Bicuspid Aortic Valve Subjects Research Articles

Metabolic plasma signatures in thoracic aortic aneurysm associated to tricuspid and bicuspid aortic valves

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III with co-funding from the ERDF and Comunidad de Madrid Background/Introduction Thoracic aortic aneurysm (TAA) develops asymptomatic with life-threatening consequences and its diagnosis is usually fortuitous. TAA is mostly idiopathic, although its prevalence is significantly higher in subjects with bicuspid aortic valve (BAV) for unknown reasons. We hypothesize that it is essential to investigate idiopathic TAA by differentiating between BAV and tricuspid aortic valve (TAV) patients for personalized diagnosis and treatment. Purpose We aimed to identify plasma metabolic profiles of aortic dilatation in idiopathic TAA, differentiating between subjects with BAV or TAV. Methods Plasma samples from 41 idiopathic TAA patients and 57 subjects without aortic dilatation (control, C) were collected and classified according to aortic valve type (BAV or TAV). Full metabolomics coverage was carried out by 1H RMN and LC-MS/MS untargeted analysis, including reverse phase and hydrophilic interaction chromatography and positive and negative electrospray ionization modes. Significant variation in metabolite levels were considered if FDR-adjusted p-value <0.05. Results Our analyses highlighted a metabolic signature specific for BAV and TAV subjects. BAV patients presented a marked glycerophospholipid metabolism alteration involving different lysophospholipids (LPAs, LPCs and LPEs) and phospholipids (PCs, PEs, PAs and PIs). Particularly, LPCs and LPEs were increased in BAV-TAA vs BAV-C, being an indicator of stimulation of glucose utilization through glycolysis and suppression of fatty acid biosynthesis. In contrast, carnitine-related metabolism was the most altered pathway observed in TAV subjects. In particular, we detected an increment in plasma acylcarnitines in TAV-TAA compared to TAV-C suggesting an altered β-oxidation of fatty acids and mitochondrial overload. Conclusions Idiopathic TAA development is differentially reflected in plasma from BAV and TAV patients, supporting an individualized diagnosis valve-dependent and suggesting also differential therapeutic targets.

The effect of aortic valve replacement on 4D flow-measured flow displacement in patients with bicuspid and tri-leaflet aortic valves with severe aortic stenosis

Abstract Introduction Eccentric outflow jet direction in the ascending aorta is correlated with the altered haemodynamic flow patterns thought to contribute to bicuspid aortic valve (BAV)-associated aortopathy. Purpose We aimed to analyse the impact of surgical aortic valve replacement (AVR) on outflow jet displacement in the ascending aorta, and determine if differences exist between individuals with BAV and tri-leaflet aortic valves (TAV). Method Four-dimensional flow-cardiac magnetic resonance imaging (4D Flow) of the aorta was performed in prospectively recruited patients with BAV and TAV and severe symptomatic aortic stenosis (AS), before and 12 months after AVR. Healthy individuals with BAV and TAV morphology, but no significant valve disease, were also recruited as controls. Outflow direction was calculated from the in-plane, normalised flow displacement (NFD), defined as the distance between the centre of the aortic lumen (Clum) and the centre of velocity (Cvel) of the forward flow and normalised to the lumen diameter (Figure 1). Mean NFDs were evaluated at peak systole on planes perpendicular to 25 equidistant nodes along the centreline between the aortic root to the level of the pulmonary artery bifurcation in all subjects using custom Matlab code. Results 32 subjects with severe symptomatic AS (BAV n=11, TAV n=21; mean age 68±10 years) and 17 controls (BAV n=8, TAV n=9; mean age 57±7 years) were assessed (Table 1). In those with TAV, there were no differences in NFD between patients with severe AS pre-AVR compared to post-AVR, or compared to TAV controls. However, in BAV subjects, pre-AVR BAV patients with severe AS had a significantly higher mean NFD compared to BAV controls, and compared to pre-AVR TAV patients with severe AS. Post-AVR, there was no longer a significant difference in mean displacement between BAV vs TAV. Conclusion Our observations suggest that the BAV morphology plays a predominant role in the abnormal eccentric flow displacement in the ascending aorta, which may be normalised following bioprosthetic valve replacement. This may have implications for monitoring aortas post-AVR in BAV subjects.

Urinary Metabolomics Study of Patients with Bicuspid Aortic Valve Disease.

Bicuspid aortic valve (BAV) is the most common congenital heart defect responsible for valvular and aortic complications in affected patients. Causes and mechanisms of this pathology are still elusive and thus the lack of early detection biomarkers leads to challenges in its diagnosis and prevention of associated cardiovascular anomalies. The aim of this study was to explore the potential use of urine Nuclear Magnetic Resonance (NMR) metabolomics to evaluate a molecular fingerprint of BAV. Both multivariate and univariate statistical analyses were performed to compare the urinary metabolome of 20 patients with BAV with that of 24 matched controls. Orthogonal partial least squared discriminant analysis (OPLS-DA) showed statistically significant discrimination between cases and controls, suggesting seven metabolites (3-hydroxybutyrate, alanine, betaine, creatine, glycine, hippurate, and taurine) as potential biomarkers. Among these, glycine, hippurate and taurine individually displayed medium sensitivity and specificity by receiver operating characteristic (ROC) analysis. Pathway analysis indicated two metabolic pathways likely perturbed in BAV subjects. Possible contributions of gut microbiota activity and energy imbalance are also discussed. These results constitute encouraging preliminary findings in favor of the use of urine-based metabolomics for early diagnosis of BAV.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Long-Term Risk Factors for Dilatation of the Proximal Aorta in a Large Cohort of Children With Bicuspid Aortic Valve.

Patients with bicuspid aortic valve (BAV) have a higher risk of developing aortic valve dysfunction and progressive proximal aorta dilatation, which can lead to aortic dissection. To this day, identification of children at risk of developing severe aortic dilatation during their pediatric follow-up is still challenging because most studies were restricted to adult subjects. The overarching goal of this study was to identify risk factors of aortic dilatation in children with BAV. We extracted clinical and echocardiographic data of all BAV subjects aged 0 to 20 years followed at Centre Hospitalier Universitaire Sainte-Justine between 1999 and 2016. We excluded subjects with concomitant heart defects and conditions affecting proximal aorta dimensions. Proximal aorta diameters (expressed as Z scores) were modeled in relation to age and potential predictive variables in a linear mixed model. The primary outcome was the rate of dilatation. We included 761 subjects (3134 echocardiograms) in final analyses. The mean ascending aorta Z score progression rate for BAV patient with a normally functioning aortic valve was estimated at 0.05 Z score unit per year. The strongest predictors of an increased dilatation rate were severe aortic stenosis, moderate and severe aortic regurgitation, and uncorrected coarctation of the aorta. Aortic valve leaflet fusion pattern and sex were not associated with progression rate. Children with a normally functioning BAV exhibited a very slow proximal aorta dilatation rate. Ascending aorta dilatation rate was significantly increased in patients with more than mild aortic valve dysfunction but was independent from BAV leaflet fusion type.

Bicuspid aortic valve area in normal heart.

Bicuspid aortic valve (BAV) is a common congenital valve abnormality. There are no data in the literature regarding the range of aortic valve area (AVA) in normal functioning BAV. We aimed to evaluate the normal range of BAV area and to compare it to subjects with tricuspid aortic valve (TAV). Bicuspid aortic valve subjects were identified from Sheba medical center echocardiographic database and were compared with TAV subjects. Inclusion criteria were normal tissue leaflets appearance and normal functioning valve in the presence of normal echocardiogram. Echocardiographic data, patients hemodynamics, and size were collected. AVA was measured with both planimetry and the continuity equation. Fifty BAV and 50 control subjects were studied (37 men, age 40±13years). All studies were performed with normal hemodynamics. Fusion between the coronary leaflets was the most common morphology (82%), followed by fusion between the right coronary leaflet with the noncoronary leaflet (18%). The left ventricular outflow tract (LVOT) diameter in BAV group was significantly larger (2.3±0.3cm vs 2.1±0.2; P<.001). The BAV group presented with a larger AVA planimetry (3.8±0.9 vs 3.3±0.6; P<.001). However, measuring AVA using continuity equation has shown no differences between groups. If using the principles of coefficient of contraction, it seems that measuring AVA by planimetry overestimates the real anatomic AVA. This data provide normal values for echocardiographically determined AVA in BAV subjects. This population was characterized by large LVOT diameter and large AVA. The larger AVA measured with the planimetry emphasizes the limitation of this method in BAV population.

Aortic arch tortuosity, a novel biomarker for thoracic aortic disease, is increased in adults with bicuspid aortic valve

IntroductionArterial tortuosity has emerged as a predictor of adverse outcomes in congenital aortopathies using 3D reconstructed images. We validated a new method to estimate aortic arch tortuosity on 2D CT. We hypothesize that arch tortuosity may identify bicuspid aortic valve (BAV) patients at high risk to develop thoracic aortic aneurysms or aortic dissections (TAD). MethodsBAV subjects with chest CT scans were retrospectively identified in our clinical records and matched to tricuspid aortic valve (TAV) controls by age, gender, and presentation with TAD. Subjects with prior ascending aortic intervention were excluded. Measurements included aortic arch tortuosity, length, angle, width and height. Total aortic tortuosity was estimated in subjects with available abdominal images. Results120 BAV and 234 TAV subjects were included. Our 2D measurements were highly correlated with 3D midline arch measurements and had high inter- and intra-observer reliability. Compared to TAV, BAV subjects had increased arch tortuosity (median 1.76 [Q1-Q3: 1.62–1.95] vs. 1.63 [1.53–1.78], P < 0.01), length (149 [136–160] vs. 135 [122–152] mm, P < 0.01), height (46 [41–53] vs. 39 [34–47] mm, P < 0.01), and vertex acuity (70 [61–77] vs. 75 [68–81] degree, P < 0.01). In a multivariable analysis, arch tortuosity remained independently associated with BAV after adjusting for aortic diameter and other clinical characteristics. ConclusionsWe found that aortic arch tortuosity is significantly increased in BAV and may identify BAV patients who are at increased risk for TAD. Further studies to evaluate the association between tortuosity and clinical outcomes are in progress.

Deregulation of Notch1 pathway and circulating endothelial progenitor cell (EPC) number in patients with bicuspid aortic valve with and without ascending aorta aneurysm

Bicuspid aortic valve (BAV) is frequently associated with the development of ascending aortic aneurysm, even if the underlying mechanisms remain to be clarified. Here, we investigated if a deregulation of Notch1 signaling pathway and endothelial progenitor cells (EPCs) number is associated with BAV disease and an early ascending aortic aneurysm (AAA) onset. For this purpose, 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) and AAA complicated or not, were included. Interestingly, patients with AAA showed a significant increase in circulating Notch1 levels and EPC number than subjects without AAA. However, circulating Notch1 levels and EPC number were significantly lower in BAV subjects than TAV patients either in the presence or absence of AAA. Finally, Notch pathway was activated to a greater extent in aortic aneurysmatic portions with respect to healthy aortic fragments in both BAV and TAV patients. However, the expression of genes encoding components and ligands of Notch pathway in aortic tissues was significantly lower in BAV than TAV subjects. Our study demonstrates that BAV subjects are characterized by a significant decrease in both tissue and circulating levels of Notch pathway, and in blood EPC number than TAV patients, either in presence or absence of AAA disease.

Aortic stenosis exacerbates flow aberrations related to the bicuspid aortic valve fusion pattern and the aortopathy phenotype.

A bicuspid aortic valve (BAV) is characterized by variable phenotypic manifestations, as well as longitudinal evolution of valve dysfunction and ascending aorta dilatation. The present study investigated the impact of severe aortic stenosis (AS) on the flow patterns and wall shear stress (WSS) distribution in BAV patients with right-left (RL) and right-non-coronary (RN) cusp fusion types, and the study aimed to reveal whether aortic dysfunction could further alter intrinsic aortic haemodynamic aberrations generated by abnormal BAV cusp fusion patterns. Four-dimensional flow magnetic resonance imaging was performed in 120 BAV subjects and 20 tricuspid aortic valve controls. BAV patients were evenly categorized into 4 cohorts, including RL and RN BAV with no more than mild aortic dysfunction as well as RL and RN BAV-AS with isolated severe AS. BAV subjects exhibited eccentric outflow jets resulting in regional WSS elevation at the right-anterior position of the ascending aorta in the RL group and the right-posterior location in the RN group (P < 0.005). The presence of severe AS resulted in accelerated outflow jets and more prominent flow and WSS eccentricity (P < 0.005) by marked helical (P = 0.014) and vortical flow formation (P < 0.005), as well as increased prevalence of tubular and transverse arch dilatation. The changes to the flow jet in BAV-AS subjects blurred the differences in peak flow velocity and WSS distribution between RL and RN BAV. Differences in the phenotypes of aortopathy were associated with changes in functional haemodynamic parameters such as flow displacement and WSS eccentricity. Severe AS markedly exacerbated aortic flow aberrations in BAV patients and masked the existing distinct flow features deriving from RL and RN fusion types. Longitudinal studies are needed to investigate the evolution of ascending aortic dilatation relative to the interaction between intrinsic cusp fusion types and acquired severe valve dysfunction.

Valve mediated hemodynamics and their association with distal ascending aortic diameter in bicuspid aortic valve subjects.

Valve mediated hemodynamics have been postulated to contribute to pathology of the ascending aorta (AAo). The objective of this study is to assess the association of aortic valve morphology and hemodynamics with downstream AAo size in subjects with bicuspid aortic valve (BAV) disease. Four-dimensional flow MRI at 1.5 or 3 Tesla was used to evaluate the hemodynamics in the proximal AAo of 52 subjects: size-matched controls with tricuspid aortic valves (n = 24, mid ascending aorta [MAA] diameter = 38.0 ± 4.9 mm) and BAV patients with aortic dilatation (n = 14 right and left coronary leaflet fusion [RL]-BAV, MAA diameter = 38.1 ± 5.3 mm; n = 14 right and noncoronary leaflet fusion [RN]-BAV, MAA diameter = 36.5 ± 6.6 mm). A validated semi-automated technique was used to evaluate hemodynamic metrics (flow angle, flow displacement, and jet quadrant) and valve morphology (orifice circularity) for all subjects. Regression analysis of these metrics to AAo diameter was performed. RN-BAV subjects displayed a stronger correlation between hemodynamic metrics in the proximal AAo with diameter in the distal AAo compared with size-matched tricuspid aortic valve (TAV) controls and RL-BAV subjects. The distal AAo diameter was found to be strongly correlated to the upstream flow displacement (R2adjusted = 0.75) and flow angle (R2adjusted = 0.66) measured at the sino-tubular junction (STJ). Orifice circularity was also strongly correlated (R2adjusted = 0.53) to the distal AAo diameter in RN-BAV subjects. For TAV controls and RL-BAV subjects, correlations were weaker (R2adjusted < 0.2). Hemodynamics in the STJ were strongly correlated to the distal AAo diameter for the RN-BAV subjects. Hemodynamic metrics were more strongly correlated to the downstream aortic size when compared with valve morphology metrics. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:246-254.

Cine-CMR partial voxel segmentation demonstrates increased aortic stiffness among patients with Marfan syndrome.

Standard cine-cardiac magnetic resonance (CMR) imaging is commonly used to evaluate cardiac structure, geometry and function. Prior studies have shown that automated segmentation via partial voxel interpolation (PVI) accurately quantifies phantom-based cardiac chamber volumes and necropsy left ventricular myocardial mass. Despite this, the applicability and usefulness of PVI in the determination of physiologic parameters of the aorta such as aortic stiffness has yet to be investigated. Routine CMR was conducted with a 1.5T (GE) scanner with pulse sequences similar to that of standard CMR (parameters: TR 3.4 msec, TE 1.14 msec, flip angle 60°, temporal resolution ~30-40 msec). Views were obtained in standard cardiac-oriented longitudinal or axial views (2, 3 and 4 chambers). Within non-dilated regions of the descending thoracic aorta, aortic area was quantified via a novel PVI automated process (LV-METRIC), which discerns relative amounts of blood pool in each voxel. Aortic stiffness, as calculated from brachial artery pulse pressure and aortic area at maximal and minimal dimensions, was evaluated in 60 total segments (one segment per patient). All segments were in the descending aorta and were not aneurysmal. Sixty patients in total were studied, including 50 that had genetically-related aortic disorder [35 bicuspid aortic valve (BAV), 15 Marfan syndrome (MFS)]. Ten normal controls without aortic disease were included for comparison purposes. All patients (n=60) had evaluable CMR images for assessment of the descending aorta with use of automated segmentation. Patients with BAV and MFS were similar to controls in age, systolic blood pressure, brachial artery pulse pressure, smoking status or hypercholesterolemia (all P=NS). There were more women (P<0.001), lower body mass index (P=0.008), and greater height (P<0.001) in the MFS cohort compared to BAV and controls. Descending aortic area in either systole (maximal) or diastole (minimal) was similar among all three cohorts. However, change in aortic area (ΔArea) throughout the cardiac cycle was substantially lower in MFS than control subjects (P<0.001). In contrast, change in aortic area throughout the cardiac cycle was not significantly different between BAV vs. controls (P=0.62). Aortic stiffness was increased among MFS patients versus control subjects (P=0.014). When comparing MFS to BAV subjects, a comparable trend was observed (P=0.09). No statistical difference was evident in aortic stiffness in patients with BAV versus control subjects (P=0.29). The application of PVI to standard CMR imaging can assess abnormal descending aorta functional indices in normal caliber segments in MFS subjects. Future prospective studies with larger subject populations are warranted to further determine the overall utility of automated aortic segmentation as a possible early biomarker of aortic dysfunction before overt dilatation.

Abstract 17616: Recurrent Copy Number Variants are Enriched in Bicuspid Aortic Valve and Affect Cardiac Developmental Genes

Introduction: Bicuspid Aortic Valve (BAV) is the most common adult congenital heart defect. The spectrum of BAV ranges from chromosomal disorders such as Turner syndrome to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to BAV. Methods: We conducted genome-wide SNP array analyses of BAV cases in six European American cohorts (3533 total subjects, 31% BAV, 45% female, ages 1-94 years) with sporadic or familial thoracic aortic aneurysms (37%), congenital left ventricular outflow tract obstructive defects (47%) or Turner syndrome (10%). Genotyping was performed on Illumina Omni microarrays, using PennCNV, Nexus and CNVPartition for CNV detection. Thresholds were set at a minimum of six consecutive SNPs for CNVs that were identified by at least two algorithms and intersect with known genes. A total of 1380 BAV cases were compared to 1065 cases with tricuspid aortic valves and 7013 dbGAP controls without a history of cardiovascular disease using association tests for rare CNVs as implemented in PLINK. Pathway and functional analyses of rare CNVs were performed using the ToppGene analysis suite. Genes within rare CNVs were prioritized by their connectivity to genes in the Notch pathway or established roles in human or animal cardiac phenotypes. Results: We identified 12 rare CNV regions that were recurrent in at least three different BAV groups and were absent or extremely rare (frequency &lt;0.1%) in controls. Four of these regions involved genes that cause aortic valve or outflow tract defects when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (four duplications and two deletions), at 22q11.21, telomeric to the DiGeorge syndrome critical region (four deletions, three duplications), and at 7p15.2 (four deletions). The percentage of individuals harboring rare CNVs was significantly greater in BAV cases than in tricuspid or dbGAP controls. Conclusions: We identified multiple loci affected by rare CNVs in BAV subjects, demonstrating the genetic heterogeneity of BAV and implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

3D ASSESSMENT OF LOCAL NORMALIZED HELICITY IN AORTIC BICUSPID VALVE AND AORTIC DILATATION

Elevated helical flow in the thoracic aorta may result from hemodynamic and anatomic alterations such as aortic dilation and bicuspid aortic valve (BAV). In particular, local normalized helicity (LNH) can quantify helical flow using 4D flow MRI and preserve the rotational direction information. This study aims to demonstrate that 1) LNH quantification may differentiate helical flow alterations in the aorta between healthy controls and BAV subjects; 2) elevated LNH may be correlated with aortic dilatation. 115 subjects (65 healthy controls and 50 subjects with bicuspid valve (BAV) and aortic dilatation were identified via IRB-approved retrospective chart review. ECG-gated 4D flow MRI was performed on 1.5T (n=74) and 3T (n=41) scanners. A phase contrast MR angiogram (MRA) was calculated from 4D flow MRI data (Fig. 1A) and used to perform a 3D segmentation of the entire aorta (Fig. 1B). The aorta 3D segmentation was subdivided in 3 segments: ascending aorta, aortic arch, and descending aorta (Fig. 1C). The mean velocity in the entire aorta was used to identify peak systole, systole deceleration and mid-diastole phases. LNH in was calculated by LNH=(V.ω)/(|V||ω|), where V is the velocity vector field from 4D flow MRI and ω is the vorticity as given by ω=curl (V). LNH calculation results in values between -1 and 1 (left-handed and right-handed rotation respectively). A LNH threshold was set at ±0.8 to identify elevated helicity within the flow domain (Fig. 1D). Positive relative fraction was then calculated as PRF = Positive LNH/ (Positive LNH + Negative LNH) volumes. Controls presented right-handed helical flow whereas BAV showed a preference to left-handed rotation (Fig. 1E). PRF in the full aorta showed significant differences between controls and BAV (P<0.001) at measured time-points. Sub-domain analysis showed significant differences (P<0.001) in the ascending aorta and in the aortic arch between controls and BAV. PRF in the full aorta correlated with MAA diameter at peak systole (r=-0.19, P<0.05), at systole deceleration (r=-0.34, p<0.001), and at mid-diastole (r=-0.19, p<0.05). PRF in the full aorta also correlated well with aortic peak velocity at peak systole (r=-0.39, P<0.001), and at systole deceleration (r=-0.42, p<0.001). Elevated LNH differentiated helical flow alterations in healthy and BAV subjects and was associated aortic diameter and peak velocity.

