Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Ceramic and Materials Science and Engineering." Includes bibliographical references.

Resumo: A exposição à fumaça do cigarro resulta em remodelação cardíaca e está relacionada com disfunção ventricular. A atenuação da remodelação cardíaca pode ser importante para melhor prognóstico cardiovascular. A vitamina D (VD) tem se destacado por seu papel na função cardíaca e por atenuar a remodelação cardíaca em modelos de sobrecarga de pressão ou de volume. Objetivo: avaliar a influência da suplementação de VD sobre a remodelação cardíaca induzida pela exposição à fumaça do cigarro (EFC) em ratos, se a VD atua de forma dose dependente e verificar se esta atuação é por mecanismos anti-inflamatórios ou antioxidantes. Métodos: Ratos machos Wistar com 200 a 250g foram alocados em seis grupos: 1) VD0-NEFC, sem suplementação de VD e não EFC; 2) VD1-NEFC, suplementação de 1000 UI VD/kg de ração e não EFC (n=8); 3) VD3-NEFC, suplementação com 3000 UI VD/kg de ração e não EFC; 4) VD0-EFC, sem suplementação de VD e EFC; 5) VD1-EFC, suplementação de 1000 UI VD/kg de ração e EFC; 6) VD3-EFC, suplementação de 3000 UI VD/kg de ração e EFC. Após dois meses, os animais foram submetidos à ecocardiografia e eutanasiados para coleta de material biológico. Foram avaliados porcentagem de colágeno, área seccional do miócito (ASM), estresse oxidativo e marcadores inflamatórios no tecido cardíaco e dosagens sanguíneas de cálcio, fósforo e do metabólito 25-hidroxicolecalciferol. Os dados foram analisados por ANOVA de duas vias e apresentados em media ± erro-padrão. Foi utilizado teste de tendência (correlação de Spearman) para avaliar a resposta de dose dependência. Resultados: a EFC promoveu maior valor de parede posterior do ventrículo esquerdo (EFC = 1,38 ± 0,03; NEFC = 1,26 ± 0,03; p = 0,009), maior diâmetro diastólico do VE corrigido pela tíbia (EFC = 17,7 ± 0,20; NEFC = 17,0 ± 0,002; p = 0,033), maior massa do VE (MVE) ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Exposure to tobacco smoke (ETS) results in cardiac remodeling and it is associated with ventricular dysfunction. Attenuation of cardiac remodeling may be important for better cardiovascular prognosis. Vitamin D (VD) has become known for its role in cardiac function and VD supplementation attenuate cardiac remodeling in models of pressure or volume overload in previous studies. Objective: To evaluate the influence of VD supplementation on cardiac remodeling induced by ETS in rats and whether VD actions are dose-dependent and if these actions involve anti-inflammatory and antioxidant mechanisms. Methods: Male Wistar rats with 200 to 250g were allocated into six groups: 1) VD0- NETS, with no supplementation of VD and no ETS, 2)-VD1-NETS, supplementation with 1000 IU VD/kg of diet and no ETS (n = 8); 3) VD3-NETS, supplemented with 3000 IU VD/kg of diet and no ETS, 4) VD0-ETS, no supplementation of VD and ETS, 5)VD1-ETS, VD supplementation with 1000 IU/kg of diet and ETS, 6) VD3-ETS, VD supplementation of 3000 IU/kg of diet and ETS. After two months, the animals underwent echocardiography and euthanized for tissue collection. The collagen percentage, myocyte cross-sectional area (MCA), oxidative stress and inflammation biomarkers in cardiac tissue were determined. Blood levels of calcium, phosphorus and 25-hydroxycholecalciferol were also evaluated. Data were analyzed by two-way ANOVA and presented as mean ± standard error. Spearman correlation test was used to evaluate the dose dependent response. Results: ETS promoted greater value of left ventricular posterior wall (ETS = 1.38 ± 0.03; NETS = 1.26 ± 0.03, p = 0.009), LV diastolic diameter corrected by the tibia (ETS = 17.7 ± 0.20, 17.0 ± NETS = 0.002, p = 0.033), higher LV mass (LVM) (ETS = 603 ± 23; NETS = 509 ± 25, p = 0.007), higher LMV index (ETS = 1.8 ± 0.06; NETS = 1.5 ± 0.07, p = 0.004), increased MCA ... (Complete abstract click electronic access below) / Orientador: Sergio Alberto Rupp de Paiva / Coorientador: Leonardo Antonio Mamede Zornoff / Banca: Lilian Cuppari Valle / Banca: Daniela de Rezende Duarte Maksymczuk / Mestre

