Die bikuspide Aortenklappe gilt als Risikofaktor für das frühzeitige und häufige Auftreten von Aortenklappenvitien, Aneurysmen und Dissektionen. Das Ziel dieser Arbeit ist es, ein begründetes chirurgisches Therapiekonzept für Patienten mit bikuspider Aortenklappe und Dilatation der Aorta ascendens zu entwickeln. Wir analysierten die Daten von 555 Patienten mit bikuspider und 2015 Patienten mit trikuspider Aortenklappe, die sich in unserer Einrichtung einer Operation an der Aortenklappe und/ oder einem Eingriff im Bereich der Aorta ascendens unterzogen. Die Aorta ascendens wurde angiographisch, echokardiographisch und mittels CT auf ihre Konfiguration analysiert und histologisch und histomorphometrisch beschrieben. Auch wurden die Langzeitergebnisse nach Aorta ascendens Reduktionsplastik erfasst. Bei Patienten mit bikuspider Aortenklappe sind mit zunehmendem Durchmesser der Aorta ascendens häufiger die histologischen Zeichen einer Dilatation zu finden. Schwerere strukturelle Veränderungen, insbesondere eine höhergradige zystische Medianekrose, sind nicht zu beobachten. Die Aorta Ascendens Reduktionsplastik zeigt bei Patienten mit bikuspider Aortenklappe und Dilatation der Aorta ascendens gute Langzeitergebnisse. Nur bei Patienten mit nicht optimaler Durchmesser-Reduktion bei der Operation kommt es zu einer späteren Redilatation. / The bicuspid aortic valve is a known risk factor for the early and frequent occurrence of aortic valve defects, aneurysms and dissections. This study aims to develop an appropriate surgical therapy concept for patients with bicuspid aortic valve and dilatation of the ascending aorta. The data of 555 patients with bicuspid and 2015 patients with tricuspid aortic valve who underwent surgical treatment of the aortic valve and/or of the ascending aorta at our institution were evaluated. We analyzed the configuration of the ascending aorta by angiography, echocardiography and CT and described the aortic wall by histological and histomorphometric examination. We also analyzed the long-term results after reduction aortoplasty of the ascending aorta. Histological examination of the aortic wall specimens showed that patients with bicuspid aortic valve with increased diameter of the ascending aorta more often have histological signs of dilatation. More severe histological changes such as cystic media necrosis did not occur. Reduction aortoplasty of the ascending aorta shows good long-term results in patients with bicuspid aortic valve and dilatation of the ascending aorta. Only in patients in whom surgical reduction is less than optimal does redilatation occur later.

<p>Uvod. Usled kompromitovanja strukturnog integriteta, rekonstruktivne procedure na endodontski lečenim zubima moraju se veoma pažljivo isplanirati, pogotovo u specifičnoj grupi zuba kao &scaron;to su premolari. U stomatolo&scaron;koj naučnoj i stručnoj javnosti ne postoji usagla&scaron;en stav o tome koja endodontska instrumentacija i rekonstruktivna procedura primenjena u slučajevima ekstenzivnog gubitka zubne supstance predstavlja metodu izbora sa biomehaničkog aspekta. U okviru prezentovane doktorske disertacije ispitivan je uticaj varijacija u endodontskoj instrumentaciji i restaurativnim procedurama na promene naponskih stanja u zubnim tkivima i rekonstruktivnim materijalima kod premolara sa ekstenzivnim gubitkom zubne strukture. Metode. Osnovni 3D model je kreiran pomoću CT snimaka zdravog drugog gornjeg premolara u SolidWorks programu za modelovanje. Kreirano je 135 različitih modela, u kojima su metodom konačnih elemenata proračunati fon Mizesovi naponi u položaju maksimalne interkuspidacije pod dejstvom sile od 150 N. Statistička analiza je izvr&scaron;ena koristeći Op&scaron;ti linearni model. Rezultati. Indirektne zubne rekonstrukcije imaju povoljniji uticaj na naponska stanja u zubnim tkivima. Ukoliko se koristi direktna restauracija, povoljniji su naponi u dentinu i gleđi ukoliko se redukuje palatinalna kvržca. Upotreba kočića uz ispun snižava napone u zubnim tkivima samo u slučaju MOD kaviteta. Naponi u dentinu su niži pri apikalnom terminusu 0,5 mm i instrumentaciji instrumentima manje veličine (kod modela sa kočićem i indirektnim