Bicuspid Aortic Valve Patients Research Articles

Clinical outcomes and the impact of valve morphology for transcatheter aortic valve replacement in bicuspid aortic valves: A systematic review and meta-analysis.

Bicuspid aortic valve (BAV) is present in approximately 0.5%-2% of the general population, causing significant aortic stenosis (AS) in 12%-37% of affected individuals. Transcatheter aortic valve replacement (TAVR) is being considered the treatment of choice in patients with symptomatic AS across all risk spectra. Aim Our study aims to compare TAVR outcomes in patients with BAV versus tricuspid aortic valves (TAV). A comprehensive literature search was performed in PubMed, Web of Science, and Cochrane trials. Studies were included if they included BAV and TAV patients undergoing TAVR with quantitative data available for at least one of our predefined outcomes. Meta-analysis was performed by the random-effects model using Stata software. Fifty studies of 203,288 patients were included. BAV patients had increased 30-day all-cause mortality (odds ratio [OR] = 1.23 [1.00-1.50], p = 0.05), in-hospital stroke (OR = 1.39 [1.01-1.93], p = 0.05), in-hospital and 30-day PPI (OR = 1.13 [1.00-1.27], p = 0.04; OR = 1.16 [1.04-1.13], p = 0.01) and in-hospital, 30-day and 1-year aortic regurgitation (AR) (OR = 1.48 [1.19-1.83], p < 0.01; OR = 1.79 [1.26-2.52], p < 0.01; OR = 1.64 [1.03-2.60], p = 0.04). Subgroup analysis on new-generation valves showed a reduced 1-year all-cause mortality (OR = 0.86 [CI = 0.75-0.98], p = 0.03), despite higher in-hospital and 30-day PPI (OR = 0.1.21 [1.04-1.41], p = 0.01; OR = 1.17 [1.05-1.31], p = 0.01) and in-hospital AR (OR = 1.62 [1.14-2.31], p = 0.01) in the BAV group. The quality of included studies was moderate-to-high, and only three analyses presented high heterogeneity. TAVR is associated with comparable outcomes in patients with BAV and TAV. Careful selection of BAV cases by preprocedural assessment of valve anatomy and burden of calcification, pre- and post-procedural dilation, and implementing newer generations of valves may improve the safety and efficacy of TAVR in BAV patients.

Lipidomics plasma analysis supports a differential thoracic aortic aneurysm diagnosis for bicuspid or tricuspid aortic valve patients

Lipidomics plasma analysis supports a differential thoracic aortic aneurysm diagnosis for bicuspid or tricuspid aortic valve patients

Transcatheter Aortic Valve Replacement in Bicuspid Versus Tricuspid Aortic Valve Stenosis: Meta-Analysis and Systemic Review

Because of its anatomic and procedural complexities, bicuspid aortic valve (BAV) has been excluded from previous trials investigating transcatheter aortic valve replacement (TAVR). We aimed to compare the clinical outcomes of TAVR in BAV and tricuspid aortic valve patients. We searched the databases systematically from inception until March 2023 for studies that reported the outcomes of TAVR in BAV and tricuspid aortic valve patients. The primary focus was all-cause mortality at 1year. Additional outcomes included outcomes at 30-day follow-up. Secondary and subgroup analyses were performed on propensity-matched patients, patients at low surgical risk, and based on the type of transcatheter valve type. We included 30 studies with a total of 193,274 patients who underwent TAVR, of which 14,353 patients had BAV stenosis. The rate of 1-year mortality was lower in the BAV group compared with the tricuspid group with the results reaching statistical significance (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.75 to 0.98, p=0.02). The rate of 30-day stroke, however, was higher in patients with BAV who underwent TAVR (OR 1.24, 95% CI 1.08 to 1.43, p<0.05). Other 30-day clinical outcomes were similar between the 2 groups. Similar outcomes were observed in secondary analysis of matched populations with less mortality and higher rate of stroke in patients with BAV (OR 0.84, 95% CI 0.72 to 0.96, p=0.01, and OR 1.38, 95% CI 1.09 to 1.75, p<0.05, respectively). Comparing the outcomes for self-expandable and balloon-expandable valves resulted in similar results. Subgroup analysis of low-surgical-risk patients similarly showed lower 1-year mortality in patients with BAV (OR 0.67, 95% CI 0.50 to 0.91, p=0.01), without difference in 30-day stroke between the 2 groups (OR 1.24, 95% CI 0.83 to 1.88, p=0.30). In conclusion, this report indicates that TAVR is safe and feasible in patients with BAV, including patients at low surgical risk. The higher rate of 30-day stroke, however, warrants caution when pursuing TAVR in this population. More studies, specifically randomized trials, are still warranted to further assess the safety and the long-term outcomes in this group.

