Case Of Bicuspid Aortic Valve Research Articles

1040 Morphometric Study of Human Aortic Valve Along with a Case of Bicuspid Aortic Valve in Cadaver

Abstract Aim The morphometric data pertaining to the aortic valve is very relevant for aortic valvular diseases and prosthetic valve transplant thereof, but such data is variably described in autopsy studies which prompted us to study the same in cadaveric hearts of Indian population. We also present a case of symmetrical bicuspid aortic valve (BAV). Method Thirty formalin fixed cadaveric hearts of both genders, aged between 58 -83 years were taken. Guidelines for using cadaver for teaching and research were followed. Various attributes of the aortic valve viz. number, width and height of cusps, number and depth of aortic sinuses, number of coronary ostia were recorded. All measurements were made with Vernier callipers and statistical analysis was performed with Microsoft Excel version 2019. Results The mean cusp heights were 18.28±0.54 mm, 19.52±0.34 mm and 20.91±0.46 mm respectively for the right, left and the non-coronary cusps. The mean depths of the aortic sinuses were 17.3±0.68 mm, 16.8±0.74 mm and 15.9±0.32 mm respectively for the right, left and the non-coronary sinus. We also observed symmetrical BAV in 1 (2.5%) out of the 30 specimens but the death of the individual was unrelated to the presence of the anomaly. Conclusions The morphometric parameters obtained in the study would help in transplanting prosthetic aortic valve with greater compatibility. The chance of encountering congenital BAV even in individuals with no cardiac ailment should be borne in mind.

Transcatheter aortic valve replacement in the treatment of bicuspid aortic stenosis with "down-size" interventional valves: procedural and mid-term follow-up.

Due to the influence of anatomical structure, replacing the bicuspid valve using transcatheter aortic valve replacement (TAVR) would increase the risk of perivalvular leakage and conduction block, affecting the hemodynamic effect of the interventional valve. In this study, for bicuspid and tricuspid valves, we implemented different valve selection strategies to explore the safety and effectiveness of TAVR in the treatment of bicuspid aortic stenosis with "down-size" interventional valves using the VenusA-valve system. The operation was performed with the VenusA-valve via transfemoral approach. The selected valves were appropriately sized based on the results of transthoracic echocardiography (TTE), contrast-enhanced computed tomography (CT), and the morphology of intraoperative pre-dilation balloons. For tricuspid valve cases, the VenusA valve is usually larger than the annulus diameter, whereas the "down-size" approach was adopted for bicuspid aortic valve (BAV) cases. The shape of the pre-dilation balloon allowed further sizing of the annulus diameter by the degree of lumbar constriction of the balloon, aiding in intervention valve size selection, particularly in cases of BAVs. A total of 65 patients underwent TAVR for aortic stenosis with VenusA-valve systems. Of these, 29 cases had a BAV and 36 cases had a tricuspid aortic valve (TAV). The distribution of VenusA-valve sizes differed between TAV and BAV cases (P=0.007). Furthermore, there was a significant decrease in the average mean gradient in TAV patients from 54.7 to 12.2 mmHg (P<0.001), and in BAV patients from 61.6 to 14.3 mmHg (P<0.001). The percentage of paravalvular leakage greater than mild was 6.90% in the BAVs and 5.56% in the TAVs at procedural outcomes (P=0.955). The mean follow-up period was 22.23 months (range, 12 to 39 months). The proportion of New York Heart Association (NYHA) class III/IV decreased from 78.5% preoperatively to 11.3% at the last follow-up (P<0.001). A total of 27 patients with TAV and 19 patients with BAV underwent TTE at 1-year follow-up after operation. There was no significant contrast in the average pressure difference between TAVs and BAVs at 1-year follow-up (11.9 vs. 14.3 mmHg, P=0.18). The VenusA-valve for TAVR produced positive clinical outcomes and valve functionality in both BAVs and TAVs. In the case of BAVs, selecting a smaller interventional valve size was deemed viable.

