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Plasma markers in pulmonary hypertension subgroups correlate with patient survival

Authors
  • Koudstaal, T.1
  • van Uden, D.1
  • van Hulst, J. A. C.1
  • Heukels, P.1
  • Bergen, I. M.1
  • Geenen, L. W.2
  • Baggen, V. J. M.2
  • van den Bosch, A. E.2
  • van den Toorn, L. M.1
  • Chandoesing, P. P.1
  • Kool, M.1
  • Boersma, E.2, 2
  • Hendriks, R. W.1
  • Boomars, K. A.1
  • 1 Erasmus MC, University Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands , Rotterdam (Netherlands)
  • 2 Erasmus MC, University Medical Center, Rotterdam, The Netherlands , Rotterdam (Netherlands)
Type
Published Article
Journal
Respiratory Research
Publisher
BioMed Central
Publication Date
May 04, 2021
Volume
22
Issue
1
Identifiers
DOI: 10.1186/s12931-021-01716-w
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundRecent studies have provided evidence for an important contribution of the immune system in the pathophysiology of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In this report, we investigated whether the inflammatory profile of pulmonary hypertension patients changes over time and correlates with patient WHO subgroups or survival.Methods50 PAH patients (16 idiopathic (I)PAH, 24 Connective Tissue Disease (CTD)-PAH and 10 Congenital Heart Disease (CHD)-PAH), 37 CTEPH patients and 18 healthy controls (HCs) were included in the study. Plasma inflammatory markers at baseline and after 1-year follow-up were measured using ELISAs. Subsequently, correlations with hemodynamic parameters and survival were explored and data sets were subjected to unbiased multivariate analyses.ResultsAt diagnosis, we found that plasma levels of interleukin-6 (IL-6) and the chemokines (C-X3-C) motif legend CXCL9 and CXCL13 in CTD-PAH patients were significantly increased, compared with HCs. In idiopathic PAH patients the levels of tumor growth factor-β (TGFβ), IL-10 and CXCL9 were elevated, compared with HCs. The increased CXCL9 and IL-8 concentrations in CETPH patients correlated significantly with decreased survival, suggesting that CXCL9 and IL-8 may be prognostic markers. After one year of treatment, IL-10, CXCL13 and TGFβ levels changed significantly in the PAH subgroups and CTEPH patients. Unbiased multivariate analysis revealed clustering of PH patients based on inflammatory mediators and clinical parameters, but did not separate the WHO subgroups. Importantly, these multivariate analyses separated patients with < 3 years and > 3 years survival, in particular when inflammatory mediators were combined with clinical parameters.DiscussionOur study revealed elevated plasma levels of inflammatory mediators in different PAH subgroups and CTEPH at baseline and at 1-year follow-up, whereby CXCL9 and IL-8 may prove to be prognostic markers for CTEPH patients. While this study is exploratory and hypothesis generating, our data indicate an important role for IL-8 and CXCL9 in CHD and CTEPH patients considering the increased plasma levels and the observed correlation with survival.ConclusionIn conclusion, our studies identified an inflammatory signature that clustered PH patients into WHO classification-independent subgroups that correlated with patient survival.

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