Introdução: As doenças cerebrovasculares são consideradas atualmente a segunda principal causa de óbito no mundo e a terceira causa de anos de vida perdidos por mortalidade1,2. A aterosclerose de grandes artérias é uma das principais condições subjacentes associadas ao AVC isquêmico (AVCi) e correlaciona-se com maiores taxas de recorrência. A detecção e a estratificação da estenose extracraniana podem ser feitas através do Doppler, da angiotomografia computadorizada (ATC), da angiorressonância magnética (ARM) e da angiografia intra-arterial digital (AIA), sendo esta última considerada o método padrão-ouro. Objetivo: Avaliar a acurácia diagnóstica e a concordância entre os métodos de ATC, ARM com contraste (AM CC) e AIA na análise da estenose extracraniana. Determinar a frequência e caracterizar a estenose extracraniana em população brasileira sintomática. Metodologia: Foram avaliados retrospectivamente os exames AIA, ATC e ARM, de pacientes adultos sintomáticos admitidos na Unidade de Emergência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (UE HCFMRP) no período 03/2014-03/2015, para detecção e estratificação da estenose extracraniana. Foram coletados ainda dados demográficos, clínicos e laboratoriais desses pacientes. Resultados: Observou-se alta acurácia da ATC e da ARM na avaliação de segmentos carotídeos, com sensibilidade de 100% e especificidade variando entre 78% e 100% para estenoses >=50%. Para segmentos vertebrais, observou-se menor acurácia dos métodos, sobretudo da ARM, com valores de sensibilidade e especificidade variando entre 60%-85% e 33-62%, respectivamente, para estenoses >=50%. A prevalência de estenose extracraniana >=50% em nossa população foi de 38,6% e de 23,4% para estenoses >=70%. O segmento vascular mais acometido foi a origem das artérias vertebrais. Os fatores de risco associados a estenose extracraniana foram: sexo masculino, idade avançada, tabagismo e elevada pressão arterial sistólica na admissão. Conclusão: A ATC e ARM representam métodos adequados para investigação de estenoses extracranianas, sobretudo carotídeas. Ambos os métodos, sobretudo a ARM, têm acurácia limitada na avaliação dos óstios vertebrais. / Introduction: Cerebrovascular diseases are considered the second cause of death worldwide and the third cause of years of life lost (YLL)1,2. Large arteries atherosclerosis is one of the main conditions associated with stroke and correlates with higher recurrence rates. Imaging methods such as Doppler, computed tomography angiography (CTA), magnetic resonance angiography (MRA) and intra-arterial angiography (IAA) are available for extra cranial vascular study. Intra-arterial angiography remains the gold standard. Objectives: Evaluate diagnostic accuracy and concordance between CTA, MRA (contrast enhanced) and IAA for extracranial stenosis analysis. Determine frequency and distribution of extra cranial stenosis in a brazilian symptomatic population. Methods: IAA, CTA and MRA exams from adult symptomatic patients admitted between 03/2014 and 03/3015 at the Emergency Unit of Clinics Hospital of Ribeirão Preto\'s School of Medicine were retrospectively reviewed for detection and grading of extra cranial stenosis. Clinical and laboratorial information from patients was obtained. Results: Both CTA and MRA showed high sensitivity (100%) and specificity (78%-100%) in the evaluation of carotid vessels for stenosis >=50%. However, lower sensitivity (60-85%) and specificity (33-62%) were obtained for vertebral segments, Extra cranial stenosis prevalence was 38,6% for stenosis >=50% and 23,4% for stenosis >=70% among our patients. Vertebral artery origins were the most affected segments. Risk factors identified for extra cranial stenosis were: male gender, age, smoking and high systolic blood pressure on admission. Conclusions: CTA and MRA are considered adequate methods for extra cranial stenosis, specially for carotid segments. Both methods have lower accuracy in the investigation of vertebral artery origins.

La sténose aortique (SA) est la maladie valvulaire cardiaque ayant la plus forte prévalence dans les pays occidentaux. On s’aperçoit que, malgré le respect des recommandations pour les indications opératoires, les patients présentent des évolutions très variables après chirurgie : certains patients restent symptomatiques, décèdent précocement, ou présentent une dysfonction ventriculaire gauche persistante. Il a été montré que les patients présentant à la fois une SA en bas débit (c’est-à-dire un volume d’éjection bas), une fraction d’éjection ventriculaire gauche (FEVG) altérée et un gradient de pression entre le ventricule et l’aorte abaissé avaient un pronostic péjoratif, avec un risque opératoire majoré lorsqu’ils subissaient un remplacement valvulaire chirurgical. Il a aussi été récemment démontré que, dans le contexte de la SA, un bas débit peut survenir alors que la FEVG est normale. Les objectifs généraux de ce doctorat sont d’étudier l’impact du débit (plus précisément le volume d’éjection ventriculaire gauche) sur le pronostic des patients atteints de SA, ainsi que l’évolution du débit après intervention et les déterminants de son évolution. Les résultats indiquent que le volume d’éjection ventriculaire gauche, que ce soit avant intervention, ou son évolution après TAVI (Transcatheter Aortic Valve Implantation), sont des prédicteurs indépendants puissants de mortalité chez ces patients. / Aortic stenosis (AS) is the most common valvular heart disease in occidental countries. Despite proper use of the guidelines, some patients can present adverse outcomes after surgery: some of them remain symptomatic, some die prematurely, or suffer from a persistant left ventricular dysfunction. It has been demonstrated that patients presenting an AS with low flow (i.e. low stroke volume), impaired left ventricular ejection fraction (LVEF), and a low transvalvular mean gradient, have poor prognosis, with increased risk during aortic valve replacement surgery. It has also been demonstrated that, in AS, a low flow can occur despite a preserved LVEF. The main goals of this PhD were to evaluate the impact of flow (more precisely left ventricular stroke volume) on the prognosis of patients with AS, the evolution of flow after intervention, and the factors that influence it. The results show that left ventricular stroke volume, before or after intervention, or its evolution after TAVI (Transcatheter Aortic Valve Implantation), are powerful independant predictors of mortality.