nadoknadama). Uglavnom procedure koje su povoljne za napone u dentinu, nepovoljne su za napone u zubnoj nadoknadi i obratno. Zaključci. Kod opsežnih MOD kaviteta a samo ukoliko se ne redukuje visina palatinalne kvržice, preporučuje se upotreba kompozitnog kočića. Smanjenje povr&scaron;ine zubnih tkiva u kojima su naponi visoki (iako su najvi&scaron;e vrednosti napona slične), moglo bi da utiče na dugotrajnost endodontski lečenih i rekonstruisanih zuba. Krući rekonstruktivni materijali povoljnije utiču na napone u zubnim tkivima biomehanički kompromitovanih endodontski lečenih zuba. Čini se da je optimalnije, u rekonstruktivnim re&scaron;enjima koja podrazumevaju upotrebu kočića, postaviti apikalni terminus bliže vrhu korena i koristiti instrumente srednje &scaron;irine.</p> / <p>Background. Restoration of an endodontically treated premolar with a wide and deep mesial-occlusal-distal (MOD) cavity is often complex due to biomechanical weakening of the tooth. There are no definitive recommendations on the optimal restoration in these cases. The aim of this study was to determine the effects of different endodontic and restorative procedures on von Mises stress values and distribution in dental tissues and restorative materials using finite element analysis (FEA). Methods. Based on CT scans of an second upper premolar, extracted for orthodontic reasons, 135 3D endodontically treated tooth models were created. Each model was subjected to a summary force of 150 N on the occlusal surface simulating the normal biting pattern and maximal von Mises stresses were calculated. Results. MODP cavity design seems to reduce von Mises stress values in dental tissues and P seems to transfer some of the stresses from dental tissues to the composite filling in the MOD cavity when direct restorations are used. Indirect restorations caused lower stresses within dentin. Apical terminus of 0.5 mm induces lower, while the terminus of 1.5 mm induces the highest stresses in dentin in models restored with direct composite and post. It seems that from the aspect of the tooth tissue, it is more recommended to use smaller endodontic instruments sizes. Conclusions. Stiffer restorative materials cause lower stresses in dentin of an endodontically treated structurally weakened tooth, and if a direct restoration is to be used, palatal cuspal reduction could be beneficial for the longevity of the tooth and the restoration. Further, in a wide and deep MOD cavity, without cuspal reduction, the use of a FRC post is recommended in order to reduce the stresses in the enamel and dentin. Moreover, it seems that it is beneficial for the stresses in the tooth tissue to place the apical terminus closer to the root apex as well as to use smaller size endodontic instruments.</p>

<p>Gubitak tvrdih zubnih struktura usled karijesne lezije, traume ili ekstenzivne preparacije dovodi do smanjenja otpornosti preostalih zubnih struktura na dejstvo sila prilikom žvakanja. Osnovni zadatak restaurativne procedure je da se ponovo uspostavi anatomo-morfolo&scaron;ka funkcija zuba i da se preostale zdrave zubne strukture za&scaron;tite od nepovoljnog odgovora na dejstvo sila. Cilj doktorske disertacije bio je da se ispita uticaj različitih restaurativnih procedura na biomehaničke karakteristike premolara sa ekstenzivnim kavitetima. Materijal i metode: Trodimenzionalni model intaktnog drugog gornjeg premolara kreiran je u SolidWorks računarskom programu, na osnovu snimaka ekstrahovanog zuba primenom vi&scaron;eslojnog spiralnog kompjuterizovanog tomografa. Na osnovu ovog modela potom je kreirano ukupno 48 modela, koji su podeljeni u dve grupe: modeli vitalnog premolara sa MOD kavitetom (I grupa) i modeli premolara sa endodontski lečenim kanalom korena sa MOD kavitetom (II grupa). U svakoj grupi ispitivan je uticaj 4 vrste restaurativnog materijala (direktan kompozitni ispun, direktan kompozitni ispun sa smolom modifikovanim glas-jonomer cementom u vidu podloge, indirektan kompozitni ispun, keramički ispun), 3 dizajna preparacije kaviteta (bez skraćivanja kvržica, sa skraćivanjem palatinalne kvržice 2mm, sa skraćivanjem palatinalne i bukalne kvržice 2mm) i 2 &scaron;irine istmusa (1/2 i 2/3 interkuspalnog