La chirurgie informatisée est une science nouvelle dont le but est de croiser la chirurgie avec les sciences de l’informatique afin d’aboutir à des améliorations significatives dans les deux domaines. Avec l’évolution des nouvelles techniques chirurgicales, une collaboration étroite entre chirurgiens et chercheurs est devenue à la fois inévitable et essentielle à l’optimisation des soins chirurgicaux. L’utilisation de modèles mathématiques est la pierre angulaire de ce nouveau domaine. Cette thèse démontre comment une approche systématique d’un problème clinique nous a amenés à répondre à des questions ouvertes dans le domaine chirurgical en utilisant des modèles mathématiques à grande échelle. De manière générale, notre approche inclut (i) une vision générale du problème, (ii) le ciblage du/des système(s) physiologique(s) à étudier pour y répondre, et (iii) un effort de modélisation mathématique, qui a toujours été poussé par la recherche d’un compromis entre complexité du système étudié et réalité physiologique. Nous avons consacré la première partie de cette thèse à l’optimisation des conditions limites à appliquer à un bio-réacteur utilisé pour démultiplier le tissu pulmonaire provenant d’un donneur. Un modèle géométrique de l’arbre trachéo-bronchique couplé à un modèle de dépôt de soluté nous a permis de déterminer l’ensemble des pressions à appliquer aux pompes servant le bio-réacteur afin d’obtenir une distribution optimale des nutriments à travers les cultures de tissus. Nous avons consacré la seconde partie de cette thèse au problème de resténose des greffes de veines utilisées pour contourner une occlusion artérielle. Nous avons reproduit l’apparition de resténose grâce à plusieurs modèles mathématiques qui permettent d’étudier les preuves cliniques et de tester des hypothèses cliniques avec un niveau croissant de complexité et de précision. Pour finir, nous avons développé un cadre de travail robuste pour tester les effets des thérapies géniques afin de limiter la resténose. Une découverte intéressante a été de constater qu’en contrôlant un groupe de gènes spécifique, la perméabilité à la lumière double après un mois de suivi. Grace aux résultats obtenus, nous avons démontré que la modélisation mathématique peut servir de puissant outil pour l’innovation chirurgicale. / Computational surgery is a new science that aims to intersect surgery and computational sciences in order to bring significant improvements in both fields. With the evolution of new surgical techniques, a close collaboration between surgeons and computational scientists became unavoidable and also essential to optimize surgical care. A large usage of mathematical models is the cornerstone in this new field. The present thesis shows how a systematic approach to a clinical problem brought us to answer open questions in the field of surgery by using mathematical models on a large scale. In general, our approach includes (i) an overview of the problem, (ii) the individuation of which physiological system/s is/are to be studied to address the question, and (iii) a mathematical modeling effort, which has been always driven by the pursue of a compromise between system complexity and closeness to the physiological reality. In the first part, we focused on the optimization of the boundary conditions to be applied to a bioreactor used to re-populate lung tissue from donor. A geometrical model of tracheobronchial tree combined with a solute deposition model allowed us to retrieve the set of pressures to be applied to the pumps serving the bioreactor in order to reach an optimal distribution of nourishment across the lung scaffold. In the second part, we focused on the issue of post-surgical restenosis of vein grafts used to bypass arterial occlusions. We replicated the event of restenosis with several mathematical models that allow us to study the clinical evidences and to test hypothesis with an escalating level of complexity and accuracy. Finally, we developed a solid framework to test the effect of gene therapies aimed to limit the restenosis. Interestingly, we found that by controlling a specific group of genes, the lumen patency is double after a month of follow-up. With the results achieved, we proved how mathematical modeling can be used as a powerful tool for surgical innovation.

INTRODUÇÃO: O sucesso a longo prazo da intervenção coronária percutânea, inicialmente realizada apenas com balão, era limitado pelo recolhimento elástico da artéria e pela hiperplasia neointimal. Com o advento dos stents convencionais (BMS) houve melhora nesse cenário e diminuição da reestenose, que é resultante de uma complexa cadeia de eventos iniciada após a injúria causada na parede vascular pela insuflação de balões e da aposição das hastes do stent. A proliferação excessiva de células musculares lisas (VSMC) tem papel fundamental na formação da neoíntima no contexto da reestenose intra-stent com a consequente redução da luz arterial. Com o advento dos stents farmacológicos (DES) houve diminuição importante da hiperplasia neointimal e um dos fármacos que se mostrou efetivo nesse papel é o sirolimo, que atua se ligando à proteína de ligação 12 e o heterodímero resultante se liga à mTOR impedindo sua ativação e causando parada do ciclo celular entre as fases G1 e S, desse modo inibindo a proliferação e migração de VSMC e das células endoteliais (HUVEC). Portanto a intervenção coronária acaba interferindo diretamente no endotélio, interferindo na produção das HUVEC não apenas no aspecto quantitativo, mas também na função das mesmas, e a qualidade funcional do endotélio é tão fundamental quanto à sua presença. Após o implante dos DES, principalmente os de primeira geração, ocorre disfunção endotelial cujo principal marcador é a perda da capacidade do relaxamento do vaso. Há correlação também entre cobertura