L’insuffisance cardiaque droite est la première cause de mortalité des patients atteints d’hypertension pulmonaire (HP). Au début de la maladie, le ventricule droit (VD) opère un remodelage permettant une adaptation à l’augmentation des résistances vasculaires pulmonaires. Au cours de cette adaptation, les caractéristiques morphologiques, fonctionnelles et myocardiques se modifient. L’analyse de ces modifications peut s’appliquer en clinique au niveau du dépistage, de l’évaluation pronostique et du suivi des patients atteints d’HP. Néanmoins, la physiopathologie du passage d’un état compensé à un état décompensé reste à élucider de même que l’identification de nouvelles cibles thérapeutiques ou l’élaboration de méthodes non-invasives d’évaluation du VD restent à développer. L’objectif de cette thèse était d’évaluer un moyen de dépistage de l’HP en échographie cardiaque et d’étudier la physiopathologie de la défaillance ventriculaire droite sur un cœur droit remodelé. Un large rappel des notions d’anatomie, d’embryologie et de physiologie nécessaires à la compréhension des paramètres d’évaluation du VD a été réalisé, puis des études originales publiées et en cours ont été présentées.Une première étude s’est intéressée au dépistage échocardiographique d’une HP chez des patients avec une pathologie pulmonaire avancée. Nous avons montré que la dilatation de l’oreillette droite, du VD et certains paramètres fonctionnels étaient liés à une HP. Lorsque la fuite tricuspidienne était quantifiable (chez 52% des patients), l’évaluation d’autres paramètres du VD n‘améliorait pas le dépistage d’une HP. La présence de paramètres du VD anormaux chez les patients dont la fuite tricuspidienne n’était pas quantifiable n’améliorait pas le dépistage ; 20% des patients sans HP présentaient une dilatation du VD. Une validation extrinsèque chez l’animal avec une obstruction vasculaire pulmonaire modérée et progressive confirmait que la dilatation du VD était un des paramètres les plus précoces quantifiable lors du développement d’une HP. Le développement d’indices non-invasifs du VD plus spécifique d’une l’HP est nécessaire.Une seconde étude, nous avons caractérisé les modifications du VD au cours d’une insuffisance cardiaque droite aigue survenant dans le cadre d’une HP dans une nouveau modèle animal. Le VD était évalué avec des paramètres de courbes pression-volume, d’échocardiographie, de cathétérisme cardiaque droit et par des biomarqueurs circulants. L’analyse anatomopathologique et protéique du VD, environ 3 heures après la restauration hémodynamique, retrouvait des lésions d’ischémie sous-endocardiques et sous-épicardiques et des stigmates d’activation d’autophagie. Nous avons retrouvé des lésions sous-endocardiques du VD similaires chez 5 patients avec une HP ayant bénéficié d’une transplantation cardiopulmonaire dans un contexte de défaillance hémodynamique. Des données préliminaires suggèrent que ces lésions sont associées aux défaillances rénales et hépatiques et à une altération de la survie après transplantation cardiopulmonaire.En conclusion, certains signes de remodelage du VD peuvent être présents chez des patients avec des pathologies pulmonaires avancés en l’absence d’HP, ce qui limite leur intérêt pour le diagnostic non-invasif d’une HP. A l’autre extrémité du spectre de sévérité d’une HP, nous avons modélisé pour la première fois une insuffisance cardiaque droite aigue dans un modèle animal d’HP. Nous avons démontré pour la première fois que des lésions ischémiques pouvaient se développer dans le VD en quelques heures malgré l’induction d’une restauration hémodynamique avec de la dobutamine. Ces données apportent un rationnel fort pour l’évaluation des lésions tissulaires du VD à l’aide de biomarqueurs circulant en pratique clinique dont les applications restent à établir. / Right heart failure is the leading cause of mortality in patients with pulmonary hypertension (PH). At early stage of PH the right ventricle (RV) remodels to adapt to the increased pulmonary vascular resistances. This adaptation is characterized by morphological, functional and myocardial changes. The evaluation of these changes may be applied for screening, prognosis evaluation and follow-up of patients with PH. However, the pathophysiology of the transition from adaptive to maladaptive phenotypes remains unclear; and identification of RV therapeutic targets and noninvasive methods for its evaluation remains to developed. The aim of this thesis was to evaluate non-invasive screening of PH with echocardiography and to study the pathophysiology of acute right heart failure in the setting of chronic PH by performing precise phenotyping of a new large animal model. A wide review of anatomic, embryologic and physiologic concepts was performed to help for the understanding of parameters of RV evaluation; then published and ongoing original studies were presented.In a first study, we investigated PH screening with echocardiography in patients with advanced lung disease. In this study, we showed that enlargement of the RV and of the right atrium, as well as function parameters of the RV were associated with PH. When the tricuspid regurgitation was available (52% of cases), RV morphology and function parameters did not improve PH diagnosis. Abnormal RV morphology and function without available tricuspid regurgitation provided moderate detection value; whereas 20% of patients without PH presented enlargement of the