Strain estimation in aortic roots from 4D echocardiographic images using medial modeling and deformable registration.

Even though the central role of mechanics in the cardiovascular system is widely recognized, estimating mechanical deformation and strains in-vivo remains an ongoing practical challenge. Herein, we present a semi-automated framework to estimate strains from four-dimensional (4D) echocardiographic images and apply it to the aortic roots of patients with normal trileaflet aortic valves (TAV) and congenital bicuspid aortic valves (BAV). The method is based on fully nonlinear shell-based kinematics, which divides the strains into in-plane (shear and dilatational) and out-of-plane components. The results indicate that, even for size-matched non-aneurysmal aortic roots, BAV patients experience larger regional shear strains in their aortic roots. This elevated strains might be a contributing factor to the higher risk of aneurysm development in BAV patients. The proposed framework is openly available and applicable to any tubular structures.

The outcomes of three decades of the David and Yacoub procedures in bicuspid aortic valve patients-a systematic review and meta-analysis.

Valve-sparing aortic procedures, including the David and Yacoub procedures, have emerged as the dominant approaches in aortic aneurysm surgery, preserving the native aortic valve and thereby conferring significant prognostic benefits to the patient. Over the years, these procedures have also shown promise in patients with bicuspid valve-related aortopathy. This systematic review and meta-analysis presents the most up-to-date data on perioperative outcomes, freedom from secondary reoperation, and freedom from mortality for bicuspid valve patients undergoing valve-sparing aortic operations. The methods for this systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Four databases were searched, ultimately yielding 19 papers for inclusion, using appropriate search terminology. Meta-analysis using proportions or means, as appropriate, were applied. Kaplan-Meier curves were digitized and aggregated using previously validated techniques. A total of 1,159 patients were included. Males accounted for 87.4% of the cohort. The mean age of the cohort was 44.9 years. The mean aortic root diameter was estimated to be 46.3 mm, with an estimated range from 38 to 54 mm. Thirty-day mortality rate was estimated to be 1.7%. Eighty-five percent of patients in this series received the David approach, with the remainder receiving the Yacoub approach. Overall, there was low heterogeneity observed for the mean length of intensive care stay, while high heterogeneity was observed for the other remaining variables of interest. Kaplan-Meier survival estimation at 5, 10, and 15 years was 96%, 90%, and 87%, respectively. Kaplan-Meier freedom from secondary reoperation at 5, 10, and 15 years was 96%, 91%, and 88%, respectively. This review demonstrates the durability and safety of the David and Yacoub valve-sparing procedures across long-term follow-up in bicuspid aortic valve patients. These procedures offer significant freedom from mortality and secondary reoperations on the aorta and valve and will likely continue to demonstrate excellent results into the future. There is a clear transition towards the David procedure, with the bulk of contemporary literature publishing on this technique.

Intrinsic histological and morphological abnormalities of the pediatric thoracic aorta in bicuspid aortic valve patients are predictive for future aortopathy

