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.