Healthy Aorta Research Articles

A geometric reappraisal of proximal landing zones for thoracic endovascular aortic repair according to aortic arch types

ObjectiveThis study assessed whether the additional use of the aortic arch classification in type I, II, and III may complement Ishimaru's aortic arch map and provide valuable information on the geometry and suitability of proximal landing zones for thoracic endovascular aortic repair. MethodsAnonymized thoracic computed tomography scans of healthy aortas were reviewed and stratified according to the aortic arch classification, and 20 of each type of arch were selected. Further processing allowed calculation of angulation and tortuosity of each proximal landing zone. Data were described indicating both proximal landing zone and type of arch (eg, 0/I). ResultsAngulation was severe (>60°) in 2/III and in 3/III. Comparisons among the types of arch showed an increase in proximal landing zones angulation (P < .001) and tortuosity (P = .009) depending on the type of arch. Comparisons within type of arch showed no change in angulation and tortuosity across proximal landing zones within type I arch (P = .349 and P = .409), and increases in angulation and tortuosity toward more distal proximal landing zones within type II (P = .003 and P = .043) and type III (P < .001 in both). ConclusionsThe aortic arch classification is associated with a consistent geometric pattern of the aortic arch map, which identifies specific proximal landing zones with suboptimal angulation for stent graft deployment. Arches II and III also appear to have progressively less favorable anatomy for thoracic endovascular aortic repair compared with arch I.

Integrated strategy for in vitro characterization of a bileaflet mechanical aortic valve

BackgroundHaemodynamic performance of heart valve prosthesis can be defined as its ability to fully open and completely close during the cardiac cycle, neither overloading heart work nor damaging blood particles when passing through the valve. In this perspective, global and local flow parameters, valve dynamics and blood damage safety of the prosthesis, as well as their mutual interactions, have all to be accounted for when assessing the device functionality. Even though all these issues have been and continue to be widely investigated, they are not usually studied through an integrated approach yet, i.e. by analyzing them simultaneously and highlighting their connections.ResultsAn in vitro test campaign of flow through a bileaflet mechanical heart valve (Sorin Slimline 25 mm) was performed in a suitably arranged pulsatile mock loop able to reproduce human systemic pressure and flow curves. The valve was placed in an elastic, transparent, and anatomically accurate model of healthy aorta, and tested under several pulsatile flow conditions. Global and local hydrodynamics measurements and leaflet dynamics were analysed focusing on correlations between flow characteristics and valve motion. The haemolysis index due to the valve was estimated according to a literature power law model and related to hydrodynamic conditions, and a correlation between the spatial distribution of experimental shear stress and pannus/thrombotic deposits on mechanical valves was suggested. As main and general result, this study validates the potential of the integrated strategy for performance assessment of any prosthetic valve thanks to its capability of highlighting the complex interaction between the different physical mechanisms that govern transvalvular haemodynamics.ConclusionsWe have defined an in vitro procedure for a comprehensive analysis of aortic valve prosthesis performance; the rationale for this study was the belief that a proper and overall characterization of the device should be based on the simultaneous measurement of all different quantities of interest for haemodynamic performance and the analysis of their mutual interactions.

Development of Polymer Microcapsules Functionalized with Fucoidan to Target P-Selectin Overexpressed in Cardiovascular Diseases.

New tools for molecular imaging and targeted therapy for cardiovascular diseases are still required. Herein, biodegradable microcapsules (MCs) made of polycyanoacrylate and polysaccharide and functionalized with fucoidan (Fuco-MCs) are designed as new carriers to target arterial thrombi overexpressing P-selectin. Physicochemical characterizations demonstrated that microcapsules have a core-shell structure and that fucoidan is present onto the surface of Fuco-MCs. Furthermore, their sizes range from 2 to 6 µm and they are stable on storage over 30 d at 4 °C. Flow cytometry experiments evidenced the binding of Fuco-MCs for human activated platelets as compared to MCs (mean fluorescence intensity: 12 008 vs. 9, p < 0.001) and its absence for nonactivated platelets (432). An in vitro flow adhesion assay showed high specific binding efficiency of Fuco-MCs to P-selectin and to activated platelet aggregates under arterial shear stress conditions. Moreover, both types of microcapsules reveal excellent compatibility with 3T3 cells in cytotoxicity assay. One hour after intravenous injection of microcapsules, histological analysis revealed that Fuco-MCs are localized in the rat abdominal aortic aneurysm thrombotic wall and that the binding in the healthy aorta is low. In conclusion, these microcapsules appear as promising carriers for targeting of tissues characterized by P-selectin overexpression and for their molecular imaging or treatment.

