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Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. However, prospectively acquired data describing the natural history and prognostic factors in a large population of dogs affected by this disease are sparse. Thus, the Longitudinal Outcome of canine (K9) myxomatous mitral valve disease registry (LOOKmitral) was established to prospectively collect clinical and diagnostic data from a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in the LOOK-mitral registry from November 1st, 2015, to October 31st, 2018, in thirteen cardiology specialty practices. We first described the baseline characteristics of the dogs enrolled in the registry, which mainly confirmed previous findings. Moreover, we provided new additional results, such as the presence of systolic dysfunction in some small breed dogs and how the intensity of the murmur correlates with the severity of MMVD also in large breed dogs. Second, we described the baseline treatment characteristics at the time of enrollment. These data showed that the results of the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial and left atrial and left ventricular dimensions, assessed by echocardiography, influenced veterinary cardiologist's prescription of cardiovascular drugs in affected dogs. Lastly, we evaluated predictors of reoccurrence of congestive signs within 180 days after successfully treating the first episodes of heart failure in dogs enrolled in the LOOKMitral registry. While this study failed to identify accurate predictors of recurrence, dogs with larger left ventricular internal dimensions at end-diastole were more likely to present with reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended. / Doctor of Philosophy / Despite being the most common heart disease in dogs, data on a large group of dogs affected by myxomatous mitral valve disease (MMVD) are currently sparse in veterinary medicine. The Longitudinal Outcome Of canine (K9) Mitral valve disease (LOOK-Mitral) was established in 2015 to collect data on a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in thirteen referral centers over three years. First, the baseline characteristics of dogs enrolled in the registry were described. These data mainly confirmed previous findings. Moreover, they provided some new insight like the possible presence of contractile dysfunction in some small breed dogs and the correlation between the intensity of the heart murmur and the severity of the disease also in large breed dogs. Second, we described the medical treatment prescribed or modified by veterinary cardiologists at the enrollment visit. These data showed that the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial, a clinical trial published during the enrollment period, and the heart ultrasound (echocardiography) data influence cardiologist prescription habits. Lastly, we evaluated if any clinical or echocardiographic variable could predict the reoccurrence of clinical signs of heart failure within 180 days from the first manifestation of those clinical signs in dogs enrolled in the LOOK-Mitral registry. While this study failed to accurately identify predictors of reoccurrence, dogs with larger left ventricular chamber sizes were more likely to present reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended.

La sténose aortique (SA) est la maladie valvulaire la plus fréquente dans notre société. Elle est caractérisée par un remodelage fibrocalcique conduisant à une obstruction progressive du flux sanguin. La lipoprotéine(a) (Lp[a]), une lipoprotéine similaire à la lipoprotéine de faible densité, est un facteur de risque génétique fortement associé à la SA. Malheureusement, les concentrations plasmatiques de Lp(a) sont très peu influencées par des facteurs extrinsèques, tels qu’un régime alimentaire ou une médication hypolipidémiante. Des études suggèrent que la Lp(a) serait associée aux processus de calcification dans le développement de la SA. La tomographie par émission de positons couplée à la tomographie axiale permet de détecter le processus précoce lié à calcification de la valve aortique. En effet, cette technique d’imagerie nucléaire permet d’identifier et de quantifier la microcalcification au niveau de la valve aortique, un marqueur fortement lié au développement futur de calcium. L’impact de la Lp(a) sur la microcalcification de la valve aortique n’a jamais été évalué. La mesure de la microcalcification chez des individus sans SA ayant des concentrations plus ou moins élevées de Lp(a) a été effectuée. Notre hypothèse était que les individus ayant des concentrations élevées de Lp(a) ont une microcalcification plus élevée, lorsque comparée aux individus ayant des concentrations plus faibles de Lp(a). Les résultats de cette étude ont révélé que les individus sans SA mais ayant des concentrations élevées de Lp(a) présentent une microcalcification plus importante que les individus ayant de plus faibles concentrations de Lp(a). La réalisation de ce projet de recherche nous a permis d’observer cliniquement un processus actif de calcification chez des individus avec des concentrations élevées de Lp(a), et ce, malgré l’absence clinique de la maladie, illustrant l’importance de cette lipoprotéine dans le développement de la SA. / Aortic stenosis (AS) is the most common valve disease in our society. It is characterized by fibrocalcific remodelling leading to progressive obstruction of blood flow. Lipoprotein(a) (Lp[a]), a lipoprotein similar to low-density lipoprotein, is a genetic risk factor strongly associated with AS. Plasma concentrations of Lp(a) are very little influenced by extrinsic factors, such as diet or lipid-lowering medication. Studies suggest that Lp(a) would be associated with calcification processes in the development of AS. Positron emission tomography coupled with computed tomography allows the early process related to calcification of the aortic valve to be detected. This nuclear imaging technique identifies and quantifies microcalcification at the aortic valve, a marker strongly linked to the future development of calcium. The impact of Lp(a) on aortic valve microcalcification has never been evaluated. Microcalcification measurements in individuals without AS with high or low concentrations of Lp(a) were performed. Our hypothesis was that individuals with high concentrations of Lp(a) have higher microcalcification when compared to individuals with lower concentrations of Lp(a). The results of this study revealed that individuals without AS but with high concentrations of Lp(a) have a higher microcalcification than individuals with lower concentrations of Lp(a). The completion of this research project allowed us to observe clinically an active calcification process in individuals with high concentrations of Lp(a) despite the clinical absence of the disease, illustrating the importance of this lipoprotein in the development of AS.

