Circulating Mirnome in Obese and Lean Heart Failure Patients: A Case-control Study

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.