razmaka). Primenom metode konačnih elemenata proračunate su vrednosti von Mises napona u zubnim strukturama i ispunu za sve modele pri dejstvu statičke sile od 200N. Rezultati: Dizajn preparacije kaviteta je pokazao najveći uticaj na vrednosti von Mises napona u zubnim strukturama. Pri tome, postupak skraćivanja palatinalne, kao i obe kvržice, doprineo je smanjenju vrednosti von Mises napona u gleđi na modelima obe grupe; dok je postupak skraćivanja bukalne i palatinalne kvržice doprineo smanjenju vrednosti von Mises napona u dentinu na modelima vitalnog premolara. U obe grupe, vrsta restaurativnog materijala pokazala je uticaj na vrednosti von Mises napona u gleđi, pri čemu je keramički ispun doveo do pojave napona značajno manjih vrednosti u odnosu na direktan i indirektan kompozitni ispun.Vrsta restaurativnog materijala je uticala i na vrednosti von Mises napona u dentinu, ali samo na modelima vitalnog premolara; pri tome su indirektni kompozitni i keramički ispun podjednako doprineli pojavi napona manjih vrednosti. &Scaron;irina istmusa je uticala na vrednosti von Mises napona u gleđi i dentinu na modelima vitalnog premolara. &Scaron;irina istmusa 1/2 interkuspalnog razmaka dovela je do pojave napona manjih vrednosti u gleđi, dok je &scaron;irina istmusa 2/3 interkuspalnog razmaka dovela do pojave napona manjih vrednosti u dentinu.</p> / <p>Loss of tooth structure from caries, trauma or extensive preparation decreases fracture resistance of tooth. The main goal of restorative procedure is to rebuild lost structures and to protect remaining tooth structures from unfavorable responses from masticatory forces. Aim of thesis was to investigate the influence of different restorative procedures on biomechanical properties of premolar with extensive cavities. Materials and Methods: Three dimensional model of intact maxillary second premolar, based on computerized tomography scan images of extracted tooth, was designed using SolidWorks software. Using this model, 48 models were designed and divided in two groups: models of vital premolars with MOD cavities (group I), and models of premolars with root canal treatment with MOD cavities (group II). In each group use of four restorative materials (direct composite resin restoration, direct composite resin restoration with resin modified glass-ionomer cement as base, indirect composite resin restoration, ceramic restoration), three cavity preparation designs (without cusp coverage, 2mm palatal cusp coverage, 2mm palatal and buccal cusp coverage) and two isthmus width (1/2 and 2/3 intercuspal width) were simulated. After applying static load of 200N, von Mises stresses in enamel, dentin and restoration were calculated using finite element analysis. Results: Cavity preparation design showed the most significant influence on von Mises stress values in tooth structures. Cusp coverage in general decreased stress values in enamel, while palatal and buccal cusp coverage decreased stress values in dentin only in group I. Restorative material affected stress values in enamel, were ceramic restoration contributed to minimal stress values. In dentin, indirect composite resin and ceramic restoration showed no difference in reducing von Mises stress values, but only for models in group I. Cavity isthmus width had influence on stress values in tooth structures only in group I. 1/2 isthmus width decreased stress values in enamel, while 2/3 isthmus width showed same effect in dentin. Conclusion: In order to provide optimal biomechanical characteristics of tooth structures, premolars with MOD cavity should be restored with ceramic overlay covering both palatal and buccal cusp.</p>

