Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study

Abstract

Background and aims: In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm control therapy. Predictors of attaining sinus rhythm at follow-up are not well known.

Methods: To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 45% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets.

Results: Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] .76 [95% confidence interval .65-.89], P < .001), bone morphogenetic protein 10 (BMP10) (OR .83 [.71-.97], P = .017), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR .73 [.60-.88], P < .001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (Pinteraction = .033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR .64 [.51-.80], P < .001; early rhythm control: OR .90 [.69-1.18], P = .453). External validation confirmed that low concentrations of ANGPT2, BMP10, and NT-proBNP predict sinus rhythm during follow-up.

Conclusions: Low concentrations of ANGPT2, BMP10, and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control.

Keywords: Angiopoietin 2; Atrial fibrillation; Blood biomarker; Bone morphogenetic protein 10; Natriuretic peptides; Rhythm control; Risk prediction; Risk score; Sinus rhythm.

Structured Graphical Abstract

In patients diagnosed with atrial fibrillation, low concentrations of NT-proBNP, BMP10, and ANGPT2 at baseline predict sinus rhythm at 12-month follow-up in context with clinical features. This was validated in additional datasets, of which AXAFA-AFNET 5 is depicted here. A treatment interaction shows that NT-proBNP’s predictive value is impacted by early rhythm control treatment. AF, atrial fibrillation; ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 1

Low concentrations of the biomarkers NT-proBNP, angiopoietin 2, and bone morphogenetic protein 10 predict sinus rhythm at 12-month follow-up in the derivation dataset (EAST-AFNET 4). Odds ratios for sinus rhythm at 12-month follow-up (A) and odds ratios by randomized treatment group (B). Forest plot showing odds ratios for each biomarker for the outcome sinus rhythm at 12-month follow-up and 95% confidence intervals. The odds ratio for NT-proBNP shows an interaction between NT-proBNP concentrations and randomized treatment group (early rhythm control or usual care). All odds ratios are corrected for clinical features, age, sex, EAST study centre, rhythm at baseline, atrial fibrillation type, randomized treatment group, body mass index, diastolic blood pressure, and left ventricular ejection fraction. Even after multiple confounding, high biomarker concentrations indicate lower odds of sinus rhythm at 12-month follow-up. Low concentrations of NT-proBNP predict sinus rhythm at 12-month follow-up in patients with usual care (only symptomatic rhythm control). High concentrations of NT-proBNP do not necessarily predict lack of sinus rhythm at 12 months if patients receive early rhythm control. ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; CA125, cancer antigen 125; CRP, C-reactive protein; D-dimer, ESM1, endothelial specific molecule 1; FABP3, fatty acid binding protein 3; FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGFBP7, insulin-like growth factor binding protein 7; IL-6, interleukin-6; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TnT, cardiac troponin; sCr, serum creatinine

Figure 2

Biomarker concentration distributions at baseline in patients with sinus rhythm (teal right part of each plot) or atrial fibrillation (orange left part of each plot) at 12-month follow-up. Violin plot of the distribution of log-transformed biomarker concentrations for each of 14 biomarkers at baseline, split by the outcome of rhythm at 12-month follow-up. Log-transformed biomarker concentrations are shown on the y-axis and the kernel estimated frequency on the x-axis. Central thick horizontal lines are the median and the thinner lines represent interquartile range. N-terminal pro-B-type natriuretic peptide, angiopoietin 2, and bone morphogenetic protein 10 show an association with sinus rhythm at 12-month follow-up based on the acceptance of a Type 1 error of 5%. P-values were calculated using mixed logistic regression model with site as random effect, adjusted for age, sex, rhythm at baseline, randomized group (early rhythm control or usual care), body mass index, diastolic blood pressure, and left ventricular ejection fraction, those clinical features that were associated with outcomes including sinus rhythm in the main EAST-AFNET 4 trial. ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; CA125, cancer antigen 125; CRP, C-reactive protein; D-dimer, ESM1, endothelial specific molecule 1; FABP3, fatty acid binding protein 3; FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGFBP7, insulin-like growth factor binding protein 7; IL-6, interleukin-6; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TnT, cardiac troponin; sCr, serum creatinine

