Dissertations / Theses on the topic 'Atriale fibrosis'

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.<br>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.

La fibrillation auriculaire est le plus souvent associée à une cardiomyopathie atriale composée de fibrose et d’infiltrats fibro-adipeux. L’identification de cette myopathie atrial en clinique est difficile, l’IRM qui permet l’imagerie tissulaire pourrait être un précieux outil diagnostic de la cardiomyopathie atriale. Méthodes: Etude de la déformation de la paroi libre de l’oreillette gauche (OG) par technique de « tracking IRM » (PLA) réalisée chez 13 patients, 24 heures avant une intervention de chirurgie valvulaire mitrale. 13 patients contrôles ont été inclus. Au cours de l’intervention, un échantillon de paroi libre de l’OG a été recueilli fixé dans le para formaldéhyde puis étudié à l’aide de technique d’histologie et par ex vitro par imagerie IRM. Résultats: La première étude a porté sur la corrélation entre les PLA et l’histologie auriculaire. Un PLA bas a été retrouvé chez les patients porteur d’un valvulopathie mitrale avec une OG remodelée par rapport à la population contrôle (P&lt;0.001). Une corrélation significative a été observée entre la valeur du PLA et le dégrée d’infiltration fibro-adipeux du myocarde auriculaire (r=0.75, P=0.017). La deuxième étude a étudié la capacité de l’imagerie IRM d’analyser les différentes composantes histologiques du myocarde auriculaire. Nous avons établi les différentes séquences d’analyse d’image T2, Dixon qui permettent d’identifié: la fibrose, le myocarde et le tissu adipeux Conclusion : La déformation du myocarde auriculaire est liée au remodelage tissulaire et est un bon biomarqueur de la myopathie atriale. L’imagerie IRM est capable ex vivo d’identifier les différentes composantes histologiques du myocarde auriculaire<br>Introduction: Atrial fibrillation is associated with an atrial cardiomyopathy composed mainly of fibrosis and adipose tissue accumulation. However, its detection is difficult in clinical practice. Notably, there is controversy on the ability of MRI to quantify these components as well as the clinical significance of this parameter. Methods: LA strain (PLAS) was evaluated with MRI feature tracking in 13 patients 24 hours before mitral valve surgery and 13 healthy controls. Histologic correlation biopsies was available in 10 patients. Atrial samples were collected from patients who underwent cardiac surgery. Samples were fixed in formaldehyde and analyzed using 3D MRI acquisitions including T1 mapping and DIXON imaging. Samples were histologically analyzed in the same orientation used for MRI study. Results: We first studied the correlation between PLAS and atrial remodeling. PLAS was lower in patients with mitral regurgitation than in healthy subjects (P˂0.001). A strong association was found between PLAS and the degree of fibrofatty replacement evaluated by histologic analysis (r=-0.75, P=0.017). In a second study, we studied the ability of MRI to discriminate the various atrial components. High correlation was observed between T1 Mapping and histology for total r=0.93, interstitial r=0.93, and fatty fibrosis r=0.96. High correlation between DIXON and histology were found in fat r=0.98. Conclusion: PLAS correlates with the degree of fibrofatty infiltration which could be used as an imaging biomarker for the atrial cardiomyopathy. High field ex vivo MRI is able to identify the various components of the atrial myocardium; however, in vivo application remains a challenge

Introduction: Cardiac fibrosis is a pathological response that causes abnormalities in cardiac conduction and mechanical function, thereby contributing to the pathophysiology of a variety of cardiac conditions, including hypertrophy, failure, and arrhythmias. Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a major cause of population morbidity and mortality. Recent studies have demonstrated that structural remodeling, involving prominent fibrotic changes, is a fundamental determinant of the perpetuation of AF, and contributes synergistically with electrical remodeling to the AF substrate. Atrial fibrosis is a hallmark feature of arrhythmogenic structural remodeling in clinical AF. Increased amounts of fibrous tissue occur not only in AF patients with identifiable cardiac diseases, but also in those with lone AF.There is a positive correlation between the amount of fibrosis and the persistence of AF,7 suggesting that AF may itself cause structural remodeling that in turn promotes AF. Evidence supporting this idea comes from animal studies showing that even when the ventricular rate is well-controlled, rapid atrial activation causes atrial fibrosis,9 and from work indicating that rapidly-activated atrial-derived cardiomyocytes secrete substances that enhance collagen synthesis by atrial fibroblasts. Methods We studied 60 male adult inbred Fisher rats. We divided the animals in 3 groups of 20 rats each. The first group received vagal stimulation and induce atrial fibrillation protocol (AF + VNS) and follow for 60 days, after 24 h 10 rats were treated with angiotensin II drugs for 60 days (AF + VNS + Ang II). The second group received vagal stimulation (VNS) and follow for 60 days, after after 24 h 10 rats were treated with angiotensin II drugs for 60 days (VNS + Ang II). The third group received induce atrial fibrillation protocol (AF) and follow for 60 days, after 24 h 10 rats were treated with angiotensin II drugs for 60 days (AF + Ang II). Results α1(I) and α1(III) procollagen mRNA levels increased statistically significant in the groups with atrial fibrillation associated or not with VNS in contrast with the group in sinus rhythm. The treatment with Angiotensin II receptor antagonist decrease proportionally in all groups the expression of mRNA levels for ventricular and atrial α1(I) and α1(III) procollagen. The VNS increase the expression of mRNA levels for ventricular and atrial α1(I) and α1(III) procollagen statistically significant between the two group in atrial fibrillation but not statistically significant when the group were treated with Angiotensin II receptor antagonist. The level of right ventricle was almost two time compare with both atria analysis or left ventricle analysis, the VNS increase the level of of mRNA levels for ventricular and atrial α1 (I) and α1(III) procollagen in the right ventricle also in the sinus rhythm group (p=0.5). Conclusion The study demonstrates that long-term VNS in the rats with permanent atria fibrillation induce an increase in cardiac procollagen mRNAs, cardiac fibrosis histologically evident with the presence of inflammatory cells and myocyte necrosis in both groups with atrial fibrillation with statistically significant of the increases in case of VNS; the highest increases of the cardiac procollagen mRNAs was observed in the right ventricle more that in the both atria, this increase was prevented from angiotensine II antagonist receptor therapy. We showed that VNS increased the inducibility of AF. We observed moreover the VNS associates with atrial fibrillation decrease significant the rate ventricular response.

