A systematic review and meta-analysis reveals a consensus transcriptional signature highlighting neutrophil degranulation as a preserved and critical biological process in atrial fibrillation

Abstract

Abstract Background Atrial fibrillation (AF) is the most frequent persistent arrhythmia, and is associated with a high burden of disease, especially when co-occurring with other cardiovascular pathologies. Despite significant advances in the understanding of its pathophysiology through transcriptomic studies, there are marked differences in the identified key AF genes between studies, potentially due to specific sociodemographic and clinical characteristics of the populations evaluated. Therefore, the transcriptional signature that is common to AF, regardless of the specific context, is currently unclear. Purpose To provide a consensus transcriptional signature of AF by comprehensively analyzing the studies comparing the gene expression patterns in patients with AF and controls in Sinus Rhythm (SR). Methods Four literature databases were searched to identify studies reporting gene expression patterns in atrial myocardial tissue from patients diagnosed with AF and comparing them with those of controls reportedly in SR. We excluded studies reporting results from in vitro experiments or those that provided incomplete information regarding the methodology for sample collection of bioinformatic analysis. After an initial descriptive analysis of the included studies, we manually curated and processed all the available datasets. At first, gene coverage was evaluated to assess the comparability of the included data, followed by meta-analysing the suitable datasets to obtain the consensus gene signature. Finally, we estimated the activities of relevant transcription factors and pathways by using biological prior knowledge bioinformatic tools (DoRothEA, and PROGENy, respectively). Results 38 studies were included, from which seven related datasets consisting of 262 AF and 86 SR control samples fulfilled the selection criteria for meta-analysis (Figure). We observed a high heterogeneity in the marker genes reported across the studies, however, disease signatures were conserved across the included studies. Gene ranking revealed a significant enrichment of fibrosis and myocyte degeneration-related gene sets; however, enriched pathways, transcription factors, and microRNAs related to neutrophil activity gene signatures, specifically those related to the degranulation process, occupied an outstanding position in the top positions of the ranking (Table). Conclusion Despite high heterogeneity amongst studies, a conserved and identifiable molecular signature in AF is present. The high relevance of neutrophil activity in this signature is consistent with previous studies performed in AF and other cardiovascular diseases, such as ischemic heart failure. The identification of a consensus transcriptional footprint is a feasible approach that provides valuable information to better understand the common molecular mechanisms underlying the different disease patterns in AF.Figure.Table.