Pour rétablir, ou maintenir, le flux coronarien dans des artères en partie ou totalement obstruées, on implante une endoprothèse qui a la forme d'un petit ressort métallique. Cependant, la pose de ces stents conduit dans 5 à 20% des interventions à une lente réocclusion qui naît en partie de la réponse des cellules pariétales aux efforts hémodynamiques.<br /><br />Notre étude vise donc à établir numériquement (à l'aide du logiciel Star-CD) et expérimentalement (par PIV et PSV) la topologie de l'écoulement intra stent, mais aussi à quantifier les niveaux de contraintes pariétales au sein du design, en écoulement newtonien et non newtonien. En préambule, une synthèse bibliographique des réponses des cellules constitutives de la paroi artérielle à différents niveaux de contrainte de cisaillement est proposée. La connaissance de ces réponses différenciées des cellules endothéliales et musculaires lisses permet alors de proposer une estimation des régions favorables à la resténose, via le calcul des contraintes de cisaillement qui leurs sont appliquées.<br /><br />Notre étude paramétrique bidimensionnelle a permis de démontrer la prépondérance de la hauteur des branches sur les risques de resténose. Les résultats tridimensionnels permettent d'estimer les lieux d'une activité mitogénique potentiellement anormale, ainsi que le caractère non newtonien et quasi-stationnaire de l'écoulement intravasculaire au niveau de la paroi artérielle.

L'implantation valvulaire (mise en place d'une stent-valve percutanée), pulmonaire ou aortique, est une procédure récente en plein (et rapide) développement. Cette procédure prometteuse, possède plusieurs écueils parmi lesquels, l'altération du matériel implanté lors de son déploiement. L'implantation valvulaire dans les voies pulmonaires dilatées, est une autre limite de la procédure. Dans notre travail, nous avons étudié le traumatisme valvulaire lié au déploiement des prothèses. Ensuite, nous avons évalué un nouveau dispositif de réduction du calibre de la voie pulmonaire, afin d'en élargir les indications ultérieurement.Nous avons donc dans un premier temps comparé 2 types de stent-valves, l'un expansible par ballon et l'autre auto-expansible. La comparaison a porté sur l'occurrence de lésions valvulaires lors du sertissage et du déploiement de ces 2 types de prothèses. Nous avons pu montrer la présence de lésions des feuillets péricardiques de ces prothèses, induites par la compression des dispositifs. Par ailleurs, la présence de lésions histologiques plus marquées avec les valves expansibles par ballon, suggère aussi un rôle de l'expansion de ces prothèses dans la genèse des lésions valvulaires post-déploiement. Nous n'avons pas constaté d'altérations des propriétés mécaniques du tissu valvulaire induites par la compression et le déploiement des feuillets.Dans une autre partie de notre travail, nous avons mis au point un modèle d'élargissement de la voie pulmonaire, associé à la création d'une insuffisance pulmonaire sévère. Nous avons pu montrer que la réduction du calibre de la voie d'éjection pulmonaire était possible avec notre réducteur, par voie endovasculaire ou transventriculaire droite. Il n'a pas été observé de migration ou de fracture du stent de ces prothèses 2 mois après la procédure. Si le modèle d'élargissement de la voie pulmonaire est intéressant pour évaluer les réducteurs et la faisabilité de leur implantation, un suivit à plus long terme est nécessaire avant d'envisager une implantation chez l'homme. Enfin, l'altération des feuillets induite par le maniement des prothèses, est un phénomène à prendre en considération. Il nécessite, compte tenu de son impact potentiel sur la durabilité des prothèses, une investigation plus approfondie.

Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events. The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28). Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not. In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.