Calcific aortic valve disease is highly prevalent, especially in the elderly. Currently, the exact mechanism of the calcification process is not completely understood, limiting our ability to prevent or cure the disease. Ex vivo investigations, however, have provided evidence that the aortic valve's biological response is sensitive to mechanical forces, including fluid shear stresses, leading to the hypothesis that adverse fluid shear stress environment play a role in leading to valve calcification. This thesis seeks to investigate this hypothesis. A method for performing experimental measurement of time-varying shear stress on aortic valve leaflets under physiologic flow conditions was first developed, based on the Laser Doppler Velocimetry technique, and was systematically validated. This method was then applied to both the aortic surface and the ventricular surface of a normal tricuspid the aortic valve, and then on a congenital bicuspid aortic valve, using suitable in vitro valve models and an in vitro pulsatile flow loop. It was found that in the tricuspid valve, the peak shear stress on the aortic surface under adult resting condition was approximately 15-19 dyn/cm². Aortic surface shear stresses were elevated during mid- to late-systole, with the development of the sinus vortex, and were low during all other instances. Aortic surface shear stresses were observed to increase with increasing stroke volume and with decreasing heart rate. On the ventricular surface, shear stresses had a systolic peak of approximately 64-71 dyn/cm² under adult resting conditions. During late systole, due to the Womersley effect, shear stresses were observed to reverse in direction to a substantial magnitude for a substantial period of time. Further, it was found that a moderately stenotic bicuspid aortic valve can experience excessive unsteadiness in shear stress experienced by its leaflets, most likely due to the turbulent forward flow resulting from the stenosis, and due to the skewed forward flow. To demonstrate that the measured shear stresses can have an effect on the aortic valve biology, ex vivo experiments were performed in specific to determine the effects of these various shear stress characteristics on the biological response of porcine aortic valve leaflets, using the cone and plate bioreactor. It was found that unsteady shear stress measured in the bicuspid valve resulted in increased calcium accumulation. Further, it was found that low shear stresses and high frequency shear stresses resulted in increased calcium accumulation. Thus, shear stress was found to affect aortic valve pathology, and low and unsteady fluid shear stresses can enhance pathology.

réalisé en cotutelle avec le Dr. Marie Kmita et Dr. Marco Horb / Chez l’humain, les maladies congénitales cardiaques (MCC) sont présentes chez 3-4% des nouveaux nés et sont une cause importante de mortalité infantile et de morbidité dans le monde. La majorité des MCCs implique les valves et les septums, qui proviennent des cellules endocardiques. Les valves aortiques bicuspides (VAB) sont la MCC la plus fréquente chez l’humain, avec un taux estimé de 1-2% dans la population. Cependant, les gènes et les mécanismes moléculaires qui causent cette malformation demeurent obscures. Le facteur de transcription GATA5 est exprimé dans les cellules et les coussins endocardiques de façon transitoire durant la septation et la formation des compartiments cardiaques. Chez le poisson zèbre, des mutations dans le gène Gata5 causent des malformations cardiaques sévères incluant l’absence de cellules endocardiques. In vitro, l’inhibition de Gata5 bloque la différentiation endocardique. Ces études suggéraient donc un rôle important de GATA5 dans la formation du cœur. Dans le cadre de ce projet de doctorat, nous avons analysé le rôle de GATA5 dans le développement du cœur en produisant des lignées de souris chez lesquelles le gène Gata5 était inactif soit dans toutes les cellules ou uniquement dans les cellules endocardiques. Les souris possédant 2 allèles mutées du gène Gata5 étaient viables mais plus de 26% des souris Gata5-/- ont développé des VABs. Par ailleurs, une incidence similaire de VABs a été obtenue chez les souris ayant une délétion spécifique de Gata5 des cellules endocardiques, obtenue en croisant les souris Gata5WT/Flox avec les souris transgéniques Tie2-Cre. Sur le plan mécanistique, une réduction significative de JAG1, un corécepteur pour Notch1, ainsi qu’une augmentation marquée de Rbj un répresseur de cette voie, ont été détectés chez les souris Gata5-/- et Tie2- cre+;Gata5Flox/Flox, suggérant qu’une dérégulation de la voie Notch dans les cellules endocardiques puisse être la cause des VABs. Ces résultats démontrent