Objectives. We sought to evaluate the safety and efficacy of Drug eluting stents (DES) in patients with significant CKD in a real world registry Background. Patients with chronic kidney disease (CKD) who undergo percutaneous coronary angioplasty have higher rates of target lesion revascularization (TLR) and mortality. DES are associated with a lower rate of restenosis compared to bare metal stents (BMS), although in patients with CKD data on DES efficacy and safety is limited. Methods. A total of 504 patients who underwent percutaneous coronary intervention with DES in two centers were included in this study. Outcomes were stratified on the basis of the presence of CKD, defined as a baseline glomerular filtration rate <60ml/min/1.73m². Results. The mean follow-up was 22.7 months. CKD was present in 165 patients (32.7%). Patients with CKD were older, had more hypertension and diabetes. CKD patients presented increased incidence of death (12.3% vs. 2.4%, p<0.001) and myocardial infarction (MI) (7.4% vs. 3.3%, p=0.04) compared to patients without CKD. TLR rates were similar between groups (4.8% vs. 5.6%, p=0.7, CKD and no CKD patients, respectively). Independent predictors of death were CKD (HR 6.93; 2.4 – 19.5, p<0.001), current smoking (HR 3.66; 1.20 – 11.10, p=0.02) and diabetes (HR 2.66; 1.03 – 6.60, p=0.045). Conclusion. In this real-world registry, coronary intervention with DES in patients with CKD was associated with similar TLR compared to patients without CKD, demonstrating the efficacy of DES in preventing in-stent restenosis in this patient population. CKD was related to significantly increased MI and mortality rates.

Até o momento, pouco se sabe sobre a influência da modificação na composição do ateroma nas bordas dos stents e a ocorrência de alterações na geometria vascular. Este estudo objetiva correlacionar, utilizando de maneira seriada (pós-implante do stent e reestudo aos nove meses) o ultrassom monocromático e a Histologia Virtual®, as modificações na composição dos ateromas nas bordas proximais e distais de stents nãofarmacológicos e farmacológicos e as alterações ocorridas nas dimensões do vaso, luz e placa que possam explicar a ocorrência da reestenose nestes segmentos. Estudo prospectivo, de centro único, que randomizou (1:1) pacientes com síndrome coronária aguda para receberem stents nãofarmacológicos (Driver®, n=20 pacientes) ou farmacológicos (Cypher®, n=20 pacientes). Após a realização do procedimento, todos os pacientes submeteram-se a avaliação com ultrassom e Histologia Virtual®, que foi repetido ao final de nove meses de seguimento. O objetivo primário foi avaliar as modificações na área do vaso, luz e placa ao ultrassom e na composição do ateroma pela Histologia Virtual® no período entre o implante e o reestudo, buscando correlacionar as alterações no ateroma com as modificações na geometria vascular. Observou-se que na borda proximal, stents farmacológicos e não-farmacológicos tem um comportamento semelhante na avaliação ultrassonográfica, com tendência a remodelamento expansivo da área do vaso para compensar o crescimento na área da placa. Por outro lado, na borda distal, há menor crescimento da área da placa entre os pacientes tratados com stents farmacológicos, resultando em maior área da luz no reestudo de nove meses. Do ponto de vista da análise com Histologia virtual, nos dois grupos e em ambas as bordas houve redução do componente fibroso e núcleo necrótico com aumento no conteúdo fibrolipidico. Observou-se ainda importante correlação entre a variação do componente fibrótico e o aumento na área da placa (r=0.78, p=0.01). O uso de stents farmacológicos não se correlaciona com \"efeito de borda\". Ao contrário, parece haver menor crescimento da placa na borda distal destas endopróteses quando comparadas às sem fármaco. A modificação na composição do ateroma, com aumento do conteúdo fibro-lipídico pode explicar em parte estes achados. / To the present, little is known about the correlation between modifications in plaque composition at stent edges and the changes in vessel geometry. This study sought to evaluate, by serial grey-scale intravascular ultrasound (IVUS) and Virtual Histology(TM), the modifications in plaque composition at the edges of drug-eluting and bare-metal stents and the correlation of these findings with changes in the measuremntes of vessel, lumen and plaque area at those segments. Single-center, prospective and randomized (1:1) evaluation of 40 patients with acute coronary syndrome treated with bare-metal (Driver(TM), n=20 patients) or drug-eluting stents (Cypher(TM), n=20 patients). Following stent deployment, all individuals underwent gray scale IVUS and Virtual Histology(TM) evaluation, which were repeated at nine months. Primary endpoint included the modification in vessel, lumen and plaque area and in the composition of the plaque in the mean time between the baseline and follow-up procedure. Additionally, we tried to determine a correlation between plaque composition variation and changes in vessel geometry. At the proximal edge of both drug-eluting and bare-metal stents there was a trend to positive vessel remodeling which compensated the modest increase in plaque area. At the distal edge, patients treated with drug-eluting stents had less plaque growth resulting in a larger lumen area at follow-up. By Virtual Histology, there was a marked reduction in the % of fibrotic tissue and necrotic core in both edges of the two stents and a positive, strong correlation was seen between increase in % of fibrofatty component and augmentation in plaque area(r=0.78, p=0.01). The use of drug-eluting stents was not associated with \"edge effect\". On the contrary, patients treated with these devices experienced less plaque growth, especially at the distal edge of the stents. Modifications in plaque composition, with increase in fibrofatty content, might partially explain these findings.

