Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease

Abstract

Background Thoracic aortic aneurysms (TAAs) develop through an asymptomatic process resulting in gross dilatation that progresses to rupture if left undetected and untreated. If detected, TAA patients are followed over time until the risk of rupture outweighs the risk of surgical repair. Current methodologies for tracking TAA size are limited to expensive computed tomography or magnetic resonance imaging, as no acceptable population screening tools are currently available. Previous studies from this laboratory and others have identified differential protein profiles for the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), in ascending TAA tissue from patients with bicuspid aortic valves (BAV), versus patients with idiopathic degenerative disease and a tricuspid aortic valve (TAV). Additionally, altered microRNA (miR) expression levels have also been reported in TAAs as compared to normal aortic tissue. The objective of the present study was to identify circulating factors within the plasma that could serve as potential biomarkers for distinguishing etiological subtypes of aneurysm disease. Methods Ascending TAA tissue and plasma specimens were obtained from BAV (n=21) and TAV (n=21) patients at the time of surgical resection. The protein abundance of key MMPs (-1, -2, -3, -8, -9) and TIMPs (-1, -2, -3, -4), and microRNAs (-1, -21, -29a, -133a, -143, -145) was examined using a multi-analyte protein profiling system or by quantitative PCR, respectively. Results were compared to normal aortic tissue and plasma obtained from patients without aortic disease (n=10). Results Significant (p < 0.05) differences in standardized miR-1 and miR-21 abundance between BAV and TAV aortic tissue samples and different tissue and plasma profiles of analyte differences from normal aorta where observed between the BAV and TAV groups. Linear regression analysis significant linear relationships in plasma and tissue measurements only for MMP-8 and TIMPs -1, -3 and -4 (p < 0.05). Receiver operator curve analysis revealed specific cassettes of analytes predictive of TAA disease. Relative to normal aorta, BAV proteolytic balance was significantly increased for MMP-1, -2 and -7, and for decreased MMP-8 and -9. In contrast, TAV proteolytic balance relative to normal aorta was significantly increased only for MMP-1 and decreased for MMP-8 and -9. Conclusions Taken together these unique data demonstrate differential plasma profiles of MMPs, TIMPs, and miRs in ascending TAA specimens from patients with BAV and TAV. These results suggest that circulating biomarkers may form the foundation for a broader platform of biomarkers capable of detecting the presence of TAA using a simple blood test and may also be useful in personalized medicine strategies to distinguish between etiological subtypes of TAAs in patients with aneurysm disease.

Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

“…MMPs, particularly MMP2, are best known as ECM-degrading enzymes, and as such, they are often associated with adverse outcomes in vascular pathologies. 20,21,41 In this study, we demonstrate 2 opposing roles for MMP2 in aortic wall remodeling whereby it contributes to production in addition to degradation of the ECM structural proteins. Ang II is a peptide hormone upregulated in several cardiovascular diseases and can trigger a range of cellular responses, including synthesis of ECM proteins, as well as enhanced proteolytic activities through activation of MMPs, such as MMP2.…”

Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis

“…Tzemos et al [11] reported significant elevation of plasma MMP-2 in non-stenotic BAV patients with ascending aorta dilatation, while their plasma MMP-9 levels hardly altered. On the contrary, Ikonomidis et al [28] advocated the predictive value of plasma MMP-9 for identifying ascending aortic aneurysm among BAV patients, regardless of their aortic valve status. We hypothesized that there might be different aortic vessel wall shear stress thresholds for the activation of these two enzymatic proteins, since MMP-2 was synthesized by resident cells within aortic wall such as fibroblasts and smooth muscle cells and expressed ubiquitously under physiological conditions, while MMP-9 existed mainly not only in neutrophils but also in other cell types responding to specific stimuli [29][30][31][32].…”

Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease

“…Neither did we find significant relations with aortic dimensions as measured by echocardiography, although a trend was observed for MMP-2 (adjusted p value 0.087). Previous studies have reported altered plasma MMP-2, -9 and TIMP-1 levels in patients with aortic valve stenosis and ascending aorta dilatation, both in bicuspid valves and in chronic thoracic aortic dissection (Ikonomidis et al, 2013;Wang et al, 2016;Zhang et al, 2014). It may therefore be worthwhile to evaluate MMPs in specific patient subgroups with a high risk of aortic dilatation, in combination with more detailed imaging modalities of the aorta, such as CT or MRI.…”

“…More specific, altered MMP-2, MMP-9 and TIMP-1 levels have been associated with left ventricular (LV) hypertrophy, chronic heart failure and diastolic dysfunction in hypertensive heart disease and coronary artery disease (Ahmed et al, 2006;Chu et al, 2013;Kang et al, 2008;Laviades et al, 1998;Martos et al, 2007). In patients with thoracic aortic aneurysms, specific MMP-2, -9 and TIMP-1 profiles have been described; however, the majority of research in this field is based on histology of the aortic wall rather than circulating blood biomarker levels (Ikonomidis et al, 2013;Wang et al, 2016;Zhang et al, 2014).…”