flow in rigid models of abdominal aortic aneurysms

Abdominal aortic aneurysms occur in as much as 2–3% of the population, and their rupture produces a mortality rate of 78–94% (1), causing 15,000 deaths per year in the U.S. alone. As an investigation into the mechanical factors that lead to aneurysm rupture, flow field measurements are presented for steady flow through a range of aneurysm sizes and Reynolds numbers. Seven rigid symmetric models of aneurysms were constructed with uniform lengths of 4d and diameters that ranged from 1.4 to 3.3d, whered is the inner diameter of the undilated entrance tube. Color Doppler flow imaging was used to visualize the flow fields, while laser Doppler velocimetry was used to quantify the flow field velocities and to determine critical Reynolds numbers for the onset of, and complete transition to, turbulent flow. Estimates of mean and peak wall shear stresses were derived from velocity measurements. Flow in these models varied from fully laminar to fully turbulent over the range of Reynolds numbers corresponding toin vivo flows. There was a large range over which the flow was intermittently turbulent. High wall shear occurred in the models when the flow was turbulent, suggesting that turbulence inin vivo aneurysms may contribute significantly to their risk of rupture.     

A patient-specific computational model of fluid-structure interaction in abdominal aortic aneurysms

It is generally believed that knowledge of the wall stress distribution could help to find better rupture risk predictors of abdominal aortic aneurysms (AAAs). Although AAA wall stress results from combined action between blood, wall and intraluminal thrombus, previously published models for patient-specific assessment of the wall stress predominantly did not include fluid-dynamic effects. In order to facilitate the incorporation of fluid–structure interaction in the assessment of AAA wall stress, in this paper, a method for generating patient-specific hexahedral finite element meshes of the AAA lumen and wall is presented. The applicability of the meshes is illustrated by simulations of the wall stress, blood velocity distribution and wall shear stress in a characteristic AAA. The presented method yields a flexible, semi-automated approach for generating patient-specific hexahedral meshes of the AAA lumen and wall with predefined element distributions. The combined fluid/solid mesh allows for simulations of AAA blood dynamics and AAA wall mechanics and the interaction between the two. The mechanical quantities computed in these simulations need to be validated in a clinical setting, after which they could be included in clinical trials in search of risk factors for AAA rupture.     

Prostaglandin receptor EP4 in abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) pathogenesis is distinguished by vessel wall inflammation. Cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1, key components of the most well-characterized inflammatory prostaglandin pathway, contribute to AAA development in the 28-day angiotensin II infusion model in mice. In this study, we used this model to examine the role of the prostaglandin E receptor subtype 4 (EP4) and genetic knockdown of COX-2 expression (70% to 90%) in AAA pathogenesis. The administration of the prostaglandin receptor EP4 antagonist AE3-208 (10 mg/kg per day) to apolipoprotein E (apoE)-deficient mice led to active drug plasma concentrations and reduced AAA incidence and severity compared with control apoE-deficient mice (P < 0.01), whereas COX-2 genetic knockdown/apoE-deficient mice displayed only a minor, nonsignificant decrease in incidence of AAA. EP4 receptor protein was present in human and mouse AAA, as observed by using Western blot analysis. Aortas from AE3-208-treated mice displayed evidence of a reduced inflammatory phenotype compared with controls. Atherosclerotic lesion size at the aortic root was similar between all groups. In conclusion, the prostaglandin E(2)-EP4 signaling pathway plays a role in the AAA inflammatory process. Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of AAA in the angiotensin II mouse model, potentially via attenuation of cytokine/chemokine synthesis and the reduction of matrix metalloproteinase activities.     

Plasma cell infiltrates in atherosclerotic abdominal aortic aneurysms

Thirty-one of 156 abdominal aortic resection specimens containing atherosclerotic aneurysm wall had an inflammatory infiltrate with a prominent plasma cell component of the media or of plaque replacing the media. The specimens in general were not examples of the so-called "inflammatory variant" of atherosclerotic aneurysm. No association between the infiltrate and syphilis, collagen vascular disease, furosemide exposure, chronic aneurysm leakage, aneurysm diameter, or duration of symptoms was found. The plasmacytic inflammation may be part of an immune response to atherosclerosis.     

