Na Síndrome Metabólica, ações lipotóxicas e glicotóxicas contribuem para a aceleração do processo aterogênico cuja base é a inflamação. O tecido adiposo epicárdico vem sendo reconhecido como metabolicamente ativo e foi relacionado à elevação da produção de citocinas e adipocinas inflamatórias e aumento de DAC. Pioglitazona e Sinvastatina comprovadamente atuam como drogas pleiotrópicas na redução do processo inflamatório sistêmico. O presente estudo teve como objetivo principal avaliar possíveis correlações entre a presença de citocinas inflamatórias plasmáticas versus teciduais e a resposta de ambas à terapia medicamentosa. Para tanto, foram utilizadas monoterapia com Sinvastatina ou Pioglitazona e terapia combinada Pioglitazona+Sinvastatina e acompanhadas as variáveis lipídicas, glicêmicas e inflamatórias sistêmicas, células e citocinas inflamatórias em TAE, um tipo de tecido adiposo branco visceral instalado nas adjacências de focos ateroscleróticos em artérias coronárias de pacientes portadores de DAC e SMet. O estudo envolveu 73 pacientes com DAC multiarterial, avaliada pela cinecoronariografia e SMet que foram submetidos a revascularização e 20 pacientes submetidos à cirurgia valvar para substituição de valva mitral. Os pacientes com DAC eram incluídos de forma não aleatória a um dos 4 subgrupos: controle (n = 17), Simvastatina (20 mg / dia, n = 20), Pioglitazona (15 mg ou 30 mg / dia, n = 18) e Simvastatina + Pioglitazona (20 mg / dia + 15 mg ou 30 mg / dia, respectivamente, n = 18). Amostras de tecido adiposo epicárdico foram obtidas durante a cirurgia. Infiltração de macrófagos, linfócitos e secreção adipocitocinas foram investigados por coloração imunohistoquímica e comparados aos biomarcadores inflamatórios plasmáticos. Os resultados mostraram que a infiltração de macrófagos e a presença de citocinas pró-inflamatórias tais como TNF-, IL-6, leptina and resistina foram reduzidas em TAE de pacientes DAC/SMet após monoterapia com Pioglitazona. Os pacientes tratados apenas com Sinvastatina apresentaram os menores valores plasmáticos de leptina, resistina and MCP-1. Pioglitazona+Sinvastatina foram associadas aos menores valores plasmáticos de IL-6, TNF-, resistina, ADMA, MMP-9 em comparação ao grupo de pacientes não tratados. Além disso, a terapia combinada revelou a mais alta concentração de adiponectina plasmática concomitante ao menor valor de PCRus. Esses achados refletiram não só a condição plasmática como se correlacionaram positivamente à condição tecidual mostrada pela porcentagem média de área ocupada por macrófagos no TAE e a quantidade de PCRus presente no plasma após os tratamentos. Houve correlação positiva também entre citocinas sistêmicas e teciduais após os tratamentos, exceto para o TNF- após o tratamento com sinvastatina ( r = - 0,025, p = 0,33) e leptina após o tratamento com pioglitazona (r = -0,877, p <0,0001). Nos pacientes tratados com Sinvastatina, os fragmentos de TAE apresentaram agregados de linfócitos T, B e macrófagos concentrados na borda e ao redor de vasos sanguíneos / In the Metabolic Syndrome, the concentration of free fatty acids and the elevation of glycemia result in lipotoxic and glycotoxic actions, respectively, which contribute to accelerate the atherogenic process. (MS). Inapropriate secretion of adipocytokines plays a critical role in chronic inflammatory states associated with obesity-linked diseases, such as type 2 diabetes and atherosclerosis. The pleiotropic anti-inflammatory action of Simvastatin and/or Pioglitazone may counteract such systemic effects but its influence upon human epicardial adipose tissue is unknown. To assess the anti-inflammatory action of Simvastatin, Pioglitazone or both in epicardial adipose tissue in patients with coronary artery disease (CAD) and metabolic syndrome. The study comprised 73 patients with multivessel CAD, evaluated by cinecoronariography, and MS who underwent bypass grafting and 20 valvar patients who underwent surgery for mitral valve replacement. The 73 who underwent elective bypass grafting were non-randomly allocated to one of 4 subgroups: control (n=17), Simvastatin alone (20 mg/day, n=20), Pioglitazone alone (15 mg or 30 mg/day, n=18), or Simvastatin+Pioglitazone (20 mg/day + 15 mg or 30 mg/day, respectively, n=18). Epicardial adipose tissue sample was obtained during surgery. Infiltration of macrophages, lymphocytes and adipocytokines secretion were investigated by immunohistochemical staining and compared to plasma inflammatory biomarkers. Among CAD/MS patients, treatment with Simvastatin alone, Pioglitazone alone and Simvastatin+Pioglitazone significantly reduced plasma CRP and cytokines compared with control group. Monotherapy with Simvastatin significantly reduced plasma IL-6, leptin, resistin, MCP-1 (p<0.001 for all), whereas monotherapy with Pioglitazone reduced IL-6, TNF-, resistin and MMP-9 (p<0.001 for all) compared with control group. Simvastatin+Pioglitazone treatment reduced more plasmatic variables (IL-6, TNF-, resistin, ADMA and MMP-9 vs. control group (p<0.001). All treatments increased adiponectin plasma levels (p<0.001). In the combined treatment group, higher concentration in plasma adiponectin and lower hsCRP, were found simultaneously. There was positive correlation between mean percentage macrophages area in EAT and plasma hsCRP; also between systemic and tecidual citokynes after the treatments, except for TNF- after treatment with simvastatin (r = -0.025, p = 0.33) and leptin after treatment with pioglitazone (r = -0.877, p <0.0001). In fat fragments of patients treated with Simvastatin, T- and B-lymphocytes, and macrophages clusters concentrated near the edge or around blood vessels were observed by first time. In patients with CAD and MS treatment with Pioglitazone, Sinvastatin or combination can substantially reduce both epicardial tissue and plasma inflammatory markers. Such tissue effects may contribute to the control of coronary atherosclerosis progression

Ce travail se proposait, à partir du cas démonstratif de la grotte du Gardon (Ambérieu-en-Bugey, Ain), de dégager le cadre évolutif des industries lithiques néolithiques du Centre-Est de la France. Avec une stratigraphie particulièrement développée et quasiment continue pour la Préhistoire récente la grotte du Gardon constitue un site exceptionnellement favorable à ce genre d'analyse.<br />Cette thèse s'organise en quatre parties principales, regroupant seize chapitres. La première est une présentation générale du travail (cadre géographique et chronologique). Elle est aussi l'occasion d'exposer les concepts à la base des analyses ainsi que la méthodologie employée. La seconde partie consiste en un état des connaissance sur les industries lithiques de l'ensemble du Néolithique haut-rhodanien. La troisième est celle de l'analyse des 17 000 silex taillés néolithiques de la grotte du Gardon. La coexistence de couches d'occupation et de niveaux d'inondation, ainsi que la présence de zone de biseautage impliquent une fiabilité différente des échantillons considérés. Chaque ensemble a été abordé individuellement d'un point de vue technologique et typologique, dans le but de dégager les schémas opératoires propres à chacune des couches. La confrontation de ces résultats à ceux obtenus sur d'autres aspects du système technique et aux données chrono-stratigraphiques permet d'affiner ou de rediscuter les attributions culturelles proposées. Dans la quatrième et dernière partie, les résultats obtenus sur la grotte sont confrontés aux données régionales. Il est alors possible de construire un cadre évolutif général des industries lithiques et, plus largement, des groupes culturels néolithiques du Centre-Est de la France.

Darbo tikslas: Sukurti kiekybinius signalų morfologijos, atspindinčių širdies veiklos reguliavimą, jos audinių gyvybingumą bei centrinę hemodinamiką, vertinimo metodus. Uždaviniai: 1. Ištirti signalų dekompozicijos baigtiniu bazinių funkcijų rinkiniu (truncated signal representation) metodų tinkamum��, širdies veiklą, jos audinių gyvybingumą bei centrinę hemodinamiką aprašančių signalų, morfologijos analizei; 2. Sukurti signalų, atspindinčių širdies audinių gyvybingumą, optimalaus aprašymo metodą; 3. Sukurti centrinę hemodinamiką atspindinčio krūtinės ląstos impedanso signalo struktūrinės bei morfologinės analizės metodą; 4. Sukurti elektrokardiogramos P-bangos morfologijos dinamikos, atspindinčios širdies veiklos autonominį reguliavimą, kiekybinio įvertinimo metodą. / The aim: To elaborate the quantitative methods for evaluation of morphology of the signals reflecting viability of heart tissue, heart function control and central/peripheral hemodynamics. Objectives: 1. Investigation of usefulness truncated signal representation methods for analysis of morphology of the signals reflecting viability of heart tissue, heart function control and central/peripheral hemodynamics; 2. Elaboration of method for optimal representation of signals reflecting heart tissue viability; 3. Elaboration of method for quantitative evaluation of ECG P-wave morphology dynamics reflecting autonomous heart function control; 4. Elaboration of method for structural and morphological analysis of the chest impedance signals reflecting central hemodynamics.