L’athérosclérose et la pathologie anévrysmale sont principalement caractérisées par un remodelage de laparoi artérielle au cours de leur évolution. Ce travail a examiné un aspect de la destruction de la paroiartérielle à travers l’étude de la métalloprotéase MMP-14 au cours de l’athérome et un aspect dereconstruction artérielle à travers l’étude d’une thérapie cellulaire d’un modèle d’Anévrysme de l’AorteAbdominale (AAA) par Cellules Souches Mésenchymateuses (CSMs).En utilisant un modèle de greffe de Moëlle Osseuse (MO) dans des souris Ldlr-/-, nous avons montré que ladélétion d’expression de MMP-14 dans les cellules issues de la MO provoquait une accumulation decollagène interstitiel dans la plaque athéromateuse sans modification de la composition cellulaire nivariation de taille. Une mesure de l’activité collagénolytique par substrat fluorescent a confirmé que ladélétion en MMP-14 chez les macrophages provoquait une baisse de l’activité collagénolytique. Cetteactivité est indépendante de l’activité MMP-2 et MMP-8 et pourrait être médiée partiellement parl’activation de MMP-13. Nous avons mis en évidence la présence de CSMs à la surface luminale de thrombus de AAA et nous avonsmontré une diminution significative des CSMs circulantes chez des patients porteurs de AAA. Nous avonspu stabiliser la croissance de AAA expérimentaux chez le rat à partir de xénogreffe artérielle par perfusionendoluminale de CSMs. La perfusion de CSMs provoquait une diminution de l’inflammation à court termeet favorisait la reconstruction artérielle par accumulation de collagène et d’élastine à moyen terme.En conclusion, l’activité collagénolytique de MMP-14 est un des mécanismes moléculaires possibles del’évolution de la plaque athéromateuse par rupture de plaque. Elle ouvre la perspective d’une nouvelleapproche thérapeutique et pourrait être une cible comme substrat pour une imagerie fonctionnelle de laplaque athéromateuse. L’évolution de la maladie anévrysmale pourrait être secondaire à une altération dessystèmes de réparation tissulaire dont les CSMs seraient des acteurs clé. La perfusion endoluminale desCSMs dans un modèle expérimental a permis la restauration de ces systèmes de réparation tissulaire etouvre la perspective d’un nouvel outil thérapeutique contre les AAA / Pas de résumé anglais

Abdominal aortic aneurysm (AAA) is a form of cardiovascular disease whereby a change in the material properties of the vessel wall results in a localised dilation of the abdominal aorta. The primary risk of AAAs is rupture with mortality rates close to 90%. Whilst surgical intervention can be performed to repair AAAs, such procedures are considered high risk. As a result, surgery is only performed upon AAAs that are considered likely to rupture. The current method of prediction is the diameter criterion, with surgical intervention performed if the diameter of the AAA exceeds 5.5cm. Research has demonstrated that this is a weak method of predicting rupture and as such other methodologies are sought. One promising method is patient specific modelling (PSM) which involves the reconstruction of individual patient AAA geometries from imaging datasets, and finite element analysis (FEA) to calculate the stresses acting on the AAA wall, with the peak stress typically used as the predictor. A weakness of this methodology is the lack of patient specific material property values defined in the simulation. A potential technique to address this limitation is magnetic resonance elastography (MRE), an MR-based technique which utilises a phase-contrast sequence to characterise displacements caused by shear waves induced into the tissue by an external mechanical driver. An inversion algorithm is used to calculate local material property values of the tissue from these displacements. The aim of this thesis was to investigate the capability of utilising MRE to obtain material property measurements from AAAs that could be incorporated into PSM. To achieve this an FE method of modelling MRE was developed. The influence of modelling parameters upon the material property measurements made using the direct inversion (DI) algorithm was investigated, with element type and boundary conditions shown to have an effect. The modelling technique was then utilised to demonstrate the influence that the size of an insert had upon shear modulus measurements of that insert using DI in both 2- and 3-dimensions, and the multi-frequency dual elasto-visco algorithm (MDEV), an extension of DI combining information from multiple frequencies. Meanwhile a comparison of the modelling technique against an MRE scan of a phantom showed that whilst measurements made from the two techniques were different at low frequencies, they became similar as the frequency increased. This suggested that such differences were attributable to increased noise in the scanned data. FEA of MRE performed on idealised AAA geometries demonstrated that AAA size, shear viscosity of the thrombus and shear modulus of the AAA wall all influenced the accuracy of MRE measurements in the thrombus. Meanwhile MRE scanning of a small cohort of AAA patients had been undertaken and phase images investigated for signs of wave propagation to investigate the capabilities of the current MRE setup. Phase images were dominated by noise and there was no wave propagation visualised in any of the AAAs. This thesis demonstrates that the current MRE setup is not capable of achieving accurate measurements of material properties of AAA for PSM. Visualisation of wave propagation in AAAs is technically demanding and requires further development. A more fundamental concern however is the size dependence of the inversion algorithm used and the inability to consistently make accurate measurements from AAA geometries.