Functional characterization of T cells in abdominal aortic aneurysms

Abdominal aortic aneurysms (AAA) exhibit features of a chronic inflammatory disorder. The functional attributes of the T cells in AAA tissue are unclear, with little quantitative or functional data. Using a novel, non-enzymatic method to isolate viable cells from AAA tissue, functional properties of AAA T cells were investigated for the first time. Composition and phenotype of AAA T cells was determined by flow cytometry and verified by immunohistochemistry. Tissue mononuclear cells (MNCs) were cultured in the presence of T-cell mitogens, and cell cycle analysis and cytokine production assessed. Typical cell yield was 4.5 x 10(6) cells per gram of AAA tissue. The majority (58.1+/-5.3%) of haematopoietic (CD45+) cells recovered were CD3+ T cells, B cells comprised 41.1+/-5.7%, natural killer cells 7.3+/-2.5%, and macrophages 2%. Freshly isolated T cells were in resting (G1) state, with 25% expressing the activation-associated cell surface antigens major histocompatibility complex II and CD25. When stimulated in vitro, a significant proportion entered S and G2 phase of the cell cycle, up-regulated CD25, and secreted tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-5 and IL-6. Despite patient differences, the composition of the AAA inflammatory infiltrate was remarkably consistent, and when re-stimulated ex-vivo T cells produced a stereotypical cytokine response, consistent with the hypothesis that AAA T cells can promote tissue inflammation by secretion of proinflammatory cytokines, and in addition provide signals for B-cell help.     

腹主动脉瘤生物力学研究的新进展

腹主动脉瘤(abdominal aortic aneurysm,AAA)是腹主动脉局部呈肿瘤状扩张的血管疾病。如果不及时治疗,持续扩张的AAA将最终破裂,具有极高的死亡率。近年来,生物力学方法被广泛地应用于AAA临床破裂风险的评估预测中。相关研究成果也极大地增进了对于AAA病理机制的理解。首先讨论基于腔内血栓和AAA的生物力学测试方法,全面了解血栓及动脉瘤组织的多种力学特性以及力学特性变化对AAA在病理环境下生长及结构重建的影响;回顾一系列运用实验和计算生物力学手段预测AAA破裂风险的代表性研究成果,具体包括有限元分析AAA的管壁应力分布、评估破裂风险指数和判断破裂发生的具体位置等方面;重点阐述AAA中血栓的老化所导致的微观结构变化,并总结AAA生物力学研究的现状和未来挑战。     

Genetic and epigenetic regulation of abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) are focal dilations of the aorta that develop from degenerative changes in the media and adventitia of the vessel. Ruptured AAAs have a mortality of up to 85%, thus it is important to identify patients with AAA at increased risk for rupture who would benefit from increased surveillance and/or surgical repair. Although the exact genetic and epigenetic mechanisms regulating AAA formation are not completely understood, Mendelian cases of AAA, which result from pathologic variants in a single gene, have helped provide a basic understanding of AAA pathophysiology. More recently, genome wide associated studies (GWAS) have identified additional variants, termed single nucleotide polymorphisms, in humans that may be associated with AAAs. While some variants may be associated with AAAs and play causal roles in aneurysm pathogenesis, it should be emphasized that the majority of SNPs do not actually cause disease. In addition to GWAS, other studies have uncovered epigenetic causes of disease that regulate expression of genes known to be important in AAA pathogenesis. This review describes many of these genetic and epigenetic contributors of AAAs, which altogether provide a deeper insight into AAA pathogenesis.     

Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response.

Cellular immunity may play a role in the pathogenesis of atherosclerosis. In this report the potential role of these cells in the formation of abdominal aortic aneurysms by immunohistochemistry was investigated. Aortic tissues from 32 patients were examined: 4 normal aortas, 6 aortas with occlusive atherosclerotic disease, 17 abdominal aortic aneurysms, and 5 inflammatory abdominal aneurysms. Using monoclonal anti-CD3 (T cells), anti-CD19 (B cells), anti-CD11c (macrophages), anti-CD4 (T helper cells), and anti-CD8 (T suppressor cells), several distinctions among these groups were found. The amount of inflammatory cell infiltrate was as follows: inflammatory aneurysms more than abdominal aortic aneurysms more than occlusive aortas more than normal aortas. CD3-positive T lymphocytes rarely were found in the adventitia of normal or occlusive aortas. In contrast, abdominal aortic aneurysms and inflammatory aneurysms exhibited most of the CD3-positive infiltrates in the adventitia. CD19-positive B lymphocytes were present mainly in the adventitia of all pathologic tissues. The CD4-positive:CD8-positive ratio was greater in abdominal aortic aneurysms and inflammatory aneurysms than in the other groups, both in the adventitia and in the media of the aortas. CD11c-positive macrophages were present throughout the diseased tissues, often surrounded by lymphoid aggregates; the greatest numbers of macrophages were found in the inflammatory aneurysm group. Our data suggests that the aneurysmal disease may progress from occlusive disease and is accompanied by an increase in chronic inflammatory cells as well as a redistribution of these cell types. Therefore it is suggested that aneurysmal disease may represent an immune-mediated event.     