Stenting remains a common treatment option for atherosclerotic arteries. The main drawback of early stent platforms was restenosis, which has been combated by drug eluting stents; however, these stents have suffered from a higher incidence of late stage thrombosis. To address current stenting limitations, the major research focuses have been the development of the next generation of drug eluting stents and first generation bioabsorbable stents. The main objective of this dissertation was the design and development of a new class of bioabsorbable stent composed of elastin mimetic protein polymers. The first phase explored different stent design schemes and fabrication strategies. Successfully fabricated stents were then mechanically tested to ensure they possessed sufficient mechanical strength. Additionally, described herein is the potential to modulate the properties of the elastin mimetics through different crosslinking strategies. We have demonstrated that chemical crosslinking allows for the tailoring of the physical, mechanical, drug delivery, and endothelialization properties of these materials. The potential for drug delivery from this elastin mimetic stent was benchmarked as was the potential to endothelialize these stents. Furthermore, we developed the necessary delivery systems to allow for deployment in the rat aorta model.

Crossing of stent graft limbs during endovascular aneurysm repair (EVAR) is often used to assist cannulation and prevent graft kinking when the aortic bifurcation is widely splayed. Little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Using computational fluid dynamics, this work numerically examines the hemodynamic differences between these two out-of-plane stent graft configurations against a planar configuration commonly found in literature. Predicted values of displacement force, wall shear stress, and oscillatory shear index were similar between the out-of-plane configurations. The planar configuration predicted similar wall shear stress values, but significantly lower displacement forces than the out-of-plane configurations. These results suggest that the hemodynamic safety of cross-limb EVAR is comparable to conventional EVAR. However, a study of clinical outcomes may reveal reduced thrombosis incidence and long-term structural implications for the stent graft in cross-limb EVAR.

Crossing of stent graft limbs during endovascular aneurysm repair (EVAR) is often used to assist cannulation and prevent graft kinking when the aortic bifurcation is widely splayed. Little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Using computational fluid dynamics, this work numerically examines the hemodynamic differences between these two out-of-plane stent graft configurations against a planar configuration commonly found in literature. Predicted values of displacement force, wall shear stress, and oscillatory shear index were similar between the out-of-plane configurations. The planar configuration predicted similar wall shear stress values, but significantly lower displacement forces than the out-of-plane configurations. These results suggest that the hemodynamic safety of cross-limb EVAR is comparable to conventional EVAR. However, a study of clinical outcomes may reveal reduced thrombosis incidence and long-term structural implications for the stent graft in cross-limb EVAR.

La resténose intra-stent (RIS) est une complication importante du traitement endovasculaire des sténoses et occlusions artérielles dont l'incidence est réduite par les stents actifs. Ces derniers entraînent un retard de cicatrisation de la paroi vasculaire et parfois une réaction d'hypersensibilité au polymère, pouvant être responsable d'une thrombose aigue tardive. En raison de l'absence de modèle ex vivo validé, le modèle animal est actuellement obligatoire pour l'étude de la RIS. Ces modèles posent des problèmes éthiques et ne permettent pas une étude satisfaisante des stents actifs en raison de l'impossibilité d'effectuer des prélèvements réguliers. Le but de ce travail est d'une part l'exploration de deux nouvelles cibles thérapeutiques dans la RIS, l'hémine et EP224283, et d'autre part la mise au point d'un bioréacteur pour