Transcriptomic Consensus of Atrial Fibrillation Unveils Mechanism-Based Drug Repurposing Opportunities: A Systematic Review and Meta-analysis

Abstract

ABSTRACTBackground and AimsDespite advances in understanding atrial fibrillation (AF) pathophysiology through the lens of transcriptomics, marked differences in the key AF genes between studies remain, while drugs targeting preserved dysregulated pathways are limited. This systematic review and meta-analysis aimed to provide a consensus transcriptional signature of AF and use it to identify potentially repurposable drugs.MethodsBibliographic databases and data repositories were systematically searched for studies reporting gene expression patterns in atrial heart auricle tissue from patients with AF and controls in sinus rhythm. A qualitative synthesis and a transcriptomics meta-analysis were performed. We calculated the pooled differences in individual gene expression to create a consensus signature (CS), from which we identified differentially regulated pathways and estimated transcription factors activity. We also created a protein-protein interaction network to identify drug interactions with highly interconnected genes (hub genes) from the AF-CS.ResultsThirty-four observational studies were assessed in the qualitative synthesis, while fourteen, comprising 511 samples (338 AF and 173 SR), were included in the meta-analysis. Despite the heterogeneity observed across individual studies, the AF-CS in both chambers were consistent and robust, showing a better performance in classifying AF status than individual studies. The functional analysis revealed commonality in the dysregulated cellular processes across the atria, including extracellular matrix remodeling, downregulation of cardiac conduction pathways, metabolic derangements, and innate immune system activity processes. Finally, drug-gene analyses highlighted several compounds as repurposing drug candidates for AF, highlighting lipid-lowering agents, antioxidants, and retinoids, among others.ConclusionsDespite variability in individual studies, this meta-analysis elucidated conserved molecular pathways involved in AF pathophysiology across its phenotypes, offering robust and potentially generalizable diagnostic biomarkers. From this AF-CS, we identified potential compounds targeting these dysregulated pathways, thereby addressing an extant gap in AF-specific pharmacotherapy.Key QuestionCan a meta-analytically derived consensus transcriptional signature effectively capture the core molecular mechanisms underlying AF and serve as a basis for identifying novel drug candidates targeting these conserved pathways?Key FindingsExtracellular matrix remodeling, downregulation of cardiac conduction pathways, and modulation of innate immune system activity emerged as conserved molecular hallmarks across the AF spectrum. Drug-gene interaction analyses highlighted the repurposing potential of lipid-lowering agents, antioxidants, and retinoids, among other compounds, for targeted intervention in these dysregulated pathways.Take Home MessageDespite AF’s complexity, a transcriptional signature derived through a meta-analysis can pinpoint conserved molecular pathways across AF phenotypes. These insights provide a foundation for identifying and repurposing drugs targeting the core dysregulated processes in the disease, offering new avenues for targeted, mechanism-based treatment of AF.GRAPHICAL ABSTRACT