La fibrillation atriale est la plus fréquente des arythmies cardiaques et sa physiopathologie reste mal comprise. Il n’existe pas actuellement de modèle animal dans lequel cette arythmie survienne de manière spontanée. Comme l’âge et l’hypertension artérielle sont deux facteurs de risque majeurs dela fibrillation atriale chez l’Homme, nous avons recherché si le rat spontanément hypertendu (SHR)vieillissant (11-13 mois d’âge) développe cette pathologie. Des enregistrements télémétriques de 24 h de l’électrocardiogramme (ECG) ont été réalisés dans 4 groupes de rats vigils. Ils ont révélé chez le rat SHR vieillissant la présence de nombreux épisodes de tachyarythmie atriale non soutenus, épisodes qui ne sont pas observés chez le rat SHR jeune ni chez lerat normotendu Wistar Kyoto jeune ou vieillissant. Les résultats rapportés ci-dessus ont été obtenus grâce à l’analyse visuelle de l’intégralité de chaque enregistrement ECG, ce qui représente une durée d’analyse incompatible avec des expérimentations de routine. Nous avons donc choisi de développer une méthode automatique de reconnaissance des arythmies atriales chez le rat vigil. Cette méthode utilise exclusivement les intervalles RR car les ondes P ne peuvent pas toujours être identifiées avec fiabilité dans les enregistrements télémétriques de l’ECG. Elle repère les motifs caractéristiques de tachyarythmie grâce à une structure d’automate, et présente une bonne performance sur les enregistrements télémétriques déjà réalisés. Le nouveau modèle animal, conjointement à la nouvelle méthode automatique d’analyse de l’ECG, devrait permettre de réaliser les analyses phénotypiques de qualité indispensables aux hypothèses physiopathologiques moléculaires actuellement avancées dans la fibrillation atriale. / Atrial fibrillation is the most common cardiac arrhythmia and its pathophysiology is still poorly understood. To date, there is no animal model in which the arrhythmia occurs spontaneously. As ageand hypertension are major risk factors of atrial fibrillation in humans, we examined whether the aging (11-13 months of age) spontaneously hypertensive rat (SHR) develops this pathology. Telemetric recordings of electrocardiogram (ECG) were obtained in four groups of conscious rats. They revealed the presence in the aging SHR of many non-sustained atrial tachyarrhythmic episodes that were observed neither in the young SHR nor in the young or aging normotensive Wistar Kyotorat. These results were obtained by visual examination of the whole ECG recordings, which is extremely time consuming and thus, not compatible with routine experiments. Therefore, we chose to develop an automated method to detect atrial arrhythmias in the conscious rat. This method only uses RR intervalsbecause P waves cannot always be accurately identified in telemetric recordings. It recognizes characteristicpatterns of tachyarrhythmia by using an automaton structure, and shows a good performance when applied to previously collected telemetric data. The new animal model, together with the new, automated method of ECG analysis, are expected to be extremely useful for producing high quality phenotypic data, which are necessary to test present molecular hypotheses of atrial fibrillation pathophysiology.

