Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: a validation study

Winnie Chua, Jonathan P Law, Victor R Cardoso, Yanish Purmah, Georgiana Neculau, Muhammad Jawad-Ul-Qamar, Kalisha Russell, Ashley Turner, Samantha P Tull, Frantisek Nehaj, Paul Brady, Peter Kastner, André Ziegler, Georgios V Gkoutos, Davor Pavlovic, Charles J Ferro, Paulus Kirchhof, Larissa Fabritz

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Abstract

Background
Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays.

Methods and findings
For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation.

Conclusions
Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF.

Trial registration
Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom
Original languageEnglish
Article numbere1003405
JournalPLoS Medicine
Volume18
Issue number2
DOIs
Publication statusPublished - 3 Feb 2021

Bibliographical note

Funding Information:
This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) and no. 116074 [BigData@Heart EU IMI] to PKi and LF, British Heart Foundation (FS/13/43/30324 to PKi and LF), German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PKi), and Leducq Foundation to PKi. The Institute of Cardiovascular Sciences has received the British Heart Foundation (BHF) Accelerator Award (AA/18/ 2/34218). https://www.bhf.org.uk/forprofessionals/information-for-researchers/ managing-your-grant/open-access-policy https:// ec.europa.eu/programmes/horizon2020/en http:// www.ehnheart.org/projects/imi-bigdata-heart/ 1086:imi-bigdataheart.html https://www. kompetenznetz-vorhofflimmern.de/en/research/ dzhk-studies The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 Chua et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ASJC Scopus subject areas

  • Medicine(all)

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