Abstract
Since aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues. To discover diagnostic biomarkers for AA, we performed proteome analysis of aortic media from patients with thoracic atherosclerotic AA (TAAA), comparing protein levels between the aneurysm and normal tissue areas. After hierarchical clustering analysis of the proteome analysis data, tissue samples were classified into three groups, regardless of morphological features. This classification was shown to reflect disease progression stage identified by pathological examination. This proteomics-based staging system enabled us to identify more significantly altered proteins than the morphological classification system. In subsequent data analysis, Niemann-Pick disease type C2 protein (NPC2) and insulin-like growth factor-binding protein 7 (IGFBP7) were selected as novel biomarker candidates for AA and were compared with the previously reported biomarker, thrombospondin 1 (THBS1). Blood concentrations of NPC2 and IGFBP7 were significantly increased, while THBS1 levels were decreased in TAAA and abdominal atherosclerotic AA patients. Receiver operating characteristic analysis of AA patients and healthy controls showed that NPC2 and IGFBP7 have higher specificity and sensitivity than THBS1. Thus, NPC2 and IGFBP7 are promising biomarkers for the detection and progression evaluation of AA.
Highlights
Since aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues
Several differences were observed in the clinical indices among thoracic atherosclerotic AA (TAAA), abdominal atherosclerotic AA (AAAA), NVDC, and healthy controls (HCs) subjects enrolled in the present study (See Methods for the indices)
The AUCs for Niemann-Pick disease type C2 protein (NPC2), insulin-like growth factor-binding protein 7 (IGFBP7), and thrombospondin 1 (THBS1) were 0.828, 0.882, and 0.742, respectively (Fig. 4E). These results demonstrated that NPC2 and IGFBP7 were biomarker candidates that were clinically useful for the diagnosis of both TAAA and AAAA, but especially for TAAA
Summary
Since aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues. D-dimer and C-reactive protein (CRP) levels in the blood have been reported to be suitable for the diagnosis of AA7–9 These markers have poor disease specificity and effectiveness due to their primary design and aims, and do not reflect aortic tissue degeneration during the formation and progression of the aneurysm[10,11]. Based on hierarchical clustering analysis of these proteome analysis data, we established a new staging method, designated as a proteomics-based progression staging method, and identified proteins with significantly altered expression levels in AAs. Niemann-Pick disease type C2 protein (NPC2) and insulin-like growth factor-binding protein 7 (IGFBP7) were selected as novel biomarker candidates, and their significant elevation was confirmed in blood samples of patients with TAAA and abdominal atherosclerotic AA (AAAA)
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