Bicuspid aortic valve

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation with a prevalence of 1% and occurs when the aortic valve has only two cusps instead of the normal three.1 BAV is a common cause of adult valve disease and accounts for the majority of acquired valvular disease in industrialised countries.2 In cases of BAV, the normally thin aortic valve cusps often prematurely calcify leading to valvular thickening and stenosis.3 These malformed valves may also present with aortic regurgitation and are at increased risk for infective endocarditis.4 BAV not only affects valvular function but is also associated with aortic and pulmonary root dilatation.5 Thoracic aorta aneurysm (TAA) is found in up to 50% of people with a BAV and may result in the development of aortic dissection.6 BAV is thus becoming increasingly recognised as an important contributor to adult cardiovascular disease, and the genetic basis of the BAV is actively being investigated.

Genetic contributions to BAV

Cardiac valve development begins when the heart is a simple tube, and at this time the extracellular matrix thickens to form the endocardial cushions in the common outflow tract. The endocardial cushions with a contribution from migrating cardiac neural crest cells undergo remodelling to form the aortic and pulmonary valves together with the proximal aortic and pulmonary walls. These initial stages of valve formation involve multiple signalling molecules including members of the TGFβ, Ras, Wnt/β-catenin, VEGF and NOTCH signalling families.7 The leaflet primordia then divide into three separate cusps for each great vessel. When this process goes awry in the aorta, two leaflet primordia do not separate or remain fused, resulting in BAV. Fusion between the right and left coronary cusps occurs most frequently while fusion of the right coronary and non-coronary cusps is the next most common location of fusion. The left coronary and non-coronary cusps rarely remain fused.8 9 The molecular mechanisms regulating these final stages of valve formation remain to be elucidated.

Population-based studies support a strong genetic component in BAV. Nearly four decades ago, case reports described families with multiple members with BAV. More formal investigations of 30 index cases and their families by Huntington et al demonstrated BAV in 17/186 (9.1%) of relatives.10 BAV often occurs in the setting of other cardiac malformations that affect left-sided cardiac structures, such as aortic coarctation and hypoplastic left heart syndrome. The article by Kerstjens-Frederikse et al published in this issue of Heart demonstrates and reviews multiple investigations that support the increased incidence of BAV in this population (see page 1228).11 Familial aggregation and genetic association studies have demonstrated high heritability for BAV alone or BAV associated with other cardiovascular malformations consistent with common genetic aetiologies.12 13

Analysis of a large pedigree with features of Anderson syndrome, which is characterised by ventricular arrhythmias, periodic paralysis, dysmorphic facies, cleft palate and scoliosis, identified a point mutation in the gene, KCNJ2, which encodes for the inward-rectifying potassium current Kir2.1.14 A subset of these family members (4/41) had BAV and provided the first genetic link to BAV in humans, but the mechanisms by which altered potassium signalling leads to aortic valve malformations remain unknown. More recently, studies involving two families with an autosomal dominant form of BAV and associated aortic valve calcification led to the discovery that mutations in NOTCH1, a single-pass transmembrane receptor that functions in a highly conserved pathway that plays critical roles in cell fate determination during organogenesis, were associated with non-syndromic BAV in humans.15 Subsequently, observations of missense NOTCH1 mutations in a subset (∼5%) of individuals with BAV have been reported with supporting functional data indicating impaired Notch signalling, but the clinical utility of genetic testing for NOTCH1 mutations remains unclear for non-familial cases as the majority were inherited from unaffected parents.16 17 BAV often occurs with a dilated ascending aorta or TAA, and investigators have identified a 30% risk of TAA or BAV in first-degree relatives of individuals with BAV.18 Consistent with this, mutations in NOTCH1 have been identified in individuals with BAV with TAA.19 Additional genetic aetiologies for BAV in humans probably exist, as disease-linked loci on chromosomes 18q, 5q and 13q have been reported, but the specific genes have not yet been identified.20

Studies in animal models have provided clues to a genetic contribution to BAV (reviewed by Garg21). The first mouse model of BAV was reported in mice with targeted deletion of the endothelial nitric oxide synthase gene and suggests that this signalling pathway is critical for aortic valvulogenesis. Furthermore, BAV was seen in a small proportion of mice haploinsufficient for NKX2.5, which encodes a cardiac transcription factor that is a genetic aetiology of non-syndromic congenital heart disease. Lastly, an inbred strain of Syrian hamsters frequently have two leaflet aortic valves, but the specific genetic variations that lead to this increased prevalence are unknown. Animal models, similar to human studies, support the presence of genetic contributors to BAV and its spectrum of associated conditions of TAA and left-sided congenital heart disease.

Screening of family members

As shown by Kerstjens-Frederikse et al and others, it is clear that family members of people with BAV often have cardiovascular disease.11 Estimated empirical risks in the above studies range from 10% to 30% for BAV or dilated ascending aorta in first-degree relatives of people with BAV. While these studies may have ascertainment bias, even the lower end of the range indicates a significant risk. Given that at least one-third of people with a BAV will develop severe complications during their lifetime, approximately 4–10% of first-degree relatives will have cardiac disease.1

Both BAV and TAA are asymptomatic and exhibit few, if any, signs until either haemodynamic changes or aortic dissection occurs. Echocardiography can reliably identify a bicuspid valve and dilated aorta in most cases, with cardiac MRI able to define the anatomy where echocardiographic imaging is suboptimal. Early diagnosis allows intervention to occur before complications arise. Clinical guidelines are well established for aortic valvular disease and thoracic aorta dilatation, and define the timing of operative interventions to prevent complications.22 23 This knowledge fulfils several important considerations for screening as outlined by WHO.24 First, the disease is asymptomatic and not readily identified during routine care. Second, a test is available that can reliably identify the disease. Third, an effective treatment for the disease exists and lastly, early intervention can alter the outcome of the disease. While no formal studies exist, in comparison with other inherited cardiac diseases such as hypertrophic cardiomyopathy and ion channelopathies, screening relatives of individuals with BAV compares favourably for meeting WHO criteria for screening. Based on this evidence from the limited populations studied, the ACC/AHA have recommended the screening of first-degree relatives of adults with BAV.25

Certainly, many unanswered questions remain. Only a single echocardiogram would be required to determine if BAV is present, but BAV is often not associated with valvular dysfunction until adulthood. Similarly, a dilated aorta, even if an individual is predisposed to develop it, is not often seen in childhood and may take years to develop. The life-threatening complication of aortic dissection in the setting of BAV is rare in childhood or adolescence. Accordingly, when cardiac screening for BAV and aortic dilatation should start, and at what intervals after the initial assessment repeat echocardiographic screening should occur, is unknown. As we mentioned above, relatives of people with coarctation of the aorta or hypoplastic left heart syndrome are more likely to have a BAV, but the converse risk for a person with BAV to have a child with the more severe cardiac malformation is unknown. ACC/AHA guidelines for adults with congenital heart disease have recommended prenatal screening of the fetus for heart defects if a parent has been diagnosed with critical aortic stenosis (usually in conjunction with a BAV).25 Finally, no studies exist examining the cost/benefit analysis of such a proposed screening programme in BAV.