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. It shows an increasing prevalence in developed countries with a strong association to cardiovascular risk factors. It has become a major challenge to the healthcare system with a high morbidity and increased AF-related mortality. Recommended treatment approaches favor rhythm control strategies, which aim to restore sinus rhythm. The pathophysiologic concept of atrial fibrillation has evolved towards defining the term atrial myopathy, recognizing inflammation mediated remodeling of the left atrium (LA) as a source for and result of arrhythmogenesis. One of many features of atrial myopathy is the development of left atrial fibrosis by fibro-fatty infiltration. This corresponds to low voltage zones (LVZ), that are characterized by impaired myocardial electrical conduction during invasive electroanatomic mapping. Epicardial adipose tissue (EAT) has been revealed to be a key player in this inflammatory process that nourishes the development of left atrial fibrosis. Traditional cardiovascular risk factors favor the transdifferentiation of EAT towards a pro-inflammatory phenotype. Recently, evidence has proven the positive effect of new generation anti-diabetic drugs like sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists on EAT by inducing a favorable phenotypic shift with local anti-inflammatory effect and potential influence on atrial reverse remodeling. This thesis sought to confirm the ability to predict LVZ from cardiac magnetic resonance (CMR) derived parameters and to describe the differences of left atrial volume and left atrial epicardial adipose tissue volume in AF patients with and without LVZ. Patients with indication for primary AF ablation were prospectively enrolled. CMR imaging sequences included an LA angiography and two different techniques for left atrial epicardial adipose tissue imaging (T1 weighted and fat-water separation DIXON-based), which were compared. Left atrial volume index (LAVi) and left atrial epicardial adipose tissue volume index (LA-EATVi) from the DIXON-based technique proofed to be significant predictors of LVZ presence. No significant results could be obtained for the epicardial adipose tissue quantified from T1 weighted imaging. LA-EATVi(DIXON) was significantly higher in patients with LVZ than without, with a mean difference of 10.13 ± 5.0 ml. The same could be shown for LAVi, with a mean difference of 24.46 ± 8.13 ml. Both parameters were independent of each other. Additionally, it could be shown that higher age and female gender are associated with LVZ occurrence. CMR based quantification of LA-EATVi(DIXON) alone or in combination with other predictive variables of LVZ, like LAVi, age and female gender was able to identify patients at low or high risk of LVZ. In the studied patient population, a combined prediction model of LAVi, LA- EATVi(DIXON), age and female gender provided the highest predictive ability to determine LVZ presence with an area under the curve (AUC) in receiver operating characteristics (ROC) of 0.91. Depending on cutoff selection for the prediction model a high positive or negative predictive value can be achieved, minimizing false results. The clinical implementation of a CMR-based prediction model of LVZ presence as a feature of LA myopathy could have a tremendous impact on treatment decisions. It would allow the selection of patients for fast and easy single shot AF-ablation procedures in case of low LVZ risk, whereas complex and more time-consuming invasive procedures were to be scheduled if relevant LA myopathy is to be suspected.:1. Introduction 1 1.1. Atrial fibrillation 1 1.1.1. Risk factors 3 1.1.2. Left atrial myopathy 4 1.1.2.1. Predictive parameters of LA myopathy and atrial fibrosis 6 1.1.2.2. Imaging methods for left atrial myopathy and fibrosis 6 1.1.4. Current treatment strategies 7 1.1.4.1. Catheter ablation 9 1.2. Epicardial adipose tissue 11 1.2.1. Physiology and pathophysiology of epicardial adipose tissue 14 1.2.2. Role of epicardial adipose tissue in atrial fibrillation 15 1.2.3. Imaging techniques of epicardial adipose tissue 18 2. Objective 21 3. Methods 22 3.2. Imaging protocol 24 3.2.1. Adipose tissue imaging with DIXON approach 24 3.2.2. Adipose tissue imaging with T1 weighted imaging approach 26 3.2.3. Left atrial anatomy imaging 26 3.3. Segmentation and Quantification 27 3.4. Electroanatomic mapping and pulmonary vein isolation procedure 31 3.5. Statistical analysis 33 4. Results 34 4.2. General patient cohort characteristics 34 4.3. Patient characteristics in LVZ subgroups 36 4.4. Selected CMR parameter evaluation 39 4.4.1. Left atrial volume 39 4.4.2. Left atrial epicardial adipose tissue volume 41 4.4.2.1. DIXON based left atrial epicardial adipose tissue imaging 41 4.4.2.2. T1 weighted left atrial epicardial adipose tissue imaging 43 4.4.3. Comparison of adipose tissue imaging techniques 45 4.4.4. Reliability analysis 48 4.5. LVZ prediction models 49 4.5.1. Univariate non-CMR based LVZ prediction models 51 4.5.2. Univariate CMR based LVZ prediction models 53 4.5.3. Multivariate LVZ prediction models 57 4.5.4. Example of clinical application 62 4.5.5. Prediction model validation 64 5. Discussion 66 5.2. General aspects 66 5.3. EAT image acquisition 68 5.4. Clinical relevance 68 5.5. Future developments 70 5.6. Limitations 72 6. Summary 74 7. Zusammenfassung 76 8. References 78 9. List of figures and tables 98 10. Acknowledgement 102 11. Curriculum vitae 103 / Vorhofflimmern (AF) ist die häufigste Herzrhythmusstörung. In den Industrieländern nimmt