Bicuspid Aortic Valve Aortopathy Research Articles

Changes in aorta hemodynamics in Left-Right Type 1 bicuspid aortic valve patients after replacement with bioprosthetic valves: An in-silico study.

Bicuspid aortic valve (BAV) is the most common cardiac congenital abnormality with a high rate of concomitant aortic valve and ascending aorta (AAo) pathologic changes throughout the patient's lifetime. The etiology of BAV-related aortopathy was historically believed to be genetic. However, recent studies theorize that adverse hemodynamics secondary to BAVs also contribute to aortopathy, but their precise role, specifically, that of wall shear stress (WSS) magnitude and directionality remains controversial. Moreover, the primary therapeutic option for BAV patients is aortic valve replacement (AVR), but the role of improved post-AVR hemodynamics on aortopathy progression is also not well-understood. To address these issues, this study employs a computational fluid dynamics model to simulate personalized AAo hemodynamics before and after TAVR for a small cohort of 6 Left-Right fused BAV patients. Regional distributions of five hemodynamic metrics, namely, time-averaged wall shear stress (TAWSS) and oscillating shear index (OSI), divergence of wall shear (DWSS), helicity flux integral & endothelial cell activation potential (ECAP), which are hypothesized to be associated with potential aortic injury are computed in the root, proximal and distal ascending aorta. BAVs are characterized by strong, eccentric jets, with peak velocities exceeding 4 m/s and axially circulating flow away from the jets. Such conditions result in focused WSS loading along jet attachment regions on the lumen boundary and weaker, oscillating WSS on other regions. The jet attachment regions also show alternating streaks of positive and negative DWSS, which may increase risk for local tissue stretching. Large WSS magnitudes, strong helical flows and circumferential WSS have been previously implicated in the progression of BAV aortopathy. Post-intervention hemodynamics exhibit weaker, less eccentric jets. Significant reductions are observed in flow helicity, TAWSS and DWSS in localized regions of the proximal AAo. On the other hand, OSI increases post-intervention and ECAP is observed to be low in both pre- and post-intervention scenarios, although significant increases are also observed in this ECAP. These results indicate a significant alleviation of pathological hemodynamics post AVR.

Age is superior to aortopathy phenotype as a predictor of aortic mechanics in patients with bicuspid valve

ObjectivesBicuspid aortic valve (BAV) aortopathy is defined by 3 phenotypes—root, ascending, and diffuse—based on region of maximal aortic dilation. We sought to determine the association between aortic mechanical behavior and aortopathy phenotype versus other clinical variables. MethodsFrom August 1, 2016, to March 1, 2023, 375 aortic specimens were collected from 105 patients undergoing elective ascending aortic aneurysm repair for BAV aortopathy. Planar biaxial data (191 specimens) informed constitutive descriptors of the arterial wall that were combined with in vivo geometry and hemodynamics to predict stiffness, stress, and energy density under physiologic loads. Uniaxial testing (184 specimens) evaluated failure stretch and failure Cauchy stress. Boosting regression was implemented to model the association between clinical variables and mechanical metrics. ResultsThere were no significant differences in mechanical metrics between the root phenotype (N = 33, 31%) and ascending/diffuse phenotypes (N = 72, 69%). Biaxial testing demonstrated older age was associated with increased circumferential stiffness, decreased stress, and decreased energy density. On uniaxial testing, longitudinally versus circumferentially oriented specimens failed at significantly lower Cauchy stress (50th [15th, 85th percentiles]: 1.0 [0.7, 1.6] MPa vs 1.9 [1.3, 3.1] MPa; P < .001). Age was associated with decreased failure stretch and stress. Elongated ascending aortas were also associated with decreased failure stress. ConclusionsAortic mechanical function under physiologic and failure conditions in BAV aortopathy is robustly associated with age and poorly associated with aortopathy phenotype. Data suggesting that the root phenotype of BAV aortopathy portends worse outcomes are unlikely to be related to aberrant, phenotype-specific tissue mechanics.

Aortic Valve Dysfunction and Aortopathy Based on the Presence of Raphe in Patients with Bicuspid Aortic Valve Disease.

(1) Background: To identify the association between the presence or absence of a raphe and aortic valve dysfunction, as well as the presence of aortopathy in patients with a bicuspid aortic valve (BAV); (2) Methods: This retrospective study enrolled 312 participants (mean (SD) age, 52.7 (14.3) years; 227 men (72.8%)) with BAV. The BAVs were divided into those with the presence (raphe+) or absence (raphe-) of a raphe. Valvular function was classified as normal, aortic regurgitation (AR), or aortic stenosis (AS) using TTE. The pattern of BAV aortopathy was determined by the presence of dilatation at the sinus of Valsalva and the middle ascending aorta using CCT; (3) Results: BAVs with raphe+ had a higher prevalence of AR (148 (79.5%) vs. 48 (37.8%), p < 0.001), but a lower prevalence of AS (90 (48.6%) vs. 99 (78.0%), p < 0.001) compared with those with raphe-. The types of BAV aortopathy were significantly different (p = 0.021) according to those with BAV-raphe+ and BAV-raphe-; (4) Conclusions: The presence of a raphe was significantly associated with a higher prevalence of AR, but a lower prevalence of AS and combined dilatation of the aortic root and middle ascending aorta. The presence of a raphe was an independent determinant of AR.

Clinical Use of Blood Flow Analysis through 4D-Flow Imaging in Aortic Valve Disease.

Bicuspid aortic valve (BAV), which affects 1% of the general population, results from the abnormal fusion of the cusps of the aortic valve. BAV can lead to the dilatation of the aorta, aortic coarctation, development of aortic stenosis (AS), and aortic regurgitation. Surgical intervention is usually recommended for patients with BAV and bicuspid aortopathy. This review aims to examine 4D-flow imaging as a tool in cardiac magnetic resonance imaging for assessing abnormal blood flow and its clinical application in BAV and AS. We present a historical clinical approach summarizing evidence of abnormal blood flow in aortic valve disease. We highlight how abnormal flow patterns can contribute to the development of aortic dilatation and novel flow-based biomarkers that can be used for a better understanding of the disease progression.

The role of transforming growth factor beta in bicuspid aortic valve aortopathy

A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac deformity, which is associated with an increased risk to develop a thoracic aortic aneurysm and/or an aortic dissection as compared to persons with a tricuspid aortic valve. Due to the high prevalence of a BAV in the general population and the associated life-long increased risk for adverse vascular events, BAV disease places a considerable burden on the public health. The aim of the present review is to discuss the role of transforming growth factor beta (TGF-β) signaling in the development of the vascular wall and on how this complex signaling pathway may be involved in thoracic aortic aneurysm formation in tricuspid and BAV patients.

Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability

Bicuspid aortic valve (BAV) is the most common congenital heart malformation frequently associated with ascending aortic aneurysm (AscAA). Epithelial to mesenchymal transition (EMT) may play a role in BAV-associated AscAA. The aim of the study was to investigate the type of EMT associated with BAV aortopathy using patients with a tricuspid aortic valve (TAV) as a reference. The state of the endothelium was further evaluated. Aortic biopsies were taken from patients undergoing open-heart surgery. Aortic intima/media miRNA and gene expression was analyzed using Affymetrix human transcriptomic array. Histological staining assessed structure, localization, and protein expression. Migration/proliferation was assessed using ORIS migration assay. We show different EMT types associated with BAV and TAV AscAA. Specifically, in BAV-associated aortopathy, EMT genes related to endocardial cushion formation were enriched. Further, BAV vascular smooth muscle cells were less proliferative and migratory. In contrast, TAV aneurysmal aortas displayed a fibrotic EMT phenotype with medial degenerative insults. Further, non-dilated BAV aortas showed a lower miRNA-200c-associated endothelial basement membrane LAMC1 expression and lower CD31 expression, accompanied by increased endothelial permeability indicated by increased albumin infiltration. Embryonic EMT is a characteristic of BAV aortopathy, associated with endothelial instability and vascular permeability of the non-dilated aortic wall.Key messagesEmbryonic EMT is a feature of BAV-associated aortopathy.Endothelial integrity is compromised in BAV aortas prior to dilatation.Non-dilated BAV ascending aortas are more permeable than aortas of tricuspid aortic valve patients.

