<p>The obligate intracellular bacterium <i>Chlamydia pneumoniae (Cp</i>), a common human pathogen, has been associated with atherosclerotic cardiovascular disease. The aetiology of non-rheumatic aortic valve sclerosis has, however, not been clarified. In two prospective studies of 42 and 46 patients undergoing surgical valve replacement because of aortic valve stenosis, the presence of <i>Cp </i>DNA could be demonstrated by polymerase chain reaction (PCR) in 49% and 35% of the sclerotic valves as compared to 9 % and 0%, respectively, of valves from forensic control cases with no heart valve disease. Some inflammatory and infectious diseases are associated with trace element changes. Eleven of 15 trace elements showed changed concentrations in sclerotic valve tissue compared to control valves in support of an active process in the sclerotic valves. Notable was an increased iron concentration in the patients´ valves suggesting a possible link to <i>Cp</i>. Furthermore, a disturbed trace element balance existed in the patients´ sera, the pattern of which was compatible with ongoing infection. In a prospective study of 38 patients operated on for thoracic aortic aneurysm or dissection, <i>Cp</i> DNA <i>w</i>as detected byPCR in 12 % of the aneurysms and the result was confirmed byelectron microscopy(EM<i>).</i> In none of the dissection patients could <i>Cp </i>be demonstratedin the removed tissues. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values for doxycycline and azithromycin increased with longer <i>Cp </i>preincubation times when tested in vitro<i>.</i> EMwas performed to visualise the inactivation at a cellular level.Thus, the results demonstrate <i>Cp </i>in the tissues in non-rheumatic aortic valve sclerosis and in thoracic aortic aneurysm but not in aortic dissection.</p>

The obligate intracellular bacterium Chlamydia pneumoniae (Cp), a common human pathogen, has been associated with atherosclerotic cardiovascular disease. The aetiology of non-rheumatic aortic valve sclerosis has, however, not been clarified. In two prospective studies of 42 and 46 patients undergoing surgical valve replacement because of aortic valve stenosis, the presence of Cp DNA could be demonstrated by polymerase chain reaction (PCR) in 49% and 35% of the sclerotic valves as compared to 9 % and 0%, respectively, of valves from forensic control cases with no heart valve disease. Some inflammatory and infectious diseases are associated with trace element changes. Eleven of 15 trace elements showed changed concentrations in sclerotic valve tissue compared to control valves in support of an active process in the sclerotic valves. Notable was an increased iron concentration in the patients´ valves suggesting a possible link to Cp. Furthermore, a disturbed trace element balance existed in the patients´ sera, the pattern of which was compatible with ongoing infection. In a prospective study of 38 patients operated on for thoracic aortic aneurysm or dissection, Cp DNA was detected byPCR in 12 % of the aneurysms and the result was confirmed byelectron microscopy(EM). In none of the dissection patients could Cp be demonstratedin the removed tissues. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values for doxycycline and azithromycin increased with longer Cp preincubation times when tested in vitro. EMwas performed to visualise the inactivation at a cellular level.Thus, the results demonstrate Cp in the tissues in non-rheumatic aortic valve sclerosis and in thoracic aortic aneurysm but not in aortic dissection.

The number of patients that are waiting for heart transplants far exceed the number of available donor hearts. Left Ventricular Assist Devices are mechanical alternatives that can help and are helping several patients. They work by taking blood from the left ventricle and ejecting that blood into the aorta. In the University of Louisville they are developing a similar device that will take the blood from the aorta instead of the ventricle. This new device is called an Artificial Vasculature Device. In this thesis the arterial system and AVD are modeled and a simple control algorithm for the AVD proposed. The arteries are modeled as a tube with linear resistance and inertia followed by a chamber with linear compliance and last a tube with linear resistance. The model is identical to the 4-element Windkessel model. The values for the resistances, inertia and compliance are identified using pressure and flow measurements from the ventricle and aortic root from a healthy patient. In addition to the Windkessel model the aortic valve is also modeled. The valve is modeled as a drum that closes the aorta and the parameters identified like before. The measurements are also used to model the left ventricle by assuming it has a constant compliance profile. The AVD is modeled using common modeling structures for servo motors and simple structures for tubes and pistons. The values for the AVD could not be measured and identified so they are fetched from preliminary motor and part specifications. The control algorithm for the AVD uses a wanted load to create a reference aortic flow. This wanted aortic flow is then achieved by using a PI controller. With these models and controller the interaction between the arterial system and AVD is investigated. With this preliminary understanding of the interaction further research can be made in the future to improve the understanding and improve the AVD itself.

