Trans-omic analysis of epicardial adipose tissue in atrial fibrillation

项目摘要 房颤是最常见的心律失常，在美国有200多万人患有 预计到2050年，它将影响800万至1200万人。它负责每年60亿美元的医疗保健 在美国的支出。虽然导管消融是一种治疗房颤的有效方法，但其 应用会产生额外的左房(LA)纤维化，这种方法可能与心律失常相关 左房功能减退。因此，最好是确定新的预防和预防目标。 房颤的治疗侧重于潜在的病理生理异常，这可能会因患者而异。 肥胖和心外膜脂肪组织(EAT)与房颤有关。Laeat，由于它与 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。一直以来 提示EAT可能在房颤的进展、发展和复发中发挥独立作用。 导管消融术。已知的房颤发病率存在种族/民族差异，这与已知的种族差异相似 饮食上的差异。然而，Eat，尤其是Laeat在房颤发病机制中的确切作用还不是很清楚。 特色化的。《美国心脏病学会杂志》在2016年发表的一篇最先进的评论中指出， 代谢组学与其他‘组学’平台的集成将使我们能够深入了解病理生理学 代谢物、蛋白质、基因和疾病状态之间的相互作用，同时推进个性化药物“。这 新的方法尚未在房颤中实施。这项研究的总体目标是评估EAT的作用 尤其是Laeat在房颤的发病机制中使用了多组体(蛋白质组、代谢组、转录组) 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)在 多种族/民族人群，评估Laeat与已知的血浆生物标记物的相关性 与房颤相关。我们将从心脏病门诊招募120名房颤患者和120名对照 -40名白人，40名黑人和40名西班牙裔，在患者和对照组中各40名，并评估 种族/民族与纤维化和炎症等生物标志物的关系。2) 检测房颤患者和非房颤患者的Laeat转录组。我们将招募60名患者接受治疗 心脏手术和获取EAT活组织检查以分析编码基因上调的因素 促进心房纤维化。Rna-seq分析将覆盖转录组的所有方面，而不需要任何事前 了解它，从而能够分析新的转录本、剪接变体和非编码RNA。3) 确定EAT和来自代谢组学的代谢组特征之间的横截面关联 动脉粥样硬化的多种族研究和鹿特丹研究和测试中的储存血液样本 已确认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。总之，这3个目标将为诊断评估提供一个新的平台 这可能使在解决房颤发病机制的基础上开发靶向治疗成为可能。

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.