Magnetic Resonance Imaging (MRI) provides unique advantages such as superior soft tissue contrast, true multiplanar imaging, variable contrast mechanisms, measurement of temperature changes, perfusion and diffusion, and no ionizing radiation. Despite considerable research efforts in the field of interventional MRI, numerous challenges remain including restricted access to the patient, high acoustic noise and a shortage of MRI-safe devices. Novel methods and devices are presented in this thesis with the primary objective of enabling effective MRI-guided interventions, particularly abdominal needle and common catheter-based endovascular interventions. Firstly, a set of MRI-safe devices (guidewires, micro guidewires, catheters and micro catheters) were developed with passive or inductively coupling resonant markers for MRI visualisation. Secondly, a method was implemented for wireless tracking and dynamic guidance of instruments. Thirdly, a framework of technologies was developed for in-room display, wireless MRI remote control and multi-user communication along with a dedicated user interface and imaging protocol. These implementations were assessed in regards to MRI-safety, performance and usability and evaluated for MRI-guided liver biopsies, balloon angioplasty procedures and also for mechanical thrombolysis. Flow phantoms, Thiel soft-embalmed human cadavers with partially re-established perfusion and a porcine model were used for in vitro, ex vivo and in vivo validation, respectively. The results demonstrate that these interventions are experimentally feasible and practical when using the presented developments: automated device tracking and equipment designed for MRI-guided interventions streamlined procedural workflow. Specifically, it was shown that fast and accurate needle placements along complex trajectories were feasible using a wireless interactive display and control device with a dedicated user interface for interventions. Moreover, safe and efficacious balloon angioplasties of the iliac artery were practical using the described framework of technologies along with a dedicated MRI protocol. Finally, it was demonstrated that these developments could be adapted and applied to MRI-guided endovascular mechanical thrombolysis of the middle cerebral artery. The technologies, described in this thesis have been shown to overcome many of the present limitations and should therefore be useful for enabling MRI-guided interventions while not further constraining the operating physician in an already complex environment. Nevertheless, it is acknowledged that many crucial issues remain to be solved in the field of iMRI and in the context of the presented research. In particular further device optimisations, improvements of the tracking implementation along with further in vivo evaluations are required before moving towards clinical evaluation. This thesis sets the groundwork for moving ahead with the eventual clinical realisation of optimised MRI-guided interventions.

Une fistule artérioveineuse (FAV) est un accès vasculaire permanent créé par voie chirurgicale en connectant une veine et une artère chez le patient en hémodialyse. Cet accès vasculaire permet de mettre en place une circulation extracorporelle partielle afin de remplacer les fonctions exocrines des reins. En France, environ 36000 patients sont atteint d’insuffisance rénale chronique en phase terminale, stade de la maladie le plus grave qui nécessite la mise en place d’un traitement de suppléance des reins : l’hémodialyse. La création et présence de la FAV modifient significativement l’hémodynamique dans les vaisseaux sanguins, au niveau local et systémique ainsi qu’à court et à plus long terme. Ces modifications de l’hémodynamiques peuvent induire différents pathologies vasculaires, comme la formation d’anévrysmes et de sténoses. L’objectif de cette étude est de mieux comprendre le comportement mécanique et l’hémodynamique dans les vaisseaux de la FAV. Nous avons étudié numériquement les interactions fluide-structure (IFS) au sein d’une FAV patient-spécifique, dont la géométrie a été reconstruite à partir d’images médicales acquises lors d’un précédent doctorat. Cette FAV a été créée chez le patient en connectant la veine céphalique du patient à l’artère radiale et présente une sténose artérielle réduisant de 80% la lumière du vaisseau. Nous avons imposé le profil de vitesse mesuré sur le patient comme conditions aux limites en entrée et un modèle de Windkessel au niveau des sorties artérielle et veineuse. Nous avons considéré des propriétés mécaniques différentes pour l’artère et la veine et pris en compte le comportement non-Newtonien du sang. Les simulations IFS permettent de calculer l’évolution temporelle des contraintes hémodynamiques et des contraintes internes à la paroi des vaisseaux. Nous nous sommes demandées aussi si des simulations non couplées des équations fluides et solides permettaient d’obtenir des résultats suffisamment précis tout en réduisant significativement le temps de calcul, afin