An aneurysm is a balloon-like bulge in the wall of blood vessels, occurring in major arteries from the heart and brain. Biodegradable stent-assisted coiling is expected to be the ideal treatment of wide-neck complex aneurysms. A number of biodegradable stents are promising, but also with issues and/or several limitations to be addressed. From the design point of view, biodegradable stents are typically designed without structure optimization. The drawbacks of these stents often cause weaker mechanical properties than native arterial vessels. From the fabrication point of view, the conventional methods of the fabricating stent are time-consuming and expensive, and also lack precise control over the stent microstructure. As an emerging fabrication technique, dispensing-based rapid prototyping (DBRP) allows for more accurate control over the scaffold microstructure, thus facilitating the fabrication of stents as designed. This thesis is aimed at developing methods for fabrication and optimal design of biodegradable stents for treating aneurysms. Firstly, a method was developed to fabricate biodegradable stents by using the DBRP technique. Then, a compression test was carried out to characterize the radial deformation of the stents fabricated. The results illustrated the stent with a zigzag structure has a higher radial stiffness than the one with a coil structure. On this basis, the stent with a zigzag structure was chosen to develop a finite element model for simulating the real compression tests. The result showed the finite element model of biodegradable stents is acceptable within a range of radial deformation around 20%. Furthermore, an optimization of the zigzag structure was performed with ANSYS DesignXplorer, and the results indicated that the total deformation could be decreased by 35% by optimizing the structure parameters, which would represent a significant advance of the radial stiffness of biodegradable stents. Finally, the optimized stent was used to investigate its deformation in a blood vessel. The deformation is found to be 0.25 mm in the simulation, and the rigidity of biodegradable stents is 7.22%, which is able to support the blood vessel all. It is illustrated that the finite element analysis indeed helps in designing stents with new structures and therefore improved mechanical properties.

published_or_final_version / Mechanical Engineering / Master / Master of Philosophy

