15 February 2020 by Junichi Omura

Circulating long non-coding RNA H19 as a novel biomarker for right ventricular failure associated with pulmonary arterial hypertension

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 novel biomarkers for diagnosis and prognosis of cardiovascular diseases. The LncRNA H19 has been implicated in cardiac hypertrophy and fibrosis but its role in 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. Similar findings were noted in several RVF rodent models. We exploited an existing cohort from Canada composed of patients with idiopathic PAH (IPAH ,n=52) and controls (n=57) and measured H19 expression in plasma. We sought replication in an independent validation cohort of subjects with IPAH (n=75) and controls (n=54) from UK. H19 plasma levels measured by qRT-PCR were significantly elevated and correlated with RVF severity in IPAH from each cohort respectively or combined cohorts. Moreover, H19 levels in plasma were predominantly increased in IPAH patients with dRV (CI<2.2) in each cohort respectively or combined cohorts. Interestingly, H19 was higher and distinguished IPAH with the future occurrence of adverse events (death or lung transplant) in each cohort respectively or combined cohorts. 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 (P<0.001) when both cohorts were combined. Furthermore, the combination of plasma H19 and NT-proBNP levels or ERS/ESC risk score demonstrated better risk stratification of IPAH patients than either value alone.

Conclusions: H19 circulating levels are a biomarker of RV function and prognosis in IPAH.

Key Contributors

Junichi Omura, Karima Habbout, Tsukasa Shimauchi, Sandra Breuils-Bonnet, Eve Tremblay, Sandra Martineau, Valérie Nadeau, François Potus, Stephen L. Archer, Allan Lawrie, Roxane Paulin, Steeve Provencher, Olivier Boucherat, Sébastien Bonnet. Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University, Canada, Department of Medicine, Queens University, Canada, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, UK

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