Yes / Background and Objective In England, the uptake of direct oral anticoagulants (DOACs) for stroke prevention in atrial fbrillation has been slow and varied across diferent Clinical Commissioning Groups (CCGs). This study aimed to profle the prescribing of oral anticoagulants for stroke prevention in patients with atrial fbrillation over 3 years in a CCG without restrictions to DOACs use to understand more about organisational and/or individual barriers to the early uptake of DOACs. Methods Data were collected from nine general practices between 1 April 2012 and 31 March 2015 of patients who were initiated on the oral anticoagulant therapy. Data were analysed descriptively and with independent Student’s t test and Chi square test to explore if there was an association between type of oral anticoagulant initiated and sex, age, type of prescriber and prior aspirin use. Results The early uptake of DOACs signifcantly increased over the study period (p<0.0001; medium size efect φc=0.372). There was no statistically signifcant diference between sex or age and type of oral anticoagulant initiated. Primary-care prescribers were responsible for initiating the majority of oral anticoagulants (71%; N=257) and driving the use of DOACs (72%, N=71). Patients switched from aspirin to an oral anticoagulant were more likely to be initiated on warfarin than a DOAC. Conclusions The early use of DOACs, in a CCG without restrictions to their use, was embraced by primary-care prescribers in this particular CCG. / Bayer Pharmaceuticals via an unrestricted educational grant.

Atrial fibrillation (AF), the most common type of cardiac arrythmia, has been a huge concern of public health. It affects more than 6 million people in the United States and over 33 million people worldwide. In the current standard of care, an electrogram and geometry map is generated by electroanatomic mapping (EAM) using a mapping catheter, to determine the origins of irregular heart rhythm. Followed by radiofrequency ablation (RFA) using ablation catheter, the targeted sites are ablated as lesions to change the electrical conduction pathway of abnormal electrogram, thus restoring the patients to normal sinus heart rhythm with minimally invasive procedure. However, a significant proportion of patients suffer from AF recurrences and requires repeated procedures, due to the lack of reliable methods to assess the cardiac structural substrates which are the potential maintaining mechanism of AF signals. In recent years, optical imaging modalities are developed to compensate this limitation, among which near-infrared spectroscopy (NIRS) is a catheter-based technique to enable direct, independent characterization of cardiac tissue pathology from spectrum morphology. In this thesis, we validate the capability of NIRS to generate map with repeatability and identify AF substrate to improve the efficacy of treatment. First, a near-infrared imaging spectroscopy was combined with an electromagnetic tracking modality, and the system was operated with high acquisition speed and real-time display to generate high-density map. Further, the robustness of NIRS optical parameters was assessed under blood mapping and various, large catheter-tissue contact angle, to simulate the dynamic circumstance of clinical procedures. A classification algorithm was introduced to predict lesion probability including both PBS and blood data, as well as to evaluate the mapping equivalence of blood and PBS. Next, the spatial resolution and the sampling density requirement of NIRS mapping method was characterized based on small gap, and the spectral properties of gap was assessed comparing to normal tissue and lesion by statistical analysis and machine learning. Lastly, we demonstrate the identification of human left atrial complex substrates using NIRS catheter with different source-detector-separations (SDSs), and reported the spectral features for the AF-related structures such as fibrosis and adipose. To summarize, the catheter-based NIRS technology is robust for in-vivo application and structural target localization, with the potential to enhance the recognition of underlying AF pathology and improve treatment efficacy.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25164号 / 医博第5050号 / 新制||医||1071(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 石見 拓, 教授 大鶴 繁, 教授 江木 盛時 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13633号 / 論医博第2324号 / 新制||医||1074(附属図書館) / (主査)教授 江木 盛時, 教授 湊谷 謙司, 教授 森田 智視 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Atrial fibrillation is diagnosed in 1-2% of the population, in next decades, it expects a significant increase in the number of patients with this arrhythmia in connection with the aging of the population and the higher incidence of some diseases that are considered as risk factors of atrial fibrillation. The aim of this work is to describe the problem of atrial fibrillation and the methods that allow its detection in the ECG record. In the first part of work there is a theory dealing with cardiac physiology and atrial fibrillation. There is also basic descreption of the detection of atrial fibrillation. In the practical part of work, there is described software for detection of atrial fibrillation, which is provided by BTL company. Furthermore, an atrial fibrillation detector is designed. Several parameters were selected to detect the variation of RR intervals. These are the parameters of the standard deviation, coefficient of skewness and kurtosis, coefficient of variation, root mean square of the successive differences, normalized absolute deviation, normalized absolute difference, median absolute deviation and entropy. Three different classification models were used: support vector machine (SVM), k-nearest neighbor (KNN) and discriminant analysis classification. The SVM classification model achieves the best results. Results of success indicators (sensitivity: 67.1%; specificity: 97.0%; F-measure: 66.8%; accuracy: 92.9%).

