Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

Thesis (M.S.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 157-161). Also available on the World Wide Web.

Thesis (M.S.)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: W. Robert Taylor; Committee Member: John Oshinski; Committee Member: Kathy Griendling; Committee Member: Raymond P. Vito; Committee Member: Rudolph L. Gleason.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

In silico models of intracranial aneurysm (IA) evolution aim to reliably represent the mechanical blood flow environment, the biology of the arterial wall and, crucially, the complex link between the two, namely the mechanobiology of healthy and diseased arteries. The ultimate goal is to create diagnostic tools for personalized management and treatment of aneurysm disease. Towards that target, the work presented in this thesis aims to establish a directly interactive link between experimental (in vivo and in vitro) and computational work for biologically and clinically relevant research on aneurysm disease. Mechanobiological hypotheses were firstly investigated in a novel 1D mathematical conceptual model of aneurysm evolution: for the first time these included representations of endothelial heterogeneity and smooth muscle cell (SMC) active stress response and apoptosis. The 1D investigations analysed and assessed the role of wall shear stress (WSS) homeostasis in elastin degradation, and the evolving role of the adventitia as a protective sheath in health and primary load-bearer in disease. The 1D framework was applied to a specific patient's aneurysm using both imaging and histological data to parameterise the model, calculating a material parameter for the adventitital collagen. The predicted evolution captured aspects of tissue changes measured with time focusing on the remodelled tissue wall thickness consistent with the experimental measurements, and physiological cyclic deformation in order to propose an approach to modelling adventitia's adaptive role to load bearing. Furthermore, an existing Fluid-Solid-Growth (FSG) computational framework was adapted and calibrated for the same patient-specific case with the help from the experimental data and the analysis from the 1D framework. This FSG model quantifies the arterial mechanical environment and captures the mechanical response of the fibrous arterial constituents. Comparing 1D and 3D investigations to establish consistency for our models, the 3Dmodel tested the hypothesis of WSS homeostasis, additionally introducing the element of spatial heterogeneity in the definition, and a new hypothesis linking cyclic deformation with collagen growth that ensures a physiological mechanical environment in stabilised aneurysms. Moreover, the FSG framework was applied in a specific rabbit aneurysm case and extended to link growth and remodeling to the detailed representation of the pulsatile blood flow mechanical environment. This research illustrates the power of computational modelling when coupled with rich data sets on the physiology, histology and geometry of healthy and diseased vascular tissue. In particular, the integrative modelling framework provides the foundation for establishing mechanobiological links crucial to aneurysm progression, and a basis for further research towards creating reliable aneurysm clinical tools.