d’envisager son utilisation par les chirurgiens. Dans la deuxième partie de l’étude, nous nous sommes intéressés à l’effet de la présence d’une sténose artérielle sur l’hémodynamique et en particulier à ses traitements endovasculaires. Nous avons dans un premier temps simulé numériquement le traitement de la sténose par angioplastie. En clinique, les sténoses résiduelles après angioplastie sont considérées comme acceptables si elles obstruent moins de 30% de la lumière du vaisseau. Nous avons donc gonflé le ballonnet pour angioplastie avec différentes pressions de manière à obtenir des degrés de sténoses résiduelles compris entre 0 et 30%. Une autre possibilité pour traiter la sténose est de placer un stent après l’angioplastie. Nous avons donc dans un deuxième temps simulé ce traitement numériquement et résolu le problème d’IFS dans la fistule après la pose du stent. Dans ces simulations, la présence du stent a été prise en compte en imposant les propriétés mécaniques équivalentes du vaisseau après la pose du stent à une portion de l’artère. Dans la dernière partie de l’étude nous avons mis en place un dispositif de mesure par PIV (Particle Image Velocimetry). Un moule rigide et transparent de la géométrie a été obtenu par prototypage rapide. Les résultats expérimentaux ont été validés par comparaison avec les résultats des simulations numériques. / An arteriovenous fistula (AVF) is a permanent vascular access created surgically connecting a vein onto an artery. It enables to circulate blood extra-corporeally in order to clean it from metabolic waste products and excess of water for patients with end-stage renal disease undergoing hemodialysis. The hemodynamics results to be significantly altered within the arteriovenous fistula compared to the physiological situation. Several studies have been carried out in order to better understand the consequences of AVF creation, maturation and frequent use, but many clinical questions still lie unanswered. The aim of the present study is to better understand the hemodynamics within the AVF, when the compliance of the vascularwall is taken into account. We also propose to quantify the effect of a stenosis at the afferent artery, the incidence of which has been underestimated for many years. The fluid-structure interactions (FSI) within a patient-specific radio-cephalic arteriovenous fistula are investigated numerically. The considered AVF presents an 80% stenosis at the afferent artery. The patient-specific velocity profile is imposed at the boundary inlet, and a Windkessel model is set at the arterial and venous outlets. The mechanical properties of the vein and the artery are differentiated. The non-Newtonian blood behavior has been taken into account. The FSI simulation advantageously provides the time-evolution of both the hemodynamic and structural stresses, and guarantees the equilibrium of the solution at the interface between the fluid and solid domains. The FSI results show the presence of large zones of blood flow recirculation within the cephalic vein, which might promote neointima formation. Large internal stresses are also observed at the venous wall, which may lead to wall remodeling. The fully-coupled FSI simulation results to be costly in computational time, which can so far limit its clinical use. We have investigated whether uncoupled fluid and structure simulations can provide accurate results and significantly reduce the computational time. The uncoupled simulations have the advantage to run 5 times faster than the fully-coupled FSI. We show that an uncoupled fluid simulation provides informative qualitative maps of the hemodynamic conditions in the AVF. Quantitatively, the maximum error on the hemodynamic parameters is 20%. The uncoupled structural simulation with non-uniform wall properties along the vasculature provides the accurate distribution of internal wall stresses, but only at one instant of time within the cardiac cycle. Although partially inaccurate or incomplete, the results of the uncoupled simulations could still be informative enough to guide clinicians in their decision-making. In the second part of the study we have investigated the effects of the arterial stenosis on the hemodynamics, and simulated its treatment by balloon-angioplasty. Clinically, balloon-angioplasty rarely corrects the stenosis fully and a degree of stenosis remains after treatment. Residual degrees of stenosis below 30% are considered as successful. We have inflated the balloon with different pressures to simulate residual stenoses ranging from 0 to 30%. The arterial stenosis has little impact on the blood flow distribution: the venous flow rate remains unchanged before and after the treatment and thus permits hemodialysis. But an increase in the pressure difference across the stenosis is observed, which could cause the heart work load to increase. To guarantee a pressure drop below 5 mmHg, which is considered as the threshold stenosis pressure difference clinically, we find that the residual stenosis degree must be 20% maximum.

