Abstract
To identify circulating proteins predictive of acute cardiovascular disease events in the general population, we performed a proteomic screen in plasma from asymptomatic individuals. A “Discovery cohort” of 25 individuals who subsequently incurred a cardiovascular event within 3 years (median age = 70 years, 80% male) was matched to 25 controls remaining event-free for > 5 years (median age = 72 years, 80% male). Plasma proteins were assessed by data independent acquisition mass spectrometry (DIA-MS). Associations with cardiovascular events were tested using Cox regression, adjusted for the New Zealand Cardiovascular Risk Score. Concentrations of leading protein candidates were subsequently measured with ELISAs in a larger (n = 151) independent subset. In the Discovery cohort, 76 plasma proteins were robustly quantified by DIA-MS, with 8 independently associated with cardiovascular events. These included (HR = hazard ratio [95% confidence interval] above vs below median): fibrinogen alpha chain (HR = 1.84 [1.19–2.84]); alpha-2-HS-glycoprotein (also called fetuin A) (HR = 1.86 [1.19–2.93]); clusterin isoform 2 (HR = 1.59 [1.06–2.38]); fibrinogen beta chain (HR = 1.55 [1.04–2.30]); hemoglobin subunit beta (HR = 1.49 [1.04–2.15]); complement component C9 (HR = 1.62 [1.01–2.59]), fibronectin isoform 3 (HR = 0.60 [0.37–0.99]); and lipopolysaccharide-binding protein (HR = 1.58 [1.00–2.49]). The proteins for which DIA-MS and ELISA data were correlated, fibrinogen and hemoglobin, were analyzed in an Extended cohort, with broader inclusion criteria and longer time to events, in which these two proteins were not associated with incident cardiovascular events. We have identified eight candidate proteins that may independently predict cardiovascular events occurring within three years in asymptomatic, low-to-moderate risk individuals, although these appear not to predict events beyond three years.
Highlights
To identify circulating proteins predictive of acute cardiovascular disease events in the general population, we performed a proteomic screen in plasma from asymptomatic individuals
The only circulating biomarkers routinely incorporated in current Cardiovascular disease (CVD) risk prediction models are lipids i.e. total cholesterol (TC), high-density lipoprotein (HDL) or their ratio (TC/HDL) and calculated low-density lipoprotein (LDL)
In the Discovery cohort, the 5-year risk PREDICT-1° score did not correspond to time-to-CVD-event (Cox model HR = 1.11 [0.79–1.56], p = 0.53), reflecting that the score alone was not able to distinguish those with subsequent CVD events from those who remained event free in this low-moderate risk sample
Summary
To identify circulating proteins predictive of acute cardiovascular disease events in the general population, we performed a proteomic screen in plasma from asymptomatic individuals. Determining an individual’s risk for developing CVD is commonly based on a set of key variables, including age, gender, ethnicity, blood pressure, diabetes mellitus, smoking and lipid status These established risk factors for CVD have been incorporated into risk prediction models such as the Framingham risk score (FRS), which is used to predict CVD incidence within 10 years[2,3]. Plasma concentrations of B-type natriuretic peptide (BNP), its amino-terminal pro-hormone congener (NT-proBNP) and the cardiac troponins T and I (TNT, TNI) are key biomarkers in the clinical diagnosis of heart failure (HF) and myocardial infarction (MI), r espectively[9,10,11,12] Both markers have been shown to provide powerful information about CVD events in asymptomatic community populations, with modest elevations in these markers being independently predictive of atherosclerotic CVD, HF, fatal coronary events and total m ortality[13,14,15]
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