La fibrillation auriculaire (FA) est le trouble du rythme le plus fréquemment observé en pratique clinique. Elle constitue un risque important de morbi-mortalité. Le traitement de la FA reste un défi majeur en lien avec les nombreux effets secondaires associés aux approches thérapeutiques actuelles. Dans ce contexte, une meilleure compréhension des mécanismes sous-jacents à la FA est essentielle pour le développement de nouvelles thérapies offrant un meilleur rapport bénéfice/risque pour les patients. La FA est caractérisée par i) un remodelage électrique délétère associé le plus souvent ii) à un remodelage structurel du myocarde favorisant la récurrence et le maintien de l’arythmie. La diminution de la période réfractaire effective au sein du tissu auriculaire est un élément clef du remodelage électrique. Le remodelage structurel, quant à lui, se manifeste principalement par une fibrose tissulaire qui altère la propagation de l’influx électrique dans les oreillettes. Les mécanismes moléculaires impliqués dans la mise en place de ces deux substrats restent mal connus. Récemment, le rôle des microARNs (miARNs) a été pointé du doigt dans de nombreuses pathologies notamment cardiaques. Dans ce contexte les objectifs principaux de ce travail ont été i) d'acquérir une compréhension approfondie du rôle des miARNs dans la régulation de l’expression des canaux ioniques et ii) de mieux comprendre le rôle de ces molécules dans l’installation d’un substrat favorable a la FA. Nous avons, dans un premier temps, effectué une analyse bio-informatique combinée à des approches expérimentales spécifiques afin d’identifier clairement les miARNs démontrant un fort potentiel de régulation des gènes codant pour l’expression des canaux ioniques cardiaques humains. Nous avons identifié un nombre limité de miARNs cardiaques qui possédaient ces propriétés. Sur la base de ces résultats, nous avons démontré que l’altération de l'expression des canaux ioniques, observée dans diverse maladies cardiaques (par exemple, les cardiomyopathies, l’ischémie myocardique, et la fibrillation auriculaire), peut être soumise à ces miARNs suggérant leur implication dans l’arythmogénèse. La régulation du courant potassique IK1 est un facteur déterminant du remodelage électrique auriculaire associée à la FA. Les mécanismes moléculaires sous-jacents sont peu connus. Nous avons émis l’hypothèse que l'altération de l’expression des miARNs soit corrélée à l’augmentation de l’expression d’IK1 dans la FA. Nous avons constaté que l’expression de miR-26 est réduite dans la FA et qu’elle régule IK1 en modulant l’expression de sa sous-unité Kir2.1. Nous avons démontré que miR-26 est sous la répression transcriptionnelle du facteur nucléaire des lymphocytes T activés (NFAT) et que l’activité accrue de NFATc3/c4, aboutit à une expression réduite de miR-26. En conséquence IK1 augmente lors de la FA. Nous avons enfin démontré que l’interférence in vivo de miR-26 influence la susceptibilité à la FA en régulant IK1, confirmant le rôle prépondérant de miR-26 dans le remodelage auriculaire électrique. La fibrose auriculaire est un constituant majeur du remodelage structurel associé à la FA, impliquant l'activation des fibroblastes et l’influx cellulaire du Ca2 +. Nous avons cherché à déterminer i) si le canal perméable au Ca2+, TRPC3, jouait un rôle dans la fibrose auriculaire en favorisant l'activation des fibroblastes et ii) étudié le rôle potentiel des miARNs dans ce contexte. Nous avons démontré que les canaux TRPC3 favorisent l’influx du Ca2 +, activant la signalisation Ca2 +-dépendante ERK et en conséquence activent la prolifération des fibroblastes. Nous avons également démontré que l’expression du TRPC3 est augmentée dans la FA et que le blocage in vivo de TRPC3 empêche le développement de substrats reliés à la FA. Nous avons par ailleurs validé que miR-26 régule les canaux TRPC3 en diminuant leur expression dans les fibroblastes. Enfin, nous avons montré que l'expression réduite du miR-26 est également due à l’activité augmentée de NFATc3/c4 dans les fibroblastes, expliquant ainsi l’augmentation de TRPC3 lors de la FA, confirmant la contribution de miR-26 dans le processus de remodelage structurel lié à la FA. En conclusion, nos résultats mettent en évidence l'importance des miARNs dans la régulation des canaux ioniques cardiaques. Notamment, miR-26 joue un rôle important dans le remodelage électrique et structurel associé à la FA et ce, en régulant IK1 et l’expression du canal TRPC3. Notre étude démasque ainsi un mécanisme moléculaire de contrôle de la FA innovateur associant des miARNs. miR-26 en particulier