Dilated Bicuspid Aortic Valve Research Articles

Thoracic aortopathy in Marfan syndrome overlaps with mechanisms seen in bicuspid aortic valve disease.

Thoracic aortopathy is a serious complication which is more often seen in patients with Marfan syndrome (MFS) and patients with a bicuspid aortic valve (BAV) than in individuals with a tricuspid aortic valve (TAV). The identification of common pathological mechanisms leading to aortic complications in non-syndromic and syndromic diseases would significantly improve the field of personalized medicine. This study sought to compare thoracic aortopathy between MFS, BAV, and TAV individuals. Bicuspid aortic valve (BAV; n = 36), TAV (n = 23), and MFS (n = 8) patients were included. Ascending aortic wall specimen were studied for general histologic features, apoptosis, markers of cardiovascular ageing, expression of synthetic and contractile vascular smooth muscle cells (VSMC), and fibrillin-1 expression. The MFS group showed many similarities with the dilated BAV. Both patient groups showed a thinner intima (p < 0.0005), a lower expression of contractile VSMCs (p < 0.05), more elastic fiber thinning (p < 0.001), lack of inflammation (p < 0.001), and a decreased progerin expression (p < 0.05) as compared to the TAV. Other features of cardiovascular ageing differed between the BAV and MFS. Dilated BAV patients demonstrated less medial degeneration (p < 0.0001), VSMC nuclei loss (p < 0.0001), apoptosis of the vessel wall (p < 0.03), and elastic fiber fragmentation and disorganization (p < 0.001), as compared to the MFS and dilated TAV. This study showed important similarities in the pathogenesis of thoracic aortic aneurysms in BAV and MFS. These common mechanisms can be further investigated to personalize treatment strategies in non-syndromic and syndromic conditions.

A Segmental Approach from Molecular Profiling to Medical Imaging to Study Bicuspid Aortic Valve Aortopathy.

Bicuspid aortic valve (BAV) patients develop ascending aortic (AAo) dilation. The pathogenesis of BAV aortopathy (genetic vs. haemodynamic) remains unclear. This study aims to identify regional changes around the AAo wall in BAV patients with aortopathy, integrating molecular data and clinical imaging. BAV patients with aortopathy (n = 15) were prospectively recruited to surgically collect aortic tissue and measure molecular markers across the AAo circumference. Dilated (anterior/right) vs. non-dilated (posterior/left) circumferential segments were profiled for whole-genomic microRNAs (next-generation RNA sequencing, miRCURY LNA PCR), protein content (tandem mass spectrometry), and elastin fragmentation and degeneration (histomorphometric analysis). Integrated bioinformatic analyses of RNA sequencing and proteomic datasets identified five microRNAs (miR-128-3p, miR-210-3p, miR-150-5p, miR-199b-5p, and miR-21-5p) differentially expressed across the AAo circumference. Among them, three miRNAs (miR-128-3p, miR-150-5p, and miR-199b-5p) were predicted to have an effect on eight common target genes, whose expression was dysregulated, according to proteomic analyses, and involved in the vascular-endothelial growth-factor signalling, Hippo signalling, and arachidonic acid pathways. Decreased elastic fibre levels and elastic layer thickness were observed in the dilated segments. Additionally, in a subset of patients n = 6/15, a four-dimensional cardiac magnetic resonance (CMR) scan was performed. Interestingly, an increase in wall shear stress (WSS) was observed at the anterior/right wall segments, concomitantly with the differentially expressed miRNAs and decreased elastic fibres. This study identified new miRNAs involved in the BAV aortic wall and revealed the concomitant expressional dysregulation of miRNAs, proteins, and elastic fibres on the anterior/right wall in dilated BAV patients, corresponding to regions of elevated WSS.

Simulation of Altered Blood Flow in Bicuspid Aortic Valve Disease: &amp;lt;i&amp;gt;A Proof of Concept Study&amp;lt;/i&amp;gt;

