Aortic aneurysm and dissections are potentially life threatening conditions. The advent of endovascular aortic repair (EVAR) and thoracic endovascular aortic repair (TEVAR) has reduced perioperative mortality and morbidity and are now established therapy methods for treatment of aortic disease. Adequate pre- and intraoperative imaging is important for optimal results in endovascular procedures. However, the standard use of CT and angiography may not always be sufficient to provide necessary information required for treatment, and complementary techniques are warranted in selected cases. TEVAR in acute complicated type B aortic dissections is proven effective in several reports, but long-term clinical outcome and aortic remodelling are still not fully evaluated. Intravascular phased array imaging (IPAI) was used in patients undergoing EVAR and TEVAR for aortic aneurysm and dissection. The combined information from IPAI and fluoroscopy allowed exact positioning of the stent graft. The colour Doppler function facilitated detection of blood-flow in relevant arteries during and after the procedures, and it also facilitated control of ceased flow in excluded false lumens or aneurysms. Clinical early and long-term results after TEVAR for acute complicated type B aortic dissection were investigated in all patients treated between 1999 and 2009 at UppsalaUniversityHospital. Results were favourable regarding survival and permanent neurological complications. Long-term follow-up of aortic morphological changes in the same patient group showed overall significant reduction of aortic and false lumen diameters, and an increase of true lumen diameter. Total thrombosis of the false lumen occured more often in patients with DeBakey IIIa aortic dissection, than in IIIb. In conclusion, IPAI may be a complementary tool to traditional imaging modalities in EVAR and TEVAR in selected cases. Long-term clinical outcome is excellent with favourable aortic remodeling after TEVAR in patients with acute complicated type B aortic dissection.

El remodelat vascular es un procés crític que present en el desenvolupament de patologies cardiovasculars com l’aterosclerosi i l’aneurisma d’aorta abdominal (AAA). La Lisil Oxidasa (LOX) i la Fibulina-5 (FBLN5) són dues proteïnes de matriu extracel•lular essencials en la formació i manteniment de les fibres elàstiques. Ambdues participen en processos fisiopatològics caracteritzats per l’alteració de l’equilibri síntesi/destrucció de la matriu extracel•lular i han estat involucrades en el remodelat vascular. Estudis en models experimentals han proporcionat indicis sobre la possible vinculació d’aquestes proteïnes en el desenvolupament d’aterosclerosi i d’AAA, si bé existeixen molts aspectes de la biologia d’aquestes proteïnes que haurien de ser analitzats en profunditat. Un aspecte crític en el remodelat vascular associat a la progressió de la lesió ateroscleròtica és l’aparició de regions d’hipòxia. L’estrès hipòxic és característic d’alguns processos fisiològics, però també de patologies com el càncer, els trastorns isquèmics, la inflamació crònica i l’aterosclerosi. Les cèl•lules endotelials són els sensors primaris d’aquest estrés hipòxic, i la seva adaptació a la hipòxia es produeix a través d’una complexa resposta finament regulada que afecta múltiples aspectes de la seva biologia, com la supervivència cel•lular, el control del to i la permeabilitat vascular, l’angiogènesi i el remodelat de la matriu extracel•lular. No obstant, no s’ha establert si la hipòxia pot regular la expressió de la LOX i la FBLN5 en cèl•lules endotelials ni la repercussió fisiològica que podria tenir. Les investigacions desenvolupades pel nostre grup indiquen que la LOX és un enzim clau en el manteniment de la integritat de l’endoteli i de la funció endotelial. La capacitat d’aquest enzim de controlar l’expressió gènica, en base a la seva activitat al nucli, així com l’activitat de factors de creixement fonamentals en l’homeòstasi vascular com el bFGF i el PDGF, suggereix que aquest enzim controla funcions cel•lulars que poden ser determinants en el desenvolupament de malalties cardiovasculars. En base a aquests antecedents, ens hem plantejat com a hipòtesis de treball que la LOX i la FBLN5 són proteïnes clau en l’homeòstasi vascular, que participen en la resposta adaptativa de les cèl•lules vasculars a la hipòxia, i que contribueixen al desenvolupament de patologies vasculars com l’aterosclerosi i l’aneurisma d’aorta abdominal. Els nostres resultats han demostrat que en artèries coronàries humanes, la LOX s’expressa principalment a l’endoteli i a l’adventícia, i que és la isoforma més expressada en cèl•lules vasculars, juntament amb la LOXL2. En cèl•lules endotelials, l’expressió de LOX i FBLN5 s’incrementa en resposta a hipòxia a través de mecanismes transcripcionals, si bé amb clares diferències entre ambdues proteïnes. Així, el factor HIF-1 juga un paper secundari en la regulació de la LOX per hipòxia en cèl•lules endotelials, una resposta en la que estan involucrades proteïnes de la família Smad i l’estrès oxidatiu. Per contra, HIF-1 és el principal responsable de la inducció de la FBLN5 en cèl•lules endotelials, en les quals hem demostrat que aquesta proteïna contribueix a la resposta adaptativa a l’estrès hipòxic. Finalment, hem observat que la sobre-expressió de LOX en cèl•lules endotelials mitjançant un sistema