AbstractAimSevere functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, particularly heart failure (HF) and mortality. MicroRNAs (miRNAs) have been recently identified as novel biomarkers in different cardiovascular conditions, but no studies have focused on FTR. We sought to (1) to identify and validate circulating miRNAs as regulators of FTR and (2) to test association of miRNA with heart failure and mortality in FTR.Methods and resultsConsecutive patients with isolated severe FTR (n = 100) evaluated in the outpatient Heart Valve Clinic and age‐ and gender‐matched subjects with no TR (controls, n = 50) were prospectively recruited. The experimental design included (1) a screening phase to identify candidate miRNA differentially expressed in FTR (n = 8) compared with controls (n = 8) through miRNA array profiling of 192 miRNAs using quantitative reverse transcription PCR arrays [qRT‐PCR]) and (2) a validation phase in which candidate miRNAs identified in the initial screening were selected for further validation by qRT‐PCR in a prospectively recruited cohort of FTR (n = 92) and controls (n = 42). Bioinformatics analysis was used to predict their potential target genes and functional pathways elicited. A combined endpoint of hospital admission due to heart failure (HF) and all‐cause mortality was defined. Initial screening identified 16 differentially expressed miRNAs in FTR compared with controls, subsequently confirmed in the validation phase (n = 16 were excluded due to significant haemolysis). miR‐186‐5p, miR‐30e‐5p, and miR‐152‐3p identified FTR with high predictive value [AUC of 0.93 (0.88–0.97), 0.83 (0.75–0.91) and 0.84 (0.76–0.92), respectively]. During a median follow‐up of 20.4 months (IQR 8–35 months), 32% of FTR patients reached the combined endpoint. Patients with low relative expression of miR‐15a‐5p, miR‐92a‐3p, miR101‐3p, and miR‐363‐3p, miR‐324‐3p, and miR‐22‐3p showed significantly higher rates of events (log‐rank test for all P < 0.01). Both miR‐15a‐5p [hazard ratio: 0.21 (0.06–0.649, P = 0.007) and miR‐92a‐3p (0.27 (0.09–0.76), P = 0.01] were associated with outcomes after adjusting for age, gender, and New York Heart Association functional class.ConclusionsCirculating miRNAs are novel diagnostic and prognostic biomarkers in severe FTR. The quantification of miR‐186‐5p, miR‐30e‐5p, and miR‐152‐3p held strong diagnostic value, and the quantification of miR‐15a‐5p and miR‐92a‐3p are independently associated with outcomes. The recognition of specific miRNAs offers a novel perspective for TR evaluation.