L'ANP est une hormone cardiaque libérée lors de l'insuffisance cardiaque. Les fibroblastes cardiaques, responsables de la synthèse des composants de la matrice extracellulaire (MEC), acquièrent dans les conditions pathologiques la capacité de se différencier en myofibroblastes, conduisant ainsi à une fibrose cardiaque. Les mécanismes de régulation impliquant l'ANP et ses récepteurs (NPR) restent peu connus et font l'objet de ce travail. Les fibroblastes ventriculaires ont été isolés à partir de coeurs de rats Wistar et mis en culture afin d'induire leur différenciation. Les cultures ont ensuite été soumises à différents traitements impliqués dans la voie ANP/NPR. L'ANP diminue le taux de prolifération, la migration cellulaire, et la sécrétion de collagène des myofibroblastes. Cet effet est mimé par le 8-Br-GMPc. L'analyse protéomique et génomique a permis de confirmer la présence des récepteurs natriurétiques A et B dans nos cellules. Par ailleurs, l'expression de dix isoformes de phosphodiestérases dans les myofibroblastes a été révélée par un criblage génomique. L'inhibition non sélective de ces phosphodiestérases provoque une diminution de la prolifération et de la sécrétion de collagène. Enfin, les concentrations intracellulaires de GMPc et d'AMPc ont été trouvées augmentées en présence de l'ANP. En parallèle, la caractérisation des courants ioniques présents sur les myofibroblastes a montré une absence des courants sodique rapide et potassique ATP-dépendant. Cette étude montre le rôle de la voie ANP/NPR/GMPc dans la modulation des propriétés fibroblastiques et illustre la complexité des processus de différenciation cellulaire au cours de la fibrogenèse cardiaque<br>ANP is a cardiac hormone released during heart failure and acts as a regulator of the extracellular matrix (ECM). Cardiac fibroblasts are responsible for the synthesis of ECM components and acquire under pathological conditions the capacity to differentiate into myofibroblasts, leading to cardiac fibrosis. Regulatory mechanisms involving ANP and its receptors (NPR) are poorly known and make the subject of our work. Ventricular fibroblasts were isolated from Wistar rat hearts and cultured to induce differentiation. The cultures were then subjected to various treatments involved in the ANP/NPR pathway. ANP decreases the proliferation rate, cell migration and collagen secretion. This effect was mimicked by 8-Br-cGMP. In addition, genomic and proteomic analysis confirmed the presence of the natriuretic receptor A and B in our cells. Furthermore, the expression of ten phosphodiesterases isoforms in the myofibroblasts was revealed by genomic screening. The non-selective inhibition of these phosphodiesterases causes a decrease in the proliferation and secretion of collagen. Finally, the intracellular concentrations of cAMP and cGMP were increased in the presence of ANP. In parallel, the characterization of ionic currents present in myofibroblasts revealed the absence of rapid sodium and potassium ATP-dependent currents. This study shows the role of the ANP/NPR/cGMP pathway in modulating fibroblast properties and exposes the complexity of the cell differentiation process during cardiac fibrogenesis

La tesi descrive il T1 mapping, un metodo diagnostico non invasivo emergente per l’identificazione e la quantificazione della fibrosi atriale. Nel primo capitolo ci si è soffermati sulle caratteristiche del tessuto fibrotico e sulle cause che generano tale patologia tra cui la fibrillazione atriale. Nel secondo capitolo vengono descritte le tecniche non invasive comunemente più utilizzate per la valutazione della fibrosi tra cui: sistemi di mappaggio elettronanatomico e risonanza magnetica cardiaca con l’uso di mezzo di contrasto. Nel terzo capitolo sono approfondite tutte le sequenze necessarie per la costruzione di mappe di tempi T1 indagando anche sui fattori a cui la tecnica è più sensibile. Infine è stato dedicato ampio spazio a ricerche mediche sulla correlazione tra i tempi T1 delle camere cardiache, i potenziali elettroanatomici delle stesse e la probabilità di sviluppare fibrillazioni atriali recidive in alcuni pazienti sottoposti ad ablazione transcatetere.