The gold standard treatment for patients with AVD is surgical replacement of the aortic valve with either mechanical or fixed tissue prostheses. These implants have a limited lifespan and are associated with serious adverse events. Patient autologous tissue engineered heart valves (TEHVs) offer a solution. Vital to the development of a TEHV is determining a source of donor tissue(s) that most closely mimics the native valve tissue. In pursuit of determining an alternative cell source for patient autologous TEHVs we compared a number of phenotypic and genotypic characteristics of atrial fibroblasts, dermal fibroblasts and differentiated bone marrow-derived progenitor cells (BMCs) and made a comparison to valvular interstitial cells (VICS). We demonstrate that while VICs share some phenotypic similarities with fibroblasts and BMCs, they also possess unique characteristics and demonstrate differential mRNA expression of key regulatory pathways that may influence their phenotype. / October 2016

Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43(-/-) mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43(∆LEC)) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

A indústria automotiva exige produtos que trabalhem em condições extremas. O desenvolvimento de componentes é uma ação de aperfeiçoar os motores de combustão interna para que atinjam a vida requerida com níveis de desgaste aceitáveis, respeitando os limites legais de operação, como por exemplo, valores de emissões de poluentes. Diante dessas exigências, se faz necessário estudar componentes considerados críticos que conhecidamente influenciam no desempenho do motor. A tribologia do par válvula e sede de válvula de admissão é um importante conjunto que se deve ter atenção quanto ao seu desgaste, visto que pode influenciar na degradação do motor quanto aos parâmetros de emissões de poluentes e requisitos operacionais de manutenção e de vida do produto. O objetivo foi avaliar o comportamento do par tribológico, válvula e sede de válvula de admissão, submetidos a ensaios em dinamômetro e veiculares (condições reais de operação), quanto ao nível e tipo de desgaste ocorrido no par. Os resultados obtidos foram correlacionados com os requisitos de desempenho legais e operacionais de um motor ciclo diesel, como também foi realizada a caracterização do tipo de desgaste ocorrido no par tribológico e comparada com a literatura específica. Com base nos resultados, concluiu-se que ocorreu uma excelente compatibilidade entre a válvula e a sede da válvula de admissão; o nível de desgaste não prejudicou o desempenho do motor e as emissões de poluentes; o par tribológico atendeu aos requisitos de trabalho extremos, como operação em altas temperaturas e pressão de combustão com baixas taxas de desgaste; e os tipos de desgastes observados foram classificados como desgaste adesivo e sinais de deformação plástica. / Automotive industry demands products that work under extreme conditions. The development of components for internal combustion engines is an action to improve this product, so that it reaches the required life with acceptable levels of wear and respecting the legal operating limits, such as values of emission pollutants. In view of these requirements, it is necessary to study components considered critical, which are known to influence the performance of the engine. So within this universe the tribology of the intake valve and valve seat insert is an important set, that must receive attention to its wear and consequently its influence to the engine degradation in the parameters of emission pollutants and performance related to the operational maintenance requirements and life of the product. The aim of this work is to evaluate the behavior of the tribological intake pair, valve and valve seat insert, submitted to dynamometer and vehicular tests (real operating conditions), regarding the level and type of wear occurred in the pair. The results were compared with legal and operational performance requirements of a diesel cycle engine, as well as the characterization of the wear type occurred in the tribological pair, with the related literature. Based on the results it was concluded that there was excellent compatibility between the valve and the valve seat material; the wear level did not impar the engine performance and emissions of pollutants; the tribological pair meeting extreme work requirements, such as high temperature operation and combustion pressure while maintaining low wear rates. The wear types observed were classified as adhesive wear and slight signs of shear strain wear.