L’embolisation occupe une part croissante de l’activité de la radiologie interventionnelle endovasculaire. Les agents d’embolisation sont nombreux, présentent des propriétés variables et permettent d’obtenir une hémostase, un hémodétournement ou réaliser le vecteur d’une thérapie ciblée. Notre travail se décompose en trois parties visant successivement à un état de l'art des agents d’embolisation disponibles, puis des travaux originaux de laboratoire, et enfin l’analyse rétrospective de diverses études radio-cliniques constituées dans notre centre. La première partie basée sur une analyse de la littérature constitue un chapitre introductif dans lequel sont évalués les caractéristiques techniques, les avantages et limites des agents d’embolisation utilisés en pratique clinique courante. Le deuxième volet repose sur des travaux fondamentaux sur l’animal réalisés dans le laboratoire de cathétérisme expérimental de l’ISIT (Professeurs Boyer et Lusson) à la faculté de Médecine de Clermont-Ferrand, et dans le laboratoire des biomatériaux endovasculaires de l’université de Montréal (Professeur Lerouge et Soulez). Dans une première série d’expérimentation nous avons participé à Montréal au développement d’un agent d’embolisation qui combine les avantages d’un gel (solidification au contact du sang) et d’un sclérosant (destruction des cellules endothéliales). Le gel ainsi mis au point a fait l’objet d’un dépôt de brevet. Il pourrait permettre de prévenir et/ou traiter les fuites observées dans le traitement par endoprothèse des anévrysmes de l’aorte. Dans un deuxième protocole expérimental nous avons analysé à Clermont-Ferrand l’interaction entre agent d’embolisation et chimiothérapie en étudiant les modifications pharmacocinétiques observées en fonction de la voie d’administration et de l’association à une embolisation partielle ou complète de l’artère hépatique sur un modèle porcin. Le troisième volet repose sur des travaux cliniques originaux analysant rétrospectivement divers points sensibles en embolisation parenchymateuse. Cette partie s’appuie sur des collaborations multidisciplinaires fortes en pathologies gynécologiques, urologiques, hépatiques et spléniques. Il faut signaler enfin, la parution prévue pour le premier trimestre 2012 de l'ouvrage "Embolisation" (350 pages, Springer Ed., P. Chabrot et L. Boyer). Une version anglaise de ce livre suivra courant 2012. / Embolization is an increasing part of the activity of endovascular interventional radiology. Embolization agents are numerous, have variable properties and make it possible to obtain a hemostasis, a hemodiversion, or achieve the vector of a targeted therapy. Our work is divided into three parts, successively aimed at a state of the art of available embolization agents, then original laboratory work, and finally the retrospective analysis of various radio-clinical studies made in our research center. The first part based on an analysis of the literature constitutes an introductory chapter in which the technical characteristics, the advantages and the limits of the embolization agents used in current clinical practice are assessed. The second part is based on fundamental animal studies carried out in the experimental catheterization laboratory of ISIT (Professors Boyer and Lusson) at the Faculty of Medicine of Clermont-Ferrand, and in the laboratory of endovascular biomaterials of the university. of Montreal (Professor Lerouge and Soulez). In a first series of experiments, in Montreal, we participated in the development of an embolization agent that combines the advantages of a gel (solidification in contact with blood) and a sclerosant (destruction of endothelial cells). The gel thus developed has been the subject of a patent application. It may be able to prevent and / or treat the leaks observed in stent-graft treatment of aortic aneurysms. In a second experimental protocol, in Clermont-Ferrand, we analyzed the interaction between embolization agent and chemotherapy by studying the pharmacokinetic changes observed according to the route of administration and the association with partial or complete embolization of the hepatic artery on a porcine model. The third part is based on original clinical work analyzing retrospectively various sensitive points in parenchymal embolization. This part is based on strong multidisciplinary collaborations in gynecological, urological, hepatic and splenic pathologies. Finally, it is necessary to announce the publication scheduled for the first quarter of 2012 of the book "Embolisation" (350 pages, Springer Ed., P. Chabrot and L. Boyer). An English version of this book will follow in the course of 2012.

Publicación a texto completo no autorizada por el autor / Evalúa la eficacia del uso de la angioplastia con balón medicado respecto a la angioplastia convencional con ó sin colocación de stent en pacientes con arteriopatía diabética infrapoplítea, en base al curso clínico y la frecuencia de amputaciones y/o reintervenciones endovasculares de los pacientes sometidos a dichos procedimientos. Realiza un estudio analítico observacional caso control retrospectivo, en el que se trataron 46 pacientes, durante el periodo de Junio del 2010 a Octubre del 2012, organizados en 2 grupos de estudio. El grupo de casos estuvo constituido por los pacientes con arteriopatía diabética infrapoplítea con criterios de estenosis crítica sometidos a tratamiento endovascular de angioplastia con balón medicado y el grupo control por todos los pacientes con arteriopatía infrapoplítea con los mismo criterios de isquemia crítica sometidos a tratamiento endovascular de angioplastia con balón medicado con ó sin colocación de stent. Se buscó determinar el riesgo de amputación supracondílea. La información fue procesada con el uso del paquete estadístico SPSS, en su versión 16, empleándose la prueba de asociación de variables Chi cuadrado y la determinación del ODSS RATIO (OR). Obtiene como resultados: grupo de casos: 32,6%, grupo control 67,4% del total de la población, enfermedad renal crónica en el 53,3% del grupo de casos y de 38,7% en el grupo control, hipertensión arterial en el 86,6% en el grupo de casos y en el 83,8 % en el grupo de control, amputación supracondilea en un 6,6 % en el grupo de casos y de 12,9% en el grupo control. Concluye que el manejo endovascular de angioplastía con balón medicado presentó un menor riesgo de amputación supracondílea, en comparación al tratamiento endovascular convencional con balón no medicado con ó sin colocación de stent. Con criterios adecuados en la selección de los pacientes, esta opción terapéutica puede disminuir del riesgo de amputación supracondílea. No se encontraron asociaciones con las otras variables estudiadas. / Trabajo académico

