Aortic stenosis (AS) is a critical valvular disease often treated by Transcatheter Aortic Valve Replacement (TAVR). This thesis introduces several novel approaches for improving the assessment and management of AS and the associated TAVR procedure. The research presents new indices for characterizing AS progression, including the False Positive Rate (FPR) method for detecting and quantifying calcification in contrast-enhanced computed tomography (CT) images. This method adapts dynamically to the variability in calcium density and offers precise estimates of calcific burden. Additionally, a Minimal Variation Geometry Invariant Parametric Reconstruction (MVGIPR) method was developed to reconstruct the full geometry of the aortic valve complex (AVC). This approach enhances the accuracy of geometric models from routine CT scans, providing detailed 3D models of the aortic valve, including patient-specific anatomical and pathological features. Moreover, the Virtual Transcatheter Aortic Valve Replacement (VTAVR) framework is introduced for TAVR optimization and intervention planning using developments from both previous techniques. This novel simulation-based system incorporates kinematic modeling within a patient-specific parametric geometry to predict device deployment outcomes, including complications such as paravalvular leakage, patient-prosthesis mismatch, and left bundle branch block. By simulating patient-specific device deployment, the VTAVR framework may potentially enhance pre-procedural planning, leading to better surgical outcomes and reduced risks in TAVR procedures. / Thesis / Doctor of Philosophy (PhD) / Aortic stenosis (AS) is a condition where the heart’s aortic valve becomes narrowed due to calcification, restricting blood flow and leading to severe health risks, especially in older adults. This research introduces new ways to measure the progression of this disease and predict complications from the commonly used treatment called Transcatheter Aortic Valve Replacement (TAVR). Using advanced computational models, the study develops personalized aortic valve shape and structure assessment frameworks using routine clinical computed tomography (CT) imaging. Moreover, we introduce a virtual interventional simulation framework that can predict how a patient’s valve may respond to TAVR. This "Virtual TAVR" system may help treating physicians to plan surgeries more accurately by simulating different approaches, allowing them to identify the best treatment strategy for each patient. By improving our ability to predict complications, the system ultimately aims to increase the success rate of these life-saving procedures.

[pt] A estenose aórtica é um dos mais graves problemas decorrentes de doenças valvares. O implante da prótese valvar aórtica por cateterismo (TAVI) vem se tornando o tratamento mais indicado aos pacientes de alto risco ou inoperáveis. A estenose aórtica grave pode ser uma condição de risco à vida quando não tratada. Devido à natureza do procedimento TAVI, é esperada uma variabilidade no ângulo de inclinação da válvula implantada. O presente trabalho investigou a influência das variações de inclinação e orientação do jato transvalvar sobre o escoamento em aorta ascendente. A compreensão dos padrões hemodinâmicos do fluxo sanguíneo em aorta ascendente é importante porque eles estão intimamente relacionados ao desenvolvimento de doenças cardiovasculares. Para este fim, um modelo vascular com geometria anatômica de paciente específico foi produzido a partir de imagens de tomografia computadorizada, gerando um protótipo impresso em 3D e resina de silicone transparente. Uma configuração especial foi projetada para permitir medições tridimensionais do fluxo em diferentes seções transversais do modelo aórtico. A técnica de velocimetria por imagens estereoscópicas de partículas foi implementada para produzir informações estatísticas acerca do fluxo turbulento, tais como, campos tridimensionais de velocidade média, de energia cinética turbulenta e correlações entre os componentes de flutuação de velocidade. Os resultados obtidos indicaram que o escoamento em aorta ascendente é fortemente afetado pela direção do fluxo de entrada na aorta. / [en] Aortic stenosis is one of the most serious problems arising from valve diseases. Transcatheter Aortic Valve Implantation (TAVI) has become the preferred treatment for high-risk or inoperable patients with severe aortic stenosis that could be a lifethreatening condition when left untreated. Due to the nature of the TAVI procedure, a variability on the tilt angle of the deployed valve is expected. The present work, investigated the effects on the flow field in the ascending aorta due angle variation of the transvalvular jet. Understanding the hemodynamic patterns of blood flow in the ascending aorta is important because they are closely related to the development of cardiovascular diseases. To this end, a patient-specific vascular phantom was produced by a 3D printed model and transparent silicon resin. A special setup was designed to allow measurements of the 3D flow at different cross sections of the aorta. A stereoscopic particle image velocimetry system was implemented to yield instantaneous and averaged turbulent flow information, such as three-dimensional average velocity fields, turbulent kinetic energy, and correlations between the components of velocity fluctuation. The results obtained indicated that the velocity field in the ascending aorta is strongly affected by the inlet flow direction into the aorta.

