Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Abstract

ORCID IDs: 0000-0001-9273-4578 (J.Y.); 0000-0001-5453-425X (M.K.N.). AbstractRationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival.Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival.Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker.Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide.Conclusions: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development.

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

“…Many diverse and wideranging studies have further increased our knowledge, which include examples of studies involving epidemiologic data from patient registries (17,(19)(20)(21)(22); diagnostic strategies, including the role of cardiac catheterization and AVT (23,24); insights into the genetics and molecular strategies for precision medicine in PAH (25)(26)(27); and pediatric-specific approaches toward monitoring disease progression with novel endpoints (28)(29)(30) and interventions (31). More recently, others have formed teams to make recommendations for care guidelines, such as those recently published by European investigators (32).…”

Role of biomarkers in evaluation, treatment and clinical studies of pulmonary arterial hypertension

“…Reported candidates as diagnostic and/or prognostic biomarkers for PAH include cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, growth factors, such as vascular endothelial growth factors (VEGFs), platelet-derived growth factors (PDGFs), and TGF-beta, CC family chemokines, osteopontin, angiopoietins, matrix metalloproteinases, cardiac troponins, C reactive protein, von Willebrand factor (vWF), high density lipoprotein (HDL), thromboxane B2, fibrinogen, soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor, lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T-lymphocytes (LIGHT), asymmetric dimethylarginine, GDF15, and hepatocyte growth factor (HDGF) among others. 23 – 34 There is fairly extensive literature suggesting the potential utility of GDF15 as a biomarker for PAH. 25 , 26 , 29 , 30 , 32 , 35 , 36 HDGF has also been reported as informative of prognosis above and beyond that provided by NT-proBNP.…”

“… 25 , 26 , 29 , 30 , 32 , 35 , 36 HDGF has also been reported as informative of prognosis above and beyond that provided by NT-proBNP. 33 None of these biomarkers, however, meet the criteria for use as a surrogate endpoint. NT-proBNP is the only circulating biomarker currently employed in guidelines for risk assessment and is discussed in more detail below.…”

The Prescient Prognosticator? Hepatoma-derived Growth Factor in Pulmonary Hypertension

“…1264-1272) present intriguing data regarding a new technique for measuring the circulating angiogenic factor, hepatoma-derived growth factor (HDGF) (1). In addition, they establish an association between expression of HDGF and pulmonary arterial hypertension (PAH) disease severity and survival.…”

“…The ability to deform in response to mechanical forces is an important physiological characteristic of the arterial vessel wall that is critical for vascular homeostasis, in that it decelerates pulse wave velocity, reduces systolic pressure, and homogenizes arterial blood flow throughout the cardiac cycle (1). Loss of this property in the form of increased arterial stiffness presents an important risk factor in cardiovascular disease that is increasingly recognized as a promising target for pharmacological therapy (2).…”