Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

Abstract

Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA.

Genetics, transcriptomics, metagenomics, and metabolomics in the pathogenesis and prediction of atrial fibrillation

“…The general dissection of the molecular changes underlying AF initiation and progress in human bulk right and left atrial tissue has identified pathway changes in mechanotransduction, extracellular matrix remodelling, ion channel signalling, oxidative stress, apoptosis, fibrosis, and structural tissue organization under both developmental and inflammatory signalling. 41 , 42 These profiling studies generally credit the development of AF to deregulation of ion channels, calcium handling, structural remodelling, or autonomic neural regulation, and as such, AF is seen as a consequence of other cardiovascular pathologies. 42 However, the overlap of the results in these studies is not overwhelming at the molecular level, indicating that much remains to be discovered for targeted diagnostics and therapeutics.…”