Background: Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics.
Methods and results: We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07-1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01-1.09); white blood cell count, HR, 1.18 (95% CI, 1.04-1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05-1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05-1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07-1.26).
Conclusions: Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.
Keywords: atrial fibrillation; inflammation; older adults.