Pathophysiological biomarkers predict PAH prognosis

By Lucy Piper, Senior medwireNews Reporter

Researchers have identified three biomarkers that signify an increased risk of death or requirement for lung transplantation in patients with pulmonary arterial hypertension (PAH).

The finding is based on baseline measurement of endothelial, inflammatory and cardiac biomarkers in 65 PAH patients aged an average of 51 years enrolled in the ASA-STAT study. During 101,030 patient–days of follow-up, 17 of the patients died and two had lung transplants.

The patients were more likely to succumb to one of these outcomes if they had higher plasma levels of N-terminal fragment of pro-B-type natriuretic peptide (NT-pro-BNP), lower cholesterol levels and reduced von Willebrand factor (vWF) activity.

The team reports in the Annals of the American Thoracic Society that the risk of death or lung transplantation increased 1.13-fold with every 500 pg/mL increase in NT-pro-BNP, after accounting for age, gender, PAH aetiology and performance on the 6-minute walk distance test, confirming previous reports. But there was also a 2.35-fold increase risk with each 50 mg/dL decrease in levels of total cholesterol.

“Lower cholesterol levels could reflect a malnourished state in the setting of malabsorption due to chronic bowel wall edema and decreased hepatic synthetic function leading to bacterial translocation and a chronic inflammatory response”, say Stephen Kawut (University of Pennsylvania, Philadelphia, USA) and study co-authors.

Despite their association with worse survival, neither NT-pro-BNP nor cholesterol levels were associated with a more advanced World Health Organization (WHO) functional class after adjusting for confounders. The researchers suggest that the lack of an association with NT-pro-BNP may be due to the inclusion of 21 patients with PAH associated with systemic sclerosis or other connective tissue disease, as this disease type is associated with lower NT-pro-BNP levels compared with idiopathic PAH.

Higher plasma vWF activity was associated with a worse WHO functional class, but it was a reduction in activity that predicted an increased risk of death or lung transplantation, with a 50% absolute reduction increasing the risk 1.32-fold.

Kawut and co-workers note that this result was independent of warfarin use and suggest that as most of the patients were receiving background PAH therapy, low vWF activity in this case may “reflect a state of persistent shear-stress induced proteolysis of vWF that did not improve with PAH treatment.”

Such low activity may indicate ongoing endothelial perturbation and increased angiogenesis contributing to a more severe form of PAH and worse survival, they say.

Flow-mediated dilation, interleukin-6, tumour necrosis factor and C-reactive protein were also assessed, but none were associated with WHO functional class or survival.

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