부산대학교 도서관

Introduction:Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia in the United States. Effective, safe, and durable therapeutic interventions are lacking. Thus, it is imperative to improve clinical management by utilizing novel approaches for drug repurposing. To date, multimodal omics analysis of genomics, transcriptomics, and protein-protein interactions [PPIs] have not been fully exploited for AF drug repurposing.Hypothesis:We hypothesize that using Network Medicine-based multimodal omics analysis for drug prioritization and functional observations using induced pluripotent stem cell (iPSC) models can help us identify effective therapeutic strategies and elucidate drug’s mechanisms-of-action for restoring normal sinus rhythm.Methods:Here, we used RNA-sequencing data from a biobank of left atrial tissues obtained from cardiac surgery patients to identify testable AF disease modules under the human protein-protein interactome network model. We systematically prioritized repurposable drug candidates for AF using both network proximity and gene-set enrichment analysis approaches by leveraging AF disease module findings, drug-target network, and drug-induced gene signatures in human cell lines. RNAseq was used to assess the transcriptomic impact of a top drug candidate, metformin, on gene expression of atrial myocytes differentiated from human iPSCs (a-iCMs).Results:Via network-based screening of 2,891 FDA-approved or clinical drugs, we found nine putative drug candidates (including Metformin, Furosemide, and Rofecoxib) using both network proximity z-score and GSEA-based enrichment scores. RNA-seq analysis of metformin-treated a-iCMs identified 238 differentially expressed genes following multiple test correction (P< 2.96E-06). Several key cardiovascular or drug-related markers were differentially expressed in Metformin treated a-EHTs. Of note NMRK2 and PCK2 were upregulated, and TGFB1 and TXNIP were downregulated, suggesting an improved energy utilization following metformin treatment.Conclusions:In summary, this study presented state-of-the-art network medicine methodologies for AF drug repurposing and identified metformin as a candidate treatment for AF patients.