MicroRNAs and atrial fibrillation: mechanisms and translational potential

Abstract

Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is an important contributor to cardiac morbidity and mortality. Pharmacological approaches currently available to treat patients with AF lack sufficient efficacy and are associated with potential adverse effects. Even though ablation is generally more effective than pharmacotherapy, this invasive procedure has considerable potential complications and is limited by long-term recurrences. Novel therapies based on the underlying molecular mechanisms of AF can provide useful alternatives to current treatments. MicroRNAs (miRNAs), endogenous short RNA sequences that regulate gene expression, have been implicated in the control of AF, providing novel insights into the molecular basis of the pathogenesis of AF and suggesting miRNA targeting as a potential approach for the management of this common arrhythmia. In this Review, we provide a comprehensive analysis of the current experimental evidence supporting miRNAs as important factors in AF and discuss their therapeutic implications. We first provide background information on the pathophysiology of AF and the biological determinants of miRNA synthesis and action, followed by experimental evidence for miRNA-mediated regulation of AF, and finally provide a comprehensive overview of miRNAs as potential novel therapeutic targets for AF.

Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p

“…Post-transcriptional regulation by microRNAs (miRNAs) may be an attractive, putative mechanism for the observed reduction of I Na in AF, heart failure, and myocardial ischemia [18]. MiRNAs are small, non-coding RNAs (about 22 nucleotide long) that regulate gene expression through translational repression or mRNA degradation, typically by binding to their targeted sites located in the 3′ untranslated regions (3′-UTRs) of mRNAs [19,20].…”

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

“…Our group and others have related circulating miRNAs to distinct forms of cardiovascular diseases, including coronary artery disease, myocardial infarction, heart failure, and AF [10,25]. Recently, animal studies have shown that cardiac gene expression, atrial structure, and vulnerability to AF is enhanced when atrial miRNA expression is altered [18].…”

“…Cardiac miRNAs are central regulators of gene processes implicated in AF and cardiac miRNAs are present in the circulation and are dynamically regulated in cardiovascular disease [17][18][19]. Our findings implicate important gene regulatory pathways as mediators of reverse electrical cardiac remodeling after ablation and potentially identify novel, mechanism-based circulating biomarkers of AF recurrence.…”

“…We further hypothesized that the identified miRNAs would have mechanistic associations with electrostructural cardiac remodeling. To test these hypotheses, we quantified pre-ablation plasma expression of 86 miRNAs in 83 participants and repeated profiling 1-month post-ablation in a subset of 43 participants in a prospectively recruited, contemporary cohort with AF referred for CA and then examined associations between miRNA expressions with AF recurrence over 12 months [17][18][19][20][21][22][23][24][25].…”

Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction

“…Despite our inability to discriminate between the different cell types of the heart, our observation that the most highly expressed downregulated miRNAs include the highly cardiomyocytespecific miR1, miR133, and miR208 16 suggests that cardiomyocytes likely represent the major cell type in our tissue analysis. Over half of human homologs of the identified miRNAs have been shown to be regulated in miRNA profiling studies for atrial fibrillation 14 ( Figure 4A marked with *). The expression of pri-miRNAs exhibited good correlation with mature miRNAs differentially regulated in human myocardial infarction ( Figure 4C; Figure III in the Data Supplement; Table II in the Data Supplement).…”