BackgroundPatients with a bicuspid aortic valve (BAV) have an increased risk to develop aortic complications. Many studies are pointing towards a possible embryonic explanation for the development of both a bicuspid aortic valve as well as a defective ascending aortic wall in these patients. The fetal and newborn ascending aortic wall has however scarcely been studied in bicuspid aortic valve patients. We hypothesize that early histopathological defects might already be visible in the fetal and pediatric ascending aortic wall of bicuspid aortic valve patients, indicating at an early embryonic defect. MethodsNon-dilated BAV ascending aortic wall samples were collected (n = 40), categorized in five age groups: premature (age range 17.5 weeks + days GA till 37.6 weeks + days GA) 2. neonate (age range 1 – 21 days) 3. infant (age range 1 month – 4 years) 4. adolescent (age range 12 years – 15 years) and 5. adult (age range 41 – 72 years). Specimen were studied for intimal and medial histopathological features. ResultsThe premature ascending aortic wall has a significantly thicker intimal and significantly thinner medial layer as compared to all other age categories (p < 0.05). After birth the intimal thickness decreases significantly. The medial layer increases in thickness before adulthood (p < 0.05) with an increasing number of elastic lamellae (p < 0.01) and interlamellar mucoid extracellular matrix accumulation (p < 0.0001). Intimal atherosclerosis was scarce and medial histopathological features such as overall medial degeneration, smooth muscle cell nuclei loss and elastic fiber fragmentation were not appreciated in the BAV ascending aortic wall of any age. ConclusionsThe main characteristics of a bicuspid ascending aortic wall are already present before adulthood, albeit not before birth. Considering the early manifestations of ascending aortic wall pathology in bicuspid aortic valve patients, the pediatric population should be considered while searching for markers predictive for future aortopathy.

Lower incidence of new-onset severe conduction disturbances after transcatheter aortic valve implantation with bicuspid aortic valve in patients with no baseline conduction abnormality: a cross-sectional investigation in a single center in China.

With technological advancements, the incidence of most transcatheter aortic valve implantation (TAVI)-related complications, with the exception of conduction disturbances, has decreased. Bicuspid aortic valve (BAV) is also no longer considered a contraindication to TAVI; however, the effect of BAV on postoperative conduction disturbances after TAVI is unknown. We collected information on patients who met the indications for TAVI and successfully underwent TAVI at our center between January 2018 and January 2021. Patients with preoperative pacemaker implantation status or conduction disturbances (atrioventricular block, bundle branch block, and intraventricular block) were excluded. Based on imaging data, the patients were categorized into the BAV group and the tricuspid aortic valve (TAV) group. The incidence of new perioperative conduction disturbances was compared between the two groups. A total of 187 patients were included in this study, 64 (34.2%) of whom had BAV. The incidence of third-degree block in the BAV group was 1.6%, which was lower than that (13.0%) in the TAV group (P < 0.05). Multivariate logistic regression results showed that the risk of third-degree conduction disturbances was 15-fold smaller in the BAV group than that in the TAV group [relative risk (RR) = 0.067, 95% CI = 0.008-0.596, P < 0.05]. The risk of other blocks in the BAV group was about half of that in the TAV group (RR = 0.498, 95% CI = 0.240-1.032); however, the difference was not statistically significant (P > 0.05). The present study found that patients with BAV had a lower rate of third-degree conduction disturbances after TAVI than patients with TAV.

Lipoprotein(a) As a Potential Predictive Factor for Earlier Aortic Valve Replacement in Patients with Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) affects 0.5-2% of the general population and constitutes the major cause of severe aortic valve stenosis (AVS) in individuals ≤70 years. The aim of the present study was to evaluate the parameters that may provide information about the risk of AVS developing in BAV patients, with particular emphasis on lipoprotein(a) (Lp(a)), which is a well-recognized risk factor for stenosis in the general population. We also analyzed the impact of autotaxin (ATX) and interleukin-6 (IL-6) as parameters potentially related to the pathomechanism of Lp(a) action. We found that high Lp(a) levels (>50 mg/dL) occurred significantly more frequently in patients with AVS than in patients without AVS, both in the group below and above 45 years of age (p = 0.036 and p = 0.033, respectively). Elevated Lp(a) levels were also strictly associated with the need for aortic valve replacement (AVR) at a younger age (p = 0.016). However, the Lp(a) concentration did not differ significantly between patients with and without AVS. Similarly, we observed no differences in ATX between the analyzed patient groups, and both ATX activity and concentration correlated significantly with Lp(a) level (R = 0.465, p < 0.001 and R = 0.599, p < 0.001, respectively). We revealed a significantly higher concentration of IL-6 in young patients with AVS. However, this observation was not confirmed in the group of patients over 45 years of age. We also did not observe a significant correlation between IL-6 and Lp(a) or between CRP and Lp(a) in any of the analyzed groups of BAV patients. Our results demonstrate that a high level of Lp(a), greater than 50 mg/dL, may be a significant predictive factor for earlier AVR. Lp(a)-related parameters, such as ATX and IL-6, may be valuable in providing information about the additional cardiovascular risks associated with developing AVS.

