Morphology of bicuspid aortic valve in children and adolescents

Harvard University, Cambridge, Massachusetts, United States
Journal of the American College of Cardiology (Impact Factor: 16.5). 11/2004; 44(8):1648-51. DOI: 10.1016/j.jacc.2004.05.063
Source: PubMed


The aim of this study was to determine the relationship between aortic valve morphology and valve dysfunction.
The morphology of the bicuspid or bicommissural aortic valve (BAV) may predict the severity of valve dysfunction. Therefore, we assessed the relationship between BAV, aortic coarctation, and the degree of valve pathology in children.
A retrospective review of 1,135 patients with BAV who were identified between 1986 and 1999 was performed. Patients younger than 18 years of age with BAV that was identifiable via echocardiography were included. The most recent or last study of each patient before intervention or endocarditis was reviewed. Mild stenosis was defined as a valve gradient > or =2 m/s, moderate or greater aortic stenosis as > or =3.5 m/s. Aortic regurgitation was quantified using standard criteria.
Median age was 3 years (range, 1 day to 17.9 years), and 67% of the patients were male. Right-coronary and left-coronary leaflet fusion were the most common types of BAV (70%). Aortic stenosis that was moderate or greater was observed most often in patients with right-coronary and non-coronary leaflet fusion (odds ratio 2.4, 95% confidence interval 1.6 to 3.6; p < or = 0.001). Similarly, right-coronary and non-coronary leaflet fusion was more often associated with moderate aortic regurgitation or greater (odds ratio 2.4, 95% confidence interval 1.2 to 4.7; p = 0.01). The majority of patients with aortic coarctation had fusion of the right-coronary and left-coronary leaflets (89%), and aortic coarctation was associated with lesser degrees of valve stenosis or regurgitation.
Analysis of BAV morphology is of clinical and prognostic relevance. Fusion of the right-coronary and non-coronary leaflets was associated with more significant valve pathology, whereas fusion of the right-coronary and left-coronary leaflets was associated overwhelmingly with aortic coarctation and less aortic valve pathology.

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Available from: Peter Lang, Jan 27, 2015
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    • "Right coronary and left coronary (R-L) cusp fusion is more common than right coronary and non-coronary (R-NC) cusp fusion. Moreover, R-L cusp fusion is more often associated with additional cardiac malformations, whereas R-NC cusp fusion is more likely to be associated with aortic valve dysfunction [3]. The etiologies of these associations are unknown. "
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    ABSTRACT: Background Bicuspid aortic valve (BAV) is the most common type of congenital heart disease with a population prevalence of 1-2%. While BAV is known to be highly heritable, mutations in single genes (such as GATA5 and NOTCH1) have been reported in few human BAV cases. Traditional gene sequencing methods are time and labor intensive, while next-generation high throughput sequencing remains costly for large patient cohorts and requires extensive bioinformatics processing. Here we describe an approach to targeted multi-gene sequencing with combinatorial pooling of samples from BAV patients. Methods We studied a previously described cohort of 78 unrelated subjects with echocardiogram-identified BAV. Subjects were identified as having isolated BAV or BAV associated with coarctation of aorta (BAV-CoA). BAV cusp fusion morphology was defined as right-left cusp fusion, right non-coronary cusp fusion, or left non-coronary cusp fusion. Samples were combined into 19 pools using a uniquely overlapping combinatorial design; a given mutation could be attributed to a single individual on the basis of which pools contained the mutation. A custom gene capture of 97 candidate genes was sequenced on the Illumina HiSeq 2000. Multistep bioinformatics processing was performed for base calling, variant identification, and in-silico analysis of putative disease-causing variants. Results Targeted capture identified 42 rare, non-synonymous, exonic variants involving 35 of the 97 candidate genes. Among these variants, in-silico analysis classified 33 of these variants as putative disease-causing changes. Sanger sequencing confirmed thirty-one of these variants, found among 16 individuals. There were no significant differences in variant burden among BAV fusion phenotypes or isolated BAV versus BAV-CoA. Pathway analysis suggests a role for the WNT signaling pathway in human BAV. Conclusion We successfully developed a pooling and targeted capture strategy that enabled rapid and cost effective next generation sequencing of target genes in a large patient cohort. This approach identified a large number of putative disease-causing variants in a cohort of patients with BAV, including variants in 26 genes not previously associated with human BAV. The data suggest that BAV heritability is complex and polygenic. Our pooling approach saved over $39,350 compared to an unpooled, targeted capture sequencing strategy.
    BMC Medical Genomics 09/2014; 7(1):56. DOI:10.1186/1755-8794-7-56 · 2.87 Impact Factor
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    • "The findings and hypothesis are summarized in Fig. 5. Finally, we considered the morphological appearance of the commissure position as a determinant of susceptibility, since commissure position, which can clinically be analysed echocardiographically , is reported to be important in predicting future aortopathy [8] [11]. Previously, several studies reported that BAVs with an RCC/LCC BAV, which is the most common variant, are associated with more aortic dilatation in adults, whereas BAVs with fusion of the RCC/NCC are responsible for valve dysfunction at a younger age [13] [14] [15] [16] [17] [18]. Although the groups were small in our study, the orientation of the commissure and position of the raphe was in line with previous findings: RCC/NCC was most apparent in the BAa (the considered non-susceptible group), while the RCC/LCC was seen more often in the BAb group (the considered susceptible group) and in BAD patients (Table 2). "
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    ABSTRACT: Objectives: The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV. Methods: Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-β, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)]. Results: All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-β, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group. Conclusions: Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 08/2014; 46(5). DOI:10.1093/ejcts/ezu319 · 3.30 Impact Factor
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    • "The gender distribution of our BAV patients was the same as that of other studies [Fernandes et al. 2004; Mahle et al. 2010], with 76% male patients. Likewise, consistent with the finding of Pees and Michel-Behnke's study [Pees and Michel-Behnke, 2012], male gender does not have any significant effect on aortic distensibility. "
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    ABSTRACT: 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 cm(2) 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.
    Therapeutic Advances in Cardiovascular Disease 05/2014; 8(4). DOI:10.1177/1753944714531062 · 2.13 Impact Factor
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