das hastes incompleta e ocorrência de trombose dos stents. Consequentemente há espaço para o aprimoramento dos DES, para que se tornem dispositivos com eficácia já alcançada na prevenção da reestenose porém com um perfil de segurança maior. O presente trabalho tem como objetivo avaliar as alterações causadas pelos DES nas HUVEC e nas VSMC em cocultura na presença e na ausência do soro rico em plaquetas. MATERIAIS E MÉTODOS: Utilizamos células HUVEC e VSMC em modelos de monocultura e cocultura, na presença e na ausência de soro rico em plaquetas, tratadas com BMS ou DES. Realizamos a determinação da IC50 do inibidor da mTOR, avaliação da citotoxicidade pelo método colorimétrico do MTT, determinação da formação de peróxidos lipídicos, avaliação das fases do ciclo celular e da expressão de marcadores de controle de proliferação e inflamação. RESULTADOS: Na avaliação da citotoxicidade pelo método colorimétrico do MTT e determinação da IC50 as VSMC foram menos sensíveis ao sirolimo que as HUVEC (IC50 em 24/48 horas 14,85/10,47uM e 9,48/22,24 uM, respectivamente para HUVEC e VSMC). As plaquetas e fatores solúveis potencializam o estresse oxidativo gerado pela presença dos stents possivelmente por ampliar o ambiente inflamatório. Houve parada do ciclo celular na fase G0/G1 causada pelos DES somente com adição das plaquetas ao meio de cultura. Nos modelos de cultura celular sem as plaquetas a parada do ciclo celular foi em G2/M. Não houveaumento das células na fase DNA fragmentado (sub-G0) evidenciando que não houve indução de morte celular. CONCLUSÃO: As VSMC foram menos sensíveis ao sirolimo que as HUVEC. Nos modelos de cocultura com adição das plaquetas os DES eluídores de sirolimo causaram parada do ciclo celular na fase G0/G1 sem indução de morte celular, sugerindo que o sirolimo exerce seus efeitos anti-inflamatórios nessas populações celulares e consequentemente reduz a hiperplasia neointimal por um mecanismo citostático / INTRODUCTION: The long-term success of percutaneous coronary intervention, initially performed only with a balloon, was limited by the elastic recoil of the artery and by neointimal hyperplasia. There was improvement in this scenario with the advent of bare metal stents (BMS), because they decrease in restenosis, that resulting from a complex network of events initiated after the injury caused in the vascular wall by insufflation of balloons and apposition of the stent struts. Excessive proliferation of smooth muscle cells (VSMC) plays a key role in neointimal hyperplasia in the context of intrastent restenosis with consequent reduction of arterial lumen. With the advent of drug-eluting stents (DES) there was a significant decrease in neointimal hyperplasia and one of the drugs that proved effective in this role is sirolimus, which acts by binding to the binding protein 12 and the resulting heterodimer binds to mTOR preventing its activation and causing cell cycle arrest between G1 and S phases and thereby inhibiting the proliferation and migration of VSMC and also inhibiting endothelial cells (HUVEC). Therefore, coronary intervention interferes directly in the endothelium, interfering in the production of endothelial cells, not only in the quantitative aspect, but also in their function, and the functional quality of the endothelium is as fundamental as its presence. After the implantation of DES, especially those of the first generation, endothelial dysfunction occurs, whose main marker is the loss of the capacity of the vessel relaxation. There is also correlation between incomplete stem coverage and stent thrombosis. Consequently, it is possible to improve of the DES, so that they become devices with already achieved effectiveness in the prevention of restenosis but with a greater safety profile. The present study aims to evaluate the changes caused by DES in human HUVEC and VSMC in co-culture in the presence and absence of platelet-rich serum. MATERIALS AND METHODS: We used HUVEC and VSMC in monoculture and co-culture models in the presence and absence of platelet rich serum treated with BMS or DES. We performed the determination of IC50 for mTOR inhibitor, cytotoxicity evaluation by the colorimetric method of MTT, determination of lipid peroxide formation, cell cycle and expression of necrosis and inflammation markers. RESULTS: In the assessment of cytotoxicity by the MTT colorimetric method and determination of the IC50, VSMC were less sensitive to sirolimus than HUVEC (IC50 in 24/48 hours 14.85 uM/10.47uM and 9.48 uM/ 22.24 uM, respectively for HUVEC and VSMC). Platelets potentiate the oxidative stress generated by the presence of stents, possibly by increasing the inflammatory environment. Drug-eluting stents arrested VSMC and HUVEC in the G0/G1 phase of the cell cycle only with the addition of platelets to the culture medium. In cell culture models without platelets the cell cycle arrest was in G2/M. There was no increase of the cells in the fragmented DNA phase (sub-G0) evidencing that there was no induction of apoptosis. CONCLUSION: Human aorta smooth muscle cells of the were less sensitive to sirolimus than HUVEC. In coculture models with platelet addition, DES with sirolimus caused cell cycle arrest in the G0/G1 phase without induction of apoptosis, suggesting that sirolimus exerts its antiinflammatory effects in these cellular populations and consequently reduces neointimal hyperplasia via a cytostatic mechanism