Objetivo: Avaliar o uso de antitrombóticos em pacientes com fibrilação atrial (FA) em hospital cardiológico no Brasil (InCor).Métodos e resultados: Um estudo observacional transversal analisou os prontuários de todos os pacientes atendidos no InCor em cada um de 5 dias separados no ano de 2002 (Fase 1), sendo prospectivamente reanalisados após 1 ano (Fase 2). A prevalência da FA nos 3764 prontuários analisados foi de 8%. Antiplaquetários foram prescritos para 21,26% e 19,93%, anticoagulantes para 46,51% e 57,81%, e 32,23% e 22,26% não usavam nenhum antitrombótico nas Fases 1 e 2, respectivamente. Somente 15,60% e 23,25% apresentavam níveis de RNI terapêuticos.Conclusão: A anticoagulação é subutilizada nos pacientes com FA apesar do fato de serem tratados por cardiologistas em um hospital universitário / Objective: To assess antithrombotic therapy among atrial fibrillation (AF) patients in a Brazilian University Heart Hospital (InCor).Methods and results: A cross sectional study analyzed the charts of all patients treated at InCor in 5 separate days of 2002 (Phase 1), and prospectively reviewed them after one year (Phase 2). The prevalence of AF in the 3,764 assessed charts was of 8.0%. Antiplatelets were prescribed to 21.26% and 19.93%, anticoagulants to 46.51% and 57.81%, and 32.23% and 22.26% were not receiving any antithrombotic in Phases 1 and 2, respectively. Only 15.60% and 23.25% were within INR therapeutic range.Conclusion: Anticoagulation is underused in AF patients besides the fact of being treated by cardiologists in a University Hospital

Eventuais alterações no substrato anatômico miocárdico, no sistema nervoso autônomo (SNA) cardíaco intrínseco, envolvendo os plexos ganglionares (PG) comumente presentes em organizações de gordura epicárdicas denominadas fatpads (FP) ou a expressão dos receptores muscarínicos, poderiam ser responsáveis pela gênese e manutenção da fibrilação atrial (FA). Com o objetivo de analisar a relação entre fibrilação atrial permanente (FAP) e possíveis alterações anatômicas e micromorfológicas do coração, do SNA cardíaco intrínseco e da expressão dos receptores muscarínicos miocárdicos, foram estudados 13 corações de autópsias de portadores de FAP e cardiopatia crônica definida (grupo I) e 13 casos pareados pela mesma doença cardíaca, porém sem esta arritmia (grupo II). Foram analisados a anatomia da drenagem venosa do átrio esquerdo (AE), peso do coração, espessura do septo ventricular e diâmetro dos FP epicárdicos. Foram ressecadas duas amostras no átrio direito (AD1 e AD2), três no átrio esquerdo - no trajeto médio da VoAe (AE1), na junção da veia pulmonar superior esquerda (AE2) e na aurícula (AE3), três em FPs, atrial esquerdo superior (FP1), atrial direito posterior (FP 2) e no atrial esquerdo póstero-medial (FP 3) e uma amostra do septo ventricular (SIV), como controle. As alterações estruturais das fibras miocárdicas, as espessuras do epicárdio, endocárdio e miocárdio e o percentual de colágeno intersticial no miocárdio foram analisados através de histomorfometria computadorizada sob coloração de tricrômio de Masson. O SNA cardíaco intrínseco foi analisado através imuno-histoquímica para S-100 e tirosina-hidroxilase quanto a: quantidade e área das fibras nervosas, quantidade e área média de fibras simpáticas, quantidade e área média de fibras parassimpáticas e proporção de fibras simpáticas/parassimpáticas. A expressão miocárdica dos receptores muscarínicos 1 a 5 (M1 a M5) foi avaliada pela proporção positiva no miocárdio nos cortes AD1, AE1, AE2 e FP1. Não houve diferenças entre os grupos quanto às variáveis anatômicas e ao percentual de colágeno intersticial. A análise do SNA revelou fibras nervosas com menor área no grupo I, redução do número de fibras nervosas totais e parassimpáticas nos cortes AD1 e SIV, aumento de fibras totais e parassimpáticas AE2 e FP2 e aumento do número de fibras simpáticas nos cortes AD2, AE1, AE2 e AE3. Quanto à expressão dos receptores muscarínicos, houve aumento significante na porcentagem positiva para M1 em todas