<p>The number of patients that are waiting for heart transplants far exceed the number of available donor hearts. Left Ventricular Assist Devices are mechanical alternatives that can help and are helping several patients. They work by taking blood from the left ventricle and ejecting that blood into the aorta. In the University of Louisville they are developing a similar device that will take the blood from the aorta instead of the ventricle. This new device is called an Artificial Vasculature Device. In this thesis the arterial system and AVD are modeled and a simple control algorithm for the AVD proposed. </p><p>The arteries are modeled as a tube with linear resistance and inertia followed by a chamber with linear compliance and last a tube with linear resistance. The model is identical to the 4-element Windkessel model. The values for the resistances, inertia and compliance are identified using pressure and flow measurements from the ventricle and aortic root from a healthy patient. In addition to the Windkessel model the aortic valve is also modeled. The valve is modeled as a drum that closes the aorta and the parameters identified like before. The measurements are also used to model the left ventricle by assuming it has a constant compliance profile. </p><p>The AVD is modeled using common modeling structures for servo motors and simple structures for tubes and pistons. The values for the AVD could not be measured and identified so they are fetched from preliminary motor and part specifications. </p><p>The control algorithm for the AVD uses a wanted load to create a reference aortic flow. This wanted aortic flow is then achieved by using a PI controller. With these models and controller the interaction between the arterial system and AVD is investigated. </p><p>With this preliminary understanding of the interaction further research can be made in the future to improve the understanding and improve the AVD itself.</p>

Aortic stenosis is the most common acquired heart valve condition. Open-heart surgical aortic valve replacement is an effective treatment for patients who receive it. However, approximately one-third of patients who require this treatment do not receive it due to the risks associated with the surgery. Percutaneous aortic valve replacement (PAVR) is a minimally invasive technique that can replace the aortic valve of patients contraindicated for open-heart surgery. Although PAVR is now entering clinical practice, a closed bore hybrid x-ray/MRI (CBXMR) imaging system is under development to improve the safety and efficacy of PAVR. This system will harness the complementary strengths of x-ray imaging (surgical tool/vascular imaging) and MRI (cardiac soft tissue contrast) to deploy a bioprosthesis in the aortic annulus. An x-ray C-arm will be placed about 1 m from the entrance of the MRI scanner to facilitate smooth intermodality patient transfer during the procedure. The performance of a rotating-anode x-ray tube in the magnetic fringe field of a 1.5 T MRI scanner was investigated. A rotating-anode x-ray tube provides the fluoroscopy and angiography needed for PAVR. The magnetic fringe field can affect the ability of the x-ray tube to dissipate heat. It was shown that the fringe field perpendicular to the anode rotation axis can reduce anode rotation frequency. These effects can limit the maximum permissible power that can be safely dissipated on the anode track during a single exposure. In the fringe field strengths at the C-arm position (4-5 mT), anode rotation frequency only decreased by about 1%, which will have negligible impact on tube heat loadability. The fringe field can cause a field of view shift. The field of view shifted by approximately 3 mm, which can be corrected by active magnetic shielding and further collimation. An active magnetic shielding system was constructed that can correct focal spot deflection. These results are facilitating the construction of a prototype CBXMR system, the goal of which is to improve success rates for PAVR procedures.

