Biomarker May Help Improve Mortality Risk Prediction in PAH

Incorporating endostatin, a circulating angiostatic peptide, into commonly used risk prediction strategies for pulmonary arterial hypertension (PAH) improves prediction of mortality and thus serves as a robust, easily accessible biomarker of PAH severity, according to study findings published in ERJ Open Research.

The selection and timing of clinical interventions for PAH depends on serial assessments of disease severity and mortality risk based on a variety of prediction strategies, researchers explained. However, the clinical tools currently used for risk prediction are imperfect.

“Definitive assessment of pulmonary pressures can only be made with right heart catheterization, which is invasive,” while “common noninvasive tests suffer a variety of limitations,” they said.

Endostatin is derived from the protein collagen XVIII, α-1 (COL18A1) that inhibits both tumor angiogenesis and coronary collateral formation. Furthermore, previous research has shown it “inhibits pulmonary artery endothelial cell proliferation and migration and promotes endothelial cell apoptosis, fundamental features driving PAH pathobiology.”

To better understand the clinical potential of endostatin as a prognostic biomarker in PAH, the researchers examined its performance in a large multicenter cohort of patients with PAH. Serum samples and clinical data were obtained from 2017 patients, the majority of whom were women (80%) of European ancestry (82%) 55 years and older.

Participants had moderately severe disease with either idiopathic PAH (IPAH) or connective tissue disease–associated PAH (CTD-PAH). Median time from diagnosis to enrollment was 48 months, 1984 individuals had follow-up data available.

Over the follow-up period, 338 participants passed away. Analyses revealed:

• Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and shorter 6-minute walk distance (P <.01)
• Mortality risk doubled for each log higher endostatin (HR, 2.3; 95% CI, 1.6-3.4; P <.001)
• Adjusted models showed in the IPAH subgroup, each log higher endostatin was associated with a nearly 6-fold increase in mortality (HR, 5.68; 95% CI, 2.4-12.8; P <.001)
• In the CTD-PAH subgroup, the magnitude of the relationship between serum endostatin and mortality was attenuated, and its significance was lost (HR, 1.76; 95% CI, 0.94-3.32; P = .08)
• Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models
• Adding endostatin to REVEAL-based and European Society of Cardiology/European Respiratory Society (ESC/ERS) criteria–based risk assessment strategies improved mortality risk prediction

“Taken together, these results suggest that novel markers like endostatin could form the cornerstone of future refinements to PAH risk assessment strategies based on noninvasive parameters only,” the researchers said.

Future studies are warranted to better discern the potential effects of endostatin in pulmonary vasculature vs right ventricular myocardium, they added.

Right ventricular metrics were not available to directly examine endostatin’s association with right ventricular function, marking a limitation to the study, while risk prediction models incorporating endostatin will also require external validation. Information on comorbidities was also unavailable.

“Future studies are needed to determine the potential for endostatin to serve as a diagnostic or serial biomarker, and to clarify genetic, molecular and cellular mechanisms. Should future mechanistic studies implicate endostatin in the causal pathway for PAH development or progression, it may be a plausible target for drug development efforts,” the authors concluded.

Reference

Simpson CE, Griffiths M, Yang J, et al. The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension. ERJ Open Res. Published online October 11, 2021. doi:10.1183/23120541.00378-2021