Questo lavoro di tesi si è svolto in collaborazione con le Unità Operative di Cardiologia e di Radiologia dell’ospedale “M. Bufalini” di Cesena e della St. Jude Medical, Inc., con l’obiettivo di sviluppare e implementare un metodo per l’identificazione e la valutazione della fibrosi atriale mediante risonanza magnetica in pazienti con fibrillazione atriale, candidati a procedura di ablazione. I pazienti sono stati sottoposti all’esame di risonanza magnetica (RM) angio per la valutazione della morfologia atriale e alla DE-MRI per l’identificazione e la visualizzazione delle zone di alto enhancement sulla struttura 3D dell’atrio sinistro, ossia le zone di alta intensità corrispondenti alla fibrosi. La struttura anatomica è utile all’elettrofisiologo per conoscere la morfologia dell’atrio e delle vene polmonari, permettendo quindi di minimizzare l’uso della fluoroscopia durante la procedura di ablazione. La conoscenza dei siti e della quantificazione della fibrosi è vantaggiosa per il medico per la pianificazione preoperatoria, in quanto nei pazienti con molta fibrosi non è sufficiente l’isolamento delle vene polmonari, ma si ottengono risultati migliori effettuando un’ablazione estensiva della parete atriale. Inoltre gli studi in letteratura hanno dimostrato che i pazienti con un’estensione di fibrosi superiore al 35% della superficie atriale, hanno una probabilità superiore al 50% di soffrire nuovamente di fibrillazione atriale dopo la procedura di ablazione; lo studio della fibrosi atriale vuole quindi essere un metodo per predire se l’ablazione avrà successo, oppure se è preferibile seguire indicazioni terapeutiche diverse. Il primo passo di questo lavoro è stata la registrazione delle immagini angio-RM e DE-MR mediante il software VolView. Successivamente si è implementato un programma in Matlab per segmentare in modo automatico l’atrio sinistro e si è visualizzata la struttura tridimensionale con la mappa cromatica della fibrosi utilizzando il software ParaView. Infine per validare questo lavoro si è effettuato un confronto qualitativo dei risultati ottenuti con il mappaggio elettro-anatomico acquisito mediante il sistema EnSite Velocity della St. Jude Medical, Inc. durante la procedura di ablazione transcatetere. Per eseguire questo confronto è stato necessario interfacciare il nostro lavoro con il sistema EnSite Velocity, con lo scopo di riuscire a visualizzare le mappe elettro-anatomiche sul nostro sistema e di importare la nostra struttura anatomica nel loro.

La Fibrillazione Atriale (FA) è una delle aritmie più frequentemente riscontrate nella pratica clinica, ma i meccanismi che la generano e che la sostengono non sono ancora oggi ben chiari. L’obiettivo di questo lavoro di tesi è indagare il substrato aritmogeno della FA con particolare attenzione al legame tra rimodellamento elettrico e strutturale. La tecnica di riferimento per la valutazione della fibrosi è la risonanza magnetica con iniezione di mezzo di contrasto e acquisizione ritardata. Tipicamente, però, la presenza di fibrosi viene valutata durante la procedura di ablazione transcatetere mediante l’analisi dei potenziali elettrici rilevati, considerando le zone a basso potenziale indicative della presenza di alterazioni strutturali. In questo lavoro sono stati elaborati dati di Risonanza Magnetica (RM), in particolare sequenze Angio-RM e DE-RM. Dalle sequenze Angio-RM è stato ricostruito un modello 3D paziente-specifico dell’atrio, mentre dalle sequenze DE-RM sono state ricavate informazioni relative alla presenza di tessuto atriale fibrotico. Al modello 3D è stata poi sovrapposta l’informazione sull’intensità di grigio del dato DE-RM per poter visualizzare la localizzazione delle zone di fibrosi sulla superficie 3D dell’atrio.
 Sono stati anche esportati dal sistema di mappaggio elettroanatomico EnSite NavX (St. Jude Medical) i dati relativi alla geometria dell’atrio e ai potenziali registrati durante lo svolgimento della procedura di ablazione. Da questi dati è stato possibile ricostruire in ambiente Matlab le mappe di voltaggio raffiguranti i potenziali registrati durante la procedura. Per poter studiare e valutare il legame esistente tra rimodellamento elettrico e strutturale, sono state confrontate le mappe di voltaggio e le superfici raffiguranti fibrosi.
 Questo lavoro di tesi è stato svolto in collaborazione con l’U.O. di Cardiologia dell’Ospedale Bufalini di Cesena e la St. Jude Medical.