l’importance de GATA5 pour le développement endocardique et la formation de la valve aortique. De plus, ils identifient GATA5 comme gène candidat de MCCs chez l’humain. Environ 12-14% des MCCs sont causés par le développement anormal de la voie de chasse, menant aux malformations telles que la transposition des grandes artères, la tétralogie de Fallot ou le syndrome du ventricule droit à double issue. Des mutations dans Gata4 et Gata6 sont associés à des défauts de la voie de chasse, dans plusieurs espèces incluant l’humain. Nous avons examiné si GATA5 interagit avec GATA4 ou GATA6 dans le développement de la voie de chasse. Alors que les souris hétérozygotes pour Gata5, Gata4 ou Gata6 ont des défauts cardiaques subtiles et sont viables, les embryons Gata4+/-Gata5+/- et Gata5+/-Gata6+/- démontrent une létalité embryonnaire et périnatale due à des défauts cardiaques, tel qu’un ventricule droit à double issue et des défauts de septation ventriculaire. Ces résultats indiquent l'importance des interactions génétiques entre GATA5 et les autres facteurs GATA pour la rotation et l’alignement de la voie de chasse au cours du développement cardiaque et soulèvent la possibilité que des changements subtiles de l'activité de 2 facteurs GATA puissent mener à des MCCs chez l'humain. / Congenital heart defect (CHD) in humans occur in 3-4% of live birth and is a major cause of infant mortality and morbidity in the world. The majority of CHD involves the valves and septa, which originate from endocardial cells. Bicuspid aortic valve (BAV) is the most common CHD in humans with an estimated rate of 1-2% in the population. However, very few genes have been linked to this defect and the mechanisms underlying BAV formation remain undefined. GATA5, a member of the GATA family of transcription factors, is expressed in a spatial and temporal manner in the developing heart where it is predominantly found in endocardial cells and endocardial cushions (ECs) of the outflow tract (OFT) and atrioventricular canal between E9.5-E12.5 in the mouse. Mutations in the Gata5 gene in zebrafish (faust mutants) cause cardia bifida and lead to endocardial cell depletion. In vitro studies using antisense mRNA against Gata5 revealed a critical role for this gene in differentiation of endocardial cells. In the context of the present doctoral research project, we investigated the role of GATA5 in mammalian heart development by generating a mouse line with a null Gata5 allele. Gata5 null mice are viable but over 26% of them developed BAVs. Endocardial specific deletion of Gata5 obtained by crossing mice with floxed (Flox) Gata5 alleles with Tie2-cre transgenic mice resulted in a similar incidence of BAVs. RNA profiling revealed that Jag-1, a co-receptor for Notch1, is significantly downregulated in both Gata5 null and Tie2-cre+;Gata5Flox/Flox mice, suggesting that disruption of Notch signaling in endocardial cells may be the underlying mechanism of disease. These findings reveal an important function for GATA5 in endocardial cell development and aortic valve formation and identify GATA5 as an important candidate CHD causing gene. Abnormal development of the OFT accounts for about 12-14% of all CHDs, leading to malformations such as persistent truncus arteriosus (PTA), tetralogy of Fallot (TOF), double outlet right ventricle (DORV) and transposition of the great arteries (TGA). Both GATA4 and GATA6 play important role in OFT development. We tested whether GATA5 might interact genetically with GATA4 and GATA6 for proper heart morphogenesis. We found that, whereas mice lacking a single copy of Gata5, Gata4 or Gata6 have subtle cardiac defects, the Gata4+/-Gata5+/- and Gata5+/-Gata6+/- mutant embryos show embryonic and perinatal lethality due to severe heart defects, including double outlet right ventricle and ventricular septal defects. These findings reveal the importance of genetic interactions between GATA5 and the other cardiac GATA factors in the normal rotation and patterning of the OFT during heart development in vivo. The results raise the possibility that subtle alterations in the level or activity of 2 cardiac GATA factors might lead to congenital heart disease in human.

