Objetivo: Na cirurgia de reconstrução aórtica ou cirurgia cardíaca com oclusão da aorta, a ocorrência de isquemia mesentérica e lesão intestinal está associada à maior mortalidade a curto prazo. A proteção vascular dos estrogênios tem sido investigada e é principalmente mediada pelo aumento da disponibilidade de óxido nítrico (NO). Portanto, este estudo investigou o papel do 17beta-estradiol na lesão de isquemia-reperfusão visceral (I/R) decorrente da oclusão da aorta descendente em ratos machos. Métodos: A isquemia mesentérica foi induzida em ratos Wistar machos através da inserção de cateter de embolectomia arterial Fogarty 2F (Edwards Lifesciences, Irvine, Calif.) na aorta descendente, que permaneceu ocluída por 15 minutos, seguida por 2 horas de reperfusão. Os ratos foram divididos em quatro grupos: (1) ratos submetidos apenas à manipulação cirúrgica (falso-operado, n = 22); (2) ratos submetidos à lesão de isquemia-reperfusão I/R (n = 22); (3) ratos tratados com 17beta-estradiol intravenoso (280 ug/kg) 30 minutos antes de I/R (n = 22); (4) ou ao início da reperfusão (n = 22). As alterações histopatológicas intestinais foram avaliadas por histomorfometria. As alterações microcirculatórias mesentéricas foram avaliadas por meio de fluxometria por laser Doppler e técnica de microscopia intravital. A expressão proteica da molécula de adesão intercelular-1, P-selectina, NO sintase endotelial (eNOS) e endotelina-1 foram avaliadas por imuno-histoquímica; além disso, as expressões gênicas de eNOS e endotelina-1 foram quantificadas por Real time PCR. As citocinas séricas foram quantificadas por ensaio imunoenzimático. Resultados: O grupo I/R mostrou perda expressiva da espessura da mucosa do intestino, diminuição do fluxo sanguíneo mesentérico (P = 0,0203), aumento do número de leucócitos migrados (P < 0,05) e alta mortalidade (35%). O tratamento com 17-beta-estradiol antes da oclusão da aorta preservou a espessura da mucosa intestinal (P = 0,0437) e o fluxo sanguíneo mesentérico (P = 0,0251), reduziu o número de leucócitos migrados (P < 0,05) e preveniu qualquer ocorrência fatal. Além disso, o 17-beta-estradiol diminuiu a expressão da molécula de adesão intercelular-1 (P = 0,0001) e da P-selectina (P < 0,0001) no endotélio e aumentou a expressão proteica da eNOS (P < 0,0001). As expressões gênicas de eNOS e endotelina-1 não diferiram entre os grupos. Conclusões: O tratamento profilático com 17beta-estradiol mostrou melhor repercussão global, foi capaz de prevenir qualquer ocorrência fatal e aumentar a expressão de eNOS, preservando assim a perfusão mesentérica e a integridade intestinal, além de reduzir sua inflamação / Objective: In surgical aortic repair or cardiac surgery with aorta occlusion, the occurrence of mesenteric ischemia and bowel injury has been associated with higher short-term mortality. The vascular protection of estrogens has been investigated and is mainly mediated by increasing the availability of nitric oxide (NO). Therefore, this study investigated the role of 17beta-estradiol on visceral ischemia-reperfusion (I/R) injury after descending aorta occlusion in male rats. Methods: Mesenteric ischemia was induced in male Wistar rats by placing a 2F Fogarty arterial embolectomy catheter (Edwards Lifesciences, Irvine, Calif) in the descending aorta, which remained occluded for 15 minutes, followed by reperfusion for up to 2 hours. Rats were divided into four groups: (1) rats that underwent surgical manipulation only (sham, n = 22); (2) rats that underwent I/R injury (n = 22); (3) rats treated with intravenous 17beta-estradiol (280 umg/kg) 30 minutes before I/R (n = 22); (4) or at the beginning of reperfusion (n = 22). Intestinal histopathologic changes were evaluated by histomorphometry. Mesenteric microcirculatory alterations were assessed by laser Doppler flowmetry and intravital microscopy technique. Protein expression of intercellular adhesion molecule-1, P-selectin, endothelial NO synthase (eNOS), and endothelin-1 was evaluated by immunohistochemistry; in addition, eNOS and endothelin-1 gene expressions were quantified by real-time polymerase chain reaction. Serum cytokines were measured by enzyme-linked immunosorbent assay. Results: Relative to the sham group, the I/R group exhibited a highly pronounced loss of intestine mucosal thickness, a reduction in mesenteric blood flow (P = 0,0203), increased migrated leukocytes (P < 0,05), and high mortality rate (35%). Treatment with 17-betaestradiol before aorta occlusion preserved intestine mucosal thickness (P = 0,0437) and mesenteric blood flow (P = 0,0251), reduced the number of migrated leukocytes (P < 0,05), and prevented any fatal occurrence. Furthermore, 17-betaestradiol downregulated the expression of intercellular adhesion molecule-1 (P = 0,0001) and P-selectin (P < 0,0001) on the endothelium and increased the protein expression of eNOS (P < 0,0001). The gene expressions of eNOS and endothelin-1 did not differ between the groups. Conclusions: The prophylactic treatment with 17-betaestradiol showed better overall repercussions and was able to prevent any fatal occurrence, increase eNOS expression, thus preserving mesenteric perfusion and intestinal integrity, and reduce inflammation

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No. of bitstreams: 2 Dissertação - Juliana Bahia Reis Jordão - 2016.pdf: 2279756 bytes, checksum: 091b0cef19461c384cdf292a17d2e907 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-07-07 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Ellagic acid (EA) is a natural phenol found in many fruits, mainly in red fruits and nuts, which possessess antioxidant and antiproliferative properties. Hence, it was hypothesized that EA could improve the cardiovascular damage caused by hypertension. Hypertension was induced in male Wistar rats with L-NAME (60 mg/Kg/day in drinking water) for six weeks. EA was administered (10 or 30 mg/Kg/day) by gavage starting on the second week of hypertension induction until the end of the sixth week. The control group received only vehicle. The blood pressure was recorded every week by tail-cuff plethysmography. After six weeks, the rats were euthanized and the heart and kidney were removed and weighed in comparison with the body weight. The blood was collected in heparin vaccum tubes to nitrite/nitrate and alkaline phosphatase analysis. Aortas were isolated and cut into rings for isometric recordings in an organ bath and for histological assay with hematoxylin/eosin to evaluate vascular remodeling. The abdominal aorta was used for calcium quantification analysis. The high level of blood pressure (233.6±9.5 mmHg) was reduced (p<0.01) by treatment with AE 10 or 30 mg/Kg (194.3±11.8 and 183.1±8.3 