Synergistic Effects of Normal‐Range Serum Sodium and Potassium on Mortality: The Modifying Role of Inflammation From a NHANES Cohort Analysis

ABSTRACT Background This study aimed to investigate the associations of serum sodium and potassium levels within the normal range with cardiovascular (CV) and all‐cause mortality, and to further explore the potential roles of oxidative stress and inflammatory biomarkers in these associations. Methods We analyzed NHANES 1999–2018 data from 32,837 adults with normal baseline serum sodium (135–146 mmol/L) and potassium (3.5–5.0 mmol/L), stratified by tertiles. Weighted Cox models assessed associations with CV and all‐cause mortality, and bootstrap‐based causal mediation analysis assessed nine oxidative stress and inflammatory biomarkers. Results The lowest tertile of serum sodium was associated with an increased risk of all‐cause mortality (HR: 1.17; 95% CI: 1.03–1.32; p = 0.017), while the highest tertile of serum potassium was associated with an increased risk of CV (HR: 1.26; 95% CI: 1.00–1.58; p = 0.052) and all‐cause mortality (HR: 1.14; 95% CI: 1.02–1.29; p = 0.025). Serum sodium and potassium showed a statistically significant interaction for all‐cause mortality ( p = 0.044), with the lowest risk at sodium 138–139 mmol/L and potassium 3.5–3.8 mmol/L (HR: 0.46, 95% CI: 0.31–0.68; p < 0.001). Mediation analysis showed that inflammatory biomarkers accounted for 0.8% to 1.5% of the associations between serum sodium/potassium and CV or all‐cause mortality. Conclusion In the general population, lower normal‐range serum sodium was associated with higher all‐cause mortality, while higher serum potassium was linked to increased cardiovascular and all‐cause mortality. Inflammatory biomarkers may partially mediate these associations. Our findings provide more evidence that the “safest” sodium and potassium interval needs to be reconsidered.