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.

Cette étude à pour but de développer un concept de stent atraumatique pour le remplacement percutanée de la valve aortique. Le stent est obtenu à partir de brins de Nitinol tressés, ce qui lui permet, de part sa géométrie et sa structure, d'être compressible, auto-expansible, et atraumatique. Le principe de fabrication des prototypes et les contraintes qui lui est associé sont présentées. Les performances de ces prototypes, en terme d'ancrage, de régurgitation statique et de régurgitation dynamique sont ensuite évaluées par des essais in vitro, pour lesquel le banc de test en flux pulsé a été optimisé afin de prendre en considération la compliance de la racine aortique. Les résultats obtenus permettent de mettre en évidence les différents paramètres de fabrication stent, tant au niveau dimensionnel (hauteur du cylindre, angle du cône...) qu'au niveau structurel (rigidité), qui ont une influence significative sur le comportement de l'endoprothèse. / The goal of this work is to develop an atraumatic stent concept for percutaneous aortic valve replacement. Shape setted braided nitinol wires, thanks to their specific geometry and elasticity, allows stent's compressibility, self deployment and aortic root preservation. Prototypes manufacturing technique and relatives constraints are presented. Performance of the obtained prototypes are evaluated in vitro, in terms of sealing, static and dynamic regurgitation. More specifically, the pulsatile bench testing has been optimized to take in account the compliant constraint of the aortic valve environment. The results bring to the fore which are the dimensions (head height, cone angle...) and the structures features that do influence the endoprosthesis behavior significantly.

L’incidence et la prévalence des maladies valvulaires sont en augmentation, l’épidémiologie de ces maladies se modifie avec une prépondérance des maladies dégénératives, et le traitement considéré est le plus souvent le remplacement valvulaire prothétique, notamment dans le cadre de la sténose aortique qui est la maladie valvulaire la plus fréquente. Les techniques de remplacement valvulaire et les prothèses valvulaires ont grandement évolué ces dernières années, notamment avec le développement des implantations de prothèses par voie percutanée. Cependant les substituts valvulaires aortiques biologiques sont exposés à des complications diverses mettant en jeu la fonction de la prothèse : fuite péri-prothétique, endocardite infectieuse, dégénérescence des tissus biologiques. Ces complications restent des challenges diagnostiques et l’échographie est l’imagerie de référence. Cependant, l’imagerie cardiaque et valvulaire a réalisé de grands progrès, et l’utilisation d’autres techniques ou modalités d’imagerie peut être une alternative ou un complément à l’exploration par échocardiographie : imagerie par scanner, imagerie par résonance magnétique, imagerie nucléaire. Le recours et la combinaison de ces différentes techniques s’intègrent dans une approche globale, nommée imagerie multimodale. L’objectif général de ce projet de doctorat a été d’étudier l’apport de l’imagerie multimodale dans la surveillance des bioprothèses aortiques et l’évaluation des complications et de la dégénérescence structurelle qui peuvent survenir. / The incidence and prevalence of heart valve diseases are increasing worldwide. Their epidemiology also changes, and the required treatment is most often a prosthetic valve replacement, especially for aortic stenosis that is the most frequent heart valve disease. Techniques of valve replacement as well as prosthesis themselves have dramatically evolved in recent years, especially with the development of percutaneous transcatheter procedures. However, biologic aortic valve substitutes are at risk of several complications including prosthetic valve dysfunction, paravalvular regurgitation, infective endocarditis and structural valve deterioration. Correctly diagnose any of these complications still is a challenge but echocardiography plays a pivotal role and remains the gold-standard as per diagnostic imaging. Nonwithsanding the fact that echocardiography is the main imaging modality for valvular anomalies, great progress has been made in cardiac imaging and modalities like CT-Scan, MRI and nuclear imaging are nowadays regularly used along with echocardiography. The use and combination of these different techniques are part of a global approach, entitled multi-modality imaging.The general objective of this doctoral project was to study the contribution of the multi-imaging approach in the assessment of the bioprosthesis function and screening for complications and structural valve deterioration that may occur.

