Bicuspid Aortic Valve

Hancock II porcine (Medtronic, Minneapolis, Minnesota, USA) (27 mm), n = 1 and Mitroflow (LivaNova, London, England) pericardial (21 mm), n = 1. The Ross group had a longer time interval between operation (often in child- hood) and imaging. We compared the valve replacement groups with 30 age- and sex-matched healthy subject co- hort and 30 un-operated bicuspid aortic valve patients matched to the post-operative peak velocity values of the AVR group. All of these control patients participated in our initial cohort study [4]. A sub-group of 16 BAV pa- tients also had CMR assessment both pre- and post- operatively, allowing comparison of flow patterns before and after AVR. Thirteen of these patients participated in our initial cohort study [4] prior to their valve replace- ment. The study complies with the declaration of Helsinki and was approved by the West Berkshire ethics commit- tee. All participants gave written informed consent.

Congenital bicuspid aortic valve (BAV) is the most com- mon type of cardiac malformation, with an estimated prevalence of 1-2% in the general population [1]. BAV, in which two of the three normal aortic cusps are fused together, encompasses a wide spectrum of clinical phe- notypes. The valve abnormality may be isolated in some cases, whereas in others the aortic valve abnormality is present in conjunction with other cardiac malformations [2]. BAV may also be associated with varying degrees of aortic valve stenosis and/or insufficiency as well as with aortopathy. Among BAV patients, there is variability in cusp fusion phenotypes. Right coronary and left coron- ary (R-L) cusp fusion is more common than right coron- ary and non-coronary (R-NC) cusp fusion. Moreover, R-L cusp fusion is more often associated with add- itional cardiac malformations, whereas R-NC cusp fu- sion is more likely to be associated with aortic valve dysfunction [3]. The etiologies of these associations are unknown.

Objective: To find out, whether the degenerative process of ascending aorta is limited to the aortic sinuses only or is extending to mid and distal ascending aorta of Bicuspid Aortic Valve patients. Method: A prospective consecutive study on 25 patients of BAV (undergoing aortic valve with ±ascending aortic surgeries) was conducted from 1st Jan 2010 to 30th Dec 2011. Morphological and anatomical data of root and ascending aorta were recorded from echocardio- graphy and computed tomography angiography. Intra-operatively, aortic tissue biopsy taken from three sites: sinus, mid, and distal ascending aorta. Histological evaluation of the aortic wall was based on criteria adapted from Schlatmann and Becker and from de Sa et al. The presence and degree of the 5 variables of degeneration were studied: Linear regression and correlation were used to get relationship between histopathological scoring (HPE-T) and aortic diameter for each site of ascending aorta. Results: Significant linear relation was found between aortic sinus diameter and HPE T score with R value = 0.590 (p value 0.001) and variance of 37.5%. Analysis suggests that HPE T Score = −5.139 + (0.188× Ao. Sinus Diameter in mm). No significant linear relation could be established between mid and distal ascending aorta diameter and HPE T scoring. Conclusion: In BAV patients, a definite relationship between degenerative changes of aortic media and aortic diameter was found and was limited up to the sinus level only. Thus, the study reinforces the thought of replacing aortic sinus too while dealing with aortic valve, even without significant dilatation. By this aggres- sive management of aortic root, progression of aortic dilatation or dissection can be prevented in bicuspid aortic valve patients.

Bicuspid aortic valve (BAV) is a heritable condition, in which the aortic valve has only two leaflets. With this deformity, the valve’s function is usually impaired and the entity is associated with significant morbid- ity including aortic valve stenosis or regurgitation, as well as dilatation, aneurysm, and dissection of the ascending aorta (AA). Based on the fusion pattern of

Bicuspid aortic valve disease (BAV) is commonly associated with aortopathy which may be in part hemodynamically mediated (1). BAV is known to cluster in families (up to 25% family members affected) (2). Due to this increased incidence in first degree relatives (FDR), many clinicians will screen these. Furthermore, FDR of BAV patients might also have aortic dilation, despite a tricuspid aortic valve (TAV) (3, 4). We therefore examined FDR for evidence of aortic dysfunction. We also examined BAV fusion type in FDR as animal models suggest that fusion type may be genetically determined (5).