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis.

BackgroundAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.MethodsWound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE−/− mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.ResultsIGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE−/− mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.ConclusionsOur data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0477-3) contains supplementary material, which is available to authorized users.

Microstructure and mechanics of healthy and aneurysmatic abdominal aortas: experimental analysis and modelling

Soft biological tissues such as aortic walls can be viewed as fibrous composites assembled by a ground matrix and embedded families of collagen fibres. Changes in the structural components of aortic walls such as the ground matrix and the embedded families of collagen fibres have been shown to play a significant role in the pathogenesis of aortic degeneration. Hence, there is a need to develop a deeper understanding of the microstructure and the related mechanics of aortic walls. In this study, tissue samples from 17 human abdominal aortas (AA) and from 11 abdominal aortic aneurysms (AAA) are systematically analysed and compared with respect to their structural and mechanical differences. The collagen microstructure is examined by analysing data from second-harmonic generation imaging after optical clearing. Samples from the intact AA wall, their individual layers and the AAA wall are mechanically investigated using biaxial stretching tests. A bivariate von Mises distribution was used to represent the continuous fibre dispersion throughout the entire thickness, and to provide two independent dispersion parameters to be used in a recently proposed material model. Remarkable differences were found between healthy and diseased tissues. The out-of-plane dispersion was significantly higher in AAA when compared with AA tissues, and with the exception of one AAA sample, the characteristic wall structure, as visible in healthy AAs with three distinct layers, could not be identified in AAA samples. The collagen fibres in the abluminal layer of AAAs lost their waviness and exhibited rather straight and thick struts of collagen. A novel set of three structural and three material parameters is provided. With the structural parameters fixed, the material model was fitted to the mechanical experimental data, giving a very satisfying fit although there are only three material parameters involved. The results highlight the need to incorporate the structural differences into finite-element simulations as otherwise simulations of AAA tissues might not be good predictors for the actual in vivo stress state.

Shear accumulation as a means for evaluating risk of thromboembolic events in novel endovascular stent graft designs

ObjectiveThis study proposes to establish a simulation-based technique for evaluating shear accumulation in stent grafts and to use the technique to assess the performance of a novel branched stent graft system. MethodsComputational fluid dynamics models, with transient boundary conditions, particle injection, and rigid walls, simplifying assumptions were developed and used to evaluate the shear accumulation in various stent graft configurations with a healthy aorta as comparison. ResultsShear streamlines are presented for the various configurations. Shear accumulation was also calculated for each configuration. The number of particles with shear accumulations >3.5 Pa-s for each configuration was compared with the shear accumulation values of commercially available mechanical aortic valves from the literature. ConclusionsThe stent graft configuration with the diaphragm does have particles with shear accumulation >3.5 Pa-s. However, the percentage of particles with shear accumulation above 3.5 Pa-s is less than the two commercially available mechanical aortic valves, and more surprisingly, is smaller than in the healthy aorta.

Reverse Regulatory Pathway (H2S / PGE2 / MMP) in Human Aortic Aneurysm and Saphenous Vein Varicosity.

