INTRODUÇÃO: O objetivo deste estudo é determinar as propriedades biomecânicas e histológicas de fragmentos da parede anterior de aneurismas da aorta abdominal. MÉTODOS: Dos pacientes submetidos à correção cirúrgica aberta de aneurisma da aorta abdominal, foram removidos fragmentos da parede anterior do saco aneurismático, divididos em dois espécimes. Um, destinado à análise histológica, para a quantificação de fibras colágenas, elásticas, musculares lisas e grau de atividade inflamatória e outro, pareado, submetido a teste destrutivo uniaxial, obtendo-se características biomecânicas, como, força, tensão e estresse de falência do fragmento. As médias das variáveis paramétricas foram avaliadas com teste t-Student ou análise de variância. Quando significante, utilizou-se teste de Tukey para discriminar as diferenças. As distribuições das variáveis não paramétricas foram avaliadas com teste Mann-Whitney ou análise de Kruskal-Wallis. Quando significante, utilizou-se teste de Dunn para discriminar as diferenças. Os valores de p<0,05 foram considerados estatisticamente significantes. RESULTADOS: Foram considerados os resultados das análises de fragmentos de 90 indivíduos. Os valores médios encontrados para as propriedades biomecânicas relacionadas à resistência do tecido aórtico (falência) foram força = 4,98±2,22 N, tensão = 13,18±5,98 N/cm e estresse = 103,14±47,09 N/cm2. A deformação média dos fragmentos até a falência foi de 0,39±0,12. Os fragmentos dos aneurismas de diâmetros transversos máximos maiores ou iguais a 5,5 cm apresentaram valores médios de força, tensão e estresse de falência (5,32±2,07 N, 13,83±5,58 N/cm e 103,02 N/cm2) maiores que os fragmentos de aneurismas de diâmetros menores que 5,5 cm (4,1±2,41 N, 10,82±6,48 N/cm, 77,03 N/cm2), com significância estatística para os três parâmetros de resistência do material. Não foram identificadas diferenças entre os valores médios de deformação de falência entre estes grupos (0,41±0,12 x 0,37±0,14 p = 0,260), bem como entre os valores médios de espessura dos fragmentos (1,58±0,41 x 1,53±0,42 mm p = 0,662). Os valores percentuais médios na composição dos fragmentos foram para as fibras colágenas (coloração de tricrômico de Masson) de 44,34±0,48%, para as fibras colágenas (coloração de picrosirius) de 61,85±10,14%, para as fibras musculares lisas (imuno histoquímica/alfa actina) de 3,46±2,23% e para as fibras elásticas (coloração de Verhoeff) inferior a 1% (traços). Não foram identificadas diferenças entre o percentual destes elementos na composição de fragmentos provenientes da parede anterior de aneurismas de diâmetro transverso máximo >= 5,5 cm e < 5,5 cm. Foi caracterizada uma atividade inflamatória mais intensa nos fragmentos provenientes de aneurismas de diâmetro transverso máximo >= 5,5 cm quando comparados aos fragmentos provenientes de aneurismas de diâmetro transverso máximo < 5,5 cm (grau 3 - 70% x 28,6% p = 0,011). Comparando-se os aneurismas sintomáticos versus os assintomáticos não foram identificadas diferenças significativas para as propriedades biomecânicas de falência dos fragmentos (força = 5,32±2,36 x 4,65±2,05 N, p = 0,155; tensão = 14,08±6,11 x 12,81±5,77 N/cm, p = 0,154; estresse = 103,02 x 84,76 N/cm2, p = 0,144 e deformidade = 0,38±0,12 x 0,41±0,13, p = 0,287), assim como para a espessura (1,56±0,41 x 1,57±0,41 mm p = 0,848) e composição histológica (fibras colágenas 44,67±11,17 x 44,02±13,79 % p = 0,808; fibras musculares lisas 2,52 x 2,35 %, p = 0,751; fibras elásticas inferior a 1%). CONCLUSÃO: Os fragmentos provenientes da parede anterior do saco aneurismático de aneurismas maiores mostraram-se mais resistentes, não se identificando diferenças entre os fragmentos quanto à espessura e conteúdo da matriz protéica. A maior resistência dos fragmentos de aneurismas maiores provavelmente está relacionada à adaptação da parede para suportar maior grau de sobrecarga hemodinâmica à medida que o diâmetro aumenta. Neste estudo esta adaptação não foi revelada pela análise histológica realizada e demonstra a limitação do estudo de fragmentos isolados de aneurismas para estimar o risco de ruptura dos mesmos / INTRODUCTION: The objective of this study was to determine the biomechanical and