Circulating exosomal miRNAs as novel biomarkers for acute aortic dissection: A diagnostic accuracy study

Abstract

Background: Acute aortic dissection (AAD) is a serious and life-threatening cardiovascular emergency. This study aim to investigate whether MicroRNAs (miRNAs)in circulating exosomes could serve as novel diagnostic biomarkers for AAD.

Methods: Using miRNA microarray sequencing, the differentially expressed exosomal miRNAs between AAD patients and control subjects were found. In this study, we investigated 8 miRNAs (miR-499a-5p/miR-543/miR-143-3p/miR-4433b-3p/miR-744-5p/miR-4488/miR-202-3p/miR-206), 4 Proteins (Matrix Metalloprotein-9/12)/transforming growth factor-β/D-Dimer) in AAD (n = 75) and Control (n = 86) expression levels between the 2 groups. The combined diagnostic of exosomal miRNAs and Proteins was performed (area under curve [AUC] > 0.8, R > 0.5 and P < .01). The Receiver Operating Characteristic curve was drawn to evaluate the diagnostic efficacy. Predict the gene targets of differentially expressed miRNAs and analyze the functions and signaling pathways of these targets using online databases.

Results: The exosomes isolated from the 2 groups of serum were bilayer membranes with a diameter of about 100 nm. Stably expressed in CD9, CD63 and TSG101. Compared with the control subjects, 8 exosomal miRNAs (miR-499a-5p, miR-543, miR-206, miR-143-3p, miR-4433b-3p, miR-744-5p, miR- 4488, and miR-202-3p) were regulated to varying degrees (P < .05). miR-499a-5p, miR-202-3p, and D-Dimer had higher diagnostic efficacy (AUC > 0.90). Among them, miR-499a-5p had the highest diagnostic accuracy, reaching 95%, AUC = 0.99. Co-diagnosis of positively correlated miRNAs and Proteins improves the diagnostic performance. The combined diagnostic accuracy of miR-499a-5p and miR-202-3p was 98% (AUC = 0.998), and the sensitivity and specificity were 98%. The combined diagnostic accuracy of miR-499a-5p and matrix metalloprotein-9 was 98% (AUC = 0.996), and the sensitivity and specificity were 98%. Gene Ontology (GO) enrichment analysis and Kyoto encyclopedia of genes and genomes signaling pathway analysis, some predicted targets of these miRNAs are involved in the pathophysiological process of AAD.

Conclusion: Serum exosomal miR-499a-5p, miR-143-3p, and miR-202-3p can be used as potential diagnostic biomarkers for AAD, and the combination of various markers can coordinate and complement each other, and can significantly improve the diagnosis of aortic dissection sensitivity and specificity.