Micro-RNAs Are Related to Epicardial Adipose Tissue in Participants With Atrial Fibrillation: Data From the MiRhythm Study

Abstract

Introduction: Epicardial adipose tissue (EAT) has been linked to incidence and recurrence of atrial fibrillation (AF), but the underlying mechanisms that mediate this association remain unclear. Circulating microRNAs (miRNAs) contribute to the regulation of gene expression in cardiovascular diseases, including AF. Thus, we sought to test the hypothesis that circulating miRNAs relate to burden of EAT. Methods: We examined the plasma miRNA profiles of 91 participants from the miRhythm study, an ongoing study examining associations between miRNA and AF. We quantified plasma expression of 86 unique miRNAs commonly expressed in cardiomyocytes using quantitative reverse transcriptase polymerase chain reaction (qPCR). From computed tomography, we used validated methods to quantify the EAT area surrounding the left atrium (LA) and indexed it to body surface area (BSA) to calculate indexed LA EAT (iLAEAT). Participants were divided into tertiles of iLAEAT to identify associations with unique miRNAs. We performed logistic regression analyses adjusting for factors associated with AF to examine relations between iLAEAT and miRNA. We performed further bioinformatics analysis of miRNA predicted target genes to identify potential molecular pathways are regulated by the miRNAs. Results: The mean age of the participants was 59 ± 9, 35% were women, and 97% were Caucasian. Participants in the highest tertile of iLAEAT were more likely to have hypertension, heart failure, and thick posterior walls. In regression analyses, we found that miRNAs 155-5p (p < 0.001) and 302a-3p (p < 0.001) were significantly associated with iLAEAT in patients with AF. The predicted targets of the miRNAs identified were implicated in the regulation of cardiac hypertrophy, adipogenesis, interleukin-8 (IL-8), and nerve growth factor (NGF) signaling. Conclusion: miRNA as well as EAT have previously been linked to AF. Our finding that iLAEAT and miRNAs 155-5p and 302a-3p are associated suggest a possible direct link to between these entities in the development and maintenance of AF. Further research is needed to study causal relationships between these biomarkers.

Keywords: atrial fibrillati; cardiac remodeling; epicardial adipose tissue; inflammation; microRNA.

Figure 1

iLAEAT and left atrial function. (A) iLAEAT is higher in participants with persistent AF. (B) LAFI tended to be lower in patients with higher iLAEAT tertile. iLAEAT and LAFI data were available for 71 participants in our cohort (26 for low iLAEAT, 23 for intermediate iLAEAT, and 22 for high iLAEAT). Statistical analysis was performed using unpaired student t-test for AF subtypes (*p < 0.05) and one-way ANOVA analysis for iLAEAT tertiles. Error bars represent SEM. Panel (A) is adapted from work by Sanghai et al. (14).

Figure 2

A network analysis of predicted targets of miR-155-5p and miR-302a-3p as performed by Ingenuity Pathway Analysis. Nodes represents signaling pathways, and lines are protein targets that are common between nodes. IL-8, Interleukin 8; NGF, Nerve Growth Factor; ERK5, Extracellular Related Kinase 5.

Figure 3

Proposed functions of miR-155-5p and miR-302a-3p. Increase EAT with concurrent upregulation of miR-155-5p and miR-302a-3p cause changes in adipokine secretion such as IL-8 and NGF. These changes lead to autonomic dysregulation and increased inflammation, creating a substrate for atrial fibrillation.