mmHg, respectively). The plasmatic levels of nitrate/nitrite (NO metabolites) were reduced (p<0.05) in hypertensive rats and were restored with the EA treatment. The vascular relaxations to acetylcholine and sodium nitoprusside and the contraction to phenylephrine were impaired in hypertensive group and they were improved after EA treatment. The plasmatic levels of alkaline phosphatase in the hypertensive group were increased and returned to control levels after EA treatment. In the aorta, the EA treatment resulted in lesser aortic wall thickening and lesser calcification. EA attenuates hypertension possibly improving the NO biodisponibility. The vascular response to acetylcholine, sodium nitroprusside and phenylephrine were impaired by hypertension and improved after treatment with EA. Moreover, alkaline phosphatase levels, calcium content and hypertrophy in aortas during hypertension were attenuated by treatment with EA. / O ácido elágico (AE) é um composto fenólico de ocorrência natural encontrado em várias frutas, principalmente frutas vermelhas e nozes, que possui propriedades antioxidantes e antiproliferativas. Logo, hipotetizou-se que o AE poderia melhorar os danos cardiovasculares causados pela hipertensão. A hipertensão foi induzida em ratos Wistar machos com N-nitro-L-arginina-metil-éster, L-NAME, (60 mg/Kg/dia) por seis semanas. O AE (10 ou 30 mg/Kg/dia) foi administrado por gavagem intragástrica a partir da segunda semana de indução da hipertensão até o final da sexta semana. O grupo controle recebeu apenas veículo. A pressão arterial sistólica (PAS) foi registrada semanalmente por pletismografia de cauda. Após seis semanas os ratos foram submetidos à eutanásia, o coração e o rim foram removidos e pesados em comparação com o peso corporal. O sangue foi coletado em tubos à vácuo heparinizados para análises de nitrito/nitrato e fosfatase alcalina. As aortas foram isoladas e segmentadas em anéis para registros de tensão isométrica em banho de órgãos e para análises histológicas com hematoxilina/eosina para avaliar remodelamento vascular. A aorta abdominal foi utilizada para a quantificação de cálcio. A elevada PA (233,6±9,5 mmHg) foi reduzida (p<0.01) com o tratamento com AE 10 e 30 mg/Kg/dia (194,3±11,8 e 183,1±8,3 mmHg, respectivamente). Os níveis plasmáticos de nitrito/nitrato (metabólitos do óxido nítrico, NO) estavam reduzidos (p<0,05) em ratos hipertensos e foram restaurados com o tratamento com AE. O relaxamento vascular provocado pela acetilcolina e pelo nitroprussiato de sódio, assim como a contração provocada pela fenilefrina estavam prejudicados no grupo hipertenso e melhoraram após o tratamento com AE. As dosagens plasmáticas de fosfatase alcalina no grupo hipertenso estavam aumentadas e retornaram aos valores observados no grupo controle, após o tratamento com AE. Na aorta, o tratamento com AE resultou em menor espessamento da parede aórtica e menor calcificação. O AE atenua a hipertensão possivelmente por melhorar a biodisponibilidade de NO. A resposta vascular à acetilcolina, nitroprussiato de sodio e fenilefrina foi melhorada após o tratamento com AE. Além disso, os níveis de fosfatase alcalina, o conteúdo de cálcio e a hipertrofia na aorta durante a hipertensão foram atenuados pelo tratamento com AE.

A Angiotensina II exerce funções fisiológicas importantes para a homeostase do sistema cardiovascular e pode ainda mediar ações que levam a respostas inflamatórias. Estas ações levam à ativação de células musculares lisas vasculares (CMLVs) como também o endotélio, de modo a produzir espécies reativas de oxigênio, citocinas inflamatórias, quimiocinas e moléculas de adesão indutoras de diapedese de células de origem mielóide. Neste contexto, flutuações nas concentrações de Angiotensina II poderiam ocorrer no organismo, levando a aumentos discretos que não interferem diretamente e imediatamente na pressão arterial, mas que poderiam estimular o recrutamento e a ativação de células de origem mielóide capazes de iniciar respostas inflamatórias locais. Tal situação forneceria informações importantes para desencadeamento de um processo crônico sobre os mecanismos de manutenção da pressão arterial e potencialmente levando a doenças cardiovasculares. O objetivo deste estudo, foi verificar a capacidade da angiotensina II em induzir uma resposta inflamatória na aorta e se existe uma relação com variações de pressão arterial, mesmo que discretas. Para isso, foram utilizados camundongos C57Bl/6 tratados com solução salina (0,9%, grupo controle) ou Angiotensina II (30ng, grupo Ang II). Os animais foram canulados na artéria carótida e veia jugular, e 48 horas depois os níveis de PA e FC foram registrados em condições basais e após a administração de salina ou Ang II, nos tempos de 30 min, 1, 2, 6, 12 e 24 h. A avaliação da sensibilidade barorreflexa foi feita após administração de fenilefrina e nitroprussiato de sódio (100 e 150 ng). A avaliação da reação inflamatória na aorta foi realizada por imunohistoquímica, sendo usados TGF-beta, iNOS como mercadores inflamatórios e CD45 como marcador de macrófagos. A avaliação da alfa-actina foi realizada a fim de mostrar uma possível mudança de fenótipo das CMLVs. Ao final dos tratamentos, verificamos que não ocorreu alteração de pressão arterial ou frequência cardíaca, assim como também, não houve alteração na sensibilidade barorreflexa. Observou-se uma resposta bifásica tanto para a expressão de TGF-beta como para a presença de células positivas para CD45, ocorrendo um aumento agudo (entre 30 e 60 minutos) e outro aumento mais crônico, entre 24 e 48 horas. Já a imunomarcação positiva para iNOS apresentou aumento em períodos mais longos, de 24 a 72 horas. A imunomarcação para alfa-actina não mostrou alterações, sugerindo que a dose aplicada de angiotensina II não altera o fenótipo das CMLVs de aorta. Os resultados obtidos sugerem que a angiotensina II, mesmo em doses que não alteram a pressão arterial, é capaz de induzir a expressão de marcadores inflamatórios e a migração de células inflamatórias na aorta de camundongos normotensos. Desta forma, pode-se considerar que a angiotensina II é capaz de aumentar a propensão ao desenvolvimento de lesão cardiovascular, mesmo em indivíduos normotensos / Angiotensin II exerts important physiological functions on cardiovascular system homeostasis and may mediate actions leading to inflammatory responses. These actions lead to the activation of vascular smooth muscle cells (CMLVs) as well as the endothelium, in order to produce reactive oxygen species, inflammatory cytokines, chemokines and adhesion molecules inducing diapedesis of cells of myeloid origin. In this context, variations in Angiotensin II concentrations could occur in the