Le facteur Willebrand (VWF) est une proteine multimerique qui a une sensibilite unique aux forces de cisaillement et aux variations hemodynamiques du flux sanguin comme celles rencontrees lors d’utilisation de dispositifs cardiovasculaires tels qu’un remplacement valvulaire aortique transcatheter (TAVI) ou un assistance circulatoire mecanique a flux continu (ACM-FC). Des travaux anterieurs nous ont permis de mettre en evidence une secretion endotheliale declenchee par les modifications du flux liees a l’utilisation de ces dispositifs.Dans la première partie de la these, nous avons choisi d’etudier le role de la pulsatilite arterielle dans la reponse endotheliale a l’aide de plusieurs modeles animaux porcins d’ACM-FC pour isoler le role de la pulsatilite dans un environnement a forces de cisaillement elevees et constantes. Nous avons observe dans un modele dose-reponse la relation entre le niveau de pulsatilite et la multimerisation du VWF et dans un modele en cross-over le caractere dynamique du relargage endothelial en reponse a des variations aigues de pulsatilite.Ces resultats nous ont permis de conceptualiser dans la deuxième partie l'utilisation du VWF dans l’evaluation de la severite des fuites paravalvulaires (FPV) post-procedure TAVI. Deux cohortes de 183 et 201 patients ont permis de demontrer l’excellente capacite diagnostique de l’analyse multimerique du VWF avec une sensibilite, une specificite et une valeur predictive negative de respectivement 92.3%, 94.9%, et 98.7%. Le test de diagnostic rapide TO-ADP (temps d’occlusion a l’ADP) donnait des resultats equivalents pour un seuil > 180 sec.Enfin dans la troisième partie de la these nous avons concu le design d’un essai clinique permettant d’evaluer la valeur ajoutee de l’utilisation de ce test de diagnostic rapide TO-ADP en salle de catheterisme pour l’amelioration des resultats proceduraux et cliniques des procedures TAVI. / Willebrand factor (VWF) is a multimeric protein that has a unique sensitivity to shear forces and hemodynamic variations in blood flow such as those encountered when using cardiovascular devices such as transcatheter aortic valve replacement (TAVI) or continuous flow mechanical circulatory assistance (CF-CAM).

<p>By applying a segmentation procedure to two different sets of computed tomography scans, two geometrical models of the abdominal aorta, containing one inlet and two outlets have been constructed. One of these depicts a healthy blood vessel while the other displays one afflicted with a Abdominal Aortic Aneurysm. </p><p>After inputting these geometries into the computational dynamics software FLUENT, six simulations of laminar, stationary flow of a fluid that was assumed to be Newtonian were performed. The mass flow rate across the model outlet boundaries was varied for the different simulations to produce a basis for a parameter analysis study. </p><p>The segmentation data was also used as input data to a surface description procedure which produced not only the surface itself, but also the first and second directional derivatives in every one of its defining spatial data points. These sets of derivatives were followingly applied in an additional procedure that calculated values of Gaussian curvature. </p><p>A parameter variance analysis was carried out to evaluate the performance of the surface generation procedure. An array of resultant surfaces and surface directional derivatives were obtained. Values of Gaussian curvature were calculated in the defining spatial data points of a few selected surfaces. </p><p>The curvature values of a selected data set were visualized through a contour plot as well as through a surface map. Comparisons between the curvature surface map and one wall shear stress surface map were made.</p>

<p>Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury.</p><p>Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure.</p><p>Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion.</p><p>The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed.</p><p>In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved <i>during</i> CPR, whereas a significant increase was recorded <i>after</i> ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC.</p><p>Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF_2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF_2α, and the prostaglandin 15-K-DH-PGF_2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.</p>

Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury. Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure. Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion. The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed. In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved during CPR, whereas a significant increase was recorded after ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC. Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF2α, and the prostaglandin 15-K-DH-PGF2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.

