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Review
. 2022 May 30;8(2):00009-2022.
doi: 10.1183/23120541.00009-2022. eCollection 2022 Apr.

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension

A Josien Smits  1 , Liza Botros  1 , Marijke A E Mol  2 , Kirsten A Ziesemer  2 , Martin R Wilkins  3 , Anton Vonk Noordegraaf  1 , Harm Jan Bogaard  1 , Jurjan Aman  1
Affiliations
Review

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension

A Josien Smits et al. ERJ Open Res. .

Abstract

Rationale: The blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as "PAH"). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we performed an unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance for detection of PAH.

Methods: A literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to 28 January 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles.

Results: 149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, low density lipid-cholesterol, d-dimer, N-terminal prohormone of brain natriuretic protein (NT-proBNP), interleukin-6 (IL-6) and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis.

Conclusion: This meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required as well as studies that test combinations of biomarkers to improve specificity.

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Conflict of interest statement

Conflict of interest: M.R. Wilkins reports consulting fees from Actelion, MorphogenIX and Novartis, outside the submitted work; and patent (Prognostic biomarker panel derived from discovery science); and a leadership or fiduciary role for the Pulmonary Vascular Research Institute (unpaid). H.J. Bogaard reports receiving grants or contracts from Janssen, MSD, and Ferrer, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Janssen and MSD, outside the submitted work. The remaining authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Flow chart visualising identification of publications, inclusion and exclusion criteria, and selection of publications eligible for meta-analysis. a) Biomarker search; b) omics search. #: excluding conference abstracts; : transcriptomics, proteomics, metabolomics, glycomics and lipidomics. iPAH: idiopathic pulmonary arterial hypertension; hPAH: hereditary pulmonary arterial hypertension.
FIGURE 2
FIGURE 2
Forest plots of selected biomarkers. a) The haemtological biomarker RDW: red cell distribution width; b) the metabolic biomarker LDL-c: low density lipid-cholesterol; c) the coagulation biomarker d-dimer; d) the inflammatory biomarker IL-6: interleukin-6; e) the cardiac biomarker NT-proBNP: N-terminal prohormone of brain natriuretic peptide; f) the renal biomarker UA: uric acid; CVD: cardiovascular disease. Risk of bias (QUADAS-2) – P: patient inclusion; I: index test (biomarker); R: reference standard (diagnosis); T: flow and timing. Publications in bold type represent biomarker levels of idiopathic pulmonary arterial hypertension (iPAH) and/or hereditary pulmonary arterial hypertension (hPAH) uniquely.
See this image and copyright information in PMC

References

    1. 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. doi:10.1093/eurheartj/ehv317 - DOI - PubMed
    1. Swinnen K, Quarck R, Godinas L, et al. . Learning from registries in pulmonary arterial hypertension: pitfalls and recommendations. Eur Respir Rev 2019; 28: 190050. doi:10.1183/16000617.0050-2019 - DOI - PMC - PubMed
    1. van de Veerdonk MC, Kind T, Marcus JT, et al. . Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011; 58: 2511–2519. doi:10.1016/j.jacc.2011.06.068 - DOI - PubMed
    1. Moher D, Liberati A, Tetzlaff J, et al. . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535. doi:10.1136/bmj.b2535 - DOI - PMC - PubMed
    1. Bramer WM, Giustini D, de Jonge GB, et al. . De-duplication of database search results for systematic reviews in EndNote. J Med Libr Assoc 2016; 104: 240–243. doi:10.3163/1536-5050.104.3.014 - DOI - PMC - PubMed

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