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

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

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.

Publication types

  • Clinical Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants
  • Atrial Fibrillation*
  • Biomarkers
  • Growth Differentiation Factor 15
  • Humans
  • Inflammation
  • Interleukin-6
  • Natriuretic Peptide, Brain
  • Peptide Fragments
  • Prognosis
  • Receptors, Tumor Necrosis Factor, Type I
  • Risk Assessment / methods
  • Risk Factors
  • Stroke* / prevention & control
  • Troponin T

Substances

  • Anticoagulants
  • Biomarkers
  • Growth Differentiation Factor 15
  • Interleukin-6
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor, Type I
  • Troponin T
  • Natriuretic Peptide, Brain

Associated data

  • ClinicalTrials.gov/NCT00412984
  • ClinicalTrials.gov/NCT00262600