Plasma Biomarkers Associated With Heart Failure Hospitalization Among Patients With Atrial Fibrillation and Subtypes of Heart Failure

Background Atrial fibrillation is associated with heart failure (HF) through a complex cause‐and‐effect relationship. We performed multiplex screening of plasma proteins in patients with atrial fibrillation to identify biomarkers and pathways associated with hospitalization for HF. Additionally, we aimed to identify potential pathophysiological differences between HF with reduced ejection fraction and HF with preserved ejection fraction at baseline in patients with atrial fibrillation. Methods Using a case–cohort design of patients with atrial fibrillation from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 596 cases with HF hospitalizations during follow‐up and 4029 randomly selected controls without HF hospitalization. Plasma obtained at randomization was analyzed with conventional immunoassays and proximity extension assay panels. Biomarker associations with HF hospitalization were evaluated using random survival forest, Boruta, and Cox‐regression analyses. Associations between biomarkers and HF subtype were evaluated with Wilcoxon−Mann–Whitney test with Bonferroni–Holm adjustment for multiplicity. Results The biomarkers most strongly and significantly associated with increased risk of HF hospitalization after adjustment for clinical characteristics, renal function, and cardiac biomarkers, and after correction for multiplicity ( P ≤0.00027), were NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), BNP (B‐type natriuretic peptide), hs‐cTnT (high‐sensitivity cardiac troponin T), fibroblast growth factor 23, spondin 1, insulin‐like growth factor binding protein 7, urokinase‐type plasminogen activator receptor, osteopontin, pentraxin‐related protein 3, and transferrin receptor protein 1R. Among patients with prevalent HF, 9 biomarkers remained significant after adjustment for multiplicity; NT‐proBNP, BNP, hs‐cTnT, renin, angiotensin‐converting enzyme 2, growth differentiation factor 15, and interleukin‐6 levels were higher in HF with reduced ejection fraction, whereas levels of stem cell factor and leptin were higher in HF with preserved ejection fraction (all P