Proteomic Profiling Captures Residual Cardiovascular Risk Beyond the PREVENT Model in Individuals With Cardiovascular–Kidney–Metabolic Syndrome Stages 2–3

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome reflects complex pathobiological interactions among metabolic disorders, kidney injury, and cardiovascular disease (CVD). Stages 2 and 3 represent critical phases of disease progression characterised by high pathological heterogeneity. This study aimed to develop a CVD protein risk score (PRS) for this population and evaluate its incremental predictive value over the PREVENT model. METHODS: This study included 24 017 participants with CKM Stages 2-3 from the UK Biobank. Using 2923 plasma proteins measured via the Olink platform, a PRS was developed in a training set (n = 19 218) using the LASSO method. In the validation set (n = 4799), the incremental predictive performance of this score over the PREVENT model was assessed using Harrell's C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: A risk score comprising 63 proteins was constructed, primarily reflecting inflammation, kidney injury and matrix remodelling. Key proteins included growth differentiation factor 15 (GDF15), hepatitis A virus cellular receptor 1 (HAVCR1), matrix metallopeptidase 12 (MMP12) and NT-proBNP. In the validation set, after adjusting for PREVENT risk factors, individuals in the high PRS group had a 2.56-fold higher risk of CVD compared to those in the low score group (HR: 2.56, 95% CI: 1.96-3.37). Integrating the score into the PREVENT model improved the C-statistic by 0.034 (0.672-0.706) and achieved a 10-year NRI of 15.8% (95% CI: 9.5%-20.9%) and an IDI of 2.2% (95% CI: 1.3%-3.3%). CONCLUSION: Combining the PREVENT model with the PRS developed in this study enhances the prediction of future CVD events in the CKM Stages 2-3 population. This approach facilitates the capture of residual risk and supports precision risk stratification and management for this high-risk group.