Association of Subclinical Airflow Obstruction with Cardiovascular Mortality and the Exploratory Statistical Indirect Effect of the Systemic Immune-Inflammation Index: A Cohort Study Based on NHANES 2007-2012

Background Small airway dysfunction (SAD) is an early manifestation of airway pathology, yet its association with long-term cardiovascular mortality remains insufficiently understood. This study aimed to evaluate the association between subclinical airflow obstruction (SAO), assessed by forced expiratory flow at 25%-75% of forced vital capacity (FEF _25-75 ), and cardiovascular mortality, and to preliminarily explore whether the systemic immune-inflammation index (SII) serves as an indirect pathway in this association. Methods This cohort study included 12,677 adults aged 20–79 years from the National Health and Nutrition Examination Survey (NHANES) 2007–2012, linked to mortality data through December 31, 2019. SAO was defined as FEF _25-75 z-score < − 1.645 (below the lower limit of normal) using the Global Lung Function Initiative 2012 reference equations. The primary outcome was cardiovascular mortality. Survey-weighted cause-specific Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Exploratory mediation analysis via Weibull accelerated failure time models with bootstrap resampling was performed to decompose the total effect of SAO on cardiovascular death-free time into direct and indirect effects through ln(SII). Results Over a median follow-up of 9.75 years, 270 cardiovascular deaths were recorded. SAO was independently associated with an increased risk of cardiovascular mortality (fully adjusted HR = 1.89, 95% CI 1.26–2.83, P = 0.002). This association remained consistent across multiple sensitivity analyses and persisted among individuals without traditional airflow obstruction. Exploratory mediation analysis suggested that ln(SII) accounted for an indirect effect time ratio of 0.976 (bootstrap 95% CI 0.960–0.991, P = 0.006), corresponding to a mediation proportion of approximately 6.3% (95% CI 2.4%-13.4%). Given the concurrent baseline measurement of SAO and SII and the strong assumptions required for mediation analysis, these indirect effect findings should be considered exploratory and hypothesis-generating. Conclusions Subclinical airflow obstruction, defined by FEF _25-75 below the lower limit of normal, was independently associated with cardiovascular mortality in a nationally representative US adult population. The exploratory indirect effect via SII suggests that systemic inflammation may partially participate in this association, although the modest mediation proportion indicates that other pathways likely contribute. FEF _25-75 assessment may provide additional information for cardiovascular risk stratification even when conventional spirometry is within normal limits, though the clinical utility of this strategy requires further prospective validation.