représente apres ces travaux une nouvelle cible thérapeutique prometteuse pour traiter la FA. / Atrial fibrillation (AF) is the most frequently-encountered arrhythmia in clinical practice and constitutes a major cause of cardiac morbidity and mortality. The management of AF remains a major challenge as current therapeutic approaches are limited by potential adverse effects and high rate of AF recurrence/persistence. A better understanding of the mechanisms underlying AF is of great importance to improve AF therapy. AF is characterized by impaired electrical and structural remodeling, both of which favors the recurrence and maintenance of the arrhythmia. A key feature in electrical remodeling is the reduced atrial effective refractory period, due to ion channel alteration. Structural remodeling, on the other hand, mainly results from atrial fibrosis. However, the precise molecular mechanisms underlying these remodeling processes are still incompletely understood. The importance of microRNAs (miRNAs) in various pathophysiological conditions of the heart has been well established, but little is known with regard to cardiac arrhythmias. Emerging evidence suggests that dysregulation of miRNAs may underlie heart rhythm disturbances. The aim of the present work was to acquire a comprehensive understanding of miRNA-mediated regulation of ion channels in cardiac arrhythmias. Notably, we will focus on the mechanistic insights of miRNAs related to the control of AF. Currently available experimental approaches do not permit thorough characterization of miRNA targeting. For this purpose, we performed bioinformatic analyses in conjunction with experimental approaches to identify miRNAs from the database that potentially regulate human cardiac ion channel genes. We found that only a subset of miRNAs target cardiac ion channel genes. Based on these results, we further demonstrated that the dysregulation of ion channel gene expression observed in various cardiac disorders (e.g. cardiomyopathy, myocardial ischemia, and atrial fibrillation) can be explained by the dysregulation of miRNAs. These findings further support the potential implication of miRNAs in arrhythmogenesis under these cardiac conditions. The upregulation of the cardiac inward rectifying potassium current, IK1, is a key determinant of adverse atrial electrical remodeling associated with AF. The molecular mechanisms underlying this ionic remodeling are poorly understood. We hypothesized that altered miRNA expression is responsible for IK1 upregulation in AF. We found that miR-26 is significantly downregulated in AF and regulates IK1 by controlling the expression of its underlying subunit Kir2.1. Moreover, we demonstrated that miR-26 is under the transcriptional repression of the nuclear factor of activated T cells (NFAT) and enhanced activities of members of the NFAT family, NFATc3/c4, results in miR-26 downregulation, which accounts for IK1 enhancement in AF. Furthermore, we observed that in vivo interference of miR-26 affects AF susceptibility via the regulation of IK1, suggesting an important role of miR-26 in atrial electrical remodeling. Atrial fibrosis is a major constituent in AF-associated adverse atrial structural remodeling, involving the activation of fibroblasts and cellular Ca2+ entry. Here, we sought to determine whether the Ca2+ permeable channel, TRPC3, plays a role in AF-induced fibrosis by promoting fibroblast activation. Furthermore, we investigated the potential role of miRNAs in this context. We found that TRPC3 channels promote Ca2+-entry, which results in activation of Ca2+-dependent ERK-signaling and consequently fibroblast activation. We also demonstrated that TRPC3 is upregulated in AF and in vivo TRPC3 blockade suppresses the development of AF-promoting substrate. Furthermore, we observed that miR-26 regulates TRPC3 channels via controlling the expression of the underlying channel subunit and is downregulated in AF-fibroblasts. Finally, we showed that the reduced expression of miR-26 is also due to the enhanced NFATc3/c4 activities in AF-fibroblasts and accounts for AF-induced upregulation of TRPC3, suggesting the potential contribution of miR-26 in AF-related adverse structural remodeling process. In conclusion, our findings emphasize the importance of miRNAs in the regulation of cardiac ion channels. Notably, miR-26 plays a crucial role in AF-associated electrical and structural remodeling via the regulation of IK1 and TRPC3 channel genes. Thus, our study unravels a novel molecular control mechanism of AF at the miRNA level, suggesting miR-26 as a new and promising therapeutic target for AF.

