Topology of the fibrinolytic system within the mural thrombus of human abdominal aortic aneurysms

Development and progression of acquired abdominal aortic aneurysms (AAAs) involve proteolytic activity. In the present study, we investigate the distribution of fibrinolytic system components within mural thrombi of human AAAs. 20 mural thrombi and the remaining AAA walls were dissected. The luminal, intermediate and abluminal thrombus layers, and media and adventitia were separately incubated in cell culture medium. Conditioned media were then analysed for plasminogen activators (PAs), plasminogen activator inhibitor-1 (PAI-1), free-plasmin, plasmin alpha(2)-antiplasmin complexes (PAPs) and D-dimers release. In parallel, PA and PAI-1 mRNA expression analysis was performed by RT-PCR. The study was completed by immunohistochemical localization of these components in AAA, ex vivo functional imaging using (99m)Tc-aprotinin as a ligand and measurement of PAP and D-dimer plasma levels. All fibrinolytic system components were present in each aneurysmal layer. However, the mural thrombus was the main source of active serine-protease release. Interestingly, the luminal layer of the thrombus released greater amounts of PAPs and D-dimers. This paralleled the preferential immunolocalization of plasminogen and PAs, and the (99m)Tc-aprotinin scintigraphic signal observed in the luminal pole of the thrombus. In contrast, mRNA expression analysis showed an exclusive synthesis of tPA and PAI-1 within the wall, whereas uPA mRNA was also expressed within the thrombus. Taken together, these results suggest that the increased plasma concentrations of PAPs and D-dimers found in AAA patients are related to mural thrombus proteolytic activity, thus explaining their known link with AAA progression. Components of the fibrinolytic system could also represent a target for functional imaging of thrombus activities in AAA.     

Three-dimensional thrombus segmentation in abdominal aortic aneurysms using graph search based on a triangular mesh

An abdominal aortic aneurysm (AAA) is the area of a localized widening of the abdominal aorta, with a frequent presence of thrombus. Segmentation and quantitative analysis of the thrombus in AAA are of paramount importance for diagnosis, risk assessment and determination of treatment options. The proposed thrombus segmentation method utilizes the power and flexibility of the 3-D graph search approach based on a triangular mesh. The method was tested in 9 3-D MDCT angiography data sets (9 patients with AAA, 1300 image slices), and the mean unsigned errors for the luminal and thrombotic surfaces were and . To achieve these results, 9.9±10.3 control points needed to be interactively entered on 2.1±2.2 image slices per 3-D CTA data set.     

基质金属蛋白酶及其抑制剂在腹主动脉瘤发病中的作用

随着现代医学的发展 ,腹主动脉瘤 (ａｂｄｏｍｉｎａｌａｏｒｔｉｃａｎｅｕｒｙｓｍｓ ,ＡＡＡ)在临床上已得到有效治疗 ,但本病的促发因素以及持续扩张以致破裂的控制因素仍存在较大的争议 ,经过免疫、遗传、分子生物学及血流动力学等方面的广泛研究 ,所有学者均认为腹主动脉壁的基质降解是ＡＡＡ形成和发展的关键环节 ,基质金属蛋白酶 (ｍａｔｒｉｘｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅ ,ＭＭＰ)是破坏细胞外基质 (ｅｘｔｒａｃｅｌｌｕｌａｒｍａｔｒｉｘ ,ＥＣＭ )中最主要一类酶系 ,本文就ＭＭＰ及其抑制剂类别功能、来源与表达以及两…     

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.     

Inflammatory abdominal aortic aneurysms: A disease entity?

Summary Sixty inflammatory aortic aneurysms of unknown aetiology were examined by serial sections. The histological findings failed to reveal significant differences in either thoracic or abdominal aneurysms with or without marked adventitial fibrosis. Their identical morphology does not favour the existence of a special disease entity of so-called inflammatory abdominal aortic aneurysms (IAAA). Absence or existence of giant cells of any type, occurrence of plasma cells, eosinophils, granulomas, fibrinoid necrosis and adventitial fibrotic thickening cannot be considered as variables which help in differentiation. IAAA are characterized by a marked predominance of male patients and a rather benign clinical course. They usually affect the age group around 60 years. They are not rare and do not seem to be restricted to certain races. Their aetiology, like that of the cases affecting the thoracic aorta (Takayasu's disease, non-specific aortitis) remains unknown, although autoimmune diseases, the retroperitoneal fibrosis of Ormond and arteriosclerosis may be related. However, on the basis of the present evidence we cannot consider them to be one of these diseases. There are no morphological findings which would justify the separation of IAAA from Takaysu's disease.     

A comparison of cytoplasmic immunoglobulins in retroperitoneal fibrosis and abdominal aortic aneurysms

Retroperitoneal fibrosis is associated with Riedel's thyroiditis, in which an unexpectedly high proportion of the plasma cells have been reported to contain IgA and lambda light chains. It has been suggested that retroperitoneal fibrosis and the inflammation and fibrosis in thick-walled abdominal aortic aneurysms are caused by a hypersensitivity reaction to antigens leaked from aortic atheroma. We examined cases of retroperitoneal fibrosis and aortic aneurysms in order to quantify the types of heavy and light chains in the plasma cells. A mean of 44% of the plasma cells contained IgA and 52% contained lambda light chain. These results provide further evidence of the pathological relationship between retroperitoneal fibrosis and Riedel's thyroiditis. It is suggested that a cross-reaction between antigens in mucosal surfaces and in the thyroid or retroperitoneum may be implicated, possibly involving vessel walls. Of the total plasma cells in the wall of the aortic aneurysms 24% contained IgA and 40% lambda, although there was a significant trend towards a higher proportion of IgA with increasing thickness of the wall. No definite support for a relationship between atheroma and retroperitoneal fibrosis is provided by this study.     

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.     

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.     

BAK1 gene variation and abdominal aortic aneurysms

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic‐promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in “minority” forms within specific nondiseased tissues and be selected for, when intra‐ and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny. Hum Mutat 30:1–5, 2009. © 2009 Wiley‐Liss, Inc.     

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。     

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.