Trans-omic analysis of epicardial adipose tissue in atrial fibrillation

项目摘要 心房颤动（AF）是最常见的心律失常，影响美国超过200万人， 预计到2050年，它将影响800万至1200万人。它负责每年超过60亿美元的医疗保健 在美国的支出。虽然导管消融术是房颤的一种有效治疗方法， 应用程序会产生额外的左心房（LA）纤维化，这是一种可能与致心律失常相关的方法 以及左心房功能下降。因此，有必要确定新的预防目标， AF治疗的重点是潜在的病理生理异常，这些异常可能因患者而异。 肥胖和心外膜脂肪组织（EAT）与AF相关。 LA可能通过促纤维化、炎症和其他脂肪细胞因子直接影响LA底物。已经 表明EAT可能在AF的进展、发展和复发中发挥独立作用， 导管消融术已知AF发生率存在种族/种族差异，与所述种族/种族差异平行。 吃的差异。然而，EAT，特别是LAEAT在AF发病机制中的确切作用尚不清楚。 表征了《美国心脏病学会杂志》2016年的一篇最新评论指出， 代谢组学与其他“组学”平台的整合将使我们能够深入了解病理生理学， 代谢物，蛋白质，基因和疾病状态的相互作用，同时推进个性化医疗”。这 本研究的总体目标是评估EAT在AF中的作用 特别是使用多组学（蛋白质组、代谢组、转录组）研究AF发病机制中的LAEAT 方法，以确定新的潜在的诊断和治疗目标。我们的具体目标是：1）在 多种族/民族人群，评价LAEAT与已知 我们将从门诊心脏病学实践中招募120名AF患者和120名对照者 - 每组患者和对照组各40名白色、40名黑人和40名西班牙裔，并评估 种族/民族对LAEAT与纤维化和炎症的生物标志物的关系的影响。（二） 检查患有和不患有AF的患者的LAEAT转录组。 心脏手术和获得EAT活组织检查用于分析编码因子的基因上调， 促进心房纤维化。RNA-seq分析将涵盖转录组的所有方面，而无需任何事先的分析。 它的知识，允许分析新的转录本，剪接变体和非编码RNA。第三章 确定EAT和代谢组学特征之间的横截面关联， 动脉粥样硬化多种族研究和鹿特丹研究中储存的血液标本， 确定的代谢物和事件AF之间的关联。我们将在 达拉斯心脏研究。总的来说，这3个目标将提供一个新的诊断评估平台， AF，这可能有助于开发基于AF发病机制的靶向治疗。

Project Summary Atrial fibrillation (AF) is the most common arrhythmia affecting well over 2 million people in the US with projections that it will affect 8-12 million people by 2050. It is responsible for >$6 billion in annual health care expenditures in the United States. While catheter ablation is a somewhat effective treatment for AF, its application generates additional left atrial (LA) fibrosis, an approach that can be associated with proarrhythmia and reduction in left atrial function. Thus, it would be desirable to identify new targets for prevention and treatment of AF that focus on the underlying pathophysiologic abnormalities which may vary among patients. Obesity and epicardial adipose tissue (EAT) have been associated with AF. LAEAT, due to its contiguity to the LA, may directly influence LA substrate via profibrotic, inflammatory, and other adipocytokines. It has been shown that EAT may play an independent role in the progression, development and recurrence of AF after catheter ablation. There are known racial/ethnic differences in the incidence of AF that parallel the noted racial differences in EAT. Yet, the precise role of EAT and, in particular, LAEAT in the pathogenesis of AF is not well characterized. A 2016 State-of-the-Art review in the Journal of the American College of Cardiology noted “the integration of metabolomics with other ‘omics’ platforms will allow us to gain insight into pathophysiological interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine”. This novel approach has not been implemented in AF. The overall goal of this study is to evaluate the role of EAT and, in particular, LAEAT in the pathogenesis of AF using a multi-omic (proteome, metabolome, transcriptome) approach in order to identify novel potential diagnostics and therapeutic targets. Our specific aims are to: 1) In a multiracial/ethnic population, evaluate associations of LAEAT with plasma biomarkers known to be associated with AF. We will enroll 120 patients with AF and 120 controls from the outpatient cardiology practice – 40 white, 40 black, and 40 Hispanic in each group of both patients and controls and evaluate the effects of race/ethnicity on the relationship of LAEAT to biomarkers of fibrosis and inflammation, among others. 2) Examine the LAEAT transcriptome in patients with and without AF. We will enroll 60 patients undergoing cardiac surgery and obtain EAT biopsies for analysis for upregulation of genes encoding for factors that can promote atrial fibrosis. RNA-seq analysis will cover all aspects of the transcriptome without any prior knowledge of it, allowing for the analysis of novel transcripts, splice variants and noncoding RNAs. 3) Determine cross-sectional associations between EAT and metabolomic features derived from metabolomics of stored blood specimens in the Multi-Ethnic Study of Atherosclerosis and the Rotterdam Study and test for associations between the identified metabolites and incident AF. We will perform an external validation in the Dallas Heart Study. In the aggregate, these 3 aims will provide a novel platform for the diagnostic evaluation of AF which may enable development of targeted treatments based on addressing the pathogenesis of AF.