Patient-specific computer modelling to predict anatomical risk factors preventing post transcatheter aortic valve implantation coronary re-access in bicuspid aortic valve; a modelling study

Abstract Background Post Transcatheter aortic valve implantation (TAVI) coronary re-access is predicted to become more common as TAVI expands into lower risk cohorts. The use of a self-expanding valve (SEV) has been recognised as an independent predictor for unsuccessful coronary cannulation. Other predictors include reduced transcatheter heart valve (THV) to coronary distance and small sino-tubular junction. Despite this however a patient cohort remains in which the use of a SEV is preferable due to anatomical complexity or extensive calcification. Purpose Using patient-specific computer modelling, we aimed to assess how the deployment of different sized THVs and at different depths affected the distance from valve to coronary and valve to sino-tubular junction in bicuspid aortic valve cases. Methods In this modelling study we have used pre-procedural, CT-derived, patient-specific finite element analysis computer models to predict the eventual valve result. We studied two anatomical measures for both right and left coronary sinuses. The distance from coronary ostium to nearest structure, either THV or displaced native leaflet – Sinus of Valsalva (SoV) free space. The second distance was from the STJ to THV – STJ free space. THVs were modelled at both high and medium implant positions. THV size was based upon annular dimensions. Where the annular dimensions fell near an anatomical grey-zone, a second size THV was modelled. For each patient and measure, a mean of all distances was calculated, in addition to both minimum and maximum distances. Results The free space SOV left main coronary artery (LMCA) mean was 6.39 mm (4.87-7.91 mm). The difference between maximum and minimum was 0.9461 mm (0.54–1.36 mm), p&amp;lt;0.01. The largest patient-specific difference between minimum and maximum was 2.41 mm, using the same THV size but at different depths. The free space SOV right coronary artery (RCA) mean was 5.73 mm (4.17-7.30 mm). The difference between maximum and minimum was 0.789 mm (0.49-1.09 mm), p&amp;lt;0.01. The STJ free space LMCA mean was 4.3 mm (2.35–6.27 mm), The difference between maximum and minimum was 0.99 mm (0.63-1.35 mm), p&amp;lt;0.01. The STJ free space RCA mean was 3.76 mm (2.2-5.32 mm).The difference between maximum and minimum was 1.18 mm (0.9-1.56 mm), p&amp;lt;0.01. The largest patient-specific difference between minimum and maximum was 2.02 mm, using the same valve size but at different depths. Data presented as mean (95% confidence intervals), n=16 patients/48 models. Conclusions This modelling study has indicated a significant difference in all four measured parameters when different THVs are modelled at different depths. Note some of the largest differences are seen with the same size THV but at a different depth. We would highlight the small mean effect size seen across the results, however in cases where the difference is &amp;gt;2mm, this could have an effect on coronary re-access and warrants further investigation.

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.

Abstract 15501: Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve

Introduction: Bicuspid Aortic Valve (BAV), the most common adult congenital heart defect, is a major cause of aortic insufficiency or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications to sporadic late onset disease. We determined the frequency and gene content of rare genomic copy number variants (CNVs) in isolated BAV cases. Methods: We performed genome-wide SNP microarray analysis of familial BAV cases with early onset complications in the UTHealth BAV Research Registry (EBAV, n=394) and elderly probands from the International BAV Consortium (BAVCON, n=4216). CNVs were detected in Illumina genotypes using the PennCNV, QuantiSNP and cnvPartition algorithms. BAV cases were compared to 16,576 controls without known cardiovascular disease from the Database of Genotypes and Phenotypes. Only CNV calls with &gt;6 consecutive variants, &gt;20 kb in length, identified by at least two algorithms and intersected with known genes were included. For comparison, we assessed a cohort with left ventricular outflow tract obstructive lesions including BAV (LVOTO, n=1561) using identical methods. CNV burden and associations were tested using PLINK. Results: We identified 84 large recurrent CNVs in BAV cases that are absent or rare (&lt;0.1%) in controls. 34 rare CNVs overlap between BAV and LVOTO cases and involve candidate genes that interact with each other during heart development. The largest and most prevalent of the recurrent CNVs are 8p23 duplications involving GATA4 (OR 340, CI: 42-2700). CNVs of genes that cause BAV when mutated were significantly enriched in cases (n=135, P =1x10 -27 ). The overall burden of rare genic CNVs, specifically large deletions, was also increased in BAV cases (empiric P &lt; 1x10 -5 ) and was higher in younger EBAV cases than in older BAVCON cases. Conclusion: We identified likely pathogenic CNVs in more than 10% of BAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

Family screening in patients with isolated bicuspid aortic valve : Restriction to those with aortic dilatation is not justified.

