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Familial bicuspid aortic valve disease: should we look more closely at the valve?
  1. Romain Capoulade,
  2. Jean-Jacques Schott,
  3. Thierry Le Tourneau
  1. l’institut du thorax, INSERM, CNRS, CHU Nantes, Univ Nantes, Nantes, France
  1. Correspondence to Dr Romain Capoulade, l’institut du thorax, INSERM, CNRS, CHU Nantes, Univ Nantes, Nantes 44004, France; romain.capoulade{at}univ-nantes.fr

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Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 0.5%–2% of the adult population, with a male predominance of 3:1.1 BAV is usually characterised by the presence of two unequal-sized leaflets, the larger being the one with the raphe, which arises more frequently (approximately 70%–80%) between right and left coronary cusps.2

Several variants have been identified in sporadic BAV, such as NOTCH1 (9q34.3), FBN1 (15q21.1), NKX2-5 (5q34), MATR3 (5q31.2) and GATA5 (20q13.33), but none of them have provided consistent insight regarding causal mechanisms associated with this pathology. There is some evidence that BAV is the result of abnormal embryonic aortic cusps formation, but complete understanding of the mechanisms underlying this developmental disease remain elusive. In addition, non-valvular phenotypes are commonly documented in patients with BAV: aortic dilation or/and aneurysm are frequently associated abnormalities. This inter-relationship observed between BAV and other coexisting diseases can explain the gaps in understanding mechanisms associated with BAV formation and evolution over time.

Even if BAV is usually considered as a benign condition, an important clinical burden is associated with the disease. During adulthood, patients with BAV are more likely to develop life-threatening conditions such as infective endocarditis or severe aortic regurgitation and/or aortic stenosis, highlighting the important morbidity associated with BAV.2 This is also emphasised by the higher risk of undergoing valve surgery reported in patients with BAV as compared with patients with tricuspid aortic valve (TAV; almost 50% of patients undergoing surgery for isolated severe aortic stenosis present BAV).3 Nevertheless, even if such complications and rates of surgery could be associated with higher long-term risks for patients with BAV, no survival penalty has been reported.4 Recent approaches based on early identification of patients with BAV and familial screening, coupled with further close follow-up and ‘prophylactic’ surgery management could explain, at least in part, these findings. However, despite compelling supportive data, their clinical applications remain subject to a better understanding of BAV heritability, familial inheritance pattern and subclinical expression, three important aspects mandatory to enhance early identification and management of patients with BAV, as well as reinforce the level of evidences for the familial screening in the current recommendations.

To date, only sparse data from relatively small clinical studies have addressed familial clustering of BAV and have reported controversial autosomal-dominant or polygenic inheritance patterns, with incomplete penetrance and expression of the disease.5 In these studies, prevalence of BAV in first-degree relatives (FDR) was reported between 4.6% and 11%, and aortic dilation in FDR between 3% and 32%.

In their Heart paper, Galian-Gay and colleagues report interesting data on familial BAV6: they have compiled data from a multicentre BAV registry on familial clustering and prevalence of BAV in FDR, on the impact of BAV morphological types and associated aortic dilation on the inheritance pattern. This study is the largest series of BAV families, including 256 BAV probands and 724 FDR. Authors report a prevalence of BAV in FDR of 6.4% (ie, within the range of published data), with a male-to-female ratio of 3:1 similar to the one observed in probands (figure 1). The 46 FDR diagnosed with BAV came from 38 families, and they were more frequently diagnosed with concomitant hypertension. Right-left BAV morphological type was the more frequent in FDR with BAV (approximately 70%–80% as also documented in BAV), but there was no relationship between proband and FDR valve morphological type. A moderate heritability (0.47) was found, in a lower range as compared with the previous studies, but in the present study only sporadic BAV without any other associated syndromes or congenital defects were included. Based on the finding from this large series of BAV families, the authors confirm (1) the relatively frequent occurrence of BAV in FDR (6.3%; figure 1), (2) the at least moderate heritability of BAV (0.47) in sporadic cases, mostly following genetic pattern and (3) the independence of the inheritance according to morphological types of BAV, suggesting that morphology of the BAV would not only be strictly defined by genetics but also by other environmental or epigenetic factors/stimuli during valvulogenesis. Taking all together, these findings re-enforce the need of familial screening in BAV patients, without focus on morphological type of BAV, and support an increase of the level of recommendation. This should allow identification of patients at higher risk of developing BAV-related complications that will need a closer follow-up (figure 1).