The bicuspid aortic valve (BAV) is a major congenital valvular abnormality and is associated with a high prevalence of aortic dilation, whose expression depends on the type of leaflet fusion. Al- though BAV hemodynamics is considered a potential pathogenic contributor, the impact of BAV fusion on ascending aorta (AA) wall shear stress (WSS) remains largely unknown. A fluid-struc- ture interaction approach was implemented to predict the hemodynamics and WSS characteristics in realistic AA models subjected to the flow of a normal tricuspid aortic valve (TAV) and three BAV morphotypes (left-right coronary cusp fusion (LR), right-non coronary cusp fusion (RN) and non- left coronary cusp fusion (NL)). TAV flow conditions subjected the proximal and middle AA to a streamlined flow typical of flows in bends, while BAV flow conditions generated increased flow helicity. The LR-BAV orifice jet generated flow abnormalities primarily in the proximal AA, which were marked by a uniform WSS overload along the wall circumference and contrasted WSS direc- tionalities on the wall convexity and concavity. Flow abnormalities generated by the RN-BAV and NL-BAV inlet flow conditions were more diffuse and consisted of WSS overloads in the convexity of the proximal and middle AA and contrasted WSS directionalities in the anterior and posterior wall regions. This study demonstrates the impact of the BAV morphotype on AA hemodynamics and provides quantitative evidence for the existence of WSS abnormalities in aortic wall regions prone to dilation.

outflow tract view (RVOT) evaluation of the aortic valve revealed a bicuspid aortic valve (Fig. 3; Video Clip S3). Parasternal short axis view at the level of the papillary muscles showed right ventricular pressure and volume overload with a D-shaped left ventricle present during both systole and diastole and a large dilated right ventricle (Fig. 4; Video Clip S4). Color Doppler evaluation of the tricuspid valve in the right ventricular inflow tract view (RVIT) revealed tricuspid regurgitation (Fig. 5; Video Clip S5). In

An overlap of 4 cm between the Gore endograft and the 26 mm Terumo graft was secured. At least 8 cm of overlap was also assured between the two separate endografts. After de-airing, aortic clamp was applied proximal to the debranching 14 mm Terumo graft. Perfusion to the distal body with systemic rewarming was initiated. The ascend- ing aorta was excised at the level of the sinotubular junc- tion and send to pathology. The bicuspid aortic valve was reconstructed using subcommissural annuloplasty tech- nique performed with 4–0 Prolene pledgeted felt sutures. A second piece of 26 mm Terumo graft was used to re- place the ascending aorta. The anastomosis at the sinotub- ular junction was created in end-to-end manner using 4– 0 Prolene suture. After adequate tailoring, required be- cause of the cardiac dextrorotation with abnormal pos- ition for the aortic root (very deep in the posterior mediastinum), the neo-ascending aorta was anastomosed to the neo arch with 4–0 Prolene suture in a running fash- ion (Fig. 2). After de-airing, the aortic cross clamp was re- moved. The patient was subsequently weaned off from cardiopulmonary bypass without difficulties. Time of cir- culatory arrest was 28 min. Cross-Clamp time was 95 min and cardio-pulmonary bypass time was 170 min. For car- dioprotection, we utilized Del Nido solution delivered in retrograde fashion through the coronary sinus.

Bicuspid aortic valve (BAV) is the most common type of congenital cardiac malformation. Patients with a BAV have a predisposition for the development of thoracic aortic aneurysm (TAA). This pathological aortic dilation may result in aortic rupture, which is fatal in most cases. The abnormal aortic morphology of TAAs results from a complex series of events that alter the cellular structure and extracellular matrix (ECM) composition of the aortic wall. Because the major degeneration is located in the media of the aorta, most studies aim to unravel impaired smooth muscle cell (SMC) function in BAV TAA. However, recent studies suggest that endothelial cells play a key role in both the initiation and progression of TAAs by influencing the medial layer. Aortic endothelial cells are activated in BAV mediated TAAs and have a substantial influence on ECM composition and SMC phenotype, by secreting several key growth factors and matrix modulating enzymes. In recent years there have been significant advances in the genetic and molecular understanding of endothelial cells in BAV associated TAAs. In this review, the involvement of the endothelial cells in BAV TAA pathogenesis is discussed. Endothelial cell functioning in vessel homeostasis, flow response and signalling will be highlighted to give an overview of the importance and the under investigated potential of endothelial cells in BAV-associated TAA.