l'étude ex vivo hémodynamique de la RIS. Analyse in vivo. Les modèles de RIS utilisés étaient le stenting d'aorte de rat et le stenting d'artères iliaques de lapins hypercholestérolémiques. Sept ou 28 jours après l'implantation du stent, les artères stentées étaient prélevées puis soit incluses en résine pour analyse morphologique, soit congelées pour analyse de l'expression protéique. L'hémine était administrée par voie intrapéritonéale et EP224283 par voie sous cutanée toutes les 48 heures. Les témoins recevaient du sérum physiologique. L'analyse histomorphométrique après traitement par hémine montrait une réduction significative de 30% de la formation de néointima chez le rat et de 48% chez le lapin. La ré-endothélialisation des mailles du stent, analysée en microscopie électronique, était comparable à celle des témoins. L'analyse protéique montrait chez les rats traités par hémine : une réduction de l'expression des cytokines inflammatoires et des protéines impliquées dans la prolifération et la migration des CMLV (ERK1/2 et RhoA), associée à une augmentation de l'expression des protéines régulatrices de la prolifération (p21 et p27), et une réduction de l'apoptose. L'analyse histomorphométrique montrait chez les rats traités par EP224283 une réduction significative de formation de néointima de 20%. L'analyse protéique montrait une réduction de l'expression des protéines impliquées dans la prolifération des CMLV (ERK1/2 et Akt) associée à une augmentation de la forme active de p38, régulatrice de la prolifération. L'expression de Ki67 était réduite chez l'ensemble des rats traités témoignant d'une réduction de prolifération cellulaire. Analyse ex vivo : En partenariat avec l'ENSAM (Paris), nous avons confectionné et breveté un bioréacteur pour l'étude ex vivo de la RIS en conditions hémodynamiques et biologiques semblables au vivant. Ce bioréacteur fait circuler un flux pulsé dans 6 artères branchées en dérivation et immergées dans du milieu de culture cellulaire. Ce circuit est logé dans un incubateur afin de maintenir les tissus vivants durant l'expérimentation. Son objectif est d'affiner l'étude des nouveaux stents actifs par la possibilité de prélèvements multiples, d'analyser les écoulements, de travailler avec des artères humaines (prélevées lors de dons d'organes) et de s'affranchir en partie du modèle animal. Ces travaux montrent l'intérêt de deux nouvelles molécules thérapeutiques dans la RIS. Celles-ci limitent la prolifération cellulaire sans empêcher la cicatrisation de la paroi vasculaire. Notre modèle d'étude ex vivo hémodynamique de la RIS n'a jamais été décrit dans la littérature et permettra une analyse précise des nouveaux stents. Ce modèle va réduire le recours à l'expérimentation animale. Nos travaux futurs comprendront la mise au point de nouveaux stents actifs à l'hémine et à EP224283, ainsi que la validation et l'exploitation du modèle de RIS hémodynamique ex vivo.

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Made available in DSpace on 2015-07-22T20:49:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-04-28. Added 1 bitstream(s) on 2015-08-11T03:26:29Z : No. of bitstreams: 1 Publico-398a.pdf: 2056142 bytes, checksum: 435d31609f3433aa89597919533d4fe3 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:30Z : No. of bitstreams: 2 Publico-398a.pdf: 2056142 bytes, checksum: 435d31609f3433aa89597919533d4fe3 (MD5) Publico-398b.pdf: 1161589 bytes, checksum: 66a8321d2112124a94637a2890591de5 (MD5) / Recentemente tem se consolidado o conceito de que a aterosclerose, bem como a doença arterial coronariana, é uma doença inflamatória. Níveis elevados de marcadores inflamatórios são encontrados na angina estável e nas síndromes coronarianas agudas e tem valor prognóstico nestas situações. As intervenções coronárias percutâneas também cursam com elevação sérica de marcadores, e eles guardam correlação com a restenose intra-stent. A liberação local de drogas como o sirolimus, através dos stents farmacológicos, tem sido usada para prevenir e tratar a restenose intra-stent (RIS). O tratamento com sirolimus por via oral foi testado com sucesso para tratar e prevenir a RIS. Nós estudamos o efeito do sirolimus oral para