Circulating angiogenic factor shows PAH biomarker potential

Hepatoma-derived growth factor (HDGF) predicts disease severity and survival in patients with pulmonary arterial hypertension (PAH), showing some possible clinical advantages over N-terminal pro-brain natriuretic peptide (NTproBNP), researchers report.

They found that levels of the circulating angiogenic factor, measured using an enzyme-linked immunosorbent assay, were significantly elevated in two independent cohorts of PAH patients, totalling 112 individuals, but not in a control group of 39 healthy individuals or a non-cardiac chronic disease control group of 66 individuals.

Levels were elevated irrespective of PAH subtype, the researchers note in the American Journal of Respiratory and Critical Care Medicine.

Receiver operating curve analysis gave an HDGF cutoff of 0.7 ng/mL; levels above this identified PAH patients from controls with 89% accuracy and a sensitivity and specificity of 73% and 85%, respectively. And likelihood ratios for the presence of PAH increased dramatically from 0.3 at HDGF levels below 0.5 ng/mL to 8.1 for levels of 0.75 ng/mL or above. The test also performed well when tested against the non-cardiac chronic disease group, which included patients with diabetes, hypertension, elevated cholesterol and obesity.

Among the PAH patients, 56% with high HDGF levels had a significantly shorter 6-minute walk test distance than those with levels below this threshold (357 vs 410 m) and were more often of New York Heart Association Functional Class III or IV (n=24 vs 9). They also had higher NT-proBNP levels, on average, at 894 vs 341 pg/mL.

This evidence of worse disease severity was borne out in PAH disease outcomes, with HDGF levels found to be significantly lower among survivors than non-survivors, at an average of 0.2 ng/mL versus 1.4 ng/mL. And the risk of death was 4.5 times higher for patients with high than low HDGF levels.

Researcher Allen Everett (Johns Hopkins University, Baltimore, Maryland, USA) and colleagues note that the relationship between HDGF levels and mortality persisted after adjusting for age, PAH subtype, invasive haemodynamic variables and NT-proBNP.

"Thus circulating HDGF may have prognostic utility in the risk-stratification of PAH that extends past current clinical measures", they say.

The association between elevated HDGF levels and cardiac haemodynamics was only weak and there was no association with worse right heart haemodynamics, which suggests that "HDGF is not a biomarker of heart failure similar to NTproBNP", the researchers add.

Recent clinical studies have indicated a role for HDGF in disordered pathological cell growth, which epitomises PAH, Everett and colleagues note, but they acknowledge that "whether HDGF is a mediator and/or a surrogate of PAH progression remains unclear."

They believe: "HDGF is uniquely suited to be a PAH biomarker given its ability to predict survival in PAH, equivalency to NTproBNP performance, correlation with a decline in 6MWD and not confounded by chronic disease."

And add that HDGF also has some physical attributes that increase its suitability as a clinical measure, including remaining stable over repeat freeze-thaw cycles, being thermostable for days at room temperature and no significant differences between serum and plasma levels.

Lucy Piper

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