body, leading to discrete increases that do not directly and immediately interfere with blood pressure but could stimulate the recruitment and activation of myeloid cells capable of initiating local inflammatory responses. Such a situation would provide important information for triggering a chronic process on the mechanisms of maintaining blood pressure and potentially leading to cardiovascular disease. This study aimed to verify the ability of angiotensin II to induce an inflammatory response in the aorta and if there is a relation with variations of arterial pressure, even if discrete. For this, C57Bl/ 6 mice treated with saline solution (0.9%, control group) or Angiotensin II (30ng, Ang II group) were used. The animals were cannulated in the carotid artery and jugular vein, and 48 hours later PA and HR levels were recorded at baseline and after administration of saline or Ang II at 30 min, 1, 2, 6, 12 and 24 h. The evaluation of the baroreflex sensitivity was performed after administration of phenylephrine and sodium nitroprusside (100 and 150 ng). The evaluation of the inflammatory reaction in the aorta was performed by immunohistochemistry, using TGF-beta, iNOS as inflammatory markers and CD45 as a marker of macrophages. The evaluation of alpha-actin was performed in order to demonstrate a possible change in CMLV phenotype. At the end of the treatments, we verified that there was no change in blood pressure or heart rate, as well as there was no change in the baroreflex sensibility. A biphasic response was observed both for TGF-beta expression and for the presence of CD45 positive cells, with an acute increase (between 30 and 60 minutes) and another more chronic increase, between 24 and 48 hours. Positive staining for iNOS increased in longer periods, from 24 to 72 hours. Immunoblotting to alpha-actin showed no alterations, suggesting that the applied dose of angiotensin II does not alter the aortic CMLV phenotype. The results suggest that angiotensin II, even at doses that do not alter blood pressure, is capable of inducing the expression of inflammatory markers and the migration of inflammatory cells into the aorta of normotensive mice. Thus, angiotensin II may be considered to be capable of increasing the propensity to develop a cardiovascular injury, even in normotensive individuals

Introdução. A morbi-mortalidade durante e após anestesia para aneurismectomia de aorta abdominal é alta, pois esta doença acomete pacientes após a sétima década de vida e que possuem várias doenças concomitantes. Objetivos. Analisar e discutir as condutas anestésicas utilizadas nos períodos pré e intra-operatório no Serviço de Anestesiologia do HCFMRP-USP. Casuística e Método. Foram analisados os prontuários de 104 pacientes submetidos à aneurismectomia de aorta no tocante às condutas utilizadas pelos anestesiologistas para a condução destes casos. Resultados. Apenas um paciente possuía menos de 40 anos de idade, 76,80% estavam na sétima ou oitava década de vida e 88,46% eram do sexo masculino. A hipertensão arterial acometeu 70,19% dos pacientes e 26,92% possuíam coronariopatia. Pacientes com obesidade foram a minoria (26,92%). O ecocardiograma pré-operatório demonstrou que a grande maioria dos pacientes apresentava função ventricular normal. A cirurgia foi realizada em regime de urgência em 7,69% dos casos. A anestesia geral exclusiva foi realizada em 17 pacientes e associada com a peridural em 57 pacientes, com a raquianestesia em 11 e com a raqui-peri combinadas em 19. O tempo cirúrgico variou de 120 a 510 minutos enquanto que o tempo de clampeamento aórtico variou de 30 a 165 minutos. Houve um óbito no período intra-operatório e a causa foi choque hipovolêmico e 10 óbitos até o vigésimo dia pós-operatório. Sessenta e seis pacientes receberam concentrado de papa de hemácias durante o período intra-operatório, mas só em 43,27% desses casos a indicação esteve suportada por exame laboratorial. Oitenta pacientes foram extubados ainda na sala de cirurgia, enquanto que os demais (23) permaneceram intubados no período pós-operatório e 19 necessitaram de suporte ventilatório que teve tempo que variou de 3 a 96 horas com média de 42,31 horas. Apenas quatro pacientes fizeram pós-operatório imediato no Centro de Terapia Intensiva enquanto que os demais permaneceram na Sala de Recuperação Pós-Anestésica. Conclusão. Não existe um protocolo único para a realização de anestesia para aneurismectomia de aorta no HCFMRP-USP e a técnica anestésica utilizada não influenciou o morbi-mortalidade. / Introduction. The morbidity and mortality during and after anesthesia for aneurysmectomy of the abdominal aorta are high since this disease affects patients after the seventh decade of life who have several concomitant diseases. Objectives. To analyze and discuss the anesthetic conducts used during the preoperative and intra-operative periods at the Service of Anesthesiology of HCFMRP-USP. Cases and Method. The medical records of 104 patients submitted to aneurysmectomy of the aorta were analyzed regarding the conducts used by the anesthesiologists for the management of these cases. Results. Only one patient was less than 40 years old, 76.80% were in he seventh or eighth decade of life, and 88.46% were male. Arterial hypertension was present in 70.19% of the patients and 26.92% had coronary artery disease. Obese patients were a minority (26.92%). The preoperative echocardiogram demonstrated that most patients had normal ventricular function. Surgery was performed on an emergency basis in 7.69% of cases. Seventeen patients received exclusive general anesthesia, while general anesthesia was associated with peridural anesthesia in 57, with rachi-anesthesia in 11 and with combined rachi-peridural anesthesia in 19. Surgical time ranged from 120 to 510 minutes and time of aortic clamping ranged from 30 to 165 minutes. One death occurred intra-operatively due to hypovolemic shock and 10 patients died up to the 20th postoperative day. Sixty-six patients received a red blood cell concentrate intra-operatively, but this indication was supported by a laboratory exam in only 43.27% of these cases. Eighty patients were extubated while still in the operating room while the remaining 23 continued to be intubated during the postoperative period and 19 required ventilatory support lasting 3 to 96 hours (mean duration: 42.31 hours). Only four patients spent the immediate postoperative period in the Intensive Care Unit, while the remaining ones stayed in the Post-Anesthesia Recovery Room. Conclusion. There is no single protocol for the application of anesthesia for aneurysmectomy of the aorta at HCFMRP-USP and the anesthetic technique used did not influence morbidity-mortality.