histological properties of fragments isolated from the anterior wall of abdominal aortic aneurysms. METHODS: Fragments of the anterior aneurysm wall were excised from the aneurysmatic sac of patients who underwent open surgery for repair of abdominal aortic aneurysm and divided into two specimens. One specimen was sent for histological analysis for quantification of collagen fibers, elastic fibers, smooth muscle cells and degree of inflammatory activity and the other, by uniaxial testing, was used to assess biomechanical properties, such as force, tension, and stress at the time of failure of the material. The means of parametric variables were evaluated with Student\'s t test or analysis of variance. When significant, we used the Tukey test to discriminate differences. The distributions of non-parametric variables were evaluated with Mann- Whitney or Kruskal-Wallis test. When significant, we used Dunn\'s test to discriminate differences. A p-value of less than 0.05 was considered statistically significant. RESULTS: Anterior-wall fragments from a total of 90 patients were considered. The average values of biomechanical parameters related to the resistance of the aorta (failure) were as follows: strength, 4.98±2.22 N; tension, 13.18±5.98 N/cm; and stress 103.14±47.09 N/cm2. The average deformation of the fragments at the time of the failure was 0.39±0.12. Fragments of aortic aneurysm with a maximum transverse diameter larger or equal to 5.5 cm showed average values for strength, tension, and stress at the time of the failure of the material (5.32±2.07 N, 13.83±5.58 N/cm, and 103.02 N/cm2, respectively), which were higher than those of fragments of aneurysms with diameters less than 5.5 cm (4.1±2.41 N, 10.82±6.48 N/cm, 77.03 N/cm2, respectively). The differences in the 3 parameters were statistically significant. However, no differences were observed between the groups in relation to average failure deformation (0.41±0.12 × 0.37±0.14; p = 0.260) and thickness of the analyzed fragments (1.58±0.41 × 1.53±0.42 mm; p = 0.662). The average values of fiber compositions of the fragments were as follows: collagen fibers, 44.34±0.48% and 61.85±10.14% (assessed using Masson trichrome staining and picrosirius red staining, respectively); smooth muscle cells, 3.46±2.23% (immunohistochemistry/alpha-actin); and elastic fibers, less than 1% (traces) (Verhoeff-van Gieson staining). No differences in fiber percentages were observed in the fragments from aneurysms with a maximum transverse diameter >= 5.5 cm and < 5.5 cm. A more intense inflammatory activity was assessed in fragments from aneurysms with maximum transverse diameter >= 5.5 cm than in fragments from aneurysms with maximum transverse diameter < 5.5 cm (grade 3 - 70% × 28.6%; p = 0.011). Compared to asymptomatic aneurysms, fragments from symptomatic aneurysms showed no significant differences in the biomechanical properties at the time of the failure (strength, 5.32±2.36 × 4.65±2.05 N, p = 0.155; tension, 14.08±6.11 × 12.81±5.77 N/cm, p = 0,154; stress, 103.02 × 84.76 N/cm2, p = 0.144; and deformity, 0.38±0.12 × 0.41±0.13, p = 0.287), thickness of the fragments (1.56±0.41 × 1.57±0.41 mm, p = 0.848) and histological composition (collagen fibers, 44.67±11.17 × 44.02±13.79%, p = 0.808; smooth muscle fibers, 2.52 × 2.35%, p = 0.751; elastic fibers, <1%). CONCLUSION: Fragments of the anterior wall removed from the aneurysmatic sac of large aneurysms appeared to be more resistant than those from small aneurysms. No differences between the aneurysm fragments were observed with respect to thickness and matrix protein content. The high resistance of fragments of larger aneurysms is probably attributable to the adaptation of the wall to support a high hemodynamic stress as the diameter of the aorta increases. In this study, this adaptation was not shown by histological analysis. This suggests a limitation of this study for assessing the risk of rupture based on isolated aneurysm fragments

