Grant: Travel Awards - Institute Community Support

Background: Right ventricular failure (RVF) is the major prognostic factor 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 RV hypertrophy (decreased cardiac output, DRVH) is needed. 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 in DRVH. Similar findings were found in the monocrotaline rat (n=64, 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, 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 delta/GSK3/beta-catenin signaling 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 human RVF by impacting both hypertrophy and fibrosis. Circulating H19 represents an attractive biomarker of RV function in PAH patients.