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

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

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.

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.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20236号 / 医博第4195号 / 新制||医||1019(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 松原 和夫, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24484号 / 医博第4926号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 YOUSSEFIAN Shohab, 教授 齊藤 博英 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introdução: O aneurisma de aorta abdominal (AAA) é uma importante causa de morbimortalidade na população idosa. O tratamento endovascular está associado a menor morbimortalidade que o tratamento convencional, no entanto, necessita de um seguimento rigoroso com exames de imagem contrastados para confirmação da exclusão do saco aneurismático. Considerando que a formação de um aneurisma é um processo multifatorial complexo, envolvendo a remodelação destrutiva do tecido conjuntivo em todo o segmento afetado da parede da aorta e que este processo envolve uma inflamação crônica local, uma diminuição no número de células do músculo liso da túnica média, e fragmentação da matriz extracelular da aorta e ainda que um perfil de expressão aberrante de miRNAs tem sido associada a doenças humanas, incluindo disfunção cardiovascular propôs-se então a realização deste estudo envolvendo todo este processo. O objetivo principal foi quantificar e avaliar a resposta da expressão dos miRNAs à correção endovascular de aneurisma de aorta abdominal com base em dosagens séricas no seguimento de seis meses. População e Método: Foram recrutados 30 pacientes consecutivos com AAA sem outras doenças inflamatórias associadas, do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRPUSP com indicação de tratamento endovascular. Foram escolhidos para estudo e dosagens séricas os miRNA-191 e miRNA-455-3p. A expressão diferencial dos miRNAs foi realizada pelo método de PCR em tempo real, após extração do RNA das amostras de sangue total em dois momentos, pré- operatório e após 6 meses de pós-operatório. Além disso, ferramentas de bioinformática foram utilizadas para determinar vias fisiopatológicas relacionadas ao AAA. Foram Colhidos dados de perfil demográfico, de seguimento clinico e exames de imagem com angiotomografia no pré-operatórios e após 6 meses. Resultados: Foi observado uma hiperexpressão dos miR-191 e miR-455-3p no sangue total dos pacientes com AAA. O tratamento endovascular dos pacientes com AAA resultou em diminuição significativa das expressões dos miRNAs estudados, indicando que a exclusão do saco aneurismático altera as expressões dos mesmos. Adicionalmente, as expressões dos miR-191 e miR-455-3p não apresentaram correlação com o diâmetro do aneurisma e a análise da influência dos diversos tipos de dispositivos utilizados para o tratamento endovascular dos AAA, não mostrou diferenças significativas nas expressões dos miR-191 e miR-455-3p. Conclusões: A hiperexpressão dos miR-191 e miR-455-3p com sua significativa redução apos o tratamento endovascular, pode sugerir a utilização dessas moléculas como potenciais biomarcadores no seguimento desses pacientes. Novos estudos com maior número de casos devem ser realizados com o objetivo de validar os dados obtidos incluindo pacientes com eventuais vazamentos. / Background: Abdominal aortic aneurysm (AAA) is an important cause of morbidity and mortality in the elderly population. Endovascular treatment is associated with lower morbidity and mortality than conventional treatment, however, it requires a rigorous follow-up with contrast imaging tests to confirm the aneurysmal sac exclusion. Considering that the formation of an aneurysm is a complex multifactorial process, involving the destructive remodeling of the connective tissue throughout the affected segment of the aortic wall and that this process involves a chronic local inflammation, a decrease in the number of smooth muscle cells of the media tunic, and fragmentation of the extracellular matrix of the aorta and although an aberrant expression profile of miRNAs has been associated with human diseases, including cardiovascular dysfunction, it was proposed to carry out this study involving this whole process. The main objective was to quantify and evaluate miRNA expression response to endovascular correction of abdominal aortic aneurysm based on serum dosages at the six-month follow-up. Population and Method: We recruited 30 consecutive patients with AAA without other associated inflammatory diseases from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRPUSP with indication of endovascular treatment. The miRNA-191 and miRNA-455-3p were selected for study and serum dosages. The differential expression of the miRNAs was performed by the real-time PCR method, after extraction of RNA from the whole blood samples at two moments, preoperatively and after 6 months of follow-up. In addition, bioinformatics tools were used to determine pathophysiological pathways related to AAA. Demographic profile, clinical follow-up and imaging examinations with angiotomography performed in the preoperative period and after 6 months were collected. Results: Hyperexpression of miR-191 and miR-455-3p in whole blood of AAA patients was observed. The endovascular treatment of patients with AAA resulted in a significant decrease in the expression of the miRNAS studied, indicating that the exclusion of the aneurysmal sac altered their expression. In addition, the expression of miR-191 and miR-455-3p showed no correlation with the diameter of the aneurysm and analysis of the influence of the various types of devices used for the endovascular treatment of AAA did not show significant differences in the expression of miR-191 And miR-455-3p. Conclusions: The hyperexpression of miR- 191 and miR-455-3p with its significant reduction after endovascular treatment may suggest the use of these molecules as potential biomarkers in the follow-up of these patients. New studies with a greater number of cases should be performed with the objective of validating the data obtained including patients with possible endoleaks.