Prognosis of Unrepaired Ascending Aorta after the Surgical Replacement of Bicuspid Aortic Valves.

The surgical threshold for bicuspid aortic valve (BAV)-related aortopathy is a matter of debate due to its uncertain etiology and prognosis. This study investigated the prognosis of unrepaired BAV aortopathy in patients undergoing surgical aortic valve replacement (SAVR). We retrospectively analyzed data from 720 patients (age, 60.8±11.5 years; 246 women) who underwent SAVR for BAV disease without aortic repair between 2005 and 2020 at Asan Medical Center. The clinical endpoints were defined as occurrences of sudden death, aortic dissection or rupture, and elective aortic repair. To estimate postoperative changes in the dimensions of the unrepaired aorta, the individual annual aortic expansion rate was calculated. Multiple linear regression models were used to evaluate the risk of aortic expansion. The mean ascending aortic diameter was 39.5±4.6 mm, and 299 patients (41.5%) had a baseline ascending aorta diameter >40 mm. During 70.0±68.3 months of follow-up, the mean annual aortic expansion rate was 0.39±1.96 mm/yr, no aortic dissection or rupture was observed, and sudden deaths were reported in 12 patients (0.34% per person-year). Linear regression analysis revealed no significant correlation between the baseline ascending aortic diameter and postoperative aortic expansion (R2=0.004, β=-0.84, p=0.082). In selected patients undergoing SAVR for a BAV (<55 mm), the risk of adverse aortic events was very low. As this observation contradicts current practice guidelines advocating for proactive aortic replacement in dilated ascending aortas measuring >45 mm, the study results need further validation by studies involving larger populations or randomized controlled trials.

Endotrophin and matrix metalloproteinase-2 levels in bicuspid aortic valve and hypertension associated aortopathy and their relationship with strain parameters of the ascending aorta.

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Ascending aorta dilatation is related to BAV- and hypertension (HTN)-associated aortopathy. The aim of this study was to investigate aortic elasticity, as well as aortic deformation of the ascending aorta, using strain imaging, and to evaluate the possible relationship of biomarkers, such as endotrophin and matrix metalloproteinase-2 (MMP-2), with ascending aorta dilatation in patients with BAV- or HTN-associated aortopathy. This prospective study included patients with ascending aorta dilatation with BAV (n = 33), or normal tricuspid aortic valve with HTN (n = 33), and 20 control subjects. The mean age of the total patients was 42.76 ± 10.4 years (67% male, 33% female). We calculated aortic elasticity parameters using the relevant formula by M-mode echocardiography and determined layer-specific longitudinal and transverse strains of the proximal aorta by speckle-tracking echocardiography. Blood samples of the participants were drawn for the analysis of endotrophin and MMP-2. Aortic strain and aortic distensibility were significantly decreased, whereas the aortic stiffness index was significantly increased in patient groups with BAV or HTN compared to the control group (p < 0.001). Moreover, longitudinal strain of both the anterior and posterior aortic walls of the proximal aorta were significantly impaired in BAV and HTN patients (p < 0.001). Serum endotrophin levels were significantly reduced in the patient cohort compared to the controls (p = 0.001). Endotrophin was noted to be significantly positively correlated with aortic strain and aortic distensibility (r = 0.37, p = 0.001; r = 0.45, p < 0.001, respectively), whereas inversely associated with aortic stiffness index (r = -0.402, p < 0.001). Furthermore, endotrophin was the single independent predictor of ascending aorta dilatation (OR = 0.986, p < 0.001). A cut-off value of endotrophin ≤ 82.38 ng/mL predicted ascending aorta dilatation with a sensitivity of 80.3% and specificity of 78.5% (p < 0.0001). The present study showed that aortic deformation parameters and elasticity are impaired in BAV and HTN patients, and strain imaging allows for a good analysis of ascending aorta deformation. Endotrophin could be a predictive biomarker of ascending aorta dilatation in BAV and HTN aortopathy.