Introdução: A angioplastia primária associada ao implante de stent é o tratamento de escolha no infarto agudo do miocárdio. Discute-se o valor de provas funcionais na abordagem de reestenose coronária, bem como o tempo ideal para sua realização. O objetivo deste estudo foi avaliar a importância do teste ergométrico, da cintilografia de perfusão miocárdica e do ecocardiograma bidimensional em repouso, no diagnóstico de reestenose em pacientes tratados durante as primeiras 12 horas de evolução do infarto com supra desnivelamento do segmento ST. Métodos: No período de agosto de 2003 a janeiro de 2006 foram selecionados 64 pacientes tratados com angioplastia primária e implante de stent nas primeiras 12 horas de evolução do primeiro infarto. Os pacientes realizaram ecocardiograma bidimensional em repouso, teste ergométrico com adição de derivações precordiais direitas e cintilografia de perfusão miocárdica com captação tomográfica (SPECT) sincronizada ao ECG (GATED SPECT), seis semanas (etapa1), seis meses (etapa 2) e um ano (etapa3) após a angioplastia primária. Foi realizado reestudo angiográfico no sexto mês de evolução. Resultados: A idade média foi 56,2 ±10,2 anos; 53 pacientes eram do sexo masculino. Doença uniarterial > = 50% foi observada em 46,9% dos casos. A artéria descendente anterior foi tratada em 48,4% dos pacientes, artéria coronária direita em 34,4%, artéria circunflexa em 10,9%, tronco de coronária esquerda em 3,1%,grande ramo diagonal em 1,6% e ponte safena em 1,6%. Reestenose angiográfica ocorreu em 28.8% dos 59 casos submetidos a reestudo. A fração de ejeção do ventrículo esquerdo ao ecocardiograma foi em média: 0,55 (etapa 1), 0,55 (etapa 2) e 0,56 (etapa 3). Observou-se diferença entre a fração de ejeção dos pacientes com e sem reestenose um ano após o procedimento (p=0,003). Sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e acurácia do teste ergométrico foram respectivamente: 53,3%, 69% , 38,1%, 80,6% e 64,9% na etapa 1 (p=0,123); 54,5%, 70,7%, 33,3%, 85,3% e 67,3% na etapa 2(p=0,159) e 38,5%, 66,7%, 27,8% ,76,5% e 59,6% na etapa 3 (p=0,747). A adição de derivações precordiais direitas não elevou os índices de sensibilidade em nenhuma das etapas. Os valores de sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e acurácía obtidos após a cintilografia de perfusão miocárdica com MIBI, quando considerada a diferença de escores entre esforço e repouso >2, foram respectivamente 40%,78,6%, 40%, 78,6% e 68,4% na etapa1(p=0,185); 54,5%,87,8%,54,5%,87,8% e 80,8% na etapa 2 (p=0,006) e 25%,91,7%,50%,78,6% e 75% na etapa 3(p=0,156). Quando considerada a diferença de escores >4 os valores foram respectivamente: 13,3%,88,1%,28,6% ,74% e 68,4% na etapa 1(p>0,999); 36,4%,95,1%,66,7%,84,8% e 82,7% na etapa 2 (p=0,014) e 8,3%,94,4 %,33,3%,75,6% e 72,9 % na etapa 3 (p >0,999). Conclusões: O teste ergométrico não permitiu discriminar reestenose na população estudada, em nenhuma das etapas durante a evolução. A cintilografia miocárdica realizada seis meses após o infarto apresentou associação com reestenose. Os pacientes com reestenose apresentaram menores valores de fração de ejeção do ventrículo esquerdo um ano após a angioplastia primária, por avaliação ecocardiográfica. / Primary coronary angioplasty and stenting during acute myocardial infarction is the first treatment choice. Non-invasive testings have been used in the diagnosis of restenosis but its efficacy and time to be performed have to be determined. The purpose of this study was to evaluate exercise treadmill test, myocardial perfusion imaging and rest two-dimensional echocardiogram in the diagnosis of restenosis in patients treated during the first 12 hours of STelevation myocardial infarction.Methods: From August 2003 to January 2006, 64 patients were selected after primary coronary angioplasty and stenting. Rest two- dimensional echocardiogram, exercise treadmill test associated to right precordial leads and myocardial perfusion imaging according to GATED-SPECT were performed 6 weeks (step 1), 6 months (step 2) and one year (step 3) after the procedure.Coronary angiography was performed during the sixth month of follow-up.Results : Mean age was 56.2 ± 10.2 years; 53 patients were male. Single vessel disease > = 50% was observed in 46.9% of patients. The left anterior descending coronary artery was treated in 48.4%, the right coronary artery in 34.4%, the left circumflex in 10.9%, the left main coronary artery in 3.1%, a large diagonal branch in 1.6% and saphenous vein graft in 1.6% of the cases. Angiographic restenosis occurred in 28.8% from 59 patients submitted to coronary angiography. Mean left ventricular ejection fraction observed during rest two-dimensional echocardiogram was: 0.55 (step 1), 0.55 (step 2) and 0.56 (step 3). It was observed in patients with and without restenosis a significant difference in the left ventricular ejection fraction one year after the procedure (p= 0.003). Exercise treadmill test sensitivity, specificity, positive and negative predictive values and accuracy were respectively: 53.3%, 69%, 38.1%, 80.6% and 64.9% in step 1(p=0.123); 54.5%, 70.7%, 33.3%, 85.3% and 67.3% in step 2 (p=0.159) and 38.5%, 66.7%, 27.8%, 76.5% and 59.6% in step 3 (p=0.747). Right precordial leads did not show any additional significance. Sensitivity, specificity, positive and negative predictive values and accuracy during myocardial perfusion imaging when considering summed difference score > 2 were respectively: 40%, 78.6%, 40%, 78.6% and 68.4% in step 1(p=0.185); 54.5%, 87.8%, 54.5%,87.8% and 80.8% in step 2(p=0.006) and 25%, 91.7%, 50%, 78.6% and 75% in step 3(p=0.156). When considering summed difference score > 4 they were respectively: 13.3%, 88.1%, 28.6%, 74% and 68.4% in step 1(p> 0.999); 36.4%, 95.1%,66.7%, 84.8% and 82.7% in step 2 (p=0.014) and 8.3%, 94.4%, 33.3%, 75.6% and 72.9% in step 3(p> 0.999). Conclusions: Exercise treadmill test did not allow to discriminate restenosis in this population in all steps.Myocardial perfusion imaging performed 6 months after acute myocardial infarction was associated to restenosis. Patients with restenosis showed lower left ventricular ejection fraction one year after acute myocardial infarction by rest two-dimensional echocardiogram.