as regiões, exceto na AE1 (média de todos os cortes, grupo I 5,84 e grupo II 2,92, p=0,002); o M2 e M3 apenas junto ao FP1 (M2 grupo I 5,67 e grupo II 3,63, p=0,037; M3 grupo I 30,95 e grupo II 20,13, p=0,026) e o M4 foi aumentado no grupo I na região AE1 (grupo I 9,90 e grupo II 4,45, p=0,023); não houve alteração estatisticamente significante no M5. A anatomia e a disposição das fibras musculares atriais, bem como a fibrose intersticial não parecem estar relacionadas à FAP nos grupos estudados. Alterações no número de fibras nervosas bem como e alterações na expressão dos receptores muscarínicos atriais, especialmente o M1, particularmente em regiões próximas aos PG, parecem estar relacionadas à FAP, indicando a importância da modulação autonômica nesta arritmia / Possible changes in myocardial substrate, in the intrinsic cardiac autonomic nervous system (ANS), involving the ganglionated plexus (GP) present in fat-pads (FP) or the expression of muscarinic receptors could be responsible for the genesis and maintenance of atrial fibrillation (AF). Aiming to analyze the relationship between permanent atrial fibrillation (pAF) and possible anatomical and micromorphological heart changes, intrinsic cardiac ANS and expression of myocardial muscarinic receptors, 13 hearts from autopsies of patients with PAF and chronic heart disease (group I) were studied; and 13 cases matched by the same heart disease, but without this arrhythmia (group II). It was analyzed the anatomy of the venous drainage of the left atrium (LA), heart weight, ventricular septal thickness and diameter of epicardial FP. Two samples were taken in the right atrium (RA1 and RA2), three in the left atrium - in the middle portion of the left atrium oblique vein (LaOv LA1), at the junction of left superior pulmonary vein (LA2) and in the auricle (LA3), three FPs, left atrial superior (FP 1), right atrial posterior (FP 2) and the left atrial posteromedial (FP 3) and one sample of the ventricular septum (VS), as control. The structural changes of the myocardial fibers, thickness of the epicardium, endocardium and myocardium, and the percentage of interstitial collagen in the myocardium were analyzed by computerized histomorphometry on Masson trichrome staining. The intrinsic cardiac ANS was analyzed through immunohistochemistry for S-100 and tyrosine hydroxylase regarding the: amount and area of nerve fibers, amount and average area of sympathetic fibers, number and average area of parasympathetic fibers and sympathetic/parasympathetic fiber proportion. The myocardial expression of muscarinic receptors 1-5 (M1 to M5) was evaluated by positive ratio in the myocardium in sections RA1, LA1, LA2 and FP1. There were no differences between groups regarding the anatomical variant and the percentage of interstitial collagen. Analysis of the ANS revealed nerve fibers with the smallest area in group I, reduction in the number of total and parasympathetic nerve fibers of sections RA1 and VS, increase of total and parasympathetic fibers LA2 and FP2 and increased numbers of sympathetic fibers in sections RA2, LA1, LA2 and LA3. Regarding the expression of muscarinic receptors, there was a significantly increase in the positive percentage for M1 in all regions except for LA1 (average of all the sections, group I 5.84 and group II 2.92, p = 0.002), M2 and M3 just adjacent to the FP1 (M2 Group I 5.67 and Group II 3.63, p = 0.037; M3 Group I 30.95 and Group II 20.13, p = 0.026) and the M4 was increased in group I in the region LA1 (group I 9.90 and group II 4.45, p = 0.023) and there was no statistically significant change in the M5. The anatomy and arrangement of atrial muscle fibers, as well as the interstitial fibrosis did not appear to be related to PAF in both studied groups. Changes in the number of nerve fibers as well as changes in expression of atrial muscarinic receptors, specially the M1, particularly in regions close to the GP appear to be related to pAF, indicating the importance of autonomic modulation in this arrhythmia