O objetivo do presente trabalho foi avaliar a morfologia e a ultraestrutura da hiperplasia intimal arterial decorrente de um modelo de estenose aórtica experimental, através da inserção de um pino de acrílico no orifício da artéria renal esquerda. Realizamos um estudo morfológico e ultraestrutural em 64 ratos Wistar, machos, com peso médio de 250 g, divididos em 4 subgrupos de acordo com o dia da eutanásia (1, 7, 15 e 30 dias de pós-operatório). O segmento da aorta envolvendo o pino foi retirado e estudado com diferentes protocolos para: microscopia óptica de alta resolução, microscopia eletrônica de transmissão e de varredura. Uma trombose se formou ao redor do pino 24 horas após a cirurgia, mostrando sinais de organização com 7 dias. Com 15 dias, uma hiperplasia intimal adjacente à base do pino foi visualizada. Esta alteração permaneceu com 30 dias de pós-operatório. Este espessamento era caracterizado principalmente por células musculares lisas provenientes da camada muscular média. A obstrução gera alterações hemodinâmicas locais com repercussão sobre as células endoteliais localizadas próximas à base do pino. Esses achados são discutidos. / Objective: To study the light and electron microscopy of intimal hyperplasia induced by experimental aortic stenosis after insertion of a plug into the aorta through the left renal artery. Methods: Sixty-four Wistar male rats, weighing an average of 250g, were allocated into two groups: group control, sham-operated, and group experimental, operated. The animals were killed on days 1, 7, 15, and 30 after surgery. The fragments of aorta implicating the plug were excised and studied using high resolution light microcopy and transmission and scanning electron microscopy. Results and Conclusions: A thrombus was observed around the plug 24 hours after surgery, organized at day 7. An intimal hyperplasia could be observed closed to the basis of the plug 15 and 30 days after surgery. The intimal thickening detected was mainly composed of smooth muscle cells migrated from the medial layer of the aorta intermixed with extracellular matrix. Moreover, the endothelial cells around the plug lost their orientation. Theses findings are discussed.

Introdução: Sabe-se que a elevada prevalência da infecção pelo HPV na população sexualmente ativa, associa-se ao desenvolvimento delesões intra-epiteliais cervicais de alto grau e de baixo grau (LIEAG e LIABG). A cirurgia dealta freqüência (CAF) veio contribuir para o tratamento da LIE, substituindo práticas invasivas e onerosas. A população contaminada pelo HPV é composta por pacientes imunocompetentes e imunodeprimidas, especialmente as infectadas pelo HIV, que poderão ter diferente resposta a esta cirurgia. Objetivos:Avaliar a efetividade da CAF no tratamento das LIEAG no colo uterino e a taxa de complicações tardias dessa modalidade terapêutica em pacientes portadoras ou não do HIV e avaliar se a infecção HIV favorece a persistência de LIEAG após a CAF. Pacientes e Métodos: Estudo observacional prospectivo longitudinal onde foram selecionadas 97 pacientes portadoras de LIEAGe tratadas com CAF divididas em dois grupos: 38 pacientes portadoras do HIV e 59 não infectadas por esse vírus, todas atendidas em Hospital Universitário de referência terciária. As pacientes foram submetidas a CAF e reavaliadas com coleta de colpocitologia e colposcopia com três, seis, nove e 12 meses após o procedimento. As taxas de efetividade da CAF consideraram a evolução da doença cervical ao longo do seguimento desses dois grupos de pacientes por um ano. Resultados:Após o seguimento de 12 meses foram observadas situações de cura (citologia e colposcopia normais), melhora (citologia e/ou comcolposcopia com sinais de infecção HPV ou LIEBG) ou de piora da LIEAG inicial (lesão microinvasora/invasora). Sendo assim, foram obtidos para as pacientes portadoras do HIV: 56,7% de cura; 32,4% de melhora e nenhum caso de piora após o tratamento inicial. Para as pacientes não portadoras do HIV os resultados foram: 75,8% de cura; 13,8% demelhora e 1,7% de piora, indicando desfecho clínico mais favorável entre as pacientes não portadoras do HIV (X 2 , p= 0,02). As taxas de estenose de canal cervical entre as pacientes portadoras do HIV (13,5%) não foram estatisticamente diferentes