Longitudinal Trajectories and Cumulative Burden of Remnant Cholesterol Inflammatory Index and Mortality Risk

BACKGROUND: Remnant cholesterol (RC) and chronic inflammation are key drivers of residual cardiovascular risk; however, the impact of their joint long-term dynamic patterns on subsequent prognosis remains unclear. This study aimed to systematically evaluate the associations of the remnant cholesterol-inflammation index (RCII) longitudinal trajectories and cumulative burden with all-cause mortality, and to explore potential biological mediators. METHODS: We analyzed 6977 participants from the China Health and Retirement Longitudinal Study (CHARLS) cohort. K-means clustering was used to identify RCII patterns based on two biomarker assessments, and cumulative RCII burden between these assessments was calculated. Multivariable Cox proportional hazards models assessed the independent associations of trajectory groups and cumulative RCII with all-cause mortality. Mediation analyses evaluated the roles of Cystatin C and HbA1c in these associations. RESULTS: Three distinct RCII trajectories were identified: persistently low, moderate, and high levels. Compared with the low-level stable group, participants in the high-level stable group had an 88% higher risk of death (HR = 1.88; 95% CI: 1.49-2.38). Cumulative RCII burden was positively and linearly associated with all-cause mortality (HR = 1.08; 95% CI: 1.06-1.11). Mediation analyses indicated that Cystatin C and HbA1c significantly mediated this association, accounting for 10.71% and 4.61% of the effect, respectively. CONCLUSIONS: RCII patterns based on repeated biomarker assessments and cumulative RCII burden were associated with elevated mortality risk among middle-aged and older adults in China. Exploratory mediation analyses suggested that renal dysfunction and glycemic dysregulation may partly explain these associations. Further prospective studies are needed to validate these findings before RCII can be recommended for clinical risk stratification.