Made available in DSpace on 2014-06-11T19:30:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-09-15Bitstream added on 2014-06-13T19:19:08Z : No. of bitstreams: 1 almeida_mj_dr_botfm.pdf: 527680 bytes, checksum: b40e49ce6cd134912d0e53aa6e29defc (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A migração da endoprótese é uma complicação do tratamento endovascular definida como deslocamento de sua ancoragem inicial. Para avaliação da migração verifica-se a posição da endoprótese em relação à determinada região anatômica. Considerando o aneurisma da aorta abdominal infra-renal, a área proximal de referência consiste na origem da artéria renal mais baixa e, na região distal, situa-se nas artérias ilíacas internas. Os pacientes deverão ser monitorizados por longos períodos a fim de serem identificadas migrações visto que estas ocorrem normalmente após 2 anos de implante. Para se evitarem migrações, forças mecânicas que propiciam fixação e determinadas por características dos dispositivos e a incorporação da endoprótese, devem predominar sobre forças gravitacional e hemodinâmica que tendem a arrastar a prótese no sentido caudal. Angulação, extensão e diâmetro do colo, além da medida transversa do saco aneurismático, são importantes aspectos morfológicos do aneurisma relacionados à migração. Com relação à técnica, o implante de endopróteses com sobredimensionamento excessivo (>30%) não é recomendado por provocar dilatação do colo do aneurisma, além de dobras e vazamentos proximais que também contribuem para migração. Por outro lado, endopróteses com mecanismos adicionais de fixação (ganchos, farpas e fixação supra-renal) parecem estar menos associadas às migrações. O processo de incorporação das endopróteses ocorre parcialmente e parece não ser suficiente para impedir migrações tardias. Neste sentido, estudos experimentais com endopróteses de maior porosidade e uso de substâncias que permitam maior fibroplasia e aderência da prótese à artéria vem sendo realizados e parecem ser promissores. Nesta revisão estes aspectos serão discutidos, em especial o uso da cola de fibrina. / Migration of the endoprosthesis is a complication of the endovascular treatment defined as misplacement of its initial fixation. In order to assess such migration, one shall verify the position of the endoprosthesis in relation to the determined anatomic site. Considering the aneurysm of the infra-renal abdominal aorta, the proximal area of reference consists on the origin of the lowest renal artery and, at the distal region, it is located next to the internal iliac arteries. Patients shall be monitored for long periods so that migrations can be spotted; these migrations usually occur 2 years after the implant. To avoid migration mechanical forces that enable fixation and that are determined by features of devices as well as the incorporation of the endoprosthesis have to predominate over gravitational and hemodynamic forces, which tend to drag the prosthesis toward to caudal direction. Angulation, extension and diameter of the neck, and transversal measure of the aneurysmatic sac, are important morphological aspects related to migration. In relation to technique, the implant of endoprosthesis with excessive oversizing (>30%) is not recommended because it leads to aortic neck dilatation, folds and proximal leaking witch contribute to its migration. On the other hand, endoprosthesis with additional fixation devices (hooks, barbs and supra-renal fixation) seem to be less associated with migration. The process of incorporation of the endoprosthesis occurs partially and does not seem to be enough to prevent later migrations. In this sense, experimental assessment with higher porosity endoprosthesis as well as the use of substances that allow higher fibroplasia and adherence of the prosthesis to the artery have been made and look promising. In this review, such aspects are discussed, specially the use of fibrin glue.

Endovascular aortic aneurysm repair (EVAR) is the procedure of choice in most patients with abdominal aortic aneurysm. The drawbacks of EVAR are a higher rate of complications and frequent need for reinterventions, requiring regular postoperative follow-up. Non-stratified follow-up may have a deleterious effect on patients and the health care system. The aim of this thesis is to develop strategies that can stratify the EVAR follow-up programme according to an individual patient´s risk profile. Study I, an international multicentre study of all abdominal aortic aneurysm (AAA) patients with EVAR in three centres (2000 to 2011) demonstrated a lower rate of late complications and reinterventions in patients with sac shrinkage during the first postoperative year, compared to the non-shrinkage group. Study II, an international multicentre study of patients treated for a ruptured aortic aneurysm with EVAR in three centres (2000 to 2012) demonstrated that ruptured EVAR (rEVAR) in patients with hostile anatomy is associated with a high rate of graft-related complications, reinterventions and increased overall mortality. Study III, a two-centre cohort study of 326 patients with EVAR (2001 to 2012), with first postoperative computerised tomographic angiography (CTA) within one year of the operation. Patients with adequate proximal and distal sealing zones and no endoleak in the first postoperative CTA had significantly lower risk for AAA-related complications and reinterventions up to five years postoperatively. Study IV, studied all complications and reinterventions in a two-centre cohort study of all EVAR patients (1998 to 2012), One-fourth of the patients in the study developed complications during a mean follow-up of five years. Most complications were asymptomatic imaging-detected. Ultrasound could detect most of the clinically significant complications.

