Exercise training promotes a beneficial endothelial cell (EC) phenotype and results in conduit vessel adaptation. The specific underlying mechanisms have been proposed (shear stress, circumferential stress, hypoxia, metabolic) but are yet to be fully elucidated. This thesis investigated the predominant stimuli responsible for conduit vessel adaptation with training. Further, it developed a method of in situ EC extraction to allow for determination of the cellular and molecular mechanisms underpinning these adaptations. The methodology utilised two-dimensional (2D) Doppler ultrasound, strain gauge plethysmography, immunocytochemistry and RT-qPCR to provide insight in to vascular characteristics, predominantly of the brachial artery and peripheral EC. Long-term repeated isometric forearm muscle contractions as performed by well-trained rock climbers promoted greater resting, peak (in response to 5 min ischaemia) and maximal (in response to ischaemic exercise) brachial artery diameters compared with controls. This structural response is dependent upon confounders associated with exercise additional to shear stress as evidenced by the lack of brachial artery remodelling in response to 8 weeks of ischaemic preconditioning (IPC). A transient increase in flow-mediated dilation (FMD)% was observed following 6 weeks exposure to IPC, which became significant when controlled for baseline artery diameter, despite an absence of augmentation following long-term (≥ 8 weeks) exposure to a shear stimulus. This is in line with the suggested timeline of conduit vessel adaptation to exercise training of a transient increase in function at 2-4 weeks. Underpinning molecular mechanisms responsible were not determined but may be further investigated given that the endovascular biopsy technique was developed and improved in this thesis. The endovascular biopsy successfully yields approximately 2100 ± 1700 EC per sample, providing sufficient material for determination of expression of both mRNA (RT-qPCR) and protein (immunocytochemistry). Specifically, type 2 diabetics (T2DM) with symptomatic cardiac abnormalities exhibited augmented eNOS mRNA and protein in brachial artery EC as compared with non-diabetic controls with symptomatic cardiac abnormalities. In conclusion, this thesis demonstrates that although shear stress promotes a transient trend for enhancement in function of the peripheral conduit arteries, additional factors are required for long-term structural adaptations. Further, the endovascular biopsy technique offers a novel method of extracting and analysing EC for genes and proteins of interest to vascular health. The use of this technique to decipher the underlying cellular and molecular mechanisms involved in vascular adaptations with exercise requires further investigation.

Introdução: A radiologia intervencionista utiliza técnicas endovasculares minimamente invasivas para se estancar hemorragias, em cenários clínicos relacionados ao trauma. O objetivo destas técnicas é conter o sangramento de forma rápida e eficaz, sem o estresse fisiológico determinado pela cirurgia aberta. Neste contexto, esta modalidade terapêutica foi descrita pela primeira vez em 1977(1), no tratamento de trauma abdominal fechado com sangramento por lesão hepática. Desde então as técnicas endovasculares e os materiais utilizados evoluíram, atingindo reconhecimento como método adjuvante no tratamento não cirúrgico de lesões pós traumáticas hemorrágicas. A angiografia por subtração digital permite a identificação e a pronta avaliação dos sítios de hemorragia, sendo por muitas vezes mais sensível que outros métodos de imagem, além deste fato, podendo oferecer o recurso terapêutico no mesmo ato do exame diagnóstico(2). Objetivo: Nosso estudo visa avaliação da eficácia e segurança relacionadas ao manejo transarterial - não cirúrgico - dos pacientes vítima de trauma, com análise dos resultados técnicos e clínicos do tratamento endovascular destes pacientes com diferentes agentes embolizantes. Materiais e métodos: Estudo de coorte retrospectiva que incluiu pacientes vítimas de traumatismo abdominopélvico fechado ou perfurante, com sangramento ativo, evidenciado por método de imagem, submetidos a embolização transarterial percutânea, na Unidade de Emergência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, entre janeiro de 2009 e janeiro de 2018. Todos os pacientes incluídos no estudo foram avaliados em conjunto pelas equipes de cirurgia e de radiologista intervencionista de plantão, que analisaram a indicação de angiografia arterial para pesquisa de sangramento e embolização transarterial baseada em protocolo pré-estabelecido na rotina do atendimento do paciente politraumatizado admitidos na Instituição. Resultados: Os achados encontrados foram consistentes com a literatura atual demonstrando altas taxas de sucesso técnico e clínica associado a baixas taxas de complicações inerentes ao procedimento transarterial percutâneo. Conclusão: O presente estudo demonstrou a segurança do procedimento com elevada taxa de sucesso clínico e angiográfico, associado com baixos índices de complicações relacionadas ao procedimento. / Introduction: Interventional radiology uses minimally invasive endovascular techniques to staunch hemorrhages in trauma-related clinical settings. The purpose of these techniques is to contain bleeding quickly and effectively, without the physiological stress determined by open surgery. In this context, this therapeutic modality was first described in 1977 (1), in the treatment of closed abdominal trauma with bleeding due to hepatic injury. Since then the endovascular techniques and the materials used have evolved, reaching recognition as an adjuvant method in the nonsurgical treatment of bleeding post traumatic lesions. Digital subtraction angiography allows the identification and prompt evaluation of hemorrhage sites, being often more sensitive than other imaging methods, besides being able to offer the therapeutic resource at the same time as the diagnostic examination (2).Objective: Our aim is to evaluate the efficacy and safety of the non-surgical transarterial management of the victims of trauma and to verify the repercussion in the technical and clinical results of the endovascular treatment of these patients with different embolizing agents. Materials and methods: A retrospective cohort study that included patients with traumatic or blunt trauma, with active bleeding, evidenced by imaging method, submitted to endovascular embolization, at the Hospital das Clínicas Emergency Unit - FMRP-USP, from January 2009. All the patients included in the study were evaluated jointly by the interventional and interventional radiology team on call at the institution, together the teams analyzed the indication of arterial angiography for bleeding and endovascular embolization based on a pre-established protocol in the routine of care of the polytraumatized patient admitted to the Emergency Unit (HCFMRP-USP). Results: The findings were consistent with current literature demonstrating high rates of technical and clinical success associated with low rates of complications inherent to the percutaneous transarterial procedure. Conclusion: The present study demonstrated the safety of the procedure as well as its high clinical and angiographic success rate, associated with a low rate of complications related to the procedure.

