Novel miRNAs are key predictors of heart failure and mortality in functional tricuspid regurgitation

Abstract

Abstract Background Functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, in particular heart failure (HF), but optimal timing for intervention remains controversial. Surgery is often performed late mainly because symptoms might go unnoticed until advance stage of the disease. While microRNA have been recently identified as prognostic biomarkers in different cardiovascular conditions, no study has been focus on patients with TR. Purpose To evaluate the potential role of circulating miRNAs as prognostic biomarkers in patients with severe FTR. Methods Consecutive patients with severe FTR evaluated in the Heart Valve Clinic were prospectively included and underwent a comprehensive clinical protocol. Patients with non-valvular permanent atrial fibrillation (and no TR) undergoing anticoagulant therapy unit were prospectively recruited as a control group. The experimental design included a first screening phase in 16 subjects (8 atrial 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 118 additional patients (77 FTR and 41 controls). A combined endpoint of hospital admission due to HF and all-cause mortality at follow-up was defined. Results The initial screening revealed 16 differentially expressed miRNAs in atrial FTR vs. AF subjects matched by age, gender and atrial dimensions. The candidate miRNAs were subsequently validated in 118 subjects. After a median follow up of 20.4 months (ICR 8-35 months), 25 (32%) reached the combined endpoint. Patients with events showed different levels of miR-15a-5p, miR-152-3p, miR101-3p, miR-92a-3p, miR-363-3p, miR-324-3p and miR-22-3p (Table 1, p<0.05 for all). Based on the high or low relative expression of selected miRNAs (below or above the median value) patients were stratified; those 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, figure). In a multivariate cox regression the analysis, the level of miR-15a-5p (HR: 3.97 [1.58-9.96], miR-92a-3p (HR: 2.64 [1.13-6.13] , and miR-363-3p (HR: 2.41 [1.04-5.60] were predictive of events independently of NYHA functional class and RV dimensions (p < 0.05 for all). Conclusions We identify for the first time circulating miRNAs in patients with severe FTR. We further show that several miRNA predict heart failure and all-cause mortality independently of RV dimension and symptomatic status. These novel biomarkers may help to identify those patients that benefit from earlier valve interventions.Differences in patients with eventsKaplan Meier Curves