Aorta pathology and pregnancy-related risks in adult congenital cardiac disease: does the aorta dilate during pregnancy?

Aortic dilatation and pregnancy are major concerns in women with aortopathy (AOP). This single-centre retrospective analysis focuses on the evolution of aortic diameters during and after pregnancy in women with Marfan syndrome (MS), Turner syndrome (TS) and bicuspid aortic valve (BAV) aortopathy. Thirty-eight women who had one or more single pregnancies were included. The ascending aorta was measured during pregnancy and postpartum. During pregnancy, a significant increase of diameters of the sinus aortae (median 1.4 mm; [-1.3; 3.8]) and ascending aorta (median 2.1 mm; [0.0; 4.0]) was noted. Systemic hypertension gives dilation of the aorta, but it did not influence the overall trajectory during pregnancy. Significant aortic dilatation is noted during pregnancy in women with underlying AOP, even persisting in the long term. Pre-existing systemic hypertension is associated with larger aortic diameters prior to pregnancy. More research on a larger study population however is needed.

Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease

The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter.

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.

Molecular and haemodynamic interplay in bicuspid aortic valve aortopathy: segmental differences across the aortic circumference

Abstract Background Bicuspid aortic valve (BAV) patients develop ascending aortic (AAo) dilation. The pathogenesis of BAV-aortopathy (genetic vs. hemodynamic) remains unclear. Purpose To identify regional changes around the AAo wall in BAV patients with aortopathy integrating clinical imaging and molecular data. Methods BAV patients with aortopathy (n=20) were recruited prospectively to surgically collect aortic tissue and perform four-dimensional cardiac magnetic resonance (CMR) scans. Molecular markers were measured analysing the tissue biopsies (n=15) and wall shear stress (WSS) across the AAo circumference was calculated from the 4D CMR data (n=11 patients, and n=7 additional healthy volunteers for comparison). Dilated (anterior/right) vs. non-dilated (posterior/left) circumferential segments were profiled for whole genomic microRNAs (Next Generation RNA-Sequencing, miRCURY LNA PCR), proteins content (Tandem Mass Spectrometry) and elastin fragmentation and degeneration (histomorphometric analysis). Picture 1 summarises the study approach (including a map of the AAo divided in the following segments: A=anterior, AR=anterior-right, PR=posterior-right, P=posterior, PL=posterior-left, AL=anterior-left). Results Integrated bioinformatic analyses of RNA-sequencing and proteomic datasets identified 5 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 vascular endothelial growth factor signalling, hippo signaling and arachidonic acid pathway. Decreased elastic fibre levels and elastic layer thickness were observed in the dilated segments in the histomorphometric analysis. Increased WSS and flow-velocity, helical streamlines and asymmetrical flow were observed at the anterior/right wall in asymmetrically and symmetrically dilated patients (the latter exhibiting higher WSS), compared to healthy volunteers. Conclusion This study has newly revealed concomitant expressional dysregulation of miRNAs, proteins, and elastic fibres on the anterior/right wall in dilated BAV patients, corresponding to regions of elevated WSS, contributing to advance the understanding of the interplay of genetic and hemodynamic factors underpinning BAV aortopathy. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation and Above &amp; Beyond

Feasibility of a longitudinal statistical atlas model to study aortic growth in congenital heart disease

