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

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

Le projet de cette thèse porte sur la graisse ectopique cardiaque et son lien avec les pathologies cardiovasculaires. Dans un premier travail, nous avons mis au point la technique de mesure du volume de graisse épicardique, et du contenu en triglycérides intramyocardique chez le patient obèse morbide en imagerie de résonance magnétique à 3T, et spectroscopie proton. Nous avons montré que les deux dépôts de graisse ectopique augmentent avec l’obésité, mais sans continuum avec la prise de poids. Alors que la graisse épicardique est liée aux paramètres de la tolérance glucidique, la graisse intramyocardique est liée à la fonction cardiaque. Dans un second travail, nous avons montré qu’une perte de poids induite par une chirurgie bariatrique induit une diminution significative de la graisse épicardique, sans modifier la graisse intramyocardique, suggérant une différence de flexibilité de ces graisses avec la perte de poids. Nous avons également exploré le lien entre graisse épicardique et athérosclérose. Sur une cohorte de volontaires sains, nous avons montré que l’accumulation de graisse épicardique était inversement corrélée à la vasoréactivité de la microcirculation coronaire, suggérant que la graisse épicardique pourrait influer de manière précoce la fonction endothéliale. Enfin, en utilisant une approche transcriptomique, nous avons montré une signature spécifique du TAE humain en fonction de sa localisation anatomique. Ces travaux ouvrent de nouvelles pistes dans la compréhension du développement de la graisse ectopique cardiaque. / Cardiac ectopic fat deposition and its link with cardiovascular pathophysiology was the aim of this PhD project. We first developed 3T cardiovascular magnetic resonance imaging assessment of epicardial fat volume, and proton spectroscopy measurement of myocardial triglyceride content in a cohort of morbid obese subjects. We demonstrated that the two cardiac depots increased with obesity, but not continuously with gain weight. While epicardial fat was related to glucose tolerance parameters, myocardial fat was related to cardiac function. We then studied the effect of bariatric surgery induced weight loss on epicardial and myocardial fat, and found a significant decrease in epicardial fat, but no change in myocardial fat, highlighting differences in the dynamics and flexibility of these two fat pads with weight loss. Focusing on epicardial fat and its potential role in atherosclerosis, we evaluated the effect of epicardial fat volume on endothelium dependent vasoreactivity of the coronary microcirculation, in highly selected healthy volunteers. We found that a high epicardial fat amount was associated with a lower coronary microvascular response, suggesting that epicardial fat could early influence endothelial function. Finally, we identified a specific signature of three anatomically distinct human epicardial adipose tissues, using a transcriptomic approach. All together, our data bring new insights in the comprehension of specific partitioning of cardiac ectopic lipid deposition.

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

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.

Le diabète est aujourd’hui la 7ème cause de mortalité dans le monde. Dans cette population, la cardiomyopathie diabétique est la principale cause de morbi-mortalité. Le développement de cette complication débutant dès l’apparition du diabète, un dépistage et une prise en charge précoces de cette pathologie sont donc de première importance et sont les deux objectifs visés par ces travaux. La première étude que nous avons réalisée a permis de démontrer l’utilité d’une évaluation compréhensive de la fonction régionale myocardique gauche par 2D speckle-tracking imaging, en conditions de stress à la dobutamine, dans le dépistage précoce de la cardiomyopathie diabétique chez des patients diabétiques de type 2 asymptomatiques. La deuxième partie de ces travaux a, quant à elle, donné lieu à deux études. L’étude clinique a permis de mettre en évidence une amélioration de la réponse au stress de la fonction régionale myocardique après 3 mois de supplémentation en vitamine D3 chez des patients carencés. L’étude expérimentale a, pour sa part, souligné les effets bénéfiques sur le remodelage et la fonction cardiaques de cette supplémentation, en prévention secondaire, dans un modèle murin de diabète de type 2 induit par un régime gras et sucré. Par ailleurs, cette étude a mis en lumière l’implication potentielle d’une modulation des taux myocardiques en espèces lipotoxiques par la vitamine D3 dans ces effets. L’ensemble de ces travaux de thèse a ainsi permis, d’une part, de proposer une technique de dépistage des signes précoces d’altération de la fonction cardiaque chez le patient diabétique de type 2 et, d’autre part, de montrer les effets bénéfiques d’une supplémentation en vitamine D3 dans ce contexte. / Diabetes has reached the 7th place in the world’s top ten mortality causes. In this population, morbi-mortality mainly originates from diabetic cardiomyopathy. This complication evolving from the onset of diabetes, early diagnosis and care are of paramount importance and are the two purposes of this work. In our first study, we demonstrated the relevance of a comprehensive 2D speckle-tracking imaging analysis, under dobutamine stress, in unmasking early left ventricular regional myocardial dysfunction in a population of asymptomatic type 2 diabetic patients. In the second part of this work, we performed two studies. In the first one, we brought to light an improvement of regional myocardial function response to dobutamine stress after a three-month vitamin D3 supplementation protocol, in deficient patients. The second study was performed in a mouse model of diet-induced type 2 diabetes. In this last work, we put forward the beneficial effects of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function. These cardioprotective effects may be, at least in part, on account of modulatory effects of vitamin D3 on myocardial lipotoxic species levels. This whole work allow us to propose a tool enabling recognition of early cardiac function impairments in type 2 diabetic patients and to demonstrate the beneficial effects of vitamin D3 supplementation in this context.

Le projet de cette thèse porte sur le développement de dépôts lipidiques ectopique et leur modulation suite à des intervenions thérapeutiques par imagerie résonance magnétique.Dans notre première étude, nous avons établi l’ordre chronologique d’apparition de graisses ectopiques et d’anomalies cardiaques dans un modèle de souris soumises à un régime riche en graisse et en sucre. Un traitement de courte durée à l’exendine-4 permet une amélioration de tous les paramètres altérés. Dans la deuxième étude, nous avons évalué l’impact d’un traitement de l’obésité sur les dépôts ectopique de graisse cardiaque (TAE et stéatose), hépatique et pancréatique à deux temps (6 mois et 32 mois) après chirurgie bariatrique. Nous avons montré que ce traitement chirurgical permet une réduction de tous ces dépôts, avec une cinétique différente. Enfin, dans la troisième étude, nous nous sommes intéressés à l’effet du poids de naissance sur le développement de tissu adipeux épicardique. Cette étude nous a permis de mettre en évidence qu’il existe une accumulation plus importante de TAE à l’âge adulte lorsque le poids de naissance est augmenté ; et que les paramètres poids de naissance et croissance entre 2 et 12 ans, jouent un rôle important dans la mise en place de ce dépôts de graisse ectopique. En somme, ces résultats permettent une avancée dans la compréhension du développement des dépôts de graisses et de leur modulation. / The project of this thesis mainly focuses on ectopic lipid deposition development and their flexibility following therapeutic intervention. In our first study, we set out chronological order of ectopic fat onset and cardiac abnormalities in a high fat high sucrose mice model. Short duration exendin-4 treatment reverses every altered parameter. In the second study, we assessed treatment of obesity effect on cardiac ectopic fat deposition (EAT and steatosis), as well as hepatic and pancreatic fat at two different time points (6 months and 32 months) after bariatric surgery. We show significant reduction of every ectopic fat deposition, however in different kinetic. Finally, in a third study, we investigate birth weight effect on epicardial adipose tissue development. This study demonstrate important EAT accumulation in adulthood when birth weight is increased. Furthermore, birth weight and catch up growth in childhood between 2 and 12 years parameters impact significantly the development of epicardial fat.In summary, these results provide better understanding of ectopic fat deposition development and modulation.