Genomics of Post-Operative Atrial Fibrillation After Cardiac Surgery

项目总结/摘要 为了改善接受心脏手术的患者的预后， 术后房颤（poAF）将使用在手术期间采集的心房组织进行评估。 外科手术大约30%的心脏手术患者处于正常窦性心律 将经历POAF，使其成为心脏手术后最常见的并发症。的患者 经验后房颤更有可能遭受一些不良后果，包括额外的时间， 重症监护室，增加中风的风险，并增加全因30天和6个月死亡率。因此，在本发明中， 有证据表明，POAF本身会导致心脏手术后患者的不良结局。 许多实验室已经确定了与非卧床房颤和持续性房颤相关的遗传变异， 尽管有这些遗传学的见解，但其发展背后的生物学机制尚未被发现。 确立了习这在很大程度上是因为人类左心房组织还没有被全面地 在这方面的特点。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患者中的基因改变，并且遗传变异显著影响 在这个组织中的转录反应。拟议的实验建立在这项工作的基础上， 使用从一个仔细收集的左心房样本， 选定的200例患者队列主要来自欧洲，他们处于正常窦性心律， 接受心脏手术。组织特异性RNA表达和DNA的分子比较 甲基化（目的1），分析poAF的数量性状基因座（目的2），以及在 心肌细胞（目标3），然后将在患者之间谁随后做和不发展 POAF，检验人类左心房中DNA、RNA和甲基化变化的总体假设 有助于POAF的发展。通过表征左半胱氨酸的转录组和甲基化组， 心脏手术患者的心房组织，并使用全基因组基因分型， 确定使个体易患POAF的基因表达差异，以及遗传学上的差异。 这种倾向背后的变异。 本研究的成功完成将通过验证现有的POAF， 靶点，识别新的预测因子和新的途径，描述组织特异性表达， 人类左心房的甲基化模式及其与POAF的相关性，并确定新的 预防和治疗POAF的药理学靶点。由此产生的见解可能会 使手术和非手术房颤患者受益，从而改善数百万患者的生活。

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.