O presente estudo avaliou próteses vasculares de pequeno calibre feitas de polidimetilsiloxano (PDMS) com reforço de poliéster implantadas em aorta de coelhos através de fluoroscopia. Os objetivos do estudo foram: (1) analisar tubo de PDMS com reforço de poliéster implantado em aorta de coelhos como possível material para prótese vascular, (2) avaliar a patência das próteses através de fluoroscopia, (3) avaliar a condição de implante cirúrgico; (4) avaliar o comportamento macroscópico biológico do implante e (5) analisar o modelo experimental proposto. Próteses vasculares de PDMS foram implantadas na aorta infrarrenal de 64 coelhos cedidos pelo biotério da Faculdade de Medicina da Univesidade de São Paulo. Os exames de fluoroscopia foram realizados em até 150 dias após implantação cirúrgica. As próteses de PDMS foram classificadas em ocluídas e patentes, sendo essas sub-classificadas em diferentes graus de estenose. O tempo de clampeamento da aorta foi aferido durante os procedimentos cirúrgicos. De maneira amostral peças foram encaminhadas para microscopia eletrônica para verificação de endotelização das próteses. As análises estatísticas foram feitas através de teste t-Studant, teste ANOVA e Kaplan-Meier. Dos 64 animais que receberam a prótese, trinta (46,88%) apresentaram boa evolução clínica, vinte e três (35,94%) morreram e onze (17,18%) apresentaram paraplegia de membros posteriores. A patência das próteses em 30 dias foi de 87% (±6,7), em 60 dias foi de 73% (±9,3), em 90 dias foi de 57% (±11) e em 120 dias foi de 48% (±12). Cinquenta por cento (oito) das próteses patente não apresentaram nenhum grau de estenose, 35,5% (seis) apresentaram cinquenta por cento ou menos de estenose e 12,5% (dois) apresentaram estenose entre cinquenta e setenta por cento. Nenhum animal apresentou estenose maior que 70%. O tempo médio de clampeamento da aorta foi de 52 minutos. Não houve diferença significante nem na associação entre tempo de clampeamento da aorta e a evolução clínica dos animais (p=0,67) nem na associação entre o tempo de clampeamento e a patência das próteses (t=1,35; p=0,18). As peças encaminhadas para microscopia apresentaram crescimento endotelial a partir do vaso nativo em direção à prótese de PDMS. Foi possível concluir com este estudo que o PDMS demonstrou-se um material adequado para futuras pesquisas no ramo de próteses vasculares e que o uso da fluoroscopia na avaliação dessas próteses foi de fundamental importância na determinação da patência dos implantes / The present study evaluated small caliber vascular prostheses made of polydimethylsiloxane (PDMS) with polyester reinforcement implanted in the aorta of rabbits by fluoroscopy. The study objectives were: (1) analyze PDMS tube with polyester reinforcement implanted in the aorta of rabbits as possible material for vascular prosthesis, (2) assess the patency of the prosthesis through fluoroscopy, (3) assess the condition of surgical implant (4) evaluate the macroscopic behavior of biological implant and (5) analyze the proposed experimental model. Vascular prostheses were implanted in PDMS infrarenal aorta of 64 rabbits assigned by the animal house of the Faculty of Medicine of the University of São Paulo. Fluoroscopic examinations were performed within 150 days after surgical implantation. The prosthesis of PDMS were classified into occluded and patents, these being sub-classified into different degrees of stenosis. The time of aortic clamping was measured during surgical procedures. Sample pieces were sent for electron microscopy to check endothelialization of prostheses. Statistical analyzes were performed using t-test Studant, ANOVA and Kaplan-Meier. Of the 64 animals that received the prosthesis, thirty (46.88%) showed clinical improvement, twenty-three (35.94%) died and eleven (17.18%) had paraplegia of hind limbs. The patency of the prosthesis in 30 days was 87% (± 6.7), at 60 days was 73% (± 9.3), at 90 days was 57% (± 11) and at 120 days was 48 % (± 12). Fifty percent (eight) of the prosthesis patent did not present any degree of stenosis, 35.5% (six) had fifty percent or less of stenosis and 12.5% (two) had stenosis between fifty and seventy percent. No animal showed stenosis greater than 70%. The mean aortic clamping was 52 minutes. There was no significant difference in the association between duration of aortic clamping and clinical evolution of animals (p = 0.67) nor the association between clamping time and patency of the prosthesis (t = 1.35, p = 0.18). The parts sent for microscopy showed endothelial growth from the native vessel toward the prosthesis PDMS. It can be concluded from this study that the PDMS proved to be a suitable material for future research in the field of vascular prostheses and the use of fluoroscopy in the evaluation of these prostheses was of fundamental importance in determining the patency of the implants

Orientadores: Konradin Metze, Carlos Lenz Cesar / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T10:46:07Z (GMT). No. of bitstreams: 1 Vieira-Damiani_Gislaine_D.pdf: 4044155 bytes, checksum: 7a862a3866981d1827845318ce37b121 (MD5) Previous issue date: 2012 / Resumo: A hipertensão arterial sistêmica (HAS) bem como o envelhecimento provoca mudanças na estrutura dos grandes vasos sanguíneos - aorta e seus ramos - propiciando o desenvolvimento de processos degenerativos que são a causa de diversas doenças. O uso de ferramentas fotônicas na aquisição de imagens, associado a recursos matemáticos para a interpretação delas representa um avanço para as análises histopatológicas, pois permitem a visualização e compreensão de pequenas estruturas que antes eram impossíveis de serem observadas. O objetivo desse trabalho foi associar estas duas tecnologias (ferramentas fotônicas e recursos matemáticos) e com isso criar uma metodologia para a análise simultânea de fibras elásticas e colágenas na aorta. Para tanto utilizamos aorta ascendente de 72 pacientes, sendo 22 normotensos, 38 portadores de HAS e 12 aortas de dissecção. As lâminas coradas com hematoxilina eosina foram examinadas no microscópio multifoton, com dois fótons: laser de argônio para fluorescência da eosina, corante de fibras elásticas e Ti:safira para SHG, sinal gerado por moléculas de colágeno. A distribuição e organização das fibras elásticas e colágenas foram analisadas pelas seguintes variáveis: morfometria geométrica, derivadas da matriz de co-ocorrência de Haralick, Transformada de Fourier e fluorescência ótica integrada. Usando estes descritores da textura associados a fractais, observamos que a geração do SHG é dependente não só da presença do colágeno como também do arranjo destas fibras. Observamos ainda que em indivíduos normotensos, quando comparados aos portadores de HAS, ocorre uma diminuição na distribuição