Introduction: Abdominal aortic aneurysms (AAA) have a prevalence of approximately 2%, and are more common in men. AAAs are generally asymptomatic, but if ruptured and untreated, the mortality rate is close to 100%. Screening programs for AAAs are implemented in Sweden, the UK, and the US. This study describes the different views of AAA screening with a special emphasis on underlying ethical issues. Aim: To analyze the scientific background of AAA screening in order to be able to discuss its ethical basis. Methods: This was a qualitative literature study with an analysis of arguments using a hermeneutic method. Articles were obtained through a literature search and consisted of official articles, scientific articles, and debate articles. Results: A recent dissertation has questioned the value of AAA screening because of decreased AAA mortality and risk for overdiagnosis. However, most studies and official recommendations are in favor of AAA screening because disease specific mortality decreases and the screening program is considered cost-effective. Conclusion: This study shows that intellectual passion has created an unusually polarized discussion. It seems that benefit outweighs harm. Since AAA screening is the first screening program which could lead to the death of a previously asymptomatic individual, well founded informed consent is extremely important. Finally, both decisions to act and not to act have moral consequences.

Endovascular aortic repair (EVAR) is a minimally invasive alternative to open surgery for the treatment of aortic aneurysms (AA). However, standard EVAR is not applicable to complex AA with involvement of vital branches, which could be occluded by the endograft. As an emerging technique, the concept of multiple overlapping uncovered stents (MOUS) have been proposed to manage complex lesions. MOUS was used to modulate the flow pattern inside the aneurysm sac, and promote the thrombus formation followed by the aneurysm shrinkage. In this dissertation, we sought to investigate the mechanism of MOUS-induced flow modulation and key factors associated with the success of this novel technique: - The mechanical behaviour of AA was characterised by uniaxial material tests (Chapter 4). A Bayesian framework was proposed for material constants identification. They were found correlated to the microstructure of tissue fibre network and were capable in differentiating tissue types. - Solid-to-solid interaction and one-way fluid-solid interaction (FSI) analysis was performed based on patient-specific computer tomography angiography (Chapters 5&6). Structural stress concentrations were observed within the landing zones, which increased with the number of stents deployed. In the parameter studies (Chapter 6), the overall porosity was identified as the dominant factor of the flow-diverting outcome, while cross-stent structures of MOUS had limited influence. - The pathological effect of structural stress concentration induced by an implanted device was further studied in rabbit models (Chapter 7). The wall structural stress and fluid shear stress were obtained from FSI analysis based on magnetic resonance imaging (MRI), and correlated to plaque characteristics. Both high structural stress and low fluid shear stress were found correlated to plaque initialisation and increased inflammation. Overall, MOUS modulates the blood flow with robust performance under different overlapping patterns. Image-based biomechanical analysis can optimise MOUS design and can contribute to personalised pre-surgery planning.