Introdução: Na última década, desde a descrição inicial da ablação das veias pulmonares, a ablação por cateter da fibrilação atrial (FA) tem evoluído consideravelmente em eficácia e segurança, consolidando-se como opção terapêutica em pacientes selecionados com FA. No entanto, a ablação da FA é um procedimento complexo e não isento de riscos. Ainda que seja uma complicação rara, o desenvolvimento de fístulas átrio-esofágicas (FAE) é a segunda complicação responsável por morte relacionada ao procedimento e responde por 16% dos casos de morte após ablação de FA. Consensos atuais não orientam recomendações definitivas para prevenção de lesões esofágicas, consideradas lesões precursoras de FAE. O objetivo deste trabalho foi comparar a incidência de lesões esofageanas e periesofageanas por ecoendoscopia após ablação de fibrilação atrial, utilizando diferentes estratégias de proteção esofágica durante as aplicações de radiofrequência na parede posterior do átrio esquerdo. Método: No período de outubro/2012 a julho/2014, foram estudados 45 pacientes submetidos à ablação percutânea de FA, portadores de FA paroxística ou persistente há menos de um ano. Todos os pacientes foram submetidos a ablação circunferencial com isolamento elétrico das veias pulmonares, com cateter de ablação 8 mm. Antes do procedimento, os pacientes foram randomizados para uma de três estratégias de proteção esofágica durante as aplicações de radiofrequência na parede posterior do átrio esquerdo para ablação da FA: Grupo I - aplicações limite fixo e de baixa energia, 30 W; Grupo II - aplicações com energia limitada pela temperatura esofágica; GIII - aplicações com limite fixo de energia durante resfriamento esofágico contínuo. A pesquisa de lesões esofágicas/periesofágicas foi feita por ecoendoscopia realizada em até 48 horas após a ablação. Resultados: As características basais foram similares nos três grupos, não sendo encontradas diferenças significativas entre as variáveis clínicas, laboratoriais, ecocardiográficas ou ecoendoscópicas prévias, com exceção da distância átrio-esofágica pré-ablação medida pela ecoendoscopia, que foi menor no Grupo III (GI = 3,9 mm +- 0,4; GII = 3,9 mm +- 0,5; GIII = 3,4 mm +- 0,4, p = 0.002). Nas ecoendoscopias pós-ablação de FA, foram encontradas 04 lesões esofágicas/periesofágicas: duas úlceras de parede esofágica e dois casos de edemas de mediastino periesofágico. Todos os casos de lesões esofágicas/periesofágicas ocorreram no grupo de resfriamento esofágico, G III (p= 0,008). A comparação das características clínicas dos pacientes que apresentaram lesões esofágicas/periesofágicas com os que não apresentaram essas alterações, pela análise bivariada, mostrou que foram similares nos dois grupos, exceto pelos valores médios de proteína C reativa (PCR) após a ablação de fibrilação atrial, que foram significativamente maiores no grupo com lesões (Grupo sem lesões: PCR = 0,82 mg/dl; Grupo com lesões: PCR = 2,12 mg/dl, p < 0,001). A comparação dos parâmetros das ablações por regiões das veias abordadas, quanto ao tempo das aplicações de radiofrequência, a potência e a temperatura do cateter de ablação, identificou que os pacientes que apresentaram lesões esofágicas/periesofágicas tiveram maiores valores de média de potência nas aplicações realizadas na parede posterior das veias pulmonares esquerdas, que os pacientes que não tiveram lesões (Grupo sem lesões esofágicas: potência média cateter = 37,7 w; Grupo com lesões esofágicas: potência média do cateter = 48,8 w, p = 0.013). A incidência de recorrência de arritmia após um único procedimento de ablação de Fibrilação Atrial, em seguimento clínico de 11 +- 5 meses, foi de 7 casos (15.6%), sem diferença significativa entre os grupos (GI = 26,7%, GII = 13,3% e GIII = 6,7%, p = 0,305). A incidência de complicações maiores relacionadas aos procedimentos de ablação realizados foi de 2,2% (um caso de congestão pulmonar no segundo dia após o procedimento, resolvido com uso de diuréticos). Conclusão: O uso da estratégia de resfriamento esofágico durante ablação de