La prise en charge en urgence des pathologies ischémiques repose dans un premier temps sur la thrombolyse et/ou l’angioplastie puis dans un second temps sur des mesures hygiéno-diététiques. L’angioplastie consiste en la destruction de l’obstacle situé dans l’artère et elle est souvent suivie (dans 70 % des cas) par la pose d’une endoprothèse ou stent afin que le vaisseau lésé retrouve son diamètre. Malgré des innovations thérapeutiques (stents libérant des principes actifs), des problèmes de thrombose et de resténose au niveau du site lésé sont observés. Or, le monoxyde d’azote, NO, un gazotransmetteur de l’organisme, possède des propriétés intéressantes (antiagrégant plaquettaire, effet de recrutement des cellules endothéliales, effet antiprolifératif sur les cellules musculaires lisses) pour lutter contre ce phénomène, à concentration physiologique. Dans ce travail, nous avons développé une formulation innovante pouvant recouvrir un stent et étant capable de délivrer du NO. Il s’agira d’incorporer des nanoparticules d’or caractérisées par une capacité de greffage par un donneur de NO (AuNP@RSNO) très importante au sein des couches d’un film constitué de polyélectrolytes (polycations et polyanions interagissant de façon électrostatique). Ici, les AuNP sont considérées comme une matière première pharmaceutique. Une méthode de dosage et un contrôle qualité de ces dernières ont donc été développés. Les films créés présentent une stabilité importante (> 1 an) et sont capables d’immobiliser un grand nombre d’AuNP (1012 AuNP/cm²/cycle). Pour augmenter le taux de chargement des AuNP au sein des films, l’optimisation de leur construction a été réalisée. Plusieurs polycations ont été testés (chlorhydrate de poly(allylamine), poly(éthylène glycol) et poly(méthacrylate d’ester)) ainsi que deux milieux de dissolution différents (tampon phosphate et tampon Tris, à pH et concentrations identiques). Le meilleur rapport stabilité/taux de chargement a été atteint avec l’utilisation du chlorhydrate de poly(allylamine) et le tampon Tris. Enfin, les films ont présenté une inertie face à des protéines, des cellules et du sang total. Le système développé représente donc une forme adaptée pour être déposé à la surface de stents / Emergency management of ischemic pathologies is initially based on thrombolysis and / or angioplasty and secondly on hygiene-dietetic measures. Angioplasty consists of the destruction of the obstacle located in the artery and is often followed (in 70% of cases) by placing a stent so that the damaged vessel regains its diameter. Despite therapeutic innovations (drug eluting stents), problems of thrombosis and restenosis in the injured site are often observed. However, nitric oxide, NO, has interesting properties (platelet antiaggregant, endothelial cell recruitment effect, antiproliferative effect on smooth muscle cells) against this phenomenon at physiological concentration. In this work, we developed an innovative formulation that can deposited on a stent and that will be able to deliver NO. AuNP grafted with a high density of NO donors (AuNP@RSNO) will be incorporated in layer-by-layer films composed of polyelectrolytes (electrostatic interactions between polycations and polyanions) Here AuNPs are considered as a pharmaceutical raw material. A quantification method and a quality control of them were therefore developed. Created films created showed an important stability (> 1 year) and were able to immobilize a large number of AuNP (1012 AuNP/cm²/cycle). In order to increase the loading rate of AuNP films, optimization of their construction was carried out. Several polycations were tested (poly (allylamine hydrochloride), poly (ethylene glycol) and poly (methacrylate ester)) as well as two different dissolution media (phosphate buffer and Tris buffer, same pH and concentrations). The best stability/loading ratio was achieved with the use of poly (allylamine) hydrochloride and Tris buffer. Finally, the films showed inertness when they were exposed to proteins, cells and whole blood. The developed system is therefore well suited to be deposited on the surface of stents

Duas técnicas invasivas para o tratamento da doença aterosclerótica coronariana oclusiva firmaram-se ao longo dos anos: revascularização cirúrgica do miocárdio e angioplastia transcutânea com stents metálicos. O estudo visa comparar as alterações histopatológicas causadas por stents metálicos coronarianos fabricados com a superliga de composição química em porcentagem em peso cromo 20%, tungstênio 15%, níquel 10% e cobalto restante, designada ASTM F.90, revestidos, ou não, com carbeto de silício pelo processo de asperção térmica originando uma superfície hidrofílica. Stents com espessura das hastes entre 80 a 90 nm, área das células entre 1,4 a 2,1 mm² e relação metal-artéria de 13 a 19%, em pacientes reestenosantes que sofreram posteriormente revascularização cirúrgica do miocárdio, com aqueles não submetidos à angioplastia prévia. Foram determinados dois grupos: grupo I ou grupo controle, pacientes que sofreram revascularização cirúrgica do miocárdio sem angioplastia prévia de qualquer natureza; grupo II pacientes submetidos à revascularização cirúrgica do miocárdio, após reestenose intra-stent coronariana. Pacientes de ambos os grupos foram avaliados rotineiramente quanto à indicação e risco cirúrgico e durante o procedimento convencional da revascularização cirúrgica do miocárdio utilizando circulação extracorpórea, antes de realizar a anastomose do enxerto vascular na coronária, amostras contendo pequenos fragmentos de endotélio foram retiradas juntamente com fragmentos dos stents, enviadas para análise histopatológica e produção de laminas coradas com H-E. Observou-se a presença de arterite crônica caracterizada por infiltrado mononuclear em conjunto com fenômeno de proliferação fibroblástica e de musculatura lisa naqueles pacientes que apresentavam reestenose intra-stent, sendo mais intenso no local do stent. A visualização das superfícies dos stents em escala nanometrica (MFA) é de suma importância para análise estrutural das próteses, avaliando irregularidades nas superfícies recobertas das hastes dos stents. A persistência de arterite crônica coronariana avaliada por infiltrado linfomononuclear e proliferação de fibrocolágeno foi constatada em pacientes reestenosantes. / Two invasive techniques for the treatment of occlusive coronary atherosclerosis disease were signed over the years: coronary artery bypass surgery and transcutaneous angioplasty with bare metal stent. The study attempts to compare the histopathological abnormality caused in patients with implantation of bare metal stent in coronary made with: Chromium 20%, Tungsten 15%, Nickel 10% and Cobalt remainder, ASTM F.90 alloy for surgical implant applications, and covered with a thin layer of amorphous silicon carbide, or not, and its total or partial obstruction, after undergoing coronary artery bypass grafting, with those who had coronary artery bypass surgery with no previous angioplasty. Two groups were studied: group I, or control group, patients who underwent coronary artery bypass grafting without previous angioplasty of any kind; group II of patients undergoing coronary artery bypass surgery after coronary-stent restenosis. Patients in both groups were evaluated for the indication and surgical risk; was done routinely during the procedure of conventional coronary artery bypass grafting with cardiopulmonary bypass. Before performing the anastomosis in coronary vascular graft, a small fragment of the endothelium was removed along whit a fragment of the stent, and sent for analysis with hematoxilin-eosin. The presence of chronic inflammatory coronary reaction was detected, mediated by mononuclear cells with phenomenon of fibroblast and smooth muscle proliferation in patients presenting in-stent restenosis. It w coronary reaction as also observed that the inflammatory and proliferative process is more intense at the site of stent implantation. The analysis of surface of the stents used atomic force microscopy proved to be an important method for the surface analysis for stents, and showed on nanometric scale an irregular coverage of silicon carbide. In conclusion, in the patients with restenosis in-stent occurs persistence of chronic inflammation with mononuclear cells and process of fibroblast proliferation.

Fundamentos: O implante de stents coronários constitui-se na técnica mais prevalente de revascularização percutânea, em especial pela prevenção da reestenose, quando comparado às intervenções com o balão. No entanto, a reestenose intra-stent, que ocorre em cerca de 25% dos casos, restringe os seus benefícios clínicos e econômicos tardios. Demonstrou-se que a hiperplasia neo-intimal decorrente da reação da parede vascular causada pelo implante do stent, é responsável pelas recidivas. Interroga-se se um protocolo de medicamentos contemplando doses máximas de manutenção de clopidogrel e atorvastatina poderia reduzir a hiperplasia neo-intimal e a reestenose. Objetivos: O objetivo primário foi aferir se esta associação de medicamentos reduziria o volume de hiperplasia neo-intimal (35% ou mais), expressa pela obstrução volumétrica da luz, mensurada pelo ultrassom intracoronário, 12 meses após a intervenção. Os objetivos secundários foram: os resultados da angiografia quantitativa e os eventos cardíacos adversos maiores (óbito, infarto e revascularização do vaso-alvo). Casuística e métodos: Foram incluídos casos eletivos e com lesões primárias nas artérias naturais. Os pacientes foram tratados com stents não farmacológicos e randomizados em dois grupos: A, com 50 pacientes medicados com doses máximas de clopidogrel e atorvastatina; e grupo B com 50 casos, medicados com 75mg de clopidogrel e doses de sinvastatina rotineiramente prescritas para obtenção das metas recomendadas para controle lipídico. Resultados: Ambos os grupos não apresentaram diferenças significantes em relação às características clínicas, angiográficas e técnicas, com exceção do diabetes, mais comum em A (36% vs 16%; p=0,02). Aos 12 meses de evolução, observaram-se eventos cardíacos maiores (12% versus 18%; p = 0,56) e revascularização do vaso-alvo (4% versus 2%; p>0,99) sem diferença significante. Nova angiografia coronária foi obtida em 98% dos casos dos dois grupos, observando-se taxa de reestenose de 8,1% e 8,2% nos grupos A e B (p>0,99). A perda tardia da luz arterial foi semelhante [0,9 mm (DP 0,5 mm) versus 1,1 mm (DP 0,7 mm); p = 0,22], o mesmo acontecendo com o diâmetro mínimo da luz [2,2 mm (DP 0,6 mm) versus 1,9 mm (DP 0,6 mm); p = 0,12]. Realizou-se ultrassom intracoronário em 98% dos pacientes de ambos os grupos, observando-se obstrução do volume da luz de 36,3% (DP 10,3%) no grupo A e de 40,1% (DP 10,9%) no grupo B (p = 0,14). Conclusões: Os resultados deste estudo demonstram que: 1) a terapêutica adjunta utilizando doses máximas de clopidogrel 150 mg/dia e atorvastatina 80 mg/dia não reduz o volume de hiperplasia neo-intimal, expressa pela obstrução volumétrica da luz; 2) as variáveis da angiografia quantitativa e os eventos cardíacos adversos maiores não mostraram diferenças significativas entre os dois grupos. / Coronary stent implantation is the current technique of choice in patients undergoing percutaneous intervention. They effectively reduce acute occlusion and restenosis even in complex lesions. However, instent restenosis occurs in up to 25% of the treated cases and there are several theories elaborating the possible relation between coronary artery thrombosis and inflammation to neointimal proliferation and the mechanism of obstruction recurrence. There are questions whether an optimized medical treatment based on maximum doses of Clopidogrel and Atorvastatin could limit neointimal hyperplasia and restenosis. Objectives: Primary endpoint was to assess the efficacy of this scheme in reducing neointimal hyperplasia volume (XX% or more), according to intravascular ultrasound measurements, 12 months after the index intervention. Secondary endpoints were quantitative angiography measurements and major adverse cardiac events (death, myocardial infarction and target vessel revascularization). Methods: We included patients with de novo lesions undergoing elective implantation of uncoated stents. Patients were divided according to the drug regimen into Group A - 50 patients receiving maximal atorvastatin and clopidogrel doses; and Group B - 50 cases treated with standard clopidogrel and simvastatin doses. Results: Groups were similar concerning clinical and angiographic characteristics, except for diabetes, more frequent in Group A (36% vs 16%, p = 0.02). At the end of 12 months major cardiac events (12% versus 18%, p = 0.56) and target vessel revascularization (4% versus 2%, p> 0.99) did not show differences between groups. Coronary angiography was obtained in 98% of the cases and the restenosis rate was 8.1% (A group) and 8,2% (B group) (p> 0.99). Late luminal loss was similar [0.9 mm (SD 0.5 mm) versus 1.1 mm (SD 0.7 mm), p = 0.22], as well as the minimum lumen diameter [2.2 mm (SD 0.6 mm) versus 1.9 mm (SD 0.6 mm), p = 0.12]. IVUS was done in 98% of patients in both groups, and the volume of neointimal hyperplasia was not significantly different in both groups [61.8 mm 3 (SD 35.4 mm3) mm3 versus 66.3 (SD 31.6 mm3), p = 0.58]. Luminal volume obstruction was 36.3% (SD 10.3%) in group A and 40.1% (SD 10.9%) in group B (p = 0.14). Conclusions: According to our results we may conclude that: 1) the therapeutic regimen using maximum doses of atorvastatin and clopidogrel did not reduce the volume of neointimal hyperplasia, 2) restenosis rate, quantitative angiography results and the rate of major adverse cardiac events were not affected by the treatment regimen.