[pt] As patologias na valva aórtica representam umas das principais causas de óbito no mundo. Nos casos de estenose aórtica grave, a substituição da valva nativa é necessária. Existem dois mecanismos de substituição de valva aórtica: cirurgia convencional, através da toracotomia, ou o implante valvar aórtico percutâneo (TAVI, Transcatheter Aortic Valve Implantation). O posicionamento coaxial da prótese valvar em relação ao ânulo aórtico influência o fluxo sanguíneo transvalvar, podendo contribuir para o remodelamento aórtico, culminando em dilatações aneurismáticas, dissecção aórtica e processo aterosclerótico. O presente estudo avalia numericamente a influência do posicionamento coaxial da prótese valvar nas estruturas hemodinâmicas na região de aorta ascendente e início do arco aórtico, durante um ciclo cardíaco. A geometria anatômica avaliada corresponde a um modelo aórtico de um paciente que foi submetido ao implante valvar percutâneo. O escoamento foi obtido com o modelo de turbulência (K - W), utilizando o software ANSYS-Fluent. A interação entre a complacência aórtica e o fluxo sanguíneo durante o ciclo cardíaco foi obtida empregando simulações do tipo FSI (Fluid Structure Interaction). A metodologia numérica foi validada através de comparações com dados experimentais nobres do tipo PIV estereoscópico, com excelente concordância do campo de velocidade e tensões de Reynolds. Observou-se a importância do posicionamento coaxial da prótese valvar aórtica com relação ao direcionamento do jato e área de impacto na parede da aorta; influenciando na formação de regiões de recirculação na raiz da aorta e aorta ascendente; com diferentes estruturas coerentes (vórtices). Identificou-se as regiões de alta pressão e tensão de cisalhamento na parede da aorta, assim como de alta intensidade das grandezas turbulentas no volume interno da aorta. A partir da análise dos resultados foi possível sugerir que a posição coaxial ideal da prótese pode ser obtida quando é direcionada à parede esquerda da aorta com uma inclinação de 4 graus. / [en] Aortic valve pathologies are one of the leading causes of death in the world. In cases of severe aortic stenosis, replacement of the native valve is necessary. There are two mechanisms of aortic valve replacement: conventional surgery through thoracotomy or Transcatheter Aortic Valve Implantation (TAVI). Coaxial positioning of the valve prosthesis in relation to the aortic annulus influences on the transvalvar blood flow, which may contribute to aortic remodeling, culminating in aneurysmal dilations, aortic dissection and atherosclerotic process. The present thesis evaluates the influence of the coaxial positioning of the valve prosthesis on hemodynamic structures in the ascending aorta and the beginning of the aortic arch, during a cardiac cycle. The anatomical geometry evaluated was the aortic model of a specific patient after being submitted to percutaneous valve implantation procedure. The flow was obtained with the (K - W) turbulence model, using ANSYS-Fluent software. Interaction between aortic compliance and blood flow during the cardiac cycle was obtained using simulations FSI (Fluid Structure Interaction). The numerical methodology was validated through comparisons with noble experimental data obtained from stereoscopic PIV method, with excellent agreement of the velocity field and Reynolds stress. It was observed the importance of the coaxial positioning of the aortic valve prosthesis in relation to the jet direction and the impact area in the aortic wall, influencing the formation of recirculation regions in the aortic root and ascending aorta; with different coherent structures (vortices). The regions of high pressure and shear stress were identified in the aortic wall, as well as high intensity turbulent quantities in the internal aortic volume. From the results analysis it was possible to suggest that the ideal coaxial position of the prosthesis can be obtained when it is directed to the left wall of the aorta with an inclination of 4 degrees.

MScEng / Thesis (MScEng (Mechanical and Mechatronic Engineering))--University of Stellenbosch, 2009. / In this project the shape and attachment method of tissue leaflets for a percutaneous aortic valve is designed and tested as a first prototype. Bovine and kangaroo pericardium was tested and compared with natural human valve tissue by using the Fung elastic constitutive model for skin. Biaxial tests were conducted to determine the material parameters for each material. The constitutive model was implemented using finite element analysis (FEA) by applying a user-specified subroutine. The FEA implementation was validated by simulating the biaxial tests and comparing it with the experimental data. Concepts for different valve geometries were developed by incorporating valve design and performance parameters, along with stent constraints. Attachment techniques and tools were developed for valve manufacturing. FEA was used to evaluate two concepts. The influence of effects such as different leaflet material, material orientation and abnormal valve dilation on the valve function was investigated. The stress distribution across the valve leaflet was examined to determine the appropriate fibre direction for the leaflet. The simulated attachment forces were compared with suture tearing tests performed on the pericardium to evaluate suture density. In vitro tests were conducted to evaluate the valve function. Satisfactory testing results for the prototype valves were found which indicates the possibility for further development and refinement.

Thesis (MScEng (Mechanical and Mechatronic Engineering))--University of Stellenbosch, 2009. / Elderly patients suffering from aortic valvular dysfunction are often denied aortic valve replacement due to the fact that they are classified as too old and fragile to handle the physical stress of open-heart surgery and cardio-pulmonary bypass. There exists a need for an alternative solution which places less physical stress on the body. The development of a percutaneous aortic heart valve (PAHV), which may be implanted through a minimally invasive procedure, will provide a solution to old and fragile patients who otherwise have a very limited life expectancy. The development of such a device entails a costly and time-consuming process which involves a number of phases, including a prototype development phase, an in-vitro testing phase, an animal trial phase and a human trial phase. This thesis focuses on the design and analysis of the stent component for a PAHV, suitable for implantation in sheep (animal trial phase). The process of developing a first prototype, involved an analysis of the stent design requirements. This analysis was followed by a concept generation phase as well as comprehensive finite element (FE) analyses of the most promising concepts. The objective of the FE analyses was to determine the effects of a variation in strut width on the performance characteristics of the concepts. Based on the results of the FE analyses, final geometries were selected for each of the two most promising concepts. Subsequent to the selection of the final geometries, a number of prototypes were manufactured. The prototypes were subjected to an electro-polishing process. An experimental analysis was also conducted on the prototypes to evaluate the accuracy of the (FE) simulations as well as the actual performance of the stent prototypes. The results of the FE analyses and experimental analyses indicated that strut width had a substantial influence on the parameters that were defined to characterise stent performance. The results of the analyses also highlighted the advantages and disadvantages of each concept and aided in identifying the concept that would be most suitable for the required application. Limitations of the study were identified and recommendations were made to assist the continued research and development of the device.

<p><i>Chlamydophila pneumoniae</i> (<i>C. pneumoniae</i>) has been suggested as a stimulator of chronic inflammation in atherosclerosis. <i>C. pneumoniae</i> DNA was demonstrated in aortic biopsies in 50% of patients with stable angina pectoris or acute coronary syndrome undergoing coronary artery bypass grafting. <i>C. pneumoniae</i> mRNA, a marker of replicating bacteria, was demonstrated in 18% of the aortic biopsies. </p><p>Inflammation may have a role in the pathogenesis of thoracic aortic aneurysm, aortic dissection and aortic valve stenosis. <i>C. pneumoniae </i>DNA was demonstrated in aortic biopsies in 26% of thoracic aortic aneurysm patients and in 11% of aortic dissection patients undergoing thoracic surgery and in 22% of stenotic aortic heart valves from patients undergoing aortic valve replacement. No bacterial mRNA was demonstrated in these aortic biopsies, nor in the valves, suggesting that the infection has passed into a persistent state. <i>C. pneumoniae</i> DNA was demonstrated in peripheral blood mononuclear cells in only 5% of aortic valve stenosis patients and not in thoracic aortic aneurysm or aortic dissection patients, suggesting that the bacterium disseminated to the cardiovascular tissue long before the patient required surgery. The copper/zinc ratio in serum, a marker of infection/inflammation, was significantly elevated in thoracic aortic aneurysm patients, supporting an inflammatory pathogenesis. Patients positive for <i>C. pneumoniae</i> in the aortic valve had more advanced coronary atherosclerosis, further supporting a possible role for <i>C. pneumoniae</i> in atherosclerosis. </p><p>Mice were infected with <i>C. pneumoniae</i> that disseminated to all organs investigated (i.e. lungs, heart, aorta, liver and spleen). Trace element concentrations were altered in infected animals with an increased copper/zinc ratio in serum, a progressively increased iron concentration in the liver and a progressively decreased iron concentration in serum. Iron is important for <i>C. pneumoniae</i> metabolism, and a changed iron homeostasis was noted in infected mice by alterations in iron-regulating proteins, such as DMT1 and hepcidin.</p>