Quantification of particle residence time in abdominal aortic aneurysms using magnetic resonance imaging and computational fluid dynamics

Hemodynamic conditions are hypothesized to affect the initiation, growth, and rupture of abdominal aortic aneurysms (AAAs), a vascular disease characterized by progressive wall degradation and enlargement of the abdominal aorta. This study aims to use magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) to quantify flow stagnation and recirculation in eight AAAs by computing particle residence time (PRT). Specifically, we used gadolinium-enhanced MR angiography to obtain images of the vessel lumens, which were used to generate subject-specific models. We also used phase-contrast MRI to measure blood flow at supraceliac and infrarenal locations to prescribe physiologic boundary conditions. CFD was used to simulate pulsatile flow, and PRT, particle residence index, and particle half-life of PRT in the aneurysms were computed. We observed significant regional differences of PRT in the aneurysms with localized patterns that differed depending on aneurysm geometry and infrarenal flow. A bulbous aneurysm with the lowest mean infrarenal flow demonstrated the slowest particle clearance. In addition, improvements in particle clearance were observed with increase of mean infrarenal flow. We postulate that augmentation of mean infrarenal flow during exercise may reduce chronic flow stasis that may influence mural thrombus burden, degradation of the vessel wall, and aneurysm growth.     

Blood flow and structure interactions in a stented abdominal aortic aneurysm model

Since the introduction of endovascular techniques in the early 1990s for the treatment of abdominal aortic aneurysms (AAAs), the insertion of an endovascular graft (EVG) into the affected artery segment has been greatly successful for a certain group of AAA patients and is continuously evolving. However, although minimally invasive endovascular aneurysm repair (EVAR) is very attractive, post-operative complications may occur. Typically, they are the result of excessive fluid-structure interaction dynamics, possibly leading to EVG migration. Considering a 3D stented AAA, a coupled fluid flow and solid mechanics solver was employed to simulate and analyze the interactive dynamics, i.e., pulsatile blood flow in the EVG lumen, pressure levels in the stagnant blood filling the AAA cavity, as well as stresses and displacements in the EVG and AAA walls. The validated numerical results show that a securely placed EVG shields the diseased AAA wall from the pulsatile blood pressure and hence keeps the maximum wall stress 20 times below the wall stress value in the non-stented AAA. The sac pressure is reduced significantly but remains non-zero and transient, caused by the complex fluid-structure interactions between luminal blood flow, EVG wall, stagnant sac blood, and aneurysm wall. The time-varying drag force on the EVG exerted by physiological blood flow is unavoidable, where for patients with severe hypertension the risk of EVG migration is very high.     

New insights into triploidy and tetraploidy, from an analysis of model systems for these conditions

While triploids and tetraploids together probably account for approximately 20% of all spontaneous abortions with a numerical chromosomal defect, and consequently give rise to a significant proportion of human pregnancy wastage, relatively little is known about their early embryogenesis and phenotypic features. We have therefore studied the early post-implantation stages of development of spontaneously occurring digynic triploid mouse embryos and experimentally induced diandric and digynic triploids, as well as diandric heterozygous diploids and homozygous tetraploid embryos. This material has been examined morphologically and cytogenetically, in order to investigate whether any relationship exists between their phenotype, genotype and developmental potential. Attention is drawn to the fact that the detailed analysis of this material has already shed important new light on the genetic factors that influence early mammalian development. In addition, it appears likely that it has the potential to provide new insights into pattern formation, in particular in relation to the craniofacial region, the heart and the post-cranial vertebral axis.     

Proteomic analysis of calcified abdominal and thoracic aortic aneurysms

Aortic aneurysm is a complex multifactorial disease with genetic and environmental risk factors. It is often accompanied by aortic calcification. Here, to uncover proteins that are significantly changed in calcified abdominal aortic aneurysms (CAAs) and calcified thoracic aortic aneurysms (CTAs) compared with those in adjacent normal aorta tissues, comprehensive analysis of differentially expressed proteins in their tissues was performed by a quantitative proteomic approach with iTRAQ labeling in combination with nanoLC-MALDI-TOF/TOF-MS/MS followed by ProteinPilot analysis. The proteomic analysis revealed 138 and 134 proteins differentially expressed in CAAs and CTAs in contrast to neighboring normal aorta tissues with high confidence, respectively. Significantly increased expression (≥1.3-fold) was found in 41 and 28 proteins, whereas decreased expression (<0.77-fold) was found in 4 and 60 proteins in CAAs and CTAs, respectively. Among them, we identified already known proteins involved in aneurysm formation and vascular calcification, such as type I and III collagen, matrix Gla protein, and α-2-HS-glycoprotein in CAAs and fibrinogen α, β and γ chains and α-2-HS-glycoprotein in CTAs with increased expression and mimecan in CAAs and fibulin-5 in CTAs with decreased expression. Based on the Panther pathway and Genesis clustering analyses, some of the proteins could be linked to corresponding biochemical pathways, such as the integrin signaling pathway with increased expression in CAAs, the blood coagulation pathway with increased expression in CTAs, and the inflammation mediated by chemokine and cytokine signaling pathway and the glycolysis pathway with decreased expression in CTAs. Interestingly, it was found by clustering analysis that samples from CAAs of patients with both CAAs and CTAs were clustered outside the samples of patients with CAAs and were clustered with samples of patients with CTAs. Our results provide a comprehensive patient-based proteomic analysis for the identification of potential biomarkers for CAAs and CTAs.     

