No description available.

Around 170000 patients worldwide receive cardiac valve substitutes each year. Valve replacement with mechanical or bioprosthetic devices enhances patient survival and quality of life. Bioprosthetic valves have a significant advantage over mechanical valves: they do not necessarily require long-term anticoagulant therapy however, dystrophic calcification can lead to early failure. The actual mechanism of calcification is still poorly understood despite several established possible factors associated with it. Amongst these is the glutaraldehyde pre-treatment of the valves during their manufacture. Glutaraldehyde has been used for the treatment of bioprosthetic valves for the last thirty years, as a cross-linking agent and a sterilant. Whilst it is assumed to introduce stable inter- and intra-fibrillar collagen cross-links, which contribute to the durability of these valves, the specific chemistry of the fixation process is not fully understood. Additionally, glutaraldehyde is thought to be involved somehow in the process of dystrophic calcification of these same bioprosthetic valves. The primary aim of this study was to gain a greater understanding of the chemistry involved in the treatment of collagenous valve tissue with glutaraldehyde. Amino acids, peptides and proteins were thus used to mimic the effect of the glutaraldehyde treatment and to model potential reactions involved in such treatment. Techniques such as MALDI-TOF MS, ESI MS, NMR, FTIR-ATR and Raman spectroscopy were utilised to study the products of the glutaraldehyde reaction and their relationship with the calcification process. Data obtained from the products of the reactions between glutaraldehyde and model compounds showed the presence of: aldol and aldol/Michael condensation products of glutaraldehyde, Schiff base moieties (including cross-links) and various cyclisation products incorporating pyridinium and dihydropyridine ring structures. Some of these structures are in agreement with the literature, whilst others are essentially new structures that have never been proposed. Glutaric acid, used to mimic the oxidation of glutaraldehyde that can occur in-vivo, was shown to have the ability to form complexes with cations such as calcium in-vitro. A similar result was found with aqueous dilute solutions of glutaraldehyde (similar concentrations to the ones used in valve manufacture), thus leading to the hypothesis of its strong role in the initiation of calcification in-vivo. However, an extrapolation of these results to the role of the nucleophilic groups of amino acids or peptides, that could behave as the collagen macromolecule, was difficult to assess using FTIR because of the complex infrared spectra. However some findings corroborated the hypothesis that amino acids of the collagen tissue may also play a role in the initiation of calcification. Secondly, methodology was developed to allow successful analysis of tissue calcification using environmental scanning electron microscopy (ESEM). This is thought to be an important step in the analysis of tissues in their native state. Investigation of the calcification process with samples from clinical investigations (explanted human calcified valves), in-vivo screening (rat subcutaneous implantation model) and in-vitro screening (pericardial tissue incubated in metastable calcification solution) was thus undertaken using ESEM, along with other techniques such as FTIR-ATR, Raman, XRD spectroscopy and ICP-OES. The data revealed both similarities and differences between in-vivo and in-vitro calcification, although the process is unequivocally different. Late calcific deposits were assigned to poorly crystalline hydroxyapatite with high Ca/P ratios due to the probable presence of carbonate and possibly cations such as silicon and magnesium. A picture of the onset of mineralisation was hypothesised involving precursors, containing various amounts of calcium and phosphate, along with the incorporation of magnesium and silicon. These precursors phases evolved with time of implantation to the poorly crystalline form of hydroxyapatite found in the late stage of calcification. This work has provided an insight into how glutaraldehyde reacts with valve tissue and a possible explanation as to why valves fail by non-calcific or calcific mechanisms. A new approach to the study of calcified valve tissue has also been developed using ESEM methodology.

No description available.