In questo studio si è sviluppato un nuovo algoritmo per la segmentazione dell'endocardio atriale sinistro, per pazienti affetti da fibrillazione atriale. A differenza delle convenzionali tecniche di segmentazione, si è fatto uso di una rete neurale convoluzionale chiamata U-Net, che è stata appositamente addestrata in modo supervisionato e testata, con dati MRI-GE e relativa etichetta di segmentazione binaria, dei volumi appartenenti a 154 pazienti diversi. Per l'addestramento si è fatto uso dei volumi di 123 pazienti (80%) e 31 pazienti sono dedicati al test (20%). Le CNN richiedono molto tempo per l'addestramento (ore) mentre hanno un funzionamento feed-foreward, con velocità di calcolo algebrico nella fase di test. I dati grezzi in uscita dalla rete, sono stati post-elaborati al fine di ottenere una purificazione dalle formazioni di volume spurio, ossia non connessi con il volume endocardico atriale sinistro (LAE). In questo studio si disponeva anche della segmentazione semantica binaria manuale delle immagini di test, le quali sono state considerate il gold standard di riferimento. Si è visualizzata la registrazione tra il volume binario di riferimento ed il volume in uscita della rete purificato per un confronto qualitativo e per l'applicazione di metriche per eseguire una analisi quantitativa, come il coefficiente di Dice e la distanza di Hausdorff. Queste misure vengono estratte e se ne produce una tabella. Sulla base di questi risultati si è potuto eseguire un'analisi statistica per esaminare il funzionamento globale della rete sulla base di variabili statistiche come la media e deviazione standard, pesati sulla base della dimensione del volume di ogni paziente e calcolati sull'errore inteso come differenza tra i due volumi. In termini globali la rete ha generalizzato bene per tutti i pazienti. Con una media di 12,2 cm^3 ed una deviazione standard 11,7 cm^3 la rete ha dimostrato di avere una tendenza a sovrastimare il d

Thesis (Ph. D.)--Ohio State University, 2004.<br>Document formatted into pages. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 18.

La scelta del trattamento migliore per un soggetto affetto da fibrillazione atriale, risulta dipendere da un gran numero di variabili legate al quadro clinico del paziente. L’ablazione transcatetere delle vene polmonari è, ad oggi, una delle strategie di maggior successo per il ripristino e il mantenimento del ritmo sinusale. Tuttavia, l’esito della procedura è difficile da prevedere sul singolo paziente e in molti casi per ottenere il ripristino del ritmo sinusale e il controllo dei sintomi risultano necessarie ulteriori ablazioni. Recenti studi hanno correlato l’informazione sull’estensione della fibrosi atriale con l’outcome della procedura di ablazione. L’integrazione di questa nozione nel quadro clinico del paziente, permette di pianificare al meglio la procedura di ablazione o, se ritenuto necessario, di optare per strategie differenti che prospettano risultati migliori. La quantificazione della fibrosi avviene a partire da immagini lge-mri del cuore del paziente. Ad oggi non esiste un gold standard per effettuare questa valutazione, e diversi gruppi di ricerca hanno sviluppato metodi differenti per quantificare la fibrosi in atrio sinistro. In questo lavoro di tesi si è valutato come l’applicazione di diversi metodi di segmentazione possa influenzare il risultato di quantificazione. Si sono implementati cinque algoritmi di segmentazione differenti per la quantificazione della fibrosi atriale:metodo basato sull’istogramma, metodo Malcolme-Lawes, metodo Image Intensity Ratio, metodo Chan-Vese e Graph-Cut. Ognuno di questi algoritmi è stato applicato su immagini lge-mri acquisite prima della procedura di ablazione per identificare le regioni di fibrosi. I risultati dimostrano come la scelta di un particolare algoritmo possa influire sulla classificazione del paziente, e, di conseguenza, sulle opzioni terapeutiche consigliate. In generale, sembrerebbe che il metodo basato sull’istogramma, il Chan-Vese e il Graph-Cut forniscano i risultati più attendibili.