Orientador: Paula Schmidt Azevedo Gaiolla / Resumo: Introdução: A influência do ácido retinoico (AR) sobre o coração é bastante relevante, ocorrendo durante a embriogênese, diferenciação e desenvolvimento cardíaco. Estudos experimentais mostram que o AR pode induzir hipertrofia excêntrica com melhora da função cardíaca em coração de ratos sadios, e também reduzir a hipertrofia, modulando o sistema renina angiotensina aldosterona (SRAA), em animais hipertensos. Pouco se sabe sobre os efeitos do AR em coração de humanos. Pacientes portadores de acne fazem uso de um tipo de AR que é o 13- cis-AR, também chamado de isotretinoína e por isso possibilitam o estudo do papel do AR em humanos. Estudo prévio mostrou que com 2 meses de uso do 13-cis-AR houve remodelação cardíaca. Entretanto, não se sabe sobre os mecanismos ou se essas alterações são reversíveis. Objetivos: Portanto, os objetivos desse trabalho foram de comparar a avaliação morfofuncional cardíaca e variáveis do SRAA entre pacientes em uso de isotretinoína com um grupo controle. Adicionalmente, avaliar se as alterações são reversíveis em pacientes em uso de isotretinoína. Casuística e Métodos: Foram estudados 35 adolescentes e adultos jovens, com idade entre 14 e 23 anos, do sexo masculino, sendo 20 deles em uso de isotretinoína oral, na dose de 0,5 mg/kg/dia a 0,75 mg/kg/dia, acompanhados no ambulatório de dermatologia do Hospital das Clínicas da Faculdade de Medicina de Botucatu (FMBUNESP), aos 6 meses de tratamento. Os outros 15 pacientes foram convidados na comunidade ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: The influence of retinoic acid (RA) in the heart is very relevant, occurring during the embryogenesis, differentiation and cardiac development. Experimental studies shown that RA induces excentric hypertrophy, with improvement of cardiac function in heart of healthy rats. In addition, it was observed that RA regulates renin angiotensin aldosterone system (RAAS), a regulatory system involved in blood pressure, volume homeostasis and cardiac hypertrophy. There is a lack of information about the role of RA on cardiac remodeling in adult humans. Otherwise there are patients with Acne that uses 13- cis-RA, also called isotretinoin, and this population allow the investigation of cardiac remodeling and RA treatment. In fact, previously study shown that the use of 13-cis-RA, for acne, for 2 months induced cardiac remodeling, however, no one knows if these changes are persistent and reversible. Objectives: the objectives of these study is to compare the cardiac morphofunctional evaluation and RASS variables in patients using isotretinoin and in control group. Additionally, evaluate if these changes are reversible in isotretinoin group. Casuistic and Methods: Study1: 35 young men, between 14 to 23 years, 20 in use of 13-cis-RA, in the dose of 0,5 mg/kg/day to 0,75 mg/kg/day, from dermatology clinic of São Paulo State University (FMB-UNESP), at 6 months of treatment. The others 15 patients had mild acne only with topic treatment. Morphofunctional evaluation, tissular Doppler... (Complete abstract click electronic access below) / Doutor

Orientador: Carlos Roberto Padovani / Resumo: Em muitas situações, existe a necessidade de estudar o comportamento de alguma característica em uma mesma unidade amostral ao longo do tempo, dose acumulada de algum nutriente ou medicamento. Na prática, a estrutura dos dados dessa natureza geralmente estabelece comportamentos não lineares nos parâmetros de interesse, já que estes caracterizam melhor a realidade biológica pesquisada. Essa conjuntura é propícia ao estudo de remodelação cardíaca (RC) por sobrecarga pressórica em ratos submetidos a diferentes manobras sequenciais de cálcio. Como o comportamento da RC não está claramente estabelecido, o objetivo deste trabalho consiste em fazer um estudo comparativo sobre a performance de quatro modelos de curvas de crescimento em quatro grupos experimentais, considerando erros normais $\theta$ generalizado multivariado. Além disso, a modelagem dos dados envolve duas estruturas de covariância: a homocedástica com a presença de autocorrelação lag 1 e a heterocedástica multiplicativa. No contexto metodológico, utiliza-se o procedimento de estimação por máxima verossimilhança com a aplicação da técnica de reamostragem bootstrap. Além disso, técnicas de simulações são implementadas para comprovação das propriedades metodológicas aplicadas. Para comparação entre os modelos, utilizam-se alguns avaliadores de qualidade de ajuste. Conclui-se, no presente estudo, que a estrutura homocedástica com autocorrelação lag 1 para os modelos Brody e de Von Bertalanffy, destacam-se por apresentar ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Many situations, there is a need to study the behavior of some characteristic in the same sample unit over time, accumulated dose of some nutrient or medication. In practice, the structure of data of this nature generally establishes non-linear behaviors in the parameters of interest, since these characterize better the biological reality researched. This situation is favorable to the study of cardiac remodeling (CR) by pressure overload in rats submitted to different sequential calcium maneuvers. As the behavior of CR is not clearly established, the objective of this work is to perform a comparative study on the performance of four models of growth curves in four experimental groups, considering normalized multivariate θ standard errors. In addition, the data modeling