Angiopoietin 2 and hsCRP are associated with pulmonary haemodynamics and long-term mortality respectively in CTEPH - results from a prospective discovery and validation biomarker study

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain aetiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension.

We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Angiopoietin 2 (Ang2) and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival.

In CTEPH patients, Ang2, interleukin (IL) 8, tumour necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary haemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality.

We hypothesise CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 maybe critical to CTEPH disease pathogenesis (impaired thrombus organisation and disease severity).