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1
Guichard, Jean-Baptiste. « Déterminants du remodelage atrial et de son effet pro-arythmique dans la fibrillation atriale ». Thesis, Lyon, 2019. http://hdl.handle.net/1866/24623.
Texte intégralRésumé :
Rationnel et objectif - La fibrillation atriale (FA) est la pathologie rythmique supra-ventriculaire la plus fréquemment diagnostiquée. Le remodelage atrial, qu’il soit électrique ou structurel, conduit à la mise en place et au développement de la cardiomyopathie atriale. La cardiomyopathie atriale est responsable de différentes complications : d’une part mécaniques conduisant à l’augmentation du risque thrombo-embolique et de l’insuffisance cardiaque, d’autre part électriques conduisant à différentes arythmies atriales dont la FA. L’objectif du présent travail est de caractériser les déterminants du remodelage atrial et de leur effet pro-arythmique à l’étage supra-ventriculaire dans la FA.
Principaux résultats –
Le premier axe de recherche a permis d’objectiver le remodelage induit par le flutter atrial (FLA) chronique à l’aide d’un modèle chronique canin. Le FLA est à l’origine d’un remodelage atrial électrique avec une augmentation de la vulnérabilité à développer de la FA et une diminution des périodes réfractaires effectives (PRE). Cependant, le FLA n’induit pas de remodelage structurel avec notamment l’absence d’augmentation de la durée de FA, de diminution des vitesses de conduction et d’augmentation du processus fibrotique atrial. À noter que la FA chronique, en présence d’un substrat anatomique de FLA, présente des caractéristiques électrophysiologiques originales, en terme de durée de cycle et de d’arythmie et de sa stabilité. De plus, l’ablation du FLA permet de diminuer significativement la durée mais pas la vulnérabilité à présenter des arythmies supra-ventriculaires.
Le second axe de recherche a permis de caractériser le rôle différentiel de l’arythmie atriale de la réponse ventriculaire rapide en cas de FA dans le développement du remodelage atrial. Nos travaux ont caractérisé le remodelage atrial induit par l’arythmie atriale isolée en cas de FA : d’une part électrique via la diminution des PRE et l’augmentation de la vulnérabilité ; d’autre part structurel via la diminution des vitesses de conduction et les anomalies des canaux sodiques, des jonctions communicantes et du processus fibrotique. La réponse ventriculaire rapide isolée induit également un remodelage atrial à type d’augmentation de la vulnérabilité, de diminution des vitesses de conduction, d’anomalies modérées du processus fibrotique et des canaux sodiques. À noter une dégradation modérée de la fonction systolique ventriculaire gauche. Cependant, ce remodelage atrial est significativement différent du remodelage induit par l’insuffisance cardiaque. De plus, il existe un effet synergique au niveau du remodelage atrial de l’arythmie atriale et de la fréquence ventriculaire élevée en cas de FA, au niveau du processus fibrotique notamment.
Le troisième axe de recherche a permis d’objectiver le rôle de la cilnidipine, un inhibiteur calcique de type N et L, dans la limitation du remodelage atrial en cas de FA chronique, à l’aide d’un modèle aigü et chronique canin. Nos travaux ont caractérisé l’action anti-remodelante de la cilnidipine au niveau électrique, via la limitation de la diminution des PRE, de l’augmentation de la vulnérabilité atriale et de la durée de FA. D’autre part, la cilnidipine semble limiter le remodelage atrial, ce qui est objectivé par la normalisation des vitesses de conduction, de l’expression des canaux sodiques, des jonctions communicantes et de la fibrose tissulaire. La cilnidipine, contrairement aux inhibiteurs calciques de type L tels que la nifédipine, possède une activité anti-remodelante via la modulation de l’activité du système nerveux autonome.
Conclusion – Différents facteurs, tels que le flutter atrial, les fréquences atriales et ventriculaires en cas de FA, ont été caractérisés comme déterminants du développement du remodelage atrial. A contrario, la modulation d’un des déterminants du remodelage atrial, le système nerveux autonome via la cilnidipine, permet de de limiter le remodelage atrial secondaire à la FA. Ce travail fournit de nouvelles données sur les mécanismes impliqués dans le remodelage atrial lié à la FA et introduit de nouvelles approches préventives au développement de la FA.Rational and objective - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Atrial remodeling, whether electrical or structural, leads to the development of atrial cardiomyopathy. The atrial cardiomyopathy results in various complications: on one hand, mechanical with an increased thromboembolic risk and heart failure, and on the other hand electrical prdeisposing to atrial arrhythmias including AF. The aim of the thesis was to characterize the determinants of atrial remodeling, and their proarrhythmic effect in AF. Main results - The first part of the thesis focused on the characterization of the atrial remodeling induced by sustained atrial flutter (AFL) in a chronic canine model in order to characterize the interrelationship between AF and AFL. AFL caused electrical remodeling, including increased AF vulnerability and decreased effective refractory periods (ERPs). However, failed to influence AF duration, atrial conduction velocities and fibrosis. Chronic AF in the presence of an anatomical substrate for AFL led to specific AF characteristics, in terms of cycle length and its variability. In addition, AFL ablation significantly reduced arrhythmia duration but not AF vulnerability. The second part of the thesis characterized the differential role of atrial arrhythmia and ventricular response in AF-induced atrial remodeling. We characterized the atrial remodeling induced by lone atrial arrhythmia in AF, with AV-block to prevent high ventricular rate: on the one hand electrical via decreased ERP, reduced expression of sodium channels and gap junctions, which increased AF vulnerability; on the other hand, structural fibrosis which contributed to conduction slowing. Lone high-rate ventricular response also induced atrial remodeling involving increased AF vulnerability, decreased atrial conduction velocities, moderate abnormalities of fibrosis and sodium channel downregulation. In addition, there was a synergistic effect on atrial remodeling of combined atrial arrhythmia and high ventricular rate, especially regarding fibrosis. Thus, atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both can contribute to the arrhythmogenic substrate. These results provide new insights into the determinants of AF-related remodeling and provide novel considerations for ventricular rate-control. The third part of the thesis studies the ability of cilnidipine, an N- and L-type calcium channel blocker, to alter autonomic, electrical and structural remodeling associated with chronic AF, in a subacute and chronic dog model. We found that the cilnidipine inhibits the electrophysiological, autonomic and structural consequences of AF-related remodeling and the AF-associated increase in AF-vulnerability and AF-duration; in contrast, the highly selective L-type calcium channel blocker nifedipine had no protective effects. The protective effects of cilnidipine on the remodeling consequences of short-term AF were principally manifested by reductions in AF-induced ERP-abbreviation. With longer-term AF, cilnidipine also attenuated conduction-velocity reductions, protecting against AF-induced fibrosis and downregulation of sodium-channel and connexin subunits. Cilnidipine’s anti-remodeling properties were associated with suppression of the changes in autonomic tone caused by AF. Conclusion - Thus, we have shown 1) the distinct remodeling phenotypes produced by the closely related atrial re-entrant arrhythmias AFL and AF, as well as the interaction when they co-exist; 2) the specific contributions of the atrial rhythm and ventricular rate consequences of AF and how they interact; and 3) the ability of autonomic outflow inhibition by blocking N-type Ca2+-channels to prevent both electrical and structural components of AF-induced profibrillatory remodeling. This work provides new insights into the mechanisms involved in AF-related atrial remodeling and introduces novel preventive approaches.
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Grabowski, Carsten [Verfasser], Andreas [Gutachter] Mügge et Axel [Gutachter] Meissner. « Der Einfluss der Therapie mit kontinuierlich positivem Atemwegsdruck bei OSAS-Patienten auf das atriale Remodeling / Carsten Grabowski ; Gutachter : Andreas Mügge, Axel Meissner ». Bochum : Ruhr-Universität Bochum, 2017. http://d-nb.info/1136131841/34.
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3
Jesel-Morel, Laurence. « Sénescence, remodelage tissulaire et membranaire, risque thrombotique au cours de la fibrillation auriculaire ». Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ051/document.
Texte intégralRésumé :
Nos travaux montrent qu’au cours de la fibrillation atriale (FA), les microparticules (MP) reflètent et contribuent à un état d’hypercoagulabilité et pro-inflammatoire. Leurs concentrations similaires dans les deux oreillettes de patients en FA témoignent d’une absence de différence de statut pro-thrombotique entre ces deux cavités cardiaques. Au cours des procédures d’ablation de FA, les concentrations de MP évoluent parallèlement à l’augmentation de l’activation cellulaire et plaquettaire. Nous avons également montré dans l'altération tissulaire des oreillettes en FA, l'importance de la sénescence qui évolue avec la progression du trouble du rythme. Nous avons caractérisé un modèle cellulaire de sénescence réplicative de cellules endothéliales auriculaires de porc permettant d'identifier l'apparition d'un phénotype pro-thrombotique, pro-inflammatoire, pro-adhésif et de mieux comprendre la physiologie de la cellule endothéliale atriale sénescente et le rôle majeur du système rénine-angiotensine dans ces mécanismesOur data evidence that during atrial fibrillation (AF), microparticles (MP) contribute to an enhanced hypercoagulable and pro-inflammatory state. Similar concentrations of MP measured in left and right atria of AF patients highlight the absence of chamber-specific enhanced thrombogenic status. During AF ablation procedures, MP concentrations progress in parallel with cell and platelet activation. We also showed that AF progression is strongly related to human atrial senescence burden pointing toward a possible network that links in human atrium, senescence burden, endothelial dysfunction, thrombogenicity and atrial remodeling. We also developed a model of left atrium endothelial cell replicative senescence providing compelling evidences indicating that atrial endothelial senescence promotes thrombogenicity, inflammation and proteolysis. These data underline the major role of renin-angiotensin system in endothelial atrial cell senescence
4
Cardin, Sophie. « Molecular mechanisms underlying atrial remodeling ». Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103457.
Texte intégralRésumé :
Atrial fibrillation (AF) is the most sustained arrhythmia in the population and is associated with increased morbidity and mortality. A variety of cardiac disease entities, including valve disease, cardiomyopathies, hypertension and diabetes increase the risk of AF. However, present drug therapies are ineffective and can even increase the risk of dangerous ventricular tachyarrhythmias. Studies in animal models show that AF is associated with atrial remodeling that favors AF induction and maintenance. The mechanisms of atrial remodeling depend on the underlying pathology. Atrial remodeling caused by atrial tachycardia or AF itself is primarily electrical, associated with changes in the expression and function of ion channels. These changes are reflected in decreased atrial refractory periods, impaired refractoriness adaptation to rate and conduction slowing. Together, these electrical changes increase the incidence of AF. Heart failure (HF), an important cause of AF, induces another type of atrial remodeling. HF-remodeling is characterized by conduction heterogeneity and altered atrial structural properties. In particular, interstitial fibrosis plays a major role in the stabilization of reentry circuits and prolongation of AF duration.Although many studies have described a large number of the changes associated with each form of remodeling, the underlying mechanisms remain poorly understood. The goal of this thesis was to clarify the molecular mechanisms underlying the atrial remodeling associated with AF. In my first study, I put forward the hypothesis that atrial remodeling caused by atrial tachycardia and that resulting from HF differ in terms of the time course and nature of underlying changes in cardiac gene expression. I indeed discovered that the changes in gene expression induced by atrial tachycardia and HF were qualitatively different and evolved differently over time. The changes by atrial tachycardia were limited and showed time-dependent adaptation, whereas the changes induced by HF were qualitatively greater and more varied, and showed qualitative evolution with the development of the pathology. In my second study, I put forward the hypothesis that HF caused by ventricular "tachycardiomyopathy" causes differential gene-expression changes in atria versus ventricles and that these changes evolve over time. This study highlighted the signaling pathways implicated in atrial remodeling like those of MAP kinases, ubiquitin/proteasome systems and apoptosis, along with specific metabolic pathways like the electron-chain transport system and Krebs cycle at the ventricular level.Even though the large-scale study of gene-expression changes allowed us to identify certain signaling systems, they do not detect post-translational alterations. In our third study, I put forward the hypothesis that tachycardia-induced HF causes progressive changes in the proteins involved in different functional groups that play an important role in atrial pathophysiology. My results highlighted proteins linked to oxidative stress, metabolism and contractile proteins.In my final study, I decided to explore a new therapeutic avenue for AF prevention based on the molecular pathophysiology of AF. I had identified the MAP kinase ERK as a particularly important molecule in atrial remodeling caused by myocardial infarction in the rat and I had obtained results implicating a microRNA (miR21) in signaling leading to pathological ERK hyperphosphorylation. I therefore suggested that atrial interstitial fibrosis could be prevented by targeting underlying microRNA-related mechanisms and thereby reduce the inducibility and maintenance of AF caused by HF. My study is not yet completed but the preliminary results suggest beneficial effects of anti-miR21 treatment in preventing AF. In conclusion, my studies indicate the molecular pathophysiology underlying AF and suggest that it can be exploited to develop new therapeutic approaches.La fibrillation auriculaire est l'arythmie supra-ventriculaire soutenue la plus commune et est associée à un taux élevé de morbidité et de mortalité. Les traitements pharmacologique actuels demeurent inefficaces et entraînent parfois même une augmentation du risque d'arythmies ventriculaires. Les études effectuées sur différents modèles animaux ont démontré que la fibrillation auriculaire était associée à un remodelage auriculaire qui favorisait son induction et son incidence. Les mécanismes de remodelage auriculaire diffèrent selon la pathologie sous-jascente. Le remodelage auriculaire induit par une tachycardie auriculaire ou une fibrillation auriculaire est principalement électrique, associé à l'altération de l'expression et de la fonction de canaux ioniques. Ces changements se reflète par un raccourcissement des périodes réfractaires, une diminution d'adaptation au rythme et un ralentissement de la vélocité de conduction, augmentant ainsi l'incidence de la fibrillation auriculaire. L'insuffisance cardiaque, induit un remodelage auriculaire principalement caractérisé par une hétérogénéité de conduction associée à une altération des propriétés structurelles de l'oreillette. Notamment, la fibrose interstitielle joue un rôle majeur dans la stabilisation de circuits de réentrée et la prolongation de la durée de la fibrillation auriculaire. Bien que plusieurs études aient décrit un grand nombre de changements associés à chacun de ces types de remodelage, les mécanismes qui sous-tendent ces changements demeurent mal connus. Dans notre première étude, nous avons émis l'hypothèse selon laquelle le remodelage auriculaire induit par la tachycardie auriculaire et celui induit par une défaillance cardiaque diffèreraient au point de vue de l'évolution temporelle et de la nature des changements au niveau génomique. Nous avons constaté que les changements d'expression génique induits par la tachycardie auriculaire et par la tachycardie ventriculaire étaient qualitativement différents et évoluaient de façon différente dans le temps. Comparativement aux changements survenant au niveau auriculaire, les changements ventriculaires observés au point de vue biochimique et histopathologique différaient en terme d'intensité et de progression temporelle. Dans notre deuxième étude, nous avons émis l'hypothèse que l'insuffisance cardiaque induite par une tachycardie soutenue entraînait des changements d'expression génique qui diffèreraient entre les oreillettes et les ventricules et ces changements seraient évolutifs. Cette étude nous a permis de mettre en évidence l'implication des voies de signalisations telles que la voie des MAP kinases, l'apoptose et le système ubiquitine/protéosome au niveau auriculaire et certaines voies métaboliques au niveau ventriculaire. Bien que l'étude des changements d'expression génique nous permette de mettre en évidence certaines voies de signalisation, les changements survenant au niveau post-transcriptionel ne sont pas toujours détectables par une approche génomique. Dans notre troisième étude, nous avons donc émis l'hypothèse que l'insuffisance cardiaque induite par une tachycardie ventriculaire entraînait un remodelage auriculaire qui impliquerait des changements évolutifs importants d'expression de protéines de différents groupes fonctionnels. Nos résultats ont montré un changement au niveau de protéines liées au stress oxydatif, au métabolisme et aux protéines contractiles. Dans notre dernière étude, nous avons exploré une nouvelle avenue thérapeutique dans le traitement préventif de la fibrillation auriculaire. Nous avons suggéré que la fibrose interstitielle pourrait être prévenue par la modulation de mécanismes de régulation de l'expression de gènes par des microARN, qui réduirait l'inductibilité et le maintien de FA en contexte d'insuffisance cardiaque. Nos résultats préliminaires suggèrent un effet bénéfique du traitement anti-miR21 pour réduire la fibrillation auriculaire.