Background: Bicuspid aortic valve (BAV) is a common congenital heart disease which is associated with aortic dilatation. There is controversy in the literature regarding the various measures of the biomechanical properties of the aorta in these patients and their relationship to aortic dilatation. The present study aimed to assess both conventional 2D Cardiac Magnetic Resonance Imaging (CMRI) measurements of aortic biomechanics (compliance and distensibility) and a computational fluid dynamics (CFD) approach in patients with BAV and either normal or dilated ascending aorta. Methods: 2D CMRI was performed in 18 patients (6 controls, 6 BAV with dilated ascending aorta and 6 BAV with normal ascending aorta i.e. <36mm diameter) and ascending aortic compliance and distensibility was calculated. CFD was performed with <i>ANSYS Fluent software </i>using 2D CMRI derived parameters to simulate the hemodynamic relationships between blood and the aortic wall. Results: The groups were similar in terms of demographics (mean age 38±13 years, 56% male, pulse pressure 56±15mmHg). There was a numerically lower but not significant difference in aortic compliance between dilated BAV and the other groups. Aortic distensibility was no different between groups. Using CFD, at the mid-ascending aorta pressure was significantly higher in patients with dilated BAV (147.6 ± 24.1 mmHg) than non-dilated BAV (118.6 ± 16.2 mmHg) and controls (124.5 ± 14.4 mmHg), p=0.04. Conclusions: We demonstrate that is possible to estimate regional aortic pressure from 2D CMRI derived parameters using a CFD approach. These novel parameters may add value to surveillance strategies in aortic disease.

P1447 Ascending aorta longitudinal strain in bicuspid aortic valve patients: a comparison with healthy volunteers and patients with degenerative aortic aneurysm

Abstract Funding Acknowledgements Spanish Ministry of Economy and Competitiveness RTC-2016-5152-1, ISCIII PI17/00381, La Marató de TV3 (20151330), Eur FP7/People 267128 and CIBERCV Background Histological findings of fibrillin-1 deficiency in bicuspid aortic valve (BAV) ascending aorta (AAo), as observed in Marfan (MFS), supported the existence of intrinsic aortic wall abnormalities, but recent studies reported the absence of an intrinsic impairment in stiffness. A recent study in MFS showed that AAo longitudinal strain was reduced in MFS and predicted dilation and aortic events. This parameter has not been studied in BAV. Purpose We investigated whether ascending aorta longitudinal strain is intrinsically altered in BAV with respect to tricuspid aortic valve (TAV) individuals. Methods 80 BAV, 31 healthy volunteers (HV) and 29 TAV with AAo aneurysm, all without moderate valvular disease, were consecutively included. AAo dilation was defined as a z-score &amp;gt; 2. The 1.5T CMR protocol included a set of 2D cine CMR stacks covering the proximal aorta in saggital, coronal and axial views. AAo longitudinal strain was computed by an in-house Matlab code performing a feature tracking of the aortic valve in each of the cine images. Results Twenty (25%) of BAV had AAo dilation. AAo longitudinal strain was lower in non-dilated BAV compared to HV, but the difference was not significant in multivariate analysis adjusted for AAo diameter and systolic blood pressure. Similarly, the difference between dilated BAV and dilated TAV found in univariate analysis was not confirmed by multivariate analysis. On the other hand, both dilated BAV and TAV showed decreased AAo longitudinal strain compared to HV, which were confirmed in multivariate analyses. Conclusions AAo longitudinal strain, a marker of aortic stiffness with predictive value in MFS, is not altered in BAV patients compared to TAV matched for dilation prevalence. Reduced AAo longitudinal strain was independently associated with dilation in both BAV and TAV. Table 1 HV vs. NON-DILATED BAV DILATED BAV vs DILATED TAV HV vs. DILATED BAV HV vs. DILATED TAV HV NON-DILATED BAV Univariate /multivariate p-value DILATED TAV DILATED BAV Univariate /multivariate p-value Univariate/ Multivariate p-value Univariate p-value N 31 20 29 60 Age [years 35 ± 8 49 ± 16 &amp;lt;0.001/ NS 66 ± 13 49 ± 14 &amp;lt;0.001 / &amp;lt;0.001 &amp;lt;0.001 / 0.052 &amp;lt;0.001 / NS Sex [% male] 42 35 0.629 24 42 0.097 / NS 0.969 0.149 BSA [m2] 1.83 ± 0.17 1.81 ± 0.14 0.702 1.95 ± 0.24 1.82 ± 0.22 0.015 / &amp;lt;0.001 0.881 0.030 / NS SBP [mmHg] 119 ± 11 132 ± 16 0.002 / 0.029 133 ± 17 138 ± 19 0.304 &amp;lt;0.001 / NS &amp;lt;0.001 / NS DBP [mmHg] 69 ± 11 73 ± 6 0.099 / NS 77 ± 9 79 ± 11 0.455 &amp;lt;0.001 / 0.016 0.004 / 0.023 Ascending aorta diameter [mm] 26 ± 4 33 ± 3 &amp;lt;0.001 / 0.006 46 ± 7 43 ± 6 0.032 / NS &amp;lt;0.001 / 0.001 &amp;lt;0.001 /0.007 AAo long strain [%] 10.5 ± 3.6 8.4 ± 4.1 0.067/ NS 5.9 ± 2.7 7.7 ± 3.6 0.023 / NS 0.001 / 0.002 &amp;lt;0.001 / 0.023 Demographics and uni- and multivariate analyses of AAo longitudinal strain

