Association and impact of inflammatory markers and cardiac structure on atrial fibrillation risk: a study integrating NHANES with real-world data

Background Inflammation plays a central role in the pathogenesis of atrial fibrillation (AF), a common cardiac arrhythmia. Complete blood count (CBC)-derived markers of inflammation, including the systemic inflammatory index (SII) and systemic inflammatory response index (SIRI), have emerged as novel biomarkers of systemic inflammation. Although small prior studies have reported associations between certain inflammatory markers and AF, their limited sample sizes and potential baseline imbalances prevent definitive conclusions. Using a large population-based cohort, this study examines the association between CBC-derived inflammatory markers—SIRI, SII, monocyte-to-lymphocyte ratio (MLR), aggregate index of systemic inflammation (AISI), neutrophil-monocyte-to-lymphocyte ratio (NMLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR)—and the risk of AF, and investigates potential mediating mechanisms by integrating clinical data. Methods This cross-sectional analysis included 10,474 adults aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES) 2013–2020 and was validated in 13,707 adults aged ≥20 years from Zibo Central Hospital 2015–2024. Seven inflammatory markers were derived from CBC data and categorized into low, medium, and high quartiles according to their distributions. A weighted multivariable logistic regression adjusted for confounders, including age, sex, hypertension, and diabetes. Associations between inflammatory markers and atrial fibrillation were expressed as odds ratios (OR) with 95% confidence intervals (CI). Restricted cubic spline (RCS) regression assessed nonlinear relationships. Subgroup and interaction analyses evaluated the influence of demographic and clinical factors. Finally, a mediation model examined the mediating role of left atrial diameter. Results Of the 10,474 participants in the NHANES database, 136 (1.3%) were diagnosed with AF. After full adjustment, the highest SIRI tertile showed a significantly increased risk of AF compared with the lowest tertile (OR = 2.182; 95% CI: 1.094–4.354; P = 0.027). RCS analysis revealed a linear positive association between SIRI and AF risk (overall P > 0.05). Subgroup analyses and interaction tests indicated that the positive association between SIRI and AF persisted across different conditions (all p -value for interaction > 0.05). Results were then validated using the case management system of Zibo Central Hospital. In that cohort, after full adjustment, the highest SIRI tertile again had a significantly increased risk of AF vs. the lowest tertile (OR = 1.436; 95% CI: 1.248–1.652; P < 0.001). Mediation analysis indicated that LA diameter mediated 13.54% of the association between SIRI and AF. Conclusion This study suggests that elevated SIRI may represent a potential biomarker and is associated with an increased risk of AF, and found that left atrial diameter may partially mediate this relationship, suggesting SIRI as a potential inflammatory biomarker for AF prediction. Although other CBC-derived markers did not show significant associations, the results underscore inflammation's role in AF pathogenesis. Further longitudinal studies are needed to validate these findings and clarify the underlying mechanisms.