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Khoo, Chee Wah. « The relationship between left atrial remodelling, atrial fibrillation burden and thrombogenesis ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6847/.
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Contemporary pacemakers allow quantification of atrial high-rate episodes (AHREs) and atrial fibrillation burden (AFB) accurately. It is generally believed that left atrial (LA) remodelling may precede the development of atrial arrhythmias (AA), and AHRE precede the clinical manifestation of atrial flutter or fibrillation. However, the relationship between LA remodelling with AHRE has not been studied. Furthermore, the relationship of AFB to progressive LA remodelling and how this relates to indices of thrombogenesis is unclear. The aim of my study is to investigate the inter-relationship between LA remodelling, AA burden and indices of thrombogenesis in patients with pacemakers. My findings suggest that the incidence of AHRE was 35%. Increased frequency of right ventricular pacing is associated with LA enlargement and reduced global left and right ventricular function. However, there was no clear association between the right atrial pacing with cardiac remodelling. The cumulative percentage right ventricular pacing and increased LA volume are associated with the development of AHREs, but AFB is independently associated with changes in LA function, left ventricular diastolic function and indices of platelet activation and thrombosis. In addition, I demonstrated the feasibility and reproducibility of a novel method of IACT measurement in patients with permanent pacemakers.
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Clauß, Sebastian [Verfasser]. « Proarrhythmic atrial remodeling mechanisms leading to arrhythmias / Sebastian Clauß ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1228271046/34.
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Hodzic, Amir. « Exploration du coeur d'athlète à l'aide d'outils échocardiographiques d'analyse de la déformation myocardique, des volumes ventriculaires et des flux intra cavitaires Accuracy of speckle tracking in the context of stress echocardiography in short axis view : an in vitro validation study Analysis of inter-system variability of systolic and diastolic intraventricular pressure gradients derived from color Doppler M-mode echocardiography Echocardiographic evidence of left ventricular untwisting-filling interplay Cardiovascular adaptations in American-style football players in response to the inter- season training Right ventricular global and regional remodeling in American-style-football athletes : a longitudinal 3D echocardiographic study ». Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC428.
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L’athlète entrainé est un modèle physiologique d’adaptation cardiaque extrême où il est parfois difficile de faire la distinction entre le remodelage cardiaque adaptatif induit par l’exercice physique et certaines cardiomyopathies débutantes. L’échocardiographie est l’examen d’imagerie de premier choix pour l’étude du cœur d’athlète au repos et à l’effort. Les développements semi-récents du speckle tracking et de l’imagerie tridimensionnelle (3D) ont montré un intérêt clinique dans la description de la réponse cardiaque à l’exercice. Toutefois certains aspects techniques nécessitent d’être investigués. De plus, les outils de post-traitement actuels ne permettent qu’une évaluation incomplète de l’hémodynamique cardiaque et de l’analyse morphofonctionnelle régionale. Dans un premier temps, à l’aide d’un modèle expérimental mimant l’échocardiographie de stress, nous avons démontré la validité du speckle tracking pour l’étude de la déformation régionale dans une large gamme de fréquences de déformation en comparaison à la technique de référence par sonomicrométrie. Secondairement, nous avons étudié chez des sujets volontaires sans cardiopathie avérée (athlètes et non athlètes) une méthode de quantification non invasive des gradients de pressions intraventriculaires (GPIVs) pour l’évaluation de la fonction systolique et diastolique ventriculaire gauche (VG), qui est basée sur le post-traitement des données de vitesses de flux intra cavitaires acquises en mode TM Doppler couleur. Nous avons montré que cet indice hémodynamique était facilement accessible, et bien corrélé au mécanisme de succion VG. L’analyse des mesures de GPIVs a mis en évidence une variabilité inter-constructeur qui était principalement liée aux différences de résolution de l’image Doppler couleur. Enfin, en utilisant une approche échocardiographique multiparamétrique (speckle tracking, GPIV, et volumes 3D), nous nous sommes intéressés à caractériser la relation physiologique entre le type d’entrainement physique et le remodelage cardiaque gauche et droit au sein d’une équipe de footballeurs canadiens suivie de manière longitudinale. L’analyse régionale des modifications morphologiques et fonctionnelles du ventricule droit (VD) induites par l’exercice chronique a été réalisée à l’aide d’un nouvel algorithme de post- traitement des acquisitions 3D permettant une segmentation tripartite (apex, chambre d’admission, chambre d’éjection) des volumes VD en échocardiographie. En conclusion, les outils de post-traitement échocardiographique étudiés dans ce travail pour l’analyse globale et régionale de la fonction et de la morphologie cardiaques semblent applicables au cœur d’athlète et pourraient avoir un intérêt dans la caractérisation du remodelage cardiaque physiologique à l’exerciceThe trained athlete is a physiological model of extreme cardiac adaptation for whom the distinction between adaptive cardiac remodeling induced by chronic exercise and certain early cardiomyopathies can be difficult to assess. Echocardiography is the first-choice imaging modality to evaluate the athlete’s heart at rest and during exercise. Semi-recent developments in speckle tracking and 3D ultrasound imaging have shown clinical interest in the echocardiographic description of the athlete’s heart. However, some technical aspects require further investigation. Moreover, current post-treatment tools provide only a partial analysis of cardiac hemodynamics and regional myocardial function. Using an experimental model mimicking stress echocardiography, we first demonstrated the validity of speckle tracking in comparison to sonomicrometry to measure regional deformation in a large range of deformation rates. Secondly, we studied in volunteers without heart disease (athletes and non- athletes) the reliability of a method to assess non-invasively the left ventricular (LV) systolic and diastolic intraventricular pressure gradients (IVPGs) based on post-processing of intracardiac flow velocity data acquired using color Doppler M-mode. This hemodynamic index was highly feasible and well correlated with LV suction. Analysis of IVPG measurements revealed inter-vendor variability which was mainly related to differences in color Doppler image resolution. Finally, using a multiparametric echocardiographic approach (speckle tracking, IVPGs, and 3D volumes), we studied the physiological relationship between the type of exercise training and the left and right cardiac remodeling among a Canadian football team followed longitudinally. The regional analysis of right ventricular (RV) morphological and functional changes induced by chronic exercise was performed using a new computational method based on 3D echocardiography that volumetrically parcellated the RV into three segments (apex, outlet, and inlet). In conclusion, our workhas shown that the echocardiographic post-processing tools studied for the global and regional analysis of cardiac function and morphology apply to the athlete’s heart and could be useful in the characterization of the exercise-induced cardiac remodeling
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Colman, Michael Alan. « Development of a biophysically detailed model of the human atria for the investigation of the mechanisms of atrial arrhythmias ». Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/development-of-a-biophysically-detailed-model-of-the-human-atria-for-the-investigation-of-the-mechanisms-of-atrial-arrhythmias(29e4f51f-6ead-43e4-8574-eae9e4e1eb26).html.
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Atrial arrhythmias are the most prevalent sustained cardiac arrhythmias. Rates of hospitalisation and costs incurred to healthcare organisations are increasing in epidemic proportions. Despite this, the mechanisms of the transition from sinus rhythm to arrhythmic states are not well understood. The high level of regional electrical heterogeneity observed in the atria is thought to contribute towards the high prevalence of atrial arrhythmias. However, current computer models of the intact human atria only account for a small degree of this regional electrical heterogeneity, and do not include descriptions of the pacemaker regions of the sinoatrial node and the atrioventricular node. In this project, a new computational model of the intact 3D human atria is developed. First, a new single cell model to simulate the electrical action potential of the human atrial myocyte is developed. This model more accurately simulated the experimentally observed properties of human atrial action potentials than previous models. A family of electrically heterogeneous models describing the major regions within the atria is then developed, including those of the sinoatrial- and atrioventricular- nodes. This set of regional cell models represents the most expansive and complete set currently available. It is demonstrated that the large range of different electrical properties results in a large range of action potential morphology and duration within the atria. Models of the effect of sympathetic and parasympathetic regulation on the electrical AP of the models of the atrial working myocardium and the pacemaker regions were also incorporated. This demonstrated that sympathetic regulation can increase the pacing rate of the sinoatrial node and the atrio-ventricular node, and has a complex dose dependent effect on the atrial working myocardium. Four distinct models of the effects of atrial fibrillation induced remodelling on the atrial working myocardium are developed. These characterised the effect of remodelling of IKur on the overall changes in action potential morphology and duration observed. It is shown that the presence or absence of remodelling of this channel accounts for two distinct observed morphologies. A previous 3D anatomical model of the human atria is improved. First, detailed anatomical models for the sinoatrial node and the atrioventricular node are incorporated into the model. Second, it is further segmented to include regions for the pulmonary veins, atrio-ventricular ring, atrial septum and sinoatrial node block zone. This model is used to investigate the effects of sympathetic and parasympathetic regulation in the 3D atria. Finally, a detailed investigation of the underlying mechanisms of atrial fibrillation in the 3D atria, and the effect of electrical remodelling on the behaviour of atrial fibrillation, is performed using the detailed 3D model. This work represents a significant advance in 3D human atrial modelling. The anatomical model incorporates a greater level of complexity than previous models, and for the first time allowed investigation of the pacemaking mechanisms in the 3D intact human atria. The atrial fibrillation protocols are more physiologically relevant than previous models and have elucidated the roles that electrophysiological remodelling, electrical heterogeneity and structural anisotropy play in the development and maintenance of atrial fibrillation.
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Drahn, Steven [Verfasser]. « Bedeutung von mikroRNA-1 und -328 für atriales Remodeling bei Vorhofflimmern / Steven Drahn ». Greifswald : Universitätsbibliothek Greifswald, 2015. http://d-nb.info/1070926280/34.
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Tsuneyoshi, Hiroshi. « Atrial natriuretic peptide (ANP) helps prevent late remodeling after left ventricular aneurysm repair ». Kyoto University, 2005. http://hdl.handle.net/2433/144751.
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Kanagaratnam, Prapakaran. « The role of connexins in the electrophysiological remodelling of human atrial fibrillation ». Thesis, Imperial College London, 2002. http://hdl.handle.net/10044/1/7530.
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Kourlioros, Antonios. « Structural remodeling, inflammation and the role of statins in atrial fibrillation following cardiac surgery ». Thesis, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547611.
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Liu, Zhao. « USING GENE THERAPY TO PREVENT ATRIAL FIBRILLATION ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481231548493874.
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Tomsits, Philipp [Verfasser], et Stefan [Akademischer Betreuer] Kääb. « microRNA-vermitteltes atriales Remodeling in einem Schweinemodell für paroxysmales Vorhofflimmern / Philipp Tomsits ; Betreuer : Stefan Kääb ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1183572301/34.
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Hanna, Nessrine. « Differences in atrial vs. ventricular remodeling in dogs with ventricular tachypaced-induced congestive heart failure ». Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80286.
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Background. Congestive Heart Failure (CHF) causes arrhythmogenic remodeling in both atria and ventricles, but potential differences between atrial and ventricular remodeling in CHF have not been studied.Methods and results. We examined atrial and ventricular tissues from dogs with CHF induced by ventricular tachypacing (VTP, 240/min) for 0 (control) or 24 hrs, 1, 2, or 5 wks. Tissue angiotensin-II concentration (ELISA) increased to steady state at 24 hrs, and was significantly higher in LA than LV. VTP caused tissue apoptosis, inflammatory-cell infiltration and cell-death, with maximum changes in LA being transient and larger than in LV. MAP kinase activation (Western blot) was rapid (within 24 hrs) in LA, but smaller and slower (p38, JNK) or non-significant (ERK) in LV. The 25-kDa activated form of TGFbeta1, a particularly important profibrotic mediator in atria, increased significantly (Western blot) in LA at 24 hrs and 1 wk, but was not changed in LV. Substantial fibrosis developed in LA, but was much less important in LV.
Conclusions. There are qualitative and quantitative differences in LA and LV remodeling in experimental CHF, with important potential consequences for underlying mechanisms and therapeutic approaches.
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Hall, Mark Charles Scott. « Effects of angiotensin receptor blockade on atrial electrical remodelling and the 'second factor' in a goat model of lone atrial fibrillation ». Thesis, University of Manchester, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489010.
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Cardoso, Acácio Fernandes. « Avaliação da gordura epicárdica e sua influência no remodelamento cardíaco de obesos mórbidos submetidos à cirurgia bariátrica ». Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-28092018-094321/.
Texte intégralRésumé :
A gordura epicárdica é biologicamente ativa e sua espessura nos obesos é aumentada. A repercussão da gordura epicárdica sobre o remodelamento cardíaco ainda não está completamente elucidada. No presente estudo, foi avaliada a gordura epicárdica e sua influência no remodelamento cardíaco de obesos mórbidos, antes e após a cirurgia bariátrica. Métodos: No Hospital das Clínicas da Universidade de São Paulo, foram recrutados de forma prospectiva 20 obesos mórbidos sem outras comorbidades e 20 controles. Os participantes realizaram avaliação clínica e laboratorial, medida da duração da onda P no ECG e ecocardiograma transtorácico. O grupo de obesos repetiu essa avaliação 12 meses após a cirurgia bariátrica. A medida da gordura epicárdica foi feita pelo ecocardiograma. Para comparar as variáveis contínuas, foram utilizados os testes t de Student (não pareado e pareado), de Mann-Whitney ou de Wilcoxson. Para definir correlação entre as variáveis lineares, foi utilizado o coeficiente de correlação de Pearson. Para definir a associação entre variáveis categóricas, foi usado o teste exato de Fisher. Para avaliar a associação entre variáveis dependentes e independentes, foi realizada uma análise de regressão múltipla. Os dados foram examinados no software R. Um valor de p abaixo de 0,05 foi considerado significativo. Resultados: No préoperatório, foram observados níveis elevados de proteína C reativa, uma maior duração da onda P, da massa ventricular e do diâmetro do átrio esquerdo nos obesos em relação aos controles (p < 0,05). Uma menor fração de ejeção do ventrículo esquerdo foi observada no grupo de obesos (p < 0,05). A gordura epicárdica foi maior nos obesos (p < 0,01). Uma correlação positiva foi encontrada entre a gordura epicárdica, a duração da onda P (r=0,70; p < 0,01), o diâmetro do átrio esquerdo (r=0,67; p < 0,01) e a massa ventricular (r=0,58; p < 0,01). Uma correlação inversa foi observada entre a gordura epicárdica e a fração de ejeção do ventrículo esquerdo (r=- 0,52; p < 0,01). Na análise de regressão múltipla, a gordura epicárdica permaneceu correlacionada com a duração da onda P, o diâmetro do átrio esquerdo e a fração de ejeção do ventrículo esquerdo (p < 0,05). Em 60% dos obesos, foi identificada alguma alteração na geometria ventricular. Uma associação entre a espessura da gordura epicárdica maior ou igual a 3,7 mm e a presença de remodelamento ventricular geométrico foi demonstrada (p=0,03). No pós-operatório, observou-se uma redução do índice de massa corporal, da proteína C reativa e da gordura epicárdica (p < 0,01). Uma redução da duração da onda P e um aumento da fração de ejeção do ventrículo esquerdo também foram observados (p < 0,01). Na análise de regressão múltipla esses achados permaneceram correlacionados à redução da gordura epicárdica (p < 0,05), independente da variação do índice de massa corporal e da proteína C reativa. Conclusões: Em obesos mórbidos sem outras comorbidades, a gordura epicárdica foi associada a um aumento da duração da onda P, do diâmetro do átrio esquerdo e da massa ventricular, além de uma menor fração de ejeção do ventrículo esquerdo. A espessura da gordura epicárdica igual ou acima de 3,7 mm foi associada a alterações do remodelamento ventricular. A redução da gordura epicárdica após a cirurgia bariátrica foi associada com a redução da duração da onda P e o aumento da fração de ejeção do ventrículo esquerdo, independente da variação do índice de massa corporal e da proteína C reativaEpicardial fat is biologically active and its thickness is increased in obese subjects. The effects of epicardial fat on cardiac remodeling are still not fully understood. In the present study we evaluated epicardial fat and its influence on cardiac remodeling of morbidly obese, before and after bariatric surgery. Methods: We prospectively recruited 20 morbid obese subjects without other comorbidities and 20 control subjects at Hospital das Clínicas, Universidade de São Paulo. Participants underwent clinical and laboratory assessment, measure of P-wave duration on ECG and transthoracic echocardiogram. The obese group repeated this evaluation 12 months after the bariatric surgery. To compare continuous variables, we used t Student test (paired and nonpaired), Mann-Whitney and Wilcoxson tests. To define the correlation between linear variables we used Pearson correlation coefficient. To define the association between categorical variables we used Fisher exact test. A multiple regression analysis was performed to assess the association between dependent and independent variables. Data were analyzed by software R. A p value below 0.05 was considered statistically significant. Results: Preoperatively, we observed high levels of C-reactive protein, longer P-wave duration, larger ventricular mass and left atrial diameter in obese subjects compared to the controls (p < 0.05). Lower left ventricle ejection fraction was observed in the obese group (p < 0.05). Epicardial fat was higher among obese subjects (p < 0.01). A positive correlation was found between epicardial fat and P-wave duration (r=0.70; p < 0.01), left atrial diameter (r=0.67; p < 0.01), and ventricular mass (r=0.58; p < 0.01). An inverse correlation was observed between epicardial fat and left ventricle ejection fraction (r=-0.52; p < 0.01). In the multiple regression analysis, epicardial fat remained correlated with P-wave duration, left atrial diameter and left ventricle ejection fraction (p < 0.05). In 60% of the obese subjects, there was some abnormality in ventricular geometry. We showed association between thickness of epicardial fat equal to or higher than 3.7 mm and presence of geometric ventricular remodeling (p=0.03). Postoperatively, we observed reduction in body mass index, C-reactive protein and epicardial fat (p < 0.01). Reduction in P-wave duration and an increase in left ventricle ejection fraction were also observed (p < 0.01). In the multiple regression analysis, these findings were correlated with reduction in epicardial fat (p < 0.05), regardless of the variation in body mass index and C-reactive protein. Conclusion: In morbid obese subjects without other comorbidities, epicardial fat was associated with increase in P-wave duration, left atrial diameter and ventricular mass, in addition to smaller left ventricle ejection fraction. Epicardial fat thickness equal to or greater than 3.7 mm was associated with abnormalities in ventricular remodeling. Reduction of epicardial fat after bariatric surgery was associated with reduction of P-wave duration and increase in left ventricle ejection fraction, regardless of the variation in body mass index and C-reactive protein
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Kourliouros, Antonios. « Structural remodelling, inflammation and the role of statins in atrial fibrillation following cardiac surgery ». Thesis, St George's, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546798.
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Nikonova, Yulia [Verfasser], et Jens [Akademischer Betreuer] Kockskämper. « Atrial remodelling in hypertensive heart disease : role of Na+ homeostasis and contractility / Yulia Nikonova. Betreuer : Jens Kockskämper ». Marburg : Philipps-Universität Marburg, 2016. http://d-nb.info/1103658174/34.
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Legallois, Damien. « Paramètres biologiques et échocardiographiques et remodelage ventriculaire gauche après syndrome coronarien aigu avec sus-décalage du segment ST Definition of left ventricular remodelling following ST-elevation myocardial infarction : a systematic review of cardiac magnetic resonance studies in the past decade Left atrial strain quantified after myocardial infarction is associated with ventricular remodeling The relationship between circulating biomarkers and left ventricular remodeling after myocardial infarction : an updated review Serum neprilysin levels are associated with myocardial stunning after ST-elevation myocardial infarction Is plasma level of Coenzyme Q10 a predictive marker for left ventricular remodeling after revascularization for ST-segment elevation myocardial infarction ? » Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC429.
Texte intégralRésumé :
Le remodelage ventriculaire gauche est une complication fréquente des patients ayantprésenté un syndrome coronarien aigu, pouvant conduire à terme à une situation d’insuffisancecardiaque. Il est donc important de connaître les facteurs associés à la survenue d’un remodelageventriculaire afin de dépister plus précocement les patients à plus haut risque d’insuffisance cardiaqueet ainsi optimiser leur prise en charge. Ce travail comprend deux axes. Le premier porte sur larecherche de nouveaux paramètres d’imagerie associés à la survenue du remodelage. Nous avonsdans un premier temps réalisé une revue de la littérature concernant la définition du remodelageventriculaire gauche en imagerie par résonance magnétique. Puis, nous avons conduit deux étudesayant pour but de rechercher une association entre (i) le strain atrial gauche et, (ii) le gradient depression intraventriculaire gauche diastolique, évalués en échocardiographie 24-48 heures après lesyndrome coronarien aigu et le remodelage ventriculaire gauche au cours du suivi. Le second axe portesur les biomarqueurs associés au remodelage ventriculaire post-infarctus. Nous avons réalisé une revuede la littérature au sujet des biomarqueurs qui, dosés lors de l’hospitalisation initiale, sont associés àl’existence d’un remodelage lors du suivi. Nous avons ensuite étudié la valeur prédictrice de deuxbiomarqueurs (la néprilysine et le coenzyme Q10) pour la survenue d’un remodelage ventriculairegaucheLeft ventricular remodeling is a common complication in patients following acutemyocardial infarction and may lead to heart failure. Some baseline parameters are associated withremodeling at follow-up, allowing to better discriminate patients with an increased risk of heart failureto optimize therapeutics. This work has two axes, focused on imaging and biological parametersassociated with left ventricular remodeling, respectively. First, we reviewed past studies that definedremodeling using cardiac magnetic resonance imaging. Then, we studied the association betweensome echocardiographic parameters (left atrial strain and diastolic intraventricular pressure gradient)and left ventricular remodeling after ST-elevation myocardial infarction. In the other axis, wereviewed biomarkers that have been associated with left ventricular remodeling in prior studies. Then,we investigated the association between neprilysin and coenzyme Q10 levels and left ventricularremodeling in STEMI patients
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Schwarzwald, Colin C. « Atrial and AV-nodal physiology in horses electrophysiologic and echocardiographic characterization and pharmacologic effects of diltiazem / ». Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1158079213.
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Castiglioni, L. « EVALUATION OF LEFT VENTRICULAR AND ATRIAL-APPENDAGE FUNCTION IN NORMAL AND ISCHEMIC MOUSE MODELS BY CARDIAC IMAGING TECHNIQUES : A PHARMACOLOGICAL VALIDATION ». Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/215127.
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Despite progress in diagnosis and treatment lead to a significant reduction of the rate of death attributable to cardiovascular disease (CVD), many efforts must to be done to modify the pathological process and enhance protection. Thus the development of new technologies for diagnosis and novel therapeutic agents is fundamental for clinicians and researcher.
In the last decade, murine model had become a useful tool to study CVDs mechanism and to test new pharmacological treatments.
Noninvasive imaging technique, specific for laboratory animals, provide the opportunity to image longitudinally the same animal, investigating the follow-up of pathologies and assessing the effect of pharmacological treatments.
Aims of this work are to set up an animal model of myocardial infarction (MI) and cardiac imaging (cardiac magnetic resonance imaging and echocardiography) of left ventricle (LV), left atrium (LA) and appendage (LAA) in healthy mice, and then evaluate the global and regional functional-structural changes and remodeling occurring on LV, LA and LAA after MI, with or without pharmacological treatment. The in vivo imaging data were supported by morphological, histological and gene expression analysis.
Results from this study described the regional area changes occurring on LV after MI with a progressive loss of contractility also in remote non-infarcted tissue; the presence of only three pulmonary veins entering LA and the presence of the large LAA which, working together with LA, plays an important role in LV filling. After MI not only LV but also LA and LAA remodel in order to maintain, with their enlargement, LV stroke volume. The pharmacological treatment with valsartan, a selective inhibitor of AT1 receptor of Ang II, influenced LV remodeling by reducing LV enlargement, infarct size, ECM gene expression (in particular collagen VIII, fibulin-2 involved in fibrosis and hypertrophy), preserving LV SV without affecting LAA and LA increase in dimension.
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Lucas, Jason Anthony. « Counterregulatory roles of transforming growth factor (TGF)-[beta] and a trial natruiretic peptide (ANP) in pressure overload-induced cardiac remodeling and fibrosis ». Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009p/lucas.pdf.
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Kim, Tu-Won [Verfasser]. « Echokardiographische Prädiktoren eines Vorhofflimmerrezidives und atriales Remodeling nach Pulmonalvenenisolation mit einem methodischen Vergleich von Strainmessungen mit Tissue-Doppler-Imaging und Speckle-Tracking-Imaging / Tu-Won Kim ». Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2011. http://d-nb.info/1025240391/34.
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Hunter, Ross J. « Catheter ablation of fractionated electrograms for atrial fibrillation : does it improve outcomes and can it be refined based on electrogram morphology or knowledge of the remodelling process ? » Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8639.
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Catheter ablation complex or fractionated atrial electrograms (CFAE) may improve outcomes for persistent AF. However, it is unclear whether CFAE are important in maintaining AF or whether targeting of CFAE can be refined based on electrogram morphology or knowledge of the remodelling process. A detailed classification of CFAE was described. Assessment of 100 CFAE by visual inspection in real time correlated well with detailed offline measurement. Targeting of different CFAE morphologies in 20 patients with persistent AF caused cycle length prolongation only with ablation of certain CFAE morphologies. Therefore, targeting CFAE is not simply atrial de-bulking, certain CFAE morphologies are more important for maintaining AF. A computer model was established to simulate LA wall stress using a 3D reconstruction of the chamber from CT imaging. Electrophysiologic data was acquired in 19 patients in persistent AF and compared to simulated wall stress data. Peaks in wall stress were associated with areas of low voltage suggestive of focal remodelling. CFAE were not associated with peaks in wall stress or areas of remodelling. Wall stress did not determine whether ablation of CFAE caused cycle length prolongation. Long term outcome of catheter ablation for AF was good with little late recurrence. Outcome for persistent AF was improved by targeting CFAE in addition to pulmonary vein isolation and may reduce late recurrence.
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Baptista, Sandra Isabel Pereira. « Repercussões electrocardiográficas em canídeos com doença mixomatosa da válvula mitral avaliados ecocardiograficamente ». Master's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2013. http://hdl.handle.net/10400.5/5977.
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Dissertação de Mestrado Integrado em Medicina VeterináriaA doença mixomatosa degenerativa da válvula mitral (DMVM) é a doença cardiovascular adquirida mais comum em cães. A sobrecarga de volume consequente à doença promove remodelação cardíaca com dilatação do átrio esquerdo (AE) e hipertrofia excêntrica (HE) do ventrículo esquerdo (VE). O objetivo deste estudo passou por avaliar as repercussões dessa remodelação no eletrocardiograma (ECG). Para tal foram avaliados ecocardiograficamente 37 canídeos com DMVM nos estadios B1, B2 e C segundo a classificação da ACVIM, com posterior avaliação eletrocardiográfica. Verificou-se que o ECG apresenta pouca sensibilidade na deteção do alargamento do AE (33,3%) e do VE (4,3%) e elevada especificidade em ambos. A frequência cardíaca (FC) tendeu a aumentar com a gravidade da insuficiência cardíaca (IC), assim como a prevalência de alterações patológicas do ritmo.
ABSTRACT - Electrocardiographic repercussions of the myxomatous mitral valve disease in dogs after echocardiographic evaluation - The myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease in dogs. The resulting volume overload causes a cardiac remodelling with a dilation of the left atrium and an eccentric hypertrophy of the left ventricle. This dissertation studies the repercussions of the cardiac remodelling by electrocardiographic evaluation. 37 canines in the B1, B2 and C stages of the MMVD disease (by the ACVIM classification) were subjected to echocardiographic assessment followed by electrocardiographic evaluation. The ECG presented low sensibility to classify the left atrium and left ventricle dilation (33.33% and 4,3%) though high specificity for both was verified. The density of pathological rhythms and the heart rate itself were found to have a tendency to increase with the severity of the cardiac insufficiency.
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Rocha, Danielle Lopes. « Remodelamento cardíaco após oclusão percutânea da comunicação interatrial tipo ostium secundum em adultos : um estudo ecocardiográfico com novas técnicas ». Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/98/98131/tde-26042016-100156/.
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Introdução: A comunicação interatrial tipo ostium secundum(CIA) é uma cardiopatia congênita frequente, sendo a mais comumente encontrada na população adulta. Seu tratamento está indicado quando há repercussão hemodinâmica caracterizada pelo aumento das dimensões das câmaras direitas à ecocardiografia, independente da presença de sintomas. Nas últimas 2 décadas o fechamento percutâneo da CIA emergiu como a modalidade terapêutica preferencial devido sua alta eficácia e menor morbidade que a correção cirúrgica.Tanto o tratamento cirúrgico como o percutâneo da CIA resultam em remodelamento cardíaco com redução progressiva do tamanho das câmaras direitas e aumento das esquerdas. Recentemente, novas técnicas ecocardiográficas vem sendo empregadas para avaliação das dimensões, geometria e função das câmaras cardíacas incluindo o ecocardiograma tridimensional e o rastreamento de marcadores acústicos. Hipótese e objetivos: Partiu-se da hipótese que o fechamento percutâneo da CIA, por ser um método não invasivo, levaria a rápido remodelamento cardíaco mesmo em adultos com sobrecarga volumétrica crônica das câmaras direitas. Tivemos como objetivo avaliar o comportamento temporal do remodelamento cardíaco e analisar possíveis diferenças existentes entre pacientes de diferentes faixas etárias e com tamanhos diversos de CIA. Material e métodos: Estudo observacional, prospectivo, não randomizado de um braço único de uma coorte de adultos submetidos ao fechamento percutâneo da CIA com a prótese Cera (Lifetech, Shenzheng, China) e acompanhados por um ano. Foram selecionados 29 adultos com CIA com repercussão hemodinâmica com anatomia favorável para a oclusão percutânea e sem contra-indicações para tal. O remodelamento cardíaco foi estudado por meio de várias técnicas ecocardiográficas incluindo as clássicas e outras de introdução recente. A ecocardiografia bidimensional foi usada para a medição das dimensões do átrio direito (AD), ventrículo direito (VD) e ventrículo esquerdo (VE), para determinação da área fracionada do VD (FAC) e da excursão anterior da valva tricúspide (TAPSE) e para análise volumétrica das câmaras cardíacas. A ecocardiografia tridimensional foi empregada para análise volumétrica e funcional do VD. O rastreamento de marcadores acústico foi utilizado para avaliação da função do AD, VD e VE. O teste ANOVA foi usado para avaliação das mudanças observadas nas variáveis repetidas ao longo do tempo com comparações múltiplas de Bonferroni quando aplicável. Uma análise intra e interobservador das medidas foi realizada utilizando coeficientes de concordância. Resultados: A média de idade e peso dos pacientes foi de 45,2 ± 17,0 anos e 68,8 ± 14,0 kgs, respectivamente. Nenhum paciente apresentada hipertensão pulmonar significativa. A média do tamanho da CIA foi de 20,2 ± 5,0 mm e a média do tamanho da prótese implantada foi de 22,9 ± 6,2 mm. Em todos os pacientes houve sucesso no implante. Não houve complicações relacionadas ao procedimento e em todos os pacientes foi observada oclusão do defeito. Após o procedimento, houve redução precoce (< 3 meses) das dimensões do AD (p<0,001) e do VD (p<0,001) e aumento das dimensões do VE (p<0,014). Não houve mudanças significativas na função de deformação longitudinal do AD para onda P (p=0,227) e para onda T (p=0,124). Houve redução abrupta da função do VD pelo TAPSE (p=0,032), pela deformação longitudinal (p=0,002) e pela ecocardiografia tridimensional (p=0,084). Não houve mudanças significativas da onda S\' (p=0,55) e da FAC (p=0789) do VD. Houve redução precoce do volume de ejeção do VD (p< 0,001) e aumento do volume de ejeção do VE (p=0,027). Houve redução da deformação longitudinal do VE (p=0,049) e não houve mudanças na função do VE pelo método de Simpson (p=0,462). Pacientes maiores que 60 anos (n=8) apresentaram valores iniciais maiores nas dimensões do AD e redução mais prolongada (p=0,0497). Pacientes com CIAs maiores que 20 mm (n=12) apresentavam valores iniciais maiores de TAPSE com redução mais retardada (p=0,013). Todas as mudanças observadas inicialmente nos primeiros 3 meses se sustentaram ao final do seguimento. Houve excelente concordância na análise intraobservador para todas as medidas repetidas (CCI> 0,9) com exceção da deformação do VE (CCI< 0,7). A concordância entre as medidas realizadas por diferentes observadores não foi tão boa, com apenas as variáveis TAPSE, deformação do VE e dimensões do AD possuindo CCI > 0,7. Conclusões: O fechamento percutâneo da CIA em adultos de meia idade leva a rápido remodelamento cardíaco tanto do ponto de vista anatômico como funcional com resultados sustentados dentro do primeiro ano de seguimento. Tais mudanças temporais são observadas independente do tamanho da CIA e da idade dos pacientes, denotando o efeito benéfico do procedimento sobre a geometria e o funcionamento cardíaco global em todos adultos portadores desta frequente cardiopatia congênita.Introduction: The atrial septal defect of the secundum type (ASD) is a frequent congenital heart disease, being the most commonly encountered in the adult population. Treatment is indicated when there is hemodynamic burden characterized by increased dimensions of the right chambers on echocardiography, regardless of the presence of symptoms. In the last two decades, percutaneous closure of the ASD has emerged as the preferred therapeutic modality due to its high efficacy and lower morbidity when compared to surgical correction. Both surgical and percutaneous treatment of the ASD result in cardiac remodeling with progressive reduction in the size of the right chambers and increase in the left chambers. Recently, new echocardiographic techniques have been employed to assess the dimensions, geometry and function of the cardiac chambers including three-dimensional echocardiography (3D echo) and acoustic speckle tracking. Hypothesis and objectives: Hypothesizing that percutaneous closure, being a non-ivasive method, results in a fast cardiac remodeling even in adults with chronic volume overload of the right chambers, our aim was to assess the temporal pattern of cardiac remodeling and analyse possible differences between patients of different age groups and different ASD sizes. Material and methods: This was an observational, prospective, non randomized, single arm study of a cohort of adults submitted to percutaneous closure of the ASD with the Cera device (Lifetech, Shenzheng, China) followed along a year. Twenty nine adults with hemodynamicaly significant ASDs with suitable anatomy for percutaneous closure and no contra-indications for the procerdure were selected. Cardiac remodeling was assessed by various echocardiographic techniques including standard and new ones. Bidimensional echocardiography was used to measure the dimensions of the right atrium (RA), right ventricle (RV) and left ventricle (LV), to determine the fractional area of the RV (FAC) and the systolic anterior excursion of the tricuspid valve (TAPSE), and to analyse the volumes of the cardiac chambers. Three-D echo was employed for volumetric and functional analysis of the RV. Acoustic speckle tracking was utilized to assess the function of the RA, RV and LV. ANOVA tests were used to assess the observed changes in the repeated variables over time with multiple Boferoni comparison as applicable. An intra and interobserver analysis of the measurements was performed using concordance coefficients. Results: Mean age and weight was 45,2 ± 17,0 years and 68,8 ± 14,0 kgs, respectively. No patient had significant pulmonar arterial hypertension. The ASD dimension and the size of the device was a mean of 20,2 ± 5,0 mm and 22,9 ± 6,2 mm, respectively. In all patients the device was implanted successfully. There were no complications related to the procedure and in all patients the ASDs were successfully closed. After the procedure, there was an early (< 3 months) reduction of the RA (< 0.001) and RV (< 0.001) sizes and an increase of the LV dimensions (p< 0.014). There were no significant changes in the function of the RA as assessed by longitudinal strain (p=0.227 for the P wave and p=0.124 for the T wave). There was an abrupt reduction of the RV function assessed by TAPSE (p=0.032), longitudinal strain (p=0.002) and 3D echo (p=0.084). There were no changes in the S\' wave (p=0.55) and FAC (p=0.789) of the RV. There was an immediate decrease in the RV stroke volume (p< 0.001) and an increase in the LV srtroke volume (p=0.027). There was a reduction in LV longitudinal strain (p=0.049) and no change in LV function as assessed by the Simpson method (p=0.462). Patients older than 60 years of age (n=8) presented with larger RA dimensions, which decreased in a slower fashion (p=0.0497). Patients with ASDs larger than 20 mm (n=12) had initial higher TAPSE values, which decreased in a slower fashion (p=0.013). All changes observed earlier on endured after a year. There was excellent concordance in the intra observer analysis for all the repeated measures (CCI > 0.9) with the exception of LV strain (CCI < 0.7). The concordance between different observers was not as good with only TAPSE, LV strain, and RA dimensions variables having a CCI > 0.7. Conclusions: Percutaneous closure of the ASD in middle aged adults results in fast cardiac remodeling from both the anatomic and functional point of view with sustained results over the first year of follow up. These temporal changes are observed regardless of the ASD size and the age of the patients, which demonstrates the beneficial effect of the procedure over the cardiac geometry and global function in all adults who have this frequent congenital heart disease.
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Grandperrin, Antoine. « Entraînement en musculation et remodelage myocardique : Influence du sexe, du niveau de pratique et de la prise régulière de stéroïdes anabolisants Myocardial adaptations after 16 weeks of high-intensity strength training in men and women Androgenic anabolic steroids induce left atrial and left ventricular remodeling and dysfunction in strength athletes Left ventricular dyssynchrony and post-systolic shortenings in young bodybuilders using anabolic-androgenic steroids Myocardial work in athletes using anabolic androgenic steroids and athletes with hypertrophic cardiomyopathy ». Thesis, Avignon, 2020. http://www.theses.fr/2020AVIG0717.
Texte intégralRésumé :
Ces dernières années, la pratique de la musculation s’est largement démocratisée et regroupe aujourd’hui différents types de pratiquants, allant de la personne sédentaire en reprise d’activité au sportif de haut niveau pratiquant le culturisme. L’objectif de ces travaux de thèse a été d’étudier l’impact cardiaque de l’entraînement en musculation chez ces différents types de pratiquants. Une première partie a eu pour objectif d’étudier l’impact longitudinal de 16 semaines d’entrainement en musculation sur la fonction cardiaque d’hommes et de femmes préalablement sédentaires. Le programme d’entraînement, supervisé, a été conçu en respectant les recommandations de l’American College of Sports Medicine (travail à 70% de la charge maximale, 4 séries, 8 à 12 répétitions, 3 séances par semaine, utilisation d’exercices polyarticulaires). Afin d’étudier la cinétique d’adaptation de la morphologie et fonction ventriculaire et atriale, nous avons réalisé une échocardiographie de repos complète, incluant des analyses en "2D-strain", toutes les quatre semaines. Une deuxième partie s’est intéressée aux sportifs de force très entraînés, et plus particulièrement à ceux qui rapportent une utilisation régulière de stéroïdes anabolisants en complément de leur entrainement. De nombreuses études rapportent des effets délétères de ces substances, avec notamment un impact négatif sur la morphologie et la fonction cardiaque qui peut conduire à la survenue de morts subites. Néanmoins, peu d’études ont à ce jour exploité les derniers outils disponibles en échocardiographie afin de comprendre les dysfonctions engendrées. Ainsi, à partir d’analyses en "2D-strain", nous avons mis en place une évaluation globale et régionalisée de la morphologie et fonction ventriculaire et atriale gauche afin d’étudier les mécanismes impliqués dans les altérations. Nous avons complété ces analyses par une étude de l’asynchronisme intra-ventriculaire. Enfin, nous avons confronté ce modèle de sportifs utilisant des stéroïdes anabolisants à des sportifs ayant une hypertrophie cardiomyopathique afin d’étudier le remodelage potentiellement pathologique engendré par les stéroïdes anabolisants. Dans cette dernière partie, une évaluation novatrice du travail myocardique a été réalisée afin de tenir compte des conditions de charge et de discriminer un peu plus nos populationsStrength training is increasingly practiced by previously untrained people or by experienced athletes. This work aimed to evaluate cardiac adaptations to strength training over these different populations. In a first time, we evaluated the longitudinal impact of 16-weeks strength training on the cardiac function of previously untrained women and men. The American College of Sports Medicine recommendations were used to build the training program (i.e. training at 70% of the repetition maximum, 4 sets, 8-12 repetitions, 3 times a week with polyarticular exercices). 2D-strain echocardiography was used to assess both left ventricular and atrial morphology and function. In a second time, we aimed to evaluate the cardiac function of strength-trained athletes, which used androgenic anabolic steroids. While previous studies reported an alteration of cardiac function in this population, with sudden-death frequently reported, any study used 2D-strain parameters to understand the dysfunctions. In this context, we used 2D-strain analysis to evaluate global and regional myocardial function in order to evaluate the underlying mechanisms of left ventricular and left atrial functions, with a specific evaluation of intra-ventricular dyssynchrony. Finally, we aimed to compare our athletes using androgenic anabolic steroids users to athletes with hypertrophic cardiomyopathy to assess the probably pathological remodelling generates by anabolic androgenic steroids. In this study, we evaluate myocardial work, a new tool in echocardiography, which take into account load conditions and could better discriminate our populations
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Le, Quang Khai. « Troubles du rythme cardiaque dans les modèles murins transgéniques ». Thèse, Nantes, 2010. http://hdl.handle.net/1866/4903.
Texte intégralRésumé :
Les maladies cardio-vasculaires sont la première cause de mortalité dans le monde. L’hypertrophie cardiaque est un processus de remodelage provoqué par une surcharge de travail du muscle cardiaque afin de mieux répondre à la demande de l’organisme. Bien que bénéfique à court terme, une hypertrophie trop accentuée conduira à long terme, à une insuffisance cardiaque. L’hypertrophie est associée à un remodelage électrique qui conduit généralement à un allongement du potentiel d’action, une des causes des arythmies ventriculaires et de la mort subite. Généralement, le mécanisme causal est la fibrillation ventriculaire, un trouble du rythme irréversible dont les mécanismes sont complexes et méconnus. Si les conséquences fonctionnelles in vitro des mutations génétiques ou du remodelage ionique sont relativement simples à étudier ou à prévoir, leur rôle dans les mécanismes des troubles du rythme in vivo sont plus difficiles à appréhender. Parmi les nombreux modèles animaux développés pour la recherche sur les troubles du rythme, la souris est de plus en plus utilisée en raison de notre capacité à muter, invalider ou sur-exprimer les gènes d'intérêt chez ces animaux. L'objectif de mon travail de thèse était de mieux comprendre le rôle des canaux ioniques en physiopathologie cardiaque, en particulier dans la survenue des troubles du rythme in vivo. Ces travaux ont permis d'améliorer notre connaissance du rôle des anomalies génétiques impliquant des canaux ioniques et du remodelage ionique dans la physiopathologie des troubles du rythme et pourrait ainsi ouvrir de nouvelles perspectives thérapeutiques dans le traitement anti-remodelage cardiaque et la prévention de la mort subite.Cardiovascular disease is the leading cause of death in the world each year. If no action is taken to improve cardiovascular health and current trends continue, WHO estimates that 25% more healthy life years will be lost to cardiovascular disease globally by 2020. Cardiac hypertrophy is the consequence of an excessive workload of the heart muscle leading to cardiac remodeling process. As the workload increases, the ventricular walls grow thicker, lose elasticity and eventually may fail to pump with as much force as a healthy heart. Furthermore, hypertrophied myocardium is not physiologically normal and may confer a predisposition to potentially fatal arrhythmias. Generally, the causal mechanism is ventricular fibrillation, a cardiac rhythm disorder which is irreversible but the pathophysiological mechanisms are complex and poorly understood. The functional consequences of mutations or ionic remodeling are relatively simple to study in vitro, but their role in the pathophysiology of arrhythmias in vivo is more difficult to grasp. Among the different animal models developed in cardiac arrhythmias research, the mouse is increasingly used because of our ability to mutate, knock-out or over-express genes of interest. The objective of my thesis was to study the role of ion channels in physiology as well as cardiac pathophysiology, particularly in the involvement of the occurrence of cardiac arrhythmias in vivo. This thesis will improve our understanding of the role of genetic abnormalities involving ionic remodeling in the pathogenesis of the heart and may also open new therapeutic perspectives in the treatment of cardiac remodeling as well as sudden cardiac death.
Thèse en cotutelle avec Université de Nantes - Pays de La Loire - France (2005-2010)
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Huber, Adrian Thomas. « Multi-organ non-invasive tissue characterization of fibrosis, adipose tissue, edema and inflammation with magnetic resonance (MR) imaging : applications to myocardium, skeletal muscle and liver interactions Cardiac MR strain : a noninvasive biomarker of fibro-fatty remodeling of the left atrial myocardium Comparison of MR T1 and T2 mapping parameters to characterize myocardial and skeletal muscle involvement in systemic Idiopathic Inflammatory Myopathy (IIM) Non-invasive differentiation of acute viral myocarditis and idiopathic inflammatory myopathy with cardiac involvement using magnetic resonance imaging T1 and T2 mapping CT predicts liver fibrosis : Prospective evaluation of morphology- and attenuationbased quantitative scores in routine portal venous abdominal scans ». Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS135.
Texte intégralRésumé :
Cette thèse réalise une preuve de concept pour quantifier la déformation de l’oreillette gauche (OG) en IRM, ainsi que la relaxométrie IRM dans le myocarde, dans les muscles squelettiques et dans le foie. Grâce à l’interaction entre radiologues et ingénieurs, deux logiciels différents ont été développés, appliqués et validés pour l'analyse de la déformation myocardique multi-chambre et pour la cartographie quantitative du T1 multi-organes. La première publication a montré une forte corrélation de la déformation de l’OG, avec le degré de remplacement fibro-graisseux en histologie. Ce biomarqueur d'imagerie fonctionnelle est prometteur, puisque le remodelage structurel du myocarde est un substrat morphologique connu du dysfonctionnement électro-physiologique et de la fibrillation atriale. La deuxième publication a démontré l'influence de la composition et de la vascularisation de différents tissus sur les paramètres cartographiques T1. ΔT1 (prise de contraste musculaire relative) et EHF (prise de contraste musculaire normalisée par la prise de contraste dans le sang) ont été introduits comme alternatives simples au volume extracellulaire (ECV). Dans la troisième publication, les paramètres de relaxométrie appliqués aux muscles squelettiques ont permis une discrimination entre patients avec myocardite aiguë et patients avec des myosites systémiques. La quatrième publication a introduit le T1 du foie pour quantifier l’insuffisance cardiaque chez des patients avec des cardiomyopathies idiopathiques dilatées, montrant de meilleures performances que les paramètres fonctionnels établis tels que les volumes, la fraction d'éjection ou la déformation myocardiqueThis thesis provides a proof of concept for MR atrial strain, as well as MR relaxometry in the myocardium, in skeletal muscles and in the liver. Thanks to a close interaction between radiologist and software engineers, two different softwares were developed, applied and validated: one for multiorgan T1 mapping in the myocardium, skeletal muscle and liver, another one for cardiac four-chamber strain analysis and volumetry. The first publication showed a strong correlation of LA strain with the degree of fibro-fatty replacement in histology. Such functional imaging biomarker in combination with LA volumetry could help to guide clinical decisions, since myocardial structural remodeling is a known morphologic substrate of LA dysfunction, atrial fibrillation and adverse outcome. In the second publication, MR relaxometry parameters applied to the myocardium and skeletal muscles in IIM patients and healthy volunteers were used as a model to demonstrate influences of different tissue composition and vascularization on T1 mapping parameters. ΔT1 and EHF were introduced as simple alternatives to ECV in highly vascularized tissues such as the myocardium. In the third publication, MR relaxometry parameters applied to the skeletal muscls allowed for an accurate discrimination of AVM and IIM with cardiac involvement. However, when applied to the myocardium, parametric mapping did not separate between the two groups. The fourth publication introduced native T1 of the liver an easily accessible and accurate non-invasive imaging associate of congestive HF in IDCM patients with better performance than established functional parameters such as LV volumes, ejection fraction or strain
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Akar, Joseph Gabriel. « Electrical, structural, and spatiotemporal remodeling in atrial fibrillation / ». 2004. http://wwwlib.umi.com/dissertations/fullcit/3144623.
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Katsouras, Grigorios. « Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling ». Thèse, 2009. http://hdl.handle.net/1866/4122.
Texte intégralRésumé :
Fond : Le substrat de fibrillation auriculaire (FA) vagale et celui secondaire à remodelage par tachycardie auriculaire (RTA) partagent beaucoup des caractéristiques : période réfractaire efficace (PRE) réduite, hétérogénéité accrue de PRE et quelques mécanismes moléculaires communs. Cette étude a comparé les 2 substrats à une abréviation comparable de PRE.