die Prävalenz zu, wobei ein enger Zusammenhang mit kardiovaskulären Risikofaktoren besteht. Vorhofflimmern ist zu einer großen Herausforderung für das Gesundheitssystem geworden, da es eine hohe Morbidität und eine erhöhte vorhofflimmerbedingte Mortalität aufweist. Die empfohlenen Behandlungsansätze favorisieren Rhythmuskontrollstrategien, die auf die Wiederherstellung des Sinusrhythmus abzielen. Das pathophysiologische Konzept des Vorhofflimmerns hat sich dahingehend weiterentwickelt, dass der Begriff Vorhofmyopathie definiert wurde, wobei unter anderem der entzündungsbedingte Umbau (Remodeling) des linken Vorhofs (LA) als eine Ursache und Folge der Arrhythmogenese anerkannt wird. Eines der vielen Merkmale der Vorhofmyopathie ist die Entwicklung einer Fibrose im Bereich des linken Vorhofs durch fibrös-fettige Infiltration. Dies entspricht Niederspannungszonen (LVZ), die bei invasiven elektroanatomischen Kartierungen durch eine beeinträchtigte elektrische Leitung des Myokards gekennzeichnet sind. Es hat sich gezeigt, dass epikardiales Fettgewebe (EAT) eine Schlüsselrolle in diesem entzündlichen Prozess spielt, der die Entwicklung einer linksatrialen Fibrose begünstigt. Traditionelle kardiovaskuläre Risikofaktoren verursachen die Transdifferenzierung des epikardialen Fettgewebes in Richtung eines pro-inflammatorischen Phänotyps. In letzter Zeit hat sich gezeigt, dass Antidiabetika der neuen Generation, wie z. B. Natrium-Glukose-Cotransporter-2-Inhibitoren (SGLT-2) und Glucagon-like Peptide-1 (GLP-1) Rezeptor Agonisten, eine positive Wirkung auf EAT haben, indem sie eine günstige phänotypische Verschiebung mit lokaler Entzündungshemmung und potenziellem Einfluss auf ein „reverses Remodeling“ des Vorhofs bewirken. Ziel dieser Arbeit war es, die Fähigkeit der Vorhersage von LVZ anhand von Parametern aus der kardialen Magnetresonanztomographie (CMR) zu bestätigen und die Unterschiede des Volumens des linken Vorhofs und des linksatrialen epikardialen Fettgewebes bei Vorhofflimmerpatienten mit und ohne LVZ zu beschreiben. Patienten mit Indikation zur primären Vorhofflimmerablation wurden prospektiv eingeschlossen. Zu den akquirierten CMR-Bildgebungssequenzen zählte eine LA- Angiographie und zwei verschiedene Techniken zur Darstellung des linksatrialen epikardialen Fettgewebes (T1-gewichtet und Fett-Wasser-Trennung auf DIXON-Basis). Letztere wurden miteinander verglichen. Der Volumenindex des linken Vorhofs (LAVi) und der Volumenindex des linksatrialen epikardialen Fettgewebes (LA-EATVi) aus der DIXON-basierten Bildgebung erwiesen sich als signifikante Prädiktoren für das Vorhandensein von LVZ. Für das epikardiale Fettgewebe, das mit der T1-gewichteten Bildgebung quantifiziert wurde, konnten keine signifikanten Ergebnisse erzielt werden. LA-EATVi(DIXON) war bei Patienten mit LVZ signifikant höher als bei Patienten ohne LVZ, mit einer mittleren Differenz von 10.13 ± 5.0 ml. Dasselbe konnte für LAVi gezeigt werden, mit einer mittleren Differenz von 24.46 ± 8.13 ml. Beide Parameter waren unabhängig voneinander. Außerdem konnte gezeigt werden, dass höheres Alter und weibliches Geschlecht mit dem Auftreten von LVZ assoziiert sind. Die CMR-basierte Quantifizierung von LA-EATVi(DIXON) allein oder in Kombination mit anderen prädiktiven Variablen für LVZ, wie LAVi, Alter und weiblichem Geschlecht, war in der Lage, Patienten mit niedrigem oder hohem Risiko für LVZ zu identifizieren. In der untersuchten Patientenpopulation lieferte ein kombiniertes Vorhersagemodell aus LAVi, LA-EATVi(DIXON), Alter und weiblichem Geschlecht die höchste Vorhersagekraft zur Bestimmung des Vorhandenseins von LVZ mit einer Fläche unter der Kurve (AUC) in der Grenzwertoptimierungskurve (ROC) von 0.91. Je nach Auswahl des Cutoffs für das Vorhersagemodell kann ein hoher positiver oder negativer Vorhersagewert erreicht werden, wodurch falsche Ergebnisse minimiert werden. Die klinische Umsetzung eines CMR-basierten Vorhersagemodells für das Vorhandensein von LVZ als Merkmal der LA-Myopathie könnte sich enorm auf die Behandlungsentscheidungen auswirken. Es würde die Auswahl von Patienten für schnelle und einfache Single-Shot-Ablationsverfahren bei geringem LVZ-Risiko ermöglichen, während bei Verdacht auf eine relevante LA-Myopathie komplexe und zeitaufwändigere invasive Verfahren geplant werden müssten.:1. Introduction 1 1.1. Atrial fibrillation 1 1.1.1. Risk factors 3 1.1.2. Left atrial myopathy 4 1.1.2.1. Predictive parameters of LA myopathy and atrial fibrosis 6 1.1.2.2. Imaging methods for left atrial myopathy and fibrosis 6 1.1.4. Current treatment strategies 7 1.1.4.1. Catheter ablation 9 1.2. Epicardial adipose tissue 11 1.2.1. Physiology and pathophysiology of epicardial adipose tissue 14 1.2.2. Role of epicardial adipose tissue in atrial fibrillation 15 1.2.3. Imaging techniques of epicardial adipose tissue 18 2. Objective 21 3. Methods 22 3.2. Imaging protocol 24 3.2.1. Adipose tissue imaging with DIXON