The glucocorticoid receptor (GR) is expressed throughout the cardiovascular system and glucocorticoids (GC) are known to influence cardiovascular processes ranging from angiogenesis and vascular tone to cardiomyocyte hypertrophy and inflammation. Genetic variation in the human GR gene that associates with relative glucocorticoid resistance is also linked to hypertension and increased risk of cardiovascular disease. Mice with global GR haploinsufficiency (GR+/-) are similarly glucocorticoid resistant, with increased hypothalamic-pituitary-adrenal (HPA) axis activity and elevated blood pressure in adulthood. Previous work from the laboratory has demonstrated that the GR is essential for normal growth and maturation of the foetal heart in late gestation and in vitro studies show that GC can alter cardiomyocyte function and induce cardiomyocyte hypertrophy. I hypothesised that reduced GR density during development would have consequences for cardiovascular function and disease risk in adulthood and that cardiovascular GR signalling is important for postnatal growth of the heart, as well as physiological and pathological cardiac remodeling in adulthood. I tested this hypothesis in GR+/- mice with global alteration in GR density as well as in SMGRKO mice, with deletion of GR in cardiomyocytes and vascular smooth muscle. To investigate the association between GC resistance and cardiovascular disease risk, I have characterised the cardiac phenotype of GR+/- mice, basally and following physiological and pathological cardiac remodeling induced by a swim training programme and Angiotensin II treatment, respectively. Survival to weaning was reduced by 35% in GR+/- mice compared with wild-type (WT) littermates. Ultrasound analysis revealed impairment of systolic cardiac function in utero (E17.5) and at postnatal day (P) 2. However, by P7 cardiac function had normalised in surviving GR+/- mice and remained equivalent to WT littermates in adulthood. Heart weight and morphology were normal in GR+/- mice in adulthood but cardiomyocyte cross sectional area was reduced, in combination with an increase in nuclei per unit area implying an increased number of cardiomyocytes. This could arise from a delay in the developmental transition from hyperplasic to hypertrophic growth of cardiomyocytes and suggests that GR+/- mice may have a reduced ability to respond to the increased cardiac workload at birth and during the early postnatal period. Further cardiac challenge may be posed by the elevated blood pressure, compensatory increase in HPA axis activity and aldosterone levels previously reported in GR+/- mice. Adaptation to pathological cardiac challenge was assessed in adult GR+/- mice and WT littermates in response to AngII treatment, which has a direct hypertrophic effect on cardiomyocytes and, at higher doses, elevates blood pressure. GR+/- and WT mice showed an equivalent, dose-dependent increase in cardiomyocyte hypertrophy and cardiac fibrosis in response to AngII, as well as similar alterations in expression of Ca2+ handling genes. Functionally, these changes to the myocardium resulted in matched reductions in ejection fraction in GR+/- and WT mice. In contrast, when cardiac hypertrophy was induced by the physiological challenge of swim training, normal cardiac function was maintained in both GR+/- mice and WT controls. The physiological cardiac hypertrophy induced by swim training was not associated with cardiac fibrosis or pathological changes to left ventricle (LV) gene expression profiles. GR+/- mice have elevated HPA axis activity at baseline and swim training increased adrenal gland weight to a greater extent in GR+/- mice suggesting that raised GC levels due to compensatory HPA activation in GR+/- mice, may mask the role of GR in cardiac remodeling. To remove the effects of compensatory HPA axis activation and to achieve a greater degree of GR deficiency in the cardiovascular system, homozygous SMGRKO mice were investigated. Similar to GR+/- mice, survival to weaning compared with control littermates was impaired, by 46% and 65% in males and females respectively. Doppler measurements of transmitral inflow and transaortic outflow of blood showed a detrimental increase in the myocardial performance index (MPI), a load-independent measure of combined systolic and diastolic function. This was due to prolongation of the isovolumetric contraction time, indicating impairment of the initial LV contractile phase. Heart/body weight ratio was increased in both and male and female SMGRKO mice. Interestingly, cross sectional area was reduced in adult female SMGRKO mice cardiomyocyte, as was found in the GR+/- mice. In contrast, in male SMGRKO mice, cardiomyocyte cross sectional area and nuclei per unit area were equivalent to control littermates at 6 weeks of age, when heart/body weight ratio was already elevated. By 12 weeks of age, cardiomyocyte cross sectional area was greater in male SMGRKO mice than control littermates. In addition, levels of mRNA encoding myosin heavy chain-β, a marker of pathological cardiac hypertrophy, were greater in the LV of male but not female SMGRKO mice at 12 weeks. These findings suggest that cardiomyocyte hyperplasia in early neonatal life, possibly in combination with physiological elongation of cardiomyocytes, may underlie the elevated heart weight in female SMGRKO mice, whereas in male SMGRKO mice there is a transition to potentially pathological hypertrophy of cardiomyocytes. This may occur at puberty, in response to increased androgens, when marked LV growth occurs in males. Histopathology showed LV fibrosis in SMGRKO mice in both sexes, accompanied by elevated levels of mRNA encoding pro-fibrotic and matrix-remodeling genes in the LV. Intriguingly, levels of mRNA encoding the mineralocorticoid receptor (MR) were elevated in both sexes, which may be causal in the development of fibrosis. Indeed, in the LV, levels of mRNA encoding MR were already elevated in 6 week old SMGRKO males, at a time when cardiac collagen levels were only modestly increased. Levels of mRNA encoding the ryanodine receptor, which is essential for cardiac excitation contraction coupling, were reduced in the LV of female, but not male SMGRKO mice. The mechanisms underlying gender differences could be further investigated by comparing neonatal cardiac development in male and female SMGRKO mice. In conclusion, deletion of GR in cardiomyocytes and vascular smooth muscle causes gender specific pathological cardiac remodeling, demonstrating the essential role of cardiovascular GR signalling in cardiac maturation and function. Global GR deficiency alters the trajectory of cardiac development and increases risk of mortality. In surviving GR+/- mice, compensatory adaptations occur in response to the functional impairment seen in utero but subtle cardiac abnormalities remain in adulthood which, together with the elevated blood pressure and GC levels, may contribute to cardiovascular disease risk.