RV. In a large animal model with progressive increase in pulmonary artery mechanical obstruction, enlargement of the RV was the earliest RV parameter associated with PH development. This study highlights the need for more specific RV indices of PH.In a second study we investigated right ventricular changes in a new large animal model of acute right heart failure occurring on chronic PH; a situation associated with around 40% mid term mortality or transplantation. We characterized right ventricular changes during acute volume and pressure overload and after hemodynamic restauration in a large animal model of chronic thromboembolic PH. The RV was evaluated with parameters derived from pressure-volume loops, echocardiography, right heart catheterism and with circulating biomarkers. Pathological and proteins content analyzes of the RV around 3 hours after hemodynamic restauration showed acute subendocardial and subepicardial focal ischemic lesions as well as signs of autophagy activation. We found similar ischemic lesions in RV of 5 patients who underwent a heart-lung transplantation for PH in the setting of hemodynamic compromise. Preliminary data suggest that these lesions are associated with end-organ injury and poor overall survival after heart-lung transplantation in patients with PH.In conclusion, abnormal echocardiographic right heart metrics may be observed in patients with advanced lung disease without PH limiting their use for PH screening in this population. This highlight the need for more specific right heart metrics associated with PH. At the other extreme of the spectrum of PH severity, we described for the first time a large animal model of acute right heart failure in chronic PH. We reproduced and described the main morphological and functional features observed in acute right heart failure on PH and we showed for the first time that acute right ventricular ischemic lesions may develop within few hours despite hemodynamic restauration with dobutamine. These data provide a strong rational to develop specific biomarkers to evaluate tissue lesions of the right ventricle and determine their clinical implications.

L’objectif de cette thèse est d'étudier le ventricule droit (VD) dans différentes conditions de charge en utilisant imagerie et modélisation. Le premier axe de ce travail est une étude prospective qui analyse la déformation VD chez des patients sains et avec hypertension pulmonaire (HTP) en utilisant l’échocardiographie trans-thoracique 3D. Les maillages VD ont été obtenus par tracking myocardique et post-traités afin d’extraire le strain de surface. Les correspondances spatiotemporelles ont été vérifiées avant de réaliser les statistiques des maillages. La forme et déformation globale VD sont associées à la sévérité de l'HTP et donnent des informations pronostiques. Le deuxième axe de ce travail présente le rôle d'une évaluation longitudinale par rapport à celui d’une évaluation instantanée, en utilisant la même méthodologie. Nous avons démontré la valeur ajoutée pronostique des modifications dans le temps de déformation VD et l'importance du septum. Dans le troisième axe, les aspects complémentaires de la forme (définie par la courbure) et déformation VD ont été évalués dans des populations de surcharge en volume VD. Alors que forme et déformation sont altérés chez les patients avec tétralogie de Fallot, seule la forme a permis de différencier les patients avec CIA des témoins. Enfin, dans le dernier axe, nous avons étudié la valeur ajoutée de la personnalisation d'un modèle circulatoire 0D pour caractériser la pathologie et prédire la réponse au traitement dans l’hypertension artérielle pulmonaire. Le modèle a été personnalisé pour 11 patients avant et après traitement spécifique de l’HTP. Les paramètres du modèle reflètent bien les changements attendus avec la thérapie. / The aim of this thesis is to study the right ventricle (RV) in different loading conditions using imaging and modelling. The first axis of this work was a prospective study in which we studied RV deformation in healthy controls and pulmonary hypertension (PH) patients (pressure overload) using 3D transthoracic RV echocardiographic sequences. Output RV meshes; obtained after myocardial tracking; were post-processed to extract area strain and spatiotemporal correspondences were checked before computing statistics on these meshes. RV shape and strain patterns were gradually deteriorated with the severity of PH and provided independent prognostic information. The second axis of this work focused on the role of a longitudinal evaluation in comparison with a single assessment at baseline, using the same methodology. We demonstrated the additional prognostic value of changes in RV area strain and the importance of septal segments. In the third axis, we assessed the complementary aspects of RV deformation and shape (using curvature index) in RV volume overload patients. While shape and strain are both altered in tetralogy of Fallot patients, only RV shape allows to differentiate atrial septal defects from normal controls. Finally, in the last axis, we focused on the added value of the personalisation of a 0D circulation model to characterize the pathology and predict the response to therapy in pulmonary arterial hypertension. The model was personalised to 11 PH patient data before and after advanced specific PH therapy. The model parameters reflected accurately the expected changes with therapy.