La circulation du flux sanguin à sens unique dans le système cardiovasculaire des vertébrés est assurée par les valves cardiaques. Leur formation est très contrôlée au cours du développement embryonnaire. Cependant, il arrive que celle-ci soit défectueuse, et donc à l’origine de maladies cardiaques congénitales. Ces maladies représentent une des causes majeures de décès à la naissance. L’étude de la formation des valves cardiaques constitue donc un champ de recherche majeur. Dans cette thèse, nous avons utilisé le poisson zèbre, comme animal d’étude modèle pour étudier la formation des valves atrio-ventriculaires. Les forces mécaniques générées par le flux sanguin constituent un signal modulant le programme génétique valvulaire. Elles initient la formation des valves en contraignant l’expression du facteur de transcription, Klf2a, à un groupe de cellules endothéliales du canal atrio-ventriculaire. Nos travaux ont démontré l’activation d’un autre facteur, Egr1, dans cette même région dans le même lapse de temps. Notre étude a cherché à élucider le réseau génétique impliquant klf2a, son paralogue klf2b, et egr1 en combinant une analyse pangénomique de l’expression génique et des sites accessibles de la chromatine avec une approche d’imagerie haute résolution in vivo. Nous avons déterminé les interactions entre ces facteurs et les réseaux qu’ils régulent. Cette étude a finalement démontré qu’egr1, klf2a/klf2b modulent la morphogénèse des valves cardiaques en contrôlant en particulier flt1, has2 et wnt9b. / Cardiac valves are necessary for maintaining a unidirectional blood flow in the cardiovascular system of vertebrates. Their efficient gating function requires a highly controlled developmental program. However, this program may be impaired and thus leading to defective valves. In fact, congenital heart valve diseases represent the most common form of birth defects. Therefore, cardiac valve development studies constitute a challenging research field. In this thesis, we used the zebrafish as a model organism for studying the formation of atrioventricular valves. To date, it is known that mechanical forces generated by blood flow constitute key modulators dictating valve formation. In particular, they initiate valvulogenesis by restricting the expression of the transcription factor Klf2a in a subset of endocardial cells of the atrio-ventricular canal. Our work demonstrated the activation of another transcription factor, Egr1, in this same region and within the same time window. We aimed at deciphering the mechanosentitive gene network involving klf2a, its paralog klf2b as well as egr1, by combining genome-wide analysis of gene expression and chromatin accessibility with live imaging. We addressed the potential interactions of these factors and studied their downstream signalling pathways. Finally, we demonstrated that egr1, klf2a/klf2b modulates valve morphogenesis by specifically controlling flt1, has2 and wnt9b expression.

Orientador: Eduardo Tavares Costa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação / Made available in DSpace on 2018-08-12T13:09:13Z (GMT). No. of bitstreams: 1 Cheade_EduardodeLima_M.pdf: 4329649 bytes, checksum: cccb5144d6d74ac9e7db94da82d1e776 (MD5) Previous issue date: 2008 / Resumo: A utilização de próteses de válvulas cardíacas tanto mecânicas quanto biológicas tem se tornado cada vez mais freqüente. Estas próteses devem ser avaliadas (testes in-vitro e in-vivo) para que sejam utilizadas clinicamente. Os testes de desempenho hidrodinâmico são realizados in vitro, e a análise dos resultados é importante para a classificação e caracterização de uma determinada prótese, sendo atualmente um dos requisitos obrigatórios exigido por órgãos reguladores para a aprovação de próteses a serem empregadas clinicamente. Os testes de desempenho hidrodinâmico são realizados por sistemas complexos, denominados duplicadores de pulso, cuja finalidade é reproduzir o comportamento hidrodinâmico do coração e simular as variáveis fisiológicas às quais as válvulas são normalmente submetidas em condições reais. Neste trabalho foi desenvolvido, para uso na empresa Braile Biomédica, utilizando a plataforma de programação LabVIEW®, um programa capaz de fazer a aquisição e interpretação dos sinais de fluxo e pressão provenientes de transdutores específicos, bem como a realização dos cálculos necessários e a geração de um relatório resultante do teste. Também foram desenvolvidos circuitos condicionadores de sinais para os transdutores de pressão e fluxo inerentes ao sistema duplicador de pulso existente na empresa. A partir das medidas e dos gráficos de pressão e fluxo é possível calcular os seguintes parâmetros: área específica do orifício, coeficiente de descarga, fração de regurgitação e índices de performance e eficiência da válvula. / Abstract: It has become very frequent the use of mechanic or biological cardiac valve prostheses. These prostheses must be evaluated (in vitro and in vivo tests) in order to be used clinically. The hydrodynamic performance tests are carried out in vitro. The analyses of the test results are very important for the characterizations and classification of a given prosthesis, being one of mandatory requirements of the regulatory organs in order to approve its clinical use. The hydrodynamic performance tests are carried out by complex systems often called pulse duplicators, which must reproduce the heart hydrodynamic behaviour and simulate the physiological variables that the cardiac valves are submitted in real conditions. In this work it has been developed a software program to be used at Braile Biomedica based on the LabVIEW® platform, capable of acquiring and processing flux and pressure signals from specific transducers, as well as all the necessary calculi and generation of the test results report. It has also been developed the signal conditioning circuits for the pressure and flux transducers inherent to the company pulse duplicator. The following parameters are calculated and reported with several graphics showing flux and pressure signals: orifice specific area, discharge coefficient, regurgitation fraction and valve performance and efficiency indices. / Mestrado / Engenharia Biomedica / Mestre em Engenharia Elétrica

No description available.