No description available.

A fibrilação atrial (FA) é a arritmia cardíaca sustentada mais comum, de origem supraventricular, em que ocorre uma completa desorganização na atividade elétrica atrial, fazendo com que os átrios percam sua capacidade de contração, não gerando sístole atrial. É uma arritmia que acomete 1-2% da população mundial, sendo mais frequente em indivíduos idosos. Geralmente, está associada a algum tipo de doença cardíaca estrutural, podendo acarretar em complicações como o acidente vascular cerebral, internações e gastos com saúde. Algumas vezes a fibrilação atrial surge de forma precoce, em indivíduos jovens, saudáveis, e sem qualquer evidência de doença cardíaca estrutural ou de fatores desencadeantes, o que leva a hipótese da doença ter um componente genético. Trata-se de um estudo observacional, transversal, para identificação de possíveis variantes genéticas em pacientes portadores de fibrilação atrial isolada, a partir do sequenciamento de nova geração de um painel genético customizado para cardiomiopatias e canalopatias hereditárias. Foram incluídos 101 pacientes encaminhados pelo ambulatório de arritmias cardíacas do Instituto do Coração, que foram avaliados quanto às características clínicas principais antes de serem submetidos ao teste genético. A classificação das variantes em genes causais foi baseada nos critérios do American College of Medical Genetics and Genomics (ACMG). Foram sequenciadas e analisadas amostras de 101 pacientes, onde foram encontradas 144 variantes raras; 14/144 foram classificadas como patogênicas em relação à fibrilação atrial, 130/144 foram classificadas como de significado incerto, e em 28 dos 101 pacientes não foram encontradas variantes raras. Dos 101 pacientes 77,2% eram do sexo masculino, 87,1 % de raça branca, 75,2 % tinham fibrilação atrial paroxística, 52,4 % eram sintomáticos, 65,3% realizaram procedimento de ablação por cateter e 62,4% tinham história familiar de FA precoce, morte súbita, marcapasso e/ou insuficiência cardíaca. A presença dos achados genéticos esteve associada nos pacientes com FA que tinham história familiar de marcapasso e/ou morte súbita. A análise genética desta população permitiu um diagnóstico precoce de miocardiopatias hereditárias que se apresentaram inicialmente como FA isolada / Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia of supraventricular origin, with a complete disorganization in the electrical activity of the atria, losing their capacity of contraction, not generating atrial systole. It is an arrhythmia that affects up to 2% of the world population, appearing more often in elderly individuals. It is usually associated with some types of structural heart disease, which can lead to complications such as stroke, hospitalizations and health costs. In some times atrial fibrillation emerges early, in younger healthy people, with no apparent evidence of structural heart disease or triggering factors, leading to the hypothesis that the disease has a genetic component. This is a cross-sectional, observational study to identify possible genetic variants in patients with isolated atrial fibrillation from new generation sequencing and a customized genetic panel for inherited cardiomyopathies and channelopathies. A total of 101 patients were referred and evaluated by the Cardiac Arrhythmias Outpatient Unit of the Heart Institute for the main clinical characteristics before being submitted to the genetic test. The classification of variants into causal genes was based on the American College of Medical Genetics and Genomics (ACMG) criteria. Samples were sequenced and analyzed from 101 patients, were found 144 rare variants; 14/144 were classified as pathogenic in relation to atrial fibrillation and 130/144 were classified as uncertain significance, and in 28 of 101 patients no rare variants were found. Of the 101 patients, 77.2% were males, 87.1% were white, 75.2% had paroxysmal atrial fibrillation, 52.4% were symptomatic, 65.3% had a catheter ablation procedure, and 62.4% had a family history of early AF, sudden death, pacemaker and/or heart failure. The presence of genetic findings was associated in patients with AF who had a family history of pacemaker and / or sudden death. The genetic analysis of this population allowed an early diagnosis of hereditary cardiomyopathies that initially presented as isolated AF