Right Ventricular (RV) dysfunction is a common cause of heart failure in patients with congenital heart defects and often leads to impaired functional capacity and premature death. 3D cardiac magnetic resonance imaging (CMR)-based RV/LV combination models with fluid-structure interactions have been introduced to perform mechanical analysis and optimize RV remodeling surgery. Obtaining accurate RV/LV morphology is a very important step in the model-constructing process. A semi-automatic segmentation process was introduced in this project to obtain RV/LV/Valve geometry from patient-specific 3D CMR images. A total of 420 contour results were obtained from one patient CMRI data using QMASS software package at Department of Cardiology of Children¡¯s hospital. The digital contour data were automatically acquired using a self-developed program written in MATLAB. 3D visualizations of the RV/LV combination model at different phases throughout the cardiac cycle were presented and RV/LV volume curves were given showing the volume variation based on digital contour data under MATLAB environment. For the patient considered, the RV stoke volume (SV) is 190.8 ml (normal value is 60-136 ml) and ejection fraction is 43.5% (normal value is 47%-63%). In future work, the surgical, CMR imaging and computational modeling will be integrated together to optimize patch design and RV volume reduction surgery procedures to maximize recovery of RV cardiac function.

Le ventricule droit (VD) fut longtemps oublié par les cardiologues mais l'expérience a montré qu'il conditionne le pronostic des patients dans de nombreuses situations cliniques et que l'évaluation de sa fonction est un élément diagnostique majeur lorsqu'une pathologie du VD est suspectée. Après une revue des différentes méthodes d'évaluation de la fonction ventriculaire droite, cette thèse explore tout d'abord les limites des deux méthodes d'évaluation du VD les plus répandues (IRM et échographie) : Premièrement, les indices de contraction longitudinale en échographie ne permettent pas de dépister correctement les altérations de la fraction d'éjection dans la situation d'une surcharge volumétrique notamment. Deuxièmement, l'IRM en coupes petit-axe présente des difficultés importantes de délinéation de l'endocarde. Les principaux écarts de contours entre deux observateurs concernent l'infundibulum pour 40% et la valve tricuspide pour 40% également. Dans une troisième partie, nous proposons un indice géométrique simple à calculer lors d'un examen IRM et permettant de pré-sélectionner les patients nécessitant une étude précise du VD. Cet indice validé sur 340 patients réduit le temps opérateur de 35% sans entrainer d'erreur diagnostique. La dernière partie de cette thèse s'intéresse à la mesure de la vitesse tissulaire du myocarde et aux indices fonctionnels qui en dérivent. Cette mesure nécessite une haute résolution temporelle qui peut être atteinte en IRM en respiration libre au prix d'une augmentation de la durée d'acquisition / The right ventricle (RV) has been neglected for a long time by cardiologists. Only recently, it has been pointed out as yielding pronostic or diagnostic value in numerous clinical situations. This thesis, after a review of the different methods used to assess the right ventricular function, stresses the limitations of the two most used methods to assess RV function: 1) Long-axis contraction indices fail to predict ejection fraction in a volumetric overload situation. 2) Short-axis MRI relies upon a rather difficult manual contouring of the endocardium. The main variation in this contouring occurs in the infundibulum (40%) and in the basal part around the tricuspid valve (40%). Then, we propose a novel geometric indice, easy to compute during a MRI examination and aimed to select the patients needing an accurate RV study. This index was validated within 340 patients and reduced the operator time of 35% without inducing any diagnostic error. The last part of this thesis concerns tissue phase-mapping. High temporal resolution is the key point for the accuracy of myocardial velocities and can be achieved by a simple averaging during free-breathing at the expense of longer acquisitions

La fonction du ventricule droit est un déterminant majeur de la capacité fonctionnelle et du pronostic dans l’hypertension pulmonaire. La survenue dans ce contexte d’une insuffisance cardiaque droite requérant un support inotrope est associée à un taux de mortalité supérieur à 40%. Les déterminants cellulaires et moléculaires du découplage entre le coeur droit et la circulation artérielle pulmonaire sont méconnus, d’autant qu’il existe une grande hétérogénéité fonctionnelle parmi les patients soumis au même niveau de résistances vasculaires pulmonaires.Dans une première étude expérimentale, nous avons mis évidence à partir d’un modèle porcin d’hypertension pulmonaire chronique que les indices fonctionnels systoliques du ventricule droit mesurés en échocardiographie sont