scholarly journals Bicuspid Aortic Valve: Role of Multiple Gene Variants in Influencing the Clinical Phenotype

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Elena Sticchi ◽  
Rosina De Cario ◽  
Alberto Magi ◽  
Sabrina Giglio ◽  
Aldesia Provenzano ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Rare Variants ◽  
Aortic Surgery ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Aortic Dilatation ◽  
Reduced Penetrance ◽  
Next Generation Sequencing Ngs

Background. Bicuspid aortic valve (BAV) is a common congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant pattern of inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with other clinical manifestations in syndromic conditions. Identification of a syndromic condition in a BAV patient is clinically relevant in order to personalize indication to aortic surgery. We aimed to point out how genetic diagnosis by next-generation sequencing (NGS) can improve management of a patient with complex BAV clinical picture. Methods and Results. We describe a 45-year-old Caucasian male with BAV, thoracic aortic root and ascending aorta dilatation, and connective features evocative but inconclusive for clinical diagnosis of Marfan syndrome (MFS). Targeted (91 genes) NGS was used. Proband genetic variants were investigated in first-degree relatives. Proband carried 5 rare variants in 4 genes: FBN1(p.Asn542Ser and p.Lys2460Arg), NOTCH1(p.Val1739Met), LTBP1(p.Arg1330Gln), and TGFBR3(p.Arg423Trp). The two FBN1 variants were inherited in cis by the mother, showing systemic features evocative of MFS, but with a milder phenotype than that observed in the proband. Careful clinical observation along with the presence of the FBN1 variants allowed diagnosis of MFS in the proband and in his mother. NOTCH1 variant was found in mother and brother, not exhibiting BAV, thus not definitely supporting/excluding association with BAV. Interestingly, the proband, his brother and father, all showing root dilatation, and his sister, with upper range aortic root dimension, were carriers of a TGFBR3 variant. LTBP1 might also modulate the vascular phenotype. Conclusions. Our results underline the usefulness of NGS together with family evaluation in diagnosis of patients with monogenic traits and overlapping clinical manifestations due to contribution of the same genes and/or presence of comorbidities determined by different genes.

scholarly journals Aortic root aortopathy in bicuspid aortic valve associated with high genetic risk

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mingjia Ma ◽  
Zongzhe Li ◽  
Mohamed Abdulkadir Mohamed ◽  
Ligang Liu ◽  
Xiang Wei
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Genetic Variants ◽  
Rare Variants ◽  
Aortic Dilatation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
High Genetic Risk ◽  
Dilatation Group

Abstract Background The bicuspid aortic valve (BAV) is prone to ascending aortic dilatation (AAD) involving both the tubular segment and the aortic root. The genetic factor was proposed as one of the most important mechanisms for AAD. We hypothesized that the rare genetic variants mainly contribute to the pathogenesis of aortic roots in affected individuals. Methods The diameter of aortic root or ascending aorta ≥ 40 mm was counted as AAD. The targeted next-generation sequencing of 13 BAV-associated genes were performed on a continuous cohort of 96 unrelated BAV patients. The rare variants with allele frequency < 0.05% were selected and analyzed. Variants frequency was compared against the Exome aggregation consortium database. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics guidelines. Results A total of 27 rare nonsynonymous coding variants involving 9 genes were identified in 25 individuals. The burden analysis revealed that variants in GATA5, GATA6, and NOTCH1 were significantly associated with BAV. Eighty percent of the pathogenic variants were detected in root group. The detection rate of rare variants was higher in root dilatation group (71.4%) compared with normal aorta (29.0%) and tubular dilatation groups (29.6%) (P = 0.018). The rare variant was identified as the independent risk factor of root dilatation [P = 0.014, hazard ratio = 23.9, 95% confidence interval (1.9–302.9)]. Conclusions Our results presented a broad genetic spectrum in BAV patients. The rare variants of BAV genes contribute the most to the root phenotype among BAV patients.

scholarly journals Differences in Aortopathy in Patients with a Bicuspid Aortic Valve with or without Aortic Coarctation

2020 ◽  
Vol 9 (2) ◽  
pp. 290
Author(s):  
Anthonie Duijnhouwer ◽  
Allard van den Hoven ◽  
Remy Merkx ◽  
Michiel Schokking ◽  
Roland van Kimmenade ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Dissection ◽  
Bicuspid Aortic Valve ◽  
Aortic Coarctation ◽  
Care Center ◽  
Aortic Surgery ◽  
Tertiary Care ◽  
Aortic Diameter ◽  
Aortic Dilatation ◽  
Significant Difference

Objective: The combination of aortic coarctation (CoA) and bicuspid aortic valve (BAV) is assumed to be associated with a higher risk of ascending aortic dilatation and type A dissection, and current European Society of Cardiology (ESC) guidelines advise therefore to operate at a lower threshold in the presence of CoA. The aim of our study is to evaluate whether the coexistence of CoA in BAV patients is indeed associated with a higher risk of ascending aortic events (AAE). Methods: In a retrospective study, all adult BAV patients visiting the outpatient clinic of our tertiary care center between February 2003 and February 2019 were included. The primary end point was an ascending aortic event (AAE) defined as ascending aortic dissection/rupture or preventive surgery. The secondary end points were aortic dilatation and aortic growth. Results: In total, 499 BAV patients (43.7% female, age 40.3 ± 15.7 years) were included, of which 121 (24%) had a history of CoA (cBAV). An aortic event occurred in 38 (7.6%) patients at a mean age of 49.0 ± 13.6 years. In the isolated BAV group (iBAV), significantly more AAE occurred, but this was mainly driven by aortic valve dysfunction as indication for aortic surgery. There was no significant difference in the occurrence of dissection or severely dilated ascending aorta (>50 mm) between the iBAV and cBAV patients (p = 0.56). The aortic diameter was significantly smaller in the cBAV group (30.3 ± 6.9 mm versus 35.7 ± 7.6 mm; p < 0.001). The median aortic diameter increase was 0.23 (interquartile range (IQR): 0.0–0.67) mm/year and was not significantly different between both groups (p = 0.74). Conclusion: Coexistence of CoA in BAV patients was not associated with a higher risk of aortic dissection, preventive aortic surgery, aortic dilatation, or more rapid aorta growth. This study suggests that CoA is not a risk factor in BAV patients, and the advice to operate at lower diameter should be reevaluated.

Fluid Structural Interaction of a Patient Specific Congenital Bicuspid Aortic Valve

2012 ◽  
Author(s):  
V. Govindarajan ◽  
H. S. Udaykumar ◽  
S. Vigmostad ◽  
M. M. Levack ◽  
J. H. Gorman ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Aortic Aneurysms ◽  
Patient Specific ◽  
Aortic Dilatation ◽  
Structural Interaction ◽  
Aortic Pathology ◽  
Specific Geometry ◽  
Opening Phase

Congenital Bicuspid Aortic Valve (BAV) is a valvular anomaly where a patient is born with a valve with two leaflets instead of a normal tri-leaflet valve. It has also been reported that BAVs are prone to progressive calcification and also other complications such as ascending aortic dilatation, dissection and rupture [1]. The geometrical variations with the BAV may be a factor in altering the deformation and stresses on the leaflets resulting in calcification of the leaflets earlier than with normal tri-leaflet aortic valves. Altered flow patterns past BAV into the ascending aorta can also be anticipated. Analysis of flow dynamics during the opening phase, and the resultant fluid forces on the aortic root could improve our understanding of aortic aneurysms and dissections observed in patients with BAV [2]. In this study, the valvular deformation and the flow across a patient-specific BAV and root are simulated using the method of fluid structural interaction analysis. The patient-specific geometry is obtained employing 3D ultrasound images segmented as point cloud data and surfaces are constructed with commercial software GAMBIT using NURBS based connectivity. The opening phase of the valve is simulated under flow with physiological Reynolds number and with realistic material properties for the leaflets and the aortic root. Such an analysis on the dynamics of BAV with patient-specific geometry may be a useful tool in stratifying BAV patients that may be at risk in developing valvular and ascending aortic pathology.

Abstract 3189: Prevalence of Bicuspid Aortic Valve in Turner Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Vandana Sachdev ◽  
Lea Ann Matura ◽  
Stanislav Sidenko ◽  
Vincent Ho ◽  
Andrew Arai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Turner Syndrome ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Ascending Aorta ◽  
Aortic Dilatation ◽  
Aortic Valves ◽  
Number Of Patients ◽  
Valve Structure ◽  
Asymptomatic Individuals

Women with Turner syndrome (TS) have an increased risk of congenital cardiovascular defects. Previous studies have reported a 10 –20% prevalence rate of bicuspid aortic valves and there are increasing reports of a vasculopathy that predisposes patients to aortic dilatation and dissection. This prospective study aimed to characterize aortic valve and aortic root structure in unselected asymptomatic individuals with TS. A total of 253 females aged 7– 67 years with karyotype proven TS were examined. Transthoracic echocardiography revealed a normal tricuspid aortic valve (TAV) in 162, a ‘probable TAV’ in 8 subjects, a bicuspid aortic valve (BAV) in 65 and ‘probable BAV’ in 3 subjects. The aortic valve could not be visualized by echocardiography in 15/253 or 6%. Magnetic resonance imaging (MRI) revealed valve structure in 11/12 of the probable cases (all confirmatory of the ‘probable’ diagnosis) and 12/15 of the non-visualized cases (8 BAV and 4 TAV), so only 3/253 subjects could not be visualized by either modality. The aortic valve was bicuspid in 76 of the 250 adequately imaged subjects (30%). Peak aortic valve flow was higher in BAV subjects (1.72±0.07 vs. 1.90v0.03 m/sec, P=0.0002), with one case of significant aortic stenosis. Among subjects with a BAV, aortic regurgitation was moderate or greater in ∼15%. Aortic diameters at the annulus, sinuses of Valsalva, sinotubular junction and ascending aorta were all significantly greater in the BAV group. Thirty patients in the BAV group (12%) had aortic root diameters that were outside of the 95% normal confidence limits based on Roman nomograms. Ascending aortic diameters by echo and MRI were highly correlated (r=0.77). In summary, echocardiography supplemented with MRI reveals an extraordinarily high prevalence of abnormal aortic valves in asymptomatic subjects with TS. The abnormal valve structure is associated with higher peak flows, evidence of clinically significant valvular dysfunction, and widening of the ascending aorta in a significant number of patients. All girls and women with TS should have careful echocardiographic evaluation upon diagnosis to identify the one in three asymptomatic individuals with an abnormal valve requiring monitoring for aortic root dilatation and valvular dysfunction.

Aortic assessment of bicuspid aortic valve patients and their first-degree relatives

2017 ◽  
Vol 25 (3) ◽  
pp. 192-198
Author(s):  
Pablo Straneo ◽  
Gabriel Parma ◽  
Natalia Lluberas ◽  
Alvaro Marichal ◽  
Gerardo Soca ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Endothelial Function ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Inverse Correlation ◽  
Hereditary Disease ◽  
Root Diameter ◽  
Aortic Dilatation ◽  
First Degree Relatives ◽  
Increased Risk

Background Bicuspid aortic valve patients have an increased risk of aortic dilatation. A deficit of nitric oxide synthase has been proposed as the causative factor. No correlation between flow-mediated dilation and aortic diameter has been performed in patients with bicuspid aortic valves and normal aortic diameters. Being a hereditary disease, we compared echocardiographic features and endothelial function in these patients and their first-degree relatives. Methods Comprehensive physical examinations, routine laboratory tests, transthoracic echocardiography, and measurements of endothelium-dependent and non-dependent flow-mediated vasodilatation were performed in 18 bicuspid aortic valve patients (14 type 1 and 4 type 2) and 19 of their first-degree relatives. Results The first-degree relatives were younger (36.7 ± 18.8 vs. 50.5 ± 13.9 years, p = 0.019) with higher ejection fractions (64.6% ± 1.7% vs. 58.4% ± 9.5%, p = 0.015). Aortic diameters indexed to body surface area were similar in both groups, the except the tubular aorta which was larger in bicuspid aortic valve patients (19.3 ± 2.7 vs. 17.4 ± 2.2 mm·m−2, p = 0.033). Flow-dependent vasodilation was similar in both groups. A significant inverse correlation was found between non-flow-dependent vasodilation and aortic root diameter in patients with bicuspid aortic valve ( R = −0.57, p = 0.05). Conclusions Bicuspid aortic valve patients without aortopathy have larger ascending aortic diameters than their first-degree relatives. Endothelial function is similar in both groups, and there is no correlation with ascending aorta diameter. Nonetheless, an inverse correlation exists between non-endothelial-dependent dilation and aortic root diameter in bicuspid aortic valve patients.

Bicuspid aortic valve and aortopathy: novel prognostic predictors for the identification of high-risk patients

2020 ◽  
Author(s):  
Luca Longobardo ◽  
Scipione Carerj ◽  
Alessandra Bitto ◽  
Maurizio Cusmà-Piccione ◽  
Maria Ludovica Carerj ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Surgical Treatment ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Primary Endpoint ◽  
Cox Regression ◽  
Aortic Surgery ◽  
Aortic Aneurysms ◽  
Aortic Dilatation ◽  
Cox Regression Analysis

Abstract Aims Bicuspid aortic valve (BAV) may be complicated by aortic aneurysms and dissection. This study aimed to evaluate the prognostic efficacy of markers from cardiac imaging, as well as genetic and new biomarkers, to early predict aortic complications. Methods and results We re-evaluated after a mean time of 48 ± 11 months 47 BAV patients who had undergone previous echocardiography for evaluation of aortic stiffness and 2D aortic longitudinal strain (LS) (by speckle-tracking analysis), and who had given a blood sample for the assessment of a single-nucleotide polymorphism of elastin gene (ELN rs2 071307) and quantification of elastin soluble fragments (ESF). Surgical treatment of aortic aneurysm/dissection was the primary endpoint, and an aortic dimension increase (of one or more aortic segments) ≥1 mm/year was the secondary endpoint. Nine patients underwent surgical treatment of ascending aorta (AA) aneurysms. Out of the 38 patients who did not need surgical intervention, 16 showed an increase of aortic root and/or AA dimension ≥1 mm/year. At multivariate Cox regression analysis, an impaired AA LS was an independent predictor of aortic surgery [P = 0.04; hazard ratio (HR) 0.961; 95% confidence interval (CI) 0.924–0.984] and aortic dilatation (P = 0.007; HR 0.960; 95% CI 0.932–0.989). An increased quantity of ESF was correlated (P = 0.015) with the primary endpoint at univariate Cox regression analysis but it did not keep statistical significance at multivariate analysis. Conclusion In BAV patients, impairment of elastic properties of the AA, as assessed by 2D LS, is an effective predictor of aortic complications.

P6505Urinary desmosine, an elastin-specific degradation product is associated with maximum aortic root size and aortic z-scores in patients with bicuspid aortic valve

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Z Iskandar ◽  
J T J Huang ◽  
I Mordi ◽  
L D Miller ◽  
C Chin ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Root ◽  
Systolic Function ◽  
Rank Test ◽  
Aortic Dilatation ◽  
Elastin Degradation ◽  
Z Scores ◽  
Lv Systolic Function ◽  
Root Size

Abstract Background Bicuspid aortic valve (BAV) is the commonest congenital cardiac abnormality affecting up to 2% of the general population. BAV is highly diverse in phenotype however a common feature is its inherent risk of morbidity and mortality from aortic root dilatation and dissection. Aortic dilatation involves elastin degradation and desmosine is an amino acid cross-link that is released into the bloodstream and urine following elastin degradation. It is known from an earlier pilot study (DESMA) of desmosine in Marfan Syndrome (MFS) patients that plasma desmosine among patients with MFS is significantly elevated and correlates with aortic size however whether this same observation is seen in other forms of inherited aortopathies such as BAV is unclear. Objectives 1. To investigate whether patients with BAV have higher elastin degradation as indicated by plasma desmosine and urinary desmosine levels. 2. To explore the relationship between plasma and urinary desmosine levels with aortic root size in patients with BAV. Methods We measured urinary (ng/mg creatinine) and plasma desmosine (ng/mL) in 20 patients with BAV and healthy control subjects using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Aortic root size and corresponding Z-scores were measured on echocardiogram. Correlation was analysed with Spearman's rank test. Results The patients with BAV were predominantly male (n=15, 75%) with a mean age of 50.5 years ± 17.6 [SD]. All the BAV patients had normal LV systolic function and none had prior aortic root surgery or were current smokers. Nine BAV patients had treated hypertension. Compared to controls, both plasma desmosine (0.30±0.10 vs 0.26±0.075 ng/mL, p=0.01) and urinary desmosine (15.9±4.6 vs 7.2±2.8 ng/mg creatinine, p<0.001) were significantly elevated in patients with BAV. Urinary and plasma desmosine (Figure 1) were also significantly correlated (r=0.55, p=0.01). There was a significant association between urinary desmosine and maximal aortic root size and Z-scores in the BAV cohort (Figure 2) compared to controls (p=0.02), however this was not seen with plasma desmosine. Conclusions Urinary and plasma desmosine levels are significantly higher in patients with BAV compared to controls. Urinary desmosine is also significantly associated with maximal aortic root size, reflecting higher elastin degradation. This suggests a potential use of desmosine as a biomarker to monitor disease progression in patients with BAV. Acknowledgement/Funding Anonymous Trust

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