Association of neutrophil-to-lymphocyte ratio with all-cause and cardiovascular mortality in patients with circadian rhythm syndrome: A longitudinal cohort study based on NHANES 2005–2018 data

Circadian rhythm syndrome (CircS) has been associated with an elevated risk of cardiovascular death. However, there is a scarcity of affordable biomarkers for its assessment. The neutrophil-to-lymphocyte ratio (NLR) is a cost-effective inflammatory marker; however, its long-term prognostic significance in CircS remains to be elucidated. This study examined NLR's association with all-cause and cardiovascular mortality in CircS patients. Using National Health and Nutrition Examination Survey (2005-2018) data, this analysis leveraged records from 9267 patients with confirmed CircS. Mortality outcomes and underlying causes of death were ascertained by linkage to the National Death Index. Subjects were stratified into elevated and reduced NLR cohorts based on established thresholds. A Cox proportional hazards regression model was employed to assess the relationship between NLR and all-cause and cardiovascular mortality. Additionally, restricted cubic splines were utilized to examine the dose-response relationship between NLR and mortality. Stratified analyses and interaction tests were conducted based on variables such as poverty-to-income ratio, body mass index, age, alcohol consumption, and smoking status. During a median observation period of 83 months, 1494 fatalities occurred among 9267 CircS patients (all-cause mortality: 16.1%), including 427 cardiovascular-specific deaths (cardiovascular mortality: 4.6%). Multivariable Cox proportional hazards modeling revealed that elevated NLR values (>3) were associated with heightened all-cause mortality risk (hazard ratio = 1.69, 95% confidence interval: 1.51-1.89, P < .001). The relationship between NLR and all-cause mortality was nonlinear (P for nonlinearity < .05), whereas NLR and cardiovascular mortality showed a positive linear correlation (P for nonlinearity > .05). Subgroup analyses consistently indicated associations across strata, though the robustness of these findings may be influenced by measurement error in self-reported stratification variables. In this large observational cohort, elevated NLR was independently associated with increased all-cause and cardiovascular mortality in CircS patients after multivariable adjustment. These findings suggest NLR may serve as a candidate prognostic biomarker; however, its clinical utility requires validation in prospective studies due to the inherent limitations of observational design.