davantage corrélés au couplage ventriculo-artériel qu’à la performance contractile propre du ventricule droit. La réponse du ventricule droit à l’exercice ou à un stress pharmacologique a été peu documentée jusqu’à présent dans l’hypertension pulmonaire. Apartir de notre modèle porcin, nous avons montré que l’altération de la réserve contractile du ventricule droit est fortement associée au découplage ventriculo-artériel. La réserve contractile pourrait être un marqueur sensible et précoce de dysfonction ventriculaire droite. Dans une troisième étude, nous montrons la relation forte entre le couplage ventriculo-artériel et la plasticitéhémodynamique, fonctionnelle et moléculaire du ventricule droit dans un contexte de surcharge de pression chronique. Les variations d’expression de l’isoforme β de la chaîne légère de la myosine cardiaque pourraient déterminer l’efficacité du travail cardiaque droit. Nous avons par ailleurs constaté expérimentalement chez le rat que le remodelage géométrique et fonctionnel du ventricule droit en condition de surcharge barométrique chronique est associé à une infiltration macrophagique dumuscle cardiaque droit.Nos résultats physiopathologiques pourraient permettre une meilleure stratification des patients souffrant d’hypertension pulmonaire chronique. Ces mécanismes pourraient par ailleurs constituer autant de cibles thérapeutiques pour optimiser la fonction cardiaque droite lorsque la postcharge du ventricule droit n’est pas complètement corrigée, d’autant que les thérapies vaso-actives pulmonaires usuelles auraient des effets directs controversés sur le remodelage du ventricule droit. / Right ventricular function is a major determinant of functional capacity and prognosis in pulmonary hypertension. Right heart failure related to pulmonary hypertension is associated with a mortality rate up to 40% when inotrope support is necessary. Cellular and molecular determinants of right ventricular-pulmonary arterial coupling are misunderstood, while a wide functional range is remarkable among patients sharing the same degree of pulmonary vascular resistance.In a first experimental study, we showed from a porcine model of chronic pulmonary hypertension that usual non-invasive indices of right ventricular function are rather associated with ventricular-arterial coupling than with contractility. Right ventricular response to exercise or to pharmacological stress has been poorly reported in pulmonary hypertension. In our piglet model, we showed that impairment of right ventricular contractile reserve is strongly associated with ventricular-arterial uncoupling. Rightventricular reserve might be a sensitive marker of early ventricular dysfunction. In a third study, we highlighted that a strong relationship between ventricular-arterial coupling and functional and molecular plasticity of the pressure overloaded right ventricle. Gene expression of the beta-myosin heavy chain may be related to right heart efficiency. We also oberved experimentally in rats that structural and functional remodeling of the pressure overloaded right ventricle is associated withmacrophagic infiltration in the myocardium.Our pathophysiologic results could improve patient’s stratification in chronic pulmonary hypertension.These mechanisms may represent innovative targeted therapies to improve right ventricular function despite persistent elevated afterload.

Submitted by Erika Demachki (erikademachki@gmail.com) on 2014-09-08T20:13:04Z No. of bitstreams: 2 Luiz Antônio Batista de Sá - 2013.pdf: 2785841 bytes, checksum: 7b5931974548bfd07b98371e20bbfbce (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-09-08T20:13:04Z (GMT). No. of bitstreams: 2 Luiz Antônio Batista de Sá - 2013.pdf: 2785841 bytes, checksum: 7b5931974548bfd07b98371e20bbfbce (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-02-22 / Introduction: Right ventricular pacing can be deleterious in patients with left ventricular dysfunction, but in patients with normal function the impact of this stimulation and triggering ventricular dyssynchrony clinically relevant is not fully established. Objectives: To evaluate clinical findings of patients with previously normal ventricular function, who underwent implantation of a pacemaker. Methods: We studied prospectively 20 patients (60% male and the average age was 58 years) underwent implantation of a pacemaker with the following inclusion criteria: normal ventricular function defined by echocardiography and the presence of ventricular pacing 90% higher (generator telemetry). We evaluated the following parameters: Class functional (New York Heart Association) 6-minute walk test, dosage of B-type natriuretic peptide (BNP), and conventional echocardiographic and evaluation dyssynchrony and intraventricular (by tissue Doppler, M-mode and pulsed Doppler) and the quality of life assessment by SF-36 Health Survey. The evaluation was done at 10 days (t1), 4 months (t2), 8 months (t3), 12 months (t4) and 24 months (t5). Data were compared over time according to ANOVA repeated measures (rmANOVA). Results: Of the following evaluated data showed no statistically significant variation (p> 0.05): conventional echocardiographic parameters, interventricular and intraventricular dyssynchrony. The six minute walk test, functional class and BNP worsened at the end of two years (p <0.05). Evaluation showed initial improvement in QOL domains: physical functioning, social and general health and worsens at the end of the two years. Conclusion: After 24 months the right ventricular pacing, in patients with normal function, correlated with worsening of ventricular function assessed clinically (class functional walk test and QOL) and measure laboratory (BNP). / Introdução: A estimulação de ventrículo direito pode ser deletéria em pacientes com disfunção ventricular, porém em pacientes com função normal o impacto desta estimulação como fator de dessincronia e desencadeamento de disfunção ventricular clinicamente relevante não é completamente estabelecido. Objetivos: Avaliar a evolução clínica e laboratorial de pacientes, com função ventricular previamente normal, submetidos a implante de marca-passo. Métodos: Durante dois anos foram estudados de forma prospectiva 20 pacientes (60% do sexo masculino) com idade média de 58 anos submetidos a implante de marca-passo com os seguintes critérios de inclusão: função ventricular esquerda normal definida pelo ecocardiograma e presença de estimulação ventricular superior a 90% (telemetria do gerador). Foram avaliados os seguintes parâmetros: classe funcional (New York Heart Association), teste de caminhada de 6 minutos(TC6’), dosagem do hormônio natriurético tipo B (BNP), avaliação ecocardiográfica convencional e com avaliação da dessincronia e intraventricular (através do Doppler tecidual, modo M e Doppler pulsado) e questionário de qualidade de vida (QV) (SF-36). A avaliação foi feita com 10dias (t1), 4 meses (t2), 8 meses (t3), 12 meses (t4) e 24 meses (t5). Os dados foram comparados ao longo do tempo segundo método ANOVA medidas repetidas (rmANOVA). Resultados: Dos dados avaliados os seguintes não apresentaram variação estatística significante (p>0,05): parâmetros ecocardiográficos convencionais, dessincronia intraventricular e interventricular. O TC6, a classe funcional e a dosagem de BNP apresentaram piora ao final dos dois anos (p<0,05). Avaliação de QV mostrou melhora inicial nos domínios: capacidade funcional, aspectos sociais e estado geral de saúde e piora destes parâmetros ao final dos dois anos Conclusão: Após 24 meses a estimulação ventricular direita, em pacientes com função normal, correlacionou com piora da função ventricular avaliada clinicamente (classe funcional, teste de caminhada e QV) e dosagem de BNP.

A doença valvar crônica de mitral (DVCM) é a principal cardiopatia adquirida dos cães e uma das suas complicações é a hipertensão arterial pulmonar (HAP), o que pode induzir a disfunção do ventriculo direito (VD). Assim, constituíram-se em objetivos do presente estudo identificar e descrever alterações de tamanho do VD, padrão de fluxo na artéria pulmonar (AP) e função sistólica ventricular direita nas diferentes fases da DVCM, além de correlacionar estas variáveis com índices de tamanho, volume, funções sistólica e diastólica do lado esquerdo do coração, bem como com a velocidade da insuficiência tricúspide (IT) e gradiente de pressão entre o ventrículo e átrio direitos nos cães que apresentavam regurgitação da valva tricúspide. Para tanto, foram incluídos 96 cães de diversas raças no estudo, que foram separados em quatro grupos de acordo com o estágio da DVCM: grupos ou estágios A, B1, B2 e C. Os cães com DVCM sintomáticos ou em estágio C apresentaram alterações no fluxo da artéria pulmonar (AP), bem evidenciadas pela redução das suas velocidades máxima e média, além da redução dos tempos de aceleração (TAC) e ejeção (TEJ) do fluxo sistólico da AP e correlação negativa com as variáveis de tamanho e funções sistólica e diastólica do coração esquerdo. O tamanho do VD foi estatisticamente maior nos animais do estágio C em comparação aos do estágio B1 e associou-se, negativamente, com os índices de função sistólica ventricular esquerda (VE). Os índices de função sistólica do VD como índice de excursão sistólica do plano anular tricúspide (iTAPSE) e variação fracional de área (FAC) foram maiores nos estágios mais avançados da DVCM e, juntamente com a velocidade de movimentação miocárdica sistólica do anel valvar tricúspide (onda Sm), correlacionou-se com índices de funções sistólica e diastólica do VE, seguindo o mesmo padrão de aumento de movimentação e estado hipercinético das variáveis do lado esquerdo do coração na evolução da DVCM. O padrão de fluxo sistólico da AP, bem caracterizado pelo TAC e TEJ, e o índice de área doVD foram os índices que mais alteraram com a evolução da hipertensão pulmonar na DVCM, enquanto que os índices de função do VD não apresentaram alterações significativas neste modelo de hipertensão arterial pulmonar em cão / Chronic mitral valvular disease (CMVD) is the most important acquired heart disease of dogs, and has as one of its complications, pulmonary arterial hypertension (PAH), which can lead to dysfunction of the right ventricle (RV). So, the objectives of the present study was to identify and describe changes in size, flow pattern in the pulmonary artery (PA) and RV systolic function at different stages of CMVD, and to correlate these variables with size, volume, systolic and diastolic function of left side of the heart, as well as the velocity of tricuspid insufficiency (TI) and pressure gradient between RV and right atrium in dogs thad had tricuspid valve regurgitation. For this purpose, 96 dogs of various breeds were included in the study, and they have been separated into 4 groups according to the stage of DVCM: group or stage A, B1, B2 and C. Dogs with symptomatic DVCM or stage C showed changes in the flow of PA, well evidenced by the reduction of the maximum and mean velocity flow of PA, besides the reduction of the acceleration (ACT) and ejection (EJT) times of systolic flow and negative correlation with the variables of size and systolic and diastolic function of the left heart. The RV size was statistically higher in the C stage of animals compared to stage B1; it was negatively associated with indices of left ventricular systolic function (LV). The systolic function indexes as index of tricuspide annular plane systolic excursion (ITAPSE) and fractional area change(FAC) were higher in more advanced stages of CMVD, and together with systolic myocardial movement of the tricuspid valve annulus velocity (wave Sm), correlated with indices of systolic and diastolic function of the left ventricle, following the same pattern of increase and hyperkinetic movement state variables of the left side of the heart in the evolution of DVCM. The pattern of systolic flow of the AP, well characterized by ACT and EJT, and RV area index are the variables that altered with the development of pulmonary hypertension in DVCM, while RV function indices showed no significant changes in this model of PAH in dogs

Background:  The right ventricle (RV) is multi-compartmental in orientation with a complex structural geometry. However, assessment of this part of the heart has remained an elusive clinical challenge. As a matter of fact, its importance has been underestimated in the past, especially its role as a determinant of cardiac symptoms, exercise capacity in chronic heart failure and survival in patients with valvular disease of the left heart. Evidence also exists that pulmonary hypertension (PH) affects primarily the right ventricular function. On the other hand, previous literature suggested that severe aortic stenosis (AS) affects left ventricular (LV) structure and function which partially recover after aortic valve replacement (AVR). However, the impact of that on RV global and segmental function remains undetermined.  Objectives: We sought to gain more insight into the RV physiology using 3D technology, Speckle tracking as well as already applicable echocardiographic measures. Our first aim was to assess the normal differential function of the RV inflow tract (IT), apical and outflow tract (OT) compartments, also their interrelations and the response to pulmonary hypertension. We also investigated the extent of RV dysfunction in severe AS and its response to AVR. Lastly, we studied the extent of global and regional right ventricular dysfunction in patients with pulmonary hypertension of different aetiologies and normal LV function. Methods: The studies were performed on three different groups; (1) left sided heart failure with (Group 1) and without (Group 2) secondary pulmonary hypertension, (2) severe aortic stenosis and six months post AVR and (3) pulmonary hypertension of different aetiologies and normal left ventricular function. We used 3D, speckle tracking echocardiography and conventionally available Doppler echocardiographic transthoracic techniques including M-mode, 2D and myocardial tissue Doppler. All patients’ measurements were compared with healthy subjects (controls). Statistics were performed using a commercially available SPSS software. Results: 1-  Our RV 3D tripartite model was validated with 2D measures and eventually showed strong correlations between RV inflow diameter (2D) and end diastolic volume (3D) (r=0.69, p&lt;0.001) and between tricuspid annular systolic excursion (TAPSE) and RV ejection fraction (3D) (r=0.71, p&lt;0.001). In patients (group 1 &amp; 2) we found that the apical ejection fraction (EF) was less than the inflow and outflow (controls:  p&lt;0.01 &amp; p&lt;0.01, Group 1:  p&lt;0.05 &amp; p&lt;0.01 and Group 2: p&lt;0.05 &amp; p&lt;0.01, respectively). Ejection fraction (EF) was reduced in both patient groups (p&lt;0.05 for all compartments). Whilst in controls, the inflow compartment reached the minimum volume 20 ms before the outflow and apex, in Group 2 it was virtually simultaneous. Both patient groups showed prolonged isovolumic contraction (IVC) and relaxation (IVR) times (p&lt;0.05 for all). Also, in controls, the outflow tract was the only compartment where the rate of volume fall correlated with the time to peak RV ejection (r = 0.62, p = 0.03). In Group 1, this relationship was lost and became with the inflow compartment (r = 0.61, p = 0.01). In Group 2, the highest correlation was with the apex (r=0.60, p&lt;0.05), but not with the outflow tract. 