do sinal SHG ao longo da espessura da camada média partindo da íntima em sentido à adventícia. Dessa maneira concluímos que os maiores distúrbios das fibras elásticas, nos indivíduos normais ocorrem na transição do terço interno para o médio, enquanto que nos portadores de HAS eles estão distribuídos em toda a espessura da aorta. Além disso, estes estudos nos permitiram verificar que a dissecção da aorta ocorre entre dois reforços de colágeno, uma vez que este fenômeno foi constatado entre dois picos de SHG / Abstract: The arterial hypertension as well as aging induces changes in the structure of large blood vessels - aorta and its branches - leading to development of degenerative processes which are the cause of many diseases. The use of photonics tools for image acquisition, associated to mathematical resources for interpretation of them represents an advance in histopathological analysis, because it allows the visualization and understanding of small structures that were impossible to be observed before. The main objective of this study was to associate both technologies (photonics tool and mathematical resources) to create a new methodology to evaluate, simultaneously, elastic and collagen fibers in aorta. For this we've used autopsies of ascending aortas from 72 patients, being 22 samples from normotensives individuals, 38 from HAS patients and 12 aortas from dissection. HE-stained paraffin sections from ascending aortas were analyzed by multifoton microscopy, with 2 types of photons: Two-photon excited fluorescence (TPEF) for elastin and Ti:safira for SHG to analyze collagen fibers. The distribution and organization of elastic and collagen fibers were analyzed by the following variables: geometric morphometric, derived from the co-occurrence matrix of Haralick, Fourier Transform and Fluorescence optics integrated. Using these texture descriptors associated to analysis of fractals, we've observed that SHG generation is not only dependent on the presence of collagen but on the arrangement of these fibers as well. We also observed that in normotensives individuals, if compared to HAS patients, occurs a decrease in the SHG intensity along the medial thickness from intimate in direction to adventitia. Thus we conclude that the major disorders of elastic fibers in normal subjects occur in the transition from the third layer to the middle, while in HAS individuals these disorders are distributed throughout the thickness of the aorta. Furthermore, this study has allowed us to verify that the aortic dissection has occurred between two peaks of SHG, since this phenomenon was observed between two ribs collagen / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutora em Fisiopatologia Médica

Background: Permanent paraplegia is a rare but feared complication of both open and endovascular thoracoabdominal aortic repair. The rate of postoperative paraplegia varies depending on the extent of open repair, from 0.9% to 4.7%, even in expert centers (Coselli et al. 2016; Etz et al. 2015). Among the currently available protective adjuncts, distal perfusion (DP) and cerebrospinal fluid (CSF) drainage are one of the most widely used ones (Etz et al. 2015). The scientific evidence of DP is based on observational clinical studies with heterogenous patients and perioperative strategies, and few experimental works with various combinations of preventive techniques analyzed simultaneously (Rose et al. 1997; Winnerkvist et al. 2002). Aim of the study: The aim of the study was to evaluate the isolated effect of DP on regional spinal cord perfusion during aortic cross-clamping, and additional deliberate CSF pressure elevation in a large animal model. Additionally, we aimed to assess DP impact on paraspinous muscle perfusion, and evaluate the efficacy of collateral network near-infrared spectroscopy (cnNIRS) as a monitoring technique during DP. Methods: The study was performed in an acute large animal model (8 juvenile female German landrace pigs) via upper left lateral thoracotomy in the 3rd intercostal space, and retroperitoneal access. Distal perfusion was performed using partial cardiopulmonary bypass (CPB) with target perfusion pressure of 60 mmHg. Arterial lines of CPB were placed into the descending thoracic and abdominal aorta, and the venous line – into the pulmonary artery. Lumbar puncture at the L3-L4 level was performed in order to perform plasma injection during CSF pressure elevation stage. Spinal cord and paraspinous muscle regional perfusion was evaluated using microspheres injections (a total of 6 colors) at four experimental time-points: on running CPB (baseline), 5 minutes after proximal aortic cross-clamping, 5 minutes after abdominal aortic cross-clamping and initiation of DP, and after 15 minutes of manually increased (tripled) CSF pressure. During the DP, proximal and distal blood flows were evaluated separately with two microsphere colors injected simultaneously via CPB arterial lines. For the analysis, the spinal cord was divided into three segments: upper (C1-T7), mid- (T8-L2) and lower (L3-S). Paraspinous muscle perfusion and oxygenation were assessed at 4 levels: mid- and lower thoracic, upper and lower lumbar levels. At the end of each experiment, the whole spinal cord and 2 cm3 samples of paraspinous muscles corresponding to the cnNIRS levels, were harvested. Results: Spinal Cord Perfusion: In the upper spinal cord, statistically significant changes of regional perfusion were observed both after DTA cross-clamping (decrease to 62% from baseline), and after distal aortic cross-clamping with initiation of DP (increase to 156% in proximal and decrease to 5% from baseline in distal flow). These were followed by a significant drop of proximal spinal cord perfusion (from 152% back to 102%, p = 0.038), and some increase of distal perfusion values (from 5% to 19%, however not reaching statistical significance) during the CSF pressure elevation stage. In the mid-spinal cord, a notable decrease of perfusion was observed after proximal aortic cross-clamping (to 27%, p = 0.025). The initiation of DP was not associated with any notable changes in proximal and distal perfusion values. Afterwards, a decrease of proximal and distal perfusion values (from 33% to 13% in proximal, and from 24% to 10% in distal perfusion) was observed during CSF pressure elevation stage. These changes were, however, not statistically significant. Lower spinal cord measurements showed, similarly to mid-segment, a decrease in perfusion after DTA cross-clamping (to 14% from baseline, p = 0.001). Initiation of DP led to normalization of proximal perfusion of the lower spinal cord (to 96% from baseline). At the same time, it was associated with extreme hyperperfusion due to distal perfusion (up to 480% from baseline). The