Tymon Pol: Novel biomarkers and their relation to clinical outcomes and pathophysiology in anticoagulated patients with atrial fibrillation

Abstract

Atrial fibrillation (AF) is a common arrhythmia and is associated with an increased risk of cardiovascular (CV) outcomes, including mortality and heart failure (HF).

The overall aim of this thesis was to evaluate the association of novel and established biomarkers with cardiovascular outcomes in patients with AF. Baseline levels of apolipoproteins A1 (ApoA1) and B (ApoB) were investigated in relation to CV outcomes. The geographic consistency of Growth differentiation factor 15 (GDF-15) and the ABC-AF risk scores in predicting bleeding and mortality were investigated. Proteomic analyses were employed to screen for novel biomarkers associated with CV death and hospitalization for HF in AF and biomarker profile differences between HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) were also explored.

The study population consisted of patients with AF on anticoagulation included in the biomarker substudies from the large randomized clinical controlled trials RE-LY (n=6,187) and ARISTOTLE (n=14,954) with a median follow up of 2.0 and 1.9 years. Biomarker levels were measured at baseline.

Higher levels of ApoA1 were independently associated with a lower risk of ischemic events, whereas ApoB was not. Neither apolipoprotein was significantly associated with major bleeding. The predictive value of GDF-15 and the biomarker-based ABC-AF risk scores for bleeding and mortality across various geographic regions was consistent. In the screening investigation for novel markers, the biomarkers most strongly and consistently associated with CV death were: NT-proBNP, cTnT-hs, IL-6, GDF-15, FGF-23, uPAR, TFF3, TNFR1, TRAILR2 and CTSL1. The biomarkers most strongly associated with HF hospitalization were NT-proBNP, BNP, cTnT-hs, FGF-23, spon1, IGFBP-7, u-par, OPN, PTX3 and TR. In comparison of HFrEF versus HFpEF, levels of NT-proBNP, BNP, cTnT-hs, renin, ACE-2, GDF-15 and IL-6 were higher in HFrEF, whereas levels of SCF and leptin were higher in HFpEF.

In conclusion, this thesis underscores the pivotal role of biomarkers in better understanding AF and its complications. The insights from this thesis suggest potential therapeutic targets and strategies for personalized management in AF, possibly enhancing risk stratification and improving patient outcomes.