2- In patients with severe aortic stenosis, time to peak RV ejection correlated with the basal cavity segment (r = 0.72, p&lt;0.001) but not with the RVOT. The same pattern of disturbance remained after 6 months of AVR (r = 0.71, p&lt;0.001). In contrast to the pre-operative and post-operative patients, time to RV peak ejection correlated with the time to peak outflow tract strain rate (r = 0.7, p&lt;0.001), but not with basal cavity function. Finally in patients, RVOT strain rate (SR) did not change after AVR but basal cavity SR fell  (p=0.04). 3- In patients with pulmonary hypertension of different aetiologies and normal LV function, RV inflow and outflow tracts were dilated (p&lt;0.001 for both). Furthermore, TAPSE (p&lt;0.001), inflow velocities (p&lt;0.001), basal and mid-cavity strain rate (SR) and longitudinal displacement (p&lt;0.001 for all) were all reduced. The time to peak systolic SR at basal, mid-cavity (p&lt;0.001 for both) and RVOT (p=0.007) was short as was that to peak displacement (p&lt;0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r=0.7, p&lt;0.001) in controls, but with that of the mid cavity in patients (r=0.71, p&lt;0.001). Finally, pulmonary ejection acceleration (PAc) was faster (p=0.001) and RV filling time shorter in patients (p=0.03) with respect to controls. Conclusion: RV has distinct features for the inflow, apical and outflow tract compartments, with different extent of contribution to the overall systolic function. In PH, RV becomes one dyssynchronous compartment which itself may have perpetual effect on overall cardiac dysfunction. In addition, critical aortic stenosis results in RV configuration changes with the inflow tract, rather than outflow tract, determining peak ejection. This pattern of disturbance remains six month after valve replacement, which confirms that once RV physiology is disturbed it does not fully recover. The findings of this study suggest an organised RV remodelling which might explain the known limited exercise capacity in such patients. Furthermore, in patients with PH of different aetiologies and normal LV function, there is a similar pattern of RV disturbance. Therefore, we can conclude that early identification of such changes might help in identifying patients who need more aggressive therapy early on in the disease process.

A doença valvar crônica de mitral (DVCM) é a principal cardiopatia adquirida dos cães e uma das suas complicações é a hipertensão arterial pulmonar (HAP), o que pode induzir a disfunção do ventriculo direito (VD). Assim, constituíram-se em objetivos do presente estudo identificar e descrever alterações de tamanho do VD, padrão de fluxo na artéria pulmonar (AP) e função sistólica ventricular direita nas diferentes fases da DVCM, além de correlacionar estas variáveis com índices de tamanho, volume, funções sistólica e diastólica do lado esquerdo do coração, bem como com a velocidade da insuficiência tricúspide (IT) e gradiente de pressão entre o ventrículo e átrio direitos nos cães que apresentavam regurgitação da valva tricúspide. Para tanto, foram incluídos 96 cães de diversas raças no estudo, que foram separados em quatro grupos de acordo com o estágio da DVCM: grupos ou estágios A, B1, B2 e C. Os cães com DVCM sintomáticos ou em estágio C apresentaram alterações no fluxo da artéria pulmonar (AP), bem evidenciadas pela redução das suas velocidades máxima e média, além da redução dos tempos de aceleração (TAC) e ejeção (TEJ) do fluxo sistólico da AP e correlação negativa com as variáveis de tamanho e funções sistólica e diastólica do coração esquerdo. O tamanho do VD foi estatisticamente maior nos animais do estágio C em comparação aos do estágio B1 e associou-se, negativamente, com os índices de função sistólica ventricular esquerda (VE). Os índices de função sistólica do VD como índice de excursão sistólica do plano anular tricúspide (iTAPSE) e variação fracional de área (FAC) foram maiores nos estágios mais avançados da DVCM e, juntamente com a velocidade de movimentação miocárdica sistólica do anel valvar tricúspide (onda Sm), correlacionou-se com índices de funções sistólica e diastólica do VE, seguindo o mesmo padrão de aumento de movimentação e estado hipercinético das variáveis do lado esquerdo do coração na evolução da DVCM. O padrão de fluxo sistólico da AP, bem caracterizado pelo TAC e TEJ, e o índice de área doVD foram os índices que mais alteraram com a evolução