A indústria automotiva exige produtos que trabalhem em condições extremas. O desenvolvimento de componentes é uma ação de aperfeiçoar os motores de combustão interna para que atinjam a vida requerida com níveis de desgaste aceitáveis, respeitando os limites legais de operação, como por exemplo, valores de emissões de poluentes. Diante dessas exigências, se faz necessário estudar componentes considerados críticos que conhecidamente influenciam no desempenho do motor. A tribologia do par válvula e sede de válvula de admissão é um importante conjunto que se deve ter atenção quanto ao seu desgaste, visto que pode influenciar na degradação do motor quanto aos parâmetros de emissões de poluentes e requisitos operacionais de manutenção e de vida do produto. O objetivo foi avaliar o comportamento do par tribológico, válvula e sede de válvula de admissão, submetidos a ensaios em dinamômetro e veiculares (condições reais de operação), quanto ao nível e tipo de desgaste ocorrido no par. Os resultados obtidos foram correlacionados com os requisitos de desempenho legais e operacionais de um motor ciclo diesel, como também foi realizada a caracterização do tipo de desgaste ocorrido no par tribológico e comparada com a literatura específica. Com base nos resultados, concluiu-se que ocorreu uma excelente compatibilidade entre a válvula e a sede da válvula de admissão; o nível de desgaste não prejudicou o desempenho do motor e as emissões de poluentes; o par tribológico atendeu aos requisitos de trabalho extremos, como operação em altas temperaturas e pressão de combustão com baixas taxas de desgaste; e os tipos de desgastes observados foram classificados como desgaste adesivo e sinais de deformação plástica. / Automotive industry demands products that work under extreme conditions. The development of components for internal combustion engines is an action to improve this product, so that it reaches the required life with acceptable levels of wear and respecting the legal operating limits, such as values of emission pollutants. In view of these requirements, it is necessary to study components considered critical, which are known to influence the performance of the engine. So within this universe the tribology of the intake valve and valve seat insert is an important set, that must receive attention to its wear and consequently its influence to the engine degradation in the parameters of emission pollutants and performance related to the operational maintenance requirements and life of the product. The aim of this work is to evaluate the behavior of the tribological intake pair, valve and valve seat insert, submitted to dynamometer and vehicular tests (real operating conditions), regarding the level and type of wear occurred in the pair. The results were compared with legal and operational performance requirements of a diesel cycle engine, as well as the characterization of the wear type occurred in the tribological pair, with the related literature. Based on the results it was concluded that there was excellent compatibility between the valve and the valve seat material; the wear level did not impar the engine performance and emissions of pollutants; the tribological pair meeting extreme work requirements, such as high temperature operation and combustion pressure while maintaining low wear rates. The wear types observed were classified as adhesive wear and slight signs of shear strain wear.