Aneurismas e dissecções da aorta ascendente são caracterizados por degradação das fibras elásticas e de colágeno e diminuição de células musculares lisas, predominantemente em áreas mucóides, as quais são relacionadas ao acúmulo de glicosaminoglicanos ou proteoglicanos. Tendo em vistas tais alterações, estudamos a topologia das metaloproteases nestas doenças. Cortes de 5?m de aortas, fixadas em fomol e embebidas em parafina, foram submetidos a reações imuno-histoquímicas para MMP-3 (estromelisina), MMP-7 (matrilisina) e plasminogênio/plasmina na camada média. Em paralelo, cortes de aortas foram submetidos a coloração pela hematoxilina e eosina e azul de Alcian (para material mucóide). Aortas de 8 pacientes com aneurisma de aorta torácica e 10 com dissecções agudas foram analisadas. Adicionalmente, 9 aortas normais foram estudadas como controle. Em todos os casos, MMP-3 e, mais expressivamente, MMP-7 apresentaram marcação dentro dos acúmulos mucóides. Em contrapartida, a marcação para plasmina/plasminogênio situou-se ao redor deles. Fora dessas áreas, a MMP-3 mostrou distribuição intra e extracelular, a MMP-7 apresentou marcação intra e extracelular predominante na segunda metade da túnica média, e plasmina/plasminogênio teve co-localização com células musculares lisas. Considerando que matrilisina e estromelisina atuam sobre os proteoglicanos e sobre outros componentes da matriz extracelular, estas enzimas poderiam estar envolvidas diretamente na gênese dos aneurismas e dissecções da aorta ascendente, com possível modulação por plasminogênio/plasmina / In dissections and non-inflammatory aneurysms of the ascending aorta there is an increase in mucoid (proteoglycan) deposition. We analyzed by immunoperoxidase the distribution of stromelysin (MMP-7), matrilysin (MMP-3) and plasminogen/plasmin, enzymes that act on proteoglycans, in sections of human aortas with these diseases and in controls. In cases with any of these diseases MMP-7 and MMP-3 were accumulated in the areas of mucoid degeneration, and plasmin around them. Such enzymes could thus be involved in these diseases. We also evaluated by morphometry the amount of collagen in the two halves of the aortic media.