La sténose valvulaire aortique (SVA) est une pathologie associée au vieillissement et aux facteurs de risque cardiovasculaire. Afin d’étudier la SVA et d’explorer de nouvelles thérapies, plusieurs modèles animaux ont été récemment développés, mais la plupart de ces modèles ciblent les mécanismes de développement de la SVA reliés à l’hypercholestérolémie. Le syndrome de Werner (WS) est une maladie caractérisée par un vieillissement prématuré. Récemment, il a été découvert que des souris mutantes ayant une délétion du domaine hélicase du gène Werner, responsable du WS, démontraient un profile hémodynamique typique de la SVA. De ce fait, nous avons émis l’hypothèse que ces souris pourraient développer une SVA plus rapidement que des souris de type sauvage. Nous avons donc étudié les effets cette mutation chez des souris WrnΔhel/Δhel, en comparant le taux de progression d’une SVA entre des souris WrnΔhel/Δhel (WrnΔhel) et des souris de type sauvage comme groupe contrôle. À la suite d’une diète riche en sucre et en gras sur une période de 24 semaines, les souris WrnΔhel ont démontré une diminution plus prononcée de leur aire de valve aortique (mesures échocardiographiques) que les souris contrôles, supportée par les analyses histologiques concernant la fibrose des valves aortiques. Les souris n’ont toutefois développé aucun signe évident d’athérosclérose comme l’infiltration de lipides ou l’inflammation, bien que certaines caractéristiques liées à la dysfonction endothéliale semblent être augmentées chez les souris WrnΔhel. D’autres mesures échocardiographiques indiquant une SVA, comme une hypertrophie du ventricule gauche dans le groupe WrnΔhel, ont été obtenues. Nous avons aussi observé des indices de vieillissement plus marqués quant aux analyses sanguines et de la moelle osseuse des souris WrnΔhel en comparaison avec les souris contrôles. Par conséquent, ce modèle expérimental de vieillissement pourrait être utilisé pour les études futures sur la SVA sans les principaux effets athérogéniques des autres modèles expérimentaux. / Aortic valve stenosis (AVS) is associated with aging and classical cardiovascular risk factors. Different animal models were recently developed to study AVS and explore new therapies, however, most of these models rely almost exclusively on hypercholesterolemia-related mechanisms for AVS development. Werner syndrome (WS) is a disorder characterized by premature aging. It was recently demonstrated that mutant mice with a deletion of the helicase domain of the Werner gene, the gene responsible for WS, showed hemodynamic profile typical of AVS. We therefore hypothesized that mice with the WrnΔhel deletion could develop AVS earlier than wild-type (WT) mice. We studied the effect of the WrnΔhel mutation by comparing the rate of progression of AVS in homozygous mutant versus WT mice. By twenty-four weeks on a high-fat/high-carbohydrate diet, WrnΔhel/Δhel (WrnΔhel) mice showed a stronger decrease of the aortic valve area measured by serial echocardiography than WT mice, supported by histological analyses of valve fibrosis but without developing major signs of atherosclerosis such as lipid infiltration or increased inflammation. Some features linked to endothelial dysfunction also appeared to be increased in WrnΔhel mice. Other echocardiographic measurements were typical of AVS, such as left ventricle hypertrophy in the WrnΔhel group. We also observed stronger aging properties from WrnΔhel mice bone marrow and blood analyses compared to the WT group. Consequently, this experimental aging model could be used for AVS research without the major confounding atherogenic effects of other experimental models.

The objectives of this thesis are: a) To examine racial/ethnic differences in coronary artery calcification (CAC) and CAD, between symptomatic South Asians and Caucasians, matched for age, gender and conventional cardiovascular risk factors, b) To assess, using a meta-analysis model, the natural history of and stability of measurements of coronary artery calcium scoring (CACs) based on data collected from two large published trials: St Francis and EBEAT, c) To investigate the prevalence of coronary artery calcification in individuals with CT evidence for AVC, mitral valve calcification (MAC) or of both of them (AVC+MAC), d) To assess any potential association between premature CAD (&lt;55 years in first-degree male relatives and &lt;65 years in first-degree female relatives) and CAC in a large cohort of asymptomatic individuals. We found that coronary artery calcification is more extensive and diffuse in symptomatic patients of South Asian ethnic origin as compared to Caucasians, despite similar conventional risk factors for CAD. This is more evident in those &gt;50 years of age, suggesting potential genetic or other risk factors yet to be determined. The natural history of coronary artery calcification was overtime progression in the majority of subjects, irrespective of gender. The higher variability in RCA measurements could be related to the low baseline CACs or exaggerated movement of the right side atrioventricular ring, whereas those for LCA brances are influenced by the branch allocation of the CACs. Valve calcification is not isolated but involve also and the coronary arteries. The presence of calcification in the aortic valve or combined aortic and mitral valves predicted coronary artery calcification. Additionally patients in whom both valves have become calcified tend to have severe coronary artery calcification. And finally, there is no relationship between the prevalence and extent of coronary artery calcification and the presence of family history of coronary heart disease in asymptomatic individuals with none of the conventional risk factors for atherosclerosis.

