The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs. First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the progression of established AAAs through distinct mechanisms that differentially influence aortic lumen and wall diameters. We also investigate whether androgen regulates aortic AT1aR expression to promote AngII-induced AAA formation. Our data demonstrated that in male and female mice, both endogenous and exogenous androgen stimulate AT1aR level particularly in abdominal aortas. This androgen-dependent enhanced expression of abdominal aortic AT1aR was correlated with increased AngIIinduced AAA formation in male and female mice. Smooth muscle AT1aR deficiency significantly reduced luminal and external diameters of abdominal aortas as well as the incidence of AngII-induced AAAs in adult female mice administered exogenous androgen. Collectively, these results indicate that in adult mice androgen stimulate smooth muscle AT1aR expression to promote AngII-induced AAA formation. To determine the role of androgen during development on AT1aR expression on SMC and AngII-induced vascular pathologies, we exposed neonatal female mice to one single dose of testosterone. Our data demonstrated that neonatal testosterone administration dramatically increased AngII-induced AAA, atherosclerosis and ascending aortic aneurysms in adult female mice. In addition, smooth muscle AT1aR deficiency reduced effects of neonatal testosterone to promote AAAs, but had no effect on the other two AngII-induced vascular pathologies. In summary, our findings demonstrated that androgen, both in adult life and during development, stimulate smooth muscle AT1aR expression and promote AngII-induced AAA in female hyperlipidemic mice.

This project concerns an exploration of the presence and interactions of long non-coding RNA transcripts in an experimental atherosclerosis mouse model with relevance for human abdominal aortic aneurysm development. 187 long noncoding RNAs, two of them entirely novel, were found to be differentially expressed between angiotensin II treated (developing abdominal aortic aneurysms) and non-treated apolipoprotein E deficient mice (not developing aneurysms) harvested after the same period of time. These transcripts were also studied with regards to co-expression network connections. Eleven previously annotated and two novel long non-coding RNAs were present in two significantly disease correlated co-expression groups that were further profiled with respect to network properties, Gene Ontology terms and MetaCore© connections.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Orientador: Winston Bonetti Yoshida / Banca: Regina Moura / Banca: Carlos Eli Piccinato / Resumo: 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. / Abstract: 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. / Doutor

Objectives: Clinical implementation of 3D ultrasound (3D-US) in vascular surgery is in its infancy. The aim of this thesis was to develop novel clinical applications for 3D-US in the diagnosis and management of abdominal aortic aneurysm (AAA). Methods: Four principle clinical applications were investigated. 1) Intraoperative imaging – The ability of 3D-US to detect and classify endoleaks was compared with digital subtraction angiography in patients undergoing EVAR. 2) Detection and classification of endoleaks following endovascular aneurysm repair (EVAR) – The abilityof 3D-US to accurately detect and classify endoleaks following EVAR was compared to CTA and the final multi-disciplinary team decision. 3) AAA volume measurement – measurements using magnetic and optically-tracked 3D-US were compared to CTA. 4) Biomechanical analysis – the challenges of using 3D-US to generate surface models for biomechanical simulation was explored by development of an interactive segmentation technique and comparison of paired CT and 3D-US datasets. Optimal results were used in finite element analysis (FEA) and computational fluid dynamic(CFD) simulations. Results: 3D-US out-performed uniplanar angiography for the detection of endoleaks during EVAR. This approach allowed contrast-free EVAR to be performed in patients with poor renal function. 3D contrast-enhanced ultrasound was superior to CTA for endoleak detection and classification when compared with the final decision of the multi-disciplinary team. Optimal results for AAA volume measurements were gained using an optically tracked 3D-US system in EVAR surveillance. However, there remained a significant mean difference of 13.6ml between CT and 3D-US. Complete technical success of generating geometries for use in biomechanical analysis using 3D-US was only 5%. When the optimal results were used, a comparable CFD analysis under the conditions of steady, laminar and Newtonian flow was achieved. Using basic modelling assumptions in FEA, peak von Mises and principle wall stress was found to be at the same anatomical location on both the CT and 3D-US models but the 3D-US model overestimated the wall stress values by 41% and 51% respectively. Conclusions: 3D-US could be clinically implemented for intra-operative imaging and EVAR surveillance in specific cases. 3D-US volume measurement is feasible but future work should aim to improve accuracy and inter-observer reliability. Although the results of biomechanical analysis using the optimal results was encouraging and provided a proof-of-principal, there are a number of technical developments required to make this approach feasible in a larger number of patients.

