Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

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.