Σκοπός: Η μελέτη είχε ως σκοπό την διερεύνηση της ασφάλειας και της αποτελεσματικότητας των sirolimus-eluting stent, σε σχέση με τα απλά μεταλλικά stent, στα πλαίσια αγγειοπλαστικής των κνημιαίων αγγείων, σε ασθενείς με χρόνια κρίσιμη ισχαιμία του κάτω άκρου. Πρόκειται για μια προοπτική ελεγχόμενη, κλινική μελέτη με διπλό σκέλος. Τα stent τοποθετήθηκαν σε περιπτώσεις μη ικανοποιητικής αγγειοπλαστικής (δηλ. σε περιπτώσεις ελαστικής επαναφοράς-υπολειμματικής στένωσης >30% και σε περιπτώσεις διαχωρισμού). Οι ασθενείς ελέγχθηκαν κλινικά και αγγειογραφικά στο εξάμηνο και στο 1 έτος. Ασθενείς και μέθοδοι: 29 ασθενείς, εκ των οποίων 8 γυναίκες και 21 άνδρες, με μέση ηλικία τα 68,7 έτη υποβλήθηκαν σε αγγειοπλαστική στα κνημιαία αγγεία, με απλά μεταλλικά stent, ομάδα Β. Σε αυτή την ομάδα τοποθετήθηκαν απλά stent σε 65 αλλοιώσεις, εκ των οποίων 38 στενώσεις και 27 αποφράξεις σε συνολικά 40 κνημιαία αγγεία. Άλλοι 29 ασθενείς, 8 γυναίκες και 21 άνδρες, με μέση ηλικία τα 68,8 έτη αντιμετωπίστηκαν με sirolimus-eluting stent, ομάδα S. Σε αυτή την ομάδα αντιμετωπίστηκαν 66 αλλοιώσεις εκ των οποίων 46 στενώσεις και 20 αποφράξεις, σε 41 συνολικά αγγεία. Οι ασθενείς επανελέγχθηκαν κλινικά και με ενδαρτηριακή αγγειογραφία στους 6 μήνες και στο 1 έτος, μετά την αρχική επέμβαση. Έγινε στατιστική ανάλυση των αποτελεσμάτων. Αποτελέσματα: Οι συνοδές νόσοι ήταν περισσότερες στην ομάδα S (όπως η συμπτωματική νόσος από την καρδιά και τις καρωτίδες, καθώς και η υπερλιπιδαιμία, p<0.05). Η τεχνική επιτυχία ήταν 96,6% (28/29 άκρα) στην ομάδα Β έναντι 100% (29/29 άκρα) στην ομάδα S (p=0.16) Στον επανέλεγχο εξαμήνου: Η βατότητα ήταν 68,1% στην ομάδα Β και 92,0% στην ομάδα S, (p<0.002). Τα μεγαλύτερα ποσοστά βατότητας των sirolimus-eluting stent, μετά από πολυπαραγοντική regression analysis είχαν OR 5.625, με 95% CI 1.711- 18.493, που ήταν στατιστικά σημαντικό (p=0.004). Η δυαδική επαναστένωση εντός του stent ήταν 55,3% ενώ η επαναστένωση στα άκρα του stent ήταν 66,0% στους ασθενείς με τα απλά μεταλλικά stent. Αντιθέτως τα ποσοστά στους ασθενείς με sirolimus-eluting stent ήταν 4,0% και 32,0% αντίστοιχα. Συγκεκριμένα η επαναστένωση εντός του stent είχε OR 0.067, με 95% CI 0.021-0.017, και η επαναστένωση στα άκρα του stent είχε OR 0.229 με 95% CI 0.099-0.533. Και τα δύο ήταν ήταν στατιστικά σημαντικά με p<0.001 και p=0.001, αντίστοιχα. Τα συνολικά ποσοστά επανεπέμβασης (TLR) στο εξάμηνο ήταν 17,0% στην ομάδα Β έναντι 4,0% στην ομάδα S, (OR 0.057, με 95% CI 0.008-0.426). Το αποτέλεσμα ήταν επίσης στατιστικά σημαντικό υπέρ των sirolimus stent. (p=0.02) Η διάσωση του άκρου ήταν 100% και στις δύο ομάδες. Η θνησιμότητα και ο ελάσσων ακρωτηριασμός στο εξάμηνο ήταν 6,9% και 17,2% στην ομάδα Β έναντι 10,3% και 3,4% στην ομάδα S (p=0.32 και p=0.04, αντίστοιχα). Στον επανέλεγχο έτους: Τα sirolimus-eluting stent σχετίζoνταν και πάλι με καλύτερη πρωτογενή βατότητα (OR 10.401, με 95% CI 3.425-31.589, p<0.001) και σημαντικά μειωμένη δυαδική επαναστένωση εντός του stent (OR 0.156, με 95% CI 0.060-0.407, p<0.001), καθώς και στα άκρα του stent. (OR 0.089, με 95% CI 0.023-0.349, p=0.001) Τα ποσοστά επανεπέμβασης στις βλάβες (TLR) ήταν πολύ μικρότερα στην ομάδα του sirolimus (OR 0.238, με 95% CI 0.067-0.841, p=0.026) . Δεν υπήρξαν στατιστικά σημαντικές διαφορές ανάμεσα στις δύο ομάδες Β και S όσον αφορά στα ποσοστά θνησιμότητας 10,3% έναντι 13,8%, στη διάσωση του άκρου 100% έναντι 96% και στους ελάσσονες ακρωτηριασμούς 17,2% έναντι 10,3% αντίστοιχα. Συμπεράσματα: Τα sirolimus-eluting stents περιορίζουν την ενδοθηλιακή υπερπλασία στα κνημιαία αγγεία. Η εφαρμογή τους έχει ως αποτέλεσμα την σημαντική μείωση των ποσοστών επαναστένωσης και μειώνει την ανάγκη για επανεπεμβάσεις. / Aim : The purpose of our study was to investigate the 6-month and 1-year angiographic and clinical outcome in the setting of a controlled clinical study. The study examined the safety and relative effectiveness of sirolimus-eluting stents opposed to conventional metal stents, in the infrapopliteal vessels, in patients with critical limb ischemia (CLI). The stents were used in a bail-out setting during infrapopliteal endovascular procedures, i. e. stenting was carried out in cases of suboptimal angioplasty results (recoil - residual stenosis >30%, or in cases of dissection, after angioplasty). Patients and Methods: Twenty-nine patients comprising 8 women and 21 men with a mean age of 68.7 years were submitted to infrapopliteal revascularization with conventional (bare) metal stents, called group B. In these patients 65 lesions were treated with bare stents, of whom 38 stenoses and 27 occlusions, in a total of 40 infrapopliteal vessels. Another 29 patients, again 8 women and 21 men, with a mean age of 68.8 years were treated with sirolimus-eluting stents, named group S. There were 66 lesions in this group with 46 of them stenoses and 20 occlusions, in a total of 41 arteries. Patients were followed-up with clinical examination and intrarterial angiography 6 months and 1 year after the procedure. Both results were subsequently analyzed statistically. 135 Results: Co morbidities like symptomatic cardiac and carotid disease, as well as hyperlipidemia were more prominent in group S (p<0.05). Technical success was 96.6% (28/29 limbs) in group B against 100.0% (29/29 limbs) in group S (p=0.16). During 6-month patient follow-up: Primary patency was 68.1% in group B opposed to 92.0% in group S (p<0.002). Sirolimus-eluting stents exhibited higher primary patency with OR 5.625 and 95% CI 1.711-18.493, which was statistically significant (p=0.004). Binary in-stent restenosis rate was 55.3% while in-segment restenosis was 66.0%, in patients who had received bare metal stents. In opposition the respective restenosis rates, in patients with sirolimus-eluting stents were 4.0% and 32.0%. Diminished in-stent (OR 0.067 with 95% CI 0.021-0.017) and insegment (OR 0.229 with 95% CI 0.099-0.533) binary restenosis were both statistically significant with p values being p<0.001 and p=0.001 respectively. Collective target lesion re-intervention (TLR) at 6 month follow-up was 17.0% in group B against 4.0% (OR 0.057 with 95% CI 0.008-0.426) in group S, which proved again statistically significant for sirolimus stents (p=0.02). Six-month limb salvage rate was 100% in both groups. Six-month mortality and minor amputation rates were respectively 6.9% and 17.2%, in group B versus 10.3% and 3.4%, in group S (p=0.32 and p=0.04, respectively). During 1-year patient follow-up: 136 SES were still related with better primary patency rate (OR 10.401 with 95% CI 3.425-31.589, p<0.001) and considerably lesser events of in-stent binary restenosis (OR 0.156, 95% CI 0.060-0.407, p<0.001) as well as insegment (OR 0.089, 95% CI 0.023-0.349, p=0.001) binary restenosis. Target lesion re-intervention (TLR), was much lower in the SES patients group during 1-year follow-up (OR 0.238 with 95% CI 0.067-0.841, p=0.026) . At 1 year follow-up there were no statistically significant differences among group B and group S regarding mortality (10.3% against 13.8%), limb salvage rates (100% vs. 96%) and minor amputation (17.2% vs. 10.3%). Conclusions: Sirolimus-eluting stents appear to limit intimal hyperplasia in the infrapopliteal vessels. The use of sirolimus-eluting stents decreases considerably restenosis rates in the infrapopliteal vessels and reduces the need for repeat interventions