O objetivo deste estudo foi avaliar retrospectivamente, em longo-prazo, os preditores de recorrência de fibrilação atrial paroxística (FA) em 139 pacientes submetidos à ablação por radiofreqüência, através das técnicas ostial ou extraostial de abordagem do átrio esquerdo, associadas ou não à ablação do istmo cavo-tricuspídeo (ICT). Variáveis pré, intra e pós-ablação foram avaliadas por análise uni e multivariada, para determinar os preditores de recorrência da FA após um procedimento. Observou-se que maior tempo de história de FA, uso de mais antiarrítmicos e recorrência de FA dentro de 60 dias pós-procedimento, aumentaram o risco de recorrência de FA a longo-prazo. Por outro lado, a associação de flutter atrial e a ablação concomitante do ICT, reduziram o risco de recorrência ao final de 33 ±12 meses. / The objective of this study was to evaluate in retrospect, in long-term, the predictors of late recurrence of atrial fibrillation (AF) in 139 patients submitted to the ablation by radiofrequency, through the techniques ostial or extra-ostial of approach of the atrium left, associated or not to the ablation of the cavotricuspid isthmus(ICT). Variables pre, intra and post-ablation were appraised for analysis uni and multivariated, to determine the predictors of recurrence of AF after one procedure. It was observed that larger time of history of AF, use of more drugs and recurrence of AF within 60 days after procedure; they increased the risk of recurrence of AF in long-term. On the other hand, the association of atrial flutter and the concomitant ablation of ICT, they reduced the recurrence risk at the end of 33 ±12 months.

Introdução: A miocardiopatia hipertrófica é a mais frequente doença cardiovascular de origem genética e está associada a arritmias e morte cardiovascular. O aumento do átrio esquerdo e a fibrilação atrial são considerados marcadores de morte por insuficiência cardíaca em pacientes com miocardiopatia hipertrófica. A apneia obstrutiva do sono é o distúrbio respiratório do sono mais comum, caracterizando-se por episódios recorrentes de colapso parcial ou total das vias aéreas superiores durante o sono. A apneia obstrutiva do sono é muito prevalente entre as populações com doença cardiovascular, como hipertensão arterial e insuficiência cardíaca, e está associada a remodelamento cardíaco e arritmias. Objetivos: O objetivo deste estudo foi determinar a prevalência dos distúrbios respiratórios do sono em pacientes com miocardiopatia hipertrófica e avaliar a associação da apneia obstrutiva do sono com o remodelamento cardíaco (ventricular e atrial) e fibrilação atrial em pacientes com miocardiopatia hipertrófica. Métodos: Foram estudados pacientes consecutivos estáveis clinicamente, com um diagnóstico confirmado de miocardiopatia hipertrófica acompanhados no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos à avaliação clínica, questionário de sonolência, bioquímica sanguínea, ecocardiograma e monitorização respiratória noturna com poligrafia portátil. Foi utilizado um valor de corte de 15 e 30 apneias e hipopneias por hora de registro para o diagnóstico de apneia obstrutiva do sono e apneia obstrutiva do sono grave, respectivamente. Resultados: Foram avaliados 80 pacientes consecutivos com miocardiopatia hipertrófica. Apneia obstrutiva do sono foi diagnosticada em 32 pacientes (40%). Apneia obstrutiva do sono grave esteve presente em 17 pacientes (21%). Pacientes com apneia obstrutiva do sono foram significativamente mais velhos (56 [41-64] vs. 39 [30-53] anos, p < 0,001), apresentaram maior índice de massa corporal (28,2 ± 3,5 vs. 25,2 ± 5,2 Kg/m2, p < 0,01), maior dimensão do átrio esquerdo (45 [42-53] vs. 41 [39-47] mm, p = 0.01) e maior