Trans-omic analysis of epicardial adipose tissue in atrial fibrillation

心房颤动心外膜脂肪组织的跨组学分析

• 批准号: 10330560
• 负责人: JEFFREY J GOLDBERGER
• 金额: $ 69.17万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330560
• 关键词: Address; Adipose tissue; Adrenergic Receptor; Affect; Age; American; Anti-Arrhythmia Agents; Arrhythmia; Atherosclerosis; Atrial Fibrillation; Biological Markers; Biopsy; Black race; Blood; Blood specimen; Body Weight decreased; Branched-Chain Amino Acids; Calcium Signaling; Cardiac; Cardiac Surgery procedures; Cardiac ablation; Cardiology; Catecholamines; Cell Adhesion; Clinical; Clinical Data; Collagen; Communication; Coronary; Data; Defect; Development; Diagnostic; Disease; Enrollment; Enzymes; Ethnic Origin; Ethnic group; Evaluation; Fascia; Fatty acid glycerol esters; Fibrosis; Genes; Goals; Health Expenditures; Heart; Heart Atrium; Hispanic; Image; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; Journals; Knowledge; Left; Left Atrial Function; Link; Lipoproteins; Longitudinal Studies; Matrix Metalloproteinases; Measures; Mediator of activation protein; Metabolism; Metabolite Interaction; Multi-Ethnic Study of Atherosclerosis; Muscarinic Acetylcholine Receptor; Myopathy; Natriuretic Peptides; Obesity; Outpatients; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pericardial body location; Peripheral; Persons; Plasma; Play; Prevention; Process; Proteins; Proteome; Proteomics; Publishing; RNA Splicing; Race; Recurrence; Risk; Role; Signal Pathway; Sinus; State-of-the-Art Reviews; Techniques; Testing; Thrombosis; Tissues; Transcript; United States; Untranslated RNA; Up-Regulation; Validation; Variant; Vascular blood supply; X-Ray Computed Tomography; activin A; adipokines; attenuation; base; college; diagnostic platform; diagnostic strategy; effective therapy; ethnic difference; heart rhythm; improved; insight; interest; lifetime risk; metabolome; metabolomics; multi-racial; multiple omics; novel; novel diagnostics; novel strategies; novel therapeutic intervention; personalized medicine; racial and ethnic; racial difference; receptor function; subcutaneous; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; validation studies

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.

项目摘要 心房颤动（AF）是最常见的心律失常，在美国影响超过200万人 预测到2050年将影响8-1200万人。它将有60亿美元的年度医疗保健 美国的支出。虽然导管消融对AF的一种有效的治疗方法，但 应用会产生额外的左心（LA）纤维化，这种方法可以与心律失常有关 和左心房功能的降低。这是希望确定预防的新目标和 AF的治疗重点是在患者中可能有所不同的潜在病理生理异常。 肥胖和心外膜脂肪组织（EAT）与AF有关。奖金，由于它与 LA，可以直接通过纤维化，炎症和其他脂肪细胞因子直接影响LA底物。它一直 表明EAT可能在AF之后的AF的进展，发展和复发中起独立的作用 导管消融。与著名种族相似的AF发生率的种族/种族差异 饮食差异。然而，饮食的确切作用，尤其是在AF发病机理中的贴心作用不好 特征。美国心脏病学院杂志上的2016年最先进的评论指出了“ 代谢组学与其他“ OMICS”平台的整合将使我们能够深入了解病理生理学 代谢产物，蛋白质，基因和疾病状态的相互作用，同时推进个性化医学”。 新颖的方法尚未在AF中实施。这项研究的总体目标是评估EAT的作用 并且，特别是使用多OMIC（蛋白质组，代谢组，转录组）的AF发病机理中的奖金 方法是为了确定新型的潜在诊断和治疗靶标。我们的具体目的是：1） 多种族/族裔人口，评估贴心与血浆生物标志物的关联 与AF相关。我们将从门诊心脏病学实践中注册120例AF患者和120例对照 - 每组患者和对照组中有40个白色，40个黑色和40个西班牙裔，并评估 奖励与纤维化和感染的生物标志物的关系/民族等。 2） 检查有或没有AF的患者的奖励转录组。我们将注册60名接受的患者 心脏手术并获得饮食活检，以分析以上调编码的基因 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 了解它，允许分析新的转录本，剪接变体和非编码RNA。 3） 确定源自代谢组学的进食和代谢组特征之间的横截面关联 在动脉粥样硬化和鹿特丹研究的多种族研究中，储存的血液标本和测试 确定的代谢产物与事件AF之间的关联。我们将在 达拉斯心脏研究。在总体中，这三个目标将为诊断评估提供一个新颖的平台 AF可能会基于解决AF的发病机理而发展有针对性治疗的AF。