lentiviral indueix canvis en l’expressió gènica que afecten la senyalització i la comunicació cèl•lula-cèl•lula, d’entre els quals en destaca la inhibició de l’α2-macroglobulina. / Vascular remodeling is a critical process in the development of cardiovascular diseases such as atherosclerosis and abdominal aorta aneurysm (AAA). Lysyl oxidase (LOX) and Fibulin-5 (FBLN5) are two extracellular matrix proteins essential for the elastic fiber development and maintenance, and they both have an active role in physiological processes in which vascular remodeling is involved. By using different animal models, these proteins have been suggested to be involved with atherosclerosis and AAA. A critical aspect of the vascular remodeling in the atherosclerotic lesion is the apparition of hypoxic areas. Endothelial cells are primary sensors to the hypoxic stress, responding to it in a complex but subtly regulated way that affects multiple aspects of its biology. Nevertheless, it has not been established if the hypoxic stimulus can modulate LOX and FBLN5 expression, nor its possible physiological repercussions. Research made in our group shows the importance of LOX in the endothelial activity and vascular function. LOX can control the genetic expression as well as the activity of growth factors essential for the vascular homeostasis, suggesting that this enzyme may control cellular functions essential for the development of cardiovascular diseases. Based on these results, we have considered as working hypothesis that LOX and FBLN5 are key proteins in the vascular homeostasis, that they take part of the vascular response to hypoxia, and that they contribute to the development of vascular diseases like atherosclerosis and the AAA. Our results show that hypoxia transcriptionally induces LOX and FBLN5 in endothelial cells. While HIF-1 plays a secondary role in the regulation of LOX, being also involved in this modulation Smad proteins and oxidative stress, it is the main factor responsible for the FBLN5 induction. We also demonstrate that the modulation of FBLN5 in endothelial cells contributes to their adaptive response to hypoxia. Moreover, we have observed that overexpressing LOX in endothelial cells downregulates α2-macroglobulin expression.

Abdominal aortic aneurysms are a leading cause of death in the U.S. where 14,000 people die from aneurysm rupture and 178,000 are diagnosed each year. A novel alternative treatment for abdominal aortic aneurysms has been proposed, where a biodegradable polymer scaffold is photopolymerized in situ around the exterior of the aneurysm. This scaffold will mechanically constrain the aneurysm from further expansion, and will deliver a drug, doxycycline, to treat the underlying biological cause of the disease. In order for device development, a suitable polymer must be designed with appropriate mechanical properties, degradation rate, polymerization, and elution rate. Poly(β-amino ester) networks have been proposed as the material of choice; however, many of their structure-property relationships have yet to be determined. Therefore, the overall goal of this work is to determine the structure-property relationships of the poly(β-amino ester) networks in order to advance the design of the treatment, and has been divided into three objectives: (1) understand the structure-property relationships of poly(β-amino ester) networks, specifically the polymerization, degradation rate, and thermo-mechanical properties, (2) determine the impact of doxycycline incorporation on degradation rate and mechanical properties, (3) evaluate the effect of simulated physiological conditions on degradation rate and mechanical properties. In the initial chapters, the fundamental structure-property relationships are established between reactant chemical structure, step-growth polymerization, photopolymerization, thermo-mechanical properties, and degradation rate using a systematic approach of two homologous series of reactants. Further tailoring of degradation rate, water content, and modulus in vitro was performed by using a copolymer network. Doxycycline inhibited photopolymerization due to overlapping absorbance spectra with the photoinitiator, but full network formation occurred by increasing the photoinitiator concentration. Networks displayed varying controlled release rates, and the underlying release mechanism was determined for each network using established methods. In order to increase mechanical properties, a co-monomer, methyl methacrylate, was added to the network to increase the glass transition temperature, toughness, and deformation capacity. These co-networks displayed temporal-control of mechanical properties in simulated physiological conditions, since degradation caused a shift in the glass transition temperature, which changed the mechanical behavior of the network. The temporal-control of mechanical properties was further investigated under degradation conditions in vitro and in vivo. Due to the mechanically active loading environment in vivo, networks displayed a decrease in toughness, yet maintained mechanical properties similar to native biological tissues. These networks establish a multifunctional biomaterials platform with materials that can be easily synthesized, photopolymerized into various geometries, and sustain mechanical properties while undergoing degradation and therapeutic agent release.