Abstract Thoracic aortic aneurysms (TAAs) are a significant source of morbidity and mortality. Classical risk factors for TAAs are hypertension, atherosclerosis, male gender, smoking, age, high body mass index, family history and chronic obstructive pulmonary disease. In addition, in certain cases of TAAs, i.e., ascending aortic aneurysms (AscAA), genetic factors are highly prominent. Matrix metalloproteinases are in a major role in the destruction of the aortic wall and the imbalance between matrix metalloproteinases, and their inhibitors are involved in the formation of aneurysms. In addition, osteopontin is a potent regulator of matrix metalloproteinases and it is widely expressed in injured arteries. Recently, telomere shortening has been shown to be involved in the development of abdominal aortic aneurysms (AAA). In this aneurysm type, atherosclerosis has a major role. Since atherosclerosis is frequently absent in the case of TAAs, the length of telomeres was measured in the blood samples of TAA patients. The purpose of this thesis was to study the genetic background of TAAs of the ascending aorta and furthermore, the molecular background of this disease. The first study was done with families with TAAs, and dissections and one chromosomal locus (5q13-14) of the studied seven loci showed a significant genetic linkage for TAAs. Two other studies were done exploiting our TAA case-control material. Study II showed elevated levels of osteopontin, matrix metalloproteinase type 2 and 9 in the plasma and tissue samples of TAA patients compared with controls. In the third study, longer blood leukocyte telomeres were found in the DNA samples of TAA patients compared with controls; furthermore, the elevation of telomere lengthening protein telomerase expression was found in the tissue samples of TAA patients. This thesis presents region 5q13-14 as a potential genetic regulator for TAAs in Finnish families. In addition, elevated levels of osteopontin, matrix metalloproteinase type 2 and 9 can be considered as a plasma biomarker for aneurysmal disease. Furthermore, longer blood leukocytes were found to be a significant risk factor for developing TAAs. / Tiivistelmä Rinta-aortan aneurysmat ovat merkittävä sairastumisiin ja kuolemiin johtava tekijä. Perinteisinä riskitekijöinä aneurysmille on pidetty korkeaa verenpainetta, ateroskleroosia, miessukupuolta, tupakointia, ikää, ylipainoa, suvussa esiintyneitä aneurysmatapauksia ja keuhkoahtaumatautia. Näiden lisäksi erityisesti nousevan rinta-aortan alueella esiintyvissä aneurysmissa myös perinnöllisillä tekijöillä on korostunut merkitys. Matriksimetalloproteinaaseilla ja niiden estäjillä on merkittävä rooli, kun aortan seinämää hajotetaan. Tasapainon järkkyminen kyseisten proteiinien keskinäisessä suhteessa voi johtaa aneurysman muodostumiseen. Myös osteopontiinin tiedetään olevan tehokas matriksimetalloproteinaasien säätelijä, ja sitä tuotetaankin yleisesti vahingoittuneessa verisuonessa. Telomeerien lyhentyminen on vastikään yhdistetty vatsa-aortan alueella esiintyviin aneurysmiin, joissa ateroskleroosilla on yleensä merkittävä rooli. Koska ateroskleroosi on vain harvoin nousevan rinta-aortan alueen aneurysmien taustalla, rinta-aortan aneurysmapotilaiden valkosolujen telomeerien suhteelliset pituudet määritettiin. Väitöskirjan ensimmäisessä osatyössä keskityttiin löytämään geneettinen kytkentä rinta-aortan aneurysmien ja jonkin seitsemän tutkitun kromosomialueen välille. Geneettinen kytkentä löydettiin kromosomialueelta 5q13-14. Osatöissä 2 ja 3 hyödynnettiin rinta-aortan aneurysmien potilas- ja verrokkiaineistoja. Osatyö 2 osoitti, että matriksimetalloproteinaasien (2 ja 9) määrät ovat kohonneet rinta-aortan aneurysmapotilaiden näytteissä verrokkeihin verrattuna. Osatyössä 3 telomeerien suhteelliset pituudet veren valkosoluissa olivat pidemmät nousevan rinta-aortan aneurysmapotilaiden näytteissä verrokkihenkilöiden näytteisiin verrattuna. Myös telomeraasin tuotto oli lisääntynyt rinta-aortan aneurysmapotilaiden aorttakudosnäytteissä. Väitöskirjassa esitetään tuloksena kromosomialue 5q13-14 geneettisenä säätelijänä suomalaisissa suvuittain esiintyvissä rinta-aortan aneurysmatapauksissa. Kohonneita matriksimetalloproteinaasien ja osteopontiinin tasoja voidaan lisäksi pitää biomarkkereina rinta-aortan aneurysmien sairastavuudelle. Veren valkosolujen pidemmät telomeerit näyttävät myös olevan yhteydessä rinta-aortan aneurysmien sairastavuuteen.

