No abstract

Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed for quality control, and individually pre-processed. Differential expression analysis was carried out for each individual dataset, and the results were meta-analytically aggregated using the r-th ordered p-value method. We analyzed the final list of differentially expressed genes through network analysis, namely topological and modularity analysis, and functional enrichment analysis. The meta-analysis of transcriptomes resulted in 589 differentially expressed genes, whose protein-protein interaction network presented 11 hubs-bottlenecks and four main identified functional modules. These modules were enriched for, respectively, 23, 54, 33, and 53 biological pathways involved with the pathophysiology of AF, especially with the disease's structural and electrical remodeling processes. Stress of the endoplasmic reticulum, protein catabolism, oxidative stress, and inflammation are some of the enriched processes. Among hubs-bottlenecks genes, which are highly connected and probably have a key role in regulating these processes, we found HSPA5 , ANK2 , CTNNB1 , and VWF . Further experimental investigation of our findings may shed light on the pathophysiology of the disease and contribute to the identification of new therapeutic targets and treatments.

Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed for quality control, and individually pre-processed. Differential expression analysis was carried out for each individual dataset, and the results were meta-analytically aggregated using the r-th ordered p-value method. We analyzed the final list of differentially expressed genes through network analysis, namely topological and modularity analysis, and functional enrichment analysis. The meta-analysis of transcriptomes resulted in 589 differentially expressed genes, whose protein-protein interaction network presented 11 hubs-bottlenecks and four main identified functional modules. These modules were enriched for, respectively, 23, 54, 33, and 53 biological pathways involved with the pathophysiology of AF, especially with the disease's structural and electrical remodeling processes. Stress of the endoplasmic reticulum, protein catabolism, oxidative stress, and inflammation are some of the enriched processes. Among hubs-bottlenecks genes, which are highly connected and probably have a key role in regulating these processes, we found HSPA5, ANK2, CTNNB1, and VWF. Further experimental investigation of our findings may shed light on the pathophysiology of the disease and contribute to the identification of new therapeutic targets and treatments.

Background: Obesity is a risk factor for cardiovascular diseases; however, in obese heart failure (HF) patients live longer than lean HF patients, this observation is known as obesity paradox. MicroRNAs (miRs) regulate processes involved in both cardiac remodeling and obesity. Objective: We investigated whether the levels of circulating miRs in HF patients are influenced by obesity. Methods: In this case–control study, twenty HF patients (10 obese and 10 lean) and 10 healthy control individuals were analyzed using Affymetrix GeneChip miRNA 4.0 Array following manufacturer's instruction. Raw data was normalized using the Robust Multiarray Average method, batch effect was adjusted with Surrogate Variable Analysis, pairwise differential expression analysis was carry-out with Limma R package, and miRPath v3.0 was used to interrogate pathways enriched for the dysregulated miRNAs based on validated targets from Tarbase v7.0 and KEGG pathways annotation database. Bioinformatics and statistical analysis were performed using R and a p-value <0.01 was considered significant. Results and conclusions: We discovered a set of 36 and 48 miRNAs that were differentially expressed in obese HF and lean HF, respectively, in relation to controls. Thirteen miRNAs were commonly dysregulated in both HF groups. In addition, we found hsa-miR-451a to be up-regulated in obese HF in relation to controls, as well as to lean HF patients, suggesting that obesity may accentuate its dysregulation. On the other hand, hsa-miR-4738-5p, hsa-miR-1260a, and hsa-miR-98-5p were differentially expressed in lean HF in relation to both remaining groups. Pathways enrichment analysis suggested that hsa-miR-451a regulates genes from the mTOR signaling pathway (p=0.002), whereas hsa-miR-1260a modulates Hippo (p=0.02) and AMPK (p=0.03) signaling pathways, all of which have been previously related to cardiac hypertrophy. Further investigation and validation of their targets may contribute to a better understanding of the obesity paradox.