403 Simulation of Altered Blood Flow in Bicuspid Aortic Valve Disease: A Proof of Concept Study

Bicuspid aortic valve (BAV) is a common congenital heart disease which is associated with aortic dilatation. There is controversy in the literature regarding the various measures of the biomechanical properties of the aorta in these patients and their relationship to aortic dilatation. The present study aimed to compare conventional 2D Cardiac Magnetic Resonance Imaging (CMRI) measurements of aortic biomechanics (compliance and distensibility) with a computational fluid dynamics (CFD) approach in patients with BAV and either normal or dilated ascending aorta. 2D CMRI was performed in 18 patients (6 controls, 6 BAV with dilated ascending aorta and 6 BAV with normal ascending aorta i.e. <36mm diameter) and ascending aortic compliance and distensibility was calculated. CFD was performed with ANSYS Fluent software using 2D CMRI derived parameters to simulate the hemodynamic relationships between blood and the aortic wall. The groups were similar in terms of demographics (mean age 38±13 years, 56% male, pulse pressure 56±15mmHg). There was a numerically lower but not significant difference in aortic compliance between dilated BAV and the other groups. Aortic distensibility was no different between groups. Using CFD, at the mid-ascending aorta pressure was significantly higher in patients with dilated BAV (19.68±3.21 kPa) than non-dilated BAV (15.81±2.17 kPa) and controls (16.6±1.92 kPa), p=0.04. We demonstrate that is possible to estimate regional aortic pressure from 2D CMRI derived parameters using a CFD approach. These novel parameters may add value to surveillance strategies in aortic disease.

The relationship between serum apelin levels and aortic dilatation in bicuspid aortic valve patients.

The bicuspid aortic valve (BAV) is the most common congenital heart disease. The process of aortic dilatation is not completely clear in patients with the BAV. Apelin is a peptide found at high levels in vascular endothelial cells which has a role in vascular regulation and cardiovascular function. The aim of this study was to determine the relationship between serum apelin levels and ascending aortic dilatation in adult patients with BAV. This cross-sectional study included 62 patients with isolated BAV and to an age, gender, and body mass index-matched control group of 58 healthy volunteers with tricuspid aortic valve. Transesophageal echocardiography was performed on all patients to determine the type of BAV. Aortic diameters of the aortic root, sinus valsalva, sinotubular junction, and ascending aorta were evaluated with echocardiography. Patients with BAV were divided into two subgroups according to the aortic diameters, as the nondilated BAV group and the dilated BAV group. Serum apelin level was analyzed with ELISA method. The serum apelin levels of the BAV patients were significantly lower than those of the control group (833.5, 25th-75th percentile (713.5-1745) pg/dL vs 1669 (936-2543) pg/dL; P=0.006). In the subgroup analysis, serum apelin level was significantly different between the nondilated BAV group and the dilated BAV group [977 (790-2433) pg/dL vs 737 (693-870) pg/dL, P<0.05] and between the dilated BAV group and the control group [737 (693-870) pg/dL vs 1669 (936-2543) pg/dL, P<0.001]. In multivariate logistic regression analysis apelin [7.27 (95% CI: 1.73-30.42), P=0.007] and age [1.05 (95% CI: 0.99-1.20), P=0.049] were determined as independent predictors for ascending aortic dilatation. Low serum apelin level was associated with dilatation of ascending aortic in BAV patients. However, apelin was not relevant to BAV without aortic dilatation.

Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance: Comparison With Marfan Syndrome and Degenerative Aortic Aneurysm