da hipertensão pulmonar na DVCM, enquanto que os índices de função do VD não apresentaram alterações significativas neste modelo de hipertensão arterial pulmonar em cão / Chronic mitral valvular disease (CMVD) is the most important acquired heart disease of dogs, and has as one of its complications, pulmonary arterial hypertension (PAH), which can lead to dysfunction of the right ventricle (RV). So, the objectives of the present study was to identify and describe changes in size, flow pattern in the pulmonary artery (PA) and RV systolic function at different stages of CMVD, and to correlate these variables with size, volume, systolic and diastolic function of left side of the heart, as well as the velocity of tricuspid insufficiency (TI) and pressure gradient between RV and right atrium in dogs thad had tricuspid valve regurgitation. For this purpose, 96 dogs of various breeds were included in the study, and they have been separated into 4 groups according to the stage of DVCM: group or stage A, B1, B2 and C. Dogs with symptomatic DVCM or stage C showed changes in the flow of PA, well evidenced by the reduction of the maximum and mean velocity flow of PA, besides the reduction of the acceleration (ACT) and ejection (EJT) times of systolic flow and negative correlation with the variables of size and systolic and diastolic function of the left heart. The RV size was statistically higher in the C stage of animals compared to stage B1; it was negatively associated with indices of left ventricular systolic function (LV). The systolic function indexes as index of tricuspide annular plane systolic excursion (ITAPSE) and fractional area change(FAC) were higher in more advanced stages of CMVD, and together with systolic myocardial movement of the tricuspid valve annulus velocity (wave Sm), correlated with indices of systolic and diastolic function of the left ventricle, following the same pattern of increase and hyperkinetic movement state variables of the left side of the heart in the evolution of DVCM. The pattern of systolic flow of the AP, well characterized by ACT and EJT, and RV area index are the variables that altered with the development of pulmonary hypertension in DVCM, while RV function indices showed no significant changes in this model of PAH in dogs

L’insuffisance cardiaque droite est la première cause de morbi-mortalité chez les patients atteints d’hypertension pulmonaire. Améliorer le phénotypage de l’adaptation du coeur droit en imagerie non-invasive est essentiel afin de mieux comprendre les mécanismes favorisant la transition d’un état adapté à un état maladapté.Le premier chapitre a démontré la fiabilité de l’échographie cardiaque pour la détection de l’hypertension pulmonaire, fournissant des conseils méthodologiques pratiques.Le second chapitre a permis d’identifier les indices télé-systoliques de remodelage du ventricule droit comme les plus puissants paramètres pronostiques en imagerie chez les patients atteints d’hypertension artérielle pulmonaire (HTAP), en association avec la classe NYHA et le taux de NT-proBNP.Le troisième chapitre est dédié à l’étude des biomarqueurs immunitaires en hypertension pulmonaire, en mettant en utilisant la méthode de phénotypage approfondi du coeur droit pour déterminer le profile circulant protéomique associé à la défaillance droite chez les patiens atteints d’HTAP. Cette étude a permis de montrer que des taux élevés plasmatiques d’hepatic growth factor, de nerve grwoth factor et de stem cell growth factor beta sont associés à la défaillance droite dans deux cohortes d’HTAP. Le rôle direct de ces biomarqueurs dans le ventricule droit reste à être élucidé. / Right heart failure is the major cause of morbi-mortality in patients with pulmonary hypertension (PH). Improving right heart adaptive phenotyping using non-invasive imaging is needed in order to better understand the transition from right ventricular (RV) adaptation to maladaptation in PH.The first chapter of this thesis has been dedicated to demonstrate the reliability of echocardiography to detect PH in patients with group 1 or 3 PH, providing methodology pearls and pitfalls.The second chapter has enabled to identify, among the multiple right heart non-invasive imaging metrics, RV end-systolic remodeling indices as the strongest prognostic biomarkers in patients with pulmonary arterial hypertension (PAH), combined with the NYHA class and NT-proBNP levels.The third chapter has explored the role of immune biomarkers in PH, providing a practical application of right heart deep phenotyping to determine the circulating immune proteomic profile associated with right heart failure in patients with PAH. This screening proteomics study has identified high plasmatic levels of hepatic growth factor, nerve growth factor and stem cell growth factor beta to be associated with right heart maladaptation in two cohorts with PAH. The role of these biomarkers within the right ventricle itself remains to be fully explored.