<p>This thesis describes the Chandler loop, which makes it possible to conduct studies in vitro of molecular and cellular interactions between whole blood and stents. It was possible to monitor activation and inhibition of the cascades systems, leukocytes and platelets by combining different platelet inhibitors and heparin coating of stents. The clinical study was performed on patients with ACS undergoing PCI and stent implantation. In this study platelet activation markers P-selectin, and αIIb/β3 as well as inflammatory markers were followed from baseline during the first 48 hours post-PCI. The same parameters were evaluated in healthy controls for comparison at baseline. </p><p>In vitro: The activation of blood in the Chandler loops were more pronounced for unmodified stent grafts than for partially heparin coated stent grafts. Heparin coated stent grafts dreated the same activation as the loops alone. This indicated that the Chandler loop system was a feasible tool for evaluation of blood compability of stents. </p><p>Heparin coating of stents significantly reduced TAT, CD11b and platelet activation. The combination of a heparin coated stent and abciximab reduced TAT and contact activation, as compared to abciximab or heparin coating alone. </p><p>Heparin coating of stents in combination with AR-C69931MX resulted in a significant reduction in TAT and preservation of the platelet count but had no effect on contact activation. </p><p>Clinical study: Abciximab resulted in an almost total inhibition of fibrinogen binding to platelets and persisted throughout the observation period. Clopidogrel effectscould be observed at four hours but was more pronounced at 24 hours. </p><p>P-selectin expression did not differ over time between groups, indicating that platelet activation with α-granule secretion was not affected by abciximab treatment. </p><p>The hs-CRP, C3a and sC5b-9 levels increased 24 to 48 hours after PCI in patients with ACS. FXIIa-C1inh was reduced in ACS patients receiving abciximab as compared to controls. The elevated bFGF levels at baseline returned to the levels observed in controls four hours after PCI and stent implantation, whereas an increase in VEGF was observed 24 hours post-PCI.</p>

This thesis describes the Chandler loop, which makes it possible to conduct studies in vitro of molecular and cellular interactions between whole blood and stents. It was possible to monitor activation and inhibition of the cascades systems, leukocytes and platelets by combining different platelet inhibitors and heparin coating of stents. The clinical study was performed on patients with ACS undergoing PCI and stent implantation. In this study platelet activation markers P-selectin, and αIIb/β3 as well as inflammatory markers were followed from baseline during the first 48 hours post-PCI. The same parameters were evaluated in healthy controls for comparison at baseline. In vitro: The activation of blood in the Chandler loops were more pronounced for unmodified stent grafts than for partially heparin coated stent grafts. Heparin coated stent grafts dreated the same activation as the loops alone. This indicated that the Chandler loop system was a feasible tool for evaluation of blood compability of stents. Heparin coating of stents significantly reduced TAT, CD11b and platelet activation. The combination of a heparin coated stent and abciximab reduced TAT and contact activation, as compared to abciximab or heparin coating alone. Heparin coating of stents in combination with AR-C69931MX resulted in a significant reduction in TAT and preservation of the platelet count but had no effect on contact activation. Clinical study: Abciximab resulted in an almost total inhibition of fibrinogen binding to platelets and persisted throughout the observation period. Clopidogrel effectscould be observed at four hours but was more pronounced at 24 hours. P-selectin expression did not differ over time between groups, indicating that platelet activation with α-granule secretion was not affected by abciximab treatment. The hs-CRP, C3a and sC5b-9 levels increased 24 to 48 hours after PCI in patients with ACS. FXIIa-C1inh was reduced in ACS patients receiving abciximab as compared to controls. The elevated bFGF levels at baseline returned to the levels observed in controls four hours after PCI and stent implantation, whereas an increase in VEGF was observed 24 hours post-PCI.