Hydrogen sulfide (H2S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E2 is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H2S may modulate PGE2, MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities. The expression of the enzyme responsible for H2S synthesis, cystathionine-γ-lyase (CSE) and its activity, were significantly higher in varicose vein as compared to SV. On the contrary, the endogenous H2S level and CSE expression were lower in AAA as compared to healthy aorta (HA). Endogenous H2S was responsible for inhibition of PGE2 synthesis mostly in varicose veins and HA. A similar effect was observed with exogenous H2S and consequently decreasing active MMP-1/TIMP ratios in SV and varicose veins. In contrast, in AAA, higher levels of PGE2 and active MMP-1/TIMP ratios were found versus HA. These findings suggest that differences in H2S content in AAA and varicose veins modulate endogenous PGE2 production and consequently the MMP/TIMP ratio. This mechanism may be crucial in vascular wall remodeling observed in different vascular pathologies (aneurysm, varicosities, atherosclerosis and pulmonary hypertension).

Lipocalin-2 deficiency or blockade protects against aortic abdominal aneurysm development in mice.

To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA). Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG. Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.

(18)F-Labeling of Mannan for Inflammation Research with Positron Emission Tomography.

Recently mannan from Saccharomyces cerevisiae has been shown to be able to induce psoriasis and psoriatic arthritis in mice, and the phenotypes resemble the corresponding human diseases. To investigate the pathological processes, we set out to label mannan with fluorine-18 ((18)F) and study the (18)F-labeled mannan in vitro and in vivo with positron emission tomography (PET). Accordingly, mannan has been transformed into (18)F-fluoromannan with (18)F-bicyclo[6.1.0]nonyne. In mouse aorta, the binding of [(18)F]fluoromannan to the atherosclerotic lesions was clearly visualized and was significantly higher compared to blocking assays (P < 0.001) or healthy mouse aorta (P < 0.001). In healthy rats the [(18)F]fluoromannan radioactivity accumulated largely in the macrophage-rich organs such as liver, spleen, and bone marrow and the excess excreted in urine. Furthermore, the corresponding (19)F-labeled mannan has been used to induce psoriasis and psoriatic arthritis in mice, which indicates that the biological function of mannan is preserved after the chemical modifications.

Abstract 105: Increased Dynamic Mechanical Energy Dissipation in Human Abdominal Aortic Aneurysm

Objectives: Individualized patient rupture risk for abdominal aortic aneurysms (AAA) remains elusive due to a limited understanding of the biomechanical events that trigger aneurysm growth and aortic wall failure. To date there has been a paucity of data describing how physiologic pulsatile energy is stored (E') and lost (E'') from AAA tissue. Our hypothesis is that AAA tissue dissipates more cyclic energy at a physiologic frequency, as determined by (E''/ E'), when compared to healthy aortic tissue. Methods: Human healthy aortic and AAA samples were obtained from cadaveric and surgical specimens. Specimens were stored at 4 o C in 0.9%NS and mechanically tested within 36 hrs of explant. Uniaxial mechanical testing (ADMET BioTense) was performed in the circumferential orientation with the tissue pre-loaded to an equivalent physiologic stress of a 5 cm at a 110 mmHg mean pressure. A sinusoidal ±5% strain was applied at 1 Hz for 40 cycles with simultaneous force measurements. After mechanical testing, immunohistochemical staining was performed to confirm tissue viability. Results: AAA tissue was significantly stiffer when compared to healthy aorta, as demonstrated by a greater average static modulus (E) 1555.4 ± 384 vs. 970 ± 128 kPa (n=5, p=0.03). Dynamic testing of the AAA tissue noted a significantly greater energy loss (E'') 137.8±36.7 vs. 43.1±21.7 (p&lt;0.01) and loss ratio (E''/ E') 0.090 ± 0.023 vs. 0.044 ± 0.023 (p=0.02), when compared to normal specimens. Figure #1 compares the static modulus (E) to the loss ratio (E''/ E') for the aortic tissue specimens. Histologic analysis confirmed tissue viability during of all specimens. Conclusions: Our data demonstrates that AAA tissue dissipates more energy (E'') and has a greater energy loss ratio (E''/ E'), suggesting that more pulsatile energy is dissipated in diseased tissue. Future work is needed to determine how this energy dissipation influences the biologic pathogenesis of AAA growth and rupture.

