Non-dilated Aorta Research Articles

Anatomic Patterns of Distribution of the Renal Arteries' Origin from the Aorta

To characterize the variation of the renal arteries' origin from the aorta, through examination of computed tomography angiographies (CTAs) in a cohort of patients, and to evaluate any gender-related difference. CTA of the thoracoabdominal district in patients with a nondilated aorta (group A), patients with aortic aneurysm involving the origin of splanchnic and/or renal vessels (group B), and patients with abdominal aortic aneurysm (group C), were retrospectively analyzed. The diameter and angles of emergence (axial and craniocaudal) of the renal arteries were measured, as well as their mutual distance, and the distance between the renal vessels and the superior mesenteric artery/the aortic bifurcation. Shapiro-Wilk, one-way analysis of variance and bivariate Pearson's Correlation tests were performed as appropriate. A P value <0.05 was considered statistically significant. Six-hundred CTA of patients (452 males) were examined, being 286 in group A, 119 in group B, and 195 in group C. When examining the whole population and also the subgroup of female patients, the clock position of the right renal artery (RRA) was the only parameter that followed a Gaussian distribution, and its ostium raised from the aorta with a mean axial angle of -61.5°±16.6°. There was a negative correlation between left renal artery (LRA) and RRA's coronal angle and aortic diameter at the same level, as well as between the LRA's clock position and the aortic diameter at the same level. The longitudinal distances between established landmarks and both renal arteries positively correlated to the aortic diameter. The LRA showed a high anatomic variability, both in males and in females. With the increase of the aortic diameters in the juxtarenal/infrarenal portion of the aorta, the renal vessels tended to have a more horizontal course in the coronal view, a more acute "clock-position" and longer longitudinal distances between their ostia and the aortic bifurcation.

Smooth muscle cell phenotypic switching occurs independent of aortic dilation in bicuspid aortic valve-associated ascending aortas.

Bicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow perturbations, are likely involved. Since loss of contractility and elaboration of extracellular matrix in the vessel wall are features of BAV-associated aortopathy, phenotypic modulation of smooth muscle cells (SMCs) may play a role. Ascending aortic tissue was collected intra-operatively from 25 individuals with normal (i.e., tricuspid) aortic valves (TAV) and from 25 individuals with BAVs. For both TAV and BAV, 10 patients had non-dilated (ND) and 15 patients had dilated (D) aortas. SMCs were isolated and cultured from a subset of patients from each group. Aortic tissue and SMCs were fluorescently immunolabeled for SMC phenotypic markers (i.e., alpha-smooth muscle actin (ASMA, contractile), vimentin (synthetic) and p16INK4a and p21Cip1 (senescence). SMCs were also analyzed for replicative senescence in culture. In normal-sized and dilated BAV aortas, SMCs switched from the contractile state to either synthetic or senescent phenotypes, as observed by loss of ASMA (ND: P = 0.001, D: P = 0.002) and associated increases in vimentin (ND: P = 0.03, D: P = 0.004) or p16/p21 (ND: P = 0.03, D: P<0.0001) compared to TAV. Dilatation of the aorta exacerbated SMC phenotypic switching in both BAV and TAV aortas (all P<0.05). In SMCs cultured from normal and dilated aortas, those isolated from BAV reached replicative senescence faster than those from TAV aortas (all P = 0.02). Furthermore, there was a stark inverse correlation between ASMA and cell passage number in BAV SMCs (ND: P = 0.0006, D: P = 0.01), but not in TAV SMCs (ND: P = 0.93, D: P = 0.20). The findings of this study provide direct evidence from cell culture studies implying that SMCs switch from the contractile state to either synthetic or senescent phenotypes in the non-dilated BAV aorta. In cultured SMCs from both non-dilated and dilated aortas, we found that this process may precede dilatation and accompany aneurysm development in BAV. Our findings suggest that therapeutically targeting SMC phenotypic modulation in BAV patients may be a viable option to prevent or delay ascending aortic aneurysm formation.

Selenium Deficiency Promotes Dilatation of the Aorta by Increasing Expression and Activity of Vascular Smooth Muscle Cell Derived Matrix Metalloproteinase-2

Selenium (Se) is a key part of the body's oxidation defence system. However, it is unclear whether Se affects the development of aortic aneurysm (AA). An animal experiment was conducted to clarify the role of Se in AA development. C57BL/6N male mice were fed with a Se deficient (Se-D, < 0.05 mg/kg), Se adequate (Se-A, 0.2 mg/kg), or Se supplemented (Se-S, 1 mg/kg) diet for 8 weeks. Subsequently, an AA murine model (Se-D, n= 11; Se-A, n= 12; Se-S, n= 15) was established using angiotensin II (Ang II, 1 mg/kg/min) for four weeks plus β-aminopropionitrile (BAPN, 1 mg/mL) for the first two weeks. Saline replaced Ang II, and BAPN was removed during the modelling process for sham mice (Se-A, n= 9). To determine whether Se deficiency promoted aortic dilation via matrix metalloproteinase-2 (MMP-2), the non-specific MMP inhibitor doxycycline (Dox, 100 mg/kg/day) was given to Se-D AA mice (n= 7) for two weeks. The maximum aortic diameter in Se-D AA model mice was significantly increased compared with Se-A AA model mice. MMP-2 expression and activity in the aortic media of Se-D AA model mice was significantly increased compared with Se-A AA model mice. A large number of vascular smooth muscle cells (VSMCs) were found aggregating in the media of the non-dilated aorta of Se-D AA model mice, which was completely inhibited by Dox. The percentage of VSMCs in aortic media of Se-D AA model mice was significantly higher than in Se-A AA model mice. The maximum aortic diameter and occurrence rate of AA in Se-D AA model mice with Dox were significantly reduced compared with Se-D AA model mice. Se deficiency promoted dilatation of the aorta in AA model mice by increasing expression and activity of VSMC derived MMP-2, causing abnormal aggregation and proliferation of VSMCs in aortic media.

Fluid-structure interaction study for biomechanics and risk factors in Stanford type A aortic dissection.

Aortic dissection is a life-threatening condition with a rising prevalence in the elderly population, possibly as a consequence of the increasing population life expectancy. Untreated aortic dissection can lead to myocardial infarction, aortic branch malperfusion or occlusion, rupture, aneurysm formation and death. This study aims to assess the potential of a biomechanical model in predicting the risks of a non-dilated thoracic aorta with Stanford type A dissection. To achieve this, a fully coupled fluid-structure interaction model was developed under realistic blood flow conditions. This model of the aorta was developed by considering three-dimensional artery geometry, multiple artery layers, hyperelastic artery wall, in vivo-based physiological time-varying blood velocity profiles, and non-Newtonian blood behaviours. The results demonstrate that in a thoracic aorta with Stanford type A dissection, the wall shear stress (WSS) is significantly low in the ascending aorta and false lumen, leading to potential aortic dilation and thrombus formation. The results also reveal that the WSS is highly related to blood flow patterns. The aortic arch region near the brachiocephalic and left common carotid artery is prone to rupture, showing a good agreement with the clinical reports. The results have been translated into their potential clinical relevance by revealing the role of the stress state, WSS and flow characteristics as the main parameters affecting lesion progression, including rupture and aneurysm. The developed model can be tailored for patient-specific studies and utilised as a predictive tool to estimate aneurysm growth and initiation of wall rupture inside the human thoracic aorta.

Identification of a biomarker and immune infiltration in perivascular adipose tissue of abdominal aortic aneurysm.

Objective: Abdominal aortic aneurysm (AAA) refers to unusual permanent dilation of the abdominal aorta, and gradual AAA expansion can lead to fatal rupture. However, we lack clear understanding of the pathogenesis of this disease. The effect of perivascular adipose tissue (PVAT) on vascular functional status has attracted increasing attention. Here, we try to identify the potential mechanisms linking AAA and PVAT. Methods: We downloaded dataset GSE119717, including 30 dilated AAA PVAT samples and 30 non-dilated aorta PVAT samples from AAA cases, from Gene Expression Omnibus to identify differentially expressed genes (DEGs). We performed pathway enrichment analysis by Metascape, ClueGo and DAVID to annotate PVAT functional status according to the DEGs. A protein-protein interaction network, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were constructed to identify feature genes. Immune infiltration analysis was explored by CIBERSORT. And the correlation between feature gene and immune cells was also calculated. Finally, we used the angiotensin II (Ang II)-ApoE−/− mouse model of AAA to verify the effect of feature gene expression by confirming protein expression using immunohistochemistry and western blot. Results: We identified 22 DEGs, including 21 upregulated genes and 1 downregulated gene. The DEGs were mainly enriched in neutrophil chemotaxis and IL-17 signaling pathway. FOS was identified as a good diagnostic feature gene (AUC = 0.964). Immune infiltration analysis showed a higher level of T cells follicular helper, activated NK cells, Monocytes, activated Mast cells in AAA group. And FOS was correlated with immune cells. Immunohistochemistry and western blot confirmed higher FOS expression in PVAT of the AAA mouse model compared to control group. Conclusion: The differentially expressed genes and pathways identified in this study provide further understanding of how PVAT affects AAA development. FOS was identified as the diagnostic gene. There was an obvious difference in immune cells infiltration between normal and AAA groups.

Transforming growth factor serum concentrations in patients with proven non-syndromic aortopathy.

BackgroundThe mechanism underlying aortic dilatation is still unknown. Vascular dilatation is thought to be the result of progressive aortic media degeneration caused by defective vascular matrix hemostasis, including TGF-β1 dysregulation. The goal of this study is to draw attention to the potential utility of TGF-β1 as a diagnostic marker in non-syndromic patients with aortic dilatation.MethodsTGF-β1 levels in plasma were measured in 50 patients who had undergone surgery and had a tricuspid or bicuspid aortic valve as well as a normal or dilated ascending aorta. A pathologist also examined thirty resected aorta samples. To specify the reference range of TGF-β1, a control group of 40 volunteers was enrolled in this study.ResultsWe discovered a significant difference in TGF-β1 levels between patients with aortic dilatation and the control group (32.5 vs. 63.92; P < 0.001), as well as between patients with non-dilated aorta but with aortic valve disease, and the control group (27.68 vs. 63.92; P < 0.001). There was no difference between the dilated ascending aorta group and the non-dilated ascending aorta group. We found a poor correlation between TGF-β1 levels and ascending aorta diameter as well as the grade of ascending aorta histopathological abnormalities.ConclusionTGF-β1 concentration does not meet the criteria to be a specific marker of aortic dilatation, but it is sensitive to aortic valvulopathy-aortopathy. A larger patient cohort study is needed to confirm these findings.

Abstract 12817: Experimental Analysis of Bicuspid Aortic Valve Hemodynamics: Effect of Mild Aortic Dilatation on Systolic Flow Characteristics

Introduction: Aortic diameter is a determinant index in deciding surgical intervention for aortic aneurysm with bicuspid aortic valve (BAV). However, the treatment of a mildly dilated ascending aorta remains controversial. We experimentally investigated influence of mild dilatation of the ascending aorta on BAV-related hemodynamics in 3 BAV morphologies. Methods: An MRI-compatible pulsatile flow circulation system incorporating an aortic valve model and aortic arch model was developed. Tricuspid aortic valve (TAV) and 3 asymmetric BAV models including RL-, RN-, and LN-BAV were constructed by suturing bovine pericardium as cusps to aorta. The aortic arch models with the ascending diameters of 30 mm (non-dilatation) and 40 mm (mildly dilatation) were compared. Streamlines and the circulations (m 2 /s) of peak systolic flow in non- and mildly dilated ascending aorta were assessed using 4D-flow MRI in each BAV morphology (Fig). Results: Streamlines showed eccentric aortic valvular outflow jets impinging on the outer curvature of the ascending aorta, proximal arch, and left-anterior supra-valvular aortic wall in RL-, RN-, and LN-BAV, respectively. Regardless of the non-dilated or mildly dilated aorta, the circulations of peak systolic flow were larger in the BAVs than the TAV model (non-dilated aorta, TAV 0.005; RL- 0.016; RN- 0.026; LN-BAV 0.011 m 2 /s, mildly dilated aorta, TAV 0.009; RL- 0.017; RN- 0.028; LN-BAV 0.025 m 2 /s). Right-handed rotation was observed in RL- and RN-BAV, whereas LN-BAV presented left-handed rotation. In LN-BAV, the circulation markedly increased in the mildly dilated ascending aorta. Conclusions: Asymmetric BAV morphology was associated with highly eccentric aortic valvular outflow jet that directly impinged on the aortic wall, and the large circulation of peak systolic flow. The dilatation of the ascending aorta, even mild dilatation, might induce further increase in the circulation of systolic flow, especially in LN-BAV morphology.

Abstract 13417: Fluid-Structure Interaction Simulations of Bicuspid Aortic Valve Disease

Introduction: Aortic dilation and aneurysm formation is common in patients with a bicuspid aortic valve. Hemodynamics and genetics are both believed to cause dilation, but the relative contributions remain controversial. Further, retrospective studies assess hemodynamics when dilation has already set in. We simulate flows through a tricuspid and three bicuspid aortic valves and study their hemodynamics from a baseline non-dilated aorta. Hypothesis: We hypothesize that the bicuspid phenotype determines flow in the ascending aortic, and high velocity jets will correlate with known regions of dilation in patients with bicuspid valves. Methods: Using methods we recently developed, we constructed a tricuspid valve and bicuspid valves with left/right (LR), right/non (RN) and non/left (NL) coronary cusp fusion. To isolate the effect of leaflet fusion phenotype, we use one healthy, patient-specific aortic geometry throughout. Fluid-structure interaction simulations were performed. Results: Dramatic differences in flow occur between all cases. The tricuspid case shows a relatively uniform flow profile, velocities of ~200cm/s, normalized streamwise momentum &lt;1.5, normalized tangential flow strength of &lt;1.6, &lt;20% reverse flow away from the sinus and sustained pressure gradients &lt;2 mmHg. All bicuspid cases show a localized jet, peak velocities &gt;300cm/s, normalized streamwise momentum &gt;2.0, normalized tangential flow strength &gt;1.0, &gt;50% transient reverse flow and sustained pressure gradients &gt;18 mmHg. With LR fusion, the jet hugs the outer curvature of the aorta from the sinotubular junction through the ascending aorta. With RN fusion, the jet moves from the inner to outer curvature of the aorta. Conclusions: With LR and RN cusp fusion, high flow rate jets occur at regions that generally correlate with dilation in prior studies, suggesting that hemodynamic factors alone may be sufficient to cause aortic dilation. This hypothesis should be tested in an animal model.

Aortic Regurgitation Is Associated With Ascending Aortic Remodeling in the Nondilated Aorta.

The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas (P=0.005) but not AS-aortas (P=0.23). This pathological remodeling included mucoid extracellular matrix accumulation (P=0.005), elastin loss (P=0.003), elastin fragmentation (P=0.008), and decreased expression of fibrillin (P=0.003) and collagen (P=0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima (P=0.0008) and in vasa vasorum (P=0.004) of AR-aortas but not AS-aortas (all P>0.05). Likewise, subendothelial apoptosis was increased in AR-aortas (P=0.03) but not AS-aortas (P=0.50). AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients.

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.

Low and Oscillatory Wall Shear Stress Is Not Related to Aortic Dilation in Patients With Bicuspid Aortic Valve: A Time-Resolved 3-Dimensional Phase-Contrast Magnetic Resonance Imaging Study.

To assess the relationship between regional wall shear stress (WSS) and oscillatory shear index (OSI) and aortic dilation in patients with bicuspid aortic valve (BAV). Approach and Results: Forty-six consecutive patients with BAV (63% with right-left-coronary-cusp fusion, aortic diameter ≤ 45 mm and no severe valvular disease) and 44 healthy volunteers were studied by time-resolved 3-dimensional phase-contrast magnetic resonance imaging. WSS and OSI were quantified at different levels of the ascending aorta and the aortic arch, and regional WSS and OSI maps were obtained. Seventy percent of BAV had ascending aorta dilation. Compared with healthy volunteers, patients with BAV had increased WSS and decreased OSI in most of the ascending aorta and the aortic arch. In both BAV and healthy volunteers, regions of high WSS matched regions of low OSI and vice versa. No regions of both low WSS and high OSI were identified in BAV compared with healthy volunteers. Patients with BAV with dilated compared with nondilated aorta presented low and oscillatory WSS in the aortic arch, but not in the ascending aorta where dilation is more prevalent. Furthermore, no regions of concomitant low WSS and high OSI were identified when BAV were compared according to leaflet fusion pattern, despite the well-known differences in regional dilation prevalence. Regions with low WSS and high OSI do not match those with the highest prevalence of dilation in patients with BAV, thus providing no evidence to support the low and oscillatory shear stress theory in the pathogenesis of proximal aorta dilation in the presence of BAV.

The Potential Role of Neutrophil Gelatinase-Associated Lipocalin in the Development of Abdominal Aortic Aneurysms

In abdominal aortic aneurysm (AAA), pathophysiology deterioration of the medial aortic layer plays a critical role. Key players in vessel wall degeneration are reactive oxygen species (ROS), smooth muscle cell apoptosis, and extracellular matrix degeneration by matrix metalloproteinase-9 (MMP-9). Lipocalin-2, also neutrophil gelatinase-associated lipocalin (NGAL), is suggested to be involved in these degenerative processes in other cardiovascular diseases. We aimed to further investigate the role of NGAL in AAA development and rupture. In this observational study, aneurysm tissue and blood of ruptured (n=13) AAA patients were investigated versus nonruptured (n=26) patients. Nondilated aortas (n=5) from deceased patients and venous blood from healthy volunteers (n=10) served as controls. NGAL concentrations in tissue and blood were measured by enzyme-linked immunosorbent assay and immunofluorescence microscopy. Nitrotyrosine (marker of ROS), MMP-9, and caspase-3 (marker of apoptosis) in aneurysm tissue were measured by immunofluorescence microscopy. AAA expansion rates were calculated retrospectively. NGAL (in μg/mL) blood concentration in ruptured AAA was 46 (range 22-122) vs. 26 (range 6-55) in nonruptured AAA (P<0.01) and 14 (range 12-22) in controls (P<0.01). In the aneurysm wall of ruptured AAA, NGAL concentration was 4.7 (range 1.4-25) vs. 4.4 (range 0.2-14) in nonruptured AAA (not significant) and 1.8 (range 1.2-2.7) in nondilated aortas (P=0.04). In the medial layer, NGAL correlated positively with nitrotyrosine (Rs=0.80, P<0.01), MMP-9 (Rs=0.56, P=0.02), and caspase-3 (Rs=0.75, P=0.01). NGAL did not correlate to AAA expansion rate in blood or tissue (P=0.34 and P=0.95, respectively). This study demonstrates that NGAL blood concentration is higher in ruptured AAA patients than in nonruptured AAA. NGAL expression in the AAA wall is also higher than in nondilated aorta. Furthermore, its expression is associated with factors of vessel wall deterioration. Based on our study results, we could not determine NGAL as a biomarker for AAA growth or rupture. However, our findings do support a potential role of NGAL in the development of AAA.

High Density of Periaortic Adipose Tissue in Abdominal Aortic Aneurysm

Perivascular adipose tissue (PVAT) is currently seen as a paracrine organ that produces vasoactive substances, including inflammatory agents, which may have an impact on the vasculature. In this study PVAT density was quantified in patients with an aortic aneurysm and compared with those with a non-dilated aorta. Since chronic inflammation, as the pathway to medial thinning, is a hallmark of abdominal aortic aneurysms (AAAs), it was hypothesised that PVAT density is higher in AAA patients. In this multicentre retrospective case control study, three groups of patients were included: non-treated asymptomatic AAA (n=140), aortoiliac occlusive disease (AIOD) (n=104), and individuals without aortic pathology (n=97). A Hounsfield units based analysis was performed by computed tomography (CT). As a proxy for PVAT, the density of adipose tissue 10mm circumferential to the infrarenal aorta was analysed in each consecutive CT slice. Intra-individual PVAT differences were reported as the difference in PVAT density between the region of the maximum AAA diameter (or the mid-aortic region in patients with AIOD or controls) and the two uppermost slices of infrarenal non-dilated aorta just below the renal arteries. Furthermore, subcutaneous (SAT) and visceral (VAT) adipose tissue measurements were performed. Linear models were fitted to assess the association between the study groups, different adipose tissue compartments, and between adipose tissue compartments and aortic dimensions. AAA patients presented higher intra-individual PVAT differences, with higher PVAT density around the aneurysm sac than the healthy neck. This association persisted after adjustment for cardiovascular risk factors and diseases and other fat compartments (β=13.175, SE 4.732, p=.006). Furthermore, intra-individual PVAT differences presented the highest correlation with aortic volume that persisted after adjustment for other fat compartments, body mass index, sex, and age (β=0.566, 0.200, p=.005). The results suggest a relation between the deposition of PVAT and AAA pathophysiology. Further research should explore the exact underlying processes.

Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve

Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded.

The combined impact of mechanical factors on the wall stress of the human ascending aorta \u2013 a finite elements study

Biomechanical factors influence stress in the aortic wall. The aim of this study was to assess how the diameter and shape of the vessel, blood pressure and longitudinal systolic aortic stretching (SAS) caused by the contraction of the myocardium influence stress in the aortic wall. Three computational models of the non-dilated aorta and aneurysms of the ascending aorta and aortic root were created. Then, finite elements analyses were carried out. The models were subjected to blood pressure (120 mmHg and 160 mmHg) and longitudinal systolic aortic stretching (0 mm, 5 mm, 10 mm and 15 mm). The influence of wall elasticity was examined too. Blood pressure had a smaller impact on the stress than the SAS. An increase in blood pressure from120 mmHg to 160 mmHg increased the peak wall stress (PWS) on average by 0.1 MPa in all models. A 5 mm SAS caused a 0.1–0. 2 MPa increase in PWS in all the models. The increase in PWS caused by a 10mm and 15mmSAS was 0.2 MPa and 0. 4 MPa in the non-dilated aorta, 0.2–0.3 MPa and 0.3–0.5 MPa in the aneurysm of the ascending aorta, and 0.1–0.2 MPa and 0.2–0.3 MPa in the aortic root aneurysm model, respectively. The loss of elasticity of the aneurysmal wall resulted in an increase of PWS by 0.1–0.2 MPa. Aortic geometry, wall stiffness, blood pressure and SAS have an impact on PWS. However, SAS had the biggest impact on wall stress. The results of this study may be useful in future patient-specific computational models used to assess the risk of aortic complications.

Simulations of morphotype-dependent hemodynamics in non-dilated bicuspid aortic valve aortas

Bicuspid aortic valves (BAVs) generate flow abnormalities that may promote aortopathy. While positive helix fraction (PHF) index, flow angle (θ), flow displacement (d) and wall shear stress (WSS) exhibit abnormalities in dilated BAV aortas, it is unclear whether those anomalies stem from the abnormal valve anatomy or the dilated aorta. Therefore, the objective of this study was to quantify the early impact of different BAV morphotypes on aorta hemodynamics prior to dilation. Fluid-structure interaction models were designed to quantify standard peak-systolic flow metrics and temporal WSS characteristics in a realistic non-dilated aorta connected to functional tricuspid aortic valve (TAV) and type-I BAVs. While BAVs generated increased helicity (PHF>0.68) in the middle ascending aorta (AA), larger systolic flow skewness (θ>11.2°) and displacement (d>6.8mm) relative to the TAV (PHF=0.51; θ<5.5°; d<3.3mm), no distinct pattern was observed between morphotypes. In contrast, WSS magnitude and directionality abnormalities were BAV morphotype- and site-dependent. Type-I BAVs subjected the AA convexity to peak-systolic WSS overloads (up to 1014% difference vs. TAV). While all BAVs increased WSS unidirectionality on the proximal AA relative to the TAV, the most significant abnormality was achieved by the BAV with left-right-coronary cusp fusion on the wall convexity (up to 0.26 decrease in oscillatory shear index vs. TAV). The results indicate the existence of strong hemodynamic abnormalities in non-dilated type-I BAV AAs, their colocalization with sites vulnerable to dilation and the superior specificity of WSS metrics over global hemodynamic metrics to the valve anatomy.

Abstract 500: DNA Methylation Profiling Reveals an Epithelial/Endothelial-Mesenchymal Transition-like Signature of Intima-Media Cells in the Ascending Aorta of Bicuspid Aortic Valve Patients

Introduction: Individuals with bicuspid aortic valves (BAV) are at increased risk of ascending aortic aneurysm than individuals with tricuspid aortic valves (TAV), but the underlying mechanism is not fully understood. Aberrant DNA methylation has been described in various human diseases, and we have shown that key enzymes in the methylation machinery are differentially expressed in the aortic intima-media of BAV and TAV patients. In the present study, we assessed the hypothesis that DNA methylation may play an important role during aneurysm formation in BAV. We undertook a global methylation approach to delineate biological processes associated with BAV aortopathy, using TAV as a reference. Methods: Ascending aortic biopsies were collected from 21 BAV and 24 TAV patients, with either a non-dilated or a dilated aorta, at the time of surgery. Global DNA methylation was measured in the intima-media layer using Illumina 450k Array. Gene expression was analyzed in the same samples using Affymetrix Exon Array. Results: Compared with TAV, the BAV dilated aorta was hypomethylated (P=0.031), correlating with an up-regulation of global gene expression. A total of 4913 differentially methylated regions (DMRs) were identified and Hallmark analysis of the DMR-associated genes with a fold change of 10% (n=3147) showed a gene signature of Epithelial Mesenchymal Transition (EMT) (FDR q=2.91e-29). This was further confirmed by functional annotation analysis of hypomethylated DMRs using the Genomic Regions Enrichment of Annotations Tool (Stanford University), showing association to actin filament bundle (P=7.09e-12), stress fibers (P=1.72e-11) and adherence junctions (P=2.97e-8). Interestingly, analysis of non-dilated BAV and TAV aorta revealed that genes involved in EMT were the most differentially methylated genes prior to dilatation (FDR q=1.18e-6). We further confirmed the EMT-related molecular signature by immunostaining of some key players of EMT. In conclusion, epigenetic profiling clearly revealed differential methylation between BAV and TAV aorta, particularly in EMT-related genes. Aberrant EMT in the ascending aorta prior to dilatation may constitute the basis for the increased aneurysm susceptibility in BAV patients.

Exercise and Physical Activity for the Post-Aortic Dissection Patient: The Clinician's Conundrum.

Despite the paucity of evidence, it is often presumed, and is physiologically plausible, that sudden, acute elevations in blood pressure may transiently increase the risk of recurrent aortic dissection (AD) or rupture in patients with a prior AD, because a post-dissection aorta is almost invariably dilated and may thus experience greater associated wall stress as compared with a nondilated aorta. Few data are available regarding the specific types and intensities of exercise that may be both safe and beneficial for this escalating patient population. The purpose of this editorial/commentary is to further explore this conundrum for clinicians caring for and counseling AD survivors. Moderate-intensity cardiovascular activity may be cardioprotective in this patient cohort. It is likely that severe physical activity restrictions may reduce functional capacity and quality of life in post-AD patients and thus be harmful, underscoring the importance of further exploring the role of physical activity and/or structured exercise in this at-risk patient population.

THORACIC AORTIC DILATIONS IN PATIENTS WITH BICUSPID AORTIC VALVE DISEASE IS MARKED BY ACCELERATED SMOOTH MUSCLE CELL AGING

Individuals with a bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation and dissection. Loss of aortic medial smooth muscle cells (SMCs) and disruption of the extracellular matrix are well-recognized pathologies, but the underlying cellular mechanisms remain elusive. We tested the hypothesis that the dilated aorta in patients with BAV was marked by accelerated cellular aging. Samples of human ascending aorta were obtained from individuals with BAV undergoing thoracic aorta replacement (n=37, age 54.7±2.2, aortic diameter 4.8±0.9 cm) or patients with a tricuspid aortic valve and non-dilated aorta undergoing heart transplantation or coronary bypass procedures (n=8, age 55.3±8.1, aortic diameter 3.1±0.3 cm). Assessment of fresh aortic samples for senescence-associated β-galactosidase revealed evidence for rare medial cell senescence that was 4.2-fold more prevalent in dilated aortas (0.83±0.10%) than in non-dilated aortas (0.20±0.10%, p=0.048). Expression of p16 was abundantly detected in medial SMCs within dilated aortas (24.0±1.5%) and 3-fold more abundant than in non-dilated aortas (8.2±1.5%, p<0.0001). Interestingly, medial p16 expression did not correlate with telomere length of medial cells, as determined by quantitative and standardized PCR (p=0.35). Immunostaining for γH2A.X (phosphorylated Ser139) interestingly revealed discrete nuclear DNA double-strand breakage signals in 25.7±3.8% of medial cells in dilated aortas from patients with BAV, which was 2.3-fold higher than that found in non-dilated aortas (11.0±4.9, p=0.03). Medial cell outgrowths from BAV patients showed increased senescence-associated ß-galactosidase activity compared to control patient SMC outgrowths (38.9±2.9 vs. 19.5±1.9, p=0.0005). Furthermore, incubation of early passage SMCs with 50nM of angiotensin II for 3 days caused a 1.4-fold increase in senescence-associated ß-galactosidase expressing SMCs from BAV patients (p=0.0006), but elicited no change in senescence-associated ß-galactosidase expression in SMCs from control patients (p=0.83). These findings identify a previously unrecognized phenomenon of accelerated SMC aging in the aortas of patients with BAV, with cellular senescence and unresolved DNA breaks. Accelerated cell aging could thus be a driver of aortic wall degeneration in these patients and a potential therapeutic target.

Biomechanical analysis of wrapping of the moderately dilated ascending aorta.

BackgroundExternal wrapping is a surgical method performed to prevent the dilatation of the aorta and to decrease the risk of its dissection and rupture. However, it is also believed to cause degeneration of the aortic wall. A biomechanical analysis was thus performed to assess the stress of the aortic wall subjected to external wrapping.MethodsA stress analysis using the finite elements method was carried out on three models: a non-dilated aorta, a moderately dilated aorta and a wrapped aorta. The models were subjected to a pulsatile flow (120/80 mmHg) and a systolic aortic annulus motion of 11 mm.ResultsThe finite elements analysis showed that the stress exerted on the outer surface of the ascending aorta in the wrapping model (0.05–0.8 MPa) was similar to that observed in the normal aorta (0.03–0.7 MPa) and was lower than in the model of a moderately dilated aorta (0.06–1.4 MPa). The stress on the inner surface of the ascending aorta ranged from 0.2 MPa to 0.4 MPa in the model of the normal aorta, from 0.3 to 1.3 MPa in the model of the dilated aorta and from 0.05 MPa to 0.4 MPa in the wrapping model.ConclusionsThe results of this study suggest that the aortic wall is subjected to similar stress following a wrapping procedure to the one present in the normal aorta.