Relevance of Angiopoietin‐2 and Soluble P‐Selectin Levels in Patients with Pulmonary Arterial Hypertension Receiving Combination Therapy with Oral Treprostinil: A FREEDOM‐C2 Biomarker Substudy

Abstract

Studies have suggested roles for angiopoietin-2 (Ang-2) and soluble P-selectin (sP-selectin) as biomarkers of disease severity and treatment response in pulmonary arterial hypertension (PAH), but additional data are required for validation. We evaluated these biomarkers using data from FREEDOM-C2, in which patients with PAH receiving stable monotherapy or combination therapy were randomized to receive additional treatment with oral treprostinil (up-titrated from 0.25 mg twice daily) or placebo for 16 weeks. Biomarker analysis was optional in FREEDOM-C2. We measured plasma Ang-2 and sP-selectin levels at baseline and at week 16, and we assessed their association with predefined outcomes (6-minute walk distance [6MWD] change from baseline >40 m, 6MWD >380 m, functional class I/II, and/or N-terminal pro-brain natriuretic peptide [NT-proBNP] <1,800 pg/mL at week 16) using Spearman correlation, receiver operating characteristics, and logistic regression. Biomarker data were available for 83 of 157 and 95 of 153 patients in the oral treprostinil and placebo groups, respectively. In the oral treprostinil group, baseline Ang-2 levels correlated with week 16 NT-proBNP levels (P < 0.0001). Baseline Ang-2 ≥12 ng/mL was associated with a reduced likelihood of having NT-proBNP <1,800 pg/mL at week 16 (multivariate odds ratio: 0.08; 95% confidence interval: 0.02-0.32). However, Ang-2 showed no significant association with the other assessed outcomes, and sP-selectin was not associated or correlated with any of the outcomes. These data suggest that Ang-2 and sP-selectin are not associated with response to oral treprostinil in patients already receiving stable PAH therapy. Trial registration: Clinicaltrials.gov identifier NCT00887978.

Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)

“…141 Circulating levels of soluble P-selectin did, however, not correlate with World Health Organization functional class (FC) or transplant-free survival in a recent biomarker study in 65 PAH patients, 142 and were not associated with changes in 6-min walk distance or FC in response to PAH therapy by trepostinil. 143 For soluble E-selectin, elevated levels have been reported in iPAH patients compared to healthy controls. 144 Likewise, soluble intercellular adhesion molecule-1 (ICAM-1) levels in serum are significantly higher in children with PAH secondary to CHD compared to children with CHD without associated PAH, or in a healthy control group.…”

“…141 Circulating levels of soluble P-selectin did, however, not correlate with World Health Organization functional class (FC) or transplant-free survival in a recent biomarker study in 65 PAH patients, 142 and were not associated with changes in 6-min walk distance or FC in response to PAH therapy by trepostinil. 143 …”

Biomarkers in Pulmonary Arterial Hypertension

“…According to studies published in previous years, the angiopoietin system (ANG ), consisting of angiopoietin 1 (ANG1) and angiopoietin 2 (ANG2) antagonists, could be involved in both disease staging and treatment response in patients with IPAH [ 87 ]. Kumpers et al showed that ANG2 was statistically significantly correlated with CI, PVR, and mvSatO 2 , confirming its involvement in the pathogenesis of IPAH [ 88 ]. However, additional information has emerged more recently, suggesting that ANG2 is not associated with treatment response in patients with IPAH [ 89 ], although it may be used as a diagnostic and prognostic marker in Group 3 patients with PH.…”

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease

“…Attempts have been made to analyze the effects of PAH drugs on markers of vascular dysfunction, [3][4][5][6][7] with potential impact on future therapeutic strategies. 8,9 Pulmonary vascular disease is a known complication in unoperated patients with large congenital cardiac communications.…”

“…It is equally important to investigate how these treatments modify parameters related to vascular biology and microcirculation, as they may eventually reflect disease stability or the onset and progression of microvascular and macrovascular complications. Attempts have been made to analyze the effects of PAH drugs on markers of vascular dysfunction, with potential impact on future therapeutic strategies …”