Η CT αγγειογραφία εγκεφάλου (CTA) είναι μέθοδος καθιερωμένη για την διερεύνηση και την θεραπεία των ενδοκρανιακών ανευρυσμάτων. Σκοπός της μελέτης μας ήταν η σύγκριση των ευρημάτων της ψηφιακής αγγειογραφίας (DSA) με αυτά της CTA και με τα χειρουργικά ευρήματα σε ασθενείς με οξεία υπαραχνοειδή αιμορραγία, καθώς επίσης και η αξιολόγηση της κλινικής χρησιμότητας της μεθόδου. Κατά την διάρκεια τριών ετών, 82 ασθενείς προσήλθαν με κλινική εικόνα και σημειολογία συμβατή με υπαραχνοειδή αιμορραγία. Η CTA έγινε αμέσως μετά την απλή CT, ενώ η DSA εντός των πρώτων 48 ωρών από την εισαγωγή. Όλα τα ανευρύσματα που ευρέθησαν με τις δύο μεθόδους υπεβλήθησαν σε χειρουργική αποκατάσταση ή ενδαγγειακό εμβολισμό. Σε όσους ασθενείς βρέθηκε αρνητικό αποτέλεσμα και με τις δύο μεθόδους, έγινε επαναληπτική DSA 15 ημέρες μετά το επεισόδιο με σκοπό την επιβεβαίωση της απουσίας ανευρύσματος. Οι CTA εξετάσεις καθώς και οι κλασσικές αγγειογραφίες μελετήθηκαν από μια ομάδα δύο ακτινολόγων για κάθε τεχνική, οι οποίοι έπρεπε να καταγράψουν την ύπαρξη ή μη ανευρύσματος, να περιγράψουν τα χαρακτηριστικά του και να αξιολογήσουν την μέθοδο. Χειρουργική ή και ενδαγγειακή θεραπεία έγινε σε 45 ασθενείς και ανευρέθησαν 53 ανευρύσματα. Χρησιμοποιώντας την CTA, ευρέθησαν 47 ανευρύσματα σε 42 ασθενείς. Η DSA ανίχνευσε 43 ανευρύσματα σε 39 ασθενείς. Η ευαισθησία της CTA για τον εντοπισμό όλων των ανευρυσμάτων με βάση το χειρουργικό/θεραπευτικό αποτέλεσμα ήταν 88,7%, η ειδικότητα 100%, η θετική προβλεπτική αξία (PPV) 100%, η αρνητική προβλεπτική αξία (NPV) 80,7% και η ακρίβεια 92,3%. Αντίστοιχα, η ευαισθησία της DSA ήταν 87,8%, η ειδικότητα 98%, η PPV 97,7%, η NPV 89,1% και η ακρίβεια 92,9%. Όσον αφορά στα ανευρύσματα ≥3 mm, η CTA είχε ευαισθησία που κυμαινόταν μεταξύ 93,3 έως 100%, ίση με αυτή της DSA. Η CTA εμφάνισε τα ίδια ποσοστά ευαισθησίας με αυτά της DSA σε ανευρύσματα ≥3 mm. Εμφάνισε επίσης 100% ποσοστό ανίχνευσης σε ανευρύσματα της πρόσθιας αναστομωτικής και του διχασμού της μέσης εγκεφαλικής αρτηρίας, ενώ μερικές εντοπίσεις όπως η οπίσθια αναστομωτική αρτηρία παραμένουν προβληματικές. 80 Κατά την διάρκεια της παρούσας μελέτης προσπαθήσαμε να δημιουργήσουμε μια τεχνική προσομοίωσης της διεγχειρητικής εικόνας των ραγέντων ενδοκρανιακών ανευρυσμάτων, με τη χρήση volume rendering techniques σε εικόνες που προκύπτουν από CT αγγειογραφία. Η τρισδιάστατη κατασκευή των εικόνων προέκυψε από την συνεργασία μιας ομάδας αποτελούμενης από τέσσερις ακτινολόγους, έναν νευροχειρουργό και έναν ιατρικό φυσικό. Το αποτέλεσμα αυτής της συνεργασίας ήταν η παραγωγή μιας εικόνας οριοθετημένης στο χώρο, με οδηγά σημεία που εύκολα μπορούσαν να αναπαραχθούν κατά την διάρκεια του χειρουργείου. Οι εικόνες χειρουργικής προσομοίωσης ενός ανευρύσματος είναι πιθανώς χρήσιμο εργαλείο για τον προεγχειρητικό σχεδιασμό