approach 24 3.2.2. Adipose tissue imaging with T1 weighted imaging approach 26 3.2.3. Left atrial anatomy imaging 26 3.3. Segmentation and Quantification 27 3.4. Electroanatomic mapping and pulmonary vein isolation procedure 31 3.5. Statistical analysis 33 4. Results 34 4.2. General patient cohort characteristics 34 4.3. Patient characteristics in LVZ subgroups 36 4.4. Selected CMR parameter evaluation 39 4.4.1. Left atrial volume 39 4.4.2. Left atrial epicardial adipose tissue volume 41 4.4.2.1. DIXON based left atrial epicardial adipose tissue imaging 41 4.4.2.2. T1 weighted left atrial epicardial adipose tissue imaging 43 4.4.3. Comparison of adipose tissue imaging techniques 45 4.4.4. Reliability analysis 48 4.5. LVZ prediction models 49 4.5.1. Univariate non-CMR based LVZ prediction models 51 4.5.2. Univariate CMR based LVZ prediction models 53 4.5.3. Multivariate LVZ prediction models 57 4.5.4. Example of clinical application 62 4.5.5. Prediction model validation 64 5. Discussion 66 5.2. General aspects 66 5.3. EAT image acquisition 68 5.4. Clinical relevance 68 5.5. Future developments 70 5.6. Limitations 72 6. Summary 74 7. Zusammenfassung 76 8. References 78 9. List of figures and tables 98 10. Acknowledgement 102 11. Curriculum vitae 103

La fibrillation auriculaire, l'arythmie la plus fréquente en clinique, affecte 2.3 millions de patients en Amérique du Nord. Pour en étudier les mécanismes et les thérapies potentielles, des modèles animaux de fibrillation auriculaire ont été développés. La cartographie électrique épicardique à haute densité est une technique expérimentale bien établie pour suivre in vivo l'activité des oreillettes en réponse à une stimulation électrique, à du remodelage, à des arythmies ou à une modulation du système nerveux autonome. Dans les régions qui ne sont pas accessibles par cartographie épicardique, la cartographie endocardique sans contact réalisée à l'aide d'un cathéter en forme de ballon pourrait apporter une description plus complète de l'activité auriculaire. Dans cette étude, une expérience chez le chien a été conçue et analysée. Une reconstruction électro-anatomique, une cartographie épicardique (103 électrodes), une cartographie endocardique sans contact (2048 électrodes virtuelles calculées à partir un cathéter en forme de ballon avec 64 canaux) et des enregistrements endocardiques avec contact direct ont été réalisés simultanément. Les systèmes d'enregistrement ont été également simulés dans un modèle mathématique d'une oreillette droite de chien. Dans les simulations et les expériences (après la suppression du nœud atrio-ventriculaire), des cartes d'activation ont été calculées pendant le rythme sinusal. La repolarisation a été évaluée en mesurant l'aire sous l'onde T auriculaire (ATa) qui est un marqueur de gradient de repolarisation. Les résultats montrent un coefficient de corrélation épicardique-endocardique de 0.8 (expérience) and 0.96 (simulation) entre les cartes d'activation, et un coefficient de corrélation de 0.57 (expérience) and 0.92 (simulation) entre les valeurs de ATa. La cartographie endocardique sans contact apparait comme un instrument expérimental utile pour extraire de l'information en dehors des régions couvertes par les plaques d'enregistrement épicardique. / Atrial fibrillation is the most common clinical arrhythmia currently affecting 2.3 million patients in North America. To study its mechanisms and potential therapies, animal models of atrial fibrillation have been developed. Epicardial high-density electrical mapping is a well-established experimental instrument to monitor in vivo the activity of the atria in response to pacing, remodeling, arrhythmias and modulation of the autonomic nervous system. In regions that are not accessible by epicardial mapping, noncontact endocardial mapping performed through a balloon catheter may provide a more comprehensive description of atrial activity. In this study, a dog experiment was designed and analyzed in which electroanatomical reconstruction, epicardial mapping (103 electrodes), noncontact endocardial mapping (2048 virtual electrodes computed from a 64-channel balloon catheter), and direct-contact endocardial catheter recordings were simultaneously performed. The recording system was also simulated in a computer model of the canine right atrium. For simulations and experiments (after atrio-ventricular node suppression), activation maps were computed during sinus rhythm. Repolarization was assessed by measuring the area under the atrial T wave (ATa), a marker of repolarization gradients. Results showed an epicardial endocardial correlation coefficient of 0.8 (experiment) and 0.96 (simulation) between activation times, and a correlation coefficient of 0.57 (experiment) and 0.92 (simulation) between ATa values. Noncontact mapping appears to be a valuable experimental device to retrieve information outside the regions covered by epicardial recording plaques.

Fundamentos O acesso percutâneo ao espaço pericárdico pela via transatrial poderia ser uma alternativa ao acesso subxifóide para o mapeamento e ablação de fibras miocárdicas subepicárdicas. O objetivo deste estudo foi avaliar a viabilidade de alcançar o espaço pericárdico normal através do apêndice auricular direito (AAD) por acesso transvenoso. Métodos e Resultados - Um sistema Mullins (8F), originalmente desenvolvido para alcançar o átrio esquerdo (AE) por punção transeptal foi utilizado neste estudo para transfixar o AAD (16) ou AE (1) em 17 suínos, com uma média de 26,9 ± 2,6 kg, e alcançar o espaço pericárdico normal. Um cateter 7F quadripolar com eletrodo distal com 4 ou 8 mm foi introduzido no espaço pericárdico para aplicações de radiofrequência. Em 15 (88%) animais o procedimento foi realizado sem instabilidade hemodinâmica (PA média inicial = 80,4 ± 11.7 mmHg; PA média final = 86,8 ± 9.7 mmHg, p = 0,11). Foi identificado e aspirado derrame pericárdico discreto (28,9 ± 27.6 ml/animal) durante o procedimento. O espaço pericárdico foi acidentalmente acessado por punção do ventrículo direito (VD) em um animal e por punção do anel da valva tricúspide em outro. Ambos apresentaram sangramento xii pericárdico importante e tamponamento cardíaco. Um dispositivo para oclusão do orifício de perfuração foi testado com sucesso em três porcos, dois no AD e um no VD, sem ocorrência de derrame pericárdico significativo. Conclusões O acesso transatrial ao espaço pericárdico pode ser potencialmente útil para mapeamento e ablação de arritmias cardíacas, bem como para drenagem imediata de um tamponamento cardíaco agudo / Background A transvenous access to the pericardial space could provide a convenient route to map and ablate subepicardial myocardial fibers. The aim of this study was to evaluate the feasibility of reaching the normal pericardial space through the right atrial appendage (RAA) by transvenous access. Methods and Results An 8F Mullins system was used to transfix the right atrium (16) and left atrium (1) in 17 pigs with a mean of 26.9 ± 2.6 kg. A 7F quadripolar catheter with 4 or 8 mm distal tip electrode was introduced into the pericardial space to perform epicardial radiofrequency lesions. The pericardial space was successfully reached in 15 (88%) animals without hemodynamic instability (initial mean BP 80.4 ± 11.7 mmHg; final 86.8 ± 9.7 mmHg, p= 0,11). However, a mild pericardial serohemorrhagic effusion was identified and aspirated in all the animals (28.9 ± 27.6 ml/pig) during the procedure. The pericardial space was accidentally accessed through the right ventricle (RV) in one animal and through the tricuspid annulus in another, which presented important pericardial bleeding and cardiac tamponade. The hypothesis that an occlusion device could be useful to close the created atrial xiv orifice was tested successfully in thee pigs (two at RAA and one at RV) and without significant pericardial bleeding. Conclusions The right atrial appendage route might be potentially useful to access the normal pericardial space for mapping and ablating cardiac arrhythmias as well as to drain promptly an acute tamponade

La fibrillation auriculaire, l'arythmie la plus fréquente en clinique, affecte 2.3 millions de patients en Amérique du Nord. Pour en étudier les mécanismes et les thérapies potentielles, des modèles animaux de fibrillation auriculaire ont été développés. La cartographie électrique épicardique à haute densité est une technique expérimentale bien établie pour suivre in vivo l'activité des oreillettes en réponse à une stimulation électrique, à du remodelage, à des arythmies ou à une modulation du système nerveux autonome. Dans les régions qui ne sont pas accessibles par cartographie épicardique, la cartographie endocardique sans contact réalisée à l'aide d'un cathéter en forme de ballon pourrait apporter une description plus complète de l'activité auriculaire. Dans cette étude, une expérience chez le chien a été conçue et analysée. Une reconstruction électro-anatomique, une cartographie épicardique (103 électrodes), une cartographie endocardique sans contact (2048 électrodes virtuelles calculées à partir un cathéter en forme de ballon avec 64 canaux) et des enregistrements endocardiques avec contact direct ont été réalisés simultanément. Les systèmes d'enregistrement ont été également simulés dans un modèle mathématique d'une oreillette droite de chien. Dans les simulations et les expériences (après la suppression du nœud atrio-ventriculaire), des cartes d'activation ont été calculées pendant le rythme sinusal. La repolarisation a été évaluée en mesurant l'aire sous l'onde T auriculaire (ATa) qui est un marqueur de gradient de repolarisation. Les résultats montrent un coefficient de corrélation épicardique-endocardique de 0.8 (expérience) and 0.96 (simulation) entre les cartes d'activation, et un coefficient de corrélation de 0.57 (expérience) and 0.92 (simulation) entre les valeurs de ATa. La cartographie endocardique sans contact apparait comme un instrument expérimental utile pour extraire de l'information en dehors des régions couvertes par les plaques d'enregistrement épicardique. / Atrial fibrillation is the most common clinical arrhythmia currently affecting 2.3 million patients in North America. To study its mechanisms and potential therapies, animal models of atrial fibrillation have been developed. Epicardial high-density electrical mapping is a well-established experimental instrument to monitor in vivo the activity of the atria in response to pacing, remodeling, arrhythmias and modulation of the autonomic nervous system. In regions that are not accessible by epicardial mapping, noncontact endocardial mapping performed through a balloon catheter may provide a more comprehensive description of atrial activity. In this study, a dog experiment was designed and analyzed in which electroanatomical reconstruction, epicardial mapping (103 electrodes), noncontact endocardial mapping (2048 virtual electrodes computed from a 64-channel balloon catheter), and direct-contact endocardial catheter recordings were simultaneously performed. The recording system was also simulated in a computer model of the canine right atrium. For simulations and experiments (after atrio-ventricular node suppression), activation maps were computed during sinus rhythm. Repolarization was assessed by measuring the area under the atrial T wave (ATa), a marker of repolarization gradients. Results showed an epicardial endocardial correlation coefficient of 0.8 (experiment) and 0.96 (simulation) between activation times, and a correlation coefficient of 0.57 (experiment) and 0.92 (simulation) between ATa values. Noncontact mapping appears to be a valuable experimental device to retrieve information outside the regions covered by epicardial recording plaques.