involves two covariance structures: the homocedastic with the presence of autocorrelation lag 1 and the multiplicative heterocedastic. In the methodological context, the procedure of estimation by maximum likelihood is used with the technique of bootstrap resampling. In addition, simulation techniques are implemented to prove the methodological properties applied. For the comparison between the models, some adjustment quality evaluators are used. It is concluded in the present study that the homocedastic structure with lag 1 autocorrelation for the Brody and Von Bertalanffy models stands out for presenting excellent estimates and good quality of adjustment of the maximum developed stress (TD) as a function of t... (Complete abstract click electronic access below) / Doutor

Nesta investigação realizamos um estudo de caso no âmbito da formação do Engenheiro Agrônomo no curso de Agronomia da Universidade Federal do Rio Grande do Sul (UFRGS). A primazia foi pelo diagnóstico da reformulação curricular iniciada em 2006 e implantada em 2009 frente às adequações do curso às Diretrizes Curriculares Nacionais. Sendo assim, realizamos um estudo, buscando detectar quais foram as contribuições na dinâmica curricular, metodológica, institucional e organizacional e, se estas criaram subsídios eficazes e inovadores para o desenvolvimento do curso. Para atingirmos nossos objetivos realizamos análise documental e de conteúdo nas Diretrizes Curriculares Nacionais para o Curso de Agronomia, nas Atas da Comissão de Reestruturação do Currículo, nas Atas de reuniões da Comissão de Graduação e no Projeto Pedagógico do Curso. Também, sistematicamente triangulamos dados oriundos das avaliações institucionais dos docentes e disciplinas, reuniões de planejamento, questionários, entrevistas, fóruns de debate para docentes e discentes via plataforma Moodle, disponibilizados no Portal da UFRGS. Os resultados apontam que o processo de reformulação curricular propiciou algumas mudanças significativas nos princípios educativos e nos elementos estruturais, componentes essenciais para a construção de um novo modelo pedagógico de formação para o Engenheiro Agrônomo e, também inovou quanto à estrutura da matriz curricular que compõe o conhecimento profissional. Diante dos dados levantados, entendemos que as configurações curriculares analisadas contemplam e condizem plenamente para uma formação de profissionais integrando formação técnica à social. Os argumentos para a defesa da tese foram construídos com as contribuições de vários autores tais como Apple (1989); Bardin (2006); Flick (2009); Lopes (1999, 2004); Lüdke (1986); Minayo (2007, 2011); Moreira (1994,1997; ); Nora (1993); Richardson (1989); Sacristán (2000); Santomé (1998); Silva (1993, 2005); Stenhouse (1987); Triviños (2009); Yin (2005), entre outros. / This research is a case study on the Graduating Course in Agronomy Engineering of the Brazilian Federal University in the state of Rio Grande do Sul (Universidade Federal do Rio Grande do Sul - UFRGS). The emphasis was on diagnosing the curricular remodeling, which began in 2006 and was implemented in 2009, such remodeling came to suit the adjustments of the national curricular guidelines. Thus, we conducted a study aiming to detect which were the contributions on organizational, institutional, methodological and curricular dynamics and if those contributions made up to effective and innovating subsidies to the course development. In order to achieve our aims, we went through documental analysis on the national curricular guidelines to the Agronomy Course. That was done also on the curricular remodeling protocols, the graduation commission meeting protocols and the course’s pedagogical project. Further, we systematically crossed the date originated from professors and courses’ evaluations, planning meetings, questionnaires, interviews, professors and students debate forums on Moodle, all of which available on UFRGS’s web portal. The results point to that the curricular remodeling process provided some meaningful changes in the educational principles and the structural elements, such components are essential to the building of a new graduating pedagogical model of the Agronomist Engineer. It also innovated the curriculum structure which draws up the professional knowledge. Giving the data collected, we understand that the analyzed curricular settings fully contemplate and favor the formation of professionals, integrating technical and social education. The theoretical bases for this thesis were upon the contribution of various authors, e.g. Apple (1989); Bardin (2006); Flick (2009); Lopes (1999, 2004); Lüdke (1986); Minayo (2007, 2011); Moreira (1994, 1997); Nora (1993); Richardson (1989); Sacristán (2000); Santomé (1998); Silva (1993, 2005); Stenhouse (1987); Triviños (2009); Yin (2005).

