High Hepatic Growth Factor Levels Add Predictive Value to PAH Risk Score

In patients with pulmonary arterial hypertension (PAH), high plasma levels of hepatic growth factor (HGF) are associated with the right heart maladaptive phenotype (RHMP) and are incremental to the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score for the prediction of patient outcomes, according to results of an analysis published in the European Respiratory Journal. Researchers conducted a single-center, prospective study that included patients with PAH enrolled in the Stanford University Pulmonary Hypertension Biobank in Stanford, California, between 2008 and 2014.

The investigators sought to examine the circulating proteomic profile associated with RHMP in patients with PAH. They performed plasma proteomic profiling in patients with PAH using a multiplex immunoassay, with patients divided into 2 cohorts: a discovery cohort (n=121; from 2008 to 2011) and a validation cohort (n=76; from 2012 to 2014). Further, plasma was obtained from 88 healthy control individuals who underwent rigorous screening to determine their state of health.

Fasting blood samples were obtained from an antecubital vein, processed to plasma, then stored based on protocols. For each participant, a targeted proteomic panel of 48 cytokines, chemokines, and growth factors was measured via a multiplex immunoassay. Transthoracic echocardiogram studies were also attained, with follow-up echocardiograms available in survivors at 1 year. In addition, researchers assessed tissue-level expression of the RHMP markers in right ventricle (RV) samples in patients with end-stage PAH and an experimental mouse model of RV pressure overload to determine whether increased circulating levels reflect RV overexpression and to validate the pulmonary arterial banding model for future mechanistic studies.

Right ventricle dimensions and functional metrics were measured on RV-focused apical 4-chamber views, with the values used to calculate 2 right heart adaptive phenotyping scores: the Mayo Clinic score (that integrated RV end-systolic remodeling index [RVESRI], New York Heart Association [NYHA] class, and N-terminal pro-brain natriuretic peptide [NT-proBNP]) and the Stanford score (that integrated RVESRI, NYHA class, and NT-proBNP).

Results showed that high levels of HGF, stem cell growth factor beta, nerve growth factor, and stromal cell-derived factor-1 were associated with worse Mayo Clinic and Stanford scores independently from pulmonary resistance or pressure in both cohorts. Individuals in the validation cohort exhibited more severe disease features, including a lower cardiac index and a higher NT-proBNP level.

In both the discovery cohort and the validation cohort, HGF concentrations added value to the REVEAL score with respect to predicting death, transplantation, or hospitalization at 3 years. Further, RV expression levels of HGF and its receptor c-Met were higher in patients with end-stage PAH than in control individuals, as well as in pulmonary arterial banding mice than in shams.

The investigators concluded that the evaluation of plasma HGF levels might help to identify patients at risk for right heart failure who warrant intensified PAH therapy and closer follow-up.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Amsallem M, Sweatt AJ, Arthur Ataam J, et al. Targeted proteomics of right heart adaptation to pulmonary arterial hypertension. Eur Respir J. Published online December 17, 2020. doi:10.1183/13993003.02428-2020