daquelas observadas entre as pacientes não portadoras do HIV (10,5%). A excisão completa da LIE que motivou a CAF ocorreu em 69 (71,2%) pacientes. Entretanto, 21 (21,7%) mulheres tiveram excisão incompleta com margens da peça cirúrgica comprometida pela LIE. Dessas 21 pacientes que apresentaram margens da peça cirúrgica comprometidas apenas cinco tiveram necessidade de novo tratamento. Também foram submetidas a novo tratamento três das mulheres que tiveram margens cirúrgicas livres da peça excisada e uma paciente com a margemcirúrgica carbonizada. Conclusões: Não foi encontrada diferença estatisticamente significativa entre os dois grupos estudados em relação ao número de complicações após a realização da CAF e também na necessidade de novo tratamento no caso de mulheres portadoras do HIV. Entretanto, o desfecho clínico favorável (cura e melhora) para essa população estudada foi significativamente melhor para as pacientes não portadoras do HIV que para as infectadas por esse vírus após um ano de seguimento pós-CAF. A recidiva da LIEAG é mais freqüente em pacientes com margens cirúrgicas comprometidas, independente da presença da infecção pelo HIV. / Introduction: It is known that the high prevalence of HPV infection in the sexually active population is associated with the development of high and low-grade squamous intraepithelial lesions (HSIL and LSIL). Loop electrosurgical excision procedure (LEEP) has contributed to the treatment of SIL, replacing invasive and expensive procedures. The population contaminated with HPV consists of immunocompetent and immunodepressed patients, especially HIV-infected patients, who may respond differently to this surgery Objectives:To assess the effectiveness of LEEP in the treatment of HSIL in the uterine cervix and the rate of late complications of this therapeutic modality in patients infected or not with HIV and to determine whether HIV infection predisposes to the persistence of HSIL after LEEP. Patients and Methods: This was a prospective longitudinal observational study conducted on 97 patients with HSIL and treated with LEEP who were divided into two groups: 38 HIV-infected and 59 non-HIV-infected patients attended at a tertiary reference University Hospital. The patients were submitted to LEEP and re-evaluated bycolpocytology and colposcopy at three, six, nine and 12 months after the procedure.The rates of LEEP effectiveness were determined on the basis of the evolution of cervical disease along a one year follow-up of the two groups of patients Results:After a follow-up of 12 months, situations of cure (normal cytology and colposcopy), improvement (cytology and/or colposcopy with signs of HPV infection or HSIL) or of worsening of the original HSIL (microinvasive/invasive lesion) were observed. On this basis, the followingresults were obtained for HIV-infected patients: 55.2% of cure, 34.3% of improvement and no case of worsening after the initial treatment. For non-HIV-infected patients, the results were: 75.4% of cure, 14.1% of improvement and 1.7% of worsening, indicating a more favorable clinical outcome among non-HIV-infected patients (X 2 , p= 0.02). The rates of cervical canal stenosis among HIV-infected patients (13.5%) did not differ significantly from those among non-HIV-infected patients (10.5%). Complete excision of the SIL that motivated LEEP occurred in 69 (71.2%) patients. However, in 21 (21.7%) women, excision was incomplete, with SIL involvement of the margins of the surgical piece. Of these 21 patients with compromised surgical piece margins, only five required new treatment. Three of the women whose surgical margins were freeof disease and one patient with a carbonized surgical margin were also submitted to new treatment. Conclusions:No statistically significant difference was detected between the two groups regarding the number of complications after LEEP or also regarding the need for new treatment among HIV-infected women. However, a favorable clinical outcome (cure and improvement) for this population was significantly better for non-HIV-infected patients than for HIV-infected patients after one year of post-LEEP follow-up. HSIL recurrence was more frequent among patients with involved surgical margins regardless of the presence of HIV infection.

