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High lethality of aortic dissection necessitates accurate predictive metrics for dissection risk assessment. The not infrequent incidence of dissection at aortic diameters <5.5 cm, the current threshold guideline for surgical intervention (Nishimura et al., 2014), indicates an unmet need for improved evidence-based risk stratification metrics. Meeting this need requires a fundamental understanding of the structural mechanisms responsible for dissection evolution within the vessel wall. We present a structural model of the repeating lamellar structure of the aortic media comprised of elastic lamellae and collagen fiber networks, the primary load-bearing components of the vessel wall. This model was used to assess the role of these structural features in determining in-plane tissue strength, which governs dissection initiation from an intimal tear. Ascending aortic tissue specimens from three clinically-relevant patient populations were considered: non-aneurysmal aorta from patients with morphologically normal tricuspid aortic valve (CTRL), aneurysmal aorta from patients with tricuspid aortic valve (TAV), and aneurysmal aorta from patients with bicuspid aortic valve (BAV). Multiphoton imaging derived collagen fiber organization for each patient cohort was explicitly incorporated in our model. Model parameters were calibrated using experimentally-measured uniaxial tensile strength data in the circumferential direction for each cohort, while the model was validated by contrasting simulated tissue strength against experimentally-measured strength in the longitudinal direction. Orientation distribution, controlling the fraction of loaded collagen fibers at a given stretch, was identified as a key feature governing anisotropic tissue strength for all patient cohorts., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Bicuspid aortic valve (BAV) is associated with asymmetric dilatation of the proximal ascending aorta. We previously demonstrated increased susceptibility of smooth muscle cells to oxidative stress in the BAV-aneurysmal aorta and hypothesized that antioxidant expression is regionally defined and influenced by the BAV morphotype., Methods: BAV valve morphology was defined according to number of raphes: type 0 (0 raphes), type 1 (1 raphe), or type 2 (2 raphes) and by the raphe location among the left (L), right (R) or non (N) coronary cusps. Ascending aortic specimens were partitioned into three regions corresponding to the sinuses of Valsalva, denoted R, N (greater curve), and L (lesser curve). Transcripts 1, 2, and 3 from the gene expressing superoxide dismutase (Sod) were quantified in all three regions. Results were compared with aneurysmal and nonaneurysmal aortic specimens from patients with a tricuspid aortic valve., Results: Region-specific Sod1 upregulation and Sod2 downregulation were dependent on the BAV morphotype. Sod3 was uniformly downregulated in all regions in a morphotype-independent manner. Sod1 upregulation was noted in the R region of the nonaneurysmal type 1 L/R morphotype. Aortic valve regurgitation, but not stenosis, affected the expression of Sod isoforms in specimens of degenerative aneurysms., Conclusions: Region-specific transcription profiles of Sod on the basis of BAV morphotype deepen our understanding of its associated aortopathy and provide biological insight on the asymmetric dilatation pattern. This work indicates regional differences exist in the oxidative stress biology of the proximal aortic wall, and this may lead to newer diagnostic techniques to adjudicate aortic catastrophe risk., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Incorporation of collagen structural information into the study of biomechanical behavior of ascending thoracic aortic (ATA) wall tissue should provide better insight into the pathophysiology of ATA. Structurally motivated constitutive models that include fiber dispersion and recruitment can successfully capture overall mechanical response of the arterial wall tissue. However, these models cannot examine local microarchitectural features of the collagen network, such as the effect of fiber disruptions and interaction between fibrous and non-fibrous components, which may influence emergent biomechanical properties of the tissue. Motivated by this need, we developed a finite element based three-dimensional structural model of the lamellar units of the ATA media that directly incorporates the collagen fiber microarchitecture. The fiber architecture was computer generated utilizing network features, namely fiber orientation distribution, intersection density and areal concentration, obtained from image