των ενδοκρανιακών ανευρυσμάτων. / Cerebral CT angiography is an established method applied to both the detection and treatment planning of intracranial aneurysms. The aim of our study was to compare DSA to CTA findings and with the surgical results mainly in patients with acute SAH and to evaluate the clinical usefulness of CTA. During the last three years, 82 consecutive patients were admitted under clinical symptoms and signs suggestive of harbouring an intracranial aneurysm. CT angiography performed immediately afterwards the plain CT, while DSA was performed within the first 48 hours of admission. All aneurysms detected, were confirmed during surgery or endovascular embolization. Repeat DSA was performed in all patients having both the initial CTA and the DSA 15 days after the onset of symptoms negative. CT angiograms and conventional angiographies were studied by a consensus of two radiologists for each technique, who performed aneurysm detection, morphological features characterization and evaluation of the technique. Surgical or/and endovascular treatment was performed in 45 patients and 53 aneurysms were confirmed. Using 3D-CT angiography we detected 47 aneurysms in 42 patients. Conventional angiography depicted 43 aneurysms in 39 patients. The sensitivity of CTA for the detection of all aneurysms versus surgery was 88.7%, the specificity 100%, the positive predictive value (PPV) 100%, the negative predictive value (NPV) 80.7% and the accuracy 92.3%. Consequently, the sensitivity of DSA was 87.8%, the specificity 98%, the PPV 97.7%, the NPV 89.1% and the accuracy 92.9%. Considering the aneurysms ≥ 3 mm, CTA showed a sensitivity ranging from 93.3% to 100%, equal to that of DSA. Cerebral CT angiography has an equal sensitivity to DSA in the detection of intracranial aneurysms greater than 3 mm. It has also 100% detection rate in AcoA and MCA bifurcation aneurysms, while some locations like posterior communicating artery aneurysms remain problematic. The delineating features of each aneurysm are better depicted with CTA due to 3D visualization. The use of Digital Subtraction Angiography as a diagnostic tool can be limited in equivocal cases. A supplement to the above work is our effort to describe a technique for simulating the surgical view of ruptured intracranial aneurysms, using volume 82 rendering techniques in spiral CT angiography data. The 3D rendered images were assessed by a team consisted of four radiologists, one neurosurgeon and one medical physicist. The resultant ‘surgical view’ image was standardized in space using a three-dimensional coordinate system, which allowed for its reproduction in the operating theatre. The surgical views are easily reproducible and αποτελούν a useful tool for the surgical planning of intracranial aneurysms.