Vu le caractère non-invasif des procédures d’électrophysiologie interventionnelle, la visualisation de régions anatomiques d'intérêt et une orientation adéquate en cours de procédure sont nécessaires. L'objectif de cette thèse est d'étudier, d'optimiser et d'étendre l’utilisation des modalités d'imagerie radiographique. La dose de radiation effective (ED) est calculée d’une façon spécifique au patient pour l’angiographie rotationnelle 3D (3DRA) et il est démontré qu'en ajustant l’acquisition en 3DRA et en fluoroscopie, une réduction de dose importante est possible sans compromettre la qualité d’image nécessaire à la procédure. Un protocole d'acquisition et post traitement pour obtenir une imagerie dynamique basée sur le 3DRA est présenté,permettant une réduction du bruit d'image et une segmentation d'images automatique. L'extraction d'informations dynamiques, structurelles et fonctionnelles à partir d'images MDCT, relatives à la gestion de la fibrillation auriculaire (FA) est étudiée. La fonction auriculaire globale est examinée et des cartes de mouvement régional et de tissu adipeux épicardique sont produites et liés à la FA à différents stades. Une méthode automatisée est présentée pour mesurer l’orifice de l’appendice auriculaire gauche au long du cycle cardiaque et pour optimiser le déploiement de dispositifs de fermeture. Optimiser l’usage des rayons X, les protocoles d'acquisition et les méthodes de post traitement d’images, permet d’obtenir des informations supplémentaires pertinentes aux procédures d'électrophysiologie interventionnelle depuis les modalités d'imagerie radiographiques sans compromettre la qualité d’image ou le flux de travail procédural. / Due to their non-invasive character, interventional electro physiological procedures require visualisation of anatomical regions of interest and adequate guidance of procedural manoeuvres. The aim of this thesis was to study, optimise and expand the use of radiographic imaging modalities. The first part focuses on the influence of C-arm system image acquisition parameters on radiation dose incurred by the patient. We developed a patient-specific way to calculate effective dose (ED) in 3Drotational angiography (3DRA) and showed in 3DRA and fluoroscopy that by applying adequate protocol adjustments, an important dose reduction could be obtained without compromising necessary image quality. The second part focuses on the development and validation of an acquisition and post-processing protocol for dynamic imaging using 3DRA. This method enables automatic image noise reduction and image segmentation. The third part focuses on the extraction of dynamic,structural and functional information from MDCT images, relevant to management of atrial fibrillation (AF). We studied atrial function and generated maps of regional atrial motion and epicardial adipose tissue and related them to AF burden. We also developed an automated method to measure LA appendage orifice dimensions through out the cardiac cycle to optimise measurements for deployment of closure devices.Overall we demonstrate that by optimising radiation usage, acquisition protocols and image post-processing methods, additional information relevant to interventional electrophysiological procedures can be extracted from radiographic imaging modalities without compromising image quality or procedural workflow.

