A Stage-Ordered Multi-Omic Continuum Underlies Cardiovascular-Kidney-Metabolic Syndrome and the Protective Association of Cardiovascular Health
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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 analyses were performed to quantify the proportion of the CKM–CVD association that was statistically accounted for by these biomarkers. The proportion of the protective association between cardiovascular health (Life’s Crucial 9 [LC9]) and incident CVD that was mediated by the same molecules was quantified.
Results
CVD risk increased across CKM stages. Beyond 11 pan-stage proteins (e.g., RTN4R,LEP) and 29 pan-stage metabolites (e.g.,GlycA), stage-specific molecular signatures emerged, whose pathway enrichment revealed a 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—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.