317 pathologisch-anatomische Befundberichte über die Morphologie des Myokards, der Koronararterien, der Aorta und der Pulmonalarterien von Herzen, die in der Homograftbank des Deutschen Herzzentrums Berlin in den Jahren 1996 bis 1998 für eine potentielle Klappenspende (Aorten- und Pulmonalklappen) seziert worden waren, wurden ausgewertet. 178 dieser Herzen stammten von Herztransplantatempfängern und zeigten naturgemäß schwere pathologische Veränderungen. Sechs Herzen stammten von Leichen. 133 Herzen waren hirntoten Menschen entnommen worden. Ursprünglich hatte bei vielen dieser 133 Spenderherzen die Absicht bestanden, sie für die Transplantation zu verwenden, was aus verschiedenen Gründen nicht möglich war. Ziel der retrospektiven Studie war die Erfassung der morphologischen Situation der Organe, wobei der Schwerpunkt auf der Gruppe der Spenderherzen lag. / This work contains an analysis of 317 records with a detailed description of the morphology of myocardium, coronary arteries, aortas and pulmonary arteries of hearts dissected for the purpose of harvesting the aortic and pulmonary valves as allografts in the Heart Valve Bank of the German Heart Institute, Berlin, from 1996 through 1998. 178 hearts stemmed from patients who recieved heart transplants. Naturally these organs revealed severe pathologic findings. Cadaveric organs (non beating hearts) amounted to six. 133 hearts were taken from brain dead human beings. Many of these 133 donor organs were originally considered to be potentially usable for transplantation, but were discarded for various reasons. The objective of this retrospective study was to ascertain the morphologic state of the hearts with special focus on the 133 donor hearts.

Ce mémoire adresse la problématique de la présentation des résultats chirurgicaux en chirurgie cardiaque. Les complications postopératoires sont d’étiologie et de sévérité variées, peuvent atteindre plusieurs systèmes physiologiques et nécessitent différents degrés de traitements. Elles consistent en une source importante de morbidités pour le patient, mais ne sont toutefois pas toujours présentées de manière optimale dans les essais cliniques. En effet, les complications sont actuellement rapportées dans les études de manière hétérogène, ce qui nuit à la recherche en compliquant les comparaisons d’études, les revues systématiques et les méta-analyses. Plusieurs complications individuelles ont des systèmes de classification utilisés sporadiquement dans certains articles en chirurgie cardiaque, mais ceux-ci ne sont pas déployés de manière répandue. D’autre part, des classifications universelles s’appliquant à toutes les complications potentielles ont été adoptées dans la littérature chirurgicale, mais n’ont toutefois pas été implémentées en chirurgie cardiaque. L’étude menée dans le cadre de ce travail a adapté et appliqué la classification de Clavien-Dindo (CCD) et le Comprehensive Complication Index (CCI) pour la première fois en chirurgie cardiaque. Mon étude démontre que les comorbidités importantes en chirurgie cardiaque et les chirurgies plus complexes sont prédictives de la sévérité des complications selon ces deux échelles. Également, le CCD et le CCI corrèlent avec les durées de séjour aux soins intensifs et à l’hôpital après une chirurgie cardiaque. En conclusion, la CCD et le CCI représentent de manière fiable la complexité de l’évolution postopératoire en chirurgie cardiaque. Cela pourrait adresser le manque de standardisation dans la présentation des complications dans les essais cliniques et uniformiser la manière de rapporter les événements adverses en chirurgie cardiaque. Cela aurait également de multiples applications dans les initiatives d'amélioration de la qualité des soins, dans les évaluations des procédures et des procédés, ainsi que dans l'avancement de la recherche. / This memoir addresses the challenge of outcome reporting in cardiac surgery. Postoperative complications are of varying etiology and severity, can affect several physiological systems and require different degrees of treatment. They are an important source of morbidity for the patient but are not always optimally presented in clinical trials. Indeed, complications are currently reported in studies in a heterogeneous manner, which hampers research by complicating study comparisons, systematic reviews and meta-analyses. Many individual complications have classification systems that are used sporadically in some articles in cardiac surgery, but these are not widely used. On the other hand, universal classifications that apply to all potential complications have been adopted in the surgical literature, but none have been implemented in cardiac surgery yet. The study conducted as part of this work adapted and applied the Clavien-Dindo Complications Classification (CDCC) and the Comprehensive Complication Index (CCI) for the first time in cardiac surgery. My study shows that the important comorbidities in cardiac surgery and more complex surgeries are predictive of the severity of complications according to both scales. Moreover, the CCD and CCI also correlate with the lengths of stay in the intensive care unit and hospital after cardiac surgery. In conclusion, the CDCC and CCI reliably represent the complexity of the postoperative evolution in cardiac surgery. This could address the inconsistency with which complications are currently presented in surgical trials and standardize the way adverse outcomes are reported in cardiac surgery. This would have multiple applications in quality of care improvement initiatives, in evaluations of procedures and processes, and in advancement of research.