Plasma markers in pulmonary hypertension subgroups correlate with patient survival

T. Koudstaal, D. van Uden, J. A.C. van Hulst, P. Heukels, I. M. Bergen, L. W. Geenen, V. J.M. Baggen, A. E. van den Bosch, L. M. van den Toorn, P. P. Chandoesing, M. Kool, E. Boersma, R. W. Hendriks, K. A. Boomars*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Background: Recent 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. Methods: 50 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. Results: At 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. Discussion: Our 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. Conclusion: In conclusion, our studies identified an inflammatory signature that clustered PH patients into WHO classification-independent subgroups that correlated with patient survival.

Original languageEnglish
Article number137
JournalRespiratory Research
Volume22
Issue number1
DOIs
Publication statusPublished - 4 May 2021

Bibliographical note

Funding Information:
This research project was supported by an unrestricting grant by Actelion pharmaceuticals, by the Dutch Heart Foundation (Grant Number 2016T052) and an unrestricting grant by Ferrer pharmaceuticals.

Funding Information:
The authors would like to thank our specialized PH nurses Miriam de Groot and Corine Kolpa at the Erasmus University Medical Centre for their contribution to this study. The authors would also like to thank Martijn Kauling, cardiologist, for his contribution to this study. Also, the authors thank Menno van Nimwegen and Madelief Vink, for their help in processing the peripheral blood samples at our research department.

Publisher Copyright:
© 2021, The Author(s).

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