Plasma level of extracellular matrix biomarkers is associated with the recurrence of atrial fibrillation

Background

Atrial fibrillation contributes significantly to morbidity and healthcare costs. More than half of the patients that undergo cardioversions experience recurrence within a few months. Through more precise identification of patients who would benefit from rhythm control interventions, management strategies could be improved, as current methods for prediction based on clinical factors present limited accuracy.

Hypothesis and aims: We hypothesized that circulating markers of inflammation and fibrosis are altered in patients with atrial fibrillation and may predict recurrence, as these processes are involved in atrial myopathy. We aimed to identify biomarkers associated with atrial fibrillation and to determine which biomarkers that predict recurrence.

Methods

This study is a substudy from a single-center, placebo-controlled trial, with the control group not receiving intervention included in this study. Eligible patients with recent-onset atrial fibrillation were assessed (n=42). Biomarkers of inflammation and fibrosis, namely interleukins (IL-1ra, 1β, -2, -4, -6, -10, -15, -17A, -18, -21, -22, and -33), chemokines (CCL2 (monocyte chemoattractant protein [MCP]-1, CCL4 [macrophage inflammatory protein (MIP)-1β], CCL11 [eotaxin], CXCL8 [IL-8], and CXCL10), growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and vascular endothelial growth factor [VEGF]), other cytokines (tumor necrosis factor [TNF] α and interferon [IFN] γ), CD40 ligand [CD40L]), and matrix metalloproteinases (MMP1, -2, -3, -7, -8, -9, -10, -12, and -13) were quantified using bead-based multiplex assays. MMP-mediated degradation of type I (C1M), III (C3M) and VI (C6M) collagen, formation of type V (PRO-C5) and VI (PRO-C6) collagen, degradation of titin (TIM), citrunillated vimentin (VICM), and versikine were quantified with ELISA. Healthy blood donors (n=34) were included as a control group.

Results

Patients with atrial fibrillation had significantly higher levels of IL-6, VICM, versikine, and IL1RA, and lower levels of PRO-C6 compared with healthy controls. During follow-up, atrial fibrillation recurred in 48% of patients. Higher levels of MMP-2 and MMP-7, and lower levels of IL-10 were associated with higher risk of recurrence. MMP-2 demonstrated the strongest predictive performance for atrial fibrillation recurrence (in-sample AUC 0.75), outperforming traditional clinical risk factors.

Conclusions

This study identified higher levels of MMP-2 and MMP-7 as being associated with atrial fibrillation recurrence. Elevated inflammatory and ECM-derived markers like IL-6, VICM, and versikine were also observed in patients with atrial fibrillation compared with healthy controls. These findings support the role of inflammation and tissue remodeling in atrial fibrillation and highlight the potential of MMP-2 as a predictive biomarker for recurrence.patients v healthyrecurrence v no