Grant: Travel Awards - Institute Community Support

Background: Right ventricular failure (RVF) is a major adverse prognostic factor in pulmonary arterial hypertension (PAH). Recent Omics analyses demonstrated the deregulation of long non-coding RNAs (LncRNAs) in cardiovascular disease. Moreover, circulating LncRNAs have been considered as promising novel biomarkers for diagnosis and prognosis of cardiovascular diseases. The LncRNA H19 has been implicated in cardiac hypertrophy and fibrosis but its role in PAH-related RVF remains unknown. Methods and Results: In human RV from control donors, patients with compensated RV hypertrophy (cRV, cardiac index (CI) >2.2) and decompensated RV (dRV, PAH patients that died from RVF), H19 was specifically up-regulated in dRV and correlated with RVF severity. Similar findings were noted in monocrotaline and pulmonary artery banding models of RVF. In patients with idiopathic PAH (IPAH) from Canada and UK H19 plasma levels, measured by qRT-PCR, were significantly elevated and correlated with RVF severity (CI and NT-proBNP). Contrary to NT-proBNP, H19 circulating levels were not significantly influenced by estimated glomerular filtration rate. H19 levels were also associated with increased risk of all-cause death or lung transplant (HR 1.61; 95% CI 1.23-2.11, p<0.0001). Event-free survival estimates at 1, 3 and 5 years were 98%, 92% and 84% for patients with H19 levels below 37.2 units versus 85%, 54% and 46% for those with H19 levels above 37.2 units (HR 5.7, 95% CI:3.0-10.7, P<0.001). Importantly, the combination of plasma H19 and NT-proBNP levels demonstrated better risk stratification of IPAH patients than either biomarker alone. Conclusions: H19 circulating levels are a biomarker of RV function and independently predict event-free survival in IPAH.