Bicuspid aortic valve (BAV) disease is the most common congenital cardiac malformation affecting 1–2% of the population [1, 2]. BAV occurs when the aortic valve forms with just two leaflets (or cusps), rather than the normal three (tricuspid aortic valve; TAV). Although be- tween 30 and 80% of patients with BAV disease will de- velop clinically significant enlargement of the ascending aorta, predictors of aortic dilation are lacking [3, 4]. The consequences of undiagnosed or rapidly progressive aneurysm can be severe, with rupture and dissection fre- quently being fatal. There is ongoing controversy regard- ing optimal timing of ascending aortic surgery for patients with BAV disease [5, 6]. Current guidelines are limited to measurement of ascending aortic diameter and the extent of aortic valve disease when planning sur- gery for aortic aneurysm in BAV patients [7]. An ability to predict which BAV patients will develop ascending aortic aneurysm would allow better individualisation of treatment and help prevent the potentially catastrophic complications of rupture and dissection.

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, occurring in 1%–2% of the population (1). It is generally diagnosed in adulthood when deterioration of the abnormal leaflets becomes clinically evident, with affected individuals developing valve disease 10 years earlier than those with normal aortic valve (AV) leaflets. Patients with BAV are at increased risks of developing serious complications, including aortic stenosis, aortic regurgitation, and endocarditis; one-third of these patients will in fact develop significant cardiovascular complications, and many will require surgical interventions. Population studies have suggested that BAV may be responsible for more mortality and morbidity than all other congenital heart diseases (CHDs) combined (2). Despite this, our understanding of the mechanisms underlying BAV formation remains limited. BAVs occur either in isolation or in association with other mal- formations, such as coarctation of the aorta, ventricular septal defects, and hypoplastic LV (3–5). Genetic studies have estab- lished that BAV is a highly heritable trait with autosomal-domi- nant transmission and incomplete penetrance (6, 7). Thus far, only 1 gene, NOTCH1, has been linked to BAV in humans, with mutations found in some but not all BAVs (8, 9). Genome-wide scans have suggested linkages to several human chromosomal regions, but no other disease-causing genes have yet been identi- fied (10). In animal models, BAVs have been found in a subset of mice lacking endocardial nitric oxide synthase (Nos3) or the

According to our data in the BAV group, some pa- tients, who have AAo diameters of less than 4.5 cm, did indeed have relatively higher AAo/DAo ratios. Dvies et al. concluded that BAV patients had a higher rate of aortic growth than TAV patients [9] and there is increas- ing evidence that an aortic dilatation in patients with BAV occurs irrespective of valve function [6,7,10]. In consideration of these studies, these patients who are in- dicated for an AVR procedure might need an additional surgical aortic intervention. Because ascending aortic dilatation may progress even after successful AVR [11], close follow-up care is prudent for BAV patients with high AAo/DAo ratios after isolated AVR. Furthermore, our data indicated that this index is also useful for predict- ing the existence of BAV when the preoperative diagnosis of BAV by echocardiography or magnetic resonance im- aging is uncertain.