The main complication of aortocoronary reconstruction with vein grafts is restenosis in the course of time. The aim was to assess the effect of a periadventitial polyester system releasing sirolimus on intimal hyperplasia of autologous grafts. The controlled-release system comprises a polyester mesh coated with a sirolimus-eluting copolymer of L lactic acid and ε-caprolactone system designed to be wrapped around an autologous venous graft during its implantation. In vitro sirolimus release and its effects on smooth muscle and endothelial cells were assessed. In vitro, the copolymer-coated polyester mesh released sirolimus over a period of 6 weeks. Mesh-eluted sirolimus inhibited the growth of smooth muscle and endothelial cells in seven-day in vitro experiments. After seven days of sirolimus release from the mesh, smooth muscle and endothelial cell counts decreased by 29% and 75%, respectively, with the cells maintaining high viability. We implanted v. jugularis ext. into a. carotis communis in rabbits. The vein graft was either intact, or was wrapped with a pure polyester mesh, or with a sirolimus-releasing mesh. Three and six weeks after surgery, the veins were subjected to standard histological staining and the thicknesses of the tunica intima, the media and the intima-media complex were...

Duas técnicas invasivas para o tratamento da doença aterosclerótica coronariana oclusiva firmaram-se ao longo dos anos: revascularização cirúrgica do miocárdio e angioplastia transcutânea com stents metálicos. O estudo visa comparar as alterações histopatológicas causadas por stents metálicos coronarianos fabricados com a superliga de composição química em porcentagem em peso cromo 20%, tungstênio 15%, níquel 10% e cobalto restante, designada ASTM F.90, revestidos, ou não, com carbeto de silício pelo processo de asperção térmica originando uma superfície hidrofílica. Stents com espessura das hastes entre 80 a 90 nm, área das células entre 1,4 a 2,1 mm² e relação metal-artéria de 13 a 19%, em pacientes reestenosantes que sofreram posteriormente revascularização cirúrgica do miocárdio, com aqueles não submetidos à angioplastia prévia. Foram determinados dois grupos: grupo I ou grupo controle, pacientes que sofreram revascularização cirúrgica do miocárdio sem angioplastia prévia de qualquer natureza; grupo II pacientes submetidos à revascularização cirúrgica do miocárdio, após reestenose intra-stent coronariana. Pacientes de ambos os grupos foram avaliados rotineiramente quanto à indicação e risco cirúrgico e durante o procedimento convencional da revascularização cirúrgica do miocárdio utilizando circulação extracorpórea, antes de realizar a anastomose do enxerto vascular na coronária, amostras contendo pequenos fragmentos de endotélio foram retiradas juntamente com fragmentos dos stents, enviadas para análise histopatológica e produção de laminas coradas com H-E. Observou-se a presença de arterite crônica caracterizada por infiltrado mononuclear em conjunto com fenômeno de proliferação fibroblástica e de musculatura lisa naqueles pacientes que apresentavam reestenose intra-stent, sendo mais intenso no local do stent. A visualização das superfícies dos stents em escala nanometrica (MFA) é de suma importância para análise estrutural das próteses, avaliando irregularidades nas superfícies recobertas das hastes dos stents. A persistência de arterite crônica coronariana avaliada por infiltrado linfomononuclear e proliferação de fibrocolágeno foi constatada em pacientes reestenosantes. / Two invasive techniques for the treatment of occlusive coronary atherosclerosis disease were signed over the years: coronary artery bypass surgery and transcutaneous angioplasty with bare metal stent. The study attempts to compare the histopathological abnormality caused in patients with implantation of bare metal stent in coronary made with: Chromium 20%, Tungsten 15%, Nickel 10% and Cobalt remainder, ASTM F.90 alloy for surgical implant applications, and covered with a thin layer of amorphous silicon carbide, or not, and its total or partial obstruction, after undergoing coronary artery bypass grafting, with those who had coronary artery bypass surgery with no previous angioplasty. Two groups were studied: group I, or control group, patients who underwent coronary artery bypass grafting without previous angioplasty of any kind; group II of patients undergoing coronary artery bypass surgery after coronary-stent restenosis. Patients in both groups were evaluated for the indication and surgical risk; was done routinely during the procedure of conventional coronary artery bypass grafting with cardiopulmonary bypass. Before performing the anastomosis in coronary vascular graft, a small fragment of the endothelium was removed along whit a fragment of the stent, and sent for analysis with hematoxilin-eosin. The presence of chronic inflammatory coronary reaction was detected, mediated by mononuclear cells with phenomenon of fibroblast and smooth muscle proliferation in patients presenting in-stent restenosis. It w coronary reaction as also observed that the inflammatory and proliferative process is more intense at the site of stent implantation. The analysis of surface of the stents used atomic force microscopy proved to be an important method for the surface analysis for stents, and showed on nanometric scale an irregular coverage of silicon carbide. In conclusion, in the patients with restenosis in-stent occurs persistence of chronic inflammation with mononuclear cells and process of fibroblast proliferation.

