Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve

Abstract

OBJECTIVES Patients with bicuspid aortic valve (BAV) are predisposed to developing ascending thoracic aortic aneurysms (TAA) at an earlier age than patients who develop degenerative TAAs and have a tricuspid aortic valve (TAV). The hypothesis tested is that BAV-associated aortopathy is mediated by a mechanism of matrix remodeling that is distinct from that seen in TAAs of TAV patients. METHODS Aortic specimens were collected during ascending aortic replacement, aortic valve replacement and heart transplants from non-aneurysmal (NA) donors and recipients. Matrix architecture of the aortic media was assessed qualitatively using multi-photon microscopy followed by quantification of collagen and elastin fiber orientation. α-elastin was determined and matrix maturity was assessed by quantifying immature and mature collagen and lysyl oxidase (Lox) expression and activity in aortic specimens. Matrix metalloproteinase (MMP)-2/9 activity was quantified in aortic smooth muscle cells. RESULTS Elastin and collagen fibers were more highly aligned in BAV-NA and BAV-TAA patients relative to TAV-TAA patients while TAV-TAA was more disorganized than TAV-NA. α-elastin content was unchanged. Immature collagen was reduced in BAV-NA and BAV-TAA when compared with TAV-NA and TAV-TAA. Mature collagen was elevated in TAV-TAA relative to TAV-NA and BAV-TAA. There was a trend toward elevated Lox gene expression and activity and MMP-2/9 activity for TAV-TAA, BAV-NA and BAV-TAA specimens. CONCLUSIONS The highly aligned matrix architecture in BAV patients indicates that wall remodeling is distinct from TAV-TAA. Altered matrix architecture and reduced collagen maturity suggests that the effector molecules mediating remodeling of TAA are different in BAV and TAV patients.

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

“…The present study performed a comprehensive survey gelatinases such as MMP-9, and tissue inhibitor TIMP-1, which could suggest both active left ventricular remodeling and possible inflammatory processes [21][22][23]. Among BAV patients with echocardiographically normal aortic valve, gelantinase MMP-2 was significantly elevated in those with aortic dilatation and was consistent with the reported up-regulation in both gene expression and enzymatic activity in ascending aorta tissues, especially among those with medium ascending aortic dimensions [24,25]. When considering aortic dilatation on the basis of isolated severe aortic stenosis in the present study, it was still the gelantinases that emerged from the boosted MMP background, although both MMP-2 and MMP-9 seemed to play important roles.…”

Structure-based constitutive model can accurately predict planar biaxial properties of aortic wall tissue

“…Like other studies [14,32,42,[46][47][48]57], the present data also show that the collagen mean orientation points in the circumferential direction in a normal aorta. However, the present data also suggest a significant gradual change in the collagen fiber orientation distribution (in the axial-circumferential plane) across the thickness of the medial layer, information that has not yet been reported in literature.…”

“…Several microscopy techniques such as classical microscopy [16], polarized light microscopy (PLM) [13,14], multi-photon microscopy [56,57] or small-angle light scattering [15] together with various imageprocessing techniques (see Ref. [16] and references therein) have been suggested to study the collagen organization in the arterial wall.…”

Is There a Role for Biomechanical Engineering in Helping to Elucidate the Risk Profile of the Thoracic Aorta?

“…The process is dynamic, highly heterogeneous, and may fluctuate as a function of local stress and biologic activity. Changes in the tissue microstructure caused by aging [23], disease progression [13], and underlying pathologies [27,28,29,30] significantly affect tissue structural organization and strength. One of the challenges of aneurysm simulation is the integration of dynamic wall weakening in the biomechanical model so that current estimates of local properties and local strength can be used to predict the risk of rupture.…”