Endovascular aortic repair (EVAR) is a minimally invasive alternative to open surgery for the treatment of aortic aneurysms (AA). However, standard EVAR is not applicable to complex AA with involvement of vital branches, which could be occluded by the endograft. As an emerging technique, the concept of multiple overlapping uncovered stents (MOUS) have been proposed to manage complex lesions. MOUS was used to modulate the flow pattern inside the aneurysm sac, and promote the thrombus formation followed by the aneurysm shrinkage. In this dissertation, we sought to investigate the mechanism of MOUS-induced flow modulation and key factors associated with the success of this novel technique: - The mechanical behaviour of AA was characterised by uniaxial material tests (Chapter 4). A Bayesian framework was proposed for material constants identification. They were found correlated to the microstructure of tissue fibre network and were capable in differentiating tissue types. - Solid-to-solid interaction and one-way fluid-solid interaction (FSI) analysis was performed based on patient-specific computer tomography angiography (Chapters 5&6). Structural stress concentrations were observed within the landing zones, which increased with the number of stents deployed. In the parameter studies (Chapter 6), the overall porosity was identified as the dominant factor of the flow-diverting outcome, while cross-stent structures of MOUS had limited influence. - The pathological effect of structural stress concentration induced by an implanted device was further studied in rabbit models (Chapter 7). The wall structural stress and fluid shear stress were obtained from FSI analysis based on magnetic resonance imaging (MRI), and correlated to plaque characteristics. Both high structural stress and low fluid shear stress were found correlated to plaque initialisation and increased inflammation. Overall, MOUS modulates the blood flow with robust performance under different overlapping patterns. Image-based biomechanical analysis can optimise MOUS design and can contribute to personalised pre-surgery planning.