Les pathologies vasculaires provoquent un remodelage de la paroi artérielle pouvant entraîner une modification de sa rigidité et de son comportement mécanique. L’objectif de cette thèse est de proposer des méthodes de caractérisation mécanique permettant d’identifier les changements de propriétés mécaniques artérielles dans le cadre de deux situations pathologiques : l’anévrysme de l’aorte abdominale (AAA) et l’hypertension artérielle (HTA). La première étude a consisté à évaluer in vitro les modifications de fonctionnalité de l’artère dans le cas d’un AAA obtenu par le modèle de xénogreffe chez le rat qui permet de reproduire certains aspects de la pathologie humaine et qui est utilisé pour la mise au point de thérapies cellulaires. Une analyse des variations régionales des propriétés mécaniques du tissu anévrysmal a d’abord été menée en effectuant des tests de traction sur anneaux d’AAA. Des tests d’extension-inflation ont ensuite été réalisés sur la structure vasculaire pour des conditions de chargement reproduisant celles observées in vivo. Dans chacun des cas, une méthode inverse couplée à un modèle numérique par éléments finis a été développée afin d’identifier les paramètres matériaux du tissu vasculaire. Dans la deuxième étude, la rigidité artérielle a été mesurée in vivo sur une population de patients atteints d’HTA et de sujets sains en utilisant deux méthodes non-invasives qui ont été développées et optimisées : l’imagerie ultrarapide de l’onde de pouls et l’élastographie par ondes de cisaillement de la paroi artérielle. Ces deux méthodes s’appuient sur un échographe ultrarapide. La vitesse de l’onde de pouls locale sur un segment de la carotide a ainsi pu être évaluée, ainsi que la vitesse de propagation d’ondes de cisaillement générées dans la paroi à plusieurs instants du cycle cardiaque. Les deux approches in vitro et in vivo ont ainsi permis d’évaluer certains changements de propriétés mécaniques de la paroi artérielle dans des cas pathologiques. Bien que tous les mécanismes biologiques de l’AAA et de l’HTA soient complexes, ce travail permet de contribuer à une meilleure compréhension des pathologies vasculaires pouvant ainsi aider au choix ou au développement de traitements adaptés, tant d’un point de vue pharmacologique que dans le cadre de nouvelles thérapies cellulaires. / Vascular pathologies are generally accompanied by a remodeling of the arterial wall that may lead to modifications of its stiffness and mechanical behavior. The goal of this thesis is to propose methods of mechanical characterization allowing to detect the changes in arterial mechanical properties in the case of two pathologies: abdominal aortic aneurysm (AAA) and arterial hypertension (HTA). The first study consisted in evaluating in vitro the arterial functional modifications in the case of an AAA obtained by the rat xenograft model which reproduces several biological features of the human pathology and is used to develop cell therapies. First, the assessment of regional variations in mechanical properties of aneurysmal tissue was conducted by carrying out traction tests on rings from AAAs. Then, extension-inflation tests were conducted on the vascular structure for loading conditions replicating those observed in vivo. In each case, an inverse method associated with a numerical finite element model was developed to identify the material parameters of vascular tissue. In the second study, arterial stiffness was measured in vivo for a population of hypertensive patients and healthy subjects using two non-invasive methods which were developed and optimized: ultrafast imaging of the pulse wave and shear wave elastography of the arterial wall. These two methods are based on an ultrafast ultrasound scanner. Thus the local pulse wave velocity on a segment of the carotid artery was assessed, as well as the propagation speed of shear waves created in the arterial wall at several moments during the cardiac cycle. Both in vitro and in vivo approaches enabled to evaluate some changes in mechanical properties of the arterial wall in pathological cases. Although all the biological mechanisms of AAA and HTA are complex, this work provides a contribution to a better understanding of vascular pathologies and can thereby assist in the choice or development of adapted treatments, from both a pharmacological point of view, and within the context of new cell therapies.

Summary of the work<p>Abdominal aortic aneurysm (AAA) is a chronic degenerative disease that usually affects men over 65 years with an estimated prevalence of 5%. Aneurysm rupture represents a catastrophic event which carries a mortality rate of almost 90%. Current therapeutic options for AAAs measuring 5.5 cm in diameter or larger are based on prophylactic surgery, including conventional open reconstruction and endovascular stent-graft insertion. For patients with small asymptomatic AAAs (4.0 up to 5.5 cm in diameter), evidence from two recent large randomized controlled trials indicates no long-term survival benefit from immediate elective surgical repair as compared to imaging surveillance until aneurysm expands to 5.5 cm. This highlights the need for development of novel medical management strategies, including selective pharmacologic approaches, directed at preventing aneurysm expansion. In this regard, it is expected that a detailed knowledge of the pathobiology of human AAA lesion and a better understanding of pathophysiological mechanisms underlying initiation and progression of aneurysmal degeneration, particularly the specific involvement of T lymphocytes, will have special relevance to this challenging issue.