Orientadores: Sebastião Araujo, Ana Terezinha Guillaumon / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T22:15:18Z (GMT). No. of bitstreams: 1 Carvalho_AdrianaCamargo_M.pdf: 1640507 bytes, checksum: d217bd19f4b6097e48dac1bb2f824e35 (MD5) Previous issue date: 2009 / Resumo: Objetivos: Avaliar os níveis plasmáticos de vasopressina (AVP) em pacientes submetidos à correção cirúrgica não-complicada de aneurisma de aorta abdominal (AAA). Desenho: Estudo prospectivo, descritivo, observacional. Intervenções: Nenhuma. Local: Hospital de Clínicas da Unicamp. Métodos: A AVP plasmática foi mensurada por radio-imuno-ensaio em 22 pacientes não-consecutivos submetidos à correção cirúrgica convencional de AAA infra-renal, sob anestesia combinada (geral e epidural) nos seguintes tempos: pré-operatório (T0); 2h (T1) e 6h (T2) após o término da cirurgia; e nas manhãs do 1º (T3), 2º (T4) e 3º (T5) dia pós-operatório (PO). Algumas variáveis clínicas e laboratoriais de interesse foram registradas concomitantemente. Resultados: A idade média dos pacientes foi de 68,2±10,2 anos (variando de 49-82 anos), sendo 17 homens e 5 mulheres. Os níveis plasmáticos de AVP (média±DP pg/mL) estavam baixos e dentro da faixa de normalidade em T0 (1,4±0,7; controle), aumentando significativamente em T1 (62,6±62,9; p<0,001) e T2 (31,5±49,7; p<0,001), com uma queda exponencial a seguir, retornando aos níveis basais em T5 (2,1±3,8; p = NS). Correlações positivas e estatisticamente significativas foram encontradas entre a AVP e a glicemia, lactatemia e leucócitos sangüíneos, mas não com a pressão arterial sistêmica ou osmolaridade plasmática no PO. Conclusões: O padrão de aumento da AVP plasmática, com picos nas primeiras horas de PO nestes pacientes, sugere que esta resposta está diretamente relacionada ao trauma cirúrgico, mas não às alterações hemodinâmicas e da osmolaridade plasmática. A fisiopatologia deste padrão de resposta ao estresse é ainda obscuro, e merece investigações adicionais em procedimentos cirúrgicos gerais / Abstract: Objectives: To evaluate plasma vasopressin (AVP) levels in patients undergoing uncomplicated conventional abdominal aortic aneurysm (AAA) repair. Design: Prospective, descriptive, observational study. Interventions: None. Setting: A tertiary academic hospital at Campinas, Sao Paulo, Brazil. Methods: Plasma AVP concentrations were measured by radioimmunoassay in 22 nonconsecutive adult patients undergoing infra-renal AAA repair under combined general and epidural anesthesia at the following moments: pre-operative (T0); 2h (T1) and 6h (T2) after surgical procedure; and by the morning at the 1st (T3), 2nd (T4) and 3rd (T5) postoperative days. Some clinical and laboratory variables were concomitantly recorded. Results: Patients mean age was 68.2±10.2 years (ranging 49-82 years), with 17 males and 05 females. AVP plasma levels (mean±SD pg/mL) were low and within the normal range at T0 (1.4±0.7; control), showing a significant increase at T1 (62.6±62.9; p<0.001) and at T2 (31.5±49.7; p<0.001), with a marked progressive fall in the subsequent days, returning to basal levels at T5 (2.1±3.8; p = NS). Positive and statistically significant correlations were found between AVP levels and glycemia, lactatemia and white blood cells counts, but not with systemic arterial pressure or plasma osmolarity during postoperative period. Conclusions: The pattern of plasma AVP increasing, peaking during the 1st postoperative hours, suggests that this response is directly related to the surgical trauma, but not to hemodynamic and/or plasmatic osmolarity derangements. The pathophysiology of this pattern of stress response is still unclear, and deserves further investigation in general surgical procedures / Mestrado / Pesquisa Experimental / Mestre em Cirurgia