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role of sex chromosomes genes to sexual dimorphism of cardiovascular diseases such as AAAs is largely unknown. The purpose of this study was to determine the role of sex chromosomes as mediators of sex differences for angiotensin II (AngII)-induced AAAs in hypercholesterolemic mice. We used the four core genotype murine model, which enables the creation of phenotypically normal male and female mice with an XX versus XY sex chromosome complement, to test the hypothesis that an XY sex chromosome complement promotes AngII-induced AAAs. Transgenic male mice expressing the Sry gene on an autosome, but not on the Y-chromosome, were bred to female low-density lipoprotein receptor deficient mice to create male and female mice with an XX or an XY sex chromosome complement. In females, an XY sex chromosome complement doubled the incidence and markedly increased the severity of AngII-induced AAAs. To define mechanisms, we examined gene expression patterns in abdominal aortas and demonstrated elevated expression of inflammatory genes that were linked to increased MMP activity and oxidative stress in aortas from XY females. Moreover, administration of testosterone to XY females, to mimic males, resulted in a striking level of aneurysm rupture. In males, transcriptional profiling of abdominal aortas revealed 450 genes that were influenced by sex chromosomes. Infusion of AngII to XY males resulted in diffuse pathology along the length of the aorta, while XX males developed focal AAAs, with pathology reduced by orchiectomy in both genotypes. Thoracic aortas of XY males exhibited adventitial thickening which was not exist in thoracic aortas from XX males. Following a prolonged period (3 months) of AngII infusions XY males had AAAs with expanded aortic walls, while XX males had thin walled dilated AAAs. In summary, our findings demonstrate a remarkable effect of sex chromosome complement to regulate aortic vasculature and disease development. Aside from demonstrating mechanisms of sexual dimorphism of aortic diseases, these findings indicate that chronic sex hormone therapy in the aging and transgender population may have cardiovascular ramifications. Moreover, identification of targets influenced by sex chromosomes and/or sex hormones in a manner that predicts disease development may identify sex-specific approaches to cardiovascular therapy.

Objective: To assess neck angulation and endograft oversizing as factors contributing to folding. Endograft folding will then be assessed on its role in endograft fixation strength. Methods: Bench top flow loop experiments were performed with barbless Gore Excluder endovascular grafts (EVG) that were deployed into silicone aorta-AAA models with neck angles of 0, 30, and 60. A total of five oversizings were tested: -7%, 2%, 12%, 24%, and 38% with N= 3 for each oversizing at each neck angle for a total of 45 experiments. Photographs of the stent apex to apex distances were taken for the entire circumference of the device for a total of 8 photos per experiment. Measurements of the apex to apex distance were taken for the top three stent layers and variance for each stent layer was calculated. Variances for all three stent layers were summed to represent the folding metric. The silicone model was then removed from the flow loop and placed on the uniaxial extension tester to for pull out testing to assess impact on attachment strength. Results: Neck angle and oversizing increases folding risk at oversizing ≥12% for 0° and 30° neck angles, and ≥ 2% oversizing for a 60° neck angle. Folding metric comparison between 0° vs. 30° and 0° vs. 60° across all oversizings had statistical significance (Mann-Whitney U, p

Rupture of abdominal aortic aneurysm (AAA) is a catastrophic event that leads to high mortality and morbidity in patients. The primary causes associated with aneurysm rupture remain poorly understood despite rigorous investigations. Reports have shown that AAA that went on to rupture or present ruptured had higher peak wall tension (stress resultant) than those that did not go on to rupture or present ruptured. Studies investigating the material strength of ruptured AAA and unruptured AAA revealed that the uniaxial failure strength in ruptured AAA is no different on average than unruptured AAA. However, it is poorly understood whether uniaxial failure properties are reliable as they are not indicative of the manner in which failure occurs in biological soft tissues. Multi-axial failure properties using a bubble inflation test (BIT) have been implemented by various groups but have not been directly compared against uniaxial failure properties. The current study seeks to develop a BIT apparatus, to compare multi-axial and uniaxial failure properties of fibrous anisotropic biological soft tissues (bovine aorta) and non-fibrous isotropic molded silicon, and to perform a survey of computational indices at the rupture sites of four ruptured AAA. Two versions of the BIT apparatus were developed: a manual that was developed allows for a large amount of failure properties to be extracted that can identify localized weaknesses. It was found that circumferentially oriented multi-axial failure was correlated with longitudinally oriented uniaxial failure properties, however, for oblique oriented multi-axial failure the correlation decreased. Utilizing the insights gained from the multi-axial experiments it was determined that the failure properties used in the computational study with the data from Raghavan et al. were appropriate for use in retrospective assessment of the rupture site in four ruptured AAA computational models. Although the study was inconclusive in finding causation, the rupture line of each aneurysm had indices ranging between the third quartile and peak values for tension to failure tension ratio, nodal displacement magnitude, strain energy per unit volume and strain energy per unit surface area. This study provides a framework for interrogating failure properties at a higher density of measurement and a heterogeneous computational model that has the potential to predict AAA rupture in the future.