<p>Inflammatory and helper T-cell responses in abdominal aortic aneurysm :controversial issues<p>Innate and inflammatory responses to endovascular versus open AAA repair. The occurrence of early acute systemic inflammatory responses after conventional open AAA repair is widely recognized and is thought to lead to the development of organ dysfunction and multiple organ failure, responsible for a large proportion of morbidity and mortality associated with aortic surgery. New therapeutic strategies designed to avoid ischemia-reperfusion injury related to aortic cross-clamping and to minimize the degree of tissue damage have thus been developed recently. Specifically, the advent of endovascular techniques has radically extended management options for patients with AAA. Although the method is believed to offer a clear short-term benefit over open repair, notably as regards restricted perioperative haemodynamic parameter fluctuations, reduced blood loss, briefer duration of surgery, shorter hospital stay, and lower 30-day mortality and complication rates, conflicting data are available regarding the exact nature and extent of the inflammatory events arising after such endoluminal procedures ;while several authors have indeed reported that endovascular AAA repair can determine a less intense and extensive inflammatory response, others have unexpectedly observed that the method may elicit a strong inflammatory response, the so-called « postimplantation syndrome ».<p>Adaptive cellular immune responses in human aneurysmal aortic lesion.<p>The inflammatory nature of AAA disease has long been suggested by the presence of a great number of CD4+ T lymphocytes in the outer media and adventitia of human AAA lesion. Interestingly, such infiltrating T-cell populations may have significant implications in the process of aneurysm dilation, since cytokines produced by T cells, notably IFN-gamma, have previously been shown to modulate production of matrix-degrading enzymes by resident macrophages and to induce apoptosis of medial SMCs. Through these key pathological mechanisms, T cells could potentially contribute to orchestrate aortic wall connective tissue disordered remodeling and degradation, and promote extensive disruption of elastic media, ultimately leading to aneurysmal degeneration. Nevertheless, despite their relative abundance in human AAA wall tissues, there is limited and controversial information as regards the functional profile of lesional lymphocytes, the exact nature of aortic wall adaptive cellular responses, and the etiologic role of T cells and their cytokines in initiation and progression of the aneurysmal process. Indeed, both Th1-type and Th2-type responses have been identified in human studies and experimental animal models of AAA.<p>Aims of the work<p>The main objectives of our work were to explore the innate and adaptive cellular immune responses in human AAA. In the first part of our work, we aimed to examine prospectively innate and inflammatory responses arising in a non-randomised cohort of patients undergoing endovascular versus open AAA repair. In the second part of our work, we focused our efforts on characterizing the nature of adaptive cellular immune responses and the phenotypic and functional repertoire of T cells in human AAA wall tissues obtained from a consecutive series of patients undergoing open AAA repair. Specifically, we sought to determine whether type 1 or type 2 responses occur predominantly in advanced AAA lesion.<p>Main experimental findings<p>Limited inflammatory response after endovascular AAA repair. Serial peripheral venous blood samples were collected preoperatively, immediately after declamping or insertion of endograft, and after 1, 3, 6, 12, 24, 48, and 72 hours. We first examined the acute phase reaction and liberation of complement cascade products using turbidimetric method and nephelometry. We found that endovascular repair produced lower postoperative CRP, leucocytosis, neutrophilia, and C3d/C3 ratio as compared to open surgery. We next analyzed surface expression of activation markers on peripheral CD3+ T cells using flow cytometry. We observed a strong upregulation of CD38 after open but not endovascular repair. Analysis of CD69 and CD25 molecules revealed no perioperative fluctuations in any group. We then investigated release of various circulating soluble cell adhesion molecules, proinflammatory cytokines, and chemokines using enzyme-linked immunosorbent assays. We demonstrated that both procedures are characterized by similar increases in ICAM-1 and IL-6 levels. Finally, tendency towards high levels of TNF-alpha and IL-8 was detected in endovascular repair, but data failed to reach statistical significance.<p>Predominance of type 1 CD4+ T cells in human aneurysmal aortic lesion. We have developed a tissue enzymatic digestion and cell extraction procedure to isolate intact mononuclear cells from aortic wall segments. This original cell isolation protocol enabled us to examine ex vivo the presence, phenotype, and cytokine secretion profile of infiltrating T lymphocytes freshly isolated from human AAA tissues for comparison with their circulating counterparts using flow cytometry. We found that both populations of infiltrating CD4+ and CD8+ T cells display a unique activated memory phenotype, as assessed by an increased expression of CD69 and HLA-DR activation antigens, downregulation of CD62L molecule, and predominant expression of the CD45RO isoform characteristics of memory cells. In addition, we identified the presence in human aneurysmal aortic wall lesion of CD4+ T cells producing high levels of IFN-gamma but not IL-4, reflecting their type 1 nature. In an additional series of experiments, cytokine gene expression was determined in whole aneurysmal and non-diseased aortic samples using LightCycler-based quantitative real-time reverse transcription-polymerase chain reaction. The molecular basis of type 1 or type 2 dominant responses was further specified by analyzing mRNA levels of transcription factors specifically involved in Th1 or Th2 differentiation such as T-bet and GATA-3. We demonstrated that aneurysmal aortic specimens exhibit high transcript levels of IFN-gamma but not IL-4, and consistently overexpressed the IFN-g-promoting cytokine IL-12 and the type 1-restricted transcription factor T-bet, further establishing the prominent type 1 nature of aortic wall responses. Moreover, such selective tissue expression of IL-12 and T-bet in the vessel microenvironment points to a potential role for these signals in directing aortic wall responses towards a type 1 phenotype.