Atrial Fibrillation: Recent Advances in Understanding the Role of MicroRNAs in Atrial Remodeling with an Electrophysiological Overview

Abstract

Atrial fibrillation (AF) is a highly prevalent condition associated with pronounced cardiovascular-related morbidity, mortality and socioeconomic burden. It accounts for more hospitalization days than does any other arrhythmia. This article reviews the basic electrophysiology of AF, electrical and structural remodeling in AF and recent advances in understanding the molecular mechanisms of AF in relation to specific microRNAs. This paper also reviews the potential role of microRNAs as novel therapeutic targets as well as biomarkers in the management of AF. AF shows characteristics typical of altered electrophysiology that promote ectopic activity and facilitate reentry, thereby contributing to the progression from short paroxysmal AF to a persistent, permanent form via atrial remodeling, even in the absence of progressive underlying heart disease. MicroRNAs have been suggested to influence the development of AF by regulating gene expression at the post-transcriptional level. Increasing evidence has identified various microRNA modifications and their impacts on AF initiation and maintenance through electrical and structural remodeling. The discovery of specific microRNAs as novel therapeutic targets and some experimental evidence implicating microRNAs as potential molecular diagnostic markers have had a significant impact on the diagnosis and management of AF and demand further research.

Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology

“…There is increasing evidence for the role of miRNAs in controlling cardiac physiology, particularly in the regulation of potassium and calcium ion channel function, where dysregulation can lead to aberrant action potential duration and cardiac conduction. 27 , 28 For this project, 7 miRNAs were prioritized for annotation (Methods and Table I in the Data Supplement ), resulting in 27 annotations with relevance to cardiac function. For example, Li et al 45 demonstrated that miR-1 (URS00001DC04F_9606) and miR-133a (URS00004C9052_9606) could regulate the slow delayed rectifier potassium current ( I Ks ) in human cells during simulated hyperglycemia.…”

“… 25 Orthologs of these 88 human proteins were identified in mouse, rat, zebrafish, and Drosophila using the Protein Analysis Through Evolutionary Relationships orthology prediction tool. 15 In addition, a list of 7 human microRNAs (miRNAs) identified as key players in modulating cardiac excitability at the time we started our curation effort was determined from 3 reviews 26 – 28 ; literature available for these miRNAs was curated up to March 2016. Prioritized human gene products described above are listed in Table I in the Data Supplement , and for all of them, GO annotations supported by experimental data were included in the GO database according to established procedural guidelines 8 , 29 , 30 (details are given in Methods in the Data Supplement ).…”

Plasma MicroRNAs Relate to Atrial Fibrillation Recurrence after Catheter Ablation: Longitudinal Findings from the MiRhythm Study

“…Additional studies have identified other cardiacenriched circulating miRNAs to be associated with atrial structural and electrical remodeling and AF [13,16,25] For the purposes of this investigation, we selected 86 miRNA expressed in the heart or associated with pathways involved in pathogenesis of AF or atrial remodeling for high-throughput miRNA expression profiling [25]. We identified validated target genes for these miRNAs through miRDB and mirTarBase (under Strong Evidence) and predicted target genes through Target Scan.…”

“…Since atrial expression of transforming growth factor-β (TGF-β), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and connexin-40 (Cx40) are associated with AF recurrence and are regulated by cardiac-enriched or specific miRNAs, atrial miRNAs likely play important roles in atrial remodeling and AF susceptibility [11,12]. We hypothesize that circulating levels of cardiac miRNAs correlate strongly in patients with AF and relate to AF prevalence in several distinct cohorts [13][14][15][16].…”

The Values of Coronary Circulating miRNAs in Patients with Atrial Fibrillation

“…miRNAs are thought to play a critical role in regulating the expression of various genes that contribute to AF [10, 11]. Recently, miRNAs detected in the circulating serum and atrial tissue have been reported [12–19].…”