Chez l’humain, les maladies congénitales cardiaques (MCC) sont présentes chez 3-4% des nouveaux nés et sont une cause importante de mortalité infantile et de morbidité dans le monde. La majorité des MCCs implique les valves et les septums, qui proviennent des cellules endocardiques. Les valves aortiques bicuspides (VAB) sont la MCC la plus fréquente chez l’humain, avec un taux estimé de 1-2% dans la population. Cependant, les gènes et les mécanismes moléculaires qui causent cette malformation demeurent obscures. Le facteur de transcription GATA5 est exprimé dans les cellules et les coussins endocardiques de façon transitoire durant la septation et la formation des compartiments cardiaques. Chez le poisson zèbre, des mutations dans le gène Gata5 causent des malformations cardiaques sévères incluant l’absence de cellules endocardiques. In vitro, l’inhibition de Gata5 bloque la différentiation endocardique. Ces études suggéraient donc un rôle important de GATA5 dans la formation du cœur. Dans le cadre de ce projet de doctorat, nous avons analysé le rôle de GATA5 dans le développement du cœur en produisant des lignées de souris chez lesquelles le gène Gata5 était inactif soit dans toutes les cellules ou uniquement dans les cellules endocardiques. Les souris possédant 2 allèles mutées du gène Gata5 étaient viables mais plus de 26% des souris Gata5-/- ont développé des VABs. Par ailleurs, une incidence similaire de VABs a été obtenue chez les souris ayant une délétion spécifique de Gata5 des cellules endocardiques, obtenue en croisant les souris Gata5WT/Flox avec les souris transgéniques Tie2-Cre. Sur le plan mécanistique, une réduction significative de JAG1, un corécepteur pour Notch1, ainsi qu’une augmentation marquée de Rbj un répresseur de cette voie, ont été détectés chez les souris Gata5-/- et Tie2- cre+;Gata5Flox/Flox, suggérant qu’une dérégulation de la voie Notch dans les cellules endocardiques puisse être la cause des VABs. Ces résultats démontrent l’importance de GATA5 pour le développement endocardique et la formation de la valve aortique. De plus, ils identifient GATA5 comme gène candidat de MCCs chez l’humain. Environ 12-14% des MCCs sont causés par le développement anormal de la voie de chasse, menant aux malformations telles que la transposition des grandes artères, la tétralogie de Fallot ou le syndrome du ventricule droit à double issue. Des mutations dans Gata4 et Gata6 sont associés à des défauts de la voie de chasse, dans plusieurs espèces incluant l’humain. Nous avons examiné si GATA5 interagit avec GATA4 ou GATA6 dans le développement de la voie de chasse. Alors que les souris hétérozygotes pour Gata5, Gata4 ou Gata6 ont des défauts cardiaques subtiles et sont viables, les embryons Gata4+/-Gata5+/- et Gata5+/-Gata6+/- démontrent une létalité embryonnaire et périnatale due à des défauts cardiaques, tel qu’un ventricule droit à double issue et des défauts de septation ventriculaire. Ces résultats indiquent l'importance des interactions génétiques entre GATA5 et les autres facteurs GATA pour la rotation et l’alignement de la voie de chasse au cours du développement cardiaque et soulèvent la possibilité que des changements subtiles de l'activité de 2 facteurs GATA puissent mener à des MCCs chez l'humain. / Congenital heart defect (CHD) in humans occur in 3-4% of live birth and is a major cause of infant mortality and morbidity in the world. The majority of CHD involves the valves and septa, which originate from endocardial cells. Bicuspid aortic valve (BAV) is the most common CHD in humans with an estimated rate of 1-2% in the population. However, very few genes have been linked to this defect and the mechanisms underlying BAV formation remain undefined. GATA5, a member of the GATA family of transcription factors, is expressed in a spatial and temporal manner in the developing heart where it is predominantly found in endocardial cells and endocardial cushions (ECs) of the outflow tract (OFT) and atrioventricular canal between E9.5-E12.5 in the mouse. Mutations in the Gata5 gene in zebrafish (faust mutants) cause cardia bifida and lead to endocardial cell depletion. In vitro studies using antisense mRNA against Gata5 revealed a critical role for this gene in differentiation of endocardial cells. In the context of the present doctoral research project, we investigated the role of GATA5 in mammalian heart development by generating a mouse line with a null Gata5 allele. Gata5 null mice are viable but over 26% of them developed BAVs. Endocardial specific deletion of Gata5 obtained by crossing mice with floxed (Flox) Gata5 alleles with Tie2-cre transgenic mice resulted in a similar incidence of BAVs. RNA profiling revealed that Jag-1, a co-receptor for Notch1, is significantly downregulated in both Gata5 null and Tie2-cre+;Gata5Flox/Flox mice, suggesting that disruption of Notch signaling in endocardial cells may be the underlying mechanism of disease. These findings reveal an important function for GATA5 in endocardial cell development and aortic valve formation and identify GATA5 as