Background: Pulmonary arterial hypertension (PAH) is a lethal disease for which the fundamental molecular mechanisms are only partially understood. Existing therapies, which primarily focus on endothelial dysfunction, have limited effects on improving outcomes. Increases in pulmonary vascular resistance in PAH may be attributed to complex lung arterial remodeling which result in obliterative “plexiform” lesions, a pathological hallmark of this disease. Recent studies have shown that endothelial cell (ECs) apoptosis may be a central trigger for PAH, resulting in the emergence of growth-dysregulated and apoptosis-resistant ECs that contribute to the formation of complex neoplastic-like vascular lesions. However, the mechanism which links ECs apoptosis to dysregulated growth is not yet known. Previous studies in our lab have identified increased expression of translationally controlled tumor protein (TCTP) and its gene (TPT1), previously implicated in the transformation of neoplastic cells in cancer, and in blood outgrowth ECs from patients with PAH. Moreover, TCTP expression was found to be elevated in the lungs of patients with PAH, and tightly localized to complex arterial lesions. In addition, it was detected in obliterative intimal lesions of an experimental rat model of severe PAH. Hypothesis: TCTP represents a central molecular mechanism linking ECs apoptosis to the emergence of growth-dysregulated lung vascular cells and occlusive, complex arterial remodelling in PAH. Specific Hypotheses: - Lentiviral overexpression of TCTP in human umbilical vein endothelial cells (HUVECs) and pulmonary artery smooth muscle cells (PASMCs) leads to a hyperproliferative and apoptosis-resistant phenotype. - Overexpression of TCTP will increase its export into apoptotic extracellular vesicles, thereby augmenting cell-cell signalling between ECs and neighbouring SMCs. Purpose: My objective was to examine the effects TCTP overexpression on ECs and SMCs survival in terms of proliferation and apoptosis, and TCTP release on the survival of nontransduced ECs and SMCs. Methods and Results: The effect of TCTP overexpression on ECs growth and survival was studied using in vitro models. TCTP was overexpressed via a lentivirus vector in HUVECs and PASMCs. Compared to non-transfected or null transfected cells, TCTP overexpression led to increases in BrdU incorporation, consistent with hyper-proliferation, and decreases in caspase activity, consistent with apoptosis resistance. As well, TCTP was selectively exported into the conditioned media of apoptotic ECs, but not SMCs, despite similar levels of overexpression. In addition, the level of release was greater in serum starved conditioned media in comparison to the exosome fraction. Finally, our data demonstrates a selective effect of conditioned media (CM) from serum-starved ECs on PASMCs, but not ECs, in terms of an increase in proliferation and a decrease in apoptosis. Conclusions: These support the idea that TCTP overexpression confers an increase in the survival of SMCs and HUVECs. Moreover, TCTP released from apoptotic ECs leads to a growth-dysregulated phenotype within SMCs (but not ECs) and may contribute to the formation of complex lung arterial lesions, leading to arteriolar obliteration in PAH. Finally, an increase in the level of TCTP expression via lentiviral transduction led to an increased TCTP export into the media, but this appeared to be mostly in the soluble portion, and less was associated with exosomes.

