Abstract 13222: Cardiopulmonary Best Abstract Award: Long Noncoding RNA H19 in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension -A Putative Novel Biomarker and Therapeutic Target.

Background: Right ventricular failure (RVF) is the major prognostic factor for both morbidity and mortality in pulmonary hypertension. A better understanding of the molecular mechanisms accounting for the transition from a compensated (preserve cardiac output) RV hypertrophy (CRVH) to a decompensated (decrease cardiac output) DRVH in PAH patients is needed. Recent Omics analyses have demonstrated the deregulation of several long non-coding RNAs (LncRNAs) in heart failure, but their role in RVF remains unknown. The LncRNA H19 and its encoded miR-675 are regulated by the epigenetic repressor EZH2 and have been implicated in both hypertrophy and fibrosis processes, (2 features of RVF) but never been studied in RVF. We hypothesized that H19/miR-675 up-regulation is implicated in the development of DRVH and is driven by EZH2 repression. Methods and Results: By qRT-PCR we showed in human RV biopsies obtained from control donors (n=10), CRVH patients (n=7, Cardiac index > 2.2) and DRVH patients (n=12, PAH patients died from RVF), that H19 and miR-675 were specifically upregulated (p<0.001) in DRVH. Similar findings were found in the monocrotaline rat (n≈50 p<0.05). Interestingly H19/miR-675 up-regulation was RV specific as no change was seen in both LV and lung of DRVH patients and rats. In ≈70 patients, we showed that H19 plasma levels were up-regulated in PAH (p<0.001) and positively correlated with PAH severity (pulmonary vascular resistance, PA pressure, cardiac index and pro-BNP, p<0.05), this was also confirmed in rats. Mechanistically, we demonstrated that the up-regulation of H19/miR-675 is driven by the repression of EZH2 and that enhanced H19 expression is associated with reduced CamKII δ/GSK3/β-catenin signaling (p<0.05) which is implicated in hypertrophy & fibrosis. Therefore, as expected H19/miR-675 expression correlated positively with both RV fibrosis (p<0.01) and cardiomyocytes hypertrophy (p<0.05). Conclusions: We demonstrated for the first time that EZH2/H19/miR-675 axis is implicated in the transition from CRVH to DRVH in RVF by impacting both hypertrophy and fibrosis. Given its RV specificity, circulating H19 represents an attractive biomarker of RV function in PAH patients. The therapeutic value of H19 remains to be established. [ABSTRACT FROM AUTHOR]