Prognosis of abdominal aortic aneurysms. A population-based study

Information is incomplete about the rate of expansion of abdominal aortic aneurysms and the risk of rupture in relation to their size. To address these questions, we conducted a population-based study. Of the 370 residents of Rochester, Minn., with an aneurysm initially diagnosed from 1951 through 1984, 181 had the aneurysm documented by ultrasound examination. Among the 103 patients who underwent more than one ultrasound study, the diameter of the aneurysm increased by a median of 0.21 cm per year. Only 24 percent had a rate of expansion of 0.4 cm or more per year. Among the 176 patients who had an unruptured aneurysm at the time of the initial ultrasound study, the cumulative incidence of rupture was 6 percent after 5 years and 8 percent after 10 years. However, the risk of rupture over five years was 0 percent for the 130 patients with an aneurysm less than 5 cm in diameter and 25 percent for the 46 patients with an aneurysm 5 cm or more in diameter. All 16 patients who had ruptures had aneurysms that were 5 cm or more in diameter at the time of the rupture. These population-based data challenge the clinical perception that aneurysms typically expand at a rate of 0.4 to 0.5 cm per year. Our data also suggest that for aneurysms less than 5 cm in diameter the risk of rupture is considerably lower than has been reported previously. However, the risk of rupture is substantial for aneurysms 5 cm or more in diameter.     

In vitro evaluation of the effects of intraluminal thrombus on abdominal aortic aneurysm wall dynamics

The optimum time to treat abdominal aortic aneurysms (AAAs) still remains an uncertain issue. The decision to intervene does not take in account the effects that wall curvature, intraluminal thrombus (ILT) properties and thickness have on rupture. The role of ILT in aneurysm dynamics and rupture has been controversial. In vitro testing of four silicone AAA models incorporating the ILT and aortic bifurcation was studied under physiological conditions. Pressures (P) and diameters (D) were analysed for models with and without ILT at different locations. The diametral strain, compliance and P/D curves were influenced by the presence, elastic stiffness and thickness of the ILT. In this case, the inclusion of ILT reduced the lumen area by 77% that resulted in a 0.5–81% reduction in compliance depending on ILT properties. With an increase in ILT stiffness from 0.05 to 0.2 MPa, the compliance was reduced by 81%. In the region of maximum diameter, there was a reduction of diametral strain and compliance except for the softer ILT which was more compliant throughout the proximal region. The shifting of the maximum diametral strain and compliance to the proximal neck was pronounced by an increase in ILT stiffness, thus creating a possible rupture site.     

New insights into the dynamics of sinusoidal endothelial fenestrae in liver sinusoidal endothelial cells

Ultrastructural studies have shown that liver sinusoidal endothelial cells (LSECs) contain a cytoskeletal framework of filamentous actin, and that the presence of actin in the form of a calmodulin—actomyosin complex is responsible for regulation of the diameter of sinusoidal endothelial fenestrae (SEF). Rho has emerged as an important regulator of the actin cytoskeleton and consequently of cell morphology. We investigated actin filaments in relation to SEF in LSEC using heavy meromyosin decorated reaction and elucidated the roles of Rho and actin cytoskeleton in morphological and functional alterations of SEF. Second, according to intracytoplasmic Ca²⁺ concentration, plasma membrane Ca²⁺Mg²⁺-ATPase activities were clearly demonstrated on the outer surface of the labyrinth-like SEF in the isolated LSECs. Furthermore, by investigating intracytoplasmic Ca²⁺ concentration, we have demonstrated plasma membrane Ca²⁺-Mg²⁺-ATPase activities on the outer surface of the labyrinth-like SEF in the isolated LSECs. Currently, the majority of fenestral studies are focused on finding ways to increase the liver sieve’s porosity, which is reduced through pathological mechanisms. Dr. Hiroaki Yokomori, of the Department of Internal Medicine, Kitasato Medical Center Hospital, Saitama, Japan, is the winner of the Japanese Society for Clinical Molecular Morphology Award for Promoting Young Researchers in 2007. Dr. Yokomori was recognized for his great contribution in elucidating the role of sinusoidal endothelial fenestrae in the physiology and pathology of the liver.