Figure 3

Biomarkers measured at baseline predicting sinus rhythm at 12-month follow-up in all participants of the biomarker study, separately analysed by rhythm at baseline (atrial fibrillation at baseline or sinus rhythm at baseline) and randomized treatment group (early rhythm control or usual care), respectively, in a post hoc analysis. Of the three biomarkers identified to be predictive of sinus rhythm in the whole cohort, NT-proBNP, ANGPT2, and BMP10, all three biomarkers retained their predictive value in the subgroup of patients randomized to usual care. All three biomarkers also retained their predictive value in the subgroup of patients in atrial fibrillation during blood draw at baseline. ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; NT-proBNP, N-terminal pro-B-type natriuretic peptide

Figure 4

Internal validation: angiopoietin 2, bone morphogenetic protein 10, and NT-proBNP biomarkers at baseline predict sinus rhythm at 24-month follow-up even after correction for multiple confounders. Odds ratios are shown for sinus rhythm at 24-month follow-up. This analysis provides an internal validation of the biomarkers predicting sinus rhythm at 12-month follow-up (Figure 1). All odds ratios are corrected for clinical age, sex, study site, rhythm at baseline, randomized treatment group (early rhythm control or usual care), body mass index, diastolic blood pressure, and left ventricular ejection fraction, those clinical features that were associated with outcomes including sinus rhythm in the main EAST-AFNET 4 trial. Low concentrations of NT-proBNP, ANGPT2, and BMP10 predict sinus rhythm at 24-month follow-up in patients. Accordingly, high concentrations predict lack of sinus rhythm at 24-month follow-up. ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; CA125, cancer antigen 125; CRP, C-reactive protein; D-dimer, ESM1, endothelial specific molecule 1; FABP3, fatty acid binding protein 3; FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGFBP7, insulin-like growth factor binding protein 7; IL-6, interleukin-6; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TnT, cardiac troponin; sCr, serum creatinine

Figure 5

Validation applying biomarker-based clusters indicating cardiovascular outcome risk: patients at high risk of cardiovascular complications as estimated by biomarker-based clusters have reduced odds of sinus rhythm at 12-month and 24-month follow-up. Odds ratio for the high cardiovascular outcome risk (red) and intermediate cardiovascular outcome risk biomarker clusters (orange and green) for sinus rhythm at 12-month follow-up (A, above) and at 24-month follow-up (B, bottom) tested against the low cardiovascular risk cluster (not depicted as used as reference). All odds ratios are corrected for age, sex, study centre, rhythm at baseline, atrial fibrillation type (depicted in grey odds ratios below the cluster odds ratios), randomized treatment group (early rhythm control or usual care), as well as body mass index, diastolic blood pressure, and left ventricular ejection fraction, the clinical features that were associated with outcomes including sinus rhythm in the main EAST-FNET 4 trial. AF, atrial fibrillation

Figure 6

Validation by random forest analyses identified highest importance for similar biomarkers, alongside rhythm at baseline and AF pattern, as predictors of sinus rhythm at 12-month follow-up (A—importance, B—SHAP value). AF, atrial fibrillation; ANGPT2, angiopoietin 2; BL, baseline; BMI, body mass index; BMP10, bone morphogenetic protein 10; CA125, cancer antigen 125; CRP, C-reactive protein; D-dimer, ESM1, endothelial specific molecule 1; FABP3, fatty acid binding protein 3; FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGFBP7, insulin-like growth factor binding protein 7; IL-6, interleukin-6; MERF, mixed effect random forest; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TnT, cardiac troponin; sCr, serum creatinine; SHAP, SHapley Additive exPlanations

Figure 7

External validation of the prediction of sinus rhythm at the end of follow-up by baseline biomarkers in AXAFA-AFNET 5. AXAFA-AFNET 5 enrolled 674 patients undergoing a first AF ablation with at least one stroke risk factor. Patients were randomized to apixaban or vitamin K antagonist therapy without affecting rhythm. Individual models with rhythm at baseline, age, and sex were constructed to determine whether each biomarker predicts sinus rhythm at the end of follow-up 120 days after randomization, 549 patients with sinus rhythm, 71 patients with atrial fibrillation, 620 patients with baseline biomarkers completed follow-up. *P-values were calculated using logistic regression, adjusted for sex, age, rhythm at baseline, and treatment group. ANGPT2, angiopoietin 2; BMP10, bone morphogenetic protein 10; NT-proBNP, N-terminal pro-B-type natriuretic peptide