Proteomic Profiling Captures Residual Cardiovascular Risk Beyond the PREVENT Model in Individuals With...

Area of Science:

• Biochemistry and Molecular Biology
• Cardiology
• Nephrology
• Metabolic Syndrome Research

Background:

• Cardiovascular-kidney-metabolic (CKM) syndrome involves complex interactions between metabolic disorders, kidney injury, and cardiovascular disease (CVD).
• Stages 2 and 3 of CKM syndrome are critical progression phases with significant pathological heterogeneity.
• Existing risk prediction models may not fully capture the complex risk in this population.

Purpose of the Study:

• To develop a novel protein risk score (PRS) for predicting CVD events in individuals with CKM Stages 2-3.
• To evaluate the incremental predictive value of this PRS when added to the established PREVENT model.
• To improve risk stratification and management strategies for high-risk CKM patients.

Main Methods:

• Utilized data from 24,017 UK Biobank participants with CKM Stages 2-3.
• Developed a PRS using 2923 plasma proteins and the LASSO method in a training set (n=19,218).
• Validated the PRS in an independent set (n=4799), assessing its performance with C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) against the PREVENT model.

Main Results:

• A 63-protein PRS was constructed, reflecting inflammation, kidney injury, and matrix remodeling pathways.
• Key proteins included GDF15, HAVCR1, MMP12, and NT-proBNP.
• The PRS significantly improved CVD prediction: high PRS group had 2.56-fold higher CVD risk; C-statistic increased by 0.034; 10-year NRI was 15.8%; IDI was 2.2% when integrated with the PREVENT model.

Conclusions:

• The developed PRS effectively enhances CVD event prediction in the CKM Stages 2-3 population.
• Integrating the PRS with the PREVENT model captures residual risk, enabling more precise patient stratification.
• This combined approach supports tailored management strategies for individuals at high risk within the CKM syndrome spectrum.