prevenir e tratar a RIS nas variações de marcadores inflamatórios após o implante de stents coronários. Todos os pacientes tinham doença coronariana clinicamente manifesta. Um grupo de pacientes com alto risco para restenose inta-stent recebeu dose de ataque de 15 mg de sirolimus oral no dia anterior ao procedimento, e 5 mg por dia durante 28 dias sujeitos a ajustes semanais guiados por níveis sanguíneos. O grupo controle foi submetido a angioplastia com stents sem o tratamento com sirolimus. Os dois grupos foram seguidos por 8 semanas. As coletas foram realizadas antes da angioplastia (pré), 24 horas apos a angioplastia (24h), 1 semana, 4 semanas e 8 semanas após a angioplastia. Soro e plasma foram acondicionados a -85 °C. Análise estatística: modelo misto de medidas repetidas e análise de covariância (ANCOVA) com ajuste para os níveis basais dos marcadores. Um grupo de voluntários sadios forneceu os valores de referência para os marcadores. Os marcadores testados foram Proteína-C reativa ultra-sensível (hs-PCR), metaloproteinase 2 (MMP-2) e metaloproteinase 9 (MMP-9), inibidor tecidual de metaloproteinases-1 (TIMP-1), P-selectina, molécula de adesão intercelular-1 (ICAM-1), proteína quimiotática de monócitos-1 (MCP-1), fração solúvel do receptor da interleucina 2 alfa (IL-2sR&#61537;), interleucina 6 (IL-6) e fator estimulador de colônias de monócitos (M-CSF). No tempo basal, o grupo sirolimus teve níveis mais altos de MMP-9 e TIMP-1, e o grupo controle teve níveis maiores de ICAM-1. Durante o seguimento, a proteína C reativa atingiu o pico em 24 horas em ambos os grupos. Após ajuste para os níveis basais, houve diferença marginalmente significativa entre as variações dos grupos sirolimus e controle em 1 semana (-0.90±4.3 vs 0.03±0.3, P = 0.0726), diferença significativa em 4 semanas (-1.50±5.0 vs -0.19±0.4, P = 0.008) e marginalmente significativa em 8 semanas (-1.73±4.3 vs -0.01±0.7, P = 0.0975). Houve uma queda progressiva nos níveis de MMP-9 no grupo sirolimus, com a maior redução em 4 semanas, voltando a ter variação positiva em 8 semanas, 1 mês após a suspensão do sirolimus. Os grupos foram diferentes na primeira semana (-258.9 ± 510 vs +363 ± 438, P = 0.0030) e na quarta semana (-352.9 ± 455 vs +395.2 ± 377, P = 0.0004). Os níveis de ICAM-1 foram mais baixos no grupo sirolimus por todo o seguimento, e após ajuste para níveis basais houve diferença entre os grupos na primeira (-13.1 ± 49.7 vs -16.4 ± 119.1, P = 0.0047) e quarta semana (-3.3 ± 46.0 vs 3.8 ± 138.4, P = 0.0096). A P-selectina mostrou uma variação positiva importante na oitava semana, 1 mês após a suspensão do sirolimus, não observada no gupo controle (46.1±67.9 vs 5.8±23.7, P = 0.0025). Outros marcadores tiveram alterações apenas pontuais, e a IL-6 e o M-CSF não foram detectados pelos métodos empregados. Estes achados sugerem que a ação anti-restenótica do sirolimus oral inclui efeitos anti-proliferativos e modulação da resposta inflamatória com inibição da expressão de moléculas de adesão. / Recent findings in basic and experimental science have supported the notion that atherosclerosis is characterized by a chronic inflammatory vascular response and it is not only a bland lipid storage disease. It is also well known that coronary artery stenting is associated with both local vascular and systemic inflammation, which in turn correlate with increased in-stent restenosis after percutaneous coronary interventions. Sirolimus is an immunossupressant drug approved in the United States to prevent renal transplant rejection. Sirolimus has proved effective to prevent and treat in-stent restenosis (ISR) both with systemic administration and local administration through drug-eluting stents. We studied the effect of oral sirolimus administered to prevent and treat instent restenosis (ISR), on the variation of serum levels of inflammatory markers following coronary stenting. All patients had clinicaly manisfested ischemia. One group of patients at high risk for ISR received a loading dose of 15 mg sirolimus and 5 mg daily thereafter 28 days after stenting (SIR-G). Whole blood concentrations of sirolimus were obtained weekly and drug dose was adjusted accordingly. A control group (CONT-G) was submitted to stenting without sirolimus therapy. Both groups were followed for 8 weeks. Peripheral blood samples were obtained before the procedure (baseline), and 24h, 1 week, 4 weeks and 8 weeks after the procedure. The following biomarkers were evaluated: high sensitivity C-reactive protein (hs-CRP), soluble interleukin-2 receptor alpha (IL-2sRα), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of MMP-1 (TIMP-1), intercellular adhesion molecule-1 (ICAM-1) P-selectin, interleukin-6 (IL-6) and Macrophage colony-stimulating factor (M-CSF). Samples were centrifugated and serum was stored at -85°C. At baseline, SIR-G had higher levels of MMP-9 and TIMP-1 and CONT-G had higher levels of ICAM-1. At follow-up, the increase in high sensitivity C-reactive protein concentration was highest at 24 h after stenting in both SIR-G and CONT-G. After adjustment for baseline values, a marginally significant difference between the groups was observed at 1 week (-0.90±4.3 vs 0.03±0.3, P = 0.0726), which became significant at 4 weeks (-1.50±5.0 vs -0.19±0.4, P = 0.008) and lost significance 1 month after sirolimus discontinuation (-1.73±4.3 vs -0.01±0.7, P = 0.0975). A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks, while a positive variation was noted at week 8, 4 weeks after sirolimus discontinuation. SIR-G and CONT-G variations were different at 1 week (-258.9 ± 510 vs +363 ± 438, P = 0.0030) and 4 weeks (-352.9 ± 455 vs +395.2 ± 377, P = 0.0004). ICAM-1 levels were lower in SIR-G throughout the study. After baseline adjustment, significant differences appeared at week 1 (-13.1 ± 49.7 vs -16.4 ± 119.1, P = 0.0047) and week 4 (-3.3 ± 46.0 vs 3.8 ± 138.4, P = 0.0096). SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 after baseline adjustment (46.1±67.9 vs 5.8±23.7, P = 0.0025). The other biomarkers presented only minor changes. The These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression. / TEDE / BV UNIFESP: Teses e dissertações

Objetivo: Avaliar os resultados clínicos e radiológicos tardios de pacientes submetidos à angioplastia carotídea com colocação de stent (ACS) por doença aterosclerótica estenosante bulbar e determinar se o método é efetivo na prevenção de novos eventos isquêmicos cerebrais e se o método é durável na manutenção perviedade arterial. Métodos: Acompanhamos clinicamente e radiologicamente, por ultra-som Doppler (USD) e angiografia cerebral com subtração óssea digital (DSA), pacientes com estenose do bulbo carotídeo por doença aterosclerótica submetidos a ACS no período de janeiro de 2002 a maio de 2005 realizadas nos INRAD-HCFMUSP e Hospital Santa Marcelina de Itaquera. Resultados: 80 pacientes submetidos 84 ACS foram acompanhados clinicamente e radiologicamente num período entre 25 a 66 meses, média 43,8 meses, com um único caso de reestenose grave intra-stent (1,2%) e um único caso de novo evento isquêmico cerebral (1,3%). Conclusão: A ACS é um método durável na manutenção da perviedade do bulbo carotídeo e eficiente a longo prazo na redução de eventos isquêmicos cerebrais em pacientes com doença aterosclerótica do bulbo carotídeo. / Objective: to evaluate the long-term clinic and radiologic results for the patients submitted to angioplasty with stent implantation because estenotic atherosclerosis disease of the carotid bulb and to determine if ACS is effective to prevent the cerebral ischemic attack and durable to keep the carotid bulb opened. Methods: We follow-up clinically and radiologically, by ultrasound with color and spectral Doppler (USD) and with digital subtraction angiography (DSA), patients with atherosclerotic disease of the carotid bulb submitted to ACS realized between January of 2002 and may of 2005 in the INRAD-HCFMUS and Hospital Santa Marcelina de Itaquera. Results: 80 patients who underwent 84 ACS were evaluated clinically and radiologically in the long-term follow-up, 25 to 66 months, with media of the 43,8 months, with only one case of restenosis (1,2%) and only one case of new ischemic event (1,3%). Conclusion: The ACS é a effective method to keep the carotid bulb opened and it is efficient to prevent new ischemic event in patients with atherosclerotic disease of the carotid bulb.