The mortality of thoracic aortic diseases (mainly aneurysms and dissections) is high, even with surgical treatment. Epidemiology and long-term outcomes are incompletely investigated. Stroke is a major complication contributing to mortality, morbidity, and possibly to reduced quality of life. Study I Increasing incidence of thoracic aortic diseases 1987 – 2002 was demonstrated (n=14229). Annual number of operations increased eight-fold. Overall long-time survival was 92%, 77%, and 57% at 1, 5, and 10 years. Risk of operative and long-term mortality was reduced across time. Study II 2634 patients operated on the proximal thoracic aorta (Swedish Heart Surgery register) were examined. Aortic valve replacement, coronary revascularization, emergency operation, and age were independently associated with surgical death. Long-term mortality was similar for aneurysms and dissections. Operative mortality was reduced (13.7% vs 7.2%) for aneurysms but remained unchanged (22.3% vs 22.4%) for dissections across time. Study III 65 patients underwent selective antegrade cerebral perfusion (SACP) uni- or bilaterally. Stroke was significantly more common after unilateral SACP (29% vs 8%, p=0.045), confirmed by propensity score-matched analysis. Subclavian artery cannulation with Seldinger-technique entailed vascular complication in one case (1.5%). Study IV Near-infrared spectroscopy (NIRS) was used to monitor cerebral tissue saturation (rSO2) during SACP in 46 patients. Lower rSO2 were encountered (1) in patients suffering a stroke (2) with unilateral SACP, and (3) in the affected hemisphere of stroke victims. A decrease of rSO2 by 14 – 21% from baseline increased the risk of stroke significantly. Study V Quality of life (QoL) in 76 survivors of thoracic aortic surgery was examined with the SF-36 health questionnaire. Except for pain, QoL was reduced in all dimensions. QoL was not affected by acuity of operation. Tendencies of lower QoL after descending aortic operations, after major complications, and with persistent dysfunction were non-significant.

<p>  </p> <p>Three key challenges in developing advanced image-based computational models of cerebral aneurysms are: (i) disentangling the effect of biomechanics and confounding clinical risk factors on aneurysmal progression, (ii) accounting for arterial wall mechanics, and (iii) incorporating the effect of surrounding tissue support on vessel motion and deformation. This thesis addresses these knowledge gaps by developing fluid-structure interaction (FSI) models of subject-specific geometries of cerebral aneurysms to elucidate the effect of coupled hemodynamics and biomechanics. A consistent methodology for obtaining physiologically realistic computational FSI models from standard-of-care imaging data is developed. In this process, a novel technique to estimate heterogeneous arterial wall thickness in the absence of subject-specific arterial wall imaging data is proposed. To address a limitation in the mesh generation workflow of the state-of-the-art cardiovascular flow modeling tool SimVascular, generation of meshes with boundary-layer mesh refinement near the blood-vessel wall interface is proposed for computational geometries with nonuniform wall thickness. Computational murine models of thoracic aortic aneurysms were developed using the proposed methodology. These models were used to inform external tissue support boundary conditions for human cerebral aneurysm subjects via a scaling analysis. Then, the methodology was applied to subjects with multiple unruptured cerebral aneurysms. A comparative computational FSI analysis of aneurysmal biomechanics was performed for each subject-specific pair of computational models for the stable and growing aneurysms, which act as self-controls for confounding clinical risk factors. A higher percentage of area exposed to low shear and high median-peak-systolic arterial wall deformation, each by factors of 1.5 to 2, was observed in growing aneurysms, compared to stable ones. Furthermore, a novel metric – the oscillatory stress index (OStI) – was defined and proposed to indicate locations of oscillating arterial wall stresses. Growing aneurysms demonstrated significant areas with a combination of low wall shear and low OStI, which were hypothesized to be associated with regions of collagen degradation and remodeling. On the other hand, such regions were either absent (or were a small percentage of the total aneurysmal area) in the stable cases. This thesis, therefore, provides a groundwork for future studies, with larger patient cohorts, which will evaluate the role of these biomechanical parameters in cerebral aneurysm growth.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.

Les endoprothèses sont devenues une solution thérapeutique de choix pour les anévrismes aortiques. Même si leur bénéfice à long terme face à la chirurgie ouverte reste incertain, elles permettent de réduire la mortalité et les complications postopératoires précoces. Elles sont toutefois soumises à un certain nombre de contraintes anatomiques. Il y a encore quinze ans, elles étaient contre-indiquées dans le traitement des anévrismes débutant au niveau ou au-dessus des artères rénales, à savoir les anévrismes juxta et suprarénaux (AJSR) et les anévrismes thoraco-abdominaux (ATA). Le développement d'endoprothèses fenêtrées et/ou branchées (EPFB) a permis de proposer une solution endovasculaire à ces patients. Il s'agit d'endoprothèses munies d'orifices ou de branches latérales destinées à maintenir la perfusion des artères rénales et viscérales. Plusieurs études rétrospectives ont rapporté des résultats encourageants à court et moyen terme. Il s'agit néanmoins de techniques complexes, exposées à la survenue de problèmes techniques au niveau des artères cibles (rénales et viscérales) et des voies d'accès fémorales. Les résultats des EPFB nous semblent améliorables par une optimisation de la sélection des patients, par des innovations techniques apportées aux dispositifs implantables, ainsi que l'amélioration des techniques d'imagerie et de navigation endovasculaire. En raisons des délais de fabrication (> 6 semaines), les patients nécessitant un traitement rapide (anévrismes douloureux ou volumineux) échappent par ailleurs aux EPFB manufacturées.Les objectifs de cette thèse étaient: (1) d'évaluer dans notre expérience la fréquence et la nature des problèmes techniques peropératoires, et d'analyser leur impact sur les suites cliniques immédiates; (2) d'évaluer la faisabilité et les performances sur modèle in vitro de la navigation endovasculaire utilisant un système de navigation électromagnétique (StealthStation®, Medtronic); (3) d'évaluer la faisabilité et la sureté de la navigation robotique au cours de la mise en place d'une EPFB; (4) d'analyser les résultats à court terme des endoprothèses avec fenêtres créées à façon par le chirurgien pour des patients porteurs d'anévrismes complexes nécessitant un traitement rapide.Au cours de ce travail, nous avons tout d'abord montré qu'en début d'expérience (113 premiers patients), les problèmes techniques peropératoires n'étaient pas rares (30 % des patients) et que ceux-ci aboutissaient dans plus de la moitié des cas à des complications postopératoires. Ces problèmes techniques sont certes en partie évitables par l'amélioration de la sélection des patients et l'expertise de l'équipe soignante, mais nous pensons que le développement de nouveaux outils d'imagerie et de navigation pourrait également jouer un rôle clé. C'est sur ce dernier point que nous avons accentué nos recherches. Bien qu'une amélioration des performances techniques de la navigation électromagnétique soit nécessaire, nous avons pu montrer qu'elle permettait de fournir des informations complémentaires à la fluoroscopie, notamment lors des étapes de déploiement de l'endoprothèse et de cathétérisme des artères cibles. Plus que concurrente de la fluoroscopie, elle pourrait être utilisée de façon combinée dans le but de diminuer l'irradiation par les rayons X et d'améliorer les performances de la navigation. Nous avons également pu montrer les bénéfices potentiels de la navigation robotique lors de la mise en place d'endoprothèses branchées et ses limites actuelles pour assister de façon efficace les procédures fenêtrées. Enfin, dans une série limitée (n=11) de patients porteurs d'ATA, nous avons montré que l'utilisation d'endoprothèses avec fenêtres créées à façon par le chirurgien était à même de fournir des résultats précoces comparables (mortalité hospitalière : 9%, ischémie médullaire : 9%) à ceux des EPFB, et constituait une solution à considérer pour les patients nécessitant un traitement rapide. / Aortic stent grafts have gained widespread acceptance for the treatment of aortic aneurysms. When compared with open repair, they have been shown to reduce significantly postoperative mortality and complication rates. However, these benefits remain uncertain in the long-term and aortic stent grafts are still limited by anatomic restrictions. Fifteen years ago, patients with complex aneurysms such as juxtarenal, suprarenal and thoracoabdominal aneurysms were not eligible for endovascular repair. With the development of fenestrated and branched stent grafts (FBSG), it is now possible to offer an endovascular solution to these patients. FBSG contains holes (fenestrations) or lateral branches. Their purpose is to allow the proximal margin of the device to sit higher than standard infrarenal devices and allow uninterrupted blood flow to renal and visceral vessels. Retrospective studies have shown encouraging short-term and mid-term results. However, fenestrated/ branched stent grafting remains a complex procedure, associated with significant risks of technical problems such as target vessel loss and difficulties with iliac or femoral accesses. Results of FBSG could be further improved by optimizing patient selection, technical innovation to optimize currently available devices, and developments