The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.
Research Article| Volume 42, ISSUE 3, P398-405, March 2023

Download started.


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

Published:September 07, 2022DOI:


      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.


      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.


      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.


      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).


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kim NH
        • Delcroix M
        • Jais X
        • et al.
        Chronic thromboembolic pulmonary hypertension.
        Eur Respir J. 2019; 531801915
        • Delcroix M
        • Torbicki A
        • Gopalan D
        • et al.
        ERS statement on chronic thromboembolic pulmonary hypertension.
        Eur RespirJ. 2021; 572002828
        • Moser KM
        • Braunwald NS.
        Successful surgical intervention in severe chronic thromboembolic pulmonary hypertension.
        Chest. 1973; 64: 29-35
        • Yi ES
        • Kim H
        • Ahn H
        • et al.
        Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study.
        Am J Respir Crit Care Med. 2000; 162: 1577-1586
        • Madani M
        • Ogo T
        • Simonneau G.
        The changing landscape of chronic thromboembolic pulmonary hypertension management.
        Eur Respir Rev. 2017; 26170105
        • Mercier O
        • Tivane A
        • Dorfmuller P
        • et al.
        Piglet model of chronic pulmonary hypertension.
        Pulm Circ. 2013; 3: 908-915
        • Dorfmuller P
        • Gunther S
        • Ghigna MR
        • et al.
        Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature.
        Eur Respir J. 2014; 44: 1275-1288
        • Azarian R
        • Wartski M
        • Collignon MA
        • et al.
        Lung perfusion scans and hemodynamics in acute and chronic pulmonary embolism.
        J Nucl Med. 1997; 38: 980-983
        • Riedel M
        • Stanek V
        • Widimsky J
        • Prerovsky I.
        Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data.
        Chest. 1982; 81: 151-158
        • Kumpers P
        • Nickel N
        • Lukasz A
        • et al.
        Circulating angiopoietins in idiopathic pulmonary arterial hypertension.
        Eur Heart J. 2010; 31: 2291-2300
        • Soon E
        • Holmes AM
        • Treacy CM
        • et al.
        Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension.
        Circulation. 2010; 122: 920-927
        • Kimura H
        • Okada O
        • Tanabe N
        • et al.
        Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension.
        Am J Respir Crit Care Med. 2001; 164: 319-324
        • Langer F
        • Schramm R
        • Bauer M
        • Tscholl D
        • Kunihara T
        • Schäfers HJ.
        Cytokine response to pulmonary thromboendarterectomy.
        Chest. 2004; 126: 135-141
        • Wynants M
        • Quarck R
        • Ronisz A
        • et al.
        Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension.
        Eur Respir J. 2012; 40: 886-894
        • Zabini D
        • Heinemann A
        • Foris V
        • et al.
        Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients.
        Eur Respir J. 2014; 44: 951-962
        • Zabini D
        • Nagaraj C
        • Stacher E
        • et al.
        Angiostatic factors in the pulmonary endarterectomy material from chronic thromboembolic pulmonary hypertension patients cause endothelial dysfunction.
        PLoS One. 2012; 7: e43793
        • Moser B
        • Megerle A
        • Bekos C
        • et al.
        Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH.
        PLoS One. 2014; 9e106440
        • Alias S
        • Redwan B
        • Panzenbock A
        • et al.
        Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension.
        Arterioscler Thromb Vasc Biol. 2014; 34: 810-819
        • Quarck R
        • Wynants M
        • Verbeken E
        • Meyns B
        Delcroix M. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension.
        Eur Respir J. 2015; 46: 431-443
        • Hobohm L
        • Kölmel S
        • Niemann C
        • et al.
        Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease.
        Eur Respir J. 2021; 582004196
        • Galie N
        • Humbert M
        • Vachiery JL
        • et al.
        2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
        Eur Heart J. 2016; 37: 67-119
        • Kloke JD
        • McKean JW.
        Rfit: rank-based estimation for linear models.
        R J. 2012; 4: 57-64
        • Skoro-Sajer N
        • Gerges C
        • Gerges M
        • et al.
        Usefulness of thrombosis and inflammation biomarkers in chronic thromboembolic pulmonary hypertension-sampling plasma and surgical specimens.
        J Heart Lung Transplant. 2018; 37: 1067-1074
        • Cannon JE
        • Su L
        • Kiely DG
        • et al.
        Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the united kingdom national cohort.
        Circulation. 2016; 133: 1761-1771
        • Naito A
        • Sakao S
        • Lang IM
        • et al.
        Endothelial cells from pulmonary endarterectomy specimens possess a high angiogenic potential and express high levels of hepatocyte growth factor.
        BMC Pulm Med. 2018; 18: 197
        • Quarck R
        • Wynants M
        • Ronisz A
        • et al.
        Characterization of proximal pulmonary arterial cells from chronic thromboembolic pulmonary hypertension patients.
        Respir Res. 2012; 13: 27
        • Belik D
        • Tsang H
        • Wharton J
        • Howard L
        • Bernabeu C
        • Wojciak-Stothard B.
        Endothelium-derived microparticles from chronically thromboembolic pulmonary hypertensive patients facilitate endothelial angiogenesis.
        J Biomed Sci. 2016; 23: 4
        • Felcht M
        • Luck R
        • Schering A
        • et al.
        Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling.
        J Clin Invest. 2012; 122: 1991-2005
        • Korhonen EA
        • Lampinen A
        • Giri H
        • et al.
        Tie1 controls angiopoietin function in vascular remodeling and inflammation.
        J Clin Invest. 2016; 126: 3495-3510
        • Maisonpierre PC
        • Suri C
        • Jones PF
        • et al.
        Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.
        Science. 1997; 277: 55-60
        • Matthews DT
        • Hemnes AR.
        Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension.
        Pulm Circ. 2016; 6: 145-154
        • Bochenek ML
        • Rosinus NS
        • Lankeit M
        • et al.
        From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension.
        Thromb Haemost. 2017; 117: 769-783
        • Akwii RG
        • Sajib MS
        • Zahra FT
        • Mikelis CM.
        Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology.
        Cells. 2019; 8: 471
        • McCabe C
        • White PA
        • Hoole SP
        • et al.
        Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter.
        J Appl Physiol. 2014; 116: 355-363
        • Klok FA
        • van der Hulle T
        • den Exter PL
        • Lankeit M
        • Huisman MV
        • Konstantinides S.
        The post-PE syndrome: a new concept for chronic complications of pulmonary embolism.
        Blood Rev. 2014; 28: 221-226
        • Coghlan JG.
        Balloon Pulmonary Angioplasty: Does It Have a Role in CTED?.
        Pulm Circ. 2018; 8: 1-4

      Related Podcast

      Episode 27: March 2023

      This month’s JHLT: The Podcast is hosted by Digital Media Editor David Schibilsky, MD, who leads a discussion of two studies from the March issue of The Journal of Heart and Lung Transplantation—and the first authors who presented them.

       First, the editors explore a study entitled “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,” which comes from Hadinnapola and colleagues at the Papworth group in Cambridge, UK.

       The editors welcome Charaka Hadinnapola, MA, MB, BChir, first author on the CTEPH study, to share the rationale in performing the research, its main findings, the changing understanding of the pathobiology of pulmonary arterial hypertension, and how Ang2 and hsCRP fit into the bigger cytokine picture in CTEPD and CTEPH patients.

       Next, the editors welcome author J.K. Peel, MD, MSc, from the University of Toronto to discuss the paper her first authored, “Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: a retrospective cohort study.”