ObjectivesThis study sought to ascertain whether patients with a bicuspid aortic valve (BAV) have an intrinsic alteration in regional aortic stiffness compared with patients with tricuspid aortic valve (TAV) and Marfan syndrome (MFS) patients with similar aortic sizes, as well as to assess the influence of ascending aorta (AAo) dilation on regional stiffness parameters in BAV patients. BackgroundImaging biomarkers as predictors of BAV, MFS, and degenerative AAo aneurysms in TAV patients (DA-TAV) are lacking. Biomechanical characterization has been proposed as a possible tool for further aneurysm stratification. MethodsA total 234 subjects (136 BAV, 44 MFS, and 18 DA-TAV patients and 36 healthy control subjects) were included. The cardiac magnetic resonance protocol comprised 4-dimensional flow to assess AAo and descending aorta (DAo) pulse wave velocities (PWVs) and double-oblique, 2-dimensional, steady-state free-precession cine cardiac magnetic resonance to compute aortic distensibility (AD). ResultsOn adjusted analysis, nondilated BAV patients had similar PWV and AD as healthy control subjects in both AAo and DAo, whereas dilated BAV did not differ from DA-TAV. In contrast, AAo and DAo stiffness in MFS patients was markedly greater than in BAV patients, increasing slightly with dilation severity. AAo PWV showed a biphasic pattern in BAV patients: it first decreased and then increased throughout AAo dilation, with a clear turning point at 50 mm, whereas distensibility did not discern mildly dilated aorta. In multivariate analysis adjusted for clinical and demographic characteristics, only PWV was related to AAo dilation in BAV patients. ConclusionsThe mechanical properties of AAo aneurysms are similar in BAV and TAV patients, whereas MFS patients have a stiffer aorta. Aortic stiffness strongly depends on dilation severity. AAo PWV resulted in a potentially clinically useful biphasic trend with respect to aneurysm diameter, whereas distensibility did not discern mildly dilated aorta. Beyond clinical risk factors, PWV but not AD was independently related to AAo dilation in BAV patients.

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.

Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy.

The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV. Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-β, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)]. All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-β, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group. Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.

Elastic Properties of Aortic Wall in Patients With Bicuspid Aortic Valve by Magnetic Resonance Imaging

Bicuspid aortic valve (BAV) is frequently associated with aortic wall abnormalities, including dilation of the ascending aorta and even dissection. We propose 2 new indexes of aortic wall biophysical properties, the maximum rates of systolic distension and diastolic recoil (MRSD and MRDR, respectively), in patients with BAV and matched control subjects. We evaluated 53 consecutive young patients with BAV (36 males, mean age 16 ± 4 years) with mild aortic valve disease and a control group of 22 age- and gender-matched healthy volunteers. All subjects underwent a cardiac magnetic resonance imaging study that included phase velocity mapping and cine acquisition at several aortic levels. The MRSD and MRDR were measured in the ascending aorta in both patients with BAV and controls. Of the 53 patients with BAV, 26 had enlarged ascending aortas (dilated BAV), and 27 had a normal aortic diameter (nondilated BAV). Compared to controls, the MRSD was significantly lower in the whole BAV group (4.37 ± 1.1 vs 9.1 ± 2.1), in patients with dilated BAV (4.5 ± 1.1 p <0.0001), and in those with nondilated BAV (4.3 ± 1.0, p <0.0001). The MRDR was greater in the whole BAV group (-4 ± 1.2 vs -7.6 ± 2.7, p <0.0001), in the dilated BAV group (-3.9 ± 1.3, p <0.0001), and in the nondilated BAV group (-4.1 ± 1.2, p <0.0001). A receiver operating characteristic curve analysis of MRSD distinguished BAV from controls with 100% sensitivity and 95% specificity. In conclusion, MRSD and MRDR were slower in the patients with BAV than in the controls, regardless of the dimensions of the ascending aorta.

Local mechanical and structural properties of healthy and diseased human ascending aorta tissue

This study investigates the mechanics and histology of healthy and dilated human ascending aortas (AA). The regional variation in mechanical response and tissue structure were compared. Rings of human AA from healthy (n=5), dilated tricuspid aortic valve (TAV, n=5), and dilated bicuspid aortic valve (BAV, n=6) patients were mechanically tested. Each aortic ring was sectioned into quadrants-anterior, posterior, medial (inner curvature) and lateral (outer curvature). Low- and high-stress elastic moduli were calculated from the equibiaxial stress strain curve to determine the local mechanical properties. Histological analysis was used to quantify the percent composition of elastin, collagen, and smooth muscle cells. BAV tissue was thinnest and contained the largest percent composition of collagen. Both TAV and BAV tissue had significantly less elastin than healthy tissue. At low strain in the circumferential direction, TAV tissue was on average the least stiff. The elastic modulus was dependent on quadrant and tissue type but not direction (isotropic). Generally, the lateral quadrant tissue was the stiffest and the medial quadrant the least stiff. There were no apparent local variations in the tissue histology. Local variations in tissue thickness and mechanical properties were evident in all samples analyzed and may be linked to the type of aortic valve present.