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens. The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view. In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins. In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

Abdominal aortic aneurysm (AAA) is a common disease that is life threatening when rupture occurs. The aims of this thesis were to study (I) the long-term survival after AAA repair, (II) the cost of repair with open (OR) and endovascular (EVAR) technique, (III) the effect of different statistical methods on interpretation of cost data, (IV) the prevalence of the disease among patients with suspected arterial disease referred to the vascular laboratory, and (V) the cost-effectiveness of selective high-risk screening. Analyses of data from the Swedish vascular registry (Swedvasc), local patient registries, patient records and hospital cost registries form the basis of this thesis. Short- and long-term survival after intact AAA repair improved over the past two decades, despite increasing patient age and rate of comorbidities over time. Compared to a general population adjusted for age, sex and calendar year, the relative 5-year survival was 90% among those surviving repair. While short-term survival improved over time after ruptured repair, relative long-term survival was stable. Despite differences in patient selection and cost structure, the total cost of AAA repair with EVAR and OR was similar in a population based setting (€28,193). There was lack of consistency in the methods used in cost-analysis in the current literature, and p-values were highly dependent on test method. The practice of selective (non-population-based) screening for AAA among patients referred to the vascular laboratory was studied. The prevalence of AAA was 4.2% among male and 1.5% among female patients. AAA was associated with high age and prevalence of arterial stenosis. Of AAAs detected through selective screening, 21.5% had undergone elective repair at 7.5 years follow-up. In a health-economic evaluation, the incremental cost-effectiveness ratio of selective screening was €11,084 per life year gained. In conclusion, survival after intact AAA repair has improved over time, despite changes in case-mix. Results of health economic reports on cost of AAA repair can be highly dependent on patient selection as well as presentation of data and the statistical methods used. Selective screening for AAA among patients referred to the vascular laboratory is cost-effective.