Méthodes : Chez chacun de 6 chiens de groupe de stimulation vagal (SV), les paramètres de stimulation cervicale bilatérale de nerves vagaux ont été ajustés pour produire la même PRE moyenne (calculé à 8 sites des oreillettes gauche et droite) avec 6 chiens de groupe de RTA assorti à sexe et poids. Des paramètres électrophysiologiques, la durée moyenne de la fibrillation auriculaire (DAF) et les fréquences dominantes (FD) locales ont étés calculés.
Résultats : En dépit des PREs assorties (SV: 80±12msec contre RTA: 79±12msec) la DAF était plus longue (*), l’hétérogénéité de conduction était plus élevée (*), la FD était plus rapide (*) et la variabilité de FD plus grande (*) chez les chiens SV. Les zones de maximum FD qui reflètent les zones d’origine de FA étaient à côté de ganglions autonomes chez les chiens SV.
Conclusions : Pour un PRE atriale comparable, la FA secondaire à SV est plus rapide et plus persistante que la FA avec un substrat de RTA. Ces résultats sont consistants avec des modèles de travail suggérant que l'hyperpolarisation SV-induite contribue de façon important à la stabilisation et à l'accélération des rotors qui maintiennent la FA. La similitude de la distribution de FD du groupe vagal avec la distribution des lésions d’ablation après cartographie des électrogrammes atriales fragmentés suggère des nouvelles techniques d’ablation. La distribution des FD entre le SV et le RTA fournit de nouvelles idées au sujet de possible rémodelage neuroreceptorial et indique des différences importantes entre ces substrats de FA superficiellement semblables.Background: Vagal nerve stimulation (VS) and atrial tachycardia remodeled (ATR) atrial fibrillation (AF) substrates share many features: reduced effective refractory period (ERP), increased ERP heterogeneity and some common molecular mechanisms. This study compared VS and ATR substrates at comparable ERP abbreviation. Methods: In each of 6 VS dogs, bilateral cervical VS parameters were adjusted to produce the same mean ERP as a sex and weight matched ATR dog. Electrophysiological parameters, mean duration of AF (DAF) and local dominant frequencies (DF) were determined (before (CTL) and after VS in VS dogs). Results: Despite matched ERPs (VG: 80±12msec vs ATR: 79±12msec) DAF was greater (*), conduction heterogeneity was greater (*), DF was faster (*) and DF variability greater (*) in VS dogs. AF drivers reflected by maximum DF zones were adjacent to autonomic ganglia in VS dogs; there was a tendency (p<0.07) to faster driver zones in the left atrium comparing to the right in ATR dogs. Conclusions: For a comparable atrial ERP, VS AF is faster and more persistent than AF with an ATR substrate. These results are consistent with modeling work suggesting that VS-induced hyperpolarization is an important contributor to AF-maintaining rotor stabilization and acceleration. Similarities in DF distribution in VS dogs with distribution of ablation lesions performed after Complex Fractionated Atrial Electrograms mapping suggests new curative ablation methods. DF distribution differences between VS and ATR provides new ideas about possible neuroreceptorial remodeling and indicates important differences between these superficially similar AF substrates.
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Neo, Melissa. « Atrial electrophysiological and structural changes in obesity and diabetes mellitus ». Thesis, 2017. http://hdl.handle.net/2440/111992.
Texte intégralRésumé :
Atrial fibrillation (AF) is the most commonly presented arrhythmia in the clinical setting, and its prevalence contributes significantly towards morbidity and mortality rates in the general population. Obesity and diabetes mellitus (DM, type I and type II DM) are recognised, well established independent risk factors of AF which can occur and contribute towards the development of AF both individually and in a concomitant fashion. The pathophysiological processes by which a proarrhythmic atrial substrate is produced in obesity and DM have not been fully elucidated. Further characterisation of the atrial substrate in obesity and DM induced AF is required. Chapter one addresses the mechanistic components which may contribute towards establishing AF, and discusses the early and current insights underlying the pathogenesis of AF; This chapter describes the current literature available on the electrophysiological and structural components which may lead to the development of a vulnerable atrial substrate; these include the role of the action potential (AP), the relationship between the AP and the effective refractory period (ERP), and the contribution of inflammation and fibrosis towards AF development. Chapter two investigates the feasibility and result of combined application of simultaneous high density conduction mapping with intracellular membrane potential recording to better understand the genesis and maintenance of arrhythmias in the isolated atria. Described are the ability to observe changes in action potential (AP) morphology at a given recording region, regional differences in AP restitution, lack of correlation between AP duration (APD) and the atrial effective refractory period (ERP), and AP alternans in amplitude, and, duration. Chapter three assesses electrophysiological and structural changes in a rat model of type I DM (T1DM) using streptozotocin (STZ), which preferentially exerts toxicity to the insulin-producing beta cells of the pancreas to elicit the T1DM phenotype. This chapter demonstrates the impact of untreated T1DM on the atrial myocardium. At the structural level, T1DM animals demonstrated atrial cardiomyocyte hypertrophy with increased fibrosis. At the electrophysiological level, there was an abbreviation of the ERP with increased heterogeneity in conduction, as well as prolongation of the AP. Chapter four describes the impact of obesity, type II DM (T2DM) and age on the electrical and structural properties of the atria using the Zucker (fa/fa) rat model. This chapter reports cardiomyocyte hypertrophy, increased fibrosis, prolongation of the APD, increased heterogeneity and slowed conduction, with differences in ERP between the left and right atrium of the DM animals. These results highlight the potential difference between the pathogenesis of T2DM from T1DM on the atrial myocardium in the predisposition towards development of AF. Chapter five summarises the observations made in the T1DM and T2DM studies of chapters three and four respectively; this chapter discusses the similarities and differences shared in the data obtained from the studies, with a brief description of the potential mechanisms involved in DM-induced pathogenesis of AF, Additionally, the potential importance of segregating the diabetic states as having individual and differential influences on the atrial myocardium is highlighted. Future directions and areas of further research conclude this chapter.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2017.
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Jungk, Luisa. « Intrazelluläre strukturelle Remodelingprozesse bei chronischem Vorhofflimmern an humanen atrialen Myokardproben ». Doctoral thesis, 2016. https://ul.qucosa.de/id/qucosa%3A15912.
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Lau, Dennis Hui Sung. « Substrate for atrial fibrillation in cardiomyopathies ». Thesis, 2010. http://hdl.handle.net/2440/65480.
Texte intégralRésumé :
Atrial Fibrillation is the most common heart rhythm disorder. However, our understanding of the underlying patho-physiological mechanisms of AF remains limited. Both hypertension and heart failure are known to play an important role as risk factors for AF. With the increase in the incidence and prevalence of both these conditions and the predicted atrial fibrillation epidemic, their underlying mechanistic associations require careful attention. This thesis focused on the evaluation of atrial remodeling in large animal models of these common substrates. Chapter 2 presents the detailed anatomical, histological and functional characterization of the cardiac changes in the ovine “one-kidney, one-clip” model of hypertension using state of the art cardiac magnetic resonance imaging. Chapter 3 presents the significant atrial electrical, structural and functional remodeling evident with short duration (mean of 7 weeks) of hypertension. Pivotal changes were seen in increased atrial interstitial fibrosis and the resultant conduction abnormalities. This highlighted the importance of early and aggressive therapy of hypertension which may prevent the development of an arrhythmogenic atrial substrate.
Chapter 4 examines the time course of atrial remodeling during the development of hypertension over a period of 15 weeks. Anatomical and functional remodeling started early while structural changes in increased fibrosis occurred later in the remodeling process. The early changes were associated with increased atrial fibrillation inducibility while the late changes were associated with more prolonged induced atrial fibrillation episodes. This understanding of the time course of remodeling provided important insights, whereby a narrow window of opportunity exists for preventing more permanent structural changes that can sustain atrial fibrillation. This work also implicates the need to maintain good blood pressure levels in atrial fibrillation patients. In particular, recent evidence has shown that pre-hypertension is associated with increased incidence of atrial fibrillation. To date, experimental studies on atrial remodeling in heart failure had utilized one single animal model of rapid ventricular tachypacing induced heart failure. This model may not be representative of all types of cardiomyopathy in the heart failure syndrome since different underlying causes of heart failure have been shown to portend different prognostic value. Chapter 5 further evaluates atrial remodeling in heart failure using a recently characterized ovine model of non-reversible doxorubicin-induced non-ischemic cardiomyopathy. The main feature of atrial remodeling lies in the structural changes of atrial interstitial fibrosis with increased conduction heterogeneity which resulted in longer induced atrial fibrillation episodes. These findings suggest a consistent substrate for atrial fibrillation in different heart failure models indicating ‘remodeling of the same sort’.
Chapter 6 presents the atrial effects of omega-3 fatty acids treatment in ovine heart failure. Omega-3 fatty acids prevented atrial enlargement, reduced atrial fibrosis and the related conduction abnormalities resulting in shorter atrial fibrillation episodes. Clinically, omega-3 fatty acids have been shown to provide additional albeit modest improvement in outcomes of heart failure patients above current evidence-based therapies. Therefore, omega-3 fatty acids may potentially provide a relatively affordable and non-toxic option to prevent adverse atrial remodeling and reduce atrial fibrillation burden in this subgroup of patients with heart failure.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
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PANG, HELEN WAI KIU. « Reverse Atrial Electrical Remodeling Induced by Continuous Positive Airway Pressure in Patients with Severe Obstructive Sleep Apnea ». Thesis, 2011. http://hdl.handle.net/1974/6625.
Texte intégralRésumé :
Background: Obstructive sleep apnea (OSA) has been associated with atrial enlargement in response to high arterial and pulmonary pressures and increased sympathetic tone. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA; its impact on atrial electrical remodeling has not been investigated however. Signal-averaged p-wave (SAPW) is a non-invasive quantitative method to determine p-wave duration, an accepted marker for atrial electrical remodeling. The objective was to determine whether CPAP induces reverse atrial electrical remodeling in patients with severe OSA.
Methods: Prospective study in consecutive patients attending the Sleep Clinic at Kingston General Hospital. All patients underwent full polysomnography. OSA-negative and severe OSA were defined as apnea-hypopnea index (AHI) < 5 events/hour and AHI ≥ 30 events/hour, respectively. In severe OSA patients, SAPW was determined pre- and post-intervention with CPAP for 4 - 6 weeks. In OSA-negative controls, SAPW was recorded at baseline and 4 - 6 weeks thereafter without any intervention.
Results: A total of 19 severe OSA patients and 10 controls were included in the analysis. Mean AHI and minimum O2 saturation were 41.4 ± 10.1 events/hour and 80.5 ± 6.5% in severe OSA patients and 2.8 ± 1.2 events/hour and 91.4 ± 2.1% in controls. Baseline BMI was different between severe OSA patients and controls (34.3 ± 5.4 vs 26.6 ± 4.6 kg/m2; p < 0.001). At baseline, severe OSA patients had a greater SAPW duration than controls (131.9 ± 10.4 vs 122.8 ± 10.5 ms; p = 0.02). After CPAP intervention, there was a significant reduction of SAPW duration in severe OSA (131.9 ± 10.4 to 126.2 ± 8.8 ms; p < 0.001). In controls, SAPW duration did not change within 4 - 6 weeks.
Conclusion: CPAP induced reverse atrial electrical remodeling in patients with severe OSA as represented by a significant reduction in SAPW duration.Thesis (Master, Physiology) -- Queen's University, 2011-07-29 12:53:09.134
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Chen, Chien-Lung, et 陳建龍. « Molecular Basis of Remodeling in Atrial Fibrillation : Alterations in Atrial Gene Expression and Matrix Metalloproteinases / Tissue Inhibitors of Metalloproteinases ». Thesis, 2008. http://ndltd.ncl.edu.tw/handle/62229391128308100005.