tripling of CSF pressure resulted in decrease of both proximal (from 96% to 59%, p = 0.131) and distal (from 480% to 468%, p = 0.999) perfusion rates. Paraspinous muscle perfusion: The analysis of paraspinous muscle (i.e. collateral network) perfusion values revealed few statistically significant changes. Proximal aortic cross-clamping resulted in a decrease of paraspinous muscle perfusion (not reaching statistical significance). The least perfused were lower thoracic and upper lumbar segments. Neither initiation of DP, nor CSF pressure elevation were associated with any statistically significant changes in paraspinous muscles perfusion at any of the analyzed levels, except the lower lumbar one. Here, the distal perfusion increased from 7% to 27% from baseline during DP, and from 27% to 60% during the CSF elevation stage (p = 0.034). cnNIRS: Continuous cnNIRS monitoring did not reveal any notable changes at the mid-thoracic level. At the other three levels, the values decreased after DTA cross-clamping (p < 0.001 according to ANOVA). At the lower thoracic level, the tissue oxygenation values crossed the 70% from baseline ischemic threshold after initiation of DP. CSF pressure elevation did not have any influence on cnNIRS values at any level. Discussion: Comparison of the present experiment with the previously published studies is limited due to discrepancy in experimental sequences, analyzed segments and possible effects of other protective adjuncts used in the studies. However, in the initial phase of the experiment, the decrease of blood flow in all the spinal cord segments, was similar to the previously published works (Brattli et al. 2007; von Aspern et al. 2020). These changes were used as a second, “ischemic” baseline during the present study. Initiation of the DP led to limited or no perfusion increase of spinal cord perfusion in upper (C1-T7) and mid-spinal cord (T8-L2). And, if in the upper spinal cord this could be compensated by increased proximal flow, the mid-spinal cord was the least protected segment. At the same time, it was associated with extreme hyperperfusion (due to distal flow) of the spinal cord in the lumbar segment (L3-S), which is a known risk factor of spinal cord injury itself (Bower et al. 1989; Gallagher et al. 2019). The CSF pressure elevation resulted in further spinal cord tissue perfusion decrease, as previously reported by Haunschild et al. in experiments without aortic cross-clamping and DP (Haunschild et al. 2020). Although these changes were statistically significant only at the upper spinal cord level, they resulted in a pronounced reduction of proximal perfusion also in the other two spinal cord segments. Similarly, the decrease was observed also in distal perfusion in the mid- and lower spinal cord. Summarizing these findings, one would suggest that not only did DP (with 60 mmHg pressure) not lead to adequate protection of the mid-spinal cord during aortic cross-clamping, but it also was not able to protect it in the presence of increased CSF pressure. One also needs to point out, that although elevated CSF pressure led to some decrease of distal flow in lumbar segment, it did not eliminate the hyperperfusion of the spinal cord. In paraspinous muscle perfusion, as previously reported by von Aspern and colleagues, the perfusion reduction was more prominent in the lower thoracic and upper lumbar segments, which corresponds with the spinal cord regional perfusion results. During the next stages, almost no changes were observed in paraspinous muscles perfusion. The exclusion was the lower lumbar level, where some increase of distal perfusion was observed, however not reflecting the hyperperfusion of the spinal cord at this level. As a reflection of collateral perfusion, collateral network oxygenation monitoring using cnNIRS demonstrated limited changes. The most pronounced decrease of oxygenation was observed after aortic cross-clamping, thus following the pattern reported by von Aspern (von Aspern et al. 2020). However, at lower thoracic level, the values did cross the 70% ischemic threshold after initiation of DP, signaling ischemia. Similarly to paraspinous muscle perfusion, cnNIRS was not able to reflect the hyperperfusion of the distal spinal cord. Conclusions: The present study points out, that DP during open thoracoabdominal aortic repair should be managed with caution. It was shown that DP with stable unadjusted perfusion pressure of 60 mmHg does not provide adequate protection at the mid-thoracic level of the spinal cord and could not counteract CSF pressure elevation. At the same time, it may be associated with hyperperfusion of its distal segment. Distal perfusion, both with normal and elevated CSF pressure, did not lead to any significant changes in paraspinous muscles perfusion, except the lower lumbar segment. However, the lowest perfusion values were observed around the mid-spinal cord (the most vulnerable) area. Moreover, despite the fact that cnNIRS was able to reflect severe spinal cord ischemia, it did not reveal the spinal cord hyperperfusion. Further studies, including chronic animal experiments, are required for precise evaluation of DP in various pressure modes, and its ability to counteract the elevated CSF pressure.:Table of contents III List of abbreviations V 1 Introduction 1 1.1 Anatomy of the aorta 1 1.2 Descending thoracic and thoracoabdominal aortic pathology 2 1.3 Open surgical and endovascular treatment of thoracic and thoracoabdominal aortic pathology 4 1.4 Postoperative spinal cord injury 7 1.5 Spinal cord anatomy 9 1.6 Spinal cord blood supply: collateral network concept 10 1.7 Perioperative and adjunctive strategies to prevent spinal cord injury 12 1.8 Swine as an experimental model for spinal cord injury research 15 2 Aim of the study 16 3 Materials 17 3.1 Experimental materials 17 3.1.1 Devices 17 3.1.2 Expendable materials and instruments 18 3.1.3 Medications and chemicals 20 3.2 Laboratory materials 22 3.2.1 Devices 22 3.2.2 Expendable materials and instruments 23 3.2.3 Chemicals 25 3.3 Software 26 4 Methods 27 4.1 Experimental model 27 4.1.1 Experimental animals 27 4.1.2 Anaesthesia 28 4.1.3 Surgical approach and experimental sequence 29 4.1.4 Tissue harvesting and preparation 33 4.2 Analysis during the experiment 33 4.2.1 Microsphere measurements 33 4.2.2 Collateral network near-infrared spectroscopy 38 4.2.3 Histopathological assessment 39 4.2.4 Statistical analysis 42 5 Results 43 5.1 Vital parameters during the experiment 43 5.2 Spinal cord regional perfusion 45 5.3 Collateral network regional perfusion 50 5.4 Collateral network oxygenation 54 5.5 Relationships between regional perfusion and oxygenation values 56 5.6 Histopathological assessment 60 6 Discussion 62 6.1 Discussion of vital parameters during the experiment 64 6.2 Discussion of spinal cord regional perfusion 66 6.3 Discussion of collateral network regional perfusion 71 6.4 Discussion of collateral network oxygenation 73 6.5 Discussion of the relationships between regional perfusion and 75 oxygenation values 6.6 Discussion of histopathological results 76 6.7 Conclusions 77 6.8 Limitations of the study 78 7 Summary 81 8 References 86 9 Figure legends 103 10 Table legends 105 Acknowledgements 106 Declaration about the independent work for dissertation 107 Curriculum vitae 108

