Description

Myriam Amsallem MD MS1,2,3*, Andrew J. Sweat MD4*, Jennifer Arthur Ataam PhD2,3, Edda Spiekerkoetter MD4, Marlene Rabinovitch MD PhD5, Elie Fadel MD PhD3, Olaf Mercier MD PhD3, François Haddad MD1,2* and Roham Zamanian MD PhD4,5*

1Div. of Cardiovascular Medicine , Stanford University School of Medicine, CA, USA; 2Stanford Cardiovascular Institute, Stanford University School of Medicine, CA, USA; 3Research and Innovation Unit, INSERM U999, Marie Lannelongue Hospital, Paris Sud University, France; 4Div. of Pulmonology and Critical Care, Stanford University School of Medicine, CA, USA; 5Vera Moulton Wall Center at Stanford University School of Medicine, CA, USA; *Both first and senior authors contributed equally to the study.

Background: Inflammatory features have been reported in pressure-overloaded right ventricle. This study sought to determine the circulating immune proteomic profile associated with right heart maladaptive phenotype (RHMP) in patients with pulmonary arterial hypertension (PAH).

Methods: This study included a discovery cohort (n=121, from 2008 to 2011) and a validation cohort (n=76, from 2011 to 2014), who underwent plasmatic proteomic profiling using 48-plex flow cytometry multiplex Luminex® (including interleukins, chemokines and growth factors). RHMP was defined using the Mayo right heart score (based on right ventricular RV longitudinal strain, NYHA class and NT-proBNP) and the Stanford right heart score (based on RV end-systolic remodeling index, NYHA class and NT-proBNP). The association between cytokines and RHMP was assessed using partial least square regression analysis.

Results: The median age of the discovery cohort was 50 [39 – 59] years, with a majority of female (74%), and 33% with connective tissue disease. Patients from the validation cohort had more severe features (lower six minute walk test distance, lower cardiac index and higher levels of NT-proBNP) than patients from the discovery cohort, with similar resistance levels and right heart echocardiography metrics. High levels of hepatic growth factor (HGF), stem cell growth factor beta (SCGFβ) and nerve growth factor (NGF) were significantly associated with worst Mayo and Stanford scores but not with pulmonary vascular resistance or mean pulmonary arterial pressure, in both cohorts.

Conclusion: High plasmatic levels of HGF, SCGFβ and NGF are associated with right heart adaptive phenotypes beyond pulmonary disease severity in patients with PAH.