Genomics of Post-Operative Atrial Fibrillation After Cardiac Surgery

心脏手术后心房颤动的基因组学

基本信息

批准号：
10372038
负责人：
JOCHEN DANIEL MUEHLSCHLEGEL
金额：
$ 74.24万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2021-03-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10372038
关键词：
Age Atrial Fibrillation Biological CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Cardiac Surgery procedures Cells Chronic Kidney Failure Clinical Closure by clamp Code Complication DNA DNA Methylation DNA Sequence Development Disease Disease susceptibility Epigenetic Process European Exhibits Gene Expression Gene Expression Profile Genetic Genetic Transcription Genetic Variation Genomics Genotype Heart Atrium Hospitals Human Hypertension Image Individual Ischemia Knowledge Left Left atrial structure Length of Stay Maps Methodology Methylation Molecular Muscle satellite cell Mutation Myocardium Obesity Operative Surgical Procedures Optics Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmacology Physiological Postoperative Period Predisposition Prevention Quantitative Trait Loci RNA methylation Research Sampling Sinus Specificity Stress Testing Time Tissues Untranslated RNA Validation Variant Work adverse outcome cohort comorbidity epigenomics experience experimental study genetic variant improved improved outcome induced pluripotent stem cell insight methylation pattern methylome mortality novel prevent response stroke risk transcriptome whole genome

项目摘要

PROJECT SUMMARY / ABSTRACT To improve outcomes for patients undergoing cardiac surgery, the genetic propensities for developing post-operative atrial fibrillation (poAF) will be assessed utilizing atrial tissue acquired during the surgical procedure. Roughly 30% of patients who present for cardiac surgery in normal sinus rhythm will experience poAF, making it the most common complication after cardiac surgery. Patients that experience poAF are more likely to suffer a number of adverse outcomes, including additional time in the ICU, increased risk of stroke, and increased all-cause 30-day and 6-month mortality. Thus, evidence suggests that poAF itself contributes to poor patient outcomes following cardiac surgery. A number of labs have identified genetic variants associated with both ambulatory AF and poAF, but despite these genetic insights, the biological mechanisms underlying its development have not been established. This is largely because human left atrial tissue has not been comprehensively characterized in this context. Previous work has demonstrated that gene transcription in atrial tissue is altered in patients with poAF, relative to those without, and that genetic variants markedly influence transcriptional responses in this tissue. Proposed experiments build upon this work, examining both genetic and epigenetic mechanisms of poAF using left atrial samples collected from a carefully selected cohort of 200 patients primarily of European origin who are in normal sinus rhythm as they undergo cardiac surgery. Molecular comparisons of tissue-specific RNA expression and DNA methylation (Aim 1), analysis of quantitative trait loci of poAF (Aim 2), and functional validation in cardiomyocytes (Aim 3) will then be made between patients who subsequently do and do not develop poAF, testing the global hypothesis that DNA, RNA, and methylation changes in the human left atrium contribute to the development of poAF. By characterizing the transcriptome and methylome of left atrial tissue from cardiac surgery patients and using whole-genome genotyping, we will be able to identify both the gene expression differences that predispose individuals to poAF, and the genetic variants that underlie this predisposition. Successful completion of this study will advance biological knowledge of poAF by validating existing targets, identifying novel predictors and novel pathways, describing the tissue-specific expression and methylation pattern in the human left atrium and its association with poAF, and identifying new pharmacological targets for the prevention and treatment of poAF. Resulting insights could potentially benefit both surgery and non-surgery AF patients, thereby improving the lives of millions of patients.

项目概要/摘要为了改善接受心脏手术的患者的结果，发展的遗传倾向术后心房颤动 (poAF) 将利用手术期间获得的心房组织进行评估手术过程。大约 30% 接受心脏手术的患者窦性心律正常会出现 POAF，使其成为心脏手术后最常见的并发症。患者认为经历 POAF 的人更有可能遭受许多不良后果，包括额外的时间重症监护病房（ICU）、中风风险增加以及 30 天和 6 个月全因死亡率增加。因此，有证据表明，POAF 本身会导致心脏手术后患者预后不良。许多实验室已经鉴定出与动态 AF 和 poAF 相关的遗传变异，但是尽管有这些遗传见解，但其发展背后的生物学机制尚未被阐明。已确立的。这很大程度上是因为人体左心房组织尚未得到全面的研究在此背景下得到表征。先前的工作已经证明心房组织中的基因转录相对于没有 POAF 的患者，POAF 患者的基因发生了改变，并且遗传变异显着影响该组织中的转录反应。拟议的实验建立在这项工作的基础上，检查了使用从仔细收集的左心房样本进行 POAF 的遗传和表观遗传机制选择了 200 名主要来自欧洲的患者组成的队列，这些患者处于正常窦性心律，因为他们接受心脏手术。组织特异性 RNA 表达和 DNA 的分子比较甲基化（目标 1）、poAF 数量性状位点分析（目标 2）以及功能验证然后，将在随后发育和未发育的患者之间制备心肌细胞（目标 3） poAF，测试人类左心房 DNA、RNA 和甲基化变化的整体假设为poAF的发展做出贡献。通过表征左侧的转录组和甲基化组来自心脏手术患者的心房组织并使用全基因组基因分型，我们将能够确定导致个体易患 POAF 的基因表达差异以及遗传因素造成这种倾向的变异。这项研究的成功完成将验证现有的 poAF 生物学知识目标，识别新的预测因子和新的途径，描述组织特异性表达和人类左心房的甲基化模式及其与 poAF 的关联，并识别新的预防和治疗 poAF 的药理学靶点。由此产生的见解可能会使手术和非手术 AF 患者受益，从而改善数百万患者的生活。