Texte intégralRésumé :
博士國立交通大學
生物科技系所
96
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. AF appears to be a progressive disease and to be self-sustaining through alterations in atrial tissue properties. The processes leading to the worsening of AF over time were characterized by electrical, contractile and structural changes, referred to as atrial remodeling. However, the underlying mechanisms involved in the remodeling of atria with AF are incompletely defined. Additionally, the knowledge of molecular mechanisms responsible for the atrial remodeling of AF inevitably require further investigation to improve the clinical management of AF and the efficacy of therapy. In this study, a rapid atrial pacing (RAP)-induced AF model was employed to investigate the alteration of the gene expression profile and the expression and activity of matrix metalloproteinases or tissue inhibitors of metalloproteinases in the atria with AF for addressing the remodeling processes at molecular level. This thesis is comprised of two parts. The first one investigates gene expression responses obtained from a low-density cDNA array in the porcine atria with fibrillation. We identified 31 genes involved in transcriptional regulation, signal transduction or structural components, which were either significantly upregulated or downregulated in the atria with AF. The genes for four and a half LIM domains protein-1 (FHL1), transforming growth factor-β (TGF-β)-stimulated clone 22 (TSC-22), and cardiac ankyrin repeat protein (CARP) were significantly upregulated, and chromosome 5 open reading frame gene 13 (P311) was downregulated in the fibrillating atria. FHL1 and CARP play important regulatory roles in cardiac remodeling by transcriptional regulation and myofilament assembly. Induced mRNA expression of both FHL1 and CARP was also observed when cardiac H9c2 cells were treated with an adrenergic agonist. Increasing TSC-22 and marked P311 deficiency could enhance the activity of TGF-β signaling and the upregulated TGF-β1 and -β2 expressions were identified in the fibrillating atria. The results presented in the first part suggest that observed alterations of underlying molecular events were involved in the rapid-pacing induced AF, possibly via activation of the β-adrenergic and TGF-β signaling. The second part focuses on the mechanisms responsible for the atrial extracellular matrix (ECM) remodeling in atrial fibrillation. The major findings presented in this part indicated the localization and alteration in profile of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) expression in the atrial myocardium with AF. The striking increase in gelatinase activity was found in the AF, which might be associated with the activation of TGF-��1 and contribute to ECM remodeling and fibrosis in the atrium. In addition, the increase in TIMP inhibitory activity in the fibrillating atria may provide regulation of proMMP-9 activation and inhibition of the activated MMPs through their inhibitory ability or complexes with proMMP-9. Another important finding was that TIMP-1 mostly colocalized with gelatinase activity over the AF tissues, showing the coexistence of gelatinase activity and TIMP-1; however, TIMP-3 appeared only partial colocalization and to discontinue the gelatinase activity surrounding the cardiomyocytes, revealing that TIMP-1 and TIMP -3 may play a differential role in inhibiting the gelatinase in vivo. The identification of changes in certain species of MMP and TIMP as well as their in vivo interplay in the RAP-induced AF model may improve understanding of the pathophysiology of atrial remodeling and fibrillation.
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Twomey, Darragh Joseph. « The Impact of Weight Fluctuation on Atrial Substrate and the Prevention of Atrial Remodelling With the Use of Anti-Fibrotics ». Thesis, 2016. http://hdl.handle.net/2440/119674.
Texte intégralRésumé :
Atrial fibrillation (AF) is the commonest sustained arrhythmia in humans and is responsible for a significant socioeconomic burden. Affected individuals can suffer significant symptoms and are at risk of potentially life-threatening complications. Obesity is increasingly recognised as risk factor for the development of this arrhythmia. Weight fluctuation is common during attempted weight loss and has detrimental cardiovascular effects in human cohort studies, including patients with AF. However, the pathophysiological mechanisms by which this occurs are unclear. The first aim of this thesis is to characterise the electrophysiological effects of weight fluctuation using an obese ovine model. Previous studies have demonstrated that obesity promotes the development of atrial fibrosis as well as the upregulation of profibrotic factors in atrial tissue. The second major aim of this thesis is to investigate the effect of blockade of these profibrotic receptors on obesity-related atrial remodelling. Chapter 2 describes the use a fluctuating weight model in order to study the electrophysiological changes over time. Weight fluctuation was associated with progressive changes in atrial electrophysiology. This group demonstrated reduction in conduction velocity when compared to a lean control group, particularly following a second cycle of weight gain followed by weight loss. These changes were less severe when compared to an obese group. Additionally, the changes in conduction were more heterogeneous than in animals with persistent obesity. This resulted in an increased propensity to AF when compared with lean controls. Chapter 3 investigates the role of endothelin receptor blockade in the prevention of atrial substrate in obesity. Obesity was again induced in ovine subjects and two groups were compared. One was treated with the endothelin receptor antagonist (ERA) bosentan whilst the other acted as a control group. Animals treated with bosentan had attenuation of obesity-related conduction slowing. This was seen on both endocardial and epicardial surfaces. Importantly, there was no effect on either haemodynamics or refractory periods. AF inducibility was also reduced by ERA treatment. Examination of atrial demonstrated reduced fibrosis and downregulation of pro-fibrotic factors with ERA treatment. Importantly, this effect was independent of the TGF-β pathway. Chapter 4 examines the effect of the TGF-β receptor antagonist tranilast on the obese ovine atrium. A similar model of induced obesity was used to compare tranilast treatment with a control group. Animals receiving tranilast demonstrated attenuation of conduction slowing. Endo and epicardial mapping showed this slowing was heterogeneous across atrial sites, perhaps suggesting a predominantly local mechanism in the development of these electrophysiological changes.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017
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John, Bobby. « Electrical remodelling of the atria and pulmonary veins due to stretch in rheumatic mitral stenosis ». 2008. http://hdl.handle.net/2440/59453.
Texte intégralRésumé :
Atrial fibrillation is the most common sustained arrhythmia; however, its mechanism is not well understood. Several conditions such as valvular disease, heart failure, and hypertension predispose to atrial fibrillation. Identifying the electrophysiological substrate in these clinical conditions would yield insight into the mechanism of atrial fibrillation and aid in developing strategies to prevent or cure it. Rheumatic mitral stenosis is associated with high prevalence of atrial fibrillation. While atrial stretch itself may be adequate to explain the occurrence of atrial fibrillation in this population, it is not known if the disease process would remodel the atria so as to increase its propensity. Chapters 2 and 3 present the results of the studies evaluating the substrate for atrial fibrillation in both the left and right atria in rheumatic mitral stenosis. These studies have demonstrated extensive conduction abnormalities both regional and site specific associated with low voltage area and scar. Despite the prolonged atrial refractoriness, the propensity for atrial fibrillation was increased; lending support to the theory that structural remodelling associated with conduction abnormalities plays a greater role in the substrate predisposing to atrial fibrillation. Chapters 4 and 5 present the results of the studies evaluating the immediate effects of chronic atrial stretch reversal on the atrial electrical remodelling. These studies demonstrated that immediately after percutaneous mitral commissurotomy there was decrease in P wave duration, improvement in site specific conduction delay and conduction velocity associated with increase in the voltage. However, there was no change in atrial refractoriness. Chapter 6 studies the substrate long-term after reduction of stretch. There was further increase in conduction velocity and voltage associated with decrease in atrial refractoriness and conduction delay across the crista terminalis. These observations suggest that strategies aimed at reducing atrial stretch in different disease conditions would potentially decrease the burden or prevent atrial fibrillation. There is mounting evidence of the effect of stretch on the atria; however, the effect of stretch on the triggers of atrial fibrillation has not been evaluated before. Chapter 7 and 8 present the results of the study examining the effect of acute and chronic stretch on human pulmonary veins. Simultaneous pacing of the right ventricle and pulmonary vein induced acute stretch. The effect of chronic stretch was evaluated in patients with mitral stenosis. The atrial refractoriness was abbreviated in acute stretch while it was prolonged in the chronic form. Nevertheless, both resulted in marked pulmonary vein conduction abnormalities that were pronounced with chronic stretch and extra-stimuli. Additionally, structural remodelling was seen with chronic stretch. These abnormalities implicate stretch in the milieu for re-entry and pulmonary vein arrhythmogenesis in conditions predisposed to atrial fibrillation. In summary, this thesis has evaluated the effects of stretch on the substrate and triggers of atrial fibrillation. It provides evidence for the importance of structural changes and the associated abnormalities in conduction in predisposing to atrial fibrillation. These observations may be important in the development of tools to treat, cure and prevent atrial fibrillation.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008
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Eikenbusch, Benjamin. « Strukturelle und funktionale Veränderungen der atrialen Kalzium-Freisetzungseinheit im Herzinsuffizienzmodell durch Junctophilin-2-Knockdown ». Doctoral thesis, 2021. http://hdl.handle.net/21.11130/00-1735-0000-0005-1597-9.
Texte intégral
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Ko, Wen-Chin, et 柯文欽. « Connective Tissue Growth Factor and Cardiovascular Disease－Focusing on the Mechanisms of Structural Remodeling in Atrial Fibrillation and Atherothrombosis ». Thesis, 2011. http://ndltd.ncl.edu.tw/handle/28874554894984081175.
Texte intégralRésumé :
博士臺北醫學大學
臨床醫學研究所
100
Cardiovascular related causes of death are the leading causes of death globally and also in Taiwan. Atrial fibrillation (AF) and atherosclerosis are both chronic disease and ultimately result in structural remodeling of atria and vessels. Accumulation of extracellular matrix, i.e., fibrosis, is a hallmark of cardiovascular structural remodeling. The molecular mechanism of structural remodeling in cardiovascular diseases is complicated and deserved investigation. Connective tissue growth factor (CTGF) is a potent profibrotic cytokine. The role of CTGF in cardiovascular diseases has not been largely studied. The aim of our study is to investigate the role of CTGF in cardiovascular diseases with focus on AF and atherosclerosis. In the first part of our research, human right atrial appendages were obtained from 20 patients who underwent cardiac surgery (10 with sinus rhythm and 10 with AF). The mRNA level, protein level and immunohistochemical staining of CTGF were significantly increased in AF patients. In a porcine AF model, tissue Angiotensin II (Ang II) and CTGF level were significantly upregulated in both atria of AF pigs. In perfused rat hearts, Ang II stimulation increased CTGF expression which could be inhibited by Ang II type I receptor antagonist. In the cell culture system, both atrial fibroblasts and myocytes were responsible for the increased CTGF expression under Ang II treatment. Ang II type I receptor antagonist could inhibit the Ang II-induced CTGF expression. Treating with recombinant CTGF, atrial fibroblasts expressed increased level of collagen I. Furthermore, CTGF level was highly correlated with tissue Ang II content in AF pigs. In the second part of our research, due to difficult to obtain human artery samples, we use a vascular smooth muscle cell (VSMC) line (A10) from the embryonic rat thoracic aorta. Treatment of A10 cells with thrombin caused concentration- and time-dependent increases in CTGF expression. Pretreating A10 cells with SCH79797, a protease-activated receptor 1 (PAR-1) antagonist, significantly inhibited thrombin-induced CTGF expression, while tcY-NH2, a PAR-4 antagonist, had no effect. The PAR-1 agonist SFLLRN-NH2 also induced CTGF expression, while a PAR-4 agonist, GYPGQV-NH2, had no effect. Using mitogen-activated protein kinase (MAPK) inhibitors, we found that thrombin-induced CTGF expression was concentration-dependently attenuated by pretreating cells with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125), a MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor (PD98059), and a p38 MAPK inhibitor (SB203580). Furthermore, thrombin caused time-dependent phosphorylation of JNK, ERK, and p38 MAPK. Thrombin-induced CTGF expression was also markedly attenuated by an activator protein-1 (AP-1) inhibitor (curcumin). Thrombin also increased AP-1-luciferase activity in A10 cells, as determined using the AP-1-luciferase reporter plasmid. This effect was inhibited by the 3 MAPK inhibitors. From the above studies, our conclusions are AF patients and animals exhibited a significantly increased expression of CTGF. Ang II stimulation upregulated CTGF expression in both atrial fibroblasts and myocytes. Ang II-induced CTGF expression might be involved in atrial substrate remodeling. As regarding the signaling pathways, thrombin acts on PAR-1 to activate the MAPK signalling pathways, which in turn initiate AP-1 activation and ultimately induce CTGF expression in VSMCs.
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Tsai, Chia-Ti, et 蔡佳醍. « Renin-angiotensin System and Cardiovascular Diseases- Focusing on Mechanisms of Structural and Electrical Remodelings in Atrial Fibrillation and Pharmacological Approach ». Thesis, 2006. http://ndltd.ncl.edu.tw/handle/89003535747642363081.