taken as a golden standard for the diagnosis of BAV as well as severity of the morphology of the aortic valve and the ascending aorta. The short- axis view is used to examine commissures, leaflet morphology, mobility, and the presence or ab- sence of a low raphe. Therefore, the diagnosis of a BAV is based on the clear demonstration of two cups and two commissures in systole and diasto- le in the short-axis view. However, the short-axis view in some cases may present as almost normal because of a fused raphe in the middle of one of the two leaflets. Moreover, BAV may show a dom- ing configuration in the long-axis view during sys- tole [71]. However, a false positive diagnosis may result from an unclear follow-up [36]. The sensi- tivity, specificity, positive predictive value, and negative predictive value for the detection of a BAV were 76.5%, 60.6%, 68.4%, and 95.2%, respectively, for echocardiography and 94.1%, 100%, 100%, and 97.1%, respectively, for com- puted tomography. The computed tomographic findings were not significantly different from the intraoperative findings, but the echocardiographic findings were [90]. Both cardiac computed tomog- raphy and MRI now offer a valuable adjunct for accurate diagnosis of BAV. The absence of three cusps forming a ”Y” configuration of the tricus- pid aortic valve is suggestive of the diagnosis of a BAV [81]. Multi-detector computed tomographic (MDCT) features of uneven cusp size, round- shaped opening, midline calcification, longer leaf- let fusion, and larger diameter of the ascending aorta can be helpful in distinguishing BAVs from tricuspid aortic valves [46].

We recently reported that the zinc-finger transcription factor Krox20 (Egr2 – Mouse Genome Informatics) is a crucial activator of fibrillar Col1a1 and Col3a1 genes during valve development (Odelin et al., 2014). Here, we provide evidence that post-otic NCCs expressing Krox20 migrate through the 3rd pharyngeal arch to later invest murine arterial valves. Previous studies have shown that Krox20 is transcribed in r3 and r5, but not in other part of the neural tube, and that its deletion results in alteration of the antero-posterior positional identity of r3 and r5 (Schneider-Maunoury et al., 1993; Wilkinson et al., 1989). Using various transgenic mouse lines, we compared neural crest origins and showed segregated distribution of their derivatives in the arterial valve leaflets. Loss of Krox20 function results in abnormal development of the aortic valve, which in 30% generates a BAV phenotype. Similar defects are observed in neural crest Krox20-deficient embryos. Genetic fate-mapping analysis in Krox20 −/− showed that additional neural crest- derived cells are found in the leaflets of the aortic valve. In addition, we used different transgenic mice to examine the contribution of pre-otic and post-otic NCCs in aortic valve development. Our study identifies an essential role for Krox20-expressing NCCs during arterial valve formation and disease.

tricuspid aortic valve) and the presence of LVNC criteria according to the three methods. The results of the univar- iable and multivariable analyses are presented in table 3. In univariable analyses, BAV was associated with a lower likelihood of presenting LVNC according to Petersen et al (OR=0.38, 95% CI 0.19 to 0.77; p=0.007) and Fazio et al’s (OR=0.34, 95% CI 0.17 to 0.68; p=0.002) LVNC criteria. In the multivariable model (model 1, table 3) adjusted for age and sex, BAV was significantly and inversely asso- ciated with the presence of Fazio et al’s LVNC criterion (OR=0.40, 95% CI 0.17 to 0.91; p=0.03). With further adjustment for valve dysfunction (stenosis or regurgita- tion more than mild) (model 2, table 3), BAV remained associated with a lower prevalence of LVNC using Fazio et al’s criterion (OR=0.33, 95% CI 0.13 to 0.83; p=0.02). Finally, with an adjustment for age, sex, valve dysfunction, indexed LVM, LVEDVi and LVEF (model 3, table 3), BAV still remained inversely associated with Jenni et al’s crite- rion (p=0.04), Fazio et al’s criterion (p=0.004) and all three criteria (p=0.04).