FA foi ineficaz como estratégia preventiva de lesões esofágicas/periesofágicas na população estudada, quando comparada às estratégias de aplicações de radiofrequência com baixa energia ou de energia limitada pela temperatura esofágica / Introduction: In the last decade, since the initial description of the ablation of pulmonary veins, the atrial fibrillation (AF) catheter ablation has evolved significantly in terms of efficacy and safety, consolidating itself as the therapeutic choice for AF selected patients. However, AF ablation is a complex procedure not without risks. Despite being a rare complication, the development of atrialesophageal fistulas (AEFs) ranks second in terms of procedure-related deaths, accounting for 16% of all post-AF ablation losses of life. Current consensus is not dispositive with regards to directives for the prevention of esophageal lesions, which come first and lead to AEFs. The objective of this work is to compare the incidence of esophageal and periesophageal lesions post-AF ablation, given use of different esophageal protection strategies during the radiofrequency applications on the left-atrium posterior wall. Method: From October 2012 through July 2014, 45 patients submitted to AF percutaneous ablation were studied. All of them were bearers of paroxistic or persistent AF for less than one year, and all of them were submitted to 8mm-catheter, pulmonary vein electric-shielding circumferential ablation. Before the procedure, patients were randomly assigned to one of three esophageal lesion protection strategies: Group I - 30w, low energy, fixed limited applications; Group II - energy applications limited by esophageal temperature; and Group III - fixed limit energy applications during continuous esophageal cooling. The survey for esophageal/periesophageal lesions was carried by means of esophageal endoscopy combined with radial ultrasound performed within 48 hours post ablation. Results: Baseline characteristics were even across groups; no significant differences in clinical, laboratorial, ecocardiographic or endoscopic variables were found, except for pre-ablation distance between posterior left atrium wall and the esophagus as measured by radial ultrasound endoscopic, smaller in Group III (GI = 3,9 mm +- 0,4; GII = 3,9 mm +- 0,5; GIII = 3,4 mm +- 0,4, p = 0.002). Post FA-ablation endoscopies revealed the existence of 4 counts of esophageal/periesophageal lesions: 2 esophageal wall ulcer and 2 periesophageal mediastin edema. All cases of esophageal/periesophageal lesions occurred in the esophageal cooling group (GIII) (p=0.008). Bivariate analysis on the clinical characteristics of patients that presented esophageal/periesophageal lesions showed no significant difference from those in the lesion-free group, except for average values for post ablation reactive-C protein (RCP), significantly greater in the lesion group (2.12 mg/dl vs. 0.82 mg/dl for the lesion-free group, p < 0.001). Ablation parameter comparison by approached vein region revealed that patients with post ablation lesions had received higher-powered applications in their posterior wall left pulmonary veins (average catheter power = 48.8 w vs. 37.7 w for lesion-free group, p=0.013). After a 11 +- 5 month clinical following, arrhythmia recurrence post a single AF ablation procedure added to 7 cases (15.6%), and no significant difference among the three different groups was found (GI = 26.7%, GII = 13.3% e GIII = 6.7%, p = 0.305). Incidence of major complications related to the ablation procedures reached 2.2% (one case of pulmonary congestion occurring in the second day post procedure, and resolved with the use of diuretics). Conclusion: The use of esophageal cooling during AF ablation was an ineffective strategy to prevent esophageal/periesophageal lesions in the studied population when compared to low-energy radiofrequency or energy limited by esophageal temperature lesion prevention strategies

