Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 4, Pages 1546-1560Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI86924
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Funding
- BHF
- Translational-Research-Program - Land Tirol
- Swedish Society for Medical Research
- Tore Nilson Foundation
- Lars Hierta Foundation
- Erwin-Schrodinger-Fellowship - Austrian Science Fund [J-3679-B13]
- Pustertaler Verein zur Pravention von Herz-und Hirngefaesserkrankungen
- Gesundheitsbezirk Bruneck
- Sudtiroler Sanitatsbetrieb
- Province of Bolzano, Italy
- excellence initiative (Competence Centers for Excellent Technologies [COMET]) of the Austrian Research Promotion Agency (FFG) - BMVIT [843536]
- BMW-FW
- Wirtschaftsagentur Wien
- Standortagentur Tirol
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London
- King's College Hospital
- Swedish Heart and Lung Foundation
- Swedish Research Council [K2009-65X-2233-01-3, K201365X-06816-30-4, 349-2007-8703]
- Uppdrag Besegra Stroke [P581/2011-123]
- Strategic Cardiovascular Programs of Karolinska Institutet
- Stockholm County Council [ALF2011-0260, ALF-2011-0279]
- Foundation for Strategic Research
- European Commission
- British Heart Foundation [CH/16/3/32406, RG/16/14/32397, RG/11/14/29056, FS/13/2/29892, RG/17/2/32808] Funding Source: researchfish
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BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology-and imaging-based definitions of the vulnerable plaque, necessitating an improved approach for predicting onset of symptoms. METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies. RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study. CONCLUSION. The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery.
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