Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation

Tymon Pol, Ziad Hijazi, Johan Lindbäck, Jonas Oldgren, John H Alexander, Stuart J Connolly, John W Eikelboom, Michael D Ezekowitz, Christopher B Granger, Renato D Lopes, Salim Yusuf, Agneta Siegbahn, Lars Wallentin, Tymon Pol, Ziad Hijazi, Johan Lindbäck, Jonas Oldgren, John H Alexander, Stuart J Connolly, John W Eikelboom, Michael D Ezekowitz, Christopher B Granger, Renato D Lopes, Salim Yusuf, Agneta Siegbahn, Lars Wallentin

Abstract

Aims: Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.

Methods and results: A case-cohort design with 1.8- to 1.9-year follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analysed with conventional immunoassays and the OLINK proximity extension assay panels: CVDII, CVDIII, and Inflammation. Association between biomarkers and CV death was evaluated using Random Survival Forest, Boruta, and adjusted Cox-regression analyses. The biomarkers most strongly and consistently associated with CV death were as follows (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide [NT-proBNP; 1.63 (1.37-1.93)], cardiac troponin T [cTnT-hs; 1.60 (1.35-1.88)], interleukin-6 [IL-6; 1.29 (1.13-1.47)], growth differentiation factor-15 [GDF-15; 1.30 (1.10-1.53)], fibroblast growth factor 23 [FGF-23; 1.21 (1.10-1.33)], urokinase receptor [uPAR; 1.38 (1.16-1.64)], trefoil factor 3 [TFF3; 1.27 (1.10-1.46)], tumour necrosis factor receptor 1 [TNFR1; 1.21 (1.01-1.45)], TNF-related apoptosis-inducing ligand receptor 2 [TRAILR2; 1.18 (1.04-1.34)], and cathepsin L1 [CTSL1; 1.22 (1.07-1.39)].

Conclusion: In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF, the underlying mechanisms most strongly associated with CV death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR), and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV death in AF.

Clinicaltrials.gov identifier: NCT00412984 and NCT00262600.

Keywords: Atrial fibrillation; Biomarkers; Cardiovascular death; Proteomics; Risk.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Variable importance for CV death according to the Random Survival Forest analyses in (A) the identification cohort and (B) the validation cohort. Red colour indicates biomarkers analysed on CVD II panel, green colour CVD III, and blue colour inflammation panel. Biomarkers listed in black were analysed with conventional immunoassays. Only the top 50 variables are shown. The evaluation included 263 PEA markers, five conventional markers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T-hs, growth differentiation factor 15 (GDF-15), cystatin C, and interleukin-6 (IL-6)] and 13 clinical characteristics. The identification cohort included 517 cases with CV death during follow-up and 4057 randomly selected patients for comparison. The validation cohort included 277 cases with CV death during follow-up and 1042 randomly selected patients for comparison.
Figure 2
Figure 2
Forest plot of the top 50 biomarkers associated with CV death according to adjusted Cox-regression analysis in (A) the identification cohort and (B) the validation cohort (by P-value). A forest plot showing all 255 biomarkers is available in Supplementary material online, Figures S1 and S2. Red colour indicates biomarkers analysed on CVD II panel, green colour CVD III, and blue colour inflammation panel. Biomarkers listed in black were analysed with conventional immunoassays. Model adjusted for baseline characteristics, renal function, and cardiac biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT-hs)]. The identification cohort included 517 cases with CV death during follow-up and 4057 randomly selected patients for comparison. The validation cohort included 277 cases with CV death during follow-up and 1042 randomly selected patients for comparison.
Figure 3
Figure 3
Conceptual figure showing top biomarkers and their associated processes in relation to CV death in AF.

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