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Clinical Trial
. 2022 Jul 20;118(9):2112-2123.
doi: 10.1093/cvr/cvab262.

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

Tymon Pol  1   2 , Ziad Hijazi  1   2 , Johan Lindbäck  2 , Jonas Oldgren  1   2 , John H Alexander  3 , Stuart J Connolly  4 , John W Eikelboom  4 , Michael D Ezekowitz  5   6 , Christopher B Granger  3 , Renato D Lopes  3 , Salim Yusuf  4 , Agneta Siegbahn  2   7 , Lars Wallentin  1   2
Affiliations
Clinical Trial

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

Tymon Pol et al. Cardiovasc Res. .

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.

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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.
See this image and copyright information in PMC

Comment in

References

    1. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA.. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ 2016;354:i4482. - PubMed
    1. Hart RG, Pearce LA, Aguilar MI.. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–867. - PubMed
    1. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators . Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992. - PubMed
    1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators . Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. - PubMed
    1. Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Alexander JH, Atar D, Gersh BJ, Hanna M, Harjola VP, Horowitz JD, Husted S, Hylek EM, Lopes RD, McMurray JJ, Granger CB; ARISTOTLE Investigators . High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol 2014;63:52–61. - PubMed

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