Introdução: Acretismo placentário é condição pouco frequente na qual há aderência anormal do tecido trofoblástico à parede uterina. É uma causa importante de hemorragia puerperal, associada a altas taxas de morbimortalidade maternofetal, grande necessidade de transfusão de hemoconcentrados. Os tratamentos propostos variam desde conduta conservadora até a histerectomia pós-parto, associada ou não a procedimentos endovasculares. Objetivo: O presente estudo visa descrever a técnica endovascular de balonamento temporário e embolização das artérias ilíacas internas durante o parto cesáreo, avaliar sua eficácia em reduzir o sangramento materno relacionado ao acretismo placentário, bem como relatar a segurança e o índice de complicações relacionadas ao tratamento endovascular. Materiais e métodos: Coorte retrospectiva de pacientes com diagnóstico pré-natal de acretismo placentário submetidas a tratamento endovascular de balonamento temporário e embolização das artérias ilíacas internas, seguido de histerectomia puerperal no nosso serviço, no período de janeiro de 2012 até novembro de 2016. Foram analisados dados relativos aos antecedentes gestacionais e cirúrgicos, achados de exames de imagem, achados histológicos, níveis de hemoglobina prévios, durante e após o parto, bem como volumes de hemoconcentrados administrados e taxa de complicações relacionadas ao procedimento endovascular. Resultados: Trinta e Siqueira FM 7 cinco pacientes foram submetidas ao manejo proposto durante o período estudado. Foi observado um volume médio de transfusão relacionado ao procedimento e perda sanguínea estimada de 540 ml e 1229 ml, respectivamente. Ocorreram complicações relacionadas ao procedimento endovascular em quatro pacientes, sendo um caso de necrose muscular glútea, um de lesão isquêmica cutânea superficial e dois casos de trombose arterial aguda de membros inferiores. Conclusão: O presente estudo demonstrou que o balonamento temporário e embolização das artérias ilíacas internas reduziu significativamente as necessidades transfusionais relacionadas ao parto nas pacientes com acretismo placentário, quando comparado com casos da literatura nos quais não foram realizadas intervenções endovasculares, com baixo índice de complicações relacionadas ao procedimento. / Introduction: Placenta accreta (PA) is the infrequent condition in which there is abnormal adherence of the trophoblastic tissue to the uterine wall. It\'s considered a major cause of puerperal bleeding, associated with high maternal morbimortality and need for blood products transfusion. Proposed treatments range from conservative to postpartum hysterectomy, combined or not to endovascular techniques. Objectives: to describe the detailed endovascular technique of temporary balloon occlusion followed by embolization of the internal iliac arteries (IIA) during cesarean section, evaluate the ability in reducing birth-related blood loss in patients with diagnosed PA and to assess safety and complications related to the endovascular procedure. Materials and methods: retrospective cohort of patients diagnosed with PA submitted to temporary balloting and embolization of the IAA followed by puerperal hysterectomy in our institution from January 2012 to November 2016. We recorded patient data such as gestational and surgical history, pre-natal radiological image findings, histopathological description, pre e postoperative hemoglobin levels and volume of blood products transfused in all patients. Follow up accounted for possible complications related to the procedure. Results: thirty-five patients were submitted to the approach during the study period. The median volume of packed red blood cells (RBC) and estimated blood loss were 540 ml and 1229 ml respectively. A total of 4 patients had complications attributed to the endovascular procedure - one case of Siqueira FM 9 deep glute tissue necrosis, one of superficial tissue necrosis and two cases of acute arterial thrombosis of the inferior limbs. Conclusion: the present study demonstrated that temporary ballooning and embolization of the IAA was able to significantly reduce birth-related blood loss and transfusion needs in patients with PA when compared to other literature series where no endovascular procedures were performed, with a low rate of procedure-related complications.

Objective: To assess neck angulation and endograft oversizing as factors contributing to folding. Endograft folding will then be assessed on its role in endograft fixation strength. Methods: Bench top flow loop experiments were performed with barbless Gore Excluder endovascular grafts (EVG) that were deployed into silicone aorta-AAA models with neck angles of 0, 30, and 60. A total of five oversizings were tested: -7%, 2%, 12%, 24%, and 38% with N= 3 for each oversizing at each neck angle for a total of 45 experiments. Photographs of the stent apex to apex distances were taken for the entire circumference of the device for a total of 8 photos per experiment. Measurements of the apex to apex distance were taken for the top three stent layers and variance for each stent layer was calculated. Variances for all three stent layers were summed to represent the folding metric. The silicone model was then removed from the flow loop and placed on the uniaxial extension tester to for pull out testing to assess impact on attachment strength. Results: Neck angle and oversizing increases folding risk at oversizing ≥12% for 0° and 30° neck angles, and ≥ 2% oversizing for a 60° neck angle. Folding metric comparison between 0° vs. 30° and 0° vs. 60° across all oversizings had statistical significance (Mann-Whitney U, p