L’anévrisme de l’aorte abdominale (AAA) est associé à des taux élevés de morbidité et de mortalité. A l’heure actuelle, le seul traitement curatif de l’AAA est chirurgical, aucune approche pharmacologique n’ayant démontré une efficacité suffisante. Une meilleure compréhension des mécanismes aboutissant au développement de l’AAA permettrait d’identifier de nouvelles cibles thérapeutiques. Bien qu’utiles dans cette démarche, les modèles animaux expérimentaux actuels ne reproduisent pas parfaitement la physiopathologie humaine. Les objectifs de ce travail étaient de : 1/ Créer et caractériser un nouveau modèle murin d’AAA associant application topique d’élastase et neutralisation du TGFβ. 2/ Etudier le rôle de l’IL1β dans ce modèle. La neutralisation du TGFβ chez des souris C57Bl6j aggravait la dilatation anévrismale induite par l’application d’élastase et favorisait la rupture aortique. Ceci était associé à une dégradation accrue de la matrice-extra-cellulaire, une infiltration de cellules inflammatoires au sein de la paroi aortique, la formation d’un thrombus intra-luminal ainsi qu’une augmentation de la néo-angiogénèse. L’utilisation de la technique d’imagerie par synchrotron a permis de montrer une destruction de la paroi aortique en l’absence de formation de dissection aboutissant à une rupture aortique transmurale fatale. L’expression génique de différentes cytokines, dont l’IL1β était augmentée dans la paroi aortique. Afin d’étudier le rôle de l’IL1β, 2 modèles d’invalidation ont été utilisé : l’induction d’AAA chez des souris déficientes en IL1β et l’injection systémique d’anticorps anti-IL1β. Les souris IL1β-/- étaient protégées du développement anévrismal et de la rupture après application d’élastase et neutralisation du TGFβ. En revanche, la neutralisation de l’IL1β par injection d’anticorps à un temps plus tardif ne limitait pas la progression de l’AAA et aboutissait à la rupture anévrismale. Cette étude a permis de créer un nouveau modèle murin d’AAA dont les caractéristiques sont proches de la physiopathologie humaine. L’invalidation génétique de l’IL1β, et non la neutralisation systémique à un temps tardif, limitait la croissance et prévenait la rupture anévrismale suggérant le rôle de cette cytokine au cours des stades précoces du développement de l’AAA. / Abdominal aortic aneurysm (AAA) is associated with extremely high morbidity and mortality rates. The only curative treatment relies on surgery as no drug has proven yet its efficacy to cure the disease. A better understanding of pathophysiological mechanisms involved in AAA development would help to identify new therapeutic targets. Even though current experimental animal models are useful to address this question, none of them perfectly mimics human disease. The aim of this study was: 1/ Create and characterize a new murine model of AAA based on topic application of elastase associated with systemic TGFβ neutralization. 2/ Study the effect of IL-1β in this model. We report that TGFβ neutralization in C57Bl6j male mice increased aneurysmal aortic dilatation induced by elastase and favored aortic rupture. This was associated with major vascular remodeling including the degradation of extracellular matrix, the infiltration of inflammatory cells in the aortic wall, the formation of an intraluminal thrombus and the increase of neoangiogenesis. Synchrotron-based ultrahigh ex-vivo resolution imaging revealed a wall disruption with no medial dissection culminating in fatal transmural aortic wall rupture. The gene expression of several cytokine including IL-1β was increased in the aortic wall. The effect of IL-1β was investigated using IL-1β-/- mice or using systemic injection of monoclonal anti-IL-1β antibody. IL-1β-/- mice were protected against aortic dilatation and aortic rupture after application of elastase associated with TGFβ neutralization. However, the injection of anti-IL-1β antibody did not limit the aortic dilatation and neither prevented the aortic rupture. In this study, we created a new murine model of AAA which reproduces the main pathophysiological human features. The genetic invalidation of IL-1β, but not its blockade after disease initiation prevented AAA dilatation and rupture, suggesting the role of this cytokine in the early stages of AAA development.

Bakgrund: Aortaaneurysm är en asymtomatisk sjukdom som främst drabbar rökande män. Sjukdomsförloppet utgörs av en långsam vidgning av aneurysmen som kan resultera i en ruptur med hög dödlighet. I Sverige kallas alla män över 65 år till screening för aortaaneurysm, i ett försök att reducera dödligheten i sjukdomen. Sjukdomen kan behandlas via konservativ behandling eller operation. Syfte: Syftet var att belysa patienters upplevelse av aortaaneurysm. Metod: En litteraturstudie med induktiv innehållsanalys användes för att analysera tio artiklar från databaserna CINAHL, PubMed och Scopus. Resultat: Efter analys av artiklarna framkom fyra teman i resultatet: Upplevelser av diagnostisering, Upplevelser av konservativ behandling, Upplevelser av det pre-operativa stadiet och Upplevelser av det postoperativa stadiet. Att diagnostiseras med aortaaneurysm reducerade patienters välbefinnande. Patienter fick inte tillräckligt med information om sjukdomen. Att infinna sig vid screening, uppföljning och operation upplevdes inte som frivilligt. Konklusion: Det är av vikt att vårdprofessionella utövar god omvårdnad genom patientinformation och upprättar en god relation med patienten. Mer forskning krävs för att kunna väga för och nackdelarna med ett nationellt screeningprogram. / Background: Aortic aneurysm is an asymptomatic disease that mainly affects smoking men. The course of the disease comprises of a slow widening of the aneurysm, which may cause a rupture that is associated with a high risk of mortality. In Sweden, all men over the age of 65 are called for screening for aortic aneurysm, to reduce the disease specific mortality. The disease can either be treated conservatively or surgically. Aim: The aim of this study was to portray patients’ experiences of aortic aneurysm. Method: A literature overview with inductive content analysis was used to analyse ten articles from the databases CINAHL, PubMed and Scopus. Result: After analysis of the articles four themes emerged: Experiences of diagnosis, Experiences of conservative treatment, Experiences of the pre-operative stage and Experiences of the post-operative stage. To be diagnosed with aortic aneurysm reduced patients’ well-being. Patients did not receive sufficient information regarding the disease. To attend screening, follow-up and operation wasn’t perceived as voluntary. Conclusion: It is important that healthcare professionals practice good care through patient-information and establish a good relationship with the affected. Further research is needed to be able to weigh the pros and cons with a national screening program.