<p>Conclusions<p>Our findings indicate that endovascular AAA repair is associated with a lesser degree of acute phase reaction, peripheral T-cell activation, and release of complement proteins as compared to conventional open surgery, suggesting that the innate and inflammatory responses to AAA repair are significantly attenuated by the endovascular approach as compared to the traditional open reconstruction. These results support the view that the endoluminal procedure represents an attractive alternative to open surgery for the treatment of large aneurysms. On the other hand, we have demonstrated that Th1 cell infiltrates predominate in human end-stage AAA lesion. These observations are relevant for helping clarify the pathobiology of human AAA tissues and defining prospects for the prevention of aneurysm expansion. Indeed, identification of such infiltrating populations of IFN-gamma-producing CD4+ T cells not only provide new insights into the pathogenesis of the disorder, but could also serve as a basis for the development of novel medical management strategies directed at preventing aneurysm formation and progression, including therapeutic approaches based on the modulation of aortic wall responses and designed to selectively target T-cell activation and cytokine production. In this respect, the present work provides experimental evidence in support of the emerging concept that, although multifactorial, aneurysm disease may be regarded as a Th1-driven immunopathological condition, and suggests that strategies targeting IFN-gamma could be a particularly exciting and fruitful avenue for further investigation. Ongoing clinical and basic research in these areas can be expected to yield design of promising pharmacologic approaches to control AAA expansion. From a clinical perspective, such efforts have the potential to dramatically influence both the outcome and management of this common and life threatening condition.<p> / Doctorat en sciences médicales / info:eu-repo/semantics/nonPublished

A total of 49 patients were studied, using invasive hemodynamic techniques with systemic arterial, pulmonary artery and right atrial pressure recordings together with thermodilution cardiac output determinations. Sixteen of the patients were also subjected to cardiometabolic studies, using measurement of coronary sinus blood flow by the continuous thermodilution technique and analyses of oxygen content and lactate concentration in the systemic and coronary circulation. A common denominator in the five investigations was, that a distributive cardiovascular dysequilibrium was either induced (for surgical or anaesthesiological reasons) or already present due to a pathological condition. Thoracic epidural block from T 1 to T 12 induced marked decrease in systemic blood pressure due to vasodilation and impairment of cardiac performance. Prenalterol administration effectively abolished the low blood pressure by its marked inotropic action, having no effect on systemic vascular resistance. Myocardial oxygen consumption changed in parallel with the changes in cardiac work following both thoracic epidural block and prenalterol. Coronary vascular resistance was markedly decreased by the block and was not affected by prenalterol. It is suggested, that the critically low perfusion pressure is the main cause of the coronary vasodilation and that alpha-blockade induced by the thoracic epidural block is of less importance. The combination of a thoracic epidural block from T 1 to T 12 and selective ßi-stimulation with prenalterol was an effective way to modify the cardiovascular response to infrarenal aortic cross clamping. This treatment transferred the patients to a more favourable cardiac function curve and possibly facilitated the redistribution of blood flow in association with clamping. In association with declamping of the infrarenal aorta or the common iliac arteries, volume loading to a slightly elevated left ventricular filling pressure shortly before declamping was an effective way to counteract the expected blood pressure drop. A normal left ventricular filling pressure prior to declamping did not prevent the blood pressure drop following declamping. It is suggested, that mismatching between vascular volume and blood volume is the main cause of declamping hypotension. In patients with low resistance, distributive septic shock caused by gram negative bacteremias and signs of impaired cardiac function, prenalterol effectively reversed the hypotension and improved tissue perfusion by selectively increasing cardiac output. In parallel to the increased cardiac work, an increase in myocardial metabolic demand was demonstrated. / digitalisering@umu.se