Introdução: O transplante renal é a terapia substitutiva de escolha para a insuficiência renal crônica. O número absoluto de transplantes renais vem aumentando mundialmente e consequentemente as complicações deste procedimento têm sido evidenciadas com maior recorrência, dentre elas a estenose na artéria renal transplantada. A técnica endovascular vem mostrando bons resultados iniciais, com boa taxa de perviedade e baixa taxa de complicações pósoperatórias quando comparadas a técnica aberta para tratamento da estenose. O objetivo deste estudo foi avaliar os resultados primários da angioplastia da artéria renal do rim transplantado secundário a processo de re-estenose. Métodos: Realizado estudo retrospectivo no período de setembro de 2009 a outubro de 2015, baseado em protocolos de seguimento pós-transplante com perfil dos pacientes submetidos a tratamento por estenose em artéria de rim transplantado e o seguimento em curto prazo com critérios clínicos, laboratoriais e ultrassonográficos. Resultados: Dentre um total de 391 transplantes, 19 pacientes foram diagnosticados com Estenose na Artéria renal transplantada. Evidenciado um tempo médio entre o transplante e o diagnóstico de 172,6 dias. As estenoses ou acotovelamentos com alterações hemodinâmicas foram evidenciadas na anastomose (47%), no terço proximal (35%) e terço médio (18%) da artéria transplantada. Todos os pacientes foram submetidos a angioplastia com balão e posicionamento de stent metálico com sucesso técnico de 94,7 %. A creatinina média evoluiu de 3,63 mg/dl para 2,69 mg/dl em 24h e para 1,81 mg/dl em 30 dias (p<0.05). A taxa de filtração glomerular melhorou de 32,66 ml/min para 41,61 ml/min após 24 horas e 51,05 ml/min após 30 dias (p<0.05). Os critérios ultrassonográficos avaliados de velocidade da artéria renal e índice reno-iliaco (368,9 cm/seg e 3,71 pré angioplastia) normalizaram e se estabilizaram durante o período estudado (211,45 cm/seg e 1,69 90 dias pós angioplastia; p<0.05). Conclusão: A abordagem endovascular utilizando de angioplastia primária e colocação de stent metálico foi segura com boa uma taxa de sucesso técnico. O procedimento foi efetivo na melhora da função renal do enxerto transplantado e na correção das alterações ultrassonográficas evidenciadas no pré-operatório. / Introduction: Renal transplantation is the substitutive therapy of choice for chronic renal failure. The absolute number of renal transplants has increased worldwide and consequently the complications of this procedure have been evidenced with greater recurrence, among them stenosis in the transplanted renal artery. The endovascular technique has shown good initial results, with good patency rate and low rate of postoperative complications when compared to the open technique for stenosis treatment. The aim of this study was to evaluate the primary results of ATP from the renal artery of the transplanted kidney secondary to the restenosis process. Methods: A retrospective study was carried out from September 2009 to October 2015, based on post-transplant follow-up protocols with a profile of patients submitted to stenosis in a transplanted kidney artery and a short-term follow-up with clinical, laboratory and ultrasonographics criteria. Results: Out of a total of 391 transplants, 19 patients were diagnosed with transplanted renal artery stenosis. An average time between transplantation and the diagnosis of 172.6 days was evidenced. Stenting or flexing with hemodynamic changes were evident in the anastomosis (47%), in the proximal third (35%) and the middle third (18%) of the transplanted artery. All patients underwent balloon angioplasty and metallic stent placement with technical success of 94.7%. Mean creatinine increased from 3.63 mg / dL to 2.69 mg / dL in 24 hours and to 1.81 mg / dL in 30 days (p <0.05). The glomerular filtration rate improved from 32.66 ml / min to 41.61 ml / min after 24 hours and 51.05 ml / min after 30 days (p <0.05). The ultrasound criteria evaluated for renal artery velocity and reno-iliac index (368.9 cm / sec and 3.71 pre angioplasty) normalized and stabilized during the study period (211.45 cm / sec and 1.69 Angioplasty, p <0.05). Conclusion: The endovascular approach using primary angioplasty and stent placement was safe with good technical success rate. The procedure was effective in improving the renal function of the transplanted graft and in correcting the ultrasound changes evidenced in the preoperative period.

Subglottic stenosis (SGS) is a narrowing of the airway in the region of the cricoid cartilage below the vocal folds and above the tracheal rings. Individuals with SGS experience difficulty breathing at rest and during exertion both of which become increasingly difficult with the level of stenosis severity. Some individuals also experience negative voice changes. Individuals whose stenoses significantly impact breathing generally require medical procedures or surgery, either balloon dilation or cricotracheal resection (CTR). CTR has been shown to improve patients' ability to breathe, but it can also result in permanent vocal changes. Alternatively, balloon dilation results in similar breathing improvements but for a relatively short period of time. Many studies have been published on the effectiveness of CTR; however, only a few have examined the effects of CTR on vocal production. The purpose of this study is to quantify the acoustic and auditory-perceptual features of subglottic stenosis and examine possible acoustic and auditory-perceptual changes in voice production following a revised CTR aimed to minimize voice impact in a group of women. A retrospective chart review identified women with idiopathic SGS who received revised CTR at The University of Utah Voice Disorders Center between 2008 and 2014. Presurgical and postsurgical groups included patients with both pre and post recordings (n = 11) as well as patients with only pre (n = 6) or post (n = 9) recordings. Acoustic quantification of voice signal periodicity, as well as cepstral, spectral, and fundamental frequency (F0) analyses were performed. Auditory-perceptual ratings of overall quality and monotonicity were performed. Cross-sectional and pre-post surgery analyses were completed. Aggregate analyses revealed that both pre and posttreatment SGS patients demonstrated voice disorders in the mild to moderate severity range. Pre-post comparisons indicated no significant voice change after surgery. Mean fundamental frequency decreased from 215 Hz (SD = 40 Hz) to 201 Hz (SD = 65 Hz). Voice disorder severity based on the cepstral spectral index of dysphoniaTM for sustained vowels decreased (i.e., improved) from 41 (SD = 41) to 25 (SD = 21) points. Semitone standard deviation (2.2 semitones) was equivalent from pretreatment to posttreatment. Auditory-perceptual ratings demonstrated similar results. These preliminary results indicate that the revised CTR procedure is promising in minimizing adverse voice effects. Future research is needed to determine causative factors for pretreatment voice disorders, as well as to optimize treatments in this population.

