Circulating MicroRNA-21 Correlates With Left Atrial Low-Voltage Areas and Is Associated With Procedure Outcome in Patients Undergoing Atrial Fibrillation Ablation

Abstract

Background: Atrial fibrosis is a hallmark of arrhythmogenic structural remodeling in patients with persistent atrial fibrillation (AF) and is negatively correlated with procedure outcome in patients undergoing ablation. However, noninvasive methods to determine the extent of atrial fibrosis are limited. Here, we used microRNA (miRNA) expression analysis to detect markers of left atrial low-voltage areas (LVAs) in patients with persistent AF undergoing catheter ablation.

Methods: We performed 3-dimensional voltage mapping in 102 patients (average age 62.1±13.1 years, CHA₂DS₂-VASc score of 2.3±1.6, LA size 41.5±5.7 mm) undergoing ablation for persistent AF and determined the extent of left atrial low-voltage. LVAs were defined if bipolar electrogram amplitudes were <0.5 mV during sinus rhythm. Before ablation, we obtained a blood sample, isolated miRNAs, and profiled them on a miRCURY LNA Universal RT microRNA PCR Human panel.

Results: Sixty-nine miRNAs were identified in all samples, with an average of 123 miRNAs detectable per sample. We found that the serum concentration of miR-21, a miRNA that has been previously linked to cardiac fibrosis development, was strongly associated with the extent of LVAs determined by voltage mapping. We could confirm that LVAs were negatively correlated with ablation success in a 1-year follow-up. In addition, miR-21 serum levels were associated with AF-free survival after catheter ablation.

Conclusions: Circulating miR-21 correlates with left atrial LVAs and is associated with procedure outcome in patients with persistent AF undergoing ablation.

Keywords: atrial fibrillation; biomarkers; fibrosis; microRNAs; pulmonary veins.

Figure 1.

Left atrial low-voltage areas (LVAs) are associated with outcome after atrial fibrillation (AF) ablation. A, Example of left atrial voltage maps. Patients were divided into 3 groups according to the extent of LVAs. B, Kaplan–Meier curves estimating freedom from AF after pulmonary vein isolation (PVI) only, which shows a strong correlation between LVAs and procedure outcome. C, Kaplan–Meier curves for patients that received PVI and—in case of significant LVAs—additional substrate modification.

Figure 2.

miR-21 correlates with left atrial low-voltage areas (LVAs) in patients with persistent atrial fibrillation. A, MicroRNA profiling of patients with extreme and no left atrial LVAs revealed dysregulation of several miRNAs. B, One of the dysregulated microRNAs, miR-21, correlates with LVAs in a linear pattern. C, Relative miR-21 serum expression according to LVA group (group 1: LVAs <10%; group 2: LVAs 10% to 30%; group 3: LVAs >30%, *P<0.05).

Figure 3.

miR-21 correlates with ablation success in patients with persistent atrial fibrillation (AF). A, Kaplan–Meier curves estimating AF-free survival dependent on miR-21 relative serum expression. B, Receiver operating characteristics (ROC) curve analysis shows an area under the curve (AUC) of 0.822. C, Extreme miR-21 serum concentrations are strongly correlated with ablation success in patients with persistent AF.

Figure 4.

Follow-up miR-21 serum concentration 6 mo after ablation. Although patients in stable sinus rhythm (SR) had a strong reduction in miR-21 expression (42.41±12.9% from baseline), patients with atrial fibrillation (AF) recurrence only showed a mild decrease in miR-21 (70.41±14.9% from baseline, P<0.05).