Abdominal Aortic Aneurysm (AAA) rupture remains a leading cause of death in westernized countries. Much remains to be understood on the biomechanics of rupture. It is not clear whether rupture is predominantly a phenomenon at the material level (aneurysm wall weakening) or due to abnormally elevated tissue wall tension (stress resultant). A computational study involving 4 ruptured and 9 unruptured abdominal aortic aneurysms (AAA) was conducted to test if ruptured aneurysms were subject to a higher pressure induced wall tension than unruptured aneurysms. The unique aspect of this study is that, regional variations in material properties (thickness, stiffness, failure strength) were documented in all the aneurysms in the study population. In addition, AAA geometry was documented using photographs from multiple rotational angles. Novel methods were developed for 3D reconstruction from photographs using voxel carving, for precise spatial mapping of measured properties onto the reconstructed 3D models and for scattered data interpolation of sparsely measured parameters to the entire finite element model. Heterogeneous, variable wall thickness models of patient-specific AAA were developed and the tension distribution under normal systolic pressure computed. Peak wall tension was the primary metric studied. Other indices found in literature (peak wall stress, peak regional tension to failure tension ratio and peak regional stress to failure stress ratio) were also compared. The peak wall tension in the ruptured aneurysm group was not higher than the unruptured aneurysms with statistical significance, but with a trend toward it (p = 0.053). Among the other metrics, the peak regional tension and stress ratios (with their respective failure counterparts) were higher in the ruptured group (p = 0.038 for both) but not so for peak wall stress (p = 0.099). Although rigorously studied, the small study population does not warrant definitive conclusions. The study methods developed however will permit larger studies of this nature to better investigate mechanisms in AAA rupture.

<div>An abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta, as defined by a 50% increase in diameter or a diameter greater than 3 cm. While typically asymptomatic, there is a risk that the AAA will rupture, causing massive hemorrhaging and high mortality rates. Thus, once detected, the clinician must choose between surveillance and elective surgical repair. The first option carries the risk of rupture; the second risks complications and graft failure. Currently, clinical metrics of rupture risk are dependent on diameter and growth rate. However, a number of studies have indicated that, although rupture risk does increase with increased diameter, there are also a large number of patients with aneurysms for which the diameter criteria is insufficient. There remains a strong need to 1) determine better estimates of rupture risk in order to accurately assess the need for surgery and 2) improve surgical treatment to reduce perioperative risk. </div><div><br></div><div>Herein, we use ultrasound in mice to address these two prevalent uncertainties in aneurysm development and treatment. First, we further develop a murine aneurysm model that forms large aneurysms with distal thrombus. To increase the applicability of the model, we modulate aneurysm growth by altering elastase concentration and lysyl oxidase inhibition. We show that initial elastase concentration impacts aneurysm size, which is driven in part by a change in the degree of initial degradation of the aortic wall. We also demonstrate that lysyl oxidase inhibition (via BAPN) remains necessary for expansion even after the initial aneurysm formation and that removal of the lysyl oxidase inhibitor effectively stops growth in this model. As a final point, we show that female mice develop larger aneurysms than the males using this model. Then, with the aim of improving surgical treatment options, we explore the patency of various design parameters involved in tissue-engineered vascular grafts. To do so, we assess the allowable parameter design space of murine textile arterial grafts, so as to lead to better selection of key design components. Overall, the findings in this thesis demonstrate the applicability of ultrasound in small animals to improve aneurysm diagnostic and treatment options.</div>