Le rétrécissement aortique calcifié dégénératif (RAC) représente la principale pathologie valvulaire cardiaque dans les pays occidentaux (2% à 7% de la population après 65 ans). Il n’existe, à ce jour, aucun traitement médical qui permette de stopper ou de prévenir la progression du RAC. Le seul traitement du RAC sévère est le remplacement valvulaire aortique chirurgical ou par cathétérisme (TAVI) en cas de symptômes (dyspnée,douleur thoracique ou syncope), de dysfonction ventriculaire gauche (FEVG<50%) ou de mauvaise tolérance fonctionnelle lors d’un test d’effort. À l’inverse, la prise en charge des patients asymptomatiques avec un RAC sévère est controversée devant le risque de mort subite ou de détérioration myocardique irréversible sans traitement et le risque de la chirurgie cardiaque prophylactique et des complications prothétiques. De plus, le RAC intéresse une population de plus en plus âgée où la présence de symptômes peut être difficilement évaluable et où s’associent des facteurs de risques et des comorbidités cardiovasculaires rendant la stratégie clinique de plus en plus compliquée. Enfin, il semble que parmi les patients avec un RAC serré asymptomatique, certains sont à plus haut risque d’évènements et bénéficieraient peut être d’une chirurgie plus précoce. L’identification de marqueurs de progression et pronostiques objectifs dans ce sous-groupe de patients constitue donc un enjeu très important. / Aortic valve stenosis (AS) is the most common valvular heart disease in Westerncountries AS (2%–7% of the population after 65 years old) for which valve replacement is theonly curative treatment. Current guidelines recommend surgery in patients with severe ASand either symptoms or left ventricular systolic dysfunction (LVEF<50%). However,treatment of asymptomatic patients remains controversial due, on the one side, to the riskof sudden death without preceding symptoms and irreversible myocardial dysfunction and,on the other side, to the risk of surgery and prosthetic valve complications. Identifyingsubsets of asymptomatic AS patients with preserved left ventricular ejection fraction whomay benefit from early or prophylactic surgery is therefore a critical clinical challenge.

Le rétrécissement aortique (RAo) est la valvulopathie la plus fréquente dans les pays industrialisés. Il entraine une augmentation chronique de la postcharge imposée au ventricule gauche (VG) se caractérisant par une hypertrophie ventriculaire gauche (HVG), une ischémie et une fibrose myocardique, une dysfonction diastolique et à long terme une insuffisance cardiaque. Indépendamment de la sévérité de la valvulopathie, plusieurs facteurs comme l’obésité, le diabète, l’insulinorésistance semblent influencer le remodelage ventriculaire dans cette condition. Ces troubles métaboliques sont associés à un état pro-inflammatoire, notamment du tissu adipeux, impliquant des médiateurs également associés à l’hypertrophie cardiomyocytaire et la fibrose myocardique. A l’heure actuelle, le remplacement valvulaire aortique (RVAo) chirurgical est le seul traitement ayant montré son impact sur la diminution de la morbi mortalité dans le RAo. Cette chirurgie est devenue peu risquée de nos jours et permet une diminution conséquente de la masse ventriculaire gauche (MVG) dans la première année. Néanmoins certains facteurs, en particulier un remodelage important en préopératoire et l’existence d’un mismatch patient-prothèse (PPM), semblent influencer le remodelage inverse après la chirurgie pouvant expliquer la persistance d’une fibrose myocardique ou de symptômes après l’opération. Nous avons émis les hypothèses suivantes : a) un état pro inflammatoire médié par le tissu adipeux épicardique (TAE) et les leucocytes circulants serait associé à un remodelage pathologique dans l’histoire naturelle du RAo, b) l’existence d’un PPM après RVAo serait associé à un moins bon pronostic indépendamment du poids corporel, c) l’horloge biologique jouerait un rôle dans la modulation de la réponse myocardique à un stimulus hypertrophique et à l’ischémie myocardique, d) l’apparition d’une dysfonction ventriculaire droite (VD) postopératoire, serait associée à un mauvais pronostic après RVAo. Nous avons donc inclus prospectivement les patients porteurs d’un RAo serré sans dysfonction VG, sans autre valvulopathie, adressés depuis 2009 au Centre des Valvulopathies du CHRU de Lille pour un premier RVAo. Une évaluation clinique, biologique ainsi qu’une échocardiographie transthoracique (ETT) pré et postopératoire (avant la sortie) ont été réalisées. Pour une partie de la population, différents prélèvements biologiques (sang et TAE) ont été effectués au moment du bloc opératoire afin de réaliser des analyses de transcriptomique sur le TAE et de cytométrie en flux sur les cellules sanguines circulantes. Une partie de la population a également été revue en ETT à 1 an et tous les patients ont été suivis à distance. Nous avons pu montrer que : a) la quantité de TAE était indépendamment associée à un remodelage VG plus sévère dans le RAo mais n’était pas associée à l’importance du remodelage inverse après RVAo. D’après nos premiers résultats, ce remodelage VG plus sévère semble associé à une dysrégulation de gènes impliqués dans la réponse immunitaire adaptative, dans la régulation de la réponse immunitaire et dans l’activation des cellules lymphocytaires T et également à un nombre de leucocytes et de monocytes circulants plus important, b) une surface fonctionnelle indexée de la prothèse aortique implantée lors du RVAo de moins de 0,85 cm²/m² était le paramètre valvulaire le plus puissant pour prédire les évènements cardiovasculaires à distance de l’opération chez les patients non obèses. De manière surprenante, chez les patients obèses aucune association n’était retrouvée entre cette surface fonctionnelle et le devenir des patients après RVAo, c) il existe une variation circadienne de la tolérance à l’ischémie-reperfusion imposée lors du RVAo [...] / Aortic stenosis (AS) is the most common valvular heart disease (VHD) in Western countries. It causes a chronic increase in left ventricular (LV) afterload characterized by left ventricular hypertrophy (LVH), ischemia and myocardial fibrosis, diastolic dysfunction and long-term heart failure. Regardless of the severity of stenosis, several factors such as obesity, diabetes, insulin resistance seems to impact the LV remodeling in this condition. These metabolic disorders are associated with a pro-inflammatory state, including adipose tissue, involving mediators perceived in cardiomyocyte hypertrophy and myocardial fibrosis. To date, surgical aortic valve replacement (SAVR) is the only option that has shown an impact on mortality. This surgery has become less risky and leads to a significant decrease in the left ventricular mass (LVM) in the first year. Nevertheless, some factors, including the existence of a patient-prosthesis mismatch (PPM), seem to influence this reverse remodeling after surgery, which may explain the persistence of myocardial fibrosis or symptoms after the surgery. We have made the following hypotheses: a) a pro-inflammatory state mediated by epicardial adipose tissue (EAT) and circulating leukocytes would be associated with pathological remodeling in the natural history of AS, b) the existence of a PPM after SAVR would be associated with a poorer prognosis regardless of body weight status, c) the circadian clock would play a role in modulating the myocardial response to a hypertrophic stimulus and myocardial ischemia, d) the onset of postoperative right ventricular (RV) dysfunction, would be associated with poorer prognosis after SAVR. We therefore prospectively included patients with severe AS without LV dysfunction, or another VHD, referred to our Heart Valve Center in Lille University Hospital since 2009 for a first SAVR. Clinical and biological evaluation and pre- and postoperative (before discharge) trans-thoracic echocardiography (TTE) were performed for all patients. In a sub-group of patients, biological samples (blood and TAE) were collected at the time of surgery to perform transcriptomic analysis on EAT and flow cytometry on the circulating blood cells. TTE was also performed 1-year after SAVR in a sub-group and all patients were followed-up for cardiovascular events. We found that: a) the amount of EAT was independently associated with worse LV remodeling in AS but not with the magnitude of reverse remodeling after SAVR. According to our first results, this more severe LV remodeling seems to be associated with dysregulation of genes involved in the adaptive immune response, in the regulation of the immune response and in the activation of T lymphocyte cells and also with a number of circulating leukocytes and monocytes more important, b) the indexed effective orifice area of the aortic prosthesis calculated by TTE with the unique cut-off of 0.85cm²/m² showed the best accuracy to predict major events after SAVR in lean or overweight patients but not in obese, c) perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing SAVR, with poorer tolerance in patients operated on in the morning, d) heart failure is more frequently observed in patients operated on in the morning, unrelated to the occurrence of acute kidney injury after SAVR, e) the early and severe post-operative decline in RV longitudinal function reverses within a year and is not predictive of long-term outcomes after SAVR. Subsequently, we will continue to explore the link between adipose tissue and the natural course of LV remodeling, cardiovascular events after SAVR in particular the impact of circadian variations on the occurrence of heart failure and the RV function after SAVR.