Abstract Background Studying anatomical shape progression over time is of utmost importance to refine our understanding of clinically relevant processes. These include vascular remodelling, such as aortic dilation, which is particularly important in some congenital heart defects (CHD). Purpose A novel methodological framework for analysing three-dimensional (3D) shape changes over time (“growth”) has been applied for the first time in a CHD scenario, i.e., bicuspid aortic valve (BAV) disease, the most common CHD. Methods Three-dimensional aortic shapes (n=94) reconstructed as surface meshes from cardiovascular magnetic resonance imaging (MRI) data represented the input for a longitudinal shape atlas model, using multiple scans over time (n=2–4 scans per patient). This model relies on diffeomorphic transformations in the absence of point-to-point correspondence, and on the correct combination of initialization, estimation, and registration parameters. Results We computed the 3D shape trajectory of an average disease progression over time in our cohort (Picture 1, grey to blue shapes), as well as time-dependent parameters, geometric variations and the average shape of the population (Picture 1, red shape). Results cover a spatiotemporal spectrum of visual and numerical information that can be further used to investigate clinical associations and stratify patients, as such capturing aortic remodelling in the presence of BAV aortopathy. Conclusion This proof-of-concept study demonstrates the feasibility of applying advanced statistical shape models to track disease progression and stratify patients with CHD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation and NIHR BRC

Clinical implications of the biomechanics of bicuspid aortic valve and bicuspid aortopathy.

Bicuspid aortic valve (BAV), which affects up to 2% of the general population, results from the abnormal fusion of the cusps of the aortic valve. Patients with BAV are at a higher risk for developing aortic dilatation, a condition known as bicuspid aortopathy, which is associated with potentially life-threatening sequelae such as aortic dissection and aortic rupture. Although BAV biomechanics have been shown to contribute to aortopathy, their precise impact is yet to be delineated. Herein, we present the latest literature related to BAV biomechanics. We present the most recent definitions and classifications for BAV. We also summarize the current evidence pertaining to the mechanisms that drive bicuspid aortopathy. We highlight how aberrant flow patterns can contribute to the development of aortic dilatation. Finally, we discuss the role cardiac magnetic resonance imaging can have in assessing and managing patient with BAV and bicuspid aortopathy.

Experimental evidence of the genetic hypothesis on the etiology of bicuspid aortic valve aortopathy in the hamster model

Bicuspid aortopathy occurs in approximately 50% of patients with bicuspid aortic valve (BAV), the most prevalent congenital cardiac malformation. Although different molecular players and etiological factors (genetic and hemodynamic) have been suggested to be involved in aortopathy predisposition and progression, clear etiophysiopathological mechanisms of disease are still missing. The isogenic (genetically uniform) hamster (T) strain shows 40% incidence of BAV, but aortic dilatations have not been detected in this model. We have performed comparative anatomical, histological and molecular analyses of the ascending aorta of animals with tricuspid aortic valve (TAV) and BAV from the T strain (TTAV and TBAV, respectively) and with TAV from a control strain (HTAV). Aortic diameter, smooth muscle apoptosis, elastic waviness, and Tgf-β and Fbn-2 expression were significantly increased in T strain animals, regardless of the valve morphology. Strain and aortic valve morphology did not affect Mmp-9 expression, whereas Mmp-2 transcripts were reduced in BAV animals. eNOS protein amount decreased in both TBAV and TTAV compared to HTAV animals. Thus, histomorphological and molecular alterations of the ascending aorta appear in a genetically uniform spontaneous hamster model irrespective of the aortic valve morphology. This is a direct experimental evidence supporting the genetic association between BAV and aortic dilatation. This model may represent a population of patients with predisposition to BAV aortopathy, in which increased expression of Tgf-β and Fbn-2 alters elastic lamellae structure and induces cell apoptosis mediated by eNOS. Patients either with TAV or BAV with the same genetic defect may show the same risk to develop bicuspid aortopathy.

Elastin integrity in bicuspid valve-associated aortopathy is associated with altered biomechanical properties and influenced by age.

