A Novel Diagnostic and Prognostic Score for Abdominal Aortic Aneurysms Based on D-Dimer and a Comprehensive Analysis of Myeloid Cell Parameters

Abstract

The pathogenesis of abdominal aortic aneurysm (AAA) involves a central component of chronic inflammation which is predominantly mediated by myeloid cells. We hypothesized that the local inflammatory activity may be reflected in systemic alterations of neutrophil and monocyte populations as well as in soluble factors of myeloid cell activation and recruitment. To establish their marker potential, neutrophil and monocyte sub-sets were measured by flow cytometry in peripheral blood samples of 41 AAA patients and 38 healthy controls matched for age, sex, body mass index and smoking habit. Comparably, circulating factors reflecting neutrophil and monocyte activation and recruitment were assayed in plasma. Significantly elevated levels of CD16+ monocytes, activated neutrophils and newly released neutrophils were recorded for AAA patients compared with controls. In line, the monocyte chemoattractant C-C chemokine ligand 2 and myeloperoxidase were significantly increased in patients' plasma. The diagnostic value was highest for myeloperoxidase, a mediator which is released by activated neutrophils as well as CD16+ monocytes. Multivariable regression models using myeloid activation markers and routine laboratory parameters identified myeloperoxidase and D-dimer as strong independent correlates of AAA. These two biomarkers were combined to yield a diagnostic score which was subsequently challenged for confounders and confirmed in a validation cohort matched for cardiovascular disease. Importantly, the score was also found suited to predict rapid disease progression. In conclusion, D-dimer and myeloperoxidase represent two sensitive biomarkers of AAA which reflect distinct hallmarks (thrombus formation and inflammation) of the pathomechanism and, when combined, may serve as diagnostic and prognostic AAA score warranting further evaluation.

Histone citrullination as a novel biomarker and target to inhibit progression of abdominal aortic aneurysms

“…1 Regarding biomarkers, D-dimer proved to be significantly elevated in blood of AAA patients and has prognostic power despite its limited specificity. 3,4 Besides the progressive weakening and widening of the vessel wall, development of an intraluminal thrombus (ILT) can further promote aneurysmal dilatation. 5 Among other leukocytes, neutrophils are recruited to the aortic wall as well as the ILT and substantially contribute to AAA development, since neutrophil-derived serine proteases, matrix metalloproteinases (MMPs) and reactive oxygen species induce matrix destruction and promote smooth muscle cell apoptosis.…”

“…6 We have recently reported that the frequency of activated neutrophils and neutrophil-derived myeloperoxidase (MPO) are significantly elevated in blood of AAA patients compared to healthy controls and have investigated the diagnostic and prognostic value of a score based on MPO and D-dimer plasma levels. 4 Of note, neutrophil depletion inhibits AAA formation in mice. This effect is partly mediated by a decrease in MMP activity but additional neutrophil functions also seem to be involved.…”

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms

“…MPO gene deletion in a mouse model of AAA prevents aneurysm formation [ 115 ] and higher levels of MPO and H 2 O 2 in circulating neutrophils are observed in AAA patients [ 116 ]. Higher levels of MPO have also been associated with faster AAA growth in humans [ 117 , 118 ].…”

Complement Factor C5a Is Increased in Blood of Patients with Abdominal Aortic Aneurysm and Has Prognostic Potential for Aneurysm Growth

“…Furthermore, they secrete chemotactic mediators which may increase the number and types of cells recruited [ 6 ]. Of note, local inflammatory and haemostatic activity at the AAA site seems to be echoed at the systemic level as measured by several cellular and humoral factors in peripheral blood [ 7 , 8 ]. These components were proposed as markers of disease activity and potentially predict the rate of progression or risk of rupture [ 9 ].…”