diastolic diameter (LVEDd), left ventricle end-systolic diameter (LVESd), left atrium (LA) and aortic root (Ao) dimensions, pulse wave Doppler transmitral flow E-wave, A-wave (E/A ratio), deceleration time (DT), isovolumic relaxation time (IVRT) were calculated. The diastolic function assessment was completed analyzing the E/E’ ratio result by the Tissue Doppler Imaging (TDI) method (Galderisi et al., 2004). The evaluation of left ventricular Cardiac Mass Index g/m2 (CMI) was obtained from Devereux procedure (Devereux et al., 1987). Considering the regular shape of the myocardial chamber the Ejection Fraction (EF %) was calculated by left ventricular end-diastolic diameter, left ventricular end-systolic diameter following the formula (LVEDd–LVESd)/LVESd. The degree of the valve insufficiency was described in first line as a visual assessment determining the extension of the regurgitating jet on a 0 to 4+ scale by the colour-flow mapping method from the four-chamber view and according to the guidelines (Douglas et al., 2011). In addition a more quantitative approach to identify the subjects with mild AR jet was performed by the vena contracta value calculated from parsternal-long axis view (Lancellotti et al., 2010), just to exclude subject with a severe aortic regurgitation.

This was a longitudinal single- centre retrospective study. Consecutive BAV patients (n = 521) were identified in the cardiovascular magnetic resonance (CMR) imaging data- base between 2009 and 2017, of which 182 patients had CMR scans at two or more time- points before AVR. When patients had more than two scans available, the least and the most recent were considered. Exclusion criteria included: suboptimal image quality (n=7), unconfirmed bicuspid morphology (n=6, even after consulting trans- thoracic/trans- oesophageal echocardiography or CT angiography when in doubt), degenerative aortic valve (n=1), concomitant either moderate or complex CHD (n=2 Shone’s complex, n=2 Tetralogy of Fallot and n=1 Epstein’s anomaly), connective tissue disorders (n=1 Marfan, n=10 Turner and n=1 Ehlers Danlos syndromes, confirmed by genetic results), other diseases (n=1 pseu- do- CoA, n=1 Kawasaki disease), unrepaired CoA (n=6) and surgeries structurally affecting the aortic valve and/ or the aorta (n=1 aortic valvotomy and n=1 aortic arch reconstruction). A flowchart is provided in figure 1. All CMR data were acquired at 1.5 T (Avanto, Siemens Healthineers, Erlangen, Germany). Demographic and functional variables were collected from CMR reports, including age, height, sex, aortic valve morphology,

The participants included in this study belong to a cohort of prospective patients with BAV that were followed-up in our facilities. Upon enrolment, the participants were prospectively entered into a specific database, underwent a blood draw and provided informed written consent. The samples were stored until needed in our biological sample bank (Biobanc IISPV-HUSJR). BAV diagnosis was made when two aortic leaflets were clearly visualized, with or without a raphe, either on the parasternal short- axis view of a transthoracic echocardiogram [16], on a transesophageal echocardiogram [16] or on a cardiac magnetic resonance [17]. Explorations were performed or supervised by the same observer (JMA). This study was approved by the Institutional Review Board (the Clinical Ethics Committee) of our institution.

In patients with suitable morphology of the diseased valve (typically only patients with aortic regurgitation), repair of the aortic valve is a desirable option. The development of aortic valve repair as an alternative to replacement has been driven by potential bene fi ts of preserving the native valve, which include avoiding anticoagulation medications and fewer complications of the operated valve. 4 5 However, evidence published to date has been limited to relatively small case series. Previous systematic reviews on valve repair provided little information on the ef fi - cacy and safety of this intervention in patients with BAVD. 6 7 In recent years, several world-leading centres have published their growing experience with aortic valve repair with large sample sizes. Including this newly available information, our aim in this study was to synthesise all available evidence on immediate and long-term outcomes after aortic valve repair in patients with BAVD.

it was assumed that echocardiogra- phy detects BAV 80% of the time and that detection of BAV leads to surveil- lance, exercise restriction, or surgery to avert aortic dissection. With ap- propriate management, all dissec- tions could be prevented. The analysis is limited to a 20-year time frame. Because early detection will result in periodic outpatient cardiology follow- up, our model assumes that patients are seen every 2 years and that this assessment includes a limited echo- cardiogram with each visit. The cost of the follow-up visit (Current Proce- dural Terminology 99214) and limited echocardiogram (Current Procedural Terminology 93304) are $96.01 and $101.77, respectively. In the scenario where routine echocardiographic screen- ing is not routinely used, we assumed that 50% of siblings would be identi fi ed by age 20 years.