Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

Figures

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  Figure 1. Circulating miRNAs whose plasma levels were correlated with CHA2DS2-VASc score and/or CA. miRNAs whose plasma levels showed positive (red letters) or negative (blue letters) correlation with CHA2DS2-VASc score (q < 0.1) are presented in the red circle. miRNAs whose plasma levels showed positive (blue letters) or negative (red letters) correlation with CA operation (q < 0.1) are presented in the green circle. Underlined miRNAs are reported to be cardiac-enriched miRNAs [21].

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  Figure 2. Plasma levels of miRNAs which were correlated with both CHA2DS2-VASc score and CA. Plasma levels (i.e., −∆Cq values) of 11 miRNAs, whose plasma levels showed correlations with both CHA2DS2-VASc score and CA operation, are presented as heat maps. (A) The data was sorted with CHA2DS2-VASc score; (B) Plasma levels of the 11 miRNAs were subjected to hierarchical clustering. Based on the circulating miRNA profile, Class 1 and Class 2 patients are supposed to be associated with low and high stroke risks, respectively. The number of AF patients with paroxysmal-, persistent- and permanent-type were 48, 13 and 22, respectively, and 32 patients received CA operation during the study period. Note that plasma levels of the miRNA are high when their −∆Cq is high. Yellow, black and blue colors represent high, middle and low expression levels of miRNAs, respectively. Red, blue and white colors represent high, middle and low CHA2DS2-VASc scores, respectively.

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  Figure 3. miRNAs associated with both CHA2DS2-VASc score and CA. Plasma levels (i.e., −∆Cq values) of 11 miRNAs, whose plasma levels showed correlations with both CHA2DS2-VASc score and CA operation, are presented as dot plots. X and Y axis represent plasma level (−∆Cq value) and CHA2DS2-VASc score, respectively. Note that plasma levels of the miRNA are high when their −∆Cq is high.

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  Figure 4. Representative pathways enriched with possible target genes of eight miRNAs whose plasma levels showed positive and negative correlations with CHA2DS2-VASc score and CA, respectively. (A) Pathway maps for “Development_Regulation of epithelial-to-mesenchymal transition (EMT)” and (B) “Pathway maps for “Androgen receptor activation and downstream signaling in Prostate cancer”, the 1st and 2nd most enriched pathways, respectively, querying possible target genes of the miRNA whose plasma levels showed positive correlations with CHA2DS2-VASc score (Table 3). Red bar represents possible target genes of miRNAs whose plasma levels were positively and negatively correlated with CHA2DS2-VASc score and CA, respectively. Green and red arrows mean positive and negative regulation of the target genes, respectively.

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  Figure 5. Network model representing miRNA-target gene relationship. (A) Network model representing miRNA-target gene interactions is presented, focusing on 11 miRNAs whose plasma levels showed correlations with both CHA2DS2-VASc score and CA operation, by referring to Metabase knowledgebase. White dots represent possible target genes. Orange and cyan dots represent miRNAs whose plasma levels showed positive and negative correlation with CHA2DS2-VASc score, respectively. Supporting literature information for the miRNA-target gene relationships is provided in Figure S1, and the network model file is provided as Figure S2; (B) Possible target genes that have ≥4 edges connected to either of the selected 11 miRNAs are presented. Orange and blue nodes indicate miRNAs whose plasma levels showed positive and negative correlations to CHA2DS2-VASc scores, respectively. Red and gray edges represent negative and unknown regulations of the miRNAs on their target genes, respectively.