Aortic regurgitation in bicuspid aortic valve: know to decide

Abstract Funding Acknowledgements Type of funding sources: None. Chronic aortic regurgitation (AR) is the second cause of valve surgery in patients with bicuspid aortic valve (BAV) and has distinctive characteristics of trileaflet regurgitation. The quantification variables of aortic regurgitation do not take into account the unique characteristics of bicuspid regurgitation. Recognition of the mechanisms that lead to bicuspid AR is relevant as it allows correct treatment planning and valve repair in candidate patients. Objective a prospective study was designed to identify the mechanisms of AR and the factors (clinical and anatomical) associated with the development of significant AR (moderate/severe) in adult patients with BAV. Materials and methods We included consecutive adult patients with a confirmed diagnosis of BAV evaluated between 2014 and 2021 with at least 3 years of follow-up by the Structural Heart Disease group of our institution. Valve disease was evaluated by echocardiography and complementary methods. It was classified as mild, moderate (Mod), and severe (Sev) aortic regurgitation, according to current criteria (integral approach with quantitative and semi-quantitative criteria). The prevalence of regurgitation mechanisms, the progression of aortic regurgitation, and predictive variables of significant AR and major cardiovascular events (death, surgery) were analyzed using univariate and multivariate analyses. A p&amp;lt;0.05 was considered significant. Surgery was indicated following international recommendations (ESC guidelines): symptoms development or ventricular dysfunction. Results We included 300 patients (39.7 ± 14.9 years, 72.6% men). Regarding valvular phenotype 84% (257p) presented fused BAV (coronary leaflets) and the majority with raphe (87.5%). 71.7% of the patients had some degree of aortic regurgitation at the start of follow-up (24.1% Mod/Sev AR). Among the patients with significant AR, 50% had cusp prolapse (86% prolapse of the fused leaflet), 39.18% dilatation of the aortic root, 26.6% significant calcification of the valve, 1.3% valve perforation and 29.4% restriction of valve movement. 43% with Mod/Sev AR had mixed mechanisms of regurgitation and the combination, half represented by the combination of aortic root dilatation and cusp prolapse (Fig 2). During follow-up 18–6% of patients with Mod AR showed progression to Sev AR and 4.7% underwent surgery. On the other hand, 34.1% of patients with baseline Sev AR required aortic valve surgery (p&amp;lt;0.01). Conclusions In our cohort, AR was highly prevalent: 1 out of 4 patients had significant AR at the start of follow-up. Eccentric jets and the presence of valve prolapse were frequent in patients with significant AR. 43% of BAV patients with Mod/Sev AR exhibited mixed regurgitating mechanisms. Because mechanism affects the choice of surgical technique, comprehensive mechanism description is critical in patients with BAV and AR.

Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades years earlier than in the general population. Current treatment for CAVD remains surgical replacement with its continued durability problems, as there are no pharmaceutical therapies or other alternative treatments available. Before such therapeutic approaches can be developed, a deeper understanding of CAVD disease mechanisms is clearly required. It is known that AV interstitial cells (AVICs) maintain the AV extracellular matrix and are typically quiescent in the normal state, transitioning into an activated, myofibroblast-like state during periods of growth or disease. One proposed mechanism of CAVD is the subsequent transition of AVICs into an osteoblast-like phenotype. A sensitive indicator of AVIC phenotypic state is enhanced basal contractility (tonus), so that AVICs from diseased AV will exhibit a higher basal tonus level. The goals of the present study were thus to assess the hypothesis that different human CAVD states lead to different biophysical AVIC states. To accomplish this, we characterized AVIC basal tonus behaviors from diseased human AV tissues embedded in 3D hydrogels. Established methods were utilized to track AVIC-induced gel displacements and shape changes after the application of Cytochalasin D (an actin polymerization inhibitor) to depolymerize the AVIC stress fibers. Results indicated that human diseased AVICs from the non-calcified region of TAVs were significantly more activated than AVICs from the corresponding calcified region. In addition, AVICs from the raphe region of BAVs were more activated than from the non-raphe region. Interestingly, we observed significantly greater basal tonus levels in females compared to males. Furthermore, the overall AVIC shape changes after Cytochalasin suggested that AVICs from TAVs and BAVs develop different stress fiber architectures. These findings are the first evidence of sex-specific differences in basal tonus state in human AVICs in varying disease states. Future studies are underway to quantify stress fiber mechanical behaviors to further elucidate CAVD disease mechanisms.

Feasibility of Wave Intensity Analysis from 4D Cardiovascular Magnetic Resonance Imaging Data

Congenital heart defects (CHD) introduce haemodynamic changes; e.g., bicuspid aortic valve (BAV) presents a turbulent helical flow, which activates aortic pathological processes. Flow quantification is crucial for diagnostics and to plan corrective strategies. Multiple imaging modalities exist, with phase contrast magnetic resonance imaging (PC-MRI) being the current gold standard; however, multiple predetermined site measurements may be required, while 4D MRI allows for measurements of area (A) and velocity (U) in all spatial dimensions, acquiring a single volume and enabling a retrospective analysis at multiple locations. We assessed the feasibility of gathering hemodynamic insight into aortic hemodynamics by means of wave intensity analysis (WIA) derived from 4D MRI. Data were collected in n = 12 BAV patients and n = 7 healthy controls. Following data acquisition, WIA was successfully derived at three planes (ascending, thoracic and descending aorta) in all cases. The values of wave speed were physiological and, while the small sample limited any clinical interpretation of the results, the study shows the possibility of studying wave travel and wave reflection based on 4D MRI. Below, we demonstrate for the first time the feasibility of deriving wave intensity analysis from 4D flow data and open the door to research applications in different cardiovascular scenarios.

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.

Apoptotic Cell Death in Bicuspid-Aortic-Valve-Associated Aortopathy.

The bicuspid aortic valve (BAV) is the most common cardiovascular congenital abnormality and is frequently associated with proximal aortopathy. We analyzed the tissues of patients with bicuspid and tricuspid aortic valve (TAV) regarding the protein expression of the receptor for advanced glycation products (RAGE) and its ligands, the advanced glycation end products (AGE), as well as the S100 calcium-binding protein A6 (S100A6). Since S100A6 overexpression attenuates cardiomyocyte apoptosis, we investigated the diverse pathways of apoptosis and autophagic cell death in the human ascending aortic specimen of 57 and 49 patients with BAV and TAV morphology, respectively, to identify differences and explanations for the higher risk of patients with BAV for severe cardiovascular diseases. We found significantly increased levels of RAGE, AGE and S100A6 in the aortic tissue of bicuspid patients which may promote apoptosis via the upregulation of caspase-3 activity. Although increased caspase-3 activity was not detected in BAV patients, increased protein expression of the 48 kDa fragment of vimentin was detected. mTOR as a downstream protein of Akt was significantly higher in patients with BAV, whereas Bcl-2 was increased in patients with TAV, assuming a better protection against apoptosis. The autophagy-related proteins p62 and ERK1/2 were increased in patients with BAV, assuming that cells in bicuspid tissue are more likely to undergo apoptotic cell death leading to changes in the wall and finally to aortopathies. We provide first-hand evidence of increased apoptotic cell death in the aortic tissue of BAV patients which may thus provide an explanation for the increased risk of structural aortic wall deficiency possibly underlying aortic aneurysm formation or acute dissection.

The effects of strain history on aortic valve interstitial cell activation in a 3D hydrogel environment.