AimTo determine the prevalence of undiagnosed bicuspid aortic valve (BAV) and isolated aortic dilatation in first-degree relatives (FDRs) of patients with isolated BAV and to explore the recurrence risk of BAV in different subgroups of probands with BAV. Recent American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines recommend family screening in patients with associated aortopathy only.MethodsDuring follow-up visits, patients with isolated BAV received a printed invitation for their FDRs advising cardiac screening.ResultsFrom 2012–2019, 257 FDRs of 118 adult BAV patients were screened, among whom 63 (53%) index patients had undergone aortic valve surgery (AVS), including concomitant aortic replacement in 25 (21%). Of the non-operated index patients, 31 (26%) had aortic dilatation (> 40 mm). Mean age of the FDRs was 48 years (range 4–83) and 42% were male. The FDR group comprised 20 parents, 103 siblings and 134 offspring. Among these FDRs, 12 (4.7%) had a previously undiagnosed BAV and 23 (8.9%) had an isolated aortic dilatation. FDRs of the probands with previous AVS (n = 147) had a risk ratio for BAV of 2.25 (95% confidence interval (CI) 0.62–8.10). FDRs of the probands with BAV and repaired or unrepaired aortic dilatation (n = 127) had a risk ratio for BAV of 0.51 (95% CI 0.16–1.66).ConclusionScreening FDRs of patients with isolated BAV resulted in a reasonable yield of 14% new cases of BAV or isolated aortic dilatation. A trend towards an increased risk of BAV in FDRs was observed in the probands with previous AVS, whereas this risk seemed to be diminished in the probands with associated aortic dilatation. This latter finding does not support the restrictive ACC/AHA recommendation.

Junctional Pacemaker May Replace the Sinoatrial Node

Junctional rhythm is usually seen in the clinic with different causes. We report a case of bicuspid aortic valve accompanied by sinoatrial node dysfunction. The junctional escape beat could accelerate with physiological needs and provided for the normal needs of daily life when dysfunction of the sinoatrial node occurred, which provides a new way for the treatment of sinoatrial node dysfunction. Our findings could be potentially significant for identifying causes and choosing appropriate treatment strategies by using ECG monitoring in the clinic in the future.

A rare case of bicuspid aortic valve with blood cyst.

A rare case of bicuspid aortic valve with blood cyst.

Bicuspid aortic valve infective endocarditis and aortic root abscess presenting initially as splenic infarctions

Infective endocarditis (IE) commonly complicates bicuspid aortic valve. We report an uncommon case of bicuspid aortic valve (BAV) IE with aortic root abscess (ARA), presenting initially with abdominal pain due to splenic infarcts, delaying prompt diagnosis. A 38-year-old gentleman presented with fever and abdominal pain. He was treated for intra-abdominal sepsis, was started on intravenous antibiotics and had a computed tomography scan of the abdomen that revealed a large splenic infarct. The patient deteriorated, prompting further investigations, including echocardiography due to findings of a new murmur, signs of embolisation and blood cultures revealing Staphylococcus aureus. This revealed an otherwise unknown BAV with aortic valve vegetation and ARA. IE and ARA commonly affect patients with bicuspid aortic valve, and our case highlights the importance of systemic review, as IE often manifest clinically in various forms.

Approach to Asymptomatic Case of Bicuspid Aortic Valve with Coarctation and Massive Aortic Arteriopathy: a Ticking Time Bomb

The combination of aortic coarctation (CoA) and bicuspid aortic valve (BAV) is associated with high risk of ascending aortic dilatation and type A aortic dissection. Most of the patients having combined lesions remain asymptomatic until adulthood and are incidentally diagnosed. Several questions regarding their treatment strategies remain unanswered. Both single-and two-stage surgical procedures have been described in medical literature, to treat CoA and BAV. Lately, combined endovascular therapy (Balloon angioplasty or Stent implantation) and surgery, has become a good alternative in selected cases. Here, we describe such a asymptomatic case of BAV with massive aneurysmal root dilatation and CoA, which was managed with endovascular stenting and surgery.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) &lt; 1%, Combined Annotation Dependent Depletion (CADD) scores &gt; 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) &gt; 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF&lt;5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis.

Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities. We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography. Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models. These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.

Deregulation of TLR4 signaling pathway characterizes Bicuspid Aortic valve syndrome

Bicuspid aortic valve (BAV) disease is recognized to be a syndrome with a complex and multifaceted pathophysiology. Its progression is modulated by diverse evolutionary conserved pathways, such as Notch-1 pathway. Emerging evidence is also highlighting the key role of TLR4 signaling pathway in the aortic valve pathologies and their related complications, such as sporadic ascending aorta aneurysms (AAA). Consistent with these observations, we aimed to evaluate the role of TLR4 pathway in both BAV disease and its common complication, such as AAA. To this aim, 70 subjects with BAV (M/F 50/20; mean age: 58.8 ± 14.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M/F 35/35; mean age: 69.1 ± 12.8 years), with and without AAA were enrolled. Plasma assessment, tissue and gene expression evaluations were performed. Consistent with data obtained in the previous study on immune clonotypic T and B altered responses, we found reduced levels of systemic TNF-α, IL-1, IL-6, IL-17 cytokines in BAV cases, either in the presence or absence of AAA, than TAV cases (p < 0.0001 by ANOVA test). Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p < 0.0001 by ANOVA test). These results may suggest a deregulation in the activity or in the expression of TLR4 signaling pathway in all BAV cases. Portrait of these data is, indeed, the significantly decreased gene expression of inflammatory cytokines and TLR4, in both normal and aneurysmatic tissue samples, from BAV with AAA than TAV with AAA. In conclusion, our study demonstrates that subjects with BAV display a significant deregulation of TLR4 signaling pathway paralleled by a deregulation of Notch-1 pathway, as previously showed. This data suggests that the crosstalk between the Notch-1 and TLR4 signaling pathways may play a crucial role in both physiological embryological development, and homeostasis and functionality of aortic valve in adult life.

Ruptured Aneurysm of Sinus of the Valsalva: Case Series

Introduction: We present three cases of ruptured sinus of Valsalva aneurysm concomitant with a cardiac lesion in 2 cases of ventricular septal defect and 1 case of bicuspid aortic valve with mild aortic insufficiency. Case presentation: In 2/3 cases, the site of ruptured sinus of Valsalva aneurysm originated from right coronary cusps and one from non-coronary cusps. Both ruptured sinus of Valsalva aneurysm from right coronary cusps communicated to right ventricle, and one that originated from non-coronary cusps ruptured to right atrium. All cases were diagnosed by transthoracic echocardiography and confirmed by transesophageal echocardiography. Two underwent the surgery, while one did not want to continue treatment. Conclusion: ruptured sinus of Valsalva aneurysm is a rare cardiac anomaly. In the Eastern countries, the most common associated anomalies with ruptured sinus of Valsalva aneurysm are ventricular septal defect and aortic regurgitation. Ruptured sinus of Valsalva aneurysm mainly originates from right coronary cusps and is ruptured into right ventricle. Transthoracic echocardiography and transesophageal echocardiography are employed to confirm the diagnosis. In this cohort, the coexistences of ruptured sinus of Valsalva aneurysm with ventricular septal defect and aortic regurgitation (case 1), ventricular septal defect (case 2), aortic regurgitation and bicuspid aortic valve (case 3) are observed.

Misclassification of bicuspid aortic valves is common and varies by imaging modality and patient characteristics.

Bicuspid aortic valve (BAV) is the most prevalent adult congenital heart defect. BAV causes lifelong progressive disease that can be prevented by early diagnosis and long-term surveillance, but may be compromised by misclassification of valve morphology. The study population was derived from the UTHealth Bicuspid Aortic Valve Registry, which includes serial images on more than 200 participants over a mean follow-up interval of 2.8years. We abstracted descriptions of aortic valve morphology from transthoracic or transesophageal echocardiography, computed tomography angiography, and magnetic resonance angiography reports. We used chi-square and t tests to determine associations between reported valve morphologies (definitely bicuspid, possibly bicuspid, tricuspid, or uncertain) and clinical characteristics and assessed image quality using a validated tool. About 40% of participants were misclassified in at least one imaging report. The mean interval between misclassification and correct diagnosis was 22months. TEE, MR and CT were more sensitive than TTE and successfully reclassified 20% of participants, but were only used in 14% of patients. Misclassification was associated with age, the extent of valve calcification and image quality, but was not significantly associated with aortic regurgitation, gender, or cusp configuration. Misclassification of BAV is prevalent, frequently leads to delayed diagnosis, and is more likely to occur in the most severely affected cases. TEE, CT and MR may increase diagnostic accuracy in up to half of BAV cases but are underutilized. Additional studies are needed to determine if misclassification of BAV patients leads to increased long-term morbidity and mortality.

NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve.

Congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.4‑2% of the general population, and accounts for a markedly increased incidence of life‑threatening complications, including valvulopathy and aortopathy. Accumulating evidence has demonstrated the genetic basis of BAV. However, the genetic basis for BAV in the majority of cases remains to be elucidated. In the present study, the coding regions and splicing donors/acceptors of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene, which encodes a transcription factor essential for proper cardiovascular development, were sequenced in 176 unrelated cases of congenital BAV. The available family members of the proband carrying an identified NR2F2 mutation and 280 unrelated, sex‑ and ethnicity‑matched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dual‑luciferase reporter assay system. As a result, a novel heterozygous NR2F2 mutation, NM_021005.3: c.288C>A; p.(Cys96*), was identified in a family with BAV, which was transmitted in an autosomal dominant mode with complete penetrance. The nonsense mutation was absent from the 560 control chromosomes. Functional analysis identified that the mutant NR2F2 protein had no transcriptional activity. Furthermore, the mutation disrupted the synergistic transcriptional activation between NR2F2 and transcription factor GATA‑4, another transcription factor that is associated with BAV. These findings suggested NR2F2 as a novel susceptibility gene of human BAV, which reveals a novel molecular pathogenesis underpinning BAV.

The importance of genetics and genetic counselors in the evaluation of patients with bicuspid aortic valve and aortopathy.

Bicuspid aortic valve (BAV) is a common congenital heart defect, with an estimated frequency of 1-2% in the general population. BAV may occur as an isolated finding or as a feature of certain syndromes. This article discusses potential genetic causes of BAV, includes a list of current known and candidate genes associated with BAV, provides a hypothetical case demonstrating the importance of genetic testing and cascade screening, and highlights the value of genetic counselors specializing in cardiovascular genetics. Individuals with BAV are at significantly increased risk of progressive aortic valve disease and aortic root aneurysms. There is high heritability associated with BAV, and several specific genes have recently been associated with BAV. There is wide phenotypic variability among BAV malformations, including which cusps are involved and the degree of aortic root involvement. Genotype-phenotype correlations exist that impact treatment recommendations. Genetic testing can reduce morbidity and mortality by guiding management strategies and identifying asymptomatic relatives before significant complications occur. Identifying cases of BAV with an identifiable genetic cause can significantly impact patients and family members. The list of associated genes is constantly growing. Genetic counselors have an important role in the evaluation of families at risk of BAV.

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1–2%)1–3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations are known for ≤1% of nonsyndromic BAV cases with/without AscAA (e.g. NOTCH1, SMAD6)5–8, impeding mechanistic insight and development of therapeutic strategies. We report the identification of mutations in ROBO4, encoding a factor known to contribute to endothelial performance, that segregate with disease in two families. Targeted sequencing of ROBO4 revealed enrichment for rare variants in BAV/AscAA probands compared to controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition (EnMT); concordant BAV/AscAA-associated findings are observed in patients and animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

Ascending thoracic aorta aneurysm repair induces positive hemodynamic outcomes in a patient with unchanged bicuspid aortic valve

We report a patient-specific case of bicuspid aortic valve with fusion of right and left coronary leaflets (R-L type I BAV), moderate aortic valve deficiency and ascending thoracic aortic aneurysms (ATAA) who was treated by only ascending aorta replacement preserving the BAV. The flow eccentricity, the helicity intensity (h2), the circumferential time averaged wall shear stress (TAWSScircumferential), the cumulative viscous energy loss at the systolic peak (EL') and the pulse wave velocity (PWV) were calculated by combining 4D flow MRI and CFD analysis before (Stage I) and after (Stage II) the surgical procedure. CFD analyses assumed rigid walls, a non-Newtonian behavior for the blood and MRI measured patient-specific blood flow profiles as inlet boundary conditions. Stage II results showed suppression of recirculation in the ascending aorta, loss of jet flow impingement onto the aortic wall, maximum TAWSScircumferential decrease (from 6.69 Pa in Stage I to 6 Pa in Stage II), reduction of flow helicity (from 10.97 in Stage I to 8.47 in Stage II) and EL' (from 15.8 mW in Stage I to 11.2 mW in Stage II). However, Floweccentricity and PWV were found higher in Stage II due to the diameter reduction (Floweccentricity = 0.60 in Stage I and Floweccentricity = 0.91 in Stage II; PWV = 3.80 m/s in Stage I and PWV = 9.37 m/s in Stage II).Our work has permitted to compute for the first time the hemodynamic alterations obtained after restoration of normal ascending aorta and sinotubular junction geometry even preserving an R-L type I BAV with still acceptable function.

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined. Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells. Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice. The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.