[ES] La fibrilación auricular es la arritmia cardíaca más común. Durante la fibrilación auricular, el sustrato auricular sufre una serie de cambios o remodelados a nivel eléctrico y estructural. La remodelación eléctrica se caracteriza por la alteración de una serie de canales iónicos, lo que cambia la morfología del potential de transmembrana conocido como potencial de acción. La remodelación estructural es un proceso complejo que involucra la interacción de varios procesos de señalización, interacción celular y cambios en la matriz extracelular. Durante la remodelación estructural, los fibroblastos que abundan en el tejido cardíaco, comienzan a diferenciarse en miofibroblastos que son los encargados de mantener la estructura de la matriz extracelular depositando colágeno. Además, la señalización paracrina de los miofibroblastos afecta a los canales iónicos de los miocitos circundantes. Se utilizaron modelos computacionales muy detallados a diferentes escalas para estudiar la remodelación estructural inducida a nivel celular y tisular. Se realizó una adaptación de un modelo de fibroblastos humanos a nivel celular para reproducir la electrofisiología de los miofibroblastos durante la fibrilación auricular. Además, se evaluó la exploración de la interacción del calcio en la electrofisiología de los miofibroblastos ajustando el canal de calcio a los datos experimentales. A nivel tisular, se estudió la infiltración de miofibroblastos para cuantificar el aumento de vulnerabilidad a una arritmia cardíaca. Los miofibroblastos cambian la dinámica de la reentrada. Una baja densidad de miofibroblastos permite la propagación a través del área fibrótica y crea puntos de salida de actividad focal y roturas de ondas dentro de esta área. Además, las composiciones de fibrosis juegan un papel clave en la alteración del patrón de propagación. La alteración del patrón de propagación afecta a los electrogramas recogidos en la superficie del tejido. La morfología del electrograma se alteró dependiendo de la disposición y composición del tejido fibrótico. Se combinaron modelos detallados de tejido cardíaco con modelos realistas de los catéteres de mapeo disponibles comercialmente para comprender las señales registradas clínicamente. Se generó un modelo de ruido a partir de señales clínicas para reproducir los artefactos de señal en el modelo. Se utilizaron electrogramas de modelos de dos dominios altamente detallados para entrenar un algoritmo de aprendizaje automático para caracterizar el sustrato fibrótico auricular. Las características que cuantifican la complejidad de las señales fueron extraídas para identificar la densidad fibrótica y la transmuralidad fibrótica. Posteriormente, se generaron mapas de fibrosis utilizando el registro del paciente como prueba de concepto. El mapa de fibrosis proporciona información sobre el sustrato fibrótico sin utilizar un valor único de corte de 0,5 milivoltios. Además, utilizando la medición del flujo de información como la entropía de transferencia combinada con gráficos dirigidos, en este estudio, se siguió la dirección de propagación del frente de onda. La transferencia de entropía con gráficos dirigidos proporciona información crucial durante la electrofisiología para comprender la dinámica de propagación de ondas durante la fibrilación auricular. En conclusión, esta tesis presenta un estudio in silico multiescala que proporciona información sobre los mediadores celulares responsables de la remodelación de la matriz extracelular y su electrofisiología. Además, proporciona una configuración realista para crear datos in silico que pueden ser usados para aplicaciones clínicas y servir de soporte al tratamiento de ablación.<br>[CA] La fibril·lació auricular és l'arrítmia cardíaca més freqüent, en la qual el substrat auricular patix una sèrie de remodelacions elèctriques i estructurals. La remodelació de tipus elèctric es caracteritza per l'alteració d'un conjunt de canals iònics que modifica la morfologia del voltatge transmembrana, conegut com a potencial d'acció. La remodelació estructural és un fenomen complex que implica la relació entre diversos processos de senyalització, interaccions cel·lulars i canvis en la matriu extracel·lular. Durant la remodelació estructural, els abundants fibroblasts presents en el teixit cardíac comencen a diferenciar-se en miofibroblasts, els quals s'encarreguen de mantenir l'estructura de la matriu extracel·lular dipositant-hi col·lagen. A més, la senyalització paracrina dels miofibroblasts amb els miòcits circumdants també afectarà els canals iònics. Es van utilitzar models computacionals molt detallats a diferents escales per estudiar la remodelació estructural induïda a nivell tissular i cel·lular. Es va fer una adaptació a nivell cel·lular d'un model de fibroblasts humans per reproduir-hi l'electrofisiologia dels miofibroblasts durant la fibril·lació auricular. A més, l'exploració de la interacció del calci amb l'electrofisiologia dels miofibroblasts va ser avaluada mitjançant l'adequació del canal de calci a les dades experimentals. A nivell tissular es va estudiar la infiltració de miofibroblasts per tal de quantificar l'augment de vulnerabilitat que això conferia per patir una arrítmia cardíaca. Els miofibroblasts canvien la dinàmica de la reentrada, i presentar-ne una baixa densitat permet la propagació a través de la zona fibròtica, tot creant punts de sortida d'activitat focal i trencaments d'ones dins d'aquesta àrea. A més, les composicions de fibrosi tenen un paper clau en l'alteració del patró de propagació, afectant els electrogrames recollits en la superfície del teixit. La morfologia dels electrogrames es va veure alterada en funció de la disposició i la composició del teixit fibròtic. Per comprendre els senyals clínicament registrats es van combinar models detallats de teixits cardíacs amb models realistes dels catèters de cartografia disponibles comercialment. Es va generar un model de soroll a partir de senyals clínics per reproduir-hi els artefactes de senyal. Es van utilitzar electrogrames de models de bidominis molt detallats per entrenar un algoritme d'aprenentatge automàtic destinat a caracteritzar el substrat fibròtic auricular. Les característiques que quantifiquen la complexitat dels senyals van ser extretes per identificar la densitat i transmuralitat fibròtica. Posteriorment, es van generar mapes de fibrosi mitjançant la gravació del pacient com a prova de concepte. El mapa de fibrosi proporciona informació sobre el substrat fibròtic sense utilitzar un sol valor de tensió de tall de 0,5 mV. A més, utilitzant la mesura del flux d'informació com l'entropia de transferència combinada amb gràfics dirigits, en aquest estudi es va fer un seguiment de la direcció de propagació de l'ona. L'entropia de transferència amb gràfics dirigits proporciona informació crucial durant l'electrofisiologia per entendre la dinàmica de propagació d'ones durant la fibril·lació auricular. En conclusió, aquesta tesi presenta un estudi multi-escala in silico que proporciona informació sobre els mediadors cel·lulars responsables de la remodelació de la matriu extracel·lular i la seva electrofisiologia. A més, proporciona una configuració realista per crear dades in silico que es poden traduir a aplicacions clíniques que puguen donar suport al tractament de l'ablació.<br>[EN] Atrial fibrillation is the most common cardiac arrhythmia. During atrial fibrillation, the atrial substrate undergoes a series of electrical and structural remodeling. The electrical remodeling is characterized by the alteration of specific ionic channels, which changes the morphology of the transmembrane voltage known as action potential. Structural remodeling is a complex process involving the interaction of several signalling pathways, cellular interaction, and changes in the extracellular matrix. During structural remodeling, fibroblasts, abundant in the cardiac tissue, start to differentiate into myofibroblasts, which are responsible for maintaining the extracellular matrix structure by depositing collagen. Additionally, myofibroblasts paracrine signalling with surrounding myocytes will also affect ionic channels. Highly detailed computational models at different scales were used to study the effect of structural remodeling induced at the cellular and tissue levels.At the cellular level, a human fibroblast model was adapted to reproduce the myofibroblast electrophsyiology during atrial fibrillation. Additionally, the calcium handling in myofibroblast electrophysiology was assessed by fitting calcium ion channel to experimental data. At the tissue level, myofibroblasts infiltration was studied to quantify the increase of vulnerability to cardiac arrhythmia. Myofibroblasts alter the dynamics of reentry. A low density of myofibroblasts allows the propagation through the fibrotic area and creates focal activity exit points and wave breaks inside this area. Moreover, fibrosis composition plays a key role in the alteration of the propagation pattern. The alteration of the propagation pattern affects the electrograms computed at the surface of the tissue. Electrogram morphology was altered depending on the arrangement and composition of the fibrotic tissue. Detailed cardiac tissue models were combined with realistic models of the commercially available mapping catheters to understand the clinically recorded signals. A noise model from clinical signals was generated to reproduce the signal artifacts in the model. Electrograms from highly detailed bidomain models were used to train a machine learning algorithm to characterize the atrial fibrotic substrate. Features that quantify the complexity of the signals were extracted to identify fibrotic density and fibrotic transmurality. Subsequently, fibrosis maps were generated using patient recordings as a proof of concept. Fibrosis map provides information about the fibrotic substrate without using a single cut-off voltage value of 0.5 mV. Furthermore, in this study, using information theory measurements such as transfer entropy combined with directed graphs, the wave propagation direction was tracked. Transfer entropy with directed graphs provides crucial information during electrophysiology to understand wave propagation dynamics during atrial fibrillation. In conclusion, this thesis presents a multiscale in silico study atrial fibrillation mechanisms providing insight into the cellular mediators responsible for the extracellular matrix remodeling and its electrophysiology. Additionally, it provides a realistic setup to create in silico data that can be translated to clinical applications that could support ablation treatment.<br>Sánchez Arciniegas, JP. (2021). A Multiscale in Silico Study to Characterize the Atrial Electrical Activity of Patients With Atrial Fibrillation. A Translational Study to Guide Ablation Therapy [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/171456<br>TESIS