Hyper-Viscoelastic Behavior of Healthy Abdominal Aorta

The aim of the present study was to define biomechanical parameters of the healthy human abdominal aorta, usable to develop materials for the aortic phantom production. Such phantoms used in the training of endovascular treatment must describe the same morphology and mechanical behavior properties as the patient's aorta. To accurately identify these biomechanical parameters, ex vivo experiments in uniaxial tensile and dynamic simple shear tests were performed on six human healthy abdominal aortas (6 males, between 12 and 69 years old). A solid generalized Maxwell model including Yeoh expression for the elastic part was used to describe the hyper-viscoelastic behavior of the aorta. The results obtained from uniaxial tensile tests show an exponential-like increase in stiffness, which can be described by three hyperelastic parameters (C1, C2 and C3). From dynamic shear experiments, the viscous part of the global biomechanical behavior was expressed in a specific angular-frequency range (1 to 315 rad/s). Three Maxwell elements (β1, β2, and β3) put on three constant times (τ1=0.003 s, τ2=0.03 s, and τ3=0.3 s) respectively, were necessary to describe it. As this relatively high number of viscoelastic parameters may be difficult to control in the development of materials, we suggest defining the viscous behavior with the global viscosity η0 that combines the viscoelastic contributions of each Maxwell element. In conclusion, four biomechanical parameters: C1, C2, C3 and η0, must be considered for the development of materials used in the aortic phantom production.

Regional and directional compliance of the healthy aorta: an ex vivo study in a porcine model.

To gain differential knowledge about the physiological compliance and wall strength of the different regions of the aorta, including the ascending aorta, arch and descending aorta in both the circumferential and longitudinal directions, and to generate a hypothesis on the pathophysiological mechanisms that lead to Type A aortic dissection. Fresh tissue specimens from 22 ex vivo porcine aortas were analysed on a tensile tester. Regional and directional compliance, failure stress and failure strain were recorded. Aortic compliance appeared as a linear function of the natural logarithm (ln) of wall stress. Compliance significantly decreased along the length of the aorta. In the ascending aorta, longitudinal compliance significantly (P = 0.003) exceeded circumferential compliance, and the outer curvature was more compliant than the inner curvature (P = 0.03). In the descending aorta, this relationship is reversed: the circumferential compliance exceeded the longitudinal compliance, and the outer aspect was more compliant (P = 0.003). The median circumferential failure stress of all aortic segments was in the range of 2000-2750 kPa, whereas the longitudinal failure stress in the ascending aorta and the arch had values of 750-1000 kPa, which were significantly lower (P < 0.05). Surprisingly, the longitudinal failure stress of the inner aspect of the descending aorta was extraordinarily high (2000 kPa). Failure strain, similar to compliance, was highest in the ascending aorta and decreased along the aorta. The aorta appears to be a complex organ with distinct regional and directional differences in compliance and wall strength that is designed to effectively absorb the kinetic energy of cardiac systole and to cushion the momentum of systolic impact. Under normotensive conditions and a preconditioned physiological morphology, the aortic wall works in the steep part of the logarithmic strain-stress function; under hypertensive conditions and pathological morphology, the wall reacts in an non-compliant manner. The high longitudinal compliance and low failure stress of the ascending aorta and subsequent pathological changes may be the main determinants of the recurrent patho-anatomy of Type A aortic dissection.

Ascending aortic elongation and the risk of dissection.

Unlike aneurysm formation, the role of ascending aortic elongation in the pathogenesis of Type A aortic dissection (TAD) is largely unclear. We investigated the morphology of healthy, dissected and predissection aortas with a focus on ascending aortic length. We retrospectively compared clinical and computer tomography angiography (CTA) data from TAD patients (n = 130), patients who developed a TAD in the further clinical course (preTAD, n = 16) and healthy control patients who received a CTA for non-aortic emergencies (n = 165). The length of the ascending aorta was defined as the distance between the sinotubular junction (STJ) and the brachiocephalic trunk (BCT) at the central line, the outer and inner curvature as well as the direct distance in the frontal and sagittal planes. Additionally, the aortic diameters were analysed. In the healthy controls, we found a positive correlation of age with the aortic diameter (r = 0.57) and aortic length (r = 0.42). The correlation of the respective parameters with the body size was negligible (r < 0.2). The median ascending aortic diameter at the height of the pulmonary artery in TAD (50 mm) was significantly (P < 0.001) larger compared with the respective diameter of the healthy aortas (34 mm). The diameter of the preTAD aortas (40 mm) was also significantly larger compared with the healthy controls. These proportions were similar in all the aortic diameters. The midline length of the healthy ascending aortas was 71 mm. In the preTAD and TAD aortas, the same values were 81 mm and 92 mm, respectively (both P < 0.001). We evaluated the linear distance between the STJ and the BCT in the frontal plane as an easy-to-measure parameter of aortic length. In the TAD aortas (108 mm) and preTAD aortas (97 mm), this distance was significantly longer compared with the healthy aortas (84 mm). Aortic diameter might not be an optimal parameter to predict dissection. Most aortas dissect at diameters below 55 mm. Both the TAD and preTAD aortas were elongated compared with the healthy controls. Thus, aortic elongation may play a role in the pathogenesis of and may be a risk factor for TAD.

Experimental/numerical study to assess mechanical properties of healthy and Marfan syndrome ascending thoracic aorta under axial and circumferential loading

Ascending thoracic aortic aneurysm (ATAA) can be a life threatening disease as it leads to a lack of function in most of the connective tissues. Marfan syndrome is a congenital connective tissue disorder that may have influence on the cardiovascular system. It has been shown that Marfan syndrome invokes a degradation of the elastin and collagen content of the aortic wall and, consequently, a remarkable weakness in the mechanical strength of the arterial wall. However, so far, the mechanical properties of the aortic wall due to Marfan syndrome have not been determined. Therefore, this study was aimed to perform a comparative experimental study to quantify the linear elastic and non-linear hyperelastic mechanical properties of the healthy and Marfan syndrome ATA. Eight healthy and Marfan aorta tissues were excised from the human body during invasive cardiac surgery and autopsy respectively. The tissue samples were subjected to the longitudinal and circumferential loadings until breakage occurred. The elastic modulus, maximum stress and strain of the ATA tissues were calculated. The non-linear mechanical behaviour of the ATA tissues was also computationally investigated using Mooney–Rivlin hyperelastic material model. The results showed that the healthy ATA tissues are stiffer in the longitudinal direction compared to the circumferential direction. The highest elastic modulus (764.10 N cm− 2) and maximum stress (298.18 N cm− 2) were observed for the Marfan ATA wall in the longitudinal direction, while the healthy ATA tissues showed the axial elastic modulus and maximum stress of 367.08 and 220.14 N cm− 2 respectively. The hyperelastic material model also well defined the non-linear mechanical behaviour of the ATA tissues. These results may have implications not only for understanding the mechanical properties of the healthy and Marfan ATA tissues but also for a wide range of clinical applications, including valve repair or replacement.

Creating a model of diseased artery damage and failure from healthy porcine aorta

Large quantities of diseased tissue are required in the research and development of new generations of medical devices, for example for use in physical testing. However, these are difficult to obtain. In contrast, porcine arteries are readily available as they are regarded as waste. Therefore, reliable means of creating from porcine tissue physical models of diseased human tissue that emulate well the associated mechanical changes would be valuable. To this end, we studied the effect on mechanical response of treating porcine thoracic aorta with collagenase, elastase and glutaraldehyde. The alterations in mechanical and failure properties were assessed via uniaxial tension testing. A constitutive model composed of the Gasser-Ogden-Holzapfel model, for elastic response, and a continuum damage model, for the failure, was also employed to provide a further basis for comparison (Calvo and Peña, 2006; Gasser et al., 2006). For the concentrations used here it was found that: collagenase treated samples showed decreased fracture stress in the axial direction only; elastase treated samples showed increased fracture stress in the circumferential direction only; and glutaraldehyde samples showed no change in either direction. With respect to the proposed constitutive model, both collagenase and elastase had a strong effect on the fibre-related terms. The model more closely captured the tissue response in the circumferential direction, due to the smoother and sharper transition from damage initiation to complete failure in this direction. Finally, comparison of the results with those of tensile tests on diseased tissues suggests that these treatments indeed provide a basis for creation of physical models of diseased arteries.