L’anévrisme de l’aorte abdominale (AAA) représente un problème majeur de santé publique et est associé à des taux extrêmement élevés de mortalité en cas de rupture aortique. Il est classiquement associé à l’athérosclérose et aux facteurs de risque cardiovasculaires, à l’exception du diabète qui jouerait un rôle protecteur dans la maladie. Bien que certaines études aient montré une infiltration de macrophages et une modification de l’expression des micro-ARNs dans la paroi anévrismale, leurs rôles respectifs dans le développement de l’AAA ne sont pas encore totalement élucidés. Même si les modèles expérimentaux classiques sont utiles pour adresser cette question, ils ne miment pas parfaitement la physiopathologie humaine. Nous avons développé un nouveau modèle d’AAA associant application topique d’élastase et neutralisation systémique du TGFβ permettant de reproduire les principales caractéristiques de l’AAA humain et induisant une rupture aortique. Les objectifs de ce travail étaient de: -1/ Caractériser le phénotype des monocytes/ macrophages dans ce modèle murin d’AAA. -2/ D’étudier l’expression des micro-ARNs dans ce modèle. -3 / Les mécanismes impliqués dans la relation négative entre diabète et AAA étant à ce jour peu connus, le 3ème objectif était de mettre en place une étude clinique afin d’étudier l’expression des micro-ARNs chez des patients diabétiques ayant un AAA.L’application d’élastase associée à la neutralisation du TGFβ chez des souris C57/Bl6j entrainait une augmentation significative de la densité de macrophages infiltrés dans le tissu aortique anévrismal. L’analyse des tissus aortiques a montré des modifications significatives des marqueurs des macrophages pro-inflammatoires dits « M1 » et des marqueurs des macrophages impliqués dans la réparation tissulaire, dits « M2 ». Afin de mieux comprendre le rôle des macrophages dans ce modèle murin, des injections de clodronate ont été réalisées pour dépléter ces cellules. L’injection de clodronate diminuait de façon significative la dilatation anévrismale et prévenait la rupture. Ceci était associé à une préservation de la matrice extracellulaire et une modification de l’expression de certains marqueurs des macrophages, dont l’arginase-1 (ARG1), molécule impliquée dans la réparation tissulaire. La proportion de macrophages exprimant l’ARG1 augmentait en fonction de la sévérité de l’AAA. Enfin, la neutralisation du TGFβ induisait une diminution significative d’un type particulier de monocytes dits « Sat-Mono», impliqués dans la fibrose. Cette étude a ainsi montré le rôle des macrophages dans le développement et la rupture anévrismale avec une modification de leur phénotype. 752 micro-ARNs ont ensuite été analysés dans le tissu aortique, ce qui a permis d’identifier les micro-ARNs dont l’expression était modifiée dans ce modèle par rapport au groupe contrôle. Enfin, l’expression des micro-ARNs a été recherché chez l’homme en mettant en place une étude clinique. Bien que l’AAA chez l’homme soit classiquement associé à l’athérosclérose et aux facteurs de risque cardiovasculaire, il est paradoxalement négativement associé au diabète. Les mécanismes en cause sont encore peu connus. Nous avons comparé l’expression des micro-ARNs entre des patients diabétiques et non-diabétiques présentant un AAA. Cette étude pilote a permis d’identifier des cibles potentielles impliquées dans l’association négative entre diabète et AAA. / Abdominal aortic aneurysm (AAA) is a major public health concern and is associated with extremely high rates of mortality in case of aortic rupture. AAA is most often associated with atherosclerosis and cardiovascular risk factors, except diabetes that may rather play a protective role in the disease. Even though several studies have highlighted an infiltration of macrophages and changes of the expression of micro-RNAs in the aneurysmal wall, their role in AAA is still not fully understood. While experimental animal models are very useful to address this question, none of them perfectly mimics human pathophysiology. We recently created a new murine model of AAA based on topic application of elastase on the aorta associated with systemic TGFβ neutralization which reproduces the main human features of AAA and leads to fatal aortic rupture. The aims of this study were: -1/ Characterize the phenotype of monocytes/ macrophages in this murine model of AAA. -2/ Study the expression of micro-RNAs in this model. -3/ As the mechanisms involved in the negative association between diabetes and AAA are still poorly known, the third goal was to mount a clinical study to compare the expression of micro-RNAs between diabetic and non-diabetic patients with AAA. Topic application of elastase associated with systemic TGFβ neutralization in C57/Bl6j male mice led to a significant increase of macrophage infiltration in the aneurysmal tissue. This was associated with changes of the gene expression of the markers of the pro-inflammatory macrophages, called “M1” and of the macrophages involved in wound healing, called “M2”. To investigate the role of macrophages in this model, we used liposomes containing clodronate injections to deplete these cells. This led to significant decrease of the aortic dilatation and prevented rupture. This was associated with a better preservation of the extracellular matrix and significant changes in the gene expression of the markers of macrophages including arginase-1 (ARG1), a molecule involved in would healing. The proportion of macrophages expressing ARG1 increased with the severity of the AAA. At last, TGFβ neutralization led to a significant decrease of a population of macrophages involved in fibrosis, called “Sat-Mono”. This study highlighted the role and the phenotypic changes of macrophages during AAA development. We then analyzed the expression of 752 micro-RNAs in the aneurysmal aortic tissue which allowed identifying the micro-RNAs whose expression varied in the murine model. At last, the expression of micro-RNAs was investigated in patients with AAA. We compared the expression of micro-RNAs between diabetic and non-diabetic patients with AAA. This pilot study led to the identification of micro-RNAs that could potentially represent new targets involved in the negative association between diabetes and AAA.