Plasma proteomic signatures of subclinical atherosclerosis progression for cardiovascular risk stratification: A cohort study
Yani Huang, Ruixin Gao, Jianxin Li, Bin Yang, Keyong Huang, Shufeng Chen, Jie Cao, Xiaoqing Liu, Chong Shen, Ling Yu, Liancheng Zhao, Ying Li, Dongsheng Hu, Jianfeng Huang, Bin Lu, Dongfeng Gu, Fangchao Liu, Xiangfeng LuBackground
Existing risk stratification tools inadequately identify individuals with subclinical atherosclerosis (SA) who could benefit from early intervention. This study aimed to develop protein risk scores (ProtRSs) for SA progression and assess their incremental value for atherosclerotic cardiovascular disease (ASCVD) risk prediction.
Methods and findings
In a community cohort consisting of 903 individuals undergoing repeated SA assessments (coronary artery calcium [CAC] or carotid plaque) over 6 years (2008–2009 to 2013–2014), protein biomarkers were selected from a panel of 117 proteins using least absolute shrinkage and selection operator (LASSO) regression to construct SA ProtRSs for CAC and plaque progression, respectively, and their predictive abilities for incident ASCVD risk were evaluated based on a guideline-recommended traditional risk score in a case-cohort of 1,835 individuals (2007–2008 to 2018–2021, median follow-up of 10.4 years). The ProtRSs each included 14 proteins for CAC and plaque progression, explaining 17.1% and 18.4% of respective variances. Effect sizes of these proteins on SA progression showed strong concordance with those on incident ASCVD ( r > 0.75). Each standard deviation increase in CAC and plaque ProtRSs was associated with hazard ratios of 1.36 (95% confidence interval [CI] [1.20,1.54]) and 1.38 (95% CI [1.23,1.54]) for ASCVD risk, respectively. Addition of the SA ProtRSs to the traditional risk score yielded a net reclassification improvement of 0.127 ( p < 0.001). Importantly, 18.6% of traditional intermediate-risk individuals were reclassified into the high-risk category (10-year ASCVD event rate: 10.9%), indicating the need for preventive interventions, whereas 32.8% of traditional high-risk individuals were identified as having an even higher rate (13.7%), suggesting the requirement for intensified management. The main limitation is that the predictive value of ProtRSs warrants further large-scale external validation.
Conclusions
SA ProtRSs of coronary calcification and carotid plaque progression may provide additional value over traditional risk assessment, highlighting their potential in refining risk stratification and guiding targeted intervention strategies.