diâmetro da aorta (34 [30-37] vs. 29 [28-32] mm, p < 0,001) em comparação com pacientes sem apneia obstrutiva do sono. Dois modelos de regressão linear múltipla para identificar os fatores associados ao aumento do átrio esquerdo e da aorta ascendente mostraram que o índice de apneia e hipopneia foi a única variável associada ao aumento atrial (p = 0,05) e da aorta (p = 0,01), respectivamente. A fibrilação atrial permanente esteve presente em 31% vs. 6% dos pacientes com e sem apneia obstrutiva do sono, respectivamente (p < 0,01). A apneia obstrutiva do sono (p = 0,03) e o diâmetro do átrio esquerdo (p = 0,03) foram os únicos fatores independentemente associados à fibrilação atrial em um modelo multivariado. Conclusão: A apneia obstrutiva do sono é muito prevalente em pacientes com miocardiopatia hipertrófica e está associada com aumento do átrio esquerdo e da aorta ascendente. A apneia obstrutiva do sono está independentemente associada à fibrilação atrial, um fator de risco para óbito cardiovascular nesta população / Background: Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease and is associated with arrhythmias and cardiovascular death. Left atrial enlargement and atrial fibrillation are considered markers for death due to heart failure in patients with hypertrophic cardiomyopathy. Obstructive sleep apnea is the most common sleep disordered breathing and is characterized by recurrent episodes of partial or complete collapse of the upper airway during sleep. Obstructive sleep apnea is extremely prevalent among populations with cardiovascular disease, such as systemic hypertension and heart failure and is independently associated with heart remodelling and arrhythmias. Objectives: The aim of this study was to determine the prevalence of sleep disordered breathing in consecutive patients with hypertrophic cardiomyopathy and evaluate the association of obstructive sleep apnea with heart remodelling (ventricular and atrial) and with atrial fibrillation in patients with hypertrophic cardiomyopathy. Methods: We studied consecutive clinically stable patients with a confirmed diagnosis of hypertrophic cardiomyopathy followed in the Heart Institute Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, by clinical evaluation, sleep questionnaire, biochemical blood analysis, echocardiography and sleep study (overnight portable respiratory monitoring). We used a cut-off value of 15 and 30 apneas and hypopneas per hour of recording in the sleep study for the diagnosis of obstructive sleep apnea and severe obstructive sleep apnea, respectively. Results: We evaluated 80 consecutive patients with hypertrophic cardiomyopathy. Obstructive sleep apnea was present in 32 patients (40%). Severe obstructive sleep apnea was present in 17 patients (21%). Patients with obstructive sleep apnea were significantly older (56 [41-64] vs. 39 [30-53] years, p < 0.001), presented higher body mass index (28.2 ± 3.5 vs. 25.2 ± 5.2 Kg/m2, p < 0.01), increased left atrial diameter (45 [42-53] vs. 41 [39-47] mm, p = 0.01) and aorta diameter (34 [30-37] vs. 29 [28-32] mm, p < 0.001) compared with patients without obstructive sleep apnea. Two models of stepwise multiple linear regression to identify variables associated with left atrial and ascending aorta enlargement showed that apnea-hypopnea index was the only variable associated with left atrial enlargement (p = 0.05) and aorta diameter (p = 0.01), respectively. Permanent atrial fibrillation was present in 31% vs. 6% in patients with and without obstructive sleep apnea, respectively (p < 0.01). Obstructive sleep apnea (p = 0.03) and left atrial diameter (p = 0.03) were the only factors independently associated with atrial fibrillation in a multivariate model. Conclusions: Obstructive sleep apnea is highly prevalent in patients with hypertrophic cardiomyopathy and it is associated with left atrial and ascending aorta enlargement. Obstructive sleep apnea is independently associated with atrial fibrillation, a risk factor for cardiovascular death in this population