Joint association of C-reactive protein-triglyceride glucose index-frailty index and non-exercise estimated cardiorespiratory fitness with all-cause mortality in adults aged >=45 years with cardiovascular-kidney-metabolic syndrome stages 0-3: a cross-cohort study using NHANES and CHARLS

Background: The joint association of the C-reactive protein-triglyceride glucose index-frailty index (CTI-FI) and non-exercise estimated cardiorespiratory fitness (eCRF) with all-cause mortality (ACM) in adults aged [&ge;]45 years with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 remains unexplored. Methods: Participants were enrolled from the National Health and Nutrition Examination Survey (NHANES; derivation cohort) and the China Health and Retirement Longitudinal Study (CHARLS; external validation). Covariate selection was performed using LASSO regression. Weighted Cox models were applied across four adjustment models to evaluate the independent associations of CTI-FI and eCRF with ACM. Dose-response patterns were examined with restricted cubic splines (RCS). Subgroup, sex-stratified, and mediation analyses tested robustness and pathways. Results: A total of 6,662 participants from NHANES (median follow-up 10 years; 1,276 ACM, 19.2%) and 3,418 participants from CHARLS (9 years; 391 deaths, 11.4%) were included. Per 1-unit increase in CTI-FI, the risks increased by 44% for ACM (HR 1.44; 95% CI 1.31-1.57) and by 54% for cardiovascular mortality (CVM, HR 1.54; 95% CI 1.33-1.79); per 1-MET increase in eCRF, the risks decreased by 10% (HR 0.90; 95% CI 0.85-0.94) and by 18% (HR 0.82; 95% CI 0.75-0.90), respectively (all P < 0.001). Compared with the low CTI-FI + high eCRF group, the high CTI-FI + low eCRF group was associated with a significantly higher risk of ACM (HR 2.74; 95% CI 2.20-3.40) and CVM (HR 5.04; 95% CI 3.02-8.40). RCS analysis showed a nonlinear CTI-FI-ACM association. The model with CTI-FI and eCRF achieved a C-index of 0.78 for ACM and 0.825 for CVM. CTI-FI and eCRF bidirectionally mediated each other's associations with ACM and CVM. Specifically, eCRF accounted for 16.4%-23.5% of CTI-FI-related mortality risk, whereas CTI-FI accounted for 23.9%-32.2% of eCRF's survival benefit (all P < 0.001). Conclusions: Higher CTI-FI and lower eCRF independently and jointly predict increased mortality, with bidirectional mediation indicating that improving one may partially offset the adverse effect of the other. These findings highlight potential therapeutic targets for early CKM syndrome management.