Die bikuspide Aortenklappe gilt als Risikofaktor für das frühzeitige und häufige Auftreten von Aortenklappenvitien, Aneurysmen und Dissektionen. Das Ziel dieser Arbeit ist es, ein begründetes chirurgisches Therapiekonzept für Patienten mit bikuspider Aortenklappe und Dilatation der Aorta ascendens zu entwickeln. Wir analysierten die Daten von 555 Patienten mit bikuspider und 2015 Patienten mit trikuspider Aortenklappe, die sich in unserer Einrichtung einer Operation an der Aortenklappe und/ oder einem Eingriff im Bereich der Aorta ascendens unterzogen. Die Aorta ascendens wurde angiographisch, echokardiographisch und mittels CT auf ihre Konfiguration analysiert und histologisch und histomorphometrisch beschrieben. Auch wurden die Langzeitergebnisse nach Aorta ascendens Reduktionsplastik erfasst. Bei Patienten mit bikuspider Aortenklappe sind mit zunehmendem Durchmesser der Aorta ascendens häufiger die histologischen Zeichen einer Dilatation zu finden. Schwerere strukturelle Veränderungen, insbesondere eine höhergradige zystische Medianekrose, sind nicht zu beobachten. Die Aorta Ascendens Reduktionsplastik zeigt bei Patienten mit bikuspider Aortenklappe und Dilatation der Aorta ascendens gute Langzeitergebnisse. Nur bei Patienten mit nicht optimaler Durchmesser-Reduktion bei der Operation kommt es zu einer späteren Redilatation. / The bicuspid aortic valve is a known risk factor for the early and frequent occurrence of aortic valve defects, aneurysms and dissections. This study aims to develop an appropriate surgical therapy concept for patients with bicuspid aortic valve and dilatation of the ascending aorta. The data of 555 patients with bicuspid and 2015 patients with tricuspid aortic valve who underwent surgical treatment of the aortic valve and/or of the ascending aorta at our institution were evaluated. We analyzed the configuration of the ascending aorta by angiography, echocardiography and CT and described the aortic wall by histological and histomorphometric examination. We also analyzed the long-term results after reduction aortoplasty of the ascending aorta. Histological examination of the aortic wall specimens showed that patients with bicuspid aortic valve with increased diameter of the ascending aorta more often have histological signs of dilatation. More severe histological changes such as cystic media necrosis did not occur. Reduction aortoplasty of the ascending aorta shows good long-term results in patients with bicuspid aortic valve and dilatation of the ascending aorta. Only in patients in whom surgical reduction is less than optimal does redilatation occur later.

Introdução: O aneurisma de aorta abdominal (AAA) é uma doença prevalente e silenciosa também relacionada com a atividade inflamatória. Atualmente, a abordagem endovascular tem sido utilizada como principal técnica devido à inúmeras vantagens. Porém tem uma maior taxa de reintervenções e necessita de seguimento periódico com angiotomografias, o que aumenta custos e tem implicações como alteração da função renal além do acúmulo progressivo de radiação. Tais condições justificam a busca por possíveis biomarcadores que possam contribuir para um melhor seguimento. Objetivos: Neste estudo, buscou-se correlacionar o microRNA-1281, proteína C reativa (PCR) e a avaliação da função renal de indivíduos com AAA com a evolução dos mesmos após o tratamento endovascular. Pacientes e métodos: Foram selecionados 30 pacientes consecutivos do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRP-USP, no período de janeiro de 2104 a novembro de 2015, com aneurisma de aorta abdominal e com indicação para tratamento endovascular. As dosagens séricas e avaliações angiotomográficas foram feitas no pré-operatório e 6 meses após a intervenção. Resultados: Houve uma hiperexpressão do microRNA-1281 nos pacientes com aneurisma e uma significativa redução dos seus níveis séricos após a correção endovascular. A expressão do miRNA-1281 apresentou correlação positiva com o clearence de creatinina. Houve também correlação positiva da PCR com a presença do aneurisma, e com seu diâmetro e não houve alteração significativa da função renal mensurada através das dosagens séricas de uréia, creatinina e cálculo indireto de clearence. Conclusão: O estudo mostrou que o miRNA 1281 tem boa correlação com a evolução favorável pós-tratamento endovascular do AAA, não se observando o mesmo com a proteína C reativa. Novos estudos são necessários para validar e complementar tais achados. / Introduction: Abdominal aortic aneurysm (AAA) is a prevalent and silent disease. Currently, the endovascular approach has been widely used and is the main technique due to the innumerable advantages. However, it has a higher rate of reintervention and requires periodic follow-up with tomography over the years, which increases its costs and has implications such as altered renal function besides the accumulation of radiation. Such conditions justify the search for possible biomarkers that may perhaps replace CT. Objectives: In this study, we sought to correlate the microRNA-1281, Creactive protein (CRP) and the renal function evaluation of individuals with AAA with their evolution after endovascular treatment. Patients and methods: We selected 30 consecutive patients from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRP-USP, in the period from January of 2104 until November of 2015, with abdominal aortic aneurysm and with indication for endovascular treatment. Serum dosages were made preoperatively and 6 months after the intervention Results: There was a hyperexpression of the micro-RNA -1281 in patients with aneurysm and a significant reduction of their serum levels after endovascular correction. Expression of miRNA-1281 showed a positive correlation with creatinine clearence. There was also a positive correlation of CRP with the presence of the aneurysm, and with its diameter, and there was no significant alteration of renal function measured through serum urea, creatinine and indirect clearance calculations. Conclusion: The study showed that 1281 miRNAs may prove to be a potential biomarker for eventual follow-up of patients undergoing AAA endovascular repair. New studies are needed to validate and complement these findings.