TEVAR has been used extensively to treat TBAD. The principle of treatment involve placement of a stent graft in the true lumen to cover the primary tear, thereby excluding the false lumen. Success depends on a combination of factors: reduction of false lumen pressure and perfusion, thrombosis of the false lumen, and remodeling of the aorta leading to eventual healing. The long-term goals are to prevent continuous growth of the false lumen, reinterventions, and aneurysm rupture. The success of TEVAR depends on a combination of factors, including the blood flow and pressure in the two aortic lumens, and remodeling is a dynamic process. Much controversy exists regarding the ideal timing of TEVAR, its efficacy in effecting complete false lumen exclusion, the long-term durability of the repair, and the fate of the aortic size. The objective of this thesis is to examine the morphological and hemodynamic changes within the aortic lumens after TEVAR, using a combination of ex-vivo animal models and computational tomography analysis. The residual pressure of the true and false lumens in TBAD models was studied. Volumetric analyses of CT scan of patients were compared. The ultimate goals are to determine if it is beneficial to treat type B dissections early, and to determine long-term morphological results. In ex-vivo hemodynamic study, 28 fresh porcine aortas models were created to simulate three different pathological scenarios of TBAD: model A represented pre-treated TBAD; model B represented post-treated TBAD with patent false lumen; and model C represented chronic stage of post-treated TBAD with false lumen thrombosis. True lumen and false lumen pressure differences were compared between the three models. Pressure effect was successfully reduced by 30% in model C in comparison with the other two models. No hemodynamic parameters were significantly different between model A and model B. Aortic remodeling parameters were volumetrically analyzed and compared between two groups of patients who underwent endo-grafting for uncomplicated TBAD (group A) and dissecting aneurysms (group B). Modern DIOCM processing workstations and software were used to reconstruct thoracic aorta with serial CT scans. The true lumen, false lumen, thrombus and aortic size were measured volumetrically. Stent graft migration and area of inlet and outlet were also quantified. There were progressive migration and continuous expansion of the stent graft on patients in both groups. Favorable aortic remodeling was observed in most. One fourth of all patients demonstrated aortic volume increase at 36 months. However, there was no difference between group A and group B in terms of stent graft re-shaping and aortic remodeling. In conclusion, Aortic remodeling after TEVAR in treating TBAD is a continuous process. There were no significant differences between chronic dissections and dissecting aneurysms in all morphological parameters. Treating chronic dissections before aneurysm formation does not seem to have a morphologic advantage. Sealing of primary entry tear with introducing thrombosis could significantly reduce false lumen pressure. However, the remaining pressure accumulations should be considered to reduce by further excluding distal reentry tears in those patients who undergo progressive false lumen expansion after TEVER. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

The use of intravascular stents to restore blood flow through restricted vessels in patients with coronary artery disease has become the preferred method for treating a variety of lesion locations and pathologies. As new stent configurations and coatings are developed, a great need exists for high-throughput preclinical evaluation techniques that can interface human tissue with three-dimensional devices. Thus, the goals of this dissertation research were 1) to develop an in vitro blood vessel mimic composed of human cells for preclinical evaluation of intravascular devices, and 2) to utilize the mimic to assess neointimal responses to implanted stents.Experiments in support of these goals were broken into four specific aims. The first aim was to develop an in vitro human blood vessel mimic based on techniques for creating tissue engineered vascular grafts. The second aim was to determine the feasibility of utilizing this vessel mimic for bare metal stent evaluation. The third aim was to use the in vitro vessel to evaluate the cellular response to protein-coated stents. The fourth aim was to take advantage of the ability to control the in vitro vessel environment in order to evaluate the effect of shear rate on the neointimal response to implanted stents.Human blood vessel mimics were created by sodding fat-derived microvascular endothelial cells onto expanded polytetrafluoroethylene grafts and cultivating the vessels in bioreactor systems. This resulted in the development of a luminal lining of endothelial cells with sub-endothelial smooth muscle and mesenchymal cells. Deployment and assessment of bare metal stents within blood vessel mimics supported the feasibility of using the model for stent evaluation, and demonstrated that cell coverage of the device surface could be observed and measured. Protein-modified stents were created by submerging devices in enriched medium, and following implantation in the blood vessel mimic exhibited increased cell coverage and increased tissue thickness as compared with bare metal stents. Finally, an increase in shear rate lead to decreased neointimal coverage of implanted bare metal and modified stents. Overall, this dissertation demonstrates that in vitro human blood vessel mimics can be created and utilized for preclinical device evaluation.