Piezocision is a new periodontal method for cutting bone more precisely than conventional methods, such as bur drilling, with 3D ultrasonic vibration power. We have conducted a study on piezocision effect on periodontal tissue in rodents. Our previous animal studies demonstrated that piezocision hastens tooth movement in rodents compared to conventional methods. The histological results showed that piezocision induces bone resorption and regeneration quickly. In addition, we observed the same effect of piezocision surgery on clinical tooth movement in collaboration with the orthodontists at BUSDM. We believe that piezocision can contribute significantly to dental therapies. However, more studies of piezocision effects are necessary for a thorough understanding. Periodontal tissue healing requires the participation of regulatory molecules, cells, and scaffold or matrix. We hypothesized that piezosurgery induces alveolar bone regeneration by uncovered procedures. In this study, we focused on the cells contributing to synthesis or repair of periodontal tissue, such as osteocytes, osteoclasts, osteoblasts, white blood cells, and periodontal ligament cells in order to close the gap between clinical knowledge and cellular mechanisms Histological analysis and MRI data indicates that piezocision surgery enhanced alveolar bone degradation in the post-operative early phase (from day1 to day7), and induced bone regeneration in the post-operative mid phase (from day14 to day28). The structure of alveolar bone was similar to controls in the late phase (day70). Serum ALP activity, a bone formation marker, was significantly increased by Piezocision surgery (p<0.05). Piezocision increasd serum CTX, a bone degradation biomarker, at post-operative 7day in the 30Hz Piezocision surgery (p<0.05). In addition, Serum PINP, a bone formation biomarker, was significantly decreased in the post-operative early phase. TUNEL assays revealed that osteocyte apoptosis was induced in alveolar bone by piezocision at post-operative 1day. Apoptosis in osteocytes induces osteoclast activity that leads to bone degradation. In previous studies piezocision induced TRAP activity in the post-operative early phase. Runx2 positive osteoblast progenitor cells were observed in the post-operative day7 and 14 as assessed by Immunofluorescence microscopy analysis. The Runx2 positive cells accumulated near the new bone formation area. The structure of collagen was observed by histological staining with Pico Sirius Red. Piezocision resulted in deteriorated collagen structure in the post-operative early phase that recovered in the post-operative mid phase. Since the collagen fibers filled in the gap between alveolar bone and roots, we stained the sections with Periostin, a specific PDL biomarker. Periostin was observed on the collagen fibers that filled in the gap between bone and root. previous studies revealed that the expression of Periostin induced TGF beta, a pivotal molecule for osteoblast differentiation. Taken together, these studies indicate that periodontal tissue responds to Piezosurgery by alveolar bone decalcification and regeneration. Further elucidation of the role of the each conducting cells (eg. osteocytes, osteoclast, osteoblast, periodontal ligament cells) after piezosurgery in the periodontal tissue may provide a new target for the treatment of periodontal disease by stimulating the return to tissue homeostasis.