The general purpose of this thesis is to establish capability and accuracy of speckle tracking echocardiography (STE) in assessing left atrial (LA), left ventricular (LV) and right ventricular (RV) function and their correlation with myocardial fibrosis, filling pressure and clinical outcomes in advanced heart failure (HF) patients before and after heart transplantation (HT). I demonstrated that HT recipients had impaired LV twist dynamics in the form of reduced rotation twist angle and untwist rate but time to peak twist was not different from the age matched controls and other cardiac surgical patients. With a longitudinal study conducted on patients with refractory HF, the best prognostic power has been shown by RV strain analysis. Among the indexes of LV function, the LV ejection fraction (LVEF) demonstrated the lowest diagnostic accuracy; instead LV global circumferential strain (GCS) showed a better sensitivity and specificity than LV global longitudinal strain (GLS). When analyzing the relationship between different severity of myocardial fibrosis and LV cavity function, the strongest function parameter that correlated with severity of myocardial fibrosis was GLS. In contrast, none of diastolic LV function or even measures of exercise capacity correlated with myocardial fibrosis. In patients with end-stage HF, global peak atrial longitudinal strain (PALS), an index of atrial reservoir function was dependent by pulmonary capillary wedge pressure (PCWP) and LV fibrosis, but not influenced by LV systolic function. Results from this study confirm previous evidence of correlation between impaired global PALS and increased PCWP.

