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. 2023 Jan 14;44(3):208-218.
doi: 10.1093/eurheartj/ehac632.

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation

Ziad Hijazi  1   2 , Alexander P Benz  3   4 , Johan Lindbäck  1 , John H Alexander  5 , Stuart J Connolly  3 , John W Eikelboom  3 , Christopher B Granger  5 , Peter Kastner  6 , Renato D Lopes  5 , André Ziegler  6 , Jonas Oldgren  1   2 , Agneta Siegbahn  1   7 , Lars Wallentin  1   2
Affiliations

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation

Ziad Hijazi et al. Eur Heart J. .

Abstract

Aims: Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC).

Methods and results: BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death.

Conclusion: The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF.

One-sentence summary: In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

Keywords: Atrial fibrillation; BMP10; Biomarker; Heart failure; Risk stratification; Stroke.

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Conflict of interest statement

Conflict of interest: Dr Hijazi reports lecture and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer and Roche Diagnostics International. Dr Benz has nothing to disclose. Mr Lindbäck reports institutional research grant from Roche Diagnostics International. Dr Alexander reports institutional research grants from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, Humacyte, and XaTek and consulting or honoraria payments from AbbVie, Akros, Artivion/CryoLife, AtriCure, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, Portola, and Quantum Genomics. Dr Connolly reports institutional research grants and honoraria from Boehringer Ingelheim, Portola/Alexion Pharmaceuticals, Bristol Myers Squibb/Pfizer, Bayer, and Daiichi Sankyo. Dr Eikelboom reports institutional research grants and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi. Dr Granger reports grants and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Janssen Pharmaceutica Products, L.P., Medtronic Foundation, Novartis; grants from Daiichi Sankyo, AKROS, Apple, GlaxoSmithKline, AstraZeneca, the U.S. Food and Drug Administration; consulting fees from Abbvie, Abiomed, Athos Therapeutic, LLC, Bayer Corporation US, Boston Scientific Corporation, Espero BioPharma, National Institutes of Health, Philips, Rhoshan Pharmaceuticals, Roche Diagnostics, CeleCor Therapeutics, Correvio, Merck, NovoNordisk. Drs. Kastner and Ziegler are employees of Roche Diagnostics GmbH. Dr Lopes reports institutional research grants and consulting fees from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; consulting fees from Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Portola. Dr Oldgren reports institutional research grants and fees paid to his institution for advisory boards and lectures from Roche Diagnostics International; fees paid to his institution for advisory boards, study steering committees, and lectures from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, and Sanofi; fees paid to his institution for advisory boards, safety committees, and lectures from Daichii Sankyo. Dr Siegbahn reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics International. Dr Wallentin reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics International, Merck & Co; consulting fees from Abbott; holds two patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2).

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Figure 1
Figure 1
Association between BMP10 and other variables in adjusted models. (A) non-OAC cohort and (B) OAC cohort
Figure 2
Figure 2
Unadjusted, smoothed association between BMP10 and one-year risk of ischaemic stroke, heart failure hospitalisation, and CV death in the non-OAC cohort (left) and the OAC cohort (right)
Figure 3
Figure 3
Kaplan–Meier estimate of the cumulative event rate of ischaemic stroke, hospitalisation for heart failure, and CV death by BMP10 quartile groups in the non-OAC cohort (left) and OAC cohort (right)
Figure 4
Figure 4
Relative importance of BMP10 and other variables for different outcomes in multivariable models without (left panels) and with established biomarkers (right panels)
See this image and copyright information in PMC

Comment in

References

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