Cette thèse, née d’une collaboration entre le laboratoire LEMTA et l’entreprise Novastep, a pour but de concevoir une prothèse de resurfaçage des têtes métatarsiennes des rayons latéraux (2ème, 3ème et 4ème orteils). Ces rayons sont touchés par de nombreuses pathologies (arthrose, maladie de Freiberg, …) pouvant engendrer des douleurs et être handicapantes au quotidien. Bien que de nombreuses solutions prothétiques pour le resurfaçage des têtes métatarsiennes soient disponibles sur le marché, elles sont en majorité conçues pour le resurfaçage du 1ier rayon. La prothèse de Novastep est donc prévue pour offrir une solution viable pour le traitement de ces pathologies. Le développement de la prothèse passe par plusieurs étapes qui sont : • La recherche des exigences médicales et mécaniques à respecter ; • La conception de la prothèse ; • La mise au point de la technique opératoire (instrument pour la pose) ; • La réalisation des essais (vérification des performances de la prothèse). Ce cycle de conception permet de justifier les performances de la prothèse dans l’optique d’obtenir l’autorisation de mise sur le marché. En parallèle de la conception de la prothèse de resurfaçage, une étude de remodelage des métatarsiens après implantation a été effectuée. Cette étude a pour but, dans un premier temps, de présenter et valider un protocole pour la préparation des modèles EF de remodelage osseux à partir de données tomodensitométriques spécifiques au patient. Dans un deuxième temps, cette étude a permis d’analyser l’impact de la prothèse de Novastep sur l’os et de comparer ces résultats avec ceux obtenus pour une prothèse concurrente (LMHI de Wright Medical). Dans un dernier temps, l’influence de différents paramètres de la loi de remodelage et du modèle a été étudiée. A notre connaissance, ce travail est le premier portant sur le remodelage osseux d’un métatarsien prothésé. A terme, ce travail pourra aboutir à la création d’un outil d’aide à la décision destiné aux concepteurs pour les choix technologiques de design des prothèses et aux chirurgiens pour sélectionner la technique chirurgicale la plus adaptée à chaque patient. Pour ce faire, il sera nécessaire de valider les résultats issus des prévisions numériques de remodelage avec des résultats cliniques post-opératoires / This doctoral thesis, the result of a collaboration between LEMTA laboratory and Novastep company, explains the design of a metatarsal head resurfacing prosthesis of the lateral toes (2nd, 3rd and 4th toes). These toes can be affected by several pathologies, including arthritis and Freiberg’s disease, which are painful and can bec ripping in everyday life. Although many prosthetic solutions for the resurfacing of the metatarsal heads are available on the market, they are often developed for the first toe only. Novastep’s prosthesis was developed to afford a viable solution for the treatment of those pathologies in other toes as well. The development of this prosthesis requires several steps which are: • The definition of medical and mechanical requirements which must been taken into account ; • The design of the prosthesis ; • The development of the surgical technique, that is, the instrumentation for setting up the prosthesis ; • Mechanical and clinical testing to verify the performance of the prosthesis. This design cycle permits justification of the device’s performance necessary to obtain the market approval. In parallel with the resurfacing prosthesis, a study of metatarsal bone remodeling after implantation was realized. This study aimed to present and validate a protocol for the preparation of finite element models of bone remodeling from patient specific computed-tomography data. It also permitted analysis of the impact of the Novastep’s prosthesis on the metatarsal and comparison of those resuts with results obtained with a competitor’s equivalent prosthesis (LMHI of Wright Medical). To our knowledge, this study was the first on the bone remodeling of a prosthetic metatarsal. In the long term, this work could lead to the creation of a decision-making tool for designers for the technological choices of prosthesis design

Introdução: Níveis de fator de necrose tumoral–alfa (TNF-α), N-peptídeo do pró-colágeno III (PIIINP) e metaloproteinase de matriz –1 (MMP-1), marcadores biológicos de remodelamento ventricular, estão elevados em pacientes com insuficiência cardíaca (IC), talvez refletindo elevadas pressões de enchimento. A correlação destes marcadores com variáveis clínicas e hemodinâmicas permanece pouco compreendida, particularmente no contexto ambulatorial da IC. Objetivo: Avaliar níveis séricos de marcadores biológicos de remodelamento ventricular em pacientes com IC, comparando tratamento guiado por ecocardiografia (ECO), buscando redução de pressões de enchimento, versus tratamento convencional (CLÍNICO), baseado em sinais e sintomas. Métodos: Ensaio clínico randomizado. Pacientes