Cardiac resynchronization therapy (CRT) is an established therapy for patients with advanced congestive heart failure and prolonged QRS duration, aiming at correcting dyssynchrony in the left ventricle (LV). Apart from the beneficial effects on cardiac function and LV reverse remodeling, reduction in functional MR has been observed by Doppler echocardiography after CRT. On the other hand, functional mitral regurgitation (MR) in fact varies over the cardiac cycle that a biphasic pattern has been reported, i.e. early- and late-systolic peaks with a mid-systolic decrease in regurgitant flow. Nevertheless, it remains to be explored whether (1) the improvement of MR leads to a greater extent of LV reverse remodeling; (2) the different components (i.e. early- and late-systolic) of MR improve and their predictors if any. / Despite comparable ejection fraction, higher degree of functional MR was associated with further impairment in short-axis myocardial deformation (circumferential and radial), but not with long-axis myocardial deformation. The degree of LV basal rotation was also lower in the MR patient group. Furthermore, the decrease in myocardial deformation was associated with greater extent of LV remodeling. / In conclusion, LV global mechanical dyssynchrony play a role in determining the severity of functional MR in addition to mitral leaflet tenting in patients with LV systolic dysfunction. Functional MR is associated with further impairment of myocardial deformation, but with differential change in individual component of myocardial deformation. CRT reduces functional MR in both early- and late-systolic phases, by way of improvement in LV remodeling, LV dyssynchrony and mitral leaflet tenting. Meanwhile, the improvement of MR contributes to LV reverse remodeling after CRT. (Abstract shortened by UMI.) / The improvement of functional MR was an independent predictor of LV reverse remodeling after CRT. The extent of LV reverse remodeling (reduction of LV end-systolic volume) was greatest in patients with improvement of MR, followed by those with "mild or no" MR at baseline, and was least in those without improvement of MR. CRT reduced functional MR by reducing both its early- and late-systolic components in heart failure patients. The reductions in LV end-systolic volume and dyssynchrony were related to the improvement of early-systolic MR, while the improvement of late-systolic MR was attributable to the reductions in mitral leaflet tenting and LV dyssynchrony. / The main findings were as follows: LV global systolic dyssynchrony served as an independent predictor for the presence of significant functional MR in patients with LV systolic dysfunction. Although mitral valvular tenting area was the most powerful predictor, LV global systolic dyssynchrony added incremental value to mitral valve tenting area in predicting the presence of significant functional MR. / We performed echocardiography with TDI and 2DSTE in 147 patients of both ischemic and non-ischemic etiologies with LV systolic dysfunction (defined as LV ejection fraction <50%) and 45 normal controls. MR severity, displacement of papillary muscle, mitral annular dilation and dysfunction, mitral leaflet tenting, LV remodeling and function were assessed by 2D and Doppler echocardiography. LV mechanical dyssynchrony indices were derived from TDI velocity. Myocardial strain (i.e. amount of deformation) in longitudinal, circumferential and radial directions and torsion (opposite rotational movement between apex and base of the heart) were measured by 2DTSE. / Liang, Yujia. / "October 2009." / Adviser: Cheuk man Yu. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 169-193). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

A Tissue Engineering (TE) approach to heart valve replacement has the aim of producing an implant that is identical to healthy tissue in morphology, function and immune recognition. The aim is to harvest tissue from a patient, establish cells in culture from this tissue and then use these cells to grow a new tissue in a desired shape for the implant. The scaffold material that supports the growth of cells into a desired shape may be composed of a biodegradable polymer that degrades over time, so that the final engineered implant is composed entirely of living tissue. The approach used at Swinburne University was to induce the desired mechanical and functional properties of tissue and is to be developed in an environment subjected to flow stresses that mimicked the haemodynamic forces that natural tissue experiences. The full attainment of natural biomechanical and morphological properties of a TE structure has not as yet been demonstrated. In this thesis a review of Tissue Engineering of Heart Valves (TEHVs) is presented followed by an assessment of biocompatible materials currently used for TEHVs. The thrust of the work was the design and development of a Bioreactor (BR) system, capable of simulating the corresponding haemodynamic forces in vitro so that long-term cultivation of TEHVs and/or other structures can be mimicked. A full description of the developed BR and the verification of its functionality under various physiological conditions using Laser Doppler Anemometry (LDA) are given. An analysis of the fluid flow and shear stress forces in and around a heart valve scaffold is also provided. Finally, preliminary results related to a fabricated aortic TEHV-scaffold and the developed cell culture systems are presented and discussed. Attempts to establish viable cell lines from ovine cardiac tissue are also reported.

This thesis has been performed at Öhlins Racing AB which is known world-wide for its high quality racing shock absorbers. Öhlins have been developing shock absorbers for more than 30 years and in addition to this they also develop a technology for semi-active suspension. Semi-active suspension technology makes it possible to achieve an intelligent and dynamic vehicle chassis control. Compared to standard passive suspensions, semiactive dampers allow improving vehicle cornering performance while still providing good comfort when cruising. This is achieved by a real time adjustment of the suspensions damping characteristics. Öhlins system for semi-active suspension is called CES (Continuously controlled Electronic Suspension). The systems consist of electronically controlled hydraulic valves for uniflow dampers. These valves are mounted on all four dampers of the vehicle and are controlled individually to provide the desired ride quality. The valves are configurable to suit many types of vehicles by changing internal parts. The first goal of this thesis project was to study the behaviour of the CES valve and uniflow damper. In order to achieve this a simulation model was created using Hopsan which is a 1-dimensional multi-domain modelling tool developed at the division of Fluid and Mechatronic Systems at Linköping University. The model considers mechanical forces from for example springs together with hydraulic forces. It was validated against static and dynamic measurements made in a flow bench and a dynamometer. The second goal was to use the simulation model as part of a tool that configures the CES valve according to a requirements specification. To achieve this goal a method of estimating the characteristics of the internal damper valves was developed. This estimation method, together with the simulation model, was used to choose the best valve configuration by using weighted least-squares. The result is presented in a Matlab-based graphical user interface.