Orientador: Mauro Pedrine Santamaria / Coorientador: João Manoel Theotonio dos Santos / Banca: Maria Aparecida Neves Jardini / Banca: Germano Emilio Conceição Souza / Resumo: A doença arterial coronária (DAC), assim como a doença periodontal (PD) são patologias muito prevalentes e apresentam vias em comum na sua fisiopatologia que é a inflamação crônica. A angioplastia coronária percutânea com implante de stent se estabeleceu como a principal forma de revascularização miocárdica no tratamento da DAC porém cerca de 16% a 44% dos pacientes podem evoluir com reestenose do stent. Se a doença periodontal, pelo seu estado inflamatório sistêmico crônico estaria contribuindo para um aumento nas taxas de reestenose de stents convencionais não está definido e não é uma rotina na prática clínica a avaliação da cavidade oral antes de um procedimento de angioplastia coronária. O objetivo primário do estudo foi avaliar a correlação entre a doença periodontal com a incidência de reestenose do stent, enquanto os objetivos secundários foram avaliar a prevalência da doença periodontal, o número de dentes, o grau de perda óssea e finalmente a gravidade da doença periodontal na população do estudo. Para isto realizamos um estudo pioneiro, retrospectivo, caso controle e em um único centro no período de janeiro de 2016 a fevereiro de 2018. Foram analisados 1685 exames de cinecoronariografia dos quais 283 apresentavam imagem de stent com e sem reestenose sendo incluídos 49 pacientes separados entre o grupo caso, com reestenose (n=15) e o grupo controle, sem reestenose (n=34). Excluímos os pacientes portadores de Diabetes Mellitus (DM) não controlados, portadores de sten... (Resumo completo, clicar acesso eletrônico abaixo) / ABSTRACT: Coronary artery disease (CAD), as well as periodontal disease (PD) are very prevalent pathologies and present common pathways in their pathophysiology which is chronic inflammation. Percutaneous coronary angioplasty with stent implantation has been established as the main form of myocardial revascularization in the treatment of CAD but about 16% to 44% of patients may evolve with stent restenosis. If periodontal disease, because of its chronic systemic inflammatory state would be contributing to an increase in the rates of restenosis of conventional stents is not defined and it is not a routine in clinical practice to evaluate the oral cavity before a coronary angioplasty procedure. The primary objective of the study was to evaluate the correlation between periodontal disease and the incidence of stent restenosis, while the secondary objectives were to evaluate the prevalence of periodontal disease, number of teeth, degree of bone loss and finally severity of periodontal disease in the study population. For this, we conducted a pioneering, retrospective, case control and single-center study from January 2016 to February 2018. We analyzed 1685 coronary angiography exams, of which 283 presented stent imaging with and without restenosis and 49 patients were separated between the case group, with restenosis (n = 15) and the control group, without restenosis (n = 34). We excluded patients with uncontrolled diabetes mellitus (DM), those with stents of the pharmacological type or those with restenosis from stents implanted more than two years ago. For statistical analysis, the chi-square test in the qualitative variables, ANOVA test for quantitative variables, Odds Ratio calculation and Equality of Two Proportions test were used to compare the restenosis groups with the distribution of the type of periodontal disease. We found no statistically significant ...(Complete abstract click electronic access below) / Mestre

Experiments described in this thesis address the pathogenesis of aortic valve sclerosis/stenosis using a bench to bedside approach. In particular, the thesis begins with development of a technique using ultrasonic backscatter analyses to quantitate the early stages of aortic stenosis. Subsequent chapters utilized this methodology to quantitate aortic valve structural changes in a model and intervention study of aortic stenosis in rabbits. The last chapters are human studies designed to identify factors associated with presence of aortic sclerosis/stenosis; with particular interest in potential association of endothelial dysfunction/inflammation/platelet aggregation with abnormal aortic valve structure quantitated by ultrasonic backscatter. In Chapter 1 (Introduction) the relevant literature is reviewed. Development of ultrasonic backscatter to quantitate aortic sclerosis (Chapter 2) Aortic valve sclerosis (ASc) is detected when there is visual assessment of focal increases in echogenicity of the aortic valve most commonly assessed by echocardiography. However, there is no previously described method to quantitate degree of aortic valve structural abnormality as ASc is not associated with marked hemodynamic obstruction quantifiable by Doppler echocardiography. The current study used ultrasonic backscatter to quantitate aortic valve structural abnormality in patients assessed as having ASc based on valve appearances, compared to young healthy volunteers with normal aortic valves. The results of the study indicate: 1) that the mean levels of aortic valve backscatter in ASc patients are approximately 60% greater than in young healthy volunteers (ie aortic valve backscatter scores ≥ 16dB are not consistent with normal aortic valve structure), 2) ultrasonic backscatter scores in ASc patients are directly correlated with subjective scoring of sclerosis and with a positive trend with transvalvular pressure gradients in patients with mild-moderate aortic stenosis, and most importantly, 3) ultrasonic backscatter is a reproducible technique, with mean differences between estimates based on repeat echocardiograms of 2.3 ± 1.7 (9.1%). These results indicate that ultrasonic backscatter could be used as a quantitative measure of aortic valve structural abnormality in epidemiology and for examination of interventions. In vivo studies Development of an animal model of aortic stenosis with vitamin D2 (Chapter 3) The aim of the study was to develop an appropriate animal model for AS. The study used vitamin D2 alone at 25,000IU/4 days weekly (vit-D2) for 8 weeks to induce AS in rabbits. Results showed that: 1) rabbits in the vit-D2 group had significantly increased in transvalvular velocity and pressure gradients compared to rabbits in the control group (normal chow + drinking water); this was consistent for aortic valve ultrasonic backscatter scores; 2) aortic valve