estáveis com IC e fração de ejeção menor do que 40% foram alocados entre os grupos de tratamento e submetidos a ecocardiograma e coletas de sangue no início do estudo e em 180 dias. TNF-α e MMP- 1 foram medidos por ELISA, e PIIINP, por radioimunoensaio. Resultados: Incluiu-se 80 pacientes, com 59 ± 15 anos e fração de ejeção de 26 ± 7%; 25% isquêmicos e 52% masculinos. Houve redução dos marcadores biológicos intragrupos, não havendo diferença entre os tratamentos. No grupo CLÍNICO, os níveis de TNF-α, MMP-1 e PIIINP apresentaram diferenças estatisticamente significativas entre os momentos basal e final (respectivamente, 3,11 ± 2,90 versus 1,24 ± 0,60 pg/mL p < 0,0003; 2,66 ± 1,00 versus 1,16 ± 0,40 ng/mL p < 0,0001; 6,12 ± 2,60 versus 3,89 ± 1,60 μg/L p < 0,0001). De maneira semelhante, tal diferença também foi observada no grupo ECO para os três marcadores (respectivamente, 3,90 ± 4,90 versus 1,40 ± 1,30 pg/mL p < 0,0001; 2,50 ± 0,90 versus 1,09 ± 0,40 ng/mL p < 0,0001; 6,09 ± 2,60 versus 3,50 ± 1,30 μg/L p<0,0001). Ao final da intervenção, no entanto, não foi observada diferença significativa dos valores de TNF-α , MMP-1 e PIIINP entre os dois grupos de tratamento (p = 0,7; p = 0,8; e p = 0,2; respectivamente). A combinação dos valores basais das variáveis biológicas gerou um escore que se associou significativamente com o comportamento final das pressões atrial direita e sistólica da artéria pulmonar. Pacientes com marcadores biológicos basais no quartil 75% mantiveram níveis superiores de pressões atrial direita (13 mmHg; p = 0,034) e sistólica de artéria pulmonar (60 mmHg; p = 0,007) ao final do seguimento. Conclusão: Independente do tratamento alocado, houve redução dos níveis de marcadores biológicos ao final do seguimento; no entanto, níveis basais mais elevados destes marcadores foram preditores de menor redução das pressões em átrio direito e sistólica da artéria pulmonar. Os dados sugerem que indicativos de intenso processo de remodelamento ventricular se associam à progressão da IC e a pressões de enchimento elevadas. / Introduction: Levels of tumor necrosis factor-alpha (TNF-α), N-terminal propeptide of type III collagen (PIIINP) and type 1 matrix metalloproteinase (MMP-1), biological markers of ventricular remodeling, are elevated in heart failure (HF) patients, perhaps reflecting elevated filling pressures. The correlation of these markers with clinical and hemodynamic variables remains poorly understood, particularly in the outpatient setting. Objective: To evaluate serum levels of ventricular remodeling biological markers in patients with HF, comparing a conventional clinically-oriented treatment (Conventional Therapy), based on clinical signs and symptoms, to an echocardiography-guided treatment (Echo-guided Therapy), aiming at a reduction in filling pressure levels. Methods: Randomized trial. Stable patients with HF and ejection fraction lower than 40% were allocated to the treatment groups and submitted to echocardiography and blood sampling at the beginning of the study and after 180 days. TNF-α and MMP-1 were measured by ELISA, and PIIINP, by radioimmunoassay. Results: Eighty patients at 59 ± 15 years and a mean ejection fraction of 26 ± 7% were included; 25% were ischemic and 52%, males. There was a reduction in intragroup biological markers, without difference between treatments. TNF-α, MMP-1 and PIIINP levels were statistically different between baseline and final in patients allocated to Conventional Therapy (respectively, 3.11 ± 2.90 versus 1.24 ± 0.60 pg/mL p < 0.0003; 2.66 ± 1.00 versus 1.16 ± 0.40 ng/mL p < 0.0001; 6.12 ± 2.60 versus 3.89 ± 1.60 μg/L, p < 0.0001). Similarly, such a difference was also observed in the Echo-guided Therapy for the 3 markers (respectively, 3.90 ± 4.90 versus 1.40 ± 1.30 pg/mL p < 0.0001; 2.50 ± 0.90 versus 1.09 ± 0.40 ng/mL p < 0.0001; 6.09 ± 2.60 versus 3.50 ± 1.30 mg/L p<0.0001). By the completion of the intervention, however, no significant difference was observed in the values of TNF-α, MMP- 1 and PIIINP between the 2 treatment groups (p = 0.7; p = 0.8; and p = 0.2; respectively). A composite score incorporating baseline biological marker levels was statistically associated to final right-sided pressure levels (right atrial pressure and pulmonary artery systolic pressure). Patients with baseline biological marker levels over percentile 75 maintained higher right atrial (13 mmHg; p = 0.034) and pulmonary artery systolic pressures (60 mmHg; p = 0.007) at the end of protocol. Conclusion: Regardless of allocated treatment group, biological marker levels were lower at the end of the follow-up; however, higher baseline levels of these markers were predictive of lower reductions in right atrial pressure and pulmonary artery systolic pressure. The data obtained suggest that indicators of an intense remodeling process are associated with elevated filling pressures and progression of HF.

