Increased matrix metalloproteinase 9 activity correlates with flow-mediated intraluminal thrombus deposition and wall degeneration in human abdominal aortic aneurysm

Abstract

ObjectiveWe have previously demonstrated that human abdominal aortic aneurysm (AAA) rupture occurs in zones of low wall shear stress where flow recirculation and intraluminal thrombus (ILT) deposition are increased. Matrix metalloproteinase-9 (MMP-9) is involved in the pathogenesis of AAA via its lytic effect on collagen and elastin. We hypothesize that flow-mediated ILT deposition promotes increased local inflammatory and MMP-9 activity that leads to AAA wall degeneration. The purpose of this study was to examine the correlation between predicted pulsatile flow dynamics and regional differences in MMP-9, elastin, collagen, and ILT deposition in human AAA. MethodsFull-thickness aortic tissue samples were collected from 24 patients undergoing open AAA repair. Control infrarenal aortic tissue was obtained from 6 patients undergoing aortobifemoral bypass. Full-thickness aortic tissue and ILT were assessed for MMP-9 levels using a cytokine array assay. Histologic and immunohistochemical assessment of inflammation, collagen and elastin content, and MMP-9 levels were also measured. Three-dimensional AAA geometry was generated from computed tomography angiogram (CTA) images using Mimics software and computational fluid dynamics was used to predict pulsatile aortic blood flow. ResultsThe majority of AAA showed eccentric ILT deposition which was correlated with predicted recirculation blood flow (R2 = –0.17; P < .05). The regions of high ILT were associated with significant increases in inflammation and loss of elastin and collagen compared with regions of low ILT, or with control tissue. MMP-9 was significantly higher in areas of high ILT deposition compared with areas devoid of ILT. Tissue MMP-9 was correlated with the thickness of ILT deposition (R2 = 0.46; P < .05), and was also present in high levels in thick compared with thin ILT. ConclusionsWe have shown a correlation between flow-mediated ILT deposition with increased tissue levels of MMP-9 activity, increased inflammatory infiltrate, and decreased elastin and collagen content in stereotactically sampled human AAA, suggesting that ILT deposition is associated with local increases in proteolytic activity that may preferentially weaken and promote rupture at selected regions.