O remodelamento vascular é um determinante fundamental do lúmen em doenças vasculares, porém os mecanismos envolvidos não estão completamente elucidados. Nós investigamos o papel da chaperona redox residente do retículo endoplasmático Dissulfeto Isomerase Proteica (PDI) e sua fração localizada na superfície celular (peri/epicelular=pecPDI) no calibre e arquitetura vascular durante reparação à lesão. Em artérias ilíacas de coelho submetidas à lesão in vivo, houve importante aumento do mRNA e expressão proteica (~25x aumento 14 dias pós-lesão vs. controle) da PDI. O silenciamento da PDI por siRNA (cultura de órgãos) acentuou o estresse do retículo e apoptose, diferentemente da inibição da pecPDI com anticorpo neutralizante (PDI Ab). Bloqueio in vivo da pecPDI por aplicação de gel perivascular contendo PDI Ab no 12° dia após lesão, com análise após 48 h, promoveu ca.25% redução no calibre vascular analisado por arteriografia e diminuição similar na área total do vaso detectada por tomografia de coerência óptica. Neste processo, não ocorreu alteração no tamanho da neoíntima, indicando assim, que PDI Ab acentuou remodelamento constrictivo. Neutralização da pecPDI promoveu importantes alterações na arquitetura da matriz de colágeno e citoesqueleto, resultando em fibras com orientação invertida e desorganizadas. Diminuição na produção de espécies reativas de oxigênio e óxidos de nitrogênio também ocorreu. Análise de propriedades viscoelásticas nas artérias indicou redução na ductilidade vascular, evidenciada pela menor distância para ruptura. As alterações subcelulares no citoesqueleto observadas in vivo após PDI Ab foram recapituladas em um modelo de estiramento cíclico em células musculares lisas vasculares, com importante redução na formação das fibras de estresse. Em modelo de migração randômica de células musculares lisas, a exposição a PDI Ab reduziu a resiliência de regulação da polaridade. Embora a neutralização da pecPDI não tenha afetado a atividade global de RhoA, ela promoveu alterações no padrão de marcação em resposta ao estiramento, na redistribuição de RhoA na superfície celular e na associação com regiões contendo caveolina. Além disso, em aterosclerose nativa em humanos, a expressão da PDI correlacionou-se inversamente com remodelamento constrictivo. Dessa forma, PDI é fortemente expressa após a lesão e sua fração peri/epicelular remodela a arquitetura da matriz e citoesqueleto, promovendo um efeito anti-remodelamento constrictivo / Whole-vessel remodeling is a critical lumen caliber determinant in vascular disease, but underlying mechanisms are poorly understood. We investigated the role of endoplasmic reticulum chaperone Protein Disulfide Isomerase(PDI) and cell-surface PDI(peri/epicellular=pecPDI) pool in vascular caliber and architecture during vascular repair after injury(AI). After rabbit iliac artery balloon injury, there was marked increase in PDI mRNA and protein (25-fold vs. basal at day 14AI), with increase in both intracellular and pecPDI. Silencing PDI by siRNA (organ culture) induced ER stress augmentation and apoptosis, contrarily to pecPDI neutralization with PDI-antibody(PDI Ab). PecPDI neutralization in vivo with PDIAb-containing perivascular gel from days 12-14AI promoted ca.25% decrease in vascular caliber at arteriography and similar decreases in total vessel circumference at optical coherence tomography, without changing neointima, indicating increased constrictive remodeling. PecPDI neutralization promoted marked changes in collagen and cytoskeleton architecture, with inverted fiber orientation and disorganization. Decreased ROS and nitrogen oxide production also occurred. Viscoelastic artery properties assessment showed decreased ductility, evidenced by decreased distance to rupture. Subcellular cytoskeletal disruption by PDI Ab was recapitulated in vascular smooth muscle cell stretch model, with marked decrease in stress fiber buildup. Also, PDI Ab incubation promoted decreased regulation resilience of vascular smooth muscle migration properties. While pecPDI neutralization did not affect global RhoA activity, there was altered RhoA redistribution to the cell surface and association with caveolin-containing clusters, which mislocalized after stretch. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling. Thus, strongly-expressed PDI after injury reshapes matrix and cytoskeleton architecture to support an anticonstrictive remodeling effect