Introduction.Le fibroblaste gingival (FG) est la cellule majoritaire de la gencive. Cette dernière fait face constamment aux agressions physico-chimiques, infectieuses et thermiques. L'une des caractéristiques de la gencive est sa réparation quasi-parfaite suite à une lésion ponctuelle. Ce n'est pas le cas pour d'autres tissus comme la paroi aortique. L'anévrisme aortique (AA) est un affaiblissement de la paroi aortique provoqué par une sécrétion exhaustive de métalloprotéases (MMPs) et en particulier de MMP-9. Il en résulte une dilatation de l'artère. Dans un modèle d'anévrisme de lapin, Durand et al (2012) avait montré que le FG pouvait ralentir, voire réparer un anévrisme. Dans notre étude, nous avons mis en place un modèle de coculture FG/AA d'origine humaine.Chez l'homme, la localisation de la pathologie peut être au niveau abdominal (Anévrisme Aortique Abdominale : AAA) ou thoracique (Anévrisme Aortique Thoracique : AAT). Etant donné que leur étiologie sont différentes, nous avons souhaité savoir s'il existait des différences selon les lésions. Cela nous permettrait en effet de mieux appréhender la prise en charge. Nous avons réalisé une étude comparative histo et physiopathologique entre les AAA et AAT. L'une des différences soulevée, est la présence d'un facteur infectieux au niveau des AAA. C'est un élément à prendre en compte pour une thérapie cellulaire et ainsi nous avons mis en culture des FG en présence de LPS, une endotoxine bactérienne.De plus pour approfondir notre travail sur l'utilisation du FG dans la thérapie cellulaire, nous avons initié une étude sur la plasticité de la sous-population souche des FG en étudiant, notamment leur orientation en cellules vasculaires (cellules endothéliales).Résultats/discussionLe FG, grâce à sa secrétion de TIMP-1, contribue à l'inhibition de la MMP-9 anévrismale. La sécrétion de MMP-9 est plus importante dans les lésions avec athérome (AAA) que celles sans athérome (AAT dans notre étude). Ceci est en corrélation avec la dégradation qui est plus importante dans les AAA que dans les AAT. La MMP-9 est une protéine sécrétée entre autre par les cellules inflammatoires. Une inflammation est présente dans les AAA et pas dans les lésions thoraciques. Ceci pourrait expliquer la différence de sécrétion de MMP-9 et donc de dégradation. Concernant l'origine de cette inflammation, nous avons recherché une cause infectieuse. Porphyromonas gingivalis (Pg) qui est une bactérie importante dans le développement de la parodontite (maladie inflammatoire des tissus de soutien de la dent) a été détectée dans les AAA. Une relation pathologique existerait entre la parodontite et l'AAA mais l'étude devrait être plus poussée pour connaître le mécanisme physiopathologique de ce phénomène. Toutefois, en ce qui concerne la thérapie cellulaire, le LPS qui est une endotoxine du Pg, n'affecte pas la capacité du FG à secréter du TIMP-1.En plus de la possibilité du FG à neutraliser la MMP-9 anévrismale, nous avons souhaité savoir si le FG avait des compétences de différentiation en cellule vasculaire. Un début d'exploration de la plasticité cellulaire de la souche multipotente de FG en cellule endothéliale, donnent des résultats préliminaires encourageants.Conclusion. Le FG pourrait être une cellule prometteuse pour une thérapie cellulaire de l'anévrisme aortique mais des explorations plus poussées sont encore nécessaires pour une telle application. / IntroductionGingival fibroblast (GF) is the main cell in gingiva which is constantly facing infectious, thermal and physico-chemical attacks. When a lesion occurs, the repair of gingiva is almost perfect. It is not the case for other tissues as the aortic wall. The aortic aneurysm (AA) is a pathologic expansion of aorta due to a weakening of the wall with an exhaustive secretion of metalloproteinases (MMPs) and particularly of MMP-9. In an aneurysm rabbit model, Durand and al (2012) have showed that GF could slow down or repair the aneurysm. In our study, we have established a co-culture model of human GF and human AA.For human, the location of the aortic disease may be at abdominal level (Abdominal Aortic Aneurysm: AAA) and thoracic level (Thoracic Aortic Aneurysm: TAA). Since the aetiologies are different, we wondered if histo and physiopathologic differences would existe between the both. It is impotant to know that for better supporting the disease. One of the difference between AAA and TAA is the presence of an infectious factor in AAA. This is an element to consider for cell therapy, so we studied the behavior of GF in presence of an endotoxin, the LPS.In addition, to further our work on the use of GF in cell therapy, we have initiated a study of the plasticity of the GF multipotente subpopulation including the differentiation into vascular cells (endothelial cell in particular).Results/DiscussionThanks to its TIMP-1 secretion, GF could contribute to the inhibition of MMP-9 activity in aneurysm. The secretion of MMP-9 in AA with atheroma (AAA) is highter than in TAA (without atheroma in our study). It is correlated to the degradation of AAA which is more important than the degradation of TAA. Inflammatory cells may secrete MMP-9. Inflammation is present in AAA and not in TAA. This, could explain the highter secretion of MMP-9 in abdominal lesion and also the degradation which is more important in AAA than in TAA. As for the origin of this inflammation, we researched an infectious factor. We isolated Porphyromonas gingivalis (Pg) in AAA, which might trigger or aggravate inflammation. This is an important bacterium in the development of periodontitis (inflammatory disease of the tissues supporting the tooth). A pathological relationship may exist between periodontitis and the AAA. The study should be further to know the pathophysiology of AAA related to Pg. But as regards the cell therapy, LPS, which is an endotoxin of Pg would not affect the secretion of TIMP-1 by the GF.In addition to its abilities to inhibate MMP-9 in aneurysm, we wondered if GF would be able to differentiate into vascular cell. An early exploration of GF multipotent subpopulation plasticity reveals a possible opportunity to go further in a the cell therapy.Conclusion.GF might be a promising cell for treating aortic aneurysm but further explorations are still necessary for its application.