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Introdução: O aneurisma de aorta abdominal (AAA) é uma importante causa de morbimortalidade na população idosa. O tratamento endovascular está associado a menor morbimortalidade que o tratamento convencional, no entanto, necessita de um seguimento rigoroso com exames de imagem contrastados para confirmação da exclusão do saco aneurismático. Considerando que a formação de um aneurisma é um processo multifatorial complexo, envolvendo a remodelação destrutiva do tecido conjuntivo em todo o segmento afetado da parede da aorta e que este processo envolve uma inflamação crônica local, uma diminuição no número de células do músculo liso da túnica média, e fragmentação da matriz extracelular da aorta e ainda que um perfil de expressão aberrante de miRNAs tem sido associada a doenças humanas, incluindo disfunção cardiovascular propôs-se então a realização deste estudo envolvendo todo este processo. O objetivo principal foi quantificar e avaliar a resposta da expressão dos miRNAs à correção endovascular de aneurisma de aorta abdominal com base em dosagens séricas no seguimento de seis meses. População e Método: Foram recrutados 30 pacientes consecutivos com AAA sem outras doenças inflamatórias associadas, do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRPUSP com indicação de tratamento endovascular. Foram escolhidos para estudo e dosagens séricas os miRNA-191 e miRNA-455-3p. A expressão diferencial dos miRNAs foi realizada pelo método de PCR em tempo real, após extração do RNA das amostras de sangue total em dois momentos, pré- operatório e após 6 meses de pós-operatório. Além disso, ferramentas de bioinformática foram utilizadas para determinar vias fisiopatológicas relacionadas ao AAA. Foram Colhidos dados de perfil demográfico, de seguimento clinico e exames de imagem com angiotomografia no pré-operatórios e após 6 meses. Resultados: Foi observado uma hiperexpressão dos miR-191 e miR-455-3p no sangue total dos pacientes com AAA. O tratamento endovascular dos pacientes com AAA resultou em diminuição significativa das expressões dos miRNAs estudados, indicando que a exclusão do saco aneurismático altera as expressões dos mesmos. Adicionalmente, as expressões dos miR-191 e miR-455-3p não apresentaram correlação com o diâmetro do aneurisma e a análise da influência dos diversos tipos de dispositivos utilizados para o tratamento endovascular dos AAA, não mostrou diferenças significativas nas expressões dos miR-191 e miR-455-3p. Conclusões: A hiperexpressão dos miR-191 e miR-455-3p com sua significativa redução apos o tratamento endovascular, pode sugerir a utilização dessas moléculas como potenciais biomarcadores no seguimento desses pacientes. Novos estudos com maior número de casos devem ser realizados com o objetivo de validar os dados obtidos incluindo pacientes com eventuais vazamentos. / Background: Abdominal aortic aneurysm (AAA) is an important cause of morbidity and mortality in the elderly population. Endovascular treatment is associated with lower morbidity and mortality than conventional treatment, however, it requires a rigorous follow-up with contrast imaging tests to confirm the aneurysmal sac exclusion. Considering that the formation of an aneurysm is a complex multifactorial process, involving the destructive remodeling of the connective tissue throughout the affected segment of the aortic wall and that this process involves a chronic local inflammation, a decrease in the number of smooth muscle cells of the media tunic, and fragmentation of the extracellular matrix of the aorta and although an aberrant expression profile of miRNAs has been associated with human diseases, including cardiovascular dysfunction, it was proposed to carry out this study involving this whole process. The main objective was to quantify and evaluate miRNA expression response to endovascular correction of abdominal aortic aneurysm based on serum dosages at the six-month follow-up. Population and Method: We recruited 30 consecutive patients with AAA without other associated inflammatory diseases from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRPUSP with indication of endovascular treatment. The miRNA-191 and miRNA-455-3p were selected for study and serum dosages. The differential expression of the miRNAs was performed by the real-time PCR method, after extraction of RNA from the whole blood samples at two moments, preoperatively and after 6 months of follow-up. In addition, bioinformatics tools were used to determine pathophysiological pathways related to AAA. Demographic profile, clinical follow-up and imaging examinations with angiotomography performed in the preoperative period and after 6 months were collected. Results: Hyperexpression of miR-191 and miR-455-3p in whole blood of AAA patients was observed. The endovascular treatment of patients with AAA resulted in a significant decrease in the expression of the miRNAS studied, indicating that the exclusion of the aneurysmal sac altered their expression. In addition, the expression of miR-191 and miR-455-3p showed no correlation with the diameter of the aneurysm and analysis of the influence of the various types of devices used for the endovascular treatment of AAA did not show significant differences in the expression of miR-191 And miR-455-3p. Conclusions: The hyperexpression of miR- 191 and miR-455-3p with its significant reduction after endovascular treatment may suggest the use of these molecules as potential biomarkers in the follow-up of these patients. New studies with a greater number of cases should be performed with the objective of validating the data obtained including patients with possible endoleaks.