Fundamentos O acesso percutâneo ao espaço pericárdico pela via transatrial poderia ser uma alternativa ao acesso subxifóide para o mapeamento e ablação de fibras miocárdicas subepicárdicas. O objetivo deste estudo foi avaliar a viabilidade de alcançar o espaço pericárdico normal através do apêndice auricular direito (AAD) por acesso transvenoso. Métodos e Resultados - Um sistema Mullins (8F), originalmente desenvolvido para alcançar o átrio esquerdo (AE) por punção transeptal foi utilizado neste estudo para transfixar o AAD (16) ou AE (1) em 17 suínos, com uma média de 26,9 ± 2,6 kg, e alcançar o espaço pericárdico normal. Um cateter 7F quadripolar com eletrodo distal com 4 ou 8 mm foi introduzido no espaço pericárdico para aplicações de radiofrequência. Em 15 (88%) animais o procedimento foi realizado sem instabilidade hemodinâmica (PA média inicial = 80,4 ± 11.7 mmHg; PA média final = 86,8 ± 9.7 mmHg, p = 0,11). Foi identificado e aspirado derrame pericárdico discreto (28,9 ± 27.6 ml/animal) durante o procedimento. O espaço pericárdico foi acidentalmente acessado por punção do ventrículo direito (VD) em um animal e por punção do anel da valva tricúspide em outro. Ambos apresentaram sangramento xii pericárdico importante e tamponamento cardíaco. Um dispositivo para oclusão do orifício de perfuração foi testado com sucesso em três porcos, dois no AD e um no VD, sem ocorrência de derrame pericárdico significativo. Conclusões O acesso transatrial ao espaço pericárdico pode ser potencialmente útil para mapeamento e ablação de arritmias cardíacas, bem como para drenagem imediata de um tamponamento cardíaco agudo / Background A transvenous access to the pericardial space could provide a convenient route to map and ablate subepicardial myocardial fibers. The aim of this study was to evaluate the feasibility of reaching the normal pericardial space through the right atrial appendage (RAA) by transvenous access. Methods and Results An 8F Mullins system was used to transfix the right atrium (16) and left atrium (1) in 17 pigs with a mean of 26.9 ± 2.6 kg. A 7F quadripolar catheter with 4 or 8 mm distal tip electrode was introduced into the pericardial space to perform epicardial radiofrequency lesions. The pericardial space was successfully reached in 15 (88%) animals without hemodynamic instability (initial mean BP 80.4 ± 11.7 mmHg; final 86.8 ± 9.7 mmHg, p= 0,11). However, a mild pericardial serohemorrhagic effusion was identified and aspirated in all the animals (28.9 ± 27.6 ml/pig) during the procedure. The pericardial space was accidentally accessed through the right ventricle (RV) in one animal and through the tricuspid annulus in another, which presented important pericardial bleeding and cardiac tamponade. The hypothesis that an occlusion device could be useful to close the created atrial xiv orifice was tested successfully in thee pigs (two at RAA and one at RV) and without significant pericardial bleeding. Conclusions The right atrial appendage route might be potentially useful to access the normal pericardial space for mapping and ablating cardiac arrhythmias as well as to drain promptly an acute tamponade

Le diabète de type 2 (DbT2) est une maladie chronique caractérisée par des taux sanguins élevés de glucose pouvant engendrer de multiples complications, sources de morbidité et mortalité importantes. De façon alarmante, la prévalence mondiale est en augmentation due en grande partie au vieillissement de la population et à l’adoption d’habitudes de vie (HDV) malsaines. La sédentarité et la mauvaise qualité alimentaire sont à la base d’une épidémie d’obésité qui joue un rôle crucial dans la pathogénèse du DbT2. La modification des HDV en visant une balance calorique négative demeure un traitement primordial dans la prise en charge de cette maladie. Toutefois, il persiste un doute par rapport à la thérapie à privilégier entre une restriction calorique (RC) ou une combinaison d’une thérapie à base de RC et d’activité physique (AP), afin de favoriser une perte de masse grasse et de gras épicardique. Ce dernier représente le gras viscéral du cœur et est un marqueur émergent qui pourrait aider dans la stratification du risque cardiovasculaire. Le but général de ce mémoire est de caractériser les effets indépendants de la RC et de l’AP sur le gras total, le gras épicardique et le profil cardiométabolique des personnes atteintes de DbT2. Pour ce faire, une étude randomisée contrôlée de 16 semaines fut menée avec 73 patients répartis en 3 groupes de randomisation (Contrôle, RC, RC+AP) en visant un déficit calorique similaire dans les 2 groupes d’intervention. Les résultats ont démontré que la combinaison RC+AP favorise une réduction plus significative de la masse grasse totale et de l’épaisseur du gras épicardique. Toutefois, il n’y a pas eu d’amélioration additionnelle du profil cardiométabolique. Ces résultats doivent maintenant être validés dans de plus grosses études. / Type 2 diabetes (T2D) is a chronic disease characterized by high blood sugar that can lead to many complications with potential morbid outcomes. Alarmingly, the worldwide prevalence is increasing at a high rate mainly du to aging and harmful lifestyle habits. In fact, inactivity and poor food choices are at the heart of an obesity epidemic that plays a crucial role in the pathogenesis of T2D. Lifestyle modifications thus play an important role in patient care. However, it remains uncertain which therapy between a caloric restriction (CR) alone or a combination of CR plus physical activity (PA) should be encouraged to achieve better reduction in fat mass and in epicardial fat thickness. The latter represents the visceral fat depot of the heart and is emerging as an important marker for predicting and stratifying cardiovascular risk. The objective of this Master’s thesis is to better characterize the independent effects of CR and PA on total fat mass, epicardial fat, and overall cardiometabolic profile of patients with T2D. To achieve this, a randomized controlled 16-week trial was performed, with 73 patients randomized to 1 of 3 groups (Control, CR, or CR+PA), while aiming for a similar caloric deficit in both intervention groups. Results showed that the combination of CR+PA allows a larger reduction of fat mass and epicardial fat thickness. However, these findings did not translate into significant differences in cardiometabolic improvements between groups. These results now need to be validated in larger cohorts with longer follow-ups.