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The aim of this thesis is the problematic of abdominal aortic aneurysm wall stress in relation to a different material behavior of intraluminal thrombus, which is in most cases present in the aneurysmal volume. In this thesis, the influence of neglecting the patient-specific material properties of the intraluminal thrombus, on the aneurysmal wall stress, obtained from finite element stress-strain analysis, is investigated. In terms of solution method selection, a system approach was applied so that the solution method was selected in order to respect a system of essential variables as much as possible. The first part of this thesis is focused on a description of the problematic and the human cardiovascular system with important aspects contributing to development and growth of the abdominal aortic aneurysm. Next, this part of the thesis includes chapters devoted to the intraluminal thrombus in terms of its basic characteristics (anatomy, physiology, pathology), structure and its influence on processes within the abdominal aneurysm. The second part of this work is devoted to the accomplishment of the first and second goal of this thesis, which is analyzing the available literature to obtain mean population stiffness values of the intraluminal thrombus and conducting biaxial experimental tests of provided samples of intraluminal thrombus. The experimental testing was conducted in order to obtain the patient-specific mechanical properties, which are used as the inputs in the finite element analysis. The experimental testing confirmed the stiffness negligibility of the intraluminal thrombus’s outer layer, which is mentioned is several studies, however, the influence of this layer on resulting aneurysmal wall stress has been to this date not tested. The dominant part of this thesis is focused on the third goal of this work, which is a comparison of aneurysmal wall stress obtained from the finite element computation that included mechanical properties of intraluminal thrombus obtained either from the literature analysis of experimental testing. This part includes discerption of idealized geometry model development, which was used to analyze the sensibility of computed stresses on a number of ILT layers representing different material properties. In order to obtain this analysis, a macro was created prescribing each element of the intraluminal thrombus finite element mesh with material properties derived from its distance from the lumen. Next, this chapter contains description of patient-specific geometry models development, material models, and boundary conditions selection. In the end of this part, results of the finite element computations are presented together with their statistical analysis. Within the last part of this thesis, discussion of results and conclusions of this thesis is included. Also, an overview of important aspects entering computational modeling of abdominal aortic aneurysms is presented.

This thesis deals with stress strain analysis of an aortic abdominal aneurysm (AAA) and the influence of its contact with the spine on the extreme wall stress. The influence was tested on the idealized geometry, as well as on ten patient specific geometries obtained from computer tomography (CT-A) scans. Hyperelastic constitutive models were used for the AAA wall and intraluminal thrombus (ILT) tissue description. The prestress algorithm was used for reconstruction of the unloaded geometry to get more trustworthy results against the geometry from CT which was obtained under the blood pressure. Statistical analysis was used for the results evaluation. The maximal increase of peak wall stress was as high as 81 %.

This paper deals with the problem of abdominal aortic aneurysms (AAA), taking into account the possibility of using mechanical tests of aortic tissues for improvement of level of their constitutive models. First part of thesis deals with the introduction into the problem, description of the structure of the wall of the healthy aorta, its main components and the degenerative changes which lead to formation of AAA. This is followed by a brief excursion into constitutive modeling, which focuses closely on the description of the models used to describe the mechanical behavior of soft tissues. The theoretical part is then supplemented by a narrower selection of constitutive models used for modeling aortic wall and intraluminal thrombus, together with published results, which are reviewed and discussed at the end of this section. The main part of this thesis is devoted to tests of mechanical properties of arterial tissues. First, the methodology is presented together with the description of the customizations of the laboratory equipments together with the test rig. In addition, attention is focused on the results of mechanical tests of intraluminal thrombus, where the results of both uniaxial tensile tests and equbiaxial testing are presented. Also the influence of distance ILT from the lumen on the mechanical properties of the thrombus is examined. Another area of interest is the investigation of the effect of elastase on the chnage of mechanical properties of pig aorta. In this case, porcine aortas are experimentally tested only by biaxial testing, and the time of elastase action to alter the mechanical properties is analyzed so that the resulting tissue has a similar stress-strain response as aneurysmal tissue. Finally, the results of experimental measurements, limitations and other possible ways of research are summarized.