Abstract Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40-60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64-82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40-60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the liver, assessed by magnetic resonance imaging, in 15 young and healthy individuals. In conclusion, this thesis advances the knowledge in the pathogenesis, lipid metabolism, complications and heterogeneous nature of NAFLD. These may have implications for patient care and follow-up<br>Tiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa havaittiin myös, että metabolista oireyhtymää sairastavilla henkilöillä on suurentunut tyypin 2 diabeteksen, sydän- ja verisuonisairauksien sekä vasemman kammion koon suurentumisen riski noin 20 vuoden seurannan aikana 958 tutkittavan henkilön aineistossa riippumatta siitä, onko heillä alkoholinkäyttöön liittymätön rasvamaksa. Toisin sanoen alkoholin käyttöön liittymätön rasvamaksa ilman metabolista oireyhtymää ei lisää edellä mainittujen kolmen sairauden riskiä. Väitöstutkimuksessa esitetään lisäksi, että rifampisiinilla aikaansaatu maksan pregnane X -reseptorin aktivaatio johtaa seerumin fosfolipidien, tiettyjen rasvahappojen sekä usean eri kolesterolityypin lisääntymiseen 34 terveen nuoren henkilön aineistossa. Kirjallisuudessa näiden seerumin rasva-aineiden on esitetty aiheuttavan alkoholin käyttöön liittymätöntä maksatulehdusta ja jopa rasvamaksan vakavimpia muotoja. Toisaalta rifampisiini ei lisännyt seerumin triglyseridipitoisuutta eikä aiheuttanut magneettitutkimuksella mitattuna triglyseridien kertymistä maksaan 15 terveen nuoren henkilön aineistossa. Tämä väitöstutkimus antaa lisätietoa rasvamaksan kehittymisestä, rasva-aineenvaihdunnasta ja komplikaatioista sekä korostaa rasvamaksan monimuotoista luonnetta. Nämä löydökset saattavat parantaa rasvamaksaa sairastavien henkilöiden hoitoa ja seurantaa

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 myocardique<br>This 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

ABSTRACT Background: The epicardial adipose tissue is located between the myocardium and the visceral pericardium, lying directly above the myocardium without any fascia. Epicardial adipose tissue presents itself with histological features typical of the brown adipose tissue. It plays a cardioprotective role through thermoregulation, energy homeostasis and anti-inflammatory regulation. However, in pathological conditions, epicardial adipose tissue may have a pro-inflammatory effect. Less is known about the role played by epicardial adipose tissue in patients with a history of atrial fibrillation. Some studies suggest an association between increased epicardial adipose tissue (volume and thickness) and atrial fibrillation. Nonetheless, there is little data about histological characterisation of epicardial adipose tissue in patients with a history of atrial fibrillation. Aim of the study: To evaluate the quantitative (using echocardiography) and qualitative characteristics (intra-operatory biopsy for histological characterisation) of epicardial adipose tissue in relation to atrial fibrillation burden after coronary artery bypass graft. Patients and methods: Prospective single-centre study approved by the ethics committee of Verona and Rovigo in July 2018. Patients undergoing coronary artery bypass graft with preserved left ventricular ejection fraction were included, after giving informed consent. Patients with atrial fibrillation and immunosuppressive therapy history were excluded. All enrolled patients underwent a medical evaluation to collect clinical history, a transthoracic echocardiography to measure epicardial adipose tissue thickness and collection of a bioptic sample containing right appendage and epicardial adipose tissue during coronary artery bypass graft. After surgery post-surgical clinical course and telemetry were collected. Lastly, histological characterisation (PLIN1 and fibrosis) of the bioptic samples was performed. Results: 56 patients undergoing coronary artery bypass graft were enrolled between 10th September 2018 and 3rd September 2019 in Cardiology and Cardiac Surgery departments. The mean hospitalisation was 11,9 ± 6,9 days and the postsurgical hospitalisation was 7,9 ± 3,7 days. 44 (78,6%) patients were male and the median age was 68,45 ± 9,2 years. All patients were continuously monitored with telemetry from the day of cardiac surgery until discharge. No major complications occurred, only one death unrelated to the surgery. Out of the total number of patients, 22 (39%) had at least one episode of atrial fibrillation. In the population that developed atrial fibrillation there was a bigger atrial volume, a higher degree of diastolic disfunction (E/A rate), a thicker layer of epicardial adipose tissue and an older median age in comparison to the group that did not develop it. Epicardial adipose tissue measured using echocardiogram with a cut off of 4 mm was a predictor of atrial fibrillation with an OR of 1,49 [1,09-2,04], 73% of sensibility and 89% of specificity. Furthermore, from the histological analyses of biopsies, the patients with atrial fibrillation had a significantly higher percentage of fibrosis, while adipose infiltration was not significantly higher. Through univariate analysis, atrial volume (OR 1,05 CI 1,01-1,09, p 0,022), E/A rate (OR 0,04 CI 0,02-0,72 p 0,29), the percentage of fibrosis (OR 1,12 CI 1,00-1,25 p 0,045) and age (OR 1,17 CI 1,07-1,28 p 0,001) were predictors of atrial fibrillation as well as the thickness of the epicardial adipose tissue. Through multivariate analysis atrial volume (p 0,027), fibrosis (p 0,003) and age (p 0,039) were independent predictors of atrial fibrillation. Conclusion: Post cardiac surgical atrial fibrillation is frequent. Epicardial adipose tissue measured by echocardiogram, atrial volume, fibrosis and age are predictors of post cardiac surgical atrial fibrillation.