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT

O remodelamento vascular é um determinante fundamental do lúmen em doenças vasculares, porém os mecanismos envolvidos não estão completamente elucidados. Nós investigamos o papel da chaperona redox residente do retículo endoplasmático Dissulfeto Isomerase Proteica (PDI) e sua fração localizada na superfície celular (peri/epicelular=pecPDI) no calibre e arquitetura vascular durante reparação à lesão. Em artérias ilíacas de coelho submetidas à lesão in vivo, houve importante aumento do mRNA e expressão proteica (~25x aumento 14 dias pós-lesão vs. controle) da PDI. O silenciamento da PDI por siRNA (cultura de órgãos) acentuou o estresse do retículo e apoptose, diferentemente da inibição da pecPDI com anticorpo neutralizante (PDI Ab). Bloqueio in vivo da pecPDI por aplicação de gel perivascular contendo PDI Ab no 12° dia após lesão, com análise após 48 h, promoveu ca.25% redução no calibre vascular analisado por arteriografia e diminuição similar na área total do vaso detectada por tomografia de coerência óptica. Neste processo, não ocorreu alteração no tamanho da neoíntima, indicando assim, que PDI Ab acentuou remodelamento constrictivo. Neutralização da pecPDI promoveu importantes alterações na arquitetura da matriz de colágeno e citoesqueleto, resultando em fibras com orientação invertida e desorganizadas. Diminuição na produção de espécies reativas de oxigênio e óxidos de nitrogênio também ocorreu. Análise de propriedades viscoelásticas nas artérias indicou redução na ductilidade vascular, evidenciada pela menor distância para ruptura. As alterações subcelulares no citoesqueleto observadas in vivo após PDI Ab foram recapituladas em um modelo de estiramento cíclico em células musculares lisas vasculares, com importante redução na formação das fibras de estresse. Em modelo de migração randômica de células musculares lisas, a exposição a PDI Ab reduziu a resiliência de regulação da polaridade. Embora a neutralização da pecPDI não tenha afetado a atividade global de RhoA, ela promoveu alterações no padrão de marcação em resposta ao estiramento, na redistribuição de RhoA na superfície celular e na associação com regiões contendo caveolina. Além disso, em aterosclerose nativa em humanos, a expressão da PDI correlacionou-se inversamente com remodelamento constrictivo. Dessa forma, PDI é fortemente expressa após a lesão e sua fração peri/epicelular remodela a arquitetura da matriz e citoesqueleto, promovendo um efeito anti-remodelamento constrictivo / Whole-vessel remodeling is a critical lumen caliber determinant in vascular disease, but underlying mechanisms are poorly understood. We investigated the role of endoplasmic reticulum chaperone Protein Disulfide Isomerase(PDI) and cell-surface PDI(peri/epicellular=pecPDI) pool in vascular caliber and architecture during vascular repair after injury(AI). After rabbit iliac artery balloon injury, there was marked increase in PDI mRNA and protein (25-fold vs. basal at day 14AI), with increase in both intracellular and pecPDI. Silencing PDI by siRNA (organ culture) induced ER stress augmentation and apoptosis, contrarily to pecPDI neutralization with PDI-antibody(PDI Ab). PecPDI neutralization in vivo with PDIAb-containing perivascular gel from days 12-14AI promoted ca.25% decrease in vascular caliber at arteriography and similar decreases in total vessel circumference at optical coherence tomography, without changing neointima, indicating increased constrictive remodeling. PecPDI neutralization promoted marked changes in collagen and cytoskeleton architecture, with inverted fiber orientation and disorganization. Decreased ROS and nitrogen oxide production also occurred. Viscoelastic artery properties assessment showed decreased ductility, evidenced by decreased distance to rupture. Subcellular cytoskeletal disruption by PDI Ab was recapitulated in vascular smooth muscle cell stretch model, with marked decrease in stress fiber buildup. Also, PDI Ab incubation promoted decreased regulation resilience of vascular smooth muscle migration properties. While pecPDI neutralization did not affect global RhoA activity, there was altered RhoA redistribution to the cell surface and association with caveolin-containing clusters, which mislocalized after stretch. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling. Thus, strongly-expressed PDI after injury reshapes matrix and cytoskeleton architecture to support an anticonstrictive remodeling effect