Serum protein profiles predict coronary artery disease in symptomatic patients referred for coronary angiography

BMC Medicine

Dennis M McNamara¹  Suresh R Mulukutla³  Oscar C Marroquin³  Robert V Masterson⁶  Aleksey Lomakin²  Uma R Chandran⁵  Maureen A Lyons-Weiler⁴  Christin M Sciulli⁴  John M Krill-Burger⁴  Patricia Petrosko⁴  Lori A Kelly⁴  Rajiv Dhir⁵  William A LaFramboise⁵ 

[1] UPMC Heart and Vascular Institute, 200 Lothrop Street, Pittsburgh, PA 15213, USA;Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;University of Pittsburgh, Department of Epidemiology, Graduate School of Public Health, Pittsburgh PA, 15213, USA;University of Pittsburgh, Department of Pathology, 5230 Centre Avenue, Pittsburgh, PA 15232, USA;University of Pittsburgh, Department of Biomedical Informatics, 5150 Centre Avenue, Pittsburgh, PA 15232, USA;Prevencio LLC, 454 N 34th Street, Seattle, WA 98103, USA

关键词: multiplex proteomics;    coronary stenosis;    coronary angiography;    cardiac catheterization;    biomarkers;    atherosclerosis;   

Others  :  857267
DOI  :  10.1186/1741-7015-10-157

 received in 2012-06-03, accepted in 2012-12-05,  发布年份 2012

【 摘 要 】

Background

More than a million diagnostic cardiac catheterizations are performed annually in the US for evaluation of coronary artery anatomy and the presence of atherosclerosis. Nearly half of these patients have no significant coronary lesions or do not require mechanical or surgical revascularization. Consequently, the ability to rule out clinically significant coronary artery disease (CAD) using low cost, low risk tests of serum biomarkers in even a small percentage of patients with normal coronary arteries could be highly beneficial.

Methods

Serum from 359 symptomatic subjects referred for catheterization was interrogated for proteins involved in atherogenesis, atherosclerosis, and plaque vulnerability. Coronary angiography classified 150 patients without flow-limiting CAD who did not require percutaneous intervention (PCI) while 209 required coronary revascularization (stents, angioplasty, or coronary artery bypass graft surgery). Continuous variables were compared across the two patient groups for each analyte including calculation of false discovery rate (FDR ≤ 1%) and Q value (P value for statistical significance adjusted to ≤ 0.01).

Results

Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1β, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon γ (IFNγ) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.

Conclusions

Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation. There were surprisingly few indicators of growth factor activation or extracellular matrix remodeling in the serum of CAD patients except for elevated OPN. These data suggest that many symptomatic patients without significant CAD could be identified by a targeted multiplex serum protein test without cardiac catheterization thereby eliminating exposure to ionizing radiation and decreasing the economic burden of angiographic testing for these patients.

【 授权许可】

   
2012 LaFramboise et al; licensee BioMed Central Ltd.

【 图 表 】

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