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23057号 / 医博第4684号 / 新制||医||1048(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森田 智視, 教授 湊谷 謙司, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13420号 / 論医博第2228号 / 新制||医||1052(附属図書館) / (主査)教授 川上 浩司, 教授 湊谷 謙司, 教授 山下 潤 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DGAM

Patients with atrial fibrillation (AF) require modification of ectopic electrical activity to avoid potentially fatal health complications. Catheter ablation therapy is a minimally invasive procedure to create tissue necrosis, called lesion, in areas of abnormal electrical activity. However, significant proportion of patients require repeat treatment from AF recurrences in part by electrical reconnection from incomplete lesions and conduction recovery. Current therapeutic approaches are limited by reliable methods to assess AF structural substrates and validate lesion sufficiency during procedures. In recent years, development of near-infrared optical spectroscopy has provided a non-invasive method to evaluate biological tissue. Near infrared spectroscopy (NIRS) is an optical technique that enables direct characterization of pathological tissue based on the absorption of major chromophores and light scattering. In this thesis, we explore the use of near-infrared optical spectroscopy to identify AF substrates and quantify lesion formation to improve treatment efficacy. First, we developed a near-infrared multispectral imaging system and present a model to assess lesion adequacy by direct visualization of cardiac lesions through an endoscope-integrated probe. Then, a custom single fiber integrated radiofrequency (RF) ablation catheter was fabricated to track irrigated lesion progression real-time on ex vivo swine hearts. A machine learning model was introduced to predict lesion size and transmurality. Additionally, we assess the feasibility of near-infrared spectroscopy by fabricating a NIRS-integrated open-irrigation RF ablation catheter and an algorithm to assess lesion dimensions based on key features derived from NIRS measurements. Using this model, we demonstrate real-time tracking of irrigated lesion delivery in both ex vivo and in vivo swine model. Lastly, we show left atrial endocardial mapping with NIRS-integrated RF mapping catheter to assess AF structural substrates. We present a classification algorithm for important AF structural substrates, such as pulmonary vein sleeve, normal myocardium, ablated tissue, and fibrosis, and a regression model to validate lesion adequacy. A near-infrared spectroscopy-based techniques to localize structural complexities and validate lesion sufficiency at the catheter tip could enhance the understanding of underlying AF substrates and improve treatment efficacy.

In der hier vorliegenden Arbeit sollen die Ergebnisse einer endokardialen Kryoablation in Kombination mit einer minimal-invasiven Mitralklappenoperation bezogen auf unterschiedliche Vorhofflimmerformen ausgewertet werden. Hierzu wurden prospektiv gesammelte Daten von 732 Patienten analysiert, die zwischen 2002 und 2009 eine minimal-invasive Mitralklappenoperation mit zusätzlicher Kryoablation zur Behandlung von Vorhofflimmern (VHF) am Herzzentrum Leipzig erhielten. Insgesamt 84% der Patienten erhielten vor der Krankenhausentlassung ein 24-Stunden-Langzeit-EKG. Während jährlicher Telefongespräche wurden die Folgemedikation sowie die klinischen Symptome der Patienten abgefragt und einmalig die Lebensqualität mittels des SF-12 Fragebogens und des AFSS-Fragebogens evaluiert. Zur Beurteilung des Herzrhythmus wurde das letzte vorliegende EKG oder sofern vorhanden, ein 24h-LZ-EKG vom Hausarzt oder zuweisenden Kardiologen ausgewertet. Die Gesamtmortalität im Krankenhaus lag bei 1,5% ohne einen Unterschied zwischen Patienten mit paroxysmalem und lang-persistierendem VHF. Bedeutende Risikofaktoren für Hospitalsterblichkeit waren ein fortgeschrittenes Alter, eine präoperative Ejektionsfraktion von weniger als 50%, ein höherer CHADS2-Score sowie Angina-pectoris-Beschwerden. Das Gesamtüberleben tendierte nach einem, drei sowie fünf Jahren bei Patienten mit lang-persistierendem