Aortic stenosis is the most common acquired heart valve condition. Open-heart surgical aortic valve replacement is an effective treatment for patients who receive it. However, approximately one-third of patients who require this treatment do not receive it due to the risks associated with the surgery. Percutaneous aortic valve replacement (PAVR) is a minimally invasive technique that can replace the aortic valve of patients contraindicated for open-heart surgery. Although PAVR is now entering clinical practice, a closed bore hybrid x-ray/MRI (CBXMR) imaging system is under development to improve the safety and efficacy of PAVR. This system will harness the complementary strengths of x-ray imaging (surgical tool/vascular imaging) and MRI (cardiac soft tissue contrast) to deploy a bioprosthesis in the aortic annulus. An x-ray C-arm will be placed about 1 m from the entrance of the MRI scanner to facilitate smooth intermodality patient transfer during the procedure. The performance of a rotating-anode x-ray tube in the magnetic fringe field of a 1.5 T MRI scanner was investigated. A rotating-anode x-ray tube provides the fluoroscopy and angiography needed for PAVR. The magnetic fringe field can affect the ability of the x-ray tube to dissipate heat. It was shown that the fringe field perpendicular to the anode rotation axis can reduce anode rotation frequency. These effects can limit the maximum permissible power that can be safely dissipated on the anode track during a single exposure. In the fringe field strengths at the C-arm position (4-5 mT), anode rotation frequency only decreased by about 1%, which will have negligible impact on tube heat loadability. The fringe field can cause a field of view shift. The field of view shifted by approximately 3 mm, which can be corrected by active magnetic shielding and further collimation. An active magnetic shielding system was constructed that can correct focal spot deflection. These results are facilitating the construction of a prototype CBXMR system, the goal of which is to improve success rates for PAVR procedures.

[pt] A substituição de válvula aórtica por cateter (Transcatheter Aortic Valve Replacement, TAVR) tornou-se uma poderosa alternativa para pacientes com estenose aórtica e com alto risco de serem submetidos à cirurgia tradicional de peito aberto. O conhecimento da distribuição da pressão, bem como a tensão cisalhante na superfície da aorta podem ajudar a identificar regiões críticas, onde o processo de remodelamento da aorta pode ocorrer. O objetivo do presente trabalho é avaliar numericamente a influência do posicionamento do orifício da válvula protética no campo de escoamento. O estudo foi realizado com base em um paciente submetido a TAVR. Um modelo 3D foi gerado a partir de angiotomografia e de segmentação de imagens da aorta. Dados experimentais obtidos anteriormente na mesma geometria indicaram que o fluxo do jato através da válvula de entrada é de natureza turbulenta. O escoamento foi determinado numericamente com o software comercial FLUENT. A turbulência foi modelada com o modelo de dois equações k-omega SST. Para representar um fluxo pulsátil, foram impostos diferentes fluxo de massa na entrada da válvula. Para todas as vazões investigadas, obteve-se um padrão de escoamento semelhante. Mostrou-se que uma pequena variação dos ângulos de inclinação pode modificar a natureza do fluxo, deslocando a posição dos vórtices e alterando a localização das regiões de alta tensão de cisalhamento, assim como de alta pressão, na superfície interna da aorta. Mostrou-se também que um aumento da intensidade da turbulência na entrada diminui os valores de tensão cisalhante e de pressão nas paredes da aorta. Essas características hemodinâmicas podem ser relevantes no processo de remodelação aórtica e os estresses mecânicos podem influenciar na durabilidade da prótese valvular. / [en] Transcatheter Aortic Valve Replacement (TAVR) has become a powerful alternative for patients with aortic stenosis and a high surgical risk to face a traditional open chest surgery. The knowledge of the pressure distribution as well as shear stress at the aortic surface may help identify critical regions, where aortic remodeling process may occur. The purpose of the present work is to evaluate numerically the influence of the positioning of the prosthetic valve orifice in the flow field. The study was carried out on the basis of a particular patient who had undergone a TAVR. A 3D model was generated from computed tomography angiography and image segmentation of the aorta. Experimental data previously obtained in the same geometry indicated that the jet flow through the inlet valve is turbulent flow. The flow field was numerically determined with the commercial software Fluent. The turbulence was modeled with the two-equation k-omega SST model. To represent a pulsatile flow, different mass flow rates were imposed at the inlet valve. Similar flow pattern was observed for all flow rates investigated. It was shown that small variations of the tilt angle can modify the nature of the flow, displacing the position of the vortices and altering the location of high shear stress, as well as high pressure, at the aortic inner wall. It was also shown that an increase of the turbulent intensity at the entrance decreases the values of shear stress and pressure on the walls. These hemodynamic features may be relevant in the aortic remodeling process and the mechanical stresses may influence the durability of the valve prosthesis.

