Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension
Authors: Amsallem Myriam , Sweatt Andrew J. , Ataam Jennifer Arthur , Guihaire Julien , Lecerf Florence , Lambert Mélanie , Ghigna Maria Rosa , Ali Md Khadem , Mao Yuqiang , Fadel Elie , Rabinovitch Marlene , de Jesus Perez Vinicio , Spiekerkoetter Edda , Mercier Olaf , Haddad Francois , Zamanian Roham T. 
Published: June 2020

Rationale

No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH).

Objectives

To identify the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.

Methods

Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort from 2008-2011) and 76 (validation cohort from 2012-2014). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, NYHA and NT-proBNP] and Stanford score [RV end-systolic remodeling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Expression levels of biomarkers were measured in RV samples from PAH patients undergoing transplant and controls, and mice subjected to pulmonary artery banding (PAB).

Measurements and Main Results

High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were significantly associated with worse Mayo and Stanford scores but not with pulmonary vascular resistance or pressure in both discovery and validation cohorts (this latter had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added incremental value to the REVEAL score in the prediction of death, transplant, or hospitalization at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.

Conclusion

High plasma HGF levels are associated with a RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH.

At a Glance Commentary

Scientific Knowledge on the Subject

Right heart maladaptation is the main cause of death in patients with pulmonary arterial hypertension (PAH). Recent non-invasive imaging studies have improved right heart adaptive phenotyping in PAH, identifying right ventricular (RV) free-wall longitudinal strain and the RV end-systolic remodeling index as markers of right heart maladaptive phenotypes (RHMP). Emerging evidence suggests a link between inflammation and RV failure in PAH patients and experimental disease models, yet no prior proteomic screening study has centered on the right heart.

What This Study Adds to the Field

This targeted proteomics screening study identifies 4 plasma biomarkers of RHMP in two clinical cohorts of patients with PAH. Among them, hepatic growth factor is shown to be prognostic and incremental to the REVEAL risk score for prediction of 3-year death, lung transplant and readmission. HGF and its receptor c-Met are overexpressed in RV tissue samples from PAH patients undergoing transplant as compared to controls, and mice subjected to pulmonary artery banding (PAB), warranting further exploration as a potential right ventricular-specific therapeutic target.

Online data supplements

This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org.