The Role of Pro-Fibrotic Biomarkers in Atrial Fibrillation: How Good Are We in the Translational Interpretation?

We read with interest the paper by Takemoto et al. (1), where the translational aspect of profibrotic biomarkers in atrial fibrillation (AF) is discussed. The authors showed higher intracardiac levels of galectin-3 in patients with persistent AF compared with paroxysmal AF as well as a significant association between galectin-3 levels and arrhythmia recurrences after catheter ablation. Furthermore, in an animal model, the authors analyzed the role of GM-CT-01 inhibitor and showed a significant reduction of galectin-3 and transforming growth factor (TGF)–β1 levels, indicating protective effects on profibrotic processes in fibrillating atria.

The authors should be congratulated for their interesting translational research and the promising aspects of a potential upstream therapy in AF. Nevertheless, we have some comments, mainly on the basis of our and other studies.

Several clinical and experimental studies have highlighted the role of interstitial fibrosis in the initiation and maintenance of AF (2). Atrial fibrosis might disturb anisotropic conduction and change the duration and dispersion of the effective refractory period. This explains the intra-atrial re-entry circuits leading to the electrophysiological and structural remodeling in atrial tissue that facilitates AF initiation and perpetuation. Besides the proinflammatory state, the profibrotic pathway is the most plausible cause for arrhythmia recurrences following catheter ablation so far (3). There are several profibrotic markers of great interest that may be associated with rhythm outcome. Different studies have suggested that TGF-β1 is involved in the mechanisms of atrial fibrosis and AF pathogenesis, and plasma TGF-β1 levels might be considered as a surrogate marker for atrial fibrosis (2). Because of its involvement in profibrotic remodeling and inflammation, galectin-3 is one of the emerging biomarkers in different cardiac diseases and gains recent attention as a novel biomarker in AF.

What is the clinical reality when we try to translate hypotheses from experimental studies? Several clinical studies have aimed to analyze the role of galectin-3 in AF, but the results are not consistent (4). In contrast to the current study (1), we found significantly higher levels of proinflammatory and profibrotic biomarkers in peripheral blood than in cardiac circulation (J. Kornej et al., unpublished data, April 2016)—probably indicating the washout phenomenon. Also, we could not find any significant differences in galectin-3 levels in a subgroup of patients with blood taken from different cardiac sites (4). Furthermore, higher galectin-3 levels found in AF patients might be mediated by cardiometabolic disturbances rather than by heart rhythm itself, which is in accordance with other studies (4). Finally, galectin-3 was not useful to predict arrhythmia recurrences 4, 5.

Similar inconsistency regarding prediction of arrhythmia recurrences had also been shown in clinical studies with TGF-β1. For example, despite its known role in the pathophysiology of cardiac fibrosis, TGF-β1 failed to improve the value of widely used clinical scores for the prediction of arrhythmia recurrences (3).

In conclusion, it remains challenging to translate the findings from experimental settings to “real-world” (multi)morbid patients.