The expression of selected microRNAs enables identification of patients with functional atrial tricuspid regurgitation. New insights into TR pathophysiology

Abstract Background Functional tricuspid regurgitation (FTR) is a powerful and independent predictor of patients’ morbidity and mortality. Atrial FTR (A-FTR) is a recently defined phenotype associated with permanent atrial fibrillation. In A-FTR, the underlying pathophysiological factors behind tricuspid annulus (TA) enlargement and the subsequent development of atrial TRF are still unclear, given that despite RA enlargement, a significant fraction of patients presenting long-term persistent atrial fibrillation (AF) will fail to develop significant TR during follow-up. Different microRNAs (miRNAs) have been studied as regulators and diagnostic biomarkers in mitral and aortic valve disease, but no study has been focus on FTR so far. Purpose Our current study aims to identify and validate a selection of circulating miRNAs as potential regulators of A-FTR Methods Consecutive patients with severe A-FTR and patients with non-valvular permanent atrial fibrillation (AF without TR) undergoing anticoagulant therapy were prospectively recruited. The experimental design included a first screening phase in 16 subjects ((8 A-FTR and 8 AF controls) to identify candidate miRNAs differentially expressed in a miRNA qPCR panel containing 192 specific miRNAs, and a second validation phase in which selected miRNAs were screened for further validation by qRT-PCR in 80 additional patients (40 TR and 40 AF). Results The initial screening revealed 16 differentially expressed miRNAs in atrial FTR vs. AF subjects matched by age, gender and atrial dimensions (figure 1). In the validation phase, the expression of miR-29b-3p, miR-152-3p, miR-30e-5p, miR-186-5p, miR-126-5p and miR-148a-3p (p<0.05) were significantly different in A-FTR compared to AF. Among all, miR-186-5p, miR-152-3p and miR-30e-5p yielded the highest predictive values for the detection of A-FTR with areas under the curve of 0.96 (0.92-0.99), 0.90 (0.83-0.97) and 0.87 (0.79-0.95) respectively (p<0,001 for all, figure 2). Conclusions Patients with atrial FTR exhibited different miRNA fingerprint compared to patients with permanent AF without TR but similar degree of atrial enlargement. Additionally, our study identified 3 novel miRNAs as potential diagnostic biomarkers of A-FTR: miR-186-5p, miR-152-3p and miR-30e-5p which excellent accuracy. Whether the differential expression of such miRNAs precedes or follows the development of FTR or the subsequent leaflet adaptation or growth, will be further explored in future studies.Table and volcano plot of miRNAmiRNA ROC curves in A-FTR