Aortic valves (AVs) undergo unique stretch histories that include high rates and magnitudes. While major differences in deformation patterns have been observed between normal and congenitally defective bicuspid aortic valves (BAVs), the relation to underlying mechanisms of rapid disease onset in BAV patients remains unknown. To evaluate how the variations in stretch history affect AV interstitial cell (AVIC) activation, high-throughput methods were developed to impart varied cyclical biaxial stretch histories into 3D poly(ethylene) glycol hydrogels seeded with AVICs for 48 h. Specifically, a physiologically mimicking stretch history was compared to two stretch histories with varied peak stretch and stretch rate. Post-conditioned AVICs were imaged for nuclear shape, alpha smooth muscle actin (αSMA) and vimentin (VMN) polymerization, and small mothers against decapentaplegic homologs 2 and 3 (SMAD 2/3) nuclear activity. The results indicated that bulk gel deformations were accurately transduced to the AVICs. Lower peak stretches lead to increased αSMA polymerization. In contrast, VMN polymerization was a function of stretch rate, with SMAD 2/3 nuclear localization and nuclear shape also trending toward stretch rate dependency. Lower than physiological levels of stretch rate led to higher SMAD 2/3 activity, higher VMN polymerization around the nucleus, and lower nuclear elongation. αSMA polymerization did not correlate with VMN polymerization, SMAD 2/3 activity, nor nuclear shape. These results suggest that a negative feedback loop may form between SMAD 2/3, VMN, and nuclear shape to maintain AVIC homeostatic nuclear deformations, which is dependent on stretch rate. These novel results suggest that AVIC mechanobiological responses are sensitive to stretch history and provide insight into the mechanisms of AV disease.

Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1−1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1−/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.

Comparison of patients with bicuspid and tricuspid aortic valve in transcatheter aortic valve implantation

Background Transcatheter aortic valve implantation (TAVI) has emerged as a safe and effective alternative to surgery for aortic stenosis (AS). However, there are still differences in the procedural process and outcome of bicuspid aortic valve (BAV) treated with TAVI compared with tricuspid aortic valve. Areas covered This review paper aims to summarize the main characteristics and clinical evidence of TAVI in patients with bicuspid and tricuspid aortic valves and compare the outcomes of TAVI procedure. Expert opinion The use of TAVI in patients with BAV has shown similar clinical outcomes compared with tricuspid aortic valve. The efficacy of TAVI for challenging BAV anatomies remains a concern due to the lack of randomized trials. Detailed preprocedural planning is of great importance in low-surgical-risk BAV patients. A better understanding of which subtypes of BAV anatomy are at greater risk for adverse outcomes can potentially benefit the selection of TAVI or open-heart surgery in low surgical risk AS patients.

Methods: Aortic wall deformation assessment by ultrafast ultrasound imaging: Application to bicuspid aortic valve associated aortopathy.

Purpose: Aortic maximal rate of systolic distention (MRSD) is a prognosis factor of ascending aorta dilatation with magnetic resonance imaging. Its calculation requires precise continuous tracking of the aortic diameter over the cardiac cycle, which is not feasible by focused ultrasound. We aimed to develop an automatic aortic acquisition using ultrafast ultrasound imaging (UUI) to provide access to the aortic MRSD. Methods: A phased array probe and developed sequences at 2000 frames/s were used. A created interface automatically tracked the anterior and posterior aortic walls over the cardiac cycle. Tissue Doppler allowed a precise estimation of the walls' movements. MRSD was the maximum derivative of the aortic diameter curve over time. To assess its feasibility, 34 patients with bicuspid aortic valve (BAV) and 31 controls were consecutively included to evaluate the BAV-associated aortopathy at the sinus of Valsalva, the tubular ascending aorta, and the aortic arch. Results: UUI acquisitions and the dedicated interface allow tracking of the aortic diameter and calculating the MRSD for the BAV patients and controls (mean age of 34 vs. 43years, p = 0.120). A trend toward lower deformation in the different aortic segments was observed, as expected. Still, only the MRSD with UUI was significantly different at the sinus of Valsalva in this small series: (0.61 .103.s-1 [0.37-0.72] for BAV patients vs. 0.92 .103.s-1 [0.72-1.02] for controls, p = 0.025). Conclusion: Aortic deformation evaluated with UUI deserves attention with a simple and automated measurement technique that could assess the segmental aortic injury associated with BAV.

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.

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

BackgroundRecent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD).MethodsWe have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability.ResultsA total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4: p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4: c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development.ConclusionOur results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests.

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.