Abstract only Background: Postoperative atrial fibrillation (poAF) is one of the most common complications after cardiac surgery. It increases the length of stay in the ICU and hospital, increases the risk of stroke, and leads to death. Several clinical factors, including age, obesity, and co-occurring conditions such as prior atrial fibrillation, hypertension, kidney disease, etc., are associated with poAF. We hypothesize that the atrial transcriptome differs between patients who remain in sinus rhythm following surgery and those who develop poAF, allowing the identification of genes, pathways, and cell types necessary for the understanding and treatment of poAF. Methods: Single-cell RNA sequencing (scRNA-seq) was performed to gain insights into the heterogeneous cell populations of the left atrium. It provided an in-depth view of the variability in the cellular response to poAF through the molecular changes within cells, allowing for identifying biomarkers and therapeutic targets. Changes in gene expression associated with poAF were modeled, including batch, sex, age, atrial size, and history of atrial fibrillation and covariates. Results: sc-RNA-seq data of thirty-one human left atrium samples were analyzed. The samples included 14 females and 17 males aged 35-86 years. Cell clusters were identified after the quality check, preprocessing, and normalization. Nine distinct cell types were identified, including atrial cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, adipocytes, pericytes, myeloid, lymphoid, and neuronal cells. The atrial cardiomyocytes and fibroblasts were the most abundant identified cell types. The enrichment of these cell types and significant changes in many marker genes in the disease condition suggest their crucial role in their response to the disease. Conclusion: The comprehensive analysis revealed distinct gene expression patterns and cellular heterogeneity. It provided valuable insights into the cellular landscape and transcriptional alterations in poAF. By shedding light on the molecular mechanisms, the findings pave the way for developing targeted interventions to mitigate the impact of poAF.