Cette thèse traite plusieurs aspects scientifiques inhérents à la simulation numérique de problèmes d'interaction fluide-structure impliquant de fines membranes déformables. Deux cas spécifiques relatifs à la biomécanique cardiovasculaire sont considérés : l'interaction de l'écoulement sanguin avec la valve aortique (qui se produit à l'échelle macroscopique), et l'interaction de la membrane des globules rouges avec ses fluides interne et externe (qui se produit à l'échelle microscopique). Dans les deux cas, le couplage fluide-structure est géré par l'intermédiaire d'un formalisme de frontières immergées, en représentant la membrane par un maillage Lagrangien se mouvant au travers d'un maillage fluide Eulérien. Lorsque l'on traite la dynamique des globules rouges, la membrane est considérée comme étant une structure sans masse et infiniment fine. La première question à laquelle on s'intéresse dans cette thèse est la manière de modéliser la microstructure complexe de la membrane des globules rouges. Un moyen possible pour caractériser un modèle de membrane adapté est de simuler l'expérience des pinces optiques, qui consiste en une configuration expérimentale bien contrôlée qui permet d'étudier la mécanique individuelle d'un globule rouge isolé dans une large gamme de déformations. Plusieurs modèles pertinents sont identifiés, mais les caractéristiques de déformation mesurées durant l'expérience des pinces optiques se révèlent n'être pas assez sélectives pour être utilisées dans un contexte de validation. Des mesures de déformation additionnelles sont proposées, qui pourraient permettre une meilleure caractérisation de la mécanique de la membrane des globules rouges. En ce qui concerne les configurations macroscopiques, une méthode numérique innovante est proposée afin de gérer des simulations numériques de membranes 3D continues, en conservant le formalisme de frontières immergées. Dans cette méthode, appelée méthode des frontières immergées épaisses, la membrane a une épaisseur finie. La précision et la robustesse de la méthode sont démontrées par l'intermédiaire d'une variété de cas tests bien choisis. La méthode proposée est ensuite appliquée à un problème d'interaction fluide-structure réaliste, à savoir l'interaction d'un écoulement (sanguin) pulsé avec une valve aortique biomimétique. Une étude combinée expérimentale et numérique est menée, montrant que la méthode est capable de capturer la dynamique globale de la valve, ainsi que les principales caractéristiques de l'écoulement en aval de la valve. Tous les développements ont été effectués dans le solveur YALES2BIO (http://www.math.univ-montp2.fr/~yales2bio/) développé à l'IMAG, qui est donc disponible pour toutes autres améliorations, validations et études applicatives. / This thesis deals with several scientific aspects inherent to the numerical simulation of fluid-structure interaction problems involving thin deformable membranes. Two specific cases relevant to cardiovascular biomechanics are considered: the interaction of the blood flow with the aortic valve (which occurs at the macroscopic scale), and the interaction of the red blood cells membrane with its inner and outer fluids (which occurs at the microscopic scale). In both cases, the fluid-structure interaction coupling is handled using an immersed boundary formalism, representing the membrane by a Lagrangian mesh moving through an Eulerian fluid mesh.When dealing with red blood cells dynamics, the membrane is considered to be an infinitely thin and massless structure. The first question which is addressed in the present thesis work is how to model the complex microstructure of the red blood cells membrane. A possible way to characterize a suitable membrane model is to simulate the optical tweezers experiment, which is a well-controlled experimental configuration enabling to study the individual mechanics of an isolated red blood cell in a large range of deformation. Some relevant membrane models are identified, but the deformation characteristics measured during the optical tweezers experiment reveal to be not selective enough to be used in a validation context. Additional deformation measurements are proposed, which could allow a better characterization of the red blood cell membrane mechanics.Regarding the macroscopic configurations, an innovative numerical method is proposed to handle numerical simulations of 3D continuum membranes, still within the immersed boundary formalism. In this method, called immersed thick boundary method, the membrane has a finite thickness. The accuracy and robustness of the method are demonstrated through a variety of well-chosen test cases. Then, the proposed method is applied to a realistic fluid-structure interaction problem, namely the interaction of a pulsatile (blood) flow with a biomimetic aortic valve. A combined experimental and numerical study is led, showing that the method is able to capture the global dynamics of the valve, as well as the main features of the flow downstream of the valve.All the developments were performed within the YALES2BIO solver (http://www.math.univ-montp2.fr/~yales2bio/) developed at IMAG, which is thus available for further improvements, validations and applicative studies.