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

Charaka M Hadinnapola; Mark Southwood; Jules Hernández-Sánchez; Katherine Bunclark; Michael Newnham; Emilia M Swietlik; John Cannon; Stephen D Preston; Karen Sheares; Dolores Taboada; Nicholas Screaton; David P Jenkins; Nicholas W Morrell; Mark Toshner; Joanna Pepke-Zaba

doi:10.1016/j.healun.2022.08.021

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

J Heart Lung Transplant. 2023 Mar;42(3):398-405. doi: 10.1016/j.healun.2022.08.021. Epub 2022 Sep 8.

Authors

Affiliations

¹ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK; Norfolk and Norwich University Hospital, University of East Anglia, Colney Lane, Norwich, UK.
² Department of Histopathology, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK.
³ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK; MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, UK.
⁴ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
⁵ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK; Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, UK.
⁶ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK.
⁷ Department of Surgery, Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, UK.
⁸ Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
⁹ Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge Biomedical Campus Cambridge, Cambridge, UK. Electronic address: joanna.pepke-zaba@nhs.net.

PMID: 36609091
DOI: 10.1016/j.healun.2022.08.021

Abstract

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. 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.

Methods: 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. 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.

Results: In CTEPH patients, Ang2, interleukin (IL) 8, tumor 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 hemodynamic 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.

Conclusions: We hypothesize that 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 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

Keywords: CTEPH; angiogenesis; angiopoietin 2; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiopoietin-2*
Biomarkers
C-Reactive Protein*
Endarterectomy / adverse effects
Hemodynamics
Humans
Hypertension, Pulmonary* / diagnosis
Hypertension, Pulmonary* / etiology
Hypertension, Pulmonary* / metabolism
Vascular Endothelial Growth Factor A

Substances

Angiopoietin-2
Biomarkers
C-Reactive Protein
Vascular Endothelial Growth Factor A

Abstract

Publication types

MeSH terms

Substances

Grants and funding