Das Aortenaneurysma ist eine häufige Erkrankung, welche mit der gravierenden Kompli-kation einer Aortenruptur einhergehen kann. In den letzten 20 Jahren konnten beachtliche kurative Fortschritte erzielt werden, welche u.a. auf die Ergänzung der rein operativen Therapie um endovaskuläre und Hybridverfahren zurückzuführen sind. Dennoch ist die Aneurysmaruptur mit einer außerordentlich hohen Mortalität assoziiert. Die Genese des Aortenaneurysmas ist multifaktoriell bedingt, sodass das Wachstumsverhalten der Aorta als Surrogat des realen Rupturrisikos schwer vorherzusagen ist. Im klinischen Alltag findet überwiegend der maximale Diameter als Größen- und Verlaufsparameter Anwendung, obwohl dadurch den heterogenen Veränderungen der Aorta möglicherweise nicht ausrei-chend Rechnung getragen wird. Ziel der Studie war es, anhand einer CT-gestützten Verlaufsquantifizierung von Aorten-veränderungen Prädiktoren für das Wachstum der Aorta abzuleiten und Wachstumsraten auf Basis unterschiedlicher morphologischer Ausgangsgrößen zu vergleichen. Zwischen den definierten Aortensegmenten konnten signifikante Unterschiede der erho-benen morphologischen Parameter wie beispielsweise der Größe, der Verteilung von Ge-fäßwand und –lumen, der Verkalkung und der Krümmung aufgezeigt werden. Diese Heterogenität ließ sich auch beim Vergleich von thorakalen/abdominalen, aneurysmati-schen/nicht aneurysmatischen und wachsenden/nicht wachsenden Segmenten bestätigen. So waren beispielweise wachsende Aortensegmente initial größer als nicht wachsende (Volumen 82 cm³ vs. 53 cm³, p < 0,00; Diameter 36 mm vs. 30 mm, p< 0,00), unterschie-den sich hingegen aber nicht hinsichtlich der Wandverkalkung (Calcium-Score 894 vs. 842, p = 0,77). Im Verlauf wiesen die wachsenden Segmente unter anderem eine stärkere Zunahme der maximalen Wandstärke (+15 % vs. +4 %, p > 0,00) und eine stärkere Elongationstendenz (Segmentlänge +3,6 % vs. -0,5 %, p < 0,00) auf. Insgesamt konnte gezeigt werden, dass im Verlauf eine Wachstumsdynamik beinahe aller erhobenen Größen bestand. Ein durchschnittliches Wachstum des Aortensegmentvolumens um 5,7 % pro Jahr gezeigt konnte werden. Unter den potentiellen Einflussfaktorenkonnten konnten als relevante Prädiktoren die ma-ximale Wandstärke, die Diameter-Längen-Ratio, die Exzentrizität der Außenzirkumferenz sowie die Risikofaktoren Rauchen und die Einnahme von Kortikoiden identifiziert wer-den. Der Vergleich morphologisch unterschiedlich basierter Wachstumsraten zeigte eine erhebliche Diskrepanz insbesondere zwischen dem Routineparameter maximaler Diameter und dem sensitiveren Volumen. Schlussfolgerung: CT-morphologisch bestimmbare Parameter wie die Wandstärke, das Proportionsmaß Diameter-Längen-Ratio und die Exzentrizität des Gefäßquerschnittes sind Prädiktoren überdurchschnittlichen Aortenwachstums. Die umfassenden routinemäßige Evaluation der Aorta mit Erhebung mehrerer morphologischer Parameter – insbesondere des Volumens – ist notwendig, um das heterogene und multifaktoriell bedingte Wachstum der Aorta suffizient zu erfassen. / Purpose This study aims to identify clinical and CT-morphologic predictors of growth of the native aorta and aortic aneurysms. Material and methods Seventy-three patients (66 ±8.0 years) who underwent two subsequent computed tomography angiographies of the thoracic/thoracoabdominal/abdominal aorta for clinical reasons from 2002 - 2008 were retrospectively included. The mean interval between the CT scans was 1.8 ±0.8 years. The aortic anatomy was divided into 9 segments from sinotubular junction to iliac bifurcation. CT scans were obtained with 16- and 64-slice scanners, all series were analyzed on a commercially available workstation. Beside the collection of information about the past medical history, several morphologic parameters were measured for each segment such as aortic volume, maximum diameter, cross sectional area, surface area, calcification, tortuosity, wall thickness or cross sectional eccentricity. Annual growth rates were calculated for each parameter. Aortic total volume was considered as the standard of reference. Therefore, aortic growth was defined as a growth rate of total volume > 5 %. Multiple regression analysis was conducted to reveal predictors of aortic growth. Results For all segments, average volumes were 65.0 ± 59.0/44.7 ± 39.6/20.3 ± 27.9 cm³ (total/lumen/wall). The annual aortic growth rate of total volume was 5.7 % for all segments. All parameters that represent the initial size of the aortic segments (total and lumen volume, maximum diameter, cross sectional area, surface area) were approved as predictors of aortic growth. Further predictors were wall volume, maximum and minimum wall thickness, diameter length ratio, segmental length and tortuosity index. Among the clinical parameters, smoking, corticosteroid medication and peripheral artery disease were confirmed as aortic growth predictors. Conclusions In clinical routine, most therapeutic decisions a made based on the diameter measurement alone, which might be inappropriate. A comprehensive evaluation of aortic morphology is warranted in the presence of increased aortic size, wall thickness, cross sectional eccentricity, smoking and corticosteroid therapy.