INTRODUÇÃO: O aneurisma da aorta abdominal (AAA) tem grande importância clínica em função de sua incidência e das complicações que pode acarretar, entretanto sua etiopatogenia não está completamente esclarecida. A associação entre tabagismo e desenvolvimento de AAA tem sido repetidamente confirmada. Apesar de o AAA ter sido inicialmente atribuído à aterosclerose, observou-se associação negativa entre diabetes (um dos principais fatores de risco para aterosclerose) e doença vascular aneurismática. O estudo biomecânico e histológico da parede aórtica pode contribuir para a elucidação da etiopatogenia dos aneurismas. OBJETIVOS: Avaliar as propriedades biomecânicas e histológicas da aorta abdominal de ratos em três situações: exposição à fumaça do cigarro, induzidos ao desenvolvimento do diabetes mellitus e com a associação desses dois fatores. MÉTODOS: Setenta e cinco ratos Wistar foram distribuídos em quatro grupos: controle (GC), tabagista (GT), diabético (GD), diabético e tabagista (GDT). Os ratos dos GT e GDT foram expostos à fumaça de cigarro por 30 minutos ao dia, 5 dias por semana. O diabetes foi induzido por injeção endovenosa de estreptozotocina. Após 16 semanas, os animais foram sacrificados para a coleta da aorta abdominal. Testes de tração uniaxiais destrutivos foram realizados para a obtenção das seguintes propriedades biomecânicas: força, tensão, estresse, deformação e energia de deformação. A análise histológica desses fragmentos consistiu na avaliação das fibras colágenas e elásticas e verificação da deposição de elementos da matriz extracelular na túnica média e avaliação da sua composição. Através da zimografia foi quantificada a atividade da metaloproteinase-2 nos espécimes aórticos obtidos. RESULTADOS: Foram analisados os testes biomecânicos válidos de 52 espécimes, sendo que 11 pertenciam ao GC, 10 ao GD, 16 ao GT e 15 ao GTD. A análise biomecânica dos fragmentos não revelou diferença entre os grupos controle, GD, GT e GDT. A deposição de colágeno também não apresentou diferença estatística significativa entre os grupos estudados. A contagem total de lâminas elásticas foi maior nos ratos diabéticos (GD e GDT) quando comparados aos do GT. Foi observada resposta inflamatória mais intensa, com significância estatística, em todos os grupos estudados quando comparados ao GC. A atividade da MMP-2 apresentou diminuição no GD em relação ao GDT, com significância estatística. CONCLUSÕES: As propriedades biomecânicas da parede da aorta de ratos relacionadas à resistência e elasticidade não apresenta diferença entre o GC e os GD, GT e GDT. As alterações histológicas relacionadas à contagem total e fragmentação das lâminas elásticas, deposição de matriz pericelular e perda/substituição celular na túnica média são significativas na parede da aorta do GD, GT e GDT em relação ao GC. A atividade da MMP-2 na aorta do GD é menor que na aorta do GDT / INTRODUCTION: Abdominal aortic aneurysm (AAA) is of great clinical importance due to its incidence and complications, but its etiopathogenesis is not fully understood. The association between smoking and AAA development has been repeatedly confirmed. Although AAA was initially attributed to atherosclerosis, there was a negative association between diabetes (a major risk factor for atherosclerosis) and aneurysmal vascular disease. The biomechanical and histological study of the aortic wall may contribute to the elucidation of the etiopathogeny of the aneurysms. OBJECTIVES: To evaluate the biomechanical and histological properties of the abdominal aorta of rats in three situations: exposed to cigarette smoke, induced to the development of diabetes mellitus, and the association of these two factors. METHODS: Seventy-Five Wistar rats were divided into four groups: control (CG), smoker (GT), diabetic (GD), diabetic and smoker (GDT. The GT and GDT rats were exposed to cigarette smoke for 30 minutes a day, 5 days a week. Diabetes was induced by intravenous injection of streptozotocin. After sixteen weeks, the animals were sacrificed for collection of the abdominal aorta. Uniaxial destructive tensile tests were performed to obtain the following biomechanical properties: maximal force, failure stress, failure tension, failure strain and failure strain energy. The histological analysis of these fragments consisted in the evaluation of the collagen and elastin and verification of the deposition of elements of the extracellular matrix in the tunica media and evaluation of its composition. The activity of metalloproteinase-2 in the aortic specimens obtained was quantified by zymography. RESULTS: A total of 52 strips were studied (11 from GC, 10 from GD, 16 from GT and 15 from GDT. The biomechanical analysis of the fragments was not different between the control group and the GD, GT and GDT groups. Collagen deposition also did not present a statistically significant difference between the studied groups. The total of elastic fibers was higher in diabetic rats (GD and GDT) when compared to GT. A higher inflammatory response was observed, with statistical significance, in all groups studied when compared to CG. The activity of MMP-2 showed a decrease in GD in relation to GDT, with statistical significance. CONCLUSIONS: The biomechanical properties of the aortic wall of rats related to resistance and elasticity do not present a difference between GC and GD, GT and GDT. Histological changes related to total count and fragmentation of the elastic lamina, pericellular matrix deposition, and cell loss / substitution in the tunica media are significant in the aorta wall of GD, GT and GDT in relation to GC. The activity of MMP-2 in the GD aorta is smaller than in the GDT aorta