Aortic distensibility in bicuspid aortic valve patients with normal aortic diameter.

Bicuspid aortic valve (BAV) is associated with aortic abnormalities. The ascending aorta tends to dilate and its elasticity deteriorates. The morphology of the BAV and the elasticity of the proximal ascending aorta seem to influence the outcome. This study aimed to determine the distensibility of the ascending aorta with normal diameter in BAV patients and its relation to its morphology. This is a cross-sectional study. In the patients with BAV referred for echocardiography, the phenotype was defined as anteroposterior (AP) or mediolateral (ML) leaflet orientations. The aortic distensibility at 5-10 mm above the sinotubular junction was assessed using transthoracic echocardiography in 50 BAV patients, and 50 healthy controls with tricuspid aortic valve (TAV) matched by gender and age. The ascending aorta in BAV patients had less distensibility compared with that in the control subjects (0.00298 ± 0.0023 versus 0.00805 ± 0.0028 cm2 dynes-1 × 10-6, respectively, p < 0.001). The ML phenotype of BAVs was more frequent. However, the reduced distensibility was not related to gender and morphology of the valve. Regardless of the valve morphology and also in the absence of aortic dilation, aortic distensibility is impaired in BAV subjects compared with TAV subjects. This finding supports the idea of an intrinsic aortic wall anomalies underlying the impaired elasticity of the aorta in BAV patients.

Exercise training in athletes with bicuspid aortic valve does not result in increased dimensions and impaired performance of the left ventricle.

Background. Bicuspid aortic valve (BAV) is one of the most common congenital heart disease (0.9%–2%) and is frequently found in the athletes and in the general population. BAV can lead to aortic valve dysfunction and to a progressive aortic dilatation. Trained BAV athletes exhibit a progressive enlargement of the left ventricle (LV) compared to athletes with normal aortic valve morphology. The present study investigates the possible relationship between different aortic valve morphology and LV dimensions. Methods. In the period from 2000 to 2011, we investigated a total of 292 BAV subjects, divided into three different groups (210 athletes, 59 sedentaries, and 23 ex-athletes). A 2D echocardiogram exam to classify BAV morphology and measure the standard LV systo-diastolic parameters was performed. The study was conducted as a 5-year follow-up echocardiographic longitudinal and as cross-sectional study. Results. Typical BAV was more frequent in all three groups (68% athletes, 67% sedentaries, and 63% ex-athletes) than atypical. In BAV athletes, the typical form was found in 51% (107/210) of soccer players, 10% (21/210) of basketball players, 10% track and field athletics (20/210), 8% (17/210) of cyclists, 6% (13/210) swimmers, and 15% (32/210) of rugby players and others sport. Despite a progressive enlargement of the LV (P < 0.001) observed during the follow-up study, no statistical differences of the LV morphology and function were evident among the diverse BAV patterns either in sedentary subjects or in athletes. Conclusion. In a large population of trained BAV athletes, with different prevalence of typical and atypical BAV type, there is a progressive nonstatistically significant enlargement of the LV. In any case, the dimensions of the LV remained within normal range. The metabolic requirements of the diverse sport examined in the present investigations do not seem to produce any negative impact in BAV athletes

Surgical Thresholds for Bicuspid Aortic Valve Associated Aortopathy

This systematic review seeks to present the outcomes of the natural history of aortopathy associated with bicuspid aortic valve (ABAV) and after interventions. Aortopathy is common in patients with ABAV, and early intervention has been proposed to reduce the risk of dissection. In asymptomatic patients, the timing of surgical management is based upon imaging of aortic size, but the actual threshold is based upon observational data and expert opinion. As evidence of high risk would justify early intervention, we sought to define the natural history of this condition and after interventions. We undertook a systemic review of the evidence from observational studies of ABAV published up to June 2013. The primary outcome was annualized all-cause mortality. Secondary outcomes included acute aortic events, rates of aneurysm enlargement, and peri-operative complications. A random-effects model was used to combine outcomes. A meta-regression was undertaken to assess the impact of potential covariates. The 32 eligible papers involved 11,045 patients (9,441 BAV and 1,604 control subjects, age 46 ± 14 years). There were 3 major groups, nonoperated bicuspid aortic valve (BAV) patients (ages from 30 to 40 years), patients after aortic surgery (generally 40 to 60 years of age) and after isolated valve replacement (>60 years of age). The respective annualized mortality of nonoperated BAV patients was 0.56% (95% confidence interval [CI]: 0.13 to 0.99), compared with 0.78% (95% CI: 0.20 to 1.36) in patients after aortic surgery and 2.39% (95% CI: 1.61 to 3.16) after isolated valve replacement. The annualized acute event rate in nonoperated BAV patients was 0.29% (95% CI: 0.23 to 0.35), this risk being no different from that of a tricuspid aortic valve (risk ratio: 0.68, 95% CI: 0.34 to 1.36). In the post-surgical series, 30-day mortality varied from 0% to 2.5%, and the risk of acute events was 0.16% (95% CI: 0.0 to 0.32) in patients after aortic surgery and 0.68% (95% CI: 0.42 to 0.94) after isolated valve replacement. Aortic dilation was at a rate of 0.16mm/year over 6 decades in healthy BAV subjects and 1.1 ± 0.15 mm/year in older aortic valve replacement patients. The risk associated with ABAV varies according to age and clinical setting. Nonetheless, despite aortic dilatation, the acute aortic event risk of ABAV appears low in current practice. Decision-making regarding the timing of intervention needs to be made on the basis of the balance between this low risk and both the morbidity and mortality of surgery.

Augmentation index and aortic stiffness in bicuspid aortic valve patients with non-dilated proximal aortas

BackgroundWe compared aortic stiffness, aortic impedance and pressure from wave reflections in the setting of bicuspid aortic valve (BAV) to the tricuspid aortic valve (TAV) in the absence of proximal aortic dilation. We hypothesized BAV is associated with abnormal arterial stiffness.MethodsTen BAV subjects (47 ± 4 years, 6 male) and 13 TAV subjects (46 ± 4 years, 10 male) without significant aortic valve disease were prospectively recruited. Characteristic impedance (Zc) was derived from echocardiographic images and pulse wave Doppler of the left ventricular outflow tract. Applanation tonometry was performed to obtain pulse wave velocity (PWV) at several sites as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflection.ResultsThere were no significant differences between BAV and TAV subjects with regard to heart rate or blood pressure. Zc was similar between BAV and TAV subjects (p=0.25) as was carotid-femoral pulse wave velocity (cf-PWV) and carotid-radial PWV (cr-PWV) between BAV and TAV subjects (p=0.99). Carotid AIx was significantly higher in BAV patients compared with TAV patients (14.3 ± 4.18% versus -3.02 ± 3.96%, p=0.007).ConclusionsAortic stiffness and impedance is similar between subjects with BAV and TAV with normal aortic dimensions. The significantly higher carotid AIx in BAV, a proxy of increased pressure from wave reflections, may reflect abnormal vascular function distal to the aorta.

Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study

The involvement of different factors in the onset of thoracic aortic aneurysm (TAA) in patients with a bicuspid aortic valve (BAV) vs those with a tricuspid aortic valve (TAV) is well recognized. However, the molecular, genetic and cellular mechanisms driving TAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAV vs TAV. Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and 110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, mean age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunohistochemical analyses were performed, as well as genotyping of 10 polymorphisms. In BAV-associated ascending aortas, significant severe plurifocal apoptosis of smooth muscle cells and matrix metalloproteinase-9 (MMP-9) amounts were detected. In contrast, TAV-associated ascending aortas were characterized by a significant severity of elastic fragmentation, cystic medial necrosis, medial fibrosis and inflammation. In addition, in BAV cases, the -1562TMMP-9 and -735TMMP-2 alleles represent independent risk factors for TAA. The effects of these genotypes combined with hypertension and smoking in BAV cases result in an increase in both the apoptosis (P = 0.0001) and levels of MMP-9 (P = 0.001). In TAV cases, the D angiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combined with hypertension and age, significantly increase both the microscopic lesions and inflammation. Our data seem to suggest that TAA in BAV and TAV patients arises from different molecular, cellular and genetic mechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at high TAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascending aorta, including the aortic root with or without dilatation.

Abstract 5771: Aortic Root Dilatation is a Phenotypic Manifestation of the Bicuspid Aortic Valve Disease Prevalent in Relatives with Normal Aortic Valve.

Background: Bicuspid aortic valve (BAV) and dilated ascending aorta frequently coexist. 10% of first degree relatives (FDRs) of probands with BAV inherit a valvular abnormality, however there is limited data concerning the occurrence of dilated aortic root in families of affected subjects. We evaluated the prevalence of aortic root dilatation among FDRs with a tricuspid aortic valve. Methods: Aortic root dimensions were measured by 2D echocardiography in BAV probands (n=48), their FDRs (n = 49) and controls without structural heart disease matched by age and gender (n=44). Aortic root was measured at: annulus, sinuses of Valsalva, sino-tubular junction and proximal ascending aorta. The dimensions were indexed by body surface area (BSA). Presence of dilatation was determined using published confidence intervals relating normal aortic diameters to BSA and age. Results: Five subjects (10%) in FDR group were found to have BAV, thus they were included in BAV group. Indexed aortic diameter was significantly different in 3 groups namely BAV&gt;FDR&gt;Control at annulus (2.0±0.3, 1.7±0.2, 1.6±0.1, p&lt;0.001) and sinuses of Valsalva (2.8±0.5, 2.4±0.4, 2.2±0.3, p&lt;0.001) Figure . BAV subjects showed significantly larger dimensions in the ascending aorta compared to FDRs and controls (p&lt;0.001). The prevalence of aortic root dilatation at all levels was 51% in BAV subjects, 25% in FDRs and 0% in controls (p&lt;0.001). Conclusions: There is high prevalence of aortic root dilatation in the FDRs of subjects with BAV despite having normal tricuspid aortic valve. This finding suggests that aortic root dilatation is another phenotypic manifestation of BAV disease that is inherited independent of BAV.

Abstract 5770: Abnormal Aortic Root Elastic Properties in Family Members of Bicuspid Aortic Valve Subjects, despite Normal Aortic Valve Morphology.

Background: Abnormal aorta dilatation and elastic properties have been documented in subjects with bicuspid aortic valve (BAV). 10% of first degree relatives (FDRs) of probands with BAV inherit this valvular abnormality. There is no data regarding the elastic properties of aortic root in family members of BAV subjects. We evaluated the elastic properties in FDRs with normal tricuspid aortic valves. Methods: Systolic and diastolic aortic root dimensions were measured by 2D echocardiography in BAV probands (n=48) their FDRs (n = 49) and controls without structural heart disease matched by age and gender (n=44) at sinuses of Valsalva level. In addition, systolic (SBP) and diastolic blood pressure (DBP) were measured to calculate aortic distensibility, stiffness index and strain. Results: Five subjects (10%) in FDR group were found to have BAV, thus they were included in BAV group. There was no difference in age, gender, SBP and DBP in the three groups. History of hypertension was less prevalent in FDRs when compared to BAV and controls (16% vs 43% and 33%, p=0.03). All three parameters of aortic elastic properties including distensibility ×10 −3 mmHg (1.2±1.0 and 1.5±1.1 vs 2.3±1.5, p&lt;0.001), stiffness index (56.5±76.4 and 29.1±32.5 vs 12.6±9.2, p&lt;0.001) and strain (2.9±2.4and 3.6±2.5 vs 6.0±3.6, p&lt;0.001) were significantly worse in BAV and FDRs compared to controls (Figure ). Conclusions: Aortic root elastic properties are abnormal in the family members of subjects with BAV despite normal tricuspid aortic valve morphology. This finding supports the hypothesis that there is a common genetic basis for BAV and abnormal elastic properties of aorta.