Histone acetylation and histone acetyltransferases show significant alterations in human abdominal aortic aneurysm.

BackgroundEpigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA.ResultsA comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot. Expression of the KAT families GNAT (KAT2A, KAT2B), p300/CBP (KAT3A, KAT3B), and MYST (KAT5, KAT6A, KAT6B, KAT7, KAT8) was significantly higher in AAA than in controls (P ≤ 0.019). Highest expression was observed for KAT2B, KAT3A, KAT3B, and KAT6B (P ≤ 0.007). Expression of KAT2B significantly correlated with KAT3A, KAT3B, and KAT6B (r = 0.705, 0.564, and 0.528, respectively, P < 0.001), and KAT6B with KAT3A, KAT3B, and KAT6A (r = 0.407, 0.500, and 0.531, respectively, P < 0.05). Localization of highly expressed KAT2B, KAT3B, and KAT6B was further characterized by immunostaining. Significant correlations were observed between KAT2B with endothelial cells (ECs) (r = 0.486, P < 0.01), KAT3B with T cells and macrophages, (r = 0.421 and r = 0.351, respectively, P < 0.05), KAT6A with intramural ECs (r = 0.541, P < 0.001) and with a contractile phenotype of smooth muscle cells (SMCs) (r = 0.425, P < 0.01), and KAT6B with T cells (r = 0.553, P < 0.001). Furthermore, KAT2B was associated with AAA diameter (r = 0.382, P < 0.05), and KAT3B, KAT6A, and KAT6B correlated negatively with blood urea nitrogen (r = −0.403, −0.408, −0.478, P < 0.05). In addtion, acetylation of the histone substrates H3K9, H3K18 and H3K14 was increased in AAA compared to control aortae.ConclusionsOur results demonstrate that aberrant epigenetic modifications such as changes in the expression of KATs and acetylation of corresponding histones are present in AAA. These findings may provide new insight in the pathomechanism of AAA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0169-6) contains supplementary material, which is available to authorized users.

Effective properties of regular elastic laminated shell composite

The manuscript offers a methodology to solve an analytical model of a heterogeneous elastic problem for curvilinear layered structures, using the two scales asymptotic homogenization method (AHM). The local problems and the mechanical properties of the local functions were derived. The analytical modeling for the linear elastic problem considering quasi-periodic multi-layered curvilinear composites and the corresponding homogenized problem were obtained. The analytic expression of the effective stress for curvilinear composites is presented. In order to validate the presented model, comparisons with a computational modeling and experimental results for Fibonacci laminated composite and wavy laminated structure are given. The methodology is applied to composites with thickness variation where the effective coefficients were computed and a comparison between the results reported by AHM and numerical analysis given by finite element method (FEM) is presented. Finally, the aorta is studied as a curvilinear laminated shell composite and the above results were used to determinate the effective elastic tensor for healthy and unhealthy aorta using AHM and FEM.

Multi-modality image-based computational analysis of haemodynamics in aortic dissection.

Aortic dissection is a disease whereby an injury in the wall of the aorta leads to the creation of a true lumen and a false lumen separated by an intimal flap which may contain multiple communicating tears between the lumina. It has a high associated morbidity and mortality, but at present, the timing of surgical intervention for stable type B dissections remains an area of debate. Detailed knowledge of haemodynamics may yield greater insight into the long-term outcomes for dissection patients by providing a greater understanding of pressures, wall shear stress and velocities in and around the dissection. In this paper, we aim to gather further insight into the complex haemodynamics in aortic dissection using medical imaging and computational fluid dynamics modelling. Towards this end, several computer models of the aorta of a patient presenting with an acute Stanford type B dissection were created whereby morphometric parameters related to the dissection septum were altered, such as removal of the septum, and the variation of the number of connecting tears between the lumina. Patient-specific flow data acquired using 2D PC-MRI in the ascending aorta were used to set the inflow boundary condition. Coupled zero-dimensional (Windkessel) models representing the distal vasculature were used to define the outlet boundary conditions and tuned to match 2D PC-MRI flow data acquired in the descending aorta. Haemodynamics in the dissected aorta were compared to those in an equivalent ‘healthy aorta’, created by virtually removing the intimal flap (septum). Local regions of increased velocity, pressure, wall shear stress and alterations in flow distribution were noted, particularly in the narrow true lumen and around the primary entry tear. The computed flow patterns compared favourably with those obtained using 4D PC-MRI. A lumped-parameter heart model was subsequently used to show that in this case there was an estimated 14 % increase in left ventricular stroke work with the onset of dissection. Finally, the effect of secondary connecting tears (i.e. those excluding the primary entry and exit tears) was also studied, revealing significant haemodynamic changes when no secondary tears are included in the model, particularly in the true lumen where increases in flow over +200,% and drops in peak pressure of 18 % were observed.