Abdominal aortic aneurysm (AAA) is a common disease that is life threatening when rupture occurs. The aims of this thesis were to study (I) the long-term survival after AAA repair, (II) the cost of repair with open (OR) and endovascular (EVAR) technique, (III) the effect of different statistical methods on interpretation of cost data, (IV) the prevalence of the disease among patients with suspected arterial disease referred to the vascular laboratory, and (V) the cost-effectiveness of selective high-risk screening. Analyses of data from the Swedish vascular registry (Swedvasc), local patient registries, patient records and hospital cost registries form the basis of this thesis. Short- and long-term survival after intact AAA repair improved over the past two decades, despite increasing patient age and rate of comorbidities over time. Compared to a general population adjusted for age, sex and calendar year, the relative 5-year survival was 90% among those surviving repair. While short-term survival improved over time after ruptured repair, relative long-term survival was stable. Despite differences in patient selection and cost structure, the total cost of AAA repair with EVAR and OR was similar in a population based setting (€28,193). There was lack of consistency in the methods used in cost-analysis in the current literature, and p-values were highly dependent on test method. The practice of selective (non-population-based) screening for AAA among patients referred to the vascular laboratory was studied. The prevalence of AAA was 4.2% among male and 1.5% among female patients. AAA was associated with high age and prevalence of arterial stenosis. Of AAAs detected through selective screening, 21.5% had undergone elective repair at 7.5 years follow-up. In a health-economic evaluation, the incremental cost-effectiveness ratio of selective screening was €11,084 per life year gained. In conclusion, survival after intact AAA repair has improved over time, despite changes in case-mix. Results of health economic reports on cost of AAA repair can be highly dependent on patient selection as well as presentation of data and the statistical methods used. Selective screening for AAA among patients referred to the vascular laboratory is cost-effective.

Subarachnoid hemorrhage (SAH) is a disease with high risk of mortality and morbidity. Elderly patients have an even higher risk of poor outcome. The incidence of SAH increases with age and the elderly constitute a substantial and increasing proportion of the population. Thus, the management of elderly SAH patients is an imminent clinical challenge. Time trends in clinical management and outcome were investigated in 281 SAH patients aged ≥65 years admitted over an 18-year period. The volume of elderly patients, especially patients ≥70 years and patients in worse clinical condition increased over time. The proportion of patients with favorable outcome increased over time, without an increase in severely disabled patients. Technical results and clinical outcome of endovascular aneurysm treatment (EVT) was investigated in 62 elderly SAH patients. EVT can be performed in elderly SAH patients with high technical success, acceptable aneurysm occlusion degree, acceptable procedural complication rate, and fair outcome results. EVT was compared to neurosurgical clipping (NST) in 278 elderly SAH patients in the International Subarachnoid Aneurysm Trial. In good grade elderly SAH patients, EVT should probably be the favored treatment for internal carotid and posterior communicating artery aneurysms, while elderly patients with middle cerebral artery aneurysms appear to benefit from NST. Occurrence of secondary insults and their impact on clinical deterioration were studied in 99 patients with severe SAH. High intracranial pressure increased and high cerebral perfusion pressure decreased the risk of clinical deterioration. Elderly patients had less intracranial hypertension insults and more hypertensive, hypotensive and hypoxemic insults. Good outcome was achieved in 24% of elderly patients with severe SAH, and the proportion of severe disability was similar to that of younger patients. Patient age was not a significant predictor for vasospasm in 413 SAH patients when admission and treatment variables were adjusted for with multiple logistic regression.

During endovascular aneurysm repair (EVAR), if the stent-graft device is too long for a given patient the redundant (extra) length adopts a convex configuration in the aneurysm. Based on clinical experience, we hypothesize that redundant stent-graft configurations increase the downward force acting on the device, thereby increasing the risk of device dislodgement and failure. This work numerically studies both steady-state and physiologic pulsatile blood flow in redundant stent-graft configurations. Computational fluid dynamics simulations predicted a peak downward displacement force for the zero-, moderate- and severe-redundancy configurations of 7.36, 7.44 and 7.81 N, respectively for steady-state flow; and 7.35, 7.41 and 7.85 N, respectively for physiologic pulsatile flow. These results suggest that redundant stent-graft configurations in EVAR do increase the downward force acting on the device, but the clinical consequence depends significantly on device-specific resistance to dislodgement.