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.<br>Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017

The general purpose of this thesis is to establish the ability of Speckle Tracking Echocardiography (STE) in assessing left atrial (LA) response to pressure and volume overload respectively in aortic stenosis (AS) and mitral regurgitation (MR), and to evaluate its accuracy in predicting LA and right ventricular (RV) fibrosis in patients with end-stage heart failure (HF) undergoing heart transplantation (HTx). I demonstrated that assessment of left ventricular (LV) long axis systolic velocity and amplitude of excursion is more sensitive than simple determination of ejection fraction (EF) for revealing the beneficial impact of MR surgery on overall LV systolic performance. Severe symptomatic AS is associated with LA enlargement and compromised mechanical function with a high incidence of peri-operative atrial fibrillation (AF). Valve replacement reverses these abnormalities and regains normal atrial function, a behaviour which is directly related to the severity of pre-operative LV outflow tract obstruction. Early identification of LA size and function disturbances, as shown by myocardial strain measurements might contribute to better patient’s recruitment for a safe valve replacement. In late stage HF patients, the right ventricle is enlarged, with reduced systolic function due to significant myocardial fibrosis. RV free wall myocardial deformation is the most accurate function measure that correlates with the extent of RV myocardial fibrosis and functional capacity. In patients with preserved EF, severe MR masks LV and LA myocardial dysfunction and correlates with symptoms and post-operative cavity function instability. Three months after MVR, the underlying myocardial disturbances are unmasked suggesting that most pre-operative measurements are subject to loading conditions. Finally LA volume and PALS remain the main predictors of post-operative AF, thus should be used for stratifying surgical risk. STE has been shown to accurately determine the severity of impairment of LA myocardial function shown by suppressed PALS which was the strongest predictor of the presence and extent of fibrosis, over and above other structure and function parameters. These findings may assist in better stratifying patients with end stage HF and identifying particularly those requiring HTx.

博士<br>國防醫學院<br>醫學科學研究所<br>107<br>B-type natriuretic peptide (BNP) was approved by the US Food and Drug Administration in 2001 for the treatment of heart failure. However, the effects of BNP in clinical applications are controversial and uncertain. Recently, study indicated that high BNP levels are associated with an increased risk of developing atrial fibrillation. In this study, we investigated the direct effects of BNP on TNF--induced atrial fibrosis mice, as well as its effects on human atrial myofibroblasts. We found that injecting TNF--induced mice with recombinant human BNP enhanced atrial fibrosis via MMP-2 expression and collagen accumulation. Furthermore, we found that BNP stimulated MMP-2 expression in human atrial myofibroblasts. Treatment of human atrial myofibroblasts with cycloheximide had no effect on this outcome; however, treatment of cells with MG132 enhanced BNP-induced MMP-2 expression, indicating that protein stability and inhibition of proteasome-mediated protein degradation pathways are potentially involved. Inhibition of SIRT1 significantly decreased BNP-induced MMP-2 expression. Additionally, confocal and co-IP data indicated that BNP-regulated MMP-2 expression are likely to be mediated through direct interaction with SIRT1, which is thought to deacetylate MMP-2 and to increase its protein stability in human atrial myofibroblasts. Finally, we confirmed that SIRT1 is expressed and cytoplasmically redistributed as well as co-localized with MMP-2 in mouse fibrotic atrial tissue. We suggest a possible fibrosis-promoting role of BNP in the atrium, although the antifibrotic properties of BNP in the ventricle have been reported in previous studies, and that the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis.