Protein Biomarkers of New-Onset Cardiovascular Disease

Abstract

Objective Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk. Approach and Results We utilized discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. We then measured 59markers by targeted MS in 336 ASCVD case-control pairs. Associations with MI or ASCVD were tested in single marker and multimarker analyses adjusted for established ASCVD risk factors. Twelve single markers from discovery MS were associated with MI incidence (at p<0.01) adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, CD5 antigen-like, cell surface glycoprotein MUC18, collagen-alpha 1 [XVIII] chain, salivary alpha-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (p<0.0001) and significantly improved its prediction compared to a model with clinical risk factors alone (C-statistic of 0.71 vs. 0.84). Through targeted MS, twelve single proteins were predictors of ASCVD (at p<0.05) after adjusting for established risk factors. In multimarker analyses, four proteins in combination (alpha-1-acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like, predicted incident ASCVD (p<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 vs. 0.73). Conclusions Proteomics profiling identified single and multimarker protein panels that are associated with new onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

“…IGF1, in turn, is regulated by insulin‐like growth factor binding protein 1 (IGFBP1), which plays a role in glucose counter‐regulation. Higher IGFBP1 levels were previously found to be associated with lower metabolic risk, but greater mortality,20 and IGFBP1 was reported to predict incident HF among older adults 3, 21. We now extend these observations and show that IGFBP1 predicts incident HF, all‐cause mortality, and CVD mortality in our cohort, along with 3 other regulators of metabolic disease and adipocyte function: IGFBP2, adipsin, and leptin.…”

“…We demonstrate multiple new associations of protein biomarkers that regulate metabolic and inflammatory pathways with clinical outcomes using a multiplexed high‐throughput platform. Previous proteomics approaches among large cohorts have been predominantly focused on CVD case‐control designs 3, 12. We now extend previous promising results and test the association of targeted proteomic biomarkers with incident CVD events and death in the community.…”

“…Adipsin has been shown to regulate inflammation in adipose tissue and may improve beta‐cell function in diabetes mellitus 11, 23, 24. Among women, adipsin is correlated with metabolic parameters, including body mass index, insulin resistance, and carotid atherosclerosis,3, 12, 25 but it has not been linked to adverse CVD outcomes previously. Last, resistin is an adipokine that impairs insulin action and is thought to represent a mechanistic link of obesity with diabetes mellitus 17, 18, 26.…”

“…To that end, the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD) Initiative was established by the National Heart, Lung, and Blood Institute, to identify biomarker signatures of atherosclerotic CVD and its risk factors 3. The SABRe CVD initiative included both discovery and targeted proteomics.…”

The contribution of paraoxonase 1 and myeloperoxidase to HDL-cholesterol functionality

“…Thus, the structural variability of HDL-C makes it very sensitive to different metabolic signals which modify its structure and affect its functionality. In consequence, many authors have suggested that there is a great need for identifying the protein biomarkers for disturbances in the circulating HDL-C [25,41,95]. Recently, it has been proposed that among the proteins two enzymes -paraoxonase 1 (PON1) and myeloperoxidase (MPO) -may substantially affect and modify the HDL-C functionality.…”