analysis of multiphoton microscopy images taken from human aneurysmal ascending thoracic aortic media specimens with bicuspid aortic valve (BAV) phenotype. Our model reproduces the typical J-shaped constitutive response of the aortic wall tissue. We found that the stress state in the non-fibrous matrix was homogeneous until the collagen fibers were recruited, but became highly heterogeneous after that event. The degree of heterogeneity was dependent upon local network architecture with high stresses observed near disrupted fibers. The magnitude of non-fibrous matrix stress at higher stretch levels was negatively correlated with local fiber density. The localized stress concentrations, elucidated by this model, may be a factor in the degenerative changes in aneurysmal ATA tissue., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Ascending thoracic aortic aneurysm (ATAA) in patients with bicuspid aortic valve (BAV) commonly dilate asymmetrically compared with patients with tricuspid aortic valve (TAV). This discrepancy in aneurysm geometry led us to hypothesize that microarchitectural differences underlie the observed asymmetric dilatation pattern. The purpose of this study was to characterize the microarchitectural distinctions of the extracellular matrix of the 2 phenotypes with a focus on the proportion of radially oriented elastin and collagen fibers in different circumferential aortic regions., Methods: Aortic tissue rings were obtained just distal to the sinotubular junction from patients with BAV or TAV undergoing elective aneurysm repair. They were sectioned into three circumferentially based regions according to adjacent aortic sinus segment (left coronary sinus [L], right coronary sinus [R], or noncoronary sinus [N]). Multiphoton microscopy was used to quantify and characterize the number of radially oriented elastin and collagen fibers., Results: There were fewer radially oriented fibers in medial region N and medial-intimal region R of BAV-ATAAs when compared with TAV-ATAAs (medial region N, amplitude of angular undulation of elastin = 10.67° ± 1.35° vs 15.58° ± 1.91°; P = .041; medial-intimal region R, amplitude of angular undulation of elastin = 9.83° ± 0.83° vs 14.72° ± 1.64°; P = .015). Conversely, fibers became more radially oriented in the medial-intimal region L of BAV-ATAA when compared with TAV-ATAA (amplitude of angular undulation of collagen = 18.67° ± 0.95° vs 14.56° ± 1.37°; P = .041)., Conclusions: The differential pattern of fiber orientation noted between L and N-R regions help explain the unique pattern of greater curvature dilatation of BAV-ATAA. The distinctions noted in matrix microarchitecture may form the basis of differing aneurysm geometries and aortic wall integrities in ATAAs arising in these different valve morphologies., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

We recently reported a mechanistic model to link micro-architectural information to the delamination strength (Sd) of human ascending thoracic aorta (ATA). That analysis demonstrated that the number density (N) and failure energy (Uf) of the radially-oriented collagen fibers contribute to the Sd of both aneurysmal (ATAA) and non-aneurysmal (CTRL-ATA) aortic tissue. Among the set of ATAA samples, we studied specimens from patients displaying bicuspid (BAV) and tricuspid aortic valve (TAV) morphologic phenotypes. Results from our prior work were based on the assumption that the Uf was independent of dissection direction. In the current study, we excluded that assumption and hypothesized that Uf correlates with the Sd of ATAA. To test the hypothesis, we used previously-reported experimentally-determined Sd measurements and N of radially-oriented collagen fibers as input in our validated mechanistic model to calculate Uf for BAV-ATAA, TAV-ATAA and CTRL-ATA tissue specimens. The results of our analysis revealed that Uf is significantly lower for both BAV-ATAA and TAV-ATAA compared to CTRL-ATA cases, and does not differ between BAV-ATAA and TAV-ATAA. Furthermore, we found that Uf is consistent between circumferential-radial and longitudinal-radial planes in either of BAV-ATAA, TAV-ATAA or CTRL-ATA specimens. These findings employ a novel mechanistic model to increase our understanding of the putative interrelationship between biomechanical properties, extracellular matrix biology, and failure energy of aortic dissection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Patients with bicuspid aortic valves (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 patients with tricuspid aortic valves., Methods: Aortic specimens were collected during ascending aortic replacement, aortic valve replacement, and heart transplants from nonaneurysmal (NA) donors and recipients. Matrix architecture of the aortic media was assessed qualitatively using multiphoton 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-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 cases than in TAV-TAA cases, whereas TAV-TAA cases were more disorganized than TAV-NA cases. α-Elastin content was unchanged. Immature collagen was reduced in BAV-NA and BAV-TAA cases when compared with TAV-NA and TAV-TAA cases. Mature collagen was elevated in TAV-TAA cases compared with TAV-NA and BAV-TAA cases. There was a trend toward elevated Lox gene expression and activity and matrix metalloproteinase-2/9 activity for TAV-TAA, BAV-NA, and BAV-TAA specimens., Conclusions: The highly aligned matrix architecture in patients with BAVs indicates that wall remodeling is distinct from TAV-TAA. Altered matrix architecture and reduced collagen maturity suggest that the effector molecules mediating the remodeling of TAAs are different in BAV and TAV cases., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Ascending thoracic aortic aneurysm (ATAA) predisposes patients to aortic dissection and has been associated with diminished tensile strength and disruption of collagen. Ascending thoracic aortic aneurysms arising in patients with bicuspid aortic valve (BAV) develop earlier than in those with tricuspid aortic valves (TAV) and have a different risk of dissection. The purpose of this study was to compare aortic wall tensile strength between BAV and TAV ATAAs and determine whether the collagen content of the ATAA wall is associated with tensile strength and valve phenotype., Methods: Longitudinally and circumferentially oriented strips of ATAA tissue obtained during elective surgery were stretched to failure, and collagen content was estimated by hydroxyproline assay. Experimental stress-strain data were analyzed for failure strength and elastic mechanical variables: α, β, and maximal tangential stiffness., Results: The circumferential and longitudinal tensile strengths were higher for BAV ATAAs when compared with TAV ATAAs. The α and β were lower for BAV ATAAs when compared with TAV ATAAs. The maximal tangential stiffness was higher for circumferential when compared with longitudinal orientation in both BAV and TAV ATAAs. The amount of hydroxyproline was equivalent in BAV and TAV ATAA specimens. Although there was a moderate correlation between the collagen content and tensile strength for TAV, this correlation is not present in BAV., Conclusions: The increased tensile strength and decreased values of α and β in BAV ATAAs despite uniform collagen content between groups indicate that microstructural changes in collagen contribute to BAV-associated aortopathy., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The acute dissection of an ascending thoracic aortic aneurysm (ATAA) represents a devastating separation of elastic layers occurring when the hemodynamic loads on the diseased wall exceed the adhesive strength between layers. At present, the mechanics underlying aortic dissection are largely unclear, and the biomechanical delamination properties of the aneurysmal aorta are not defined. Individuals with bicuspid aortic valve (BAV) are particularly predisposed to ascending aortic aneurysm formation, with a marked risk of aortic dissection. The purpose of this study was to evaluate and compare the dissection properties of nonaneurysmal and aneurysmal human ascending thoracic aorta from patients with BAV morphology or normal tricuspid aortic valve (TAV) morphology using biomechanical delamination testing., Methods: The influence on the delamination strength (S(d)) of the aorta associated with BAV was compared with that in patients with TAV. After complete delamination of ATAA tissue samples, tensile tests were performed on each delaminated half for comparison of their tensile strengths., Results: The results showed that the aneurysmal aortas with BAV and TAV have lower S(d) than nonaneurysmal aortas and that ATAA with BAV has a lower S(d) than that with TAV. We have found a significant difference in S(d) between longitudinal and circumferential directions of the nondiseased aorta, suggesting anisotropic dissection properties., Conclusions: The tensile testing results suggest that the weaker intimal half of the aortic wall might fail before the outer adventitial half. Scanning electron microscope analyses suggest different failure modalities of dissection between the two morphologies, and the lower S(d) in ATAAs appears to be associated with a disorganized microstructure. BAV ATAAs have a lower S(d) than TAV ATAAs, suggesting a greater propensity for aortic dissection., (Published by Mosby, Inc.)