an important candidate CHD causing gene. Abnormal development of the OFT accounts for about 12-14% of all CHDs, leading to malformations such as persistent truncus arteriosus (PTA), tetralogy of Fallot (TOF), double outlet right ventricle (DORV) and transposition of the great arteries (TGA). Both GATA4 and GATA6 play important role in OFT development. We tested whether GATA5 might interact genetically with GATA4 and GATA6 for proper heart morphogenesis. We found that, whereas mice lacking a single copy of Gata5, Gata4 or Gata6 have subtle cardiac defects, the Gata4+/-Gata5+/- and Gata5+/-Gata6+/- mutant embryos show embryonic and perinatal lethality due to severe heart defects, including double outlet right ventricle and ventricular septal defects. These findings reveal the importance of genetic interactions between GATA5 and the other cardiac GATA factors in the normal rotation and patterning of the OFT during heart development in vivo. The results raise the possibility that subtle alterations in the level or activity of 2 cardiac GATA factors might lead to congenital heart disease in human. / réalisé en cotutelle avec le Dr. Marie Kmita et Dr. Marco Horb

L'objectif de cette thèse est l'élaboration et l'application de traitements d'images pour permettre une étude objective et fiable des sinus de Valsalva, importantes cavités de la base de l'aorte. Les méthodes proposées s'appliquent aux séquences ciné-IRM et aux examens de scanner sans qu'il n'y ait à modifier le paramétrage entre deux examens. Pour cela, nous avons d'abord étudié la morphologie de cette zone anatomique puis détaillé les différentes propriétés communes à toutes les images de sinus. Ceux-ci font en l'occurrence partie des principaux organes clairs et peu mobiles. Nous avons donc développé un algorithme qui détecte ces éléments et caractérise chacun d'entre eux par une trajectoire unique. Divers outils de morphologie mathématique ont été utilisés à cette occasion, tout comme pour l'extraction du contour des sinus dans chaque image. L'étape de segmentation repose elle sur la reconstruction géodésique, qui s'avère plus efficace et surtout plus robuste que l'usage de contours actifs usuels. L'intérieur des sinus forme un domaine simplement connexe et étoilé. Grâce à ce postulat, nous avons conçu une nouvelle reconstruction, nommée transformée en aurore, qui limite la propagation des intensités aux supports radiaux et présente les résultats dans un repère polaire pour une meilleure lecture des contours.Les points caractéristiques des sinus ont également été détectés, par étude de rayons et détermination de points dominants. Ces points fournissent les éléments nécessaires à une mesure automatique des sinus, mesure cohérente avec les mesures actuellement réalisées manuellement et les variations intra et inter-observateurs de celles-ci. D'autres outils sont enfin esquissés pour modéliser le contour par coniques, classer les images d'examens cinétiques en fonction du moment du cycle et suivre le mouvement des valves dans ces mêmes examens.L'ensemble de ces travaux ont amené à la réalisation d'un logiciel d'aide au diagnostic qui intègre nos méthodes et dont l'interface est également présentée dans le présent mémoire. / This Phd thesis deals with the design and the use of image processing tools in order to allow a reliable and objective study of the sinuses of Valsalva which are important cavities of the aortic root. The proposed methods can be applied on cine-MR sequences and CT examinations without any change in the settings between two examinations.Firstly, we studied the morphology of this anatomical area and its constant properties in all images of the dataset. Sinuses are one of the main bright organs with limited movements. Hence a new algorithm has been designed. It detects and characterizes each bright organ by a single trajectory. Various tools of mathematical morphology are used for this step, as for the extraction of the contour of the sinuses in each image.The segmentation step is based on the geodesic reconstruction, which is more effective and more robust than the usual active contours. The shape depicting the sinuses is simply connected and a star domain. With this assumption, a new reconstruction is proposed, called the Aurora transform. This transform limits the spread of intensities only on the radial lines and shows its results in a polar space for a better reading of edges.The relevant points of the sinuses are also detected by a study of radii and the determination of dominant points along edges. An automatic measurement of the sinuses is deduced from these points. The values are very close to the manual measures currently done according to the intra-and inter-observer variations.Some other tools are finally outlined. They includes the modeling of edges by conics, the image classification depending on the time of the cycle in sequences and the tracking of the aortic valves in these examinations.This work led to the devlopement of a diagnostic aid software based on our methods. Its interface is also presented herein.