A Stage-Ordered Multi-Omic Continuum Underlies Cardiovascular-Kidney-Metabolic Syndrome and the Protective Association of Cardiovascular Health

Background and aims: Cardiovascular-kidney-metabolic (CKM) syndrome stages confer graded CVD risk, but the underlying stage-specific molecular mechanisms remain undefined. Methods: In 355,724 UK Biobank participants (median follow-up 13.5 years), we mapped CKM stages (0-3) to incident CVD. Using proteomics (n=37,785) and metabolomics (n=190,112), we identified stage-specific biomarkers via LASSO and XGBoost-SHAP. Mediation analysis was used to quantify the proportion of the CKM-CVD risk association, and of the protective association of CVH (Life's Crucial 9 [LC9]) with incident CVD, that could be statistically accounted for by these molecules. Results: CVD risk increased across CKM stages. We identified 11 pan-stage proteins (e.g., RTN4R, LEP) and 29 pan-stage metabolites (e.g., GlycA). Pathway enrichment revealed a stage-associated shift from metabolic/extracellular matrix dysregulation (Stage 1) to inflammation (Stage 2) to hypoxia/fibrosis (Stage 3). The proportion of the CKM-CVD risk association statistically accounted for by these molecules shifted accordingly: ADM (42.9%) in Stage 1, FABP4 (24.6%) in Stage 2, and HAVCR1 (28.0%) in Stage 3. High CVH (LC9>80) was associated with approximately 80% lower CVD risk in Stages 0-2; a proportion of this protective association was statistically accounted for by the same stage-specific molecules. Conclusions: These findings reveal a stage-ordered molecular continuum[ndash]from ECM remodeling to inflammation to fibrosis that redefines CKM-driven CVD risk, and the strong protection of high CVH in early stages was statistically accounted for in part by these stage-specific molecules, generating the hypothesis that CVH may reduce risk through these modifiable pathways and providing a molecular framework for future stage-adapted intervention trials.