of new imaging and navigation tools. In addition, due to manufacturing delays (6-10 weeks), FBSG are not applicable to high-risk patients who need rapid treatment (painful or large aneurysms).The objectives of this thesis were: (1) to evaluate the incidence and define the nature of unexpected intraoperative adverse events and analyse their impact on the postoperative outcome; (2) to evaluate in vitro the feasibility and the performances of electromagnetic navigation using a new device (StealthStation®, Medtronic); (3) to evaluate the feasibility and safety of robotic navigation for target vessel cannulation; (4) to analyse short-term results of physician modified stent grafts for patients with complex aortic aneurysms needing rapid treatment.During this work, we showed that intraoperative adverse events were not rare (30% of the first 113 patients) during our early experience. They were responsible for postoperative complications in more than 50 % of cases. Optimal patient selection and increased experience of the medical staff may reduce the incidence of technical problems. However, we believe the development of new imaging modalities and navigation tools could play a key role to limit their occurrence. Although further developments are mandatory, the use of electromagnetic navigation as a complementary imaging modality, as tested with the StealthStation®, might be beneficial in terms of radiation exposure, cannulation performances, and accuracy in the positioning of FBSG. We also showed that robotic cannulation of renal and visceral vessels during complex endovascular aortic procedures is feasible and safe. In our experience, it was more effective for branches than for fenestrations. Finally, we used physician modified stent grafts in a limited series of eleven patients with thoracoabdominal aortic aneurysms. With a 9% in-hospital mortality rate and a 9% rate of spinal cord ischemia, they provided similar results to those of manufactured FBSG, suggesting they might be an option to consider for high-risk patients needing rapid treatment.

This thesis is focused on stress in brain aneurysms. It consists of three parts. First part is aimed for gaining information about the topic from scientific resources. Next part consists of analyses of geometry of cerebral aneurysms on the computed wall stress. Analyses are performed on four basic geometrical models and results are being discussed. The risky areas in each investigated shape have been identified as well as the comparisons of stress between those shapes have been performed and the most dangerous shape among investigated shapes has been determined. Third part investigates the influence of surrounding tissue on the brain aneurysm. Conclusion of this thesis is that brain gray tissue has positive yet negligible effect on the computed wall stress.

Cette thèse est basée sur ma contribution à différents projets liés à la recherche clinique sur les anévrismes intracrâniens, le traitement endovasculaire, la compréhension des patients et la participation aux essais cliniques. Ce travail a donné lieu à quatre publications à ce jour. Pour cette thèse, je fournis d'abord quelques informations sur les anévrismes cérébraux et la façon dont ils sont gérés. Deuxièmement, je passerai brièvement en revue les principes de l'éthique médicale et de la recherche. J'aborde ensuite l'essai de soins ‘Comprehensive Aneurysm Management (CAM)’, car une partie du travail effectué pour ma thèse consistait à rendre compte des taux de recrutement dans CAM. J'ai également contribué à un article sur la démarcation recherche-soins, et pourquoi elle doit être révisée, ainsi qu'à un éditorial qui affirme que la recherche clinique doit être conçue dans le meilleur intérêt des patients. Enfin, j'ai apporté des contributions originales en concevant une enquête et en interrogeant des patients neurovasculaires avant qu'ils ne soient vus par un médecin dans le cadre d'un suivi. Les résultats de cette étude ont montré que les patients ont une meilleure compréhension de l'incertitude clinique et de l'existence d'options alternatives de prise en charge lorsqu'ils ont participé à des essais de soins. / This thesis is based on my contribution to different projects related to clinical research on intracranial aneurysms, endovascular treatment, patient understanding and participation in clinical trials. This work has led to four publications thus far. For this thesis, I first provide some background on cerebral aneurysms and how they are managed. Second, I briefly review medical and research ethics principles. I then discuss the Comprehensive Aneurysm Management (CAM) care trial because a portion of the work done for my thesis was to report on the recruitment rates in CAM. I also contributed to a paper on the research-care demarcation and why it must be revised, as well as to an editorial claiming that clinical research should be designed in patients' best interests. Finally, I made original contributions by designing a survey and interviewing neurovascular patients prior to being seen by a physician in follow-up. The results of that study showed that patients have a better understanding of clinical uncertainty and the existence of alternative management options when participating in care trials.