Figure 1

Aortic valve phenotype and related abnormalities in first-degree relative (FDR) of patients with bicuspid aortic valve (BAV). Tricuspid or bicuspid aortic valve phenotypes in FDR of patients with BAV are associated with different risks of developing BAV-related complications, which further impact their follow-up and management. A prodromal (or non-diagnostic) form of BAV, defined by the presence of a mini-raphe, seems at least for some patients associated with BAV-related complications, supporting that this phenotype should be considered as BAV expression and then that these patients will benefit of a closer follow-up as it is suggested for relatives with BAV. Occurrence of BAV phenotype in FDR of sporadic BAV is approximately 6%–7%, but the prevalence of the prodromal BAV form remain to be determined.

Another important aspect of this study is related to the aortic dilation in FDR.6 Prevalence of aortic dilation, in this relatively young population (mean age of 42 years), was high and, as expected much more important in FDR with BAV than FDR with TAV: there was a fivefold higher occurrence of aortic dilation defined by Z-score (47.8% vs 9.6%; p=0.001), with a predominance at the tubular level as opposed to the root. Two theories have been developed to explain the association between the presence of BAV concomitantly with aortic dilation: disturbed blood flow dynamics due to the opening of a bileaflet valve may explain the dilation of aorta (ie, flow theory: dilation secondary to BAV-induced flow perturbations) or structural alterations of the aorta of patients with BAV that is independent of the haemodynamic burden imposed to the aortic wall (ie, genetic theory: structural proteins involved in BAV formation and aorta dilation).7 In light of previous data and the present study showing there was no significant heritability of aortic dilation in BAV families, it is plausible that both of the theories should be conjointly involved in the development of aortic dilation in a context of BAV.

Furthermore, these data emphasise an unexpected high rate of aortic dilation (9.6%) in a pre-specified ‘low-risk’ population, such as relatives with normal TAV. Indeed, 65 FDR were identified with a normal functioning TAV but with aortic dilation. The risk of aortic dilation in patients with BAV is well recognised even if causes remain unclear. In contrast, in FDR with TAV, the debate remains open: is aortic dilation a part of a BAV syndrome or an unrelated adverse event? The focus on the subset of patients with TAV and aortic dilation provides new insights to explain this observation. Based on the CT performed in 22 patients with this phenotype, nine (41%) patients were reclassified as ‘fruste’ BAV (figure 1).8 This phenotype only identified with high resolution four-dimensional imaging is defined as a small fusion between cusps, mostly at the right–left commissure (as observed in BAV). Interestingly, patients with this phenotype also presented an eccentric jet and a turbulent flow in the proximal aorta as imaged by cardiac magnetic resonance (CMR). These findings highlight the heterogeneity in the expression of aortic valve raphe and suggest the presence of non-diagnostic or prodromal form of BAV that could be assimilated, at least in part, to BAV phenotype and thus lead to a potential unappreciated frequency of BAV phenotype in FDR, as well as in the general population (figure 1). Identification of fruste BAV is of clinical interest at the time of the screening of BAV families, especially to identify patients with higher risk of aortic dilation, and potentially those who will be more prone to develop valve-related pathologies. As standard two-dimensional transthoracic echocardiogram (TTE) seems to be inappropriate to distinguish this minimal but clinically important form of BAV, and it appears unreasonable to perform CT or CMR in all FDR (ie, invasive nature or time-effectiveness and cost-effectiveness could be debated), the use of three-dimensional (3D) echocardiography should be tested to detect mini-raphe, and further clinical studies have to be done to confirm our ability to identify mini-raphe by 3D TTE.

There are still important limitations of this study to keep in mind.6 First, this study has inherent selection bias due to cross-sectional design. Second, the number of families and FDR screened is relatively low. Third, the analysis of FDR is based on small groups, specifically for the subgroup of the patients with TAV and aortic dilation, which limits wide application. Finally, the mid-term and long-term evolution of FDR with BAV and TAV is of interest and will need further analysis, especially to reinforce the findings of the present study: even if FDR is associated with higher rate of aortic dilation, the number of patients with a clinically significant aorta dilation defined by aorta >45 mm is very low (0.4% in FDR with TAV) and the progression of a ‘minimal’ dilation could also be insignificant in the future, without any impact on management and morbidity/mortality. Further large clinical studies should be designed to address these issues.

The present study reports important data on familial clustering, in a large cohort of BAV and FDR. Authors provide supportive data for the screening of BAV families, with a particular focus on valve phenotyping. Indeed, the identification of a prodromal form of BAV, which is associated with aortic dilation and disturbed aortic flow, could be of clinical interest to redefine the spectrum of BAV disease, its prevalence and associated comorbidities (figure 1), as well as identify genetic factors and mechanisms associated with this frequent congenital disease.

References

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Footnotes

  • Contributors RC drafted the editorial. All authors reviewed the editorial and provided intelectual content.

  • Funding RC holds a ‘Connect Talent’ research chair from Region Pays de la Loire and Nantes Metropole (France).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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