Abstract Cardiac loading induces left ventricular hypertrophy and cardiac remodeling which when prolonged, leads to heart failure, a complex syndrome affecting approximately 1-2% of the adult population of the Western world with a prevalence increasing with age. Pathological remodeling involves functional and structural changes that are associated with fetal gene expression, sarcomeric re-organization, hypertrophy of cardiomyocytes, fibrosis, inflammation, oxidative stress and impairment of metabolism. The aim of this study was to investigate the role of three novel factors during the cardiac remodeling process with different experimental models of cardiac overload. Phosphatase and actin regulator 1 (Phacr1) expression was rapidly downregulated due to myocardial infarction (MI). Adenovirus-mediated Phactr1 overexpression changed the skeletal &#945;-actin to cardiac &#945;-actin ratio in both healthy and infarcted rat hearts and cultured cardiomyocytes. Phactr1 could regulate the actin isoform switch via the serum response factor (SRF). The expression of transforming growth factor (TGF)- &#946;-stimulated clone 22 (TSC-22) was rapidly induced by multiple hypertrophic stimuli and was also evident post-MI. In addition, TSC-22 could regulate collagen 3a1 expression in the heart. The expression of retinal degeneration 3-like (Rd3l) was downregulated in response to pressure overload and also downregulated post-MI. Rd3l knockout mice expressed increased myocyte hypertrophy and cardiac dysfunction in response to a transverse aortic constriction (TAC) induced pressure overload. This thesis provides novel information about Phactr1, TSC-22 and Rd3l in load-induced cardiac hypertrophy and remodeling. Collectively these studies increase our understanding of the regulatory mechanisms underlying the progression of heart failure. / Tiivistelmä Sydämen kuormitus saa aikaan vasemman kammion liikakasvun eli hypertrofian ja sydämen uudelleenmuovautumisen, mikä pitkittyessään johtaa sydämen vajaatoimintaan. Sydämen vajaatoiminta on monimutkainen oireyhtymä, josta länsimaissa kärsii noin 1-2 % aikuisväestöstä, ja esiintyvyys nousee iän myötä. Patologisessa uudelleenmuovautumisessa tapahtuu toiminnallisia ja rakenteellisia muutoksia, joihin liittyy muutoksia geenien ilmentymisessä, sarkomeerin uudelleen järjestäytymistä, sydänlihassolujen koon kasvua, fibroosia, tulehdusta, oksidatiivista stressiä ja aineenvaihdunnan huonontumista. Tämän työn tarkoituksena oli tutkia kolmen uuden tekijän roolia sydämen uudelleenmuovautumisessa erilaisissa kokeellisissa sydämen kuormituksen malleissa. Fosfataasin ja aktiinin säätelijä 1:n (Phactr1) ilmentyminen väheni nopeasti infarktin seurauksena. Adenovirusvälitteinen Phactr1:n ylituotanto muutti luusto- ja sydänlihasaktiinien isomuotojen suhdetta sekä terveessä että infarktisydämessä, samoin viljellyissä sydänlihassoluissa. Phactr1 saattaa säädellä isomuotojen suhdetta seerumiresponsiivisen tekijän (SRF) avulla. Transformoituvan kasvutekijä &#946;1:n stimuloima proteiini 22:n (TSC-22) ilmentyminen nousi nopeasti usean hypertrofisen stimuluksen seurauksena sekä infarktin jälkeen. Lisäksi TSC-22 voisi säädellä kollageeni 3a1:n ilmentymistä sydämessä. Retinan degeneroituvan proteiinin 3 kaltaisen tekijän (Rd3l) ilmentyminen väheni sekä painekuormituksen että infarktin seurauksena. Rd3l-poistogeenisillä hiirillä aortan ahtauman aiheuttama painekuormitus sai aikaan lisääntynyttä sydänlihassolujen hypertrofiaa ja sydämen toimintahäiriöitä. Tämä väitöskirjatutkimus tuo uutta tietoa Phactr1-, TSC-22- ja Rd3l-geeneistä kuormituksen aiheuttamassa sydämen hypertrofiassa ja uudelleenmuovautumisessa. Nämä tulokset auttavat osaltaan ymmärtämään monimutkaisia molekyylitason mekanismeja, jotka johtavat sydämen vaajatoiminnan kehittymiseen.