During endovascular aneurysm repair (EVAR), if the stent-graft device is too long for a given patient the redundant (extra) length adopts a convex configuration in the aneurysm. Based on clinical experience, we hypothesize that redundant stent-graft configurations increase the downward force acting on the device, thereby increasing the risk of device dislodgement and failure. This work numerically studies both steady-state and physiologic pulsatile blood flow in redundant stent-graft configurations. Computational fluid dynamics simulations predicted a peak downward displacement force for the zero-, moderate- and severe-redundancy configurations of 7.36, 7.44 and 7.81 N, respectively for steady-state flow; and 7.35, 7.41 and 7.85 N, respectively for physiologic pulsatile flow. These results suggest that redundant stent-graft configurations in EVAR do increase the downward force acting on the device, but the clinical consequence depends significantly on device-specific resistance to dislodgement.

OBJETIVO: Intentar responder a varias preguntas relacionadas con el manejo y los resultados terapéuticos de los pacientes diagnosticados de isquemia crítica de extremidades inferiores en base a la experiencia del Hospital de la Santa Creu i Sant Pau de Barcelona en un período de 2 años.PACIENTES Y MÉTODO: Se han estudiado 36 variables en 363 pacientes, intentándose establecer relaciones entre ellas a través del análisis estadístico. El nivel de significación estadística empleado ha sido del 5% y el software empleado ha sido SPPS (VII.5)RESULTADOS: El grupo ha incluido 80,7% hombres, la edad media ha sido de 71,2 años, 70,1% eran fumadores y 64% presentaban diabetes mellitus. Un 87,6% presentaban al ingreso lesiones cutáneas y 83,9% tenían dolor. Se han practicado 106 cirugías arteriales directas y en 60 casos se ha practicado cirugía endovascular. Se han realizado 198 amputaciones primarias (88 mayores) y 20 reamputaciones (18 mayores). La permeabilidad primaria en caso de cirugía directa alcanzó 75,5% y la secundaria un 90,6%.DISCUSIÓN: La mortalidad se asoció con la edad, con la patología cardiológica y con la clínica de presentación al ingreso. La permeabilidad primaria estuvo en estrecha relación con la dislipemia, mientras la permeabilidad secundaria se relacionó con el tabaquismo y la insuficiencia renal. La simpatectomía lumbar no jugó un papel importante en la salvación de la extremidad y el tratamiento con prostaglandinas no influyó la evolución a medio y largo plazo, como tampoco la tasa de amputaciones. La diabetes no parece haber desempeñado un papel fundamental en el número de intervenciones o el número de ingresos, como tampoco en la tasa de amputacioens primarias/secundarias.CONCLUSIONES: La mayoría de los pacientes fueron hombres, añosos y con enfermedad arterial sistémica. Con cada año que se gana en edad, el éxito baja un 3%. El éxito de la cirugía alcanzó un 83,6%. La presencia de lesiones influye sobre la mortalidad, como también el sexo masculino, la edad y la cardiopatía previa. Se ha aplicado un buen criterio al decidir el grado de urgencia de cada caso, indicándose correctamente la amputación primaria como solución terapéutica en pacientes con esperanza de vida muy limitada. / OBJECTIVE: Respond to a few questiones about the management and the treatment in patients with critical lower limb isquemia by the experience of Santa Creu i Sant Pau Hospital from Barcelona in a period of 2 years.PATIENTS AND METHODS: Were studied 36 clinical variables in 363 patients, with the purpose to find relations between them through statistical analysis. The level of statistical significancy was 5% and the software employed was SPPS (VII.5).RESULTS: The group included 80,7% men, the medium age was 71,2 years, 70,1% were smokers and 64,5% diabetics. 87,6% presented at income ulcerations/gangrene and 83,9% accused rest pain. Were practiced 106 open arterial and 60 endovascular surgeries, 198 primary amputations (88 of them were majors) and 20 reamputations (18 majors). The primary patency in open surgery was 75,5% and the seccondary patency was 90,6%.DISCUSSION: The mortality was associated with the age, the heart disease and the clinical presentation (rest pain or gangrene). The primary patency was influenced by the cholesterol disorders and the seccondary patency was influenced by tobacco and the renal failure. The lumbar sympathectomy wasn´t an important factor in the limb salvage and the prostaglandin treatment didn´t influenced the evolution to medium/long term of these patients, neither the amputation ratio. The diabetes doesn´t have an significative role in the surgery results, neither in the amputation ratio.CONCLUSION: The majority of patients were aging men presenting systemic arterial disease. Every year gained in age decrease the succes of the surgery with 3%. The level of successful surgery was 83,6%. The clinical presentation (rest pain/ulceration) influenced the mortality, as the male sex, the age and the heart disease. The emergencies were judged appropriately, and the primary amputation was a good choice in patients with very short life expectance.