Fundamentos: O implante de stents coronários constitui-se na técnica mais prevalente de revascularização percutânea, em especial pela prevenção da reestenose, quando comparado às intervenções com o balão. No entanto, a reestenose intra-stent, que ocorre em cerca de 25% dos casos, restringe os seus benefícios clínicos e econômicos tardios. Demonstrou-se que a hiperplasia neo-intimal decorrente da reação da parede vascular causada pelo implante do stent, é responsável pelas recidivas. Interroga-se se um protocolo de medicamentos contemplando doses máximas de manutenção de clopidogrel e atorvastatina poderia reduzir a hiperplasia neo-intimal e a reestenose. Objetivos: O objetivo primário foi aferir se esta associação de medicamentos reduziria o volume de hiperplasia neo-intimal (35% ou mais), expressa pela obstrução volumétrica da luz, mensurada pelo ultrassom intracoronário, 12 meses após a intervenção. Os objetivos secundários foram: os resultados da angiografia quantitativa e os eventos cardíacos adversos maiores (óbito, infarto e revascularização do vaso-alvo). Casuística e métodos: Foram incluídos casos eletivos e com lesões primárias nas artérias naturais. Os pacientes foram tratados com stents não farmacológicos e randomizados em dois grupos: A, com 50 pacientes medicados com doses máximas de clopidogrel e atorvastatina; e grupo B com 50 casos, medicados com 75mg de clopidogrel e doses de sinvastatina rotineiramente prescritas para obtenção das metas recomendadas para controle lipídico. Resultados: Ambos os grupos não apresentaram diferenças significantes em relação às características clínicas, angiográficas e técnicas, com exceção do diabetes, mais comum em A (36% vs 16%; p=0,02). Aos 12 meses de evolução, observaram-se eventos cardíacos maiores (12% versus 18%; p = 0,56) e revascularização do vaso-alvo (4% versus 2%; p>0,99) sem diferença significante. Nova angiografia coronária foi obtida em 98% dos casos dos dois grupos, observando-se taxa de reestenose de 8,1% e 8,2% nos grupos A e B (p>0,99). A perda tardia da luz arterial foi semelhante [0,9 mm (DP 0,5 mm) versus 1,1 mm (DP 0,7 mm); p = 0,22], o mesmo acontecendo com o diâmetro mínimo da luz [2,2 mm (DP 0,6 mm) versus 1,9 mm (DP 0,6 mm); p = 0,12]. Realizou-se ultrassom intracoronário em 98% dos pacientes de ambos os grupos, observando-se obstrução do volume da luz de 36,3% (DP 10,3%) no grupo A e de 40,1% (DP 10,9%) no grupo B (p = 0,14). Conclusões: Os resultados deste estudo demonstram que: 1) a terapêutica adjunta utilizando doses máximas de clopidogrel 150 mg/dia e atorvastatina 80 mg/dia não reduz o volume de hiperplasia neo-intimal, expressa pela obstrução volumétrica da luz; 2) as variáveis da angiografia quantitativa e os eventos cardíacos adversos maiores não mostraram diferenças significativas entre os dois grupos. / Coronary stent implantation is the current technique of choice in patients undergoing percutaneous intervention. They effectively reduce acute occlusion and restenosis even in complex lesions. However, instent restenosis occurs in up to 25% of the treated cases and there are several theories elaborating the possible relation between coronary artery thrombosis and inflammation to neointimal proliferation and the mechanism of obstruction recurrence. There are questions whether an optimized medical treatment based on maximum doses of Clopidogrel and Atorvastatin could limit neointimal hyperplasia and restenosis. Objectives: Primary endpoint was to assess the efficacy of this scheme in reducing neointimal hyperplasia volume (XX% or more), according to intravascular ultrasound measurements, 12 months after the index intervention. Secondary endpoints were quantitative angiography measurements and major adverse cardiac events (death, myocardial infarction and target vessel revascularization). Methods: We included patients with de novo lesions undergoing elective implantation of uncoated stents. Patients were divided according to the drug regimen into Group A - 50 patients receiving maximal atorvastatin and clopidogrel doses; and Group B - 50 cases treated with standard clopidogrel and simvastatin doses. Results: Groups were similar concerning clinical and angiographic characteristics, except for diabetes, more frequent in Group A (36% vs 16%, p = 0.02). At the end of 12 months major cardiac events (12% versus 18%, p = 0.56) and target vessel revascularization (4% versus 2%, p> 0.99) did not show differences between groups. Coronary angiography was obtained in 98% of the cases and the restenosis rate was 8.1% (A group) and 8,2% (B group) (p> 0.99). Late luminal loss was similar [0.9 mm (SD 0.5 mm) versus 1.1 mm (SD 0.7 mm), p = 0.22], as well as the minimum lumen diameter [2.2 mm (SD 0.6 mm) versus 1.9 mm (SD 0.6 mm), p = 0.12]. IVUS was done in 98% of patients in both groups, and the volume of neointimal hyperplasia was not significantly different in both groups [61.8 mm 3 (SD 35.4 mm3) mm3 versus 66.3 (SD 31.6 mm3), p = 0.58]. Luminal volume obstruction was 36.3% (SD 10.3%) in group A and 40.1% (SD 10.9%) in group B (p = 0.14). Conclusions: According to our results we may conclude that: 1) the therapeutic regimen using maximum doses of atorvastatin and clopidogrel did not reduce the volume of neointimal hyperplasia, 2) restenosis rate, quantitative angiography results and the rate of major adverse cardiac events were not affected by the treatment regimen.