VHF zu schlechteren Ergebnissen (93,8%/91,4/86,1%) verglichen mit Patienten, welche ein paroxysmales VHF hatten (96,6%/93,6%/90,7%). Nach 12 Monaten waren 90,8±1,1% der gesamten Patientenkohorte frei von einem erneuten VHF, nach drei Jahren 72,5% und nach fünf Jahren 48,9%. Auch hier zeigten die Patienten mit einem lang-persistierenden VHF nach 5 Jahren schlechtere Ergebnisse (60,2% vs. 43%). In der hier präsentierten Studie konnten als bedeutende Risikofaktoren für ein Wiederauftreten von VHF im Langzeitverlauf ein präoperativ erhöhter Kreatininwert und grenzwertig signifikant ein VHF im Langzeit-EKG vor Krankenhausentlassung dargestellt werden. Die Rate an kardialen und zerebralen Komplikationen (MACCE) in der Langzeitbeobachtung war mit 26,3% in beiden Patientengruppen ähnlich und auch vergleichbar mit den Ergebnissen anderer Zentren bzw. Studien. Es konnte gezeigt werden, dass Patienten mit einem stabilen SR in der Nachbeobachtung eine wesentlich niedrigere MACCE-Rate aufwiesen (38,0% vs. 20,9%). Die Schlaganfallrate insgesamt lag sehr niedrig (1,9%), wobei auch hier die Patienten mit einem stabilen SR deutlich besser abschnitten (3,9% vs. 1,0%). Die Lebensqualität und die subjektiven Beschwerden durch das VHF waren bei beiden Patientengruppen (paroxysmal vs. lang persistierend) vergleichbar. Auch hier zeigte sich, dass Patienten mit erfolgreicher Wiederherstellung des SR einen deutlichen Gewinn an Lebensqualität aufwiesen. Insgesamt waren die Morbidität und Mortalität nach einem minimal-invasiven Mitralklappeneingriff niedrig. Diese Studie unterstützt die Hypothese, dass die Kryoablation eine sichere und effektive Methode ist, VHF bei Patienten während einer Mitralklappenoperation simultan zu abladieren. Da die Mitralklappenchirurgie allein mit nur einer geringen Rate an Konversionen in den SR verbunden ist und die endokardiale Kryoablation ein sicheres Verfahren darstellt, sollte diese Option bei jedem VHF-Patienten, der sich einer Mitralklappenoperation unterzieht, erwogen werden.

Background: Geriatric impairments and obstructive sleep apnea (OSA) are prevalent among patients with atrial fibrillation (AF) and adversely impact patient’s long-term outcomes. Little is known, however, about the association between OSA and frailty, cognitive performance, and AF-related quality of life in older men and women with AF. Objective: To examine the association of OSA with frailty, cognitive performance, and AF- related quality of life among older adults with AF. Methods: Data from the Systemic Assessment of Geriatrics Elements-AF study were used which includes participants ≥ 65 years with AF and a CHA2DS2-VASc ≥ 2. Multivariable adjusted logistic regression models were used to examine the association between OSA, as measured by the STOP-BANG questionnaire, and geriatric impairments including frailty, cognitive performance, and AF-related quality of life. Results: A total of 970 participants with AF (mean age 75 years, 51% male) were included in the analysis. Among the 680 participants without a medical history of OSA, 179 (26%) participants had low risk of OSA, 360 (53%) had an intermediate risk, and 141 participants (21%) had a high risk for OSA. Compared to those with low risk of OSA, those at intermediate or high risk for OSA were significantly more likely to be frail (aOR= 1.66, 95% CI: 1.08–2.56; aOR= 3.00, 95% CI: 1.69-5.32, respectively) after adjusting for sociodemographic, clinical, and health behavioral variables. Risk of OSA was not associated with cognitive performance and AF- related quality of life after adjusting for several potentially confounding factors. Conclusions: Older adults with AF who are at intermediate or high risk for OSA have a greater likelihood of being frail. Our findings identify a group of patients at high risk who would benefit from early screening for OSA. Future longitudinal studies are needed to assess the effect of OSA treatment on frailty, physical functioning, and QoL among patients with AF.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.