Amyloid is a form of abnormal protein aggregation within the living body. Massive deposits can lead to organ failure. There is also increasing evidence that smaller pre-amyloid aggregates exert direct toxic effects to cells. To date 25 different proteins are known to occur as amyloid deposition in human tissues, although not all of these conditions are known to be associated with clinical diseases. This thesis deals with the very common form of amyloid localized to the arterial media. The fibril protein called ‘medin’ was identified in 1999. Medin is a 50 amino acid residue internal fragment of the precursor protein lactadherin. Lactadherin, first found in human milk, is expressed in various tissues such as breast epithelium (including carcinomas), macrophages and aorta. The function of the protein is not known but it has several functional domains. There is an EFG like domain, including an RGD-sequence, in the N-terminal part of the molecule. The C-terminal part consists of C1 and C2 coagulation factor V and VIII like domains. Medin is from within the C2 domain. This region is suggested to be involved in phosphatidyl serine binding, important in phagocytosis of apoptotic cells. Medin amyloid was originally described from studies of the aorta. It is shown here that deposits are more widely spread and can be found in many large arteries, particularly within the upper part of the body. The prevalence of medin amyloid increases with age and deposits are found, to a certain degree, in virtually everyone above the age of 60 years. The amyloid is not only found extracellularly but intracellular deposits may also occur. Amyloid is usually associated with elastic lamina or lamellae which often show signs of fragmentation. Given the localization of amyloid to elastic structures of the arterial media, three different vascular diseases were studied: temporal (giant cell) arteritis, thoracic aortic aneurysm and thoracic aortic dissection. Medin amyloid was found in temporal arteries with and without inflammation. In inflamed arteries, amyloid was mainly located along the broken internal elastic lamina. Medin was also demonstrated within giant cells. It is suggested that medin may be an antigen triggering autoimmune giant cell arteritis. In the study of thoracic aortic aneurysms and dissections, we found significant less medin amyloid in diseased aortic tissues compared with a control material. On the other hand, immunoreactive medin, probably in the state of oligomeric aggregates, was regularly found in association with aneurysms and dissections but not in the control material. It is suggested that medin oligomers exert toxic effects on smooth muscle cells which may lead to weakening of the arterial wall with aneurysm or dissection as a consequence.

Crossing of stent graft limbs during endovascular aneurysm repair (EVAR) is often used to assist cannulation and prevent graft kinking when the aortic bifurcation is widely splayed. Little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Using computational fluid dynamics, this work numerically examines the hemodynamic differences between these two out-of-plane stent graft configurations against a planar configuration commonly found in literature. Predicted values of displacement force, wall shear stress, and oscillatory shear index were similar between the out-of-plane configurations. The planar configuration predicted similar wall shear stress values, but significantly lower displacement forces than the out-of-plane configurations. These results suggest that the hemodynamic safety of cross-limb EVAR is comparable to conventional EVAR. However, a study of clinical outcomes may reveal reduced thrombosis incidence and long-term structural implications for the stent graft in cross-limb EVAR.

Crossing of stent graft limbs during endovascular aneurysm repair (EVAR) is often used to assist cannulation and prevent graft kinking when the aortic bifurcation is widely splayed. Little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Using computational fluid dynamics, this work numerically examines the hemodynamic differences between these two out-of-plane stent graft configurations against a planar configuration commonly found in literature. Predicted values of displacement force, wall shear stress, and oscillatory shear index were similar between the out-of-plane configurations. The planar configuration predicted similar wall shear stress values, but significantly lower displacement forces than the out-of-plane configurations. These results suggest that the hemodynamic safety of cross-limb EVAR is comparable to conventional EVAR. However, a study of clinical outcomes may reveal reduced thrombosis incidence and long-term structural implications for the stent graft in cross-limb EVAR.