Calcific aortic valve disease (CAVD) is associated with significant cardiovascular morbidity. While late-stage valve disease is well-described, there remains an unmet scientific need to elucidate early pathobiological processes. In CAVD, pathological differentiation of valvular interstitial cells (VICs) and lesion formation occur focally in the fibrosa layer. This VIC pathological differentiation has been shown to be influenced by matrix stiffness in vitro. However, little is known about the focal layer specific mechanical properties of the aortic valve in health and disease and how these changes in matrix moduli may influence VIC pathological differentiation in vivo. In this thesis, micropipette aspiration (MA) was shown to be capable of measuring the mechanical properties of a single layer in multilayered biomaterial or tissue such as the aortic valve, if the pipette inner diameter was less than the top layer thickness. With MA, the fibrosa of normal porcine aortic valves was significantly stiffer than the ventricularis; stiffer locations found only within the fibrosa were comparable to stiffnesses shown in vitro to be permissive to VIC pathological differentiation. Early CAVD was induced in a porcine model, which developed human-like early CAVD lesion onlays. Extracellular matrix remodeling occurred in the absence of lipid deposition, macrophages, osteoblasts, or myofibroblasts, but with significant proteoglycan-rich onlays and chondrogenic cell presence. These early onlays were softer than the collagen-rich normal fibrosa, and their proteoglycan content was positively correlated with Sox9 chondrogenic expression, suggesting that soft proteoglycan-rich matrix may be permissive to chondrogenic VIC differentiation. The findings from this thesis shed new light on early disease pathogenesis and improve the fundamental understanding of aortic valve mechanics in health and disease.

Para investigar se estresse oxidativo contribui para a progressão da calcificação/estenose valvar aórtica (VA), avaliamos a produção de espécies reativas de oxigênio (ERO) e efeitos dos antioxidantes tempol e ác. lipóico em modelo de calcificação VA em coelhos. Superóxido, H2O2 e 3-nitrotirosina aumentaram em células inflamatórias e principalmente nos núcleos de calcificação, juntamente com as subunidades p22phox, Nox2 da NADPH oxidase e da proteína dissulfeto isomerase, que co-localizam. PCR mostrou aumento da Nox4 em relação a Nox1. A calcificação foi menor com ác.lipóico e maior com tempol, coicidindo com resultados de modelo in vitro em células musculares lisas. VA humanas estenóticas tiveram aumento semelhante de ERO e da expressão protéica em torno da calcificação. Estresse oxidativo pode contribuir para a progressão da estenose aórtica. / To invetigate whether oxidative stress contributes to aortic valve (AV) calcification/stenosis progression, we assessed reactive oxygen species (ROS) production and effects of antioxidants tempol and lipoic acid in a rabbit AV calcification model. Superoxide, H2O2 and 3-nitrotyrosine increased in inflammatory cells and mainly in calcifying nuclei, coincident with NADPH oxidase subunits p22phox, Nox2 and protein disulfide isomerase, which co-localized. PCR showed switch from Nox1 to Nox4. Calcification was smaller with lipoic acid and greater with tempol, similar to an in vitro smooth muscle cell calcification model results. Human stenotic AV had analogous increase in ROS and protein expression around calcifying nuclei. Oxidative stress can contribute to AV stenosis progression.

Introdução: A deposição de cálcio junto aos folhetos valvares esta intimamente relacionada à fisiopatologia da estenose valvar aórtica degenerativa (EAD). A tomografia computadorizada com multidetectores (TCMD), além de possibilitar o delineamento tridimensional das estruturas cardíacas, permite a quantificação da intensidade da calcificação valvar. Atualmente, a relação entre a localização dos depósitos valvares de cálcio e a gravidade hemodinâmica na estenose aórtica permanece incerta. Objetivo: Avaliar se a topografia da calcificação valvar influencia a repercussão hemodinâmica na EAD. Métodos: Trata-se de estudo prospectivo, unicêntrico, incluindo 97 pacientes com EAD moderada ou importante. O escore de cálcio da valva aórtica foi calculado a partir da TCMD sem contraste. A topografia da calcificação valvar foi avaliada através de análise tomográfica específica com infusão de baixa dose de contraste endovenoso, objetivando uma detalhada segmentação anatômica dos planos valvares. A medida da atenuação, expressa em unidades Hounsfield (UH), foi utilizada para quantificar o conteúdo de cálcio na região central e periférica do plano valvar aórtico. Resultados: Pacientes com EAD importante apresentaram escore de cálcio valvar aórtico superior ao dos portadores de EAD moderada (3131 ± 1828 unidades Agatston [UA] e 1302 ± 846 UA, respectivamente; p < 0,001). Quanto à topografia da calcificação, pacientes com EAD importante exibiram atenuações significativamente maiores no centro do plano valvar do que em sua periferia (507,4 ± 181,7 UH vs. 449,8 ± 114,5 UH; p = 0,001). Inversamente, pacientes com EAD moderada apresentaram menor atenuação na região central do que na periferia valvar (308,7 ± 92,9 UH vs. 347,6 ± 84,2 UH, p < 0,001). A razão da atenuação centro/periferia também foi significativamente maior nos pacientes com EAD importante (1,14 ± 0,32 vs. 0,89 ± 0,13; p < 0,001), permanecendo significativamente associada à presença de EAD importante mesmo após ajuste para o grau subjacente de calcificação Resumo valvar. Conclusão: A gravidade da EAD parece resultar não apenas do grau de calcificação, mas também da localização dos depósitos valvares de cálcio / Introduction: The pathophysiology of degenerative aortic valve stenosis (AS) is intimately related to the development of calcific deposits in the valve structure. Multidetector computed tomography (MDCT), a reliable method to delineate the tridimensional heart geometry, has been shown to accurately quantify the global aortic valve calcium content. Currently, the relationship between calcium location and hemodynamic disease severity is poorly understood. Objective: The present prospective study was conducted to test the hypothesis of whether the location of valve calcification influences the functional severity of AS. Methods: Prospective, single-arm study including 97 patients with diagnosed moderate or severe AS. Aortic valve calcium score was calculated from nocontrast multidetector computed tomography (MDCT). \"Low-contrast- os \" MDCT images were acquired for segmentation of the cardiac anatomy, with the attenuation, expressed in Hounsfield units (HU), used to quantify the calcium content at the central and peripheral regions of the aortic valve zone. Results: The calcium score was higher among patients with severe AS compared to patients without severe AS (3131±1828 Agatston units [AU] vs. 1302±846 AU respectively; p < 0.001). Patients with severe AS had significantly higher attenuations at the center of the valve than at its periphery (507.4±181.7 HU vs. 449.8±114.5 HU; p=0.001). Conversely, patients without severe AS had lower attenuation at the center than at the periphery of the valve (308.7 ± 92.9 HU vs. 347.6±84.2 HU; p < 0.001). The center/periphery attenuation ratio was significantly higher for patients with severe AS than for those without severe disease (1.14±0.32 vs. 0.89 ± 0.13; p < 0.001), and remained significantly associated with the presence of severe AS even after adjusting for the underlying degree of valve calcification. Conclusion: The severity of degenerative aortic valve stenosis appears to result not only from the degree of calcification but also from the localization of the calcific deposits within the valve

L’objectif de cette thèse de doctorat est de développer des outils expérimentaux et numériques pour la caractérisation mécanique et la modélisation des tissus, naturels ou artificiels, de valve aortique. Ces outils sont destinés à être utilisés pour l'élaboration de nouveaux implants biomimétiques en matériaux polymères. Chaque année, près de 300 000 prothèses de valves sont implantées à travers le monde. Ces implants peuvent être de deux types~: mécaniques ou biologiques. Les deux solutions souffrent cependant d'inconvénients majeurs. Dans ce contexte, les prothèses en matériaux polymères représentent une alternative prometteuse même si elles ne disposent pas encore de propriétés mécaniques suffisantes. Dans ce travail, un protocole expérimental combinant essais de traction biaxiale, mesure de champs et microscopie confocale est proposé. La mise au point de nouveaux implants peut aussi largement bénéficier de la modélisation numérique afin d'étudier leur comportement mécanique. Ainsi, un solveur structure et un solveur fluide ont été implémentés et couplés. À partir des résultats expérimentaux, les modèles de comportements ont été calibrés en utilisant une procédure d'analyse inverse. / This PhD thesis aims to develop experimental and numerical tools for the mechanical characterization and the numerical modeling of natural or artificial aortic valve tissues. These tools are intended to be used for the development of new biomimetic polymeric implants. Nowadays, almost 300 000 prosthetic valves are implanted every year worldwide. Two families of prosthetic valves are currently available~: mechanical and biological prostheses. However, both solutions suffer from major drawbacks. In this context, polymeric prostheses represent a promising alternative but currently suffer from insufficient material properties to be suitable for a long--lasting implantation. In this work, an experimental protocol using biaxial tensile tests together with full--field surface measurement and confocal microscopy is proposed. Since numerical simulation is intended to assist the design phase of new implants by predicting their mechanical behavior, a structure and a fluid solver are developed and coupled. Using experimental results, implemented constitutive models are calibrated through an inverse analysis procedure.