Cardiovascular disease is prevalent across the western world and is a major cause of morbidity and mortality, accounting for approximately a third of all fatalities. Investigating the heart by simulating its electrophysiology via the aid of mathematical models has advanced significantly over the past 60 years and is now a well established field. While much of the research focus is placed on the ventricles, the study of the atria is in comparison neglected. Therefore this Thesis is focused on the genesis and maintenance of atrial fibrillation (AF). A series of case studies are performed whereby established biophysically detailed mathematical models are implemented and modified to incorporate electrophysical alterations of atrial cells resulting from a variety of external conditions. The opening section of this Thesis is dedicated to developing a background to the field, including a discussion into the clinical aspect of the diagnosis and management of AF. The suitability of two atrial cell models is discussed and the development of single cell, 1D, 2D, and 3D multi-scale simulation protocols are described in detail. In addition measurements taken to quantify the arrhythmogenic properties of the cells susceptibility to AF are outlined. The second section is focused on the incorporation of conditions thought to enhance atrial tissues ability to initiate and maintain the genesis of AF. Included is a case study into the missence S140G gene mutation, and elevated physiological levels of the hormone Homocystein. The third section investigates the effectiveness of well established and widely used pharmacological treatments such as Beta-Blockers. In addition possible avenues of investigations for the development of atrial specific drugs are explored. These include blocking of the ultra rapid potassium channel and a more novel target for therapy via the targeting of 5HT4 receptors; which is transcribed solely in the atria and alters the electrophysical properties of the L-type Calcium current. The final part of this Thesis is dedicated to the development of a 2D atrial sheet model which includes electrical and spatial heterogeneities via the inclusion of multiple cell types and basic fiber orientation respectively. This allows for an investigation into the role that heterogeneities play in role genesis and maintenance of AF. The main finding of this Thesis is that alterations to the electrophysiology of atrial cells, due to external factors, can be successfully simulated via the implementation of mathematically detailed atrial cell models. It is concluded that simulations of the KENQ1 mutation and elevated levels of Homocystein successfully reproduce conditions which increase the onset of AF. Established treatments such as Beta-Blockers are found to have limited effectiveness. Possible theoretical treatments, such as the blocking of IKur, are found to provide a small amount of therapeutic benefit. In contrast, investigations into the effects of Serotonin were inconclusive. The study into the 2D atria indicated the importance that heterogeneities play in atria. The conclusions show that models provide a powerful tool when investigating how changes to electrophysiology of cells are manifested at a multi-scale level. The models also have their limitations and require further advancement to improve their accuracy.

The sinoatrial node (SAN) is the primary pacemaker in mammalian hearts and is vital to cardiac function. Genetic mutations in SAN can result in lose-of-function of ion channels, consequently arouse sinus node dysfunction (SND), Brugada syndrome (BrS) and progressive cardiac conduction disease (PCCD). The mechanisms underlying the he pathogenesis for cardiac pacemaker dysfunctions associated with genetic mutations has not been defined. In this project, by using computer modeling, mechanisms by which the HCN4 mutations impair cardiac pacemaking and possible pro-arrhythmic effects of ivabradine were investigated. Action potential (AP) models for rabbit sinoatrial node cells were modified to incorporate experimentally reported If changes induced by HCN4 gene mutations. At both the cellular and intact SAN-atrium tissue level, If reduction due to the HCN4 mutations slowed down pacemaking. At the tissue level, these mutations compromised the AP conduction across the SAN-atrium, leading to a possible sinus arrest or SAN exit block. Moreover, vagal nerve activity could amplify the bradycardiac effects of the HCN4 gene mutations, leading to sinus arrest and SAN exit block that was not observed with the mutations or ACh alone. Similarly, SND associated with SCN5A mutations and acquired cardiac conditions were studied. 1) Mathematical models of rabbit SAN cells and 2D tissue models were modified to investigate SAN function and intracardiac conduction in a murine model of long QT syndrome type 3. A prolonged tail current INa,L was introduced and incorporated with a normal INa,T to test the SAN pacemaker function and AP conduction from the SAN to atrial septum. Simulation results showed that a combined reduction in INa,T and introduction of INa,L achieved alterations in both pacemaking rate and conduction. 2) Mathematical models of mouse SAN cells were modified to investigate the mechanisms underlies the SAN associated with SCN5A deficiency and aging. A coupled SAN-atrium cell model was developed to replicate the experimentally observed slowing of SAN conduction with aging and SCN5A-disruption The modelling studies reconstructed the physiological mechanisms by which both aging and SCN5A-disruption lead to SND, thereby drawing parallels between these and similar conduction changes in the ventricle that occur in the possibly related condition of PCCD. At last, a 2D anatomically based model of the SAN-atrium was constructed. This model successfully reproduced the effects of vagal nerve stimulation and SCN5A-E161K gene mutation on spontaneous activity of the SAN and AP conduction across the SAN-atrium.

L’Hypertrophie Ventriculaire Gauche (HVG) est actuellement mise en évidence par échographie. Cet examen fournit des informations anatomo-fonctionnelles mais ne permet pas de déterminer l’étiologie des HVG, ce qui engendre de graves erreurs de diagnostic et de prise en charge thérapeutique. Les HVG sont classiquement séparées en 2 catégories :1. pathologies hypertrophiques induites par la modification structurelle et fonctionnelle des cardiomyocites qui tend à compenser des insuffisances cardiaques liées par exemple à des problèmes d’hypertension artérielle, de rétrécissement aortique ou de CardioMyopathies Hypertrophiques sarcomériques ;2. pathologies infiltratives correspondant au dépôt de protéines dans la matriceextracellulaire principalement dues à différentes formes d’amyloses cardiaquesNotre hypothèse est que les différents mécanismes physiopathologiques (hypertrophique ou infiltratif) pourraient se traduire dans l’image par des propriétés spécifiques du speckle échographique. Nous avons donc développé un travail d’analyse de la texture de ces images afin de discriminer les différentes HVG.Dans cette étude, la base de données de 4795 images est divisée en une base d’apprentissage de 3770 images et une base de test de 1025 images. L’analyse de texture des images est faite par les ondelettes de Gabor avec 8 orientations, 7 tailles et 5 niveaux de décomposition. Ensuite, les caractéristiques statistiques de premier et deuxième ordre sont extraites des images. Le nombre des caractéristiques est réduit pour la base d’apprentissage en appliquant l’Analyse en Composantes Principales (ACP) suivie par l’analyse discriminante linéaire (ADL) pour une séparation supervisée des classes. Les caractéristiques extraites pour la base de test sont projetées sur les vecteurs propres sélectionnés au cours de l’apprentissage. L’ADL est appliquée à ce niveau pour la classification des données du test et la qualité de cette classification est évaluée. Les résultats obtenus sont bons (qualité totale de classification de 95,51%) et sont suivis d’une étape de cross-validation afin de vérifier la robustesse de notre méthode. A cette étape, les bases de données de l’apprentissage et du test sont mélangées et 50 combinaisons différentes sont évaluées. La même méthode décrite précédemment est appliquée. La cross-validation montre une variation de la qualité de classification (entre 30% et 99.96%) probablement due à l’hétérogénéité des caractéristiques texturelles pour les patients d’une même classe que l’on peut expliquer par des degrés différents d’avancement dans la pathologie.Ces travaux montrent qu’une analyse de texture des images échocardiographiques peut permettre de déterminer des bio-marqueurs aptes à discriminer différentes cardiopathies qui s’expriment par une HVG. Ce résultat peut avoir des retombées très importantes dans la détection précoce des amyloses cardiaques, maladies engendrant un fort taux de mortalité souvent dû à un retard de diagnostic et prise en charge des patients par un centre expert / Left-Ventricular Hypertrophy (LVH) is currently detected through echocardiography. The latter imaging modality provides anatomical and functional information. However, it does not allow the determination of the HVG etiology. This can, in turn, lead to dangerous errors in the diagnosis and treatment planning of the disease. LVH pathologies are separated into two categories:- Hypertrophic pathology caused by the structural and functional modification of cardiomyocytes that lead to cardiac failure related, for example, to arterial hypertension problems, aortic narrowing or sarcomeric hypertrophic cardiomyopathies.- Infiltrative pathologies corresponding to protein deposits on the extracellular matrix, mainly due to different forms of cardiac amyloidosisOur hypothesis is that different physiopathological mechanisms (hypertrophic or infiltrative) can be translated in the image through properties specific to echographic speckle. We have therefore developed the work of texture analysis of such images in order to discriminate the different types of LVH.In this study, the database of 4795 images is divided into a learning database of 3770 images and another testing database of 1025 images. The textural analysis of these images is done using Gabor wavelets with 8 orientations, 7 sizes and 5 decomposition levels. Next, the statistical characteristics of first and second orders are extracted from the filtered images. The number of characteristics is reduced for the learning database by applying Principal Component Analysis (PCA) followed by Linear Discriminant Analysis (LDA) for a supervised separation of the classes. The extracted characteristics for the test database are projected on the eigenvectors selected in the learning step. LDA is applied at this level for the test data classification, and the quality of this classification is evaluated. The obtained results are good (total classification quality of 95.51%). A step of cross-validation follows in order to verify the robustness of our method. At this stage, the learning and testing databases are mixed, and 50 different combinations are evaluated. The same method described previously is then applied. The cross-validation shows a variation in the classification quality (between 30% and 99.96%) probably due to the heterogeneity of the texture characteristics for the patients of the same class explained by different disease advancement stages.This work shows that the textural analysis of echocardiographic images can permit the determination of bio-markers suitable to discriminate different LVH cardiopathies. Our results can have a very important impact on the early detection of cardiac amyloidosis, a pathology causing a considerable rate of mortality often due to a belated diagnosis and support by the centers of expertise

Cette thèse est dédiée au développement de méthodes numériques pour la poromécanique, et à leur application dans un contexte de modélisation cardiaque.Elle est motivée par la prise en compte, dans les modèles de coeur humain, du réseau coronarien qui perfuse le myocarde, afin de mieux décrire les maladies vasculaires coronariennes.Nous appuyant sur des travaux existants, nous proposons un modèle de coeur perfusé, ainsi qu'une réduction 0D permettant de reproduire, à moindre coût de calcul, un cycle cardiaque réaliste avec masse et pression de perfusion. Le modèle mis au point nous permet de reproduire des phénomènes physiologiques auparavant inaccessibles dans les modèles, et d'une grande importance pour des applications cliniques, tels que la vasodilatation et les pathologies coronariennes.L'intégration d'un compartiment poreux pour représenter le myocarde perfusé dans les modèles 3D représente un défi technique d'un autre ordre. Nous inspirant des schémas en temps de type splitting établis en interaction fluide-structure pour modéliser les vaisseaux sanguins, nous proposons une discrétisation semi-implicite d'une formulation générale de poromécanique, satisfaisant un bilan d'énergie au niveau discret. Afin d'illustrer et valider notre démarche, l'environnement de calcul élément finis FreeFem++ nous permet de reproduire des cas tests classiques de gonflement et de drainage de milieux poreux en 2D, puis de vérifier le bilan énergétique discret.Enfin, motivés par l'étude de la discrétisation spatiale de notre problème, nous établissons dans un cadre linéaire un résultat de convergence totale du schéma sous conditions. Cela nous permet de proposer une méthode d'implémentation facile à mettre en oeuvre et présentant de bons résultats de stabilité. FreeFem++ nous permet à nouveau de valider nos résultats en illustrant les pathologies numériques associées à l'incompressibilité, et leur traitement efficace par les stratégies proposées, dans le cadre linéaire puis dans une situation plus générale. / This thesis is dedicated to the development of numerical methods for poromechanics, and to their application in a cardiac modeling context. It is motivated by the introduction into existing cardiac models of the coronary network that perfuses the myocardium, to better describe coronary vascular diseases.Drawing our inspiration from existing works, we propose a perfused heart model, and a 0D reduction allowing the cost-effective reproduction of a realistic cardiac cycle with perfusion mass and pressure. The model derived illustrates physiological phenomena inaccessible in former models, and with great clinical application potential, such as vasodilatation and coronary diseases.The integration of a porous compartment to represent the perfused myocardium within 3D models is more challenging. Relying on splitting time schemes established for fluid-structure interaction to model blood vessels, we propose a semi-implicit discretization of a general poromechanics formulation, satisfying a discrete energy balance. In order to illustrate and validate our approach, we reproduce in the finite element software FreeFem++ classical swelling and drainage 2D test cases, and we monitor the discrete energy balance.Finally, motivated by the study of spatial discretization aspects of our problem, we establish in a linear framework a conditional total convergence result. This enables us to propose a computational method easy to implement and presenting good stability results. FreeFem++ enables us again to validate our results, illustrating numerical pathologies associated with incompressibility, and their efficient treatment with the proposed strategies, first in a linear framework and then in a more general situation.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-06T14:57:14Z No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-06T20:25:13Z (GMT) No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) / Made available in DSpace on 2017-03-06T20:25:13Z (GMT). No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) Previous issue date: 2015-07-10 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A hipertensão é uma doença crônica que está relacionada com o aumento da pressão exercida pelo sangue nas paredes dos vasos sanguíneos. Seu surgimento está relacionado a síndromes metabólicas e, frequentemente, á obesidade. Entre o período de 2000 e 2011, esta patologia foi considerada a maior causa de morte no mundo devido à complicações inerentes a sua disfunção, como por exemplo acidente vascular cerebral e o infarto do miocárdio. Diversos estudos vêm sendo realizados com o objetivo de compreender melhor os mecanismos que estão relacionados ao surgimento da hipertensão bem como as disfunções causadas pela doença. Dentre estas disfunções, existem as alterações fisiológicas que ocorrem no coração sendo que as principais alterações ocorrem na atividade elétrica e mecânica do órgão cardíaco. A modelagem computacional se mostra como uma ferramenta muito eficaz no auxílio de tais estudos. A possibilidade de simular as disfunções causadas pela hipertensão no coração permitiria realizar experimentos prévios com baixo custo e em um pequeno intervalo de tempo. Assim este trabalho tem por principal objetivo apresentar modelos computacionais capazes de reproduzir a atividade eletromecânica transmural do miócito de ratos normotensos e hipertensos. Para isto, é proposto um novo modelo matemático/computacional resultado de um acoplamento de outros dois presentes na literatura. O modelo computacional proposto obteve resultados bastante satisfatórios visto que foi capaz de reproduzir as alterações fisiológicas ocorridas em miócitos de ratos, tanto para células de origem do epicárdio quanto para células de origem do endocárdio, nas principais variáveis associadas ao batimento cardíaco: potencial de ação, transiente intracelular de cálcio e o encurtamento do sarcômero. / The hypertension is a chronic disease that is related to an increased in the pressure exerted by the blood on the walls of blood vessels. Its appearance is related to the metabolic syndrome and often with obesity. Between the years 2000 and 2011, this condition was considered the leading cause of death worldwide due to the complications inherent to its dysfunction, such as stroke and myocardial infarction. Several studies have been conducted in order to better understand the mechanisms that are related to the onset of hypertension and the dysfunctions caused by this disease. Among these disorders, there are the physiological changes that occur in the heart with the main changes occuring in electrical and mechanical activity of the heart organ. The Computational modeling can become a very effective tool in aid of such studies. The possibility of simulating the dysfunctions caused by hypertension in the heart would results in a possibility to do previous in silico experiments with low cost and in a short period of time. So this work is primarily engaged to present computational models capable of reproducing the transmural electromechanical activity of myocyte of normotensive and hypertensive rats. For this, a new mathematical / computational model was proposed resulted from a coupling of two others models presented in the literature. The proposed computational model obtained satisfactory results since it was able to reproduce the physiological changes in myocytes of rats, both for epicardial origin of cells and for endocardial cells of origin, the main variables associated with the heartbeat: the action potential, calcium intracellular transient and the shortening of the sarcomere.

La compréhension clinique et le traitement des maladies cardiovasculaires est extrêmement complexe. Pour chaque patient, les cardiologues sont confrontés à des difficultés pour déterminer la pathologie, choisir une thérapie ou encore sélectionner les patients susceptibles de bien répondre à un traitement donné. Afin de fournir une aide additionnelle aux cardiologues, de nombreuses équipes de recherche étudient la possibilité de planifier de telles thérapies grâce à des modèles biophysiques du cœur. Ils formulent l'hypothèse que l'on peut combiner les données fonctionnelles et anatomiques afin de créer des modèles cardiaques personnalisés à chaque patient qui auraient le potentiel de prédire les bénéfices des différentes thérapies. Les simulations électromécaniques du cœur sont basées sur des modèles informatiques qui peuvent représenter la géométrie, le mouvement et la propagation d'ondes électriques pendant un cycle cardiaque avec suffisamment de précision. L'intégration d'information anatomique, mécanique et électrophysiologique pour un patient donné est essentielle pour construire ce type de modèle.Dans cette thèse, nous présentons tout d'abord les méthodes de personnalisations géométriques, cinématiques et électrophysiologiques nécessaires à toutes modélisations mécaniques. Nous utilisons ensuite le modèle électromécanique de Bestel-Clément-Sorine qui a déjà prouvé avoir un bon réalisme sans être trop complexe au vu des données disponibles. Nous commençons par détailler la nouvelle implémentation de ce modèle dans une plateforme efficace de simulation médicale ayant l'avantage d'être libre et interactive, puis nous analysons les résultats de la simulation par une étude de sensibilité complète.Dans un deuxième temps, nous étudions la possibilité de personnaliser les paramètres mécaniques de ce modèle à partir d'images médicales (IRM). Pour cela, nous proposons en premier lieu une méthode automatique de calibration qui estime les paramètres mécaniques globaux à partir de courbes de pressions et volumes. Cette technique testée sur 6 volontaires et 2 cas pathologiques nous a permis de faire une étude de spécificité qui consiste à déterminer les paramètres pertinents capables de différencier les cas pathologiques des cas sains.Une fois initialisés à ces valeurs calibrées, les paramètres sont personnalisés localement avec un algorithme d'optimisation plus complexe. Le « Reduced Order Unscented Kalman Filtering » est utilisé pour estimer les contractilités de toutes les zones AHA du ventricule gauche à partir des volumes régionaux extraits des séquences d'images IRM. Cette stratégie de personnalisation a été validée et testée sur plusieurs cas pathologiques et volontaires. Ces différentes contributions ont montré des résultats prometteurs tout au long de cette thèse et certains sont déjà utilisés pour quelques études de recherche. / The clinical understanding and treatment of cardiovascular diseases is highly complex. For each patient, cardiologists face issues in determining the pathology, choosing a therapy or selecting suitable patients for the therapy. In order to provide additional guidance to cardiologists, many research groups are investigating the possibility to plan such therapies based on biophysical models of the heart. The hypothesis is that one may combine anatomical and functional data to build patient-specific cardiac models that could have the potential to predict the benefits of different therapies. Cardiac electromechanical simulations are based on computational models that can represent the heart geometry, motion and electrophysiology patterns during a cardiac cycle with sufficient accuracy. Integration of anatomical, mechanical and electrophysiological information for a given subject is essential to build such models.In this thesis, we first introduce the geometry, kinematics and electrophysiology personalizations that are necessary inputs to mechanical modeling. We propose to use the Bestel-Cl'ement-Sorine electromechanical model of the heart, which is sufficiently accurate without being over-parametrized for the available data. We start by presenting a new implementation of this model in an efficient opensource framework for interactive medical simulation and we analyze the resulting simulations through a complete sensitivity analysis.In a second step, the goal is to personalize the mechanical parameters from medical images (MRI data). To this end, we first propose an automatic calibration algorithm that estimates global mechanical parameters from volume and pressure curves. This technique was tested on 7 volunteers and 2 heart failure cases and allowed to perform a preliminary specificity study that intends to determine the relevant parameters able to differentiate the pathological cases from the control cases.Once initialized with the calibrated values, the parameters are then locally personalized with a more complex optimization algorithm. Reduced Order Unscented Kalman Filtering is used to estimate the contractilities on all of the AHA zones of the Left Ventricle, matching the regional volumes extracted from cine MRI data. This personalization strategy was validated and tested on several pathological and healthy cases. These contributions have led to promising results through this thesis and some are already used for various research studies.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-01-11T14:38:55Z No. of bitstreams: 1 danielmoutinhodesouza.pdf: 14087574 bytes, checksum: 14fbe9db31be8496c781a98af92ca3fd (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-01-23T13:42:47Z (GMT) No. of bitstreams: 1 danielmoutinhodesouza.pdf: 14087574 bytes, checksum: 14fbe9db31be8496c781a98af92ca3fd (MD5) / Made available in DSpace on 2018-01-23T13:42:47Z (GMT). No. of bitstreams: 1 danielmoutinhodesouza.pdf: 14087574 bytes, checksum: 14fbe9db31be8496c781a98af92ca3fd (MD5) Previous issue date: 2017-08-28 / A fibrilação ventricular é uma arritmia cardíaca listada como uma das principais causas de morte no mundo industrializado, por isso, a importância do estudo do comportamento elétrico cardíaco. O equipamento mais indicado para tentar reverter este quadro de arritmia é o desfibrilador, que submete o tórax do paciente a um campo elétrico de alta energia. Entretanto essa técnica pode causar efeitos graves como queimaduras e dor intensa. Técnicas menos agressivas vêm sendo estudadas e consideram, por exemplo, protocolos com múltiplos estímulos de baixa energia. Observou-se que, nessas estratégias alternativas, a rede vascular cardíaca pode ter papel importante com relação ao padrões espaço-temporais gerados pelos estímulos. Nesta mesma direção, este trabalho apresenta um estudo computacional sobre a influência da rede vascular durante estímulos por campo elétrico em tecidos cardíacos. O fenômeno é capturado por um sistema não-linear de equações diferenciais parciais. Para resolver este modelo numericamente os Métodos de Volumes Finitos (MVF) e de Phase-Field (MPF) foram combinados buscando assim a caracterização geométrica de vasos arteriais durante simulações de desfibrilação de tecido cardíaco. Os resultados obtidos sugerem que os métodos usados (MVF+MPF) são adequados para o estudo de protocolo para desfibrilação cardíaca. / The ventricular fibrillation is a cardiac arrhythmia listed as one of the leading causes of death within the industrialized world, hence the study of cardiac electrical behavior is an important research area. The most used equipment for the reversal of this condition is the defibrillator, which subjects the patient's chest to a high-energy electric field. However, it can have serious effects such as burns and severe pain. Less aggressive techniques have been studied and considered, for example, protocols with multiple low energy stimuli. It was observed that, in this alternative technique, the cardiac vascular network may play an important role in relation to the spatial-temporal patterns generated by the stimuli. This work presents a computational study about the influence of the vascular network during electrical field stimuli in cardiac tissues. The phenomenon is described by a nonlinear system of partial differential equations. To solve this model numerically the Finite Volume Method (FVM) and the Phase-Field Method (PFM) were combined, thus seeking a better geometric characterization of arterial vessels during simulations of cardiac tissue defibrillation. The results obtained in this work suggest that these methods (FVM + PFM) are suitable for the protocol study for cardiac defibrillation.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-07T12:02:26Z No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-07T15:03:55Z (GMT) No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) / Made available in DSpace on 2017-03-07T15:03:55Z (GMT). No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) Previous issue date: 2014-08-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A arritmia ventricular maligna é uma das principais causas de morte no mundo. Muitas vezes o início de um episódio de arritmia está associado a uma excitação inoportuna no coração, também denominada extra-sístole, ou Potencial de Ação Espontâneo (PAE). O surgimento de PAEs pode estar relacionado a mudanças estruturais ou moleculares nos canais iônicos e a alterações no ciclo de cálcio intracelular. Anormalidades no ciclo de cálcio podem gerar transientes de cálcio espontâneos (TCEs) e estes podem desencadear Potenciais de Ação Espontâneos (PAEs). Estudos experimentais mostram que o surgimento de TCEs é mais frequente sob a estimulação β-Adrenérgica. Em experimentos recentes, notou-se que a presença de episódios de TCEs em cardiomiócitos saudáveis não desencadeia a geração de PAEs. Em contrapartida, em camundongos com a mutação de super expressão da bomba NCX (NaCa), PAEs foram observados em miócitos isolados e foram relacionados a episódios de TCEs. O principal objetivo deste trabalho foi a simulação da formação de PAEs utilizando modelos computacionais desenvolvidos para cardiomiócitos do ventrículo esquerdo de camundongos. Em particular os modelos computacionais foram capazes de reproduzir os cenários experimentais descritos acima, relacionando a geração de PAEs com a estimulação β-Adrenérgica e alterações de canais iônicos como a mutação NCX. Dessa forma, as simulações computacionais apresentadas neste trabalho permitem uma melhor compreensão dos complexos fenômenos associados a arritmias cardíacas. / Malignant ventricular arrhythmias are the major cause of death around the world. The beginning of an episode of arrhythmia is often associated with ectopic beats in the heart, also called extrasystole, or Spontaneous Action Potential (SAP). The development of SAP may be related to structural or molecular changes in ion channels and changes in intracellular calcium cycle. Abnormalities in calcium cycle can result in Spontaneous Calcium Transientes (SCT) and these can trigger SAP. Experimental studies show that the development of SCT is more common under β1-adrenergic stimulation. However, we found, in recent experiments, that the presence of episodes of SCT in healthy cardiomyocytes does not trigger the development of SAP. On the other hand, on mice presenting mutation of overexpression of NCX (NaCa) pump, SAP were observed in isolated cardiomyocytes and were related to episodes of SCT. Thus, we aimed, in this study, to simulate development of SAP using computational models developed for cardiomyocytes of left ventricle of mice. The computational models were able to reproduce the experimental scenarios described above, relating the development of SAP to the β-adrenergic stimulation and to the changes of ion channels as the NCX mutation. Therefore, the computational simulations showed in this work allow the best comprehension of the complex phenomena associated with cardiac arrhythmia.

[EN] Atrial tachyarrhythmias present a high prevalence in the developed world, and several studies predict that in the coming decades it will be increased. Micro or macro-reentrant mechanisms of the electrical wavefronts that govern the mechanical behavior of the heart are one of the main responsibles for the maintenance of these arrhythmias. Atrial flutter is maintained by a macro-reentry around an anatomical or functional obstacle located in the atria. In the case of atrial fibrillation, the hypothesis which describes high frequency rotors as dominant sources of the fibrillation and responsible for the maintenance of the arrhythmia, has been gaining relevance in the last years. However, the therapies that target high frequency sources have a limited efficacy with current techniques. Radiofrequency ablation allows the destruction of parts of the cardiac tissue resulting in the interruption of the reentrant circuit in case of macro-reentries or the isolation of micro-reentrant circuits. The non-invasive location of reentrant circuits would increment the efficacy of these therapies and would shorten surgery interventions. In parallel, pharmacological therapies modify ionic expressions associated to the excitability and electrical refractoriness of the cardiac tissue with the objective of hindering the maintenance of reentrant behaviors. These therapies require a deep knowledge of the ionic mechanisms underlying the reentrant behavior and its properties in order to be effective. The research in these mechanisms allows the evaluation of new targets for the treatment and thus may improve the efficacy in atrial fibrillation termination. In this thesis, mathematical modeling is used to go forward in the minimization of the limitations associated to these treatments. Body surface potential mapping has been evaluated, both clinically and by means of mathematical simulations for the diagnosis and location of macro-reentrant circuits. The analysis of phase maps obtained from multiple lead electrocardiographic recordings distributed in the whole torso allowed the discrimination between different reentrant circuits. It is the reason why this technique is presented as a tool for the non-invasive location of macro and micro-reentrant circuits. A population of mathematical models designed in this thesis based on the action potentials recordings of atrial cardiomyocites from 149 patients, allowed the evaluation of the ionic mechanisms defining the properties of reentrant behaviors. This study has allowed us defining the blockade of ICaL as a target for the pharmacological treatment. The blockade of this current is associated with the increase of the movement in the core of the rotor which easies the collision of the rotor with other wavefronts or anatomical obstacles promoting the extinction of the reentry. The variability observed between patients modeled in our population has allowed showing and explaining the mechanisms promoting divergent results of a single treatment. This is why the introduction of populations of models will allow the prevention of side effects associated to inter-subject variability and to go forward in the development of individualized therapies. These works are built through a simulation platform of cardiac electrophysiology based in Graphic Processing Units (GPUs) and developed in this thesis. The platform allows the simulation of cellular models, tissues and organs with a realistic geometry and shows features comparable to that of the platforms used by the most relevant electrophysiology research groups at the moment. / [ES] Las taquiarritmias auriculares tienen una alta prevalencia en el mundo desarrollado, además diversos estudios poblacionales indican que en las próximas décadas ésta se verá incrementada. Los mecanismos de micro o macro-reentrada de los frentes de onda eléctricos que rigen el comportamiento mecánico del corazón, se presentan como una de las principales causas del mantenimiento de estas arritmias. El flutter auricular es mantenido por un macro-reentrada alrededor de un obstáculo anatómico o funcional en las aurículas, mientras que en el caso de la fibrilación auricular la hipótesis que define a los rotores de alta frecuencia como elementos dominantes y responsables del mantenimiento de la arritmia se ha ido imponiendo al resto en los últimos años. Sin embargo, las terapias que tienen como objetivo finalizar o aislar estas reentradas tienen todavía una eficacia limitada. La ablación por radiofrecuencia permite eliminar zonas del tejido cardiaco resultando en la interrupción del circuito de reentrada en el caso de macro-reentradas o el aislamiento de comportamientos micro-reentrantes. La localización no invasiva de los circuitos reentrantes incrementaría la eficacia de estas terapias y reduciría la duración de las intervenciones quirúrgicas. Por otro lado, las terapias farmacológicas alteran las expresiones iónicas asociadas a la excitabilidad y la refractoriedad del tejido con el fin de dificultar el mantenimiento de comportamientos reentrantes. Este tipo de terapias exigen incrementar el conocimiento de los mecanismos subyacentes que explican el proceso de reentrada y sus propiedades, la investigación de estos mecanismos permite definir las dianas terapéuticas que mejoran la eficacia en la extinción de estos comportamientos. En esta tesis el modelado matemático se utiliza para dar un paso importante en la minimización de las limitaciones asociadas a estos tratamientos. La cartografía eléctrica de superficie ha sido testada, clínicamente y con simulaciones matemática,s como técnica de diagnóstico y localización de circuitos macro-reentrantes. El análisis de mapas de fase obtenidos a partir de los registros multicanal de derivaciones electrocardiográficas distribuidas en la superficie del torso permite diferenciar distintos circuitos de reentrada. Es por ello que esta técnica de registro y análisis se presenta como una herramienta para la localización no invasiva de circuitos macro y micro-reentrantes. Una población de modelos matemáticos, diseñada en esta tesis a partir de los registros de los potenciales de acción de 149 pacientes, ha permitido evaluar los mecanismos iónicos que definen las propiedades asociadas a los procesos de reentrada. Esto ha permitido apuntar al bloqueo de la corriente ICaL como diana terapéutica. Ésta se asocia al incremento del movimiento del núcleo que facilita el impacto del rotor con otros frentes de onda u obstáculos extinguiéndose así el comportamiento reentrante. La variabilidad entre pacientes reflejada en la población de modelos ha permitido además mostrar los mecanismos por los cuales un mismo tratamiento puede mostrar efectos divergentes, así el uso de poblaciones de modelos matemáticos permitirá prevenir efectos secundarios asociados a la variabilidad entre pacientes y profundizar en el desarrollo de terapias individualizadas. Estos trabajos se cimientan sobre una plataforma de simulación de electrofisiología cardiaca de basado en Unidades de Procesado Gráfico (GPUs) y desarrollada en esta tesis. La plataforma permite la simulación de modelos celulares cardiacos así como de tejidos u órganos con geometría realista, mostrando unas prestaciones comparables con las de las utilizadas por los grupos de investigación más potentes en el campo de la electrofisiología. / [CAT] Les taquiarítmies auriculars tenen una alta prevalença en el món desenvolupat, a més diversos estudis poblacionals indiquen que en les pròximes dècades aquesta es veurà incrementada. Els mecanismes de micro o macro-reentrada dels fronts d'ona elèctrics que regeixen el comportament mecànic del cor, es presenten com una de les principals causes del manteniment d'aquestes arítmies. El flutter auricular és mantingut per una macro-reentrada al voltant d'un obstacle anatòmic o funcional en les aurícules, mentre que en el cas de la fibril·lació auricular la hipòtesi que defineix als rotors d'alta freqüència com a elements dominants i responsables del manteniment de l'arítmia s'ha anat imposant a la resta en els últims anys. No obstant això, les teràpies que tenen com a objectiu finalitzar o aïllar aquestes reentrades tenen encara una eficàcia limitada. L'ablació per radiofreqüència permet eliminar zones del teixit cardíac resultant en la interrupció del circuit de reentrada en el cas de macro-reentrades o l'aïllament de comportaments micro-reentrants. La localització no invasiva dels circuits reentrants incrementaria l'eficàcia d'aquestes teràpies i reduiria la durada de les intervencions quirúrgiques. D'altra banda, les teràpies farmacològiques alteren les expressions iòniques associades a la excitabilitat i la refractaritat del teixit amb la finalitat de dificultar el manteniment de comportaments reentrants. Aquest tipus de teràpies exigeixen incrementar el coneixement dels mecanismes subjacents que expliquen el procés de reentrada i les seues propietats, la recerca d'aquests mecanismes permet definir les dianes terapèutiques que milloren l'eficàcia en l'extinció d'aquests comportaments. En aquesta tesi el modelatge matemàtic s'utilitza per a fer un pas important en la minimització de les limitacions associades a aquests tractaments. La cartografia elèctrica de superfície ha sigut testada, clínicament i amb simulacions matemàtiques com a tècnica de diagnòstic i localització de circuits macro-reentrants. L'anàlisi de mapes de fase obtinguts a partir dels registres multicanal de derivacions electrocardiogràfiques distribuïdes en la superfície del tors permet diferenciar diferents circuits de reentrada. És per açò que aquesta tècnica de registre i anàlisi es presenta com una eina per a la localització no invasiva de circuits macro i micro-reentrants. Una població de models matemàtics, dissenyada en aquesta tesi a partir dels registres dels potencials d'acció de 149 pacients, ha permès avaluar els mecanismes iònics que defineixen les propietats associades als processos de reentrada. Açò ha permès apuntar al bloqueig del corrent ICaL com a diana terapèutica. Aquesta s'associa a l'increment del moviment del nucli que facilita l'impacte del rotor amb altres fronts d'ona o obstacles extingint-se així el comportament reentrant. La variabilitat entre pacients reflectida en la població de models ha permès a més mostrar els mecanismes pels quals un mateix tractament pot mostrar efectes divergents, així l'ús de poblacions de models matemàtics permetrà prevenir efectes secundaris associats a la variabilitat entre pacients i aprofundir en el desenvolupament de teràpies individualitzades. Aquests treballs es fonamenten sobre una plataforma de simulació de electrofisiologia cardíaca basat en Unitats de Processament Gràfic (GPUs) i desenvolupada en aquesta tesi. La plataforma permet la simulació de models cel·lulars cardíacs així com de teixits o òrgans amb geometria realista, mostrant unes prestacions comparables amb les de les utilitzades per els grups de recerca més importants en aquesta área. / Liberos Mascarell, A. (2016). Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166 / TESIS