immunohistochemistry/histology showed marked calcification, neutral lipids, macrophage, and leukocyte infiltrations for rabbits in the vit- D2 group (ie consistent with histology of human AS); 3) significant elevation of asymmetric dimethylarginine (ADMA) concentrations in the vit-D2 group occurred compared to controls over the 8 weeks treatment period; the change in ADMA concentrations correlated significantly with the change in transvalvular pressure gradients for rabbits in the vit-D2 group; 4) rabbits in the vit-D2 group had significantly impaired endothelium-dependent acetylcholine-induced aortic relaxation, and this effect was completely abolished by the nitric oxide synthase inhibitor (L-NAME); 5) the addition of 0.5% cholesterol-supplemented diet to the vitamin D2 regimen did not accentuate the development of AS. Thus, treatment with vitamin D2 at 25,000IU/4 days weekly for 8 weeks significantly induced AS with similar aortic valve pathology to that of human AS; therefore, the model is suitable for use in examining potential therapeutic interventions in AS. Effects of ramipril on development of AS in rabbits (Chapter 4) Using this animal model, this study aimed to examine the effects of the angiotensinconverting enzyme inhibitor (ACEi) ramipril on development of AS. Rabbits (n=28) treated for 8 weeks were divided into 2 groups: (a) vitamin D2 alone (n=10) (normal chow + 25,000IU vitamin D2 in drinking water); (b) vitamin D2/Ramipril (n=12) (normal chow+25,000IU vitamin D2/Ramipril (0.5mg/kg) in drinking water). Six further rabbits constituted a normal reference group (no treatment was given). The results for comparisons between vitamin D2/ramipril vs vitamin D2 alone were as follows: 1) ramipril-treated rabbits had significantly less severe hemodynamic obstructions (p<0.05, for both) as assessed by transvalvular velocity, and aortic valve area; with borderline reduction in aortic valve backscatter (p=0.08); 2) ramipril significantly reduced plasma ADMA concentrations; 3) there was improvement in acetylcholine-induced aortic relaxation (p=0.056), with significant improvement in sodium nitroprusside-induced relaxation (p<0.05); 4) there was a strong inverse correlation between acetylcholineinduced aortic relaxation and aortic valve backscatter score (0<0.001), thus providing further evidence of the potential role of nitric oxide in retarding the development of AS in this model. These data provide a strong rationale for the inception of a randomized trial of ACE inhibition as a strategy for limitation of AS progression in humans. Human studies Aortic stenosis is associated with elevated plasma levels of asymmetric dimethylarginine (ADMA) concentrations in humans (Chapter 5). Given the findings that aortic stenosis induced by vitamin D2 in rabbits also caused elevation of plasma ADMA concentrations, a physiological inhibitor of nitric oxide synthase, a mediator and marker of endothelial dysfunction and an indicator of incremental cardiovascular risk. The study sought to determine whether plasma ADMA concentrations are elevated independently of pre-existing coronary risk factors in subjects with at least moderate aortic stenosis (n=42) compared to age-matched patients with normal aortic valves (n=42): as determined both by visual assessment and with aortic valve backscatter scores < 16dB. Results for this study were as follows: 1) plasma ADMA concentrations were not statistically different between the AS and non-AS group (median 0.59 vs 0.54 µmol/L, p=0.13, Mann-Whitney test) on univariate analysis; 2) backward stepwise multiple linear regression showed the presence of AS was a significant predictor of elevated ADMA concentrations (p=0.04, 95% CI =0.001, 0.072). 3) in addition, elevated plasma ADMA concentrations were also associated with history of atrial fibrillation (p=0.009, 95% CI=0.015, 0.100), and negatively associated with creatinine clearance (p=0.01, 95% CI=-0.002, 0.000), and the use of statin therapy (p=0.01, 95% CI=-0.081, -0.011). Therefore, in conclusion, this study found that AS is independently associated with elevation of ADMA concentrations, beyond that implied by “conventional” risk factors for endothelial dysfunction. The clinical status of AS as an incremental marker of cardiovascular risk may reflect ADMA-mediated endothelial dysfunction. Assessment of factors associated with ASc in a random ageing population study (Chapter 6). There have been few clinical studies of factors associated with ASc. Previous population studies have established that ASc is an independent correlate of incremental risk of coronary events. Having established that patients with AS have increased plasma ADMA concentrations (Chapter 5), it was now aimed to determine whether subjects with increased aortic valve backscatter scores (ASc) also have other markers of endothelial dysfunction/NO effects, independent of preexisting coronary risk factors. The study was designed to identify such anomalies, if they existed, on an incremental basis to other putative correlates of ASc, including coronary risk factors, renal dysfunction and vitamin D levels. Random selected subjects (n=253) aged between 51 to 77 years were evaluated. All patients underwent transthoracic echocardiography examination; aortic valve ultrasonic backscatter score (AVBS), was used to quantitate echogenicity of the aortic valve. Conventional coronary risk factors were identified on history. Integrity of NO generation/response was assessed via (i) plasma ADMA concentrations; (ii) inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP); (iii) aortic augmentation index (AIx), a measure of arterial stiffness/wave reflection. All putative correlations with AVBS were examined by univariate and stepwise multiple linear regression analyses. On the basis of echocardiographic appearances, ASc was present in 63 subjects (25.4%); mean AVBS scores was 14.9±4.6dB (SD) vs 11.2±3.9dB (SD) in the presence vs absence of ASc (p<0.001). Univariate analyses revealed that platelet responsiveness to NO was inversely correlated with AVBS (β=-0.16, p=0.02); but [ADMA] and AIx were not. On multiple linear regression, significant correlates of increased AVBS were: (i) advanced age (β=0.21, p=0.003), (ii) low body mass index (β=-0.23, p=0.001); and (iii) impaired platelet responsiveness to NO (β=-0.16, p=0.02). In Chapter 7, the implications of the overall findings in this thesis are discussed in relation to future perspective. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1309350 / Thesis(Ph.D.) -- School of Medicine, 2008