BackgroundAortic wall remodelling in bicuspid aortic valve (BAV) patients is heterogeneous and characterized by elastin fiber breakdown alongside impaired biomechanics. However, the relationship between aortic histopathological changes and biomechanics are incompletely understood. We clarify the influence of elastin fiber integrity on ex vivo aortic wall mechanical properties in BAV patients, and explore the influence of patient age.MethodsAortic tissue samples (N=66) from 19 BAV patients undergoing prophylactic ascending aortic resection surgery were analyzed. Semi-quantitative histopathological analysis was conducted to assess elastin fiber integrity including elastin content and elastic fiber fragmentation. Ex vivo biaxial mechanical testing generated stress-strain curves from which physiological [low-strain tangential modulus (LTM), transition zone onset stress (TZo)] and supraphysiological [transition zone end stress (TZe) and high-strain tangential modulus (HTM)] mechanical properties were obtained. Relationships between histopathology and mechanical properties were determined using a linear mixed effect model. BAV patients were subdivided according to ‘younger’ and ‘older’ age groups (i.e., 51–60 and 61–70 years old, respectively).ResultsNo statistically significant differences in elastin content were observed between younger and older BAV patients. Older patients showed greater elastin fiber fragmentation compared to their younger cohort (74% versus 61%). Elastin fiber histopathology was associated with differences in physiological mechanical properties: elastin fragmentation corresponded with lower LTM (P=0.005) and TZo (P=0.044) in younger BAV patients and higher LTM (P=0.049) and TZo (P=0.001) in older BAV patients. Histopathology changes were significantly associated with supraphysiological mechanical properties only in older BAV patients: decreased elastin integrity was associated with increased TZe (P=0.049) and HTM (P<0.001).ConclusionsElastin histopathologic changes in BAV aortopathy correspond with differences in mechanical properties and this relationship is influenced by patient age. These novel findings provide additional mechanistic insights into aortic wall remodeling and support a more nuanced stratification of BAV patients by age.

Endurance Exercise Following Ascending Thoracic Aortic Aneurysm Resection in Bicuspid Aortic Valve Aortopathy

Endurance Exercise Following Ascending Thoracic Aortic Aneurysm Resection in Bicuspid Aortic Valve Aortopathy

Global Aortic Pulse Wave Velocity is Unchanged in Bicuspid Aortopathy With Normal Valve Function but Elevated in Patients With Aortic Valve Stenosis: Insights From a 4D Flow MRI Study of 597 Subjects.

Aortopathy is common with bicuspid aortic valve (BAV), and underlying intrinsic tissue abnormalities are believed causative. Valve-mediated hemodynamics are altered in BAV and may contribute to aortopathy and its progression. The contribution of intrinsic tissue defects versus altered hemodynamics to aortopathy progression is not known. To investigate relative contributions of tissue-innate versus hemodynamics in progression of BAV aortopathy. Retrospective. Four hundred seventy-three patients with aortic dilatation (diameter ≥40 mm; comprised of 281 BAV with varied AS severity, 192 tricuspid aortic valve [TAV] without AS) and 124 healthy controls. Subjects were 19-91 years (141/24% female). 1.5T, 3T; time-resolved gradient-echo 3D phase-contrast (4D flow) MRI. A surrogate measure for global aortic wall stiffness, pulse wave velocity (PWV), was quantified from MRI by standardized, automated technique based on through-plane flow cross-correlation maximization. Comparisons were made between BAV patients with aortic dilatation and varying aortic valve stenosis (AS) severity and healthy subjects and aortopathy patients with normal TAV. Multivariable regression, analysis of covariance (ANCOVA), Tukey's, student's (t), Mann-Whitney (U) tests, were used with significance levels P < 0.05 or P < 0.01 for post-hoc Bonferroni-corrected t/U tests. Bland-Altman and ICC calculations were performed. Multivariable regression showed age with the most significant association for increased PWV in all groups (increase 0.073-0.156 m/sec/year, R2 =0.30-48). No significant differences in aortic PWV were observed between groups without AS (P=0.20-0.99), nor were associations between PWV and regurgitation or Sievers type observed (P=0.60, 0.31 respectively). In contrast, BAV AS patients demonstrated elevated PWV and a significant relationship for AS severity with increased PWV (covariate: age, R2 =0.48). BAV and TAV patients showed no association between aortic diameter and PWV (P=0.73). No significant PWV differences were observed between BAV patients with normal valve function and control groups. However, AS severity and age in BAV patients were directly associated with PWV increases. 3 TECHNICAL EFFICACY: Stage 3.

Novel insights into bicuspid aortic valve (BAV) aortopathy: Long non-coding RNAs TUG1 and MIAT are differentially expressed in BAV ascending aortas

BackgroundWhilst a combination of genetically mediated vulnerability and hemodynamic insult is suspected to contribute to bicuspid aortic valve (BAV) aortopathy, the underlying pathophysiological mechanisms are poorly understood. MethodsUtilizing RT-qPCR, we compared the expression of 28 potentially relevant long non-coding RNA (lncRNA) in aortic tissue from BAV patients undergoing aortic surgery for aortopathy, to healthy controls. Relative lncRNA expression was measured using ΔΔCT, with fold-change calculated as RQ=2−ΔΔCT. ResultsWhen comparing samples from BAV patients (n=29, males n=25; median age 58 years, Q1-Q3 51–65, maximum aortic dimension 50±5 mm) with healthy controls (n=7; males n=4, P=.12; median age 39 years, Q1-Q3 18-47, P=.001), there were two differentially expressed lncRNA: TUG1 expression was significantly lower in BAV aortic tissue (RQ 0.59, 95% CI 0.50–0.69, P=.02), whilst MIAT expression was significantly higher (RQ 2.87, 95% CI 1.96–4.20, P=.01). Sensitivity analysis including only patients with normal BAV function showed similar trends of differential expression of TUG1 (RQ 0.69, 95% CI 0.50-0.90, P=.29) and MIAT (RQ 2.55, 95% CI 1.21-5.36, P=.29) compared to controls. ConclusionsLncRNA TUG1 and MIAT are differentially expressed in BAV aortopathy compared to healthy controls, independent of BAV hemodynamics. Aberrant lncRNA expression may be involved in the pathogenesis of BAV aortopathy

Well-functioning bicuspid aortic valves should be preserved during aortic replacement for the ascending aortopathy phenotype

ObjectivesConsensus has not been reached on whether or not to replace or preserve a well-functioning bicuspid aortic valve (BAV) in patients undergoing aortic replacement for the ascending phenotype of BAV aortopathy. We characterize morphology, evaluate progression of aortic regurgitation or aortic stenosis, and investigate the need for aortic valve replacement in patients whose well-functioning BAV was preserved during ascending aortic replacement ≥10 years prior. MethodsFrom January 1991 to August 2011, 191 patients with a well-functioning BAV underwent supracoronary aortic replacement (113 valves were minimally repaired). Aortic morphology was evaluated, aortic regurgitation grade and transvalvular aortic gradient modeled parametrically, and survival assessed by the Kaplan-Meier method. Median follow-up was 10 years. ResultsMean aortic diameter was 2.9 ± 0.53 cm at the annulus and 4.2 ± 0.55 cm at the sinuses. Mean maximum ascending diameter was 5.1 ± 0.49 cm. All patients exhibited a cusp-fusion BAV phenotype. Fifteen-year progression to severe aortic regurgitation was 3.2%. Mean aortic valve gradient began to rise 5 years postoperatively to 27 mm Hg by 14 years. Freedom from aortic valve replacement at 1, 5, 10, and 15 years was 100%, 95%, 83%, and 63%, respectively. Minimal valve repair was not associated with late aortic valve replacement. Fifteen-year survival was 74%. ConclusionsPreserving a well-functioning BAV should be considered in carefully selected patients undergoing aortic replacement for the ascending phenotype of BAV aortopathy. The valves remain durable in the long term, with slow progression of regurgitation or stenosis, and low probability of aortic valve replacement through 10 years.