Trans-omic analysis of epicardial adipose tissue in atrial fibrillation

项目概要 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 8-1200 万人。每年的医疗保健费用超过 60 亿美元 在美国的支出。虽然导管消融是治疗 AF 的一种较为有效的治疗方法，但其 应用会产生额外的左心房（LA）纤维化，这种方法可能与致心律失常有关 和左心房功能下降。因此，需要确定新的预防和预防目标 AF 的治疗侧重于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）与房颤相关。 LAEAT，由于它毗邻 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。已经是 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。已知 AF 发病率存在种族/民族差异，与上述种族相似 EAT 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 特点。 《美国心脏病学会杂志》2016 年最新评论指出“ 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”。这个 新方法尚未在 AF 中实施。本研究的总体目标是评估 EAT 的作用 特别是，LAEAT 使用多组学（蛋白质组、代谢组、转录组）研究 AF 的发病机制 方法以确定新的潜在诊断和治疗靶点。我们的具体目标是： 1) 多种族/族裔人群，评估 LAEAT 与已知的血浆生物标志物的关联 与 AF 有关。我们将从门诊心脏病学诊所招募 120 名 AF 患者和 120 名对照患者 – 每组患者和对照组有 40 名白人、40 名黑人和 40 名西班牙裔，并评估效果 种族/族裔对 LAEAT 与纤维化和炎症等生物标志物关系的影响。 2） 检查患有和不患有 AF 患者的 LAEAT 转录组。我们将招募 60 名接受治疗的患者 进行心脏手术并获得 EAT 活检，以分析编码基因的上调，这些因素可 促进心房纤维化。 RNA-seq 分析将涵盖转录组的所有方面，无需任何事先准备 的知识，允许分析新的转录本、剪接变体和非编码 RNA。 3） 确定 EAT 与源自代谢组学的代谢组学特征之间的横断面关联 动脉粥样硬化多种族研究和鹿特丹研究中储存的血液样本 已确定的代谢物与房颤事件之间的关联。我们将在 达拉斯心脏研究。总的来说，这三个目标将为诊断评估提供一个新的平台 AF 可能有助于开发基于解决 AF 发病机制的靶向治疗方法。

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.