Texte intégralRésumé :
博士國立臺灣大學
臨床醫學研究所
95
The aim of the present doctoral thesis is to investigate the detailed molecular mechanism by which angiotensin II (AngII) is involved in the pathegenesis of atrial fibrillation (AF). Recently, it has been shown that local atrial rennin-angiotensin system (RAS) is activated with increased tissue AngII level during AF. AngII activates the downstream mitogen-activated protein kinase pathway (MAPK) signaling pathways, resulting in atrial structural remodeling. AngII is also involved in atrial electrical remodeling, and it has also been shown that blockage of endogenous AngII prevents rapid-pacing induced shortening of atrial effective refractory period (AERP). In our previous study, we first demonstrated the genetic association between RAS genetic variations and the development of AF. In the present study, we further increased the sample size of our genetic association study to more than 2 fold, and have found more significant results. We also showed that RAS genetic variations and gene-gene interactions among RAS genes were also associated with the development of various cardiovascular diseases, including hypertension and coronary artery disease, in addition to AF. Because the molecular mechanisms by which AngII is involved in the pathogenesis of hypertension or coronary artery disease are well known, the following study subjects were focusing on the molecular mechanisms by which AngII is involved in the pathogenesis of AF, with emphases on the structural and electrical remodelings. Regarding AngII and structural remodeling, we used a rapid-pacing porcine AF model. AF was induced by atrial pacing at 600/min in adult pigs. Significant structural and inflammatory changes were noted in the AF pigs. Although atrial tissue angiotensin II level was elevated in the AF pigs, the MAPK pathways were not activated. However, signal transducers and activators of transcription-1 (STAT1) and STAT3 were activated with increased STAT3 nuclear translocation in the AF pigs. Membrane translocation and activation of Rac1 was also noted. Furthermore, in cultured atrial myocytes and fibroblasts, angiotensin II activated STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant negative Rac1, losartan and simvastatin. We found that the STATs pathways, but not the MAPKs, were activated by angiotensin II and might contribute to structural and inflammatory changes in AF. The activation of STAT3 was dependent on Rac1 and was blocked by losartan and simvastatin. Regarding AngII and electrical remodeling, we investigated whether AngII modulates L-type calcium channel (LCC) current through transcriptional regulation, using a murine atrial HL-1 cells model. AngII increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient. AngII significantly increased promoter activity of LCC α1C subunit gene in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE)(-1853 to –1845) was an important cis-element in Ang II-induced LCC α1C subunit gene expression. AngII induced serine 133 phosphorylation of CRE binding protein (CREB), binding of CREB to CRE, and increase of LCC α1C subunit gene promoter activity through a protein kinase C (PKC)/NADPH oxidase/reactive oxygen species (ROS) dependent pathway, which was blocked by the AngII type 1 receptor blocker losartan and the antioxidant simvastatin. In summary, Ang II increases LCC α1C subunit expression, LCC current density, and amplitude of the calcium transient in atrial myocytes. AngII-induced LCC α1C subunit expression was PKC-, ROS-, and CREB-dependent, and was blocked by losartan and simvastatin. Why local atrial tissue angiotensin II (AngII) production is up-regulated during atrial fibrillation (AF)? It is possible that atrial myocytes express all the components of renin-angiotensin system (RAS), and AF or rapid depolarization per se could increase AngII production by up-regulating the expressions of components of RAS. Again, we used porcine and cellular models to prove this hypothesis. In the cell model, AF was simulated in the cultured murine atrial HL-1 cells by rapid field pacing (RES)(1.0 V/cm, 10 Hz). AngII concentration was measured by ELISA, and expressions of angiotensin converting enzyme (ACE), chymase, angiotensinogen (AGT), renin, AngII type 1 receptor (AT1R) and type 2 receptor (AT2R) were measured by immnunoblotting. In the porcine model, atrial tissue AngII, ACE, chymase and AGT were up-regulated in the AF pigs, but renin was down-regulated. AT1R was up-regulated in the left atria, but down-regulated in the right atria. AT2R was up-regulated in both left atria and right atria. In the cellular model, RES induced a similar pattern of expressions of RAS components, and increased AngII concentrations in the mediums and cellular extracts. RES induced AngII production was attenuated by ACEI Enalapril and chymase inhibitor chymostatin. These results suggest that combination of ACEI and chymase inhibitor prevents rapid-depolarization induced AngII production and atrial structural remodeling. Regarding clinical studies, to evaluate whether echocardiography could be used to evaluate atrial volume and function that may be related to atrial structural remodeling, we first designed a study to evaluate the left atrial (LA) volume, and LA systolic (contractile) and diastolic (expansion) functions in different stages of hypertension with or without atrial fibrillation, as well as the effects of good blood pressure control. This was a prospective observational study. Individuals including 22 normotensive controls, 23 patients with mild hypertension (MH), 20 with severe hypertension (SH), and 17 with both hypertension and paroxysmal atrial fibrillation (AH) were recruited for paired echocardiography studies at baseline and 6 months after medical control of hypertension. We found that with increasing severity of hypertension, LV diastolic function deteriorated progressively from controls, MH, SH, to AH patients. LA expansion index was reduced in parallel. LA expansion index was correlated positively with LV E’/A’ ratio and inversely with LV E/E’ ratio. Significant improvement of LV diastolic function and LA expansion index preceded the reduction of LA volume after 6 months of effective blood pressure control. In summary, with progressive LV diastolic dysfunction in different stages of hypertension, there was a corresponding deterioration in LA expansion or diastolic function, which preceded changes in LA volume and LA contractile function. Recently there is increasing evidence that AF is an inflammatory disease. It has also been shown that statin is a potent anti-inflammatory agent. Furthermore, in the above studies, we have showed that statin blocked AngII signaling pathways, which play important roles in atrial structural and electrical remodeling. Therefore, we hypothesized that statin therapy may provide an effective treatment strategy for AF. We conducted a prospective randomzed clinical study to test the efficacy of atorvastatin in the treatment of paroxysmal AF (PAF). We chose patients who have received implantation of a pacemaker. By pacemaker interrogation, we could accurately detect the first attack of AF to see the effect of atorvastatin to prevent AF attack. Fifty-two patients (23 males, 70±13 years old) were randomized to the statin group and 54 (25 males, 72±13 years old) to the control group. Around 70 % of the patients had SSS and the remaining AVB. Around 75 % of the patients had underwent implantation of a dual chamber pacemaker (DDD[R]), and the remaining single chamber PM (AAI[R]). Three patients did not complete the follow-up and the other patients completed the followed-up for one year. Significant atrial high rate episode (AHE)(rate>180/min and duration≧10 min) occurred in 3 of 50 patients (6.0%) in the statin group, and 10 of 53 patients (18.9%)(OR=0.27; 95% confidence interval [CI] 0.05-0.96, p=0.03) in the control group. Patients in the non-statin group were more likely to develop significant AHE that those in the statin group (log-rank p=0.028). The present study clearly and accurately demonstrated the efficacy of atorvastatin to prevent the occurrence of AF in patients with bradycardia. The possible molecular mechanisms warrant further studies. In conclusions, the present doctoral thesis combined genetic association studies, molecular studies and clinical studies to demonstrate how AngII is involved in the pathogeneses of atrial structural and electrical remodeling, which are important substrates of AF. We first showed the association between RAS genetic variants and the development of AF. Second, we further investigated the possible molecular mechanisms by which AngII is involved in the pathogeneses of atrial structural and electrical remodelings. Third, we found that echocardiography was a useful tool to non-invasively evaluate atrial volume and function, which could serve as a clinical surrogate to represent atrial structural remodeling. Finally, we performed a prospective and randomized clinical trial showing a decrease of AF by statin, which has been shown to block AngII signaling pathways in the former basic molecular studies.
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Vahdatihassani, Faezeh. « Regulation of the inositol 1,4,5-trisphosphate receptor 1 (IP3R1) by microRNA-26a in atrial fibrillation ». Thesis, 2020. http://hdl.handle.net/1866/24707.
Texte intégralRésumé :
Contexte: La physiopathologie de la fibrillation auriculaire (FA) a été caractérisée par des changements de concentration cellulaire de Ca2+ et des processus connexes menant à l'apparition et au maintien de la maladie. Les récepteurs de trisphosphate d'inositol (IP3R) sont des canaux calciques ligand-dépendants pour lesquels la surexpression dans la FA a été liée à un remodelage cardiaque. Les microARN (miR, miARN), petits ARN non codants, sont d'une longueur d'environ 22 nucléotides et régulent l'expression des gènes par déstabilisation de l'ARN ou inhibition de sa traduction. De plus en plus de preuves ont été apportées sur le rôle des miARN dans la physiopathologie des troubles cardiaques, y compris le remodelage défavorable induit par la FA.
Objectif: Notre laboratoire a montré que le niveau nucléaire IP3R1 est régulé à la hausse dans le modèle canin de FA, ce qui produit une augmentation de la charge nucléaire en calcium. Cette étude vise donc à étudier le rôle des miARN dans la régulation d'IP3R1 qui initie et/ou perpétue la FA dans les cardiomyocytes auriculaires du modèle de FA chez le chien.
Méthodes: Nous avons utilisé un modèle canin de AF établi par méta-cardiographie auriculaire pendant 600 bpm × une semaine; des cœurs perfusés par Langendorff pour isoler les cardiomyocytes auriculaires pour des expériences moléculaires; le criblage des miRs qui ciblent le gène ITPR1, codant IP3R1, en utilisant des bases de données en ligne; RT-qPCR pour mesurer l'expression de l'ARNm de ITPR1 et confirmer le niveau d'expression des miARN criblés; l'analyse Western Blot pour évaluer le niveau de protéine d’IP3R1; le test de la double luciférase reporter, la surexpression et l'abattement des miARN en culture primaire de cardiomyocytes isolées ou de lignées cellulaires appropriées; et l'imagerie par fluorescence calcique Fluo-4 AM pour évaluer le rôle potentiel des miARN sur la manipulation du Ca2+. Pour les expériences de manipulation des miARN, les cellules ont été transfectées avec 1) un miARN non codant (miR-NC, groupe témoin), 2) un miARN mimétique et 3) un inhibiteur du miARN (AMO). La signification statistique est calculée avec le test t de Student ou l'analyse unidirectionnelle de variance (ANOVA) suivie par le test de Tukey à comparaisons multiples en utilisant le logiciel GraphPad Prism version 6.00.
Résultats: Nos données indiquent une augmentation du niveau de la protéine IP3R1 sans changement apparent de l'expression du gène ITPR1 dans les cardiomyocytes de l'oreillette gauche par rapport à notre modèle canin de FA. Sur la base de l'analyse informatique, il a été prédit que miR-26a ciblerait l'ARNm de l'ITPR1. La FA a considérablement réduit la régulation du miR-26a dans les cardiomyocytes de l'oreillette gauche. Le dosage de la double luciférase reporté dans les cellules H9C2 a montré que le miR-26a agissait directement sur la région non traduite 3′ (3′UTR) de l'ARNm ITPR1. De plus, la surexpression de miR-26a a réduit le niveau de la protéine IP3R1 et a diminué le taux diastolique [Ca2+] dans le noyau et le cytosol des cardiomyocytes de chien, des transistors de Ca2+ stimulés électriquement; tandis que le knockdown de miR-26a a inversé ces effets. L'expression de l'ARNm de l'ITPR1 est restée inchangée dans les cardiomyocytes de chien isolées après la transfection avec l'imitateur et l'inhibiteur de l'ARNm.
Conclusion: La régulation à la hausse d'IP3R1 dans la FA est due à l'inhibition de la traduction par le miR-26a, qui est régulé à la baisse dans les cardiomyocytes auriculaires du modèle canin de FA. Ce changement est associé à une altération de la manipulation du Ca2+, qui se traduit par une augmentation des taux de Ca2+ diastolique nucléaire. Nos résultats suggèrent que la régulation à la baisse de miR-26a augmente l'expression de l’IP3R1, contribuant au remodelage pro-arythmique dans la FA.Background: The pathophysiology of atrial fibrillation (AF) has been characterized by changes in the cellular concentration of Ca2+ and related processes leading to the initiation and maintenance of the condition. Inositol trisphosphate-receptors (IP3Rs) are ligand-gated calcium channels for which overexpression in AF has been linked to cardiac remodeling. microRNA (miR, miRNA)s, small non-coding RNAs, are around 22 nucleotides in length and regulate gene expression by mRNA destabilization or inhibition of its translation. A growing body of evidence has emerged about miRNA's role in the pathophysiology of cardiac disorders, including AF-induced adverse remodeling. Objective: Our laboratory has shown that nuclear IP3R1 level is upregulated in the dog AF model, producing increased nuclear calcium loading. Hence, this study aims to investigate the role of miRNAs in the regulation of IP3R1 initiating and/or perpetuating AF in atrial cardiomyocytes of the dog AF model. Methods: We used AF dog model established by atrial-tachypacing for 600 bpm × one week; Langendorff-perfused hearts to isolate atrial cardiomyocytes for molecular experiments; screening miRs that target ITPR1 gene, encoding IP3R1, using online databases; RT-qPCR to measure ITPR1 mRNA expression and confirm the expression level of the screened miRNAs; western blot analysis to evaluate the protein level of IP3R1; dual-luciferase reporter assay, overexpression and knockdown of miRNAs in primary culture of isolated cardiomyocytes or appropriate cell lines; and Fluo-4 AM calcium fluorescence imaging to assess the potential role of the miRNA on Ca2+ handling. For miRNA manipulation experiments, cells were transfected with 1) non-coding miRNA (miR-NC, control group), 2) miRNA mimic, and 3) inhibitor of the miRNA (AMO). Statistical significance is calculated with Student's t-test or one-way analysis of variance (ANOVA) followed by Tukey's multiple comparisons test using GraphPad Prism software version 6.00. Results: Our data indicated a rise in IP3R1 protein level with no apparent change in ITPR1 gene expression in left atrial cardiomyocytes from our dog AF model. Based on the computational analysis, miR-26a was predicted to target the ITPR1 mRNA. AF significantly downregulated miR-26a in left atrial cardiomyocytes. The dual-luciferase reporter assay in H9C2 cells showed that miR-26a directly acted on the 3′ untranslated region (3′UTR) of ITPR1 mRNA. In addition, miR-26a overexpression reduced the IP3R1 protein level and decreased the diastolic [Ca2+] in both nucleus and cytosol of the electrically-stimulated Ca2+ -transients, dog cardiomyocytes, while miR-26a knockdown reversed these effects. ITPR1 mRNA expression remained unaltered in isolated dog cardiomyocytes after transfection with the miRNA mimic and inhibitor. Conclusion: IP3R1 upregulation in AF is due to translation inhibition by miR-26a, which is downregulated in the atrial cardiomyocytes of the dog AF model. This change is associated with altered Ca2+ handling, reflected as enhanced nuclear diastolic Ca2+ levels. Our results suggest that miR-26a downregulation enhances the IP3R1 expression, contributing to pro-arrhythmic remodeling in AF.