Brahma-related gene 1 inhibits proliferation and migration of human aortic smooth muscle cells by directly up-regulating Ras-related associated with diabetes in the pathophysiologic processes of aortic dissection

ObjectiveTo elucidate the mechanisms of Brahma-related gene 1 (Brg1) involvement in the pathophysiologic processes of aortic dissection. MethodsSeventeen dissecting, 4 dilated, and 10 healthy human aorta samples were collected. Expression of Brg1 in the medium of aorta was evaluated by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining, respectively. The regulation effect of Brg1 on proliferation and migration of human aortic smooth muscle cells (HASMCs) was analyzed in 3 ways: using cell counting, a migration chamber, and a wound scratch assay. A polymerase chain reaction array was used for screening potential target genes of Brg1. A chromatin immunoprecipitation assay was adopted for direct deoxyribonucleic acid–protein binding detection. ResultsExpression levels of Brg1 were increased in aortic dissection and aortic dilation patients. In vitro results indicated that overexpression of Brg1 inhibited proliferation and migration of HASMCs. The candidate proliferation- and migration-related Brg1 target gene found was Ras-related associated with diabetes (RRAD), expression levels of which were enhanced in dissecting aortic specimens. The direct regulation effect of Brg1 on RRAD was verified by chromatin immunoprecipitation assay results. Furthermore, down-regulating RRAD significantly alleviated the suppression effects of Brg1 on proliferation and migration of HASMCs. ConclusionsOur study illustrated that Brg1 inhibited the proliferation and migration capacity of HASMCs, via the mechanism of direct up-regulation of RRAD, thus playing an important role in the pathophysiologic processes of aortic dissection.

Prior Distributions of Material Parameters for Bayesian Calibration of Growth and Remodeling Computational Model of Abdominal Aortic Wall.

For the accurate prediction of the vascular disease progression, there is a crucial need for developing a systematic tool aimed toward patient-specific modeling. Considering the interpatient variations, a prior distribution of model parameters has a strong influence on computational results for arterial mechanics. One crucial step toward patient-specific computational modeling is to identify parameters of prior distributions that reflect existing knowledge. In this paper, we present a new systematic method to estimate the prior distribution for the parameters of a constrained mixture model using previous biaxial tests of healthy abdominal aortas (AAs). We investigate the correlation between the estimated parameters for each constituent and the patient's age and gender; however, the results indicate that the parameters are correlated with age only. The parameters are classified into two groups: Group-I in which the parameters ce,ck1,ck2,cm2,Ghc, and ϕe are correlated with age, and Group-II in which the parameters cm1,Ghm,G1e,G2e, and α are not correlated with age. For the parameters in Group-I, we used regression associated with age via linear or inverse relations, in which their prior distributions provide conditional distributions with confidence intervals. For Group-II, the parameter estimated values were subjected to multiple transformations and chosen if the transformed data had a better fit to the normal distribution than the original. This information improves the prior distribution of a subject-specific model by specifying parameters that are correlated with age and their transformed distributions. Therefore, this study is a necessary first step in our group's approach toward a Bayesian calibration of an aortic model. The results from this study will be used as the prior information necessary for the initialization of Bayesian calibration of a computational model for future applications.