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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

基本信息

批准号：
10096986
负责人：
JEFFREY J GOLDBERGER
金额：
$ 72.59万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10096986
关键词：
Address Adipose tissue Adrenergic Receptor Affect Age American Anti-Arrhythmia Agents Arrhythmia Atherosclerosis Atrial Fibrillation Biological Markers Biopsy 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 Hispanics 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 Plasma Play Prevention Process Proteins Proteome Proteomics Publishing RNA Splicing Race Recurrence Risk Role Signal Pathway Sinus State-of-the-Art Reviews Structure 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 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

项目摘要

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.

项目总结