Bicuspid aortic valve (BAV) disease is the most commonly encountered defect among adult congenital heart diseases. Complications are common and can be related to valve disease, including aortic stenosis, aortic regurgitation, and infective endocarditis, or can be the result of BAV-related aortopathy, which can result in ascending aortic dilatation, aneurysm formation, and aortic dissection. With heterogeneous presentations and variable phenotypes, the surveillance and decision making in BAV disease remain challenging in view of the parallel considerations given to the valve and the aorta. Recent investigations have provided a better appreciation of clinical outcomes, improved the timing of surgical interventions, and enhanced our understanding of the biology and genetics behind BAV disease.

The most common congenital heart malformation, BAV has a prevalence between 0.5% and 2% in the general population. There is a clear male predominance of at least 3:1. Recently, racial variations have been reported with a very low rate of BAV among African-Americans, noted in echocardiographic and surgical cohort studies.

The majority of BAVs occur in isolation, but in certain groups, they may be associated with other cardiac and congenital anomalies (Table 3.1). The most common cardiac abnormality is dilatation of the ascending aorta (the aortic root, ascending portion, and/or arch), which is present in 50% to 60% of cases.

Among the most common associated congenital conditions is coarctation of the aorta. About 50% to 75% of patients with coarctation of the aorta have a BAV. Numerous congenital defects can also coexist with BAV, including ventricular septal defects, patent ductus arteriosus, atrial septal defects, sinus of Valsalva aneurysms, and coronary artery anomalies. Genetic syndromes that include a BAV may occur; among them are Shone syndrome, Turner syndrome (˜30% have BAV), Loeys-Dietz syndrome (˜20% have BAV), and Williams syndrome.

The exact etiology of BAV remains unknown, but evidence predominantly favors an underlying genetic abnormality leading to a developmental defect early in valvulogenesis. This model, the genetic theory, is more widely accepted as opposed to the hemodynamic molding theory of altered or diminished blood flow through the valve during valvulogenesis. The aortic valve and ascending aorta develop from the remodeled endocardial cushions, with involvement of migrating cardiac neural crest cells. Valve and outflow tract formation in this early stage relies on molecular signaling pathways to regulate development, and perturbations during this time likely result in the altered formation or septation of the leaflet primordia.

In support of a predominant genetic component, pedigree-based reports have demonstrated the heritability of BAV. Familial clustering of BAV disease occurs with an estimated prevalence of 9% among first-degree relatives, and 24% to 37% of families have at least one other affected relative; these studies suggest an inheritance pattern that is autosomal dominant with reduced penetrance and variable expressivity.

In addition to BAV, family members of BAV probands have high heritability for other cardiac and congenital heart defects including ascending aortic abnormalities. Despite these findings, most BAVs occur as sporadic cases. Even though most accept a genetic basis for BAV, the identification of a specific gene abnormality has not been consistent. From both human studies and animal models, there have been a number of identified gene mutations linked to BAV. The recognized genes include NOTCH1, NOS3, KCNJ2, GATA5, HOXA1, NKX2.5, ACTA2, TGFB1, TGFB2, FGF8, AXIN1, and UFD1L. In addition, family-based linkage studies have found associations between BAV and chromosomes 18q, 5q, and 13q.

Given its apparent genetic heterogeneity, it seems that BAV disease is the result of a polygenic disease complicated with variable patterns of penetrance and expressivity, influenced by epigenetic and environmental factors.

The normal aortic valve is a trileaflet (tricuspid) valve, made up of three leaflets (cusps) named by their association with the coronary arteries (left, right, and noncoronary cusps). A BAV results from defective cusp development, leading to a valve possessing two asymmetric leaflets (due to fusion of two cusps) and two commissural attachments. The larger conjoined leaflet typically has a central raphe or a false commissure, a fibrous ridge of tissue where the cusps failed to divide or remained fused. The anatomic variations of BAV have been well described and depend on which commissures remain fused (Fig. 3.1).

The most common BAV morphology is fusion of the right and left coronary cusps (type 1, RL pattern; 70% to 85% of cases), which results in a horizontal commissure and leaflets oriented in an anterior-posterior location. The RL pattern is the most common BAV associated with coarctation of the aorta. The second most common morphology is fusion of the right and noncoronary cusps (type 2, RN pattern; 15% to 25% of cases), which results in a vertical commissure and leaflets oriented in a right-left position. The RN-pattern BAV usually leads to significant valvular dysfunction. Finally, the LN pattern, fusion of the left and noncoronary cusps, is rare (type 3, less than 5% of cases). In over 90% of BAVs, the two cusps are unequal in size, with the fused cusp always being the larger cusp. Finding a BAV with symmetric cusps and no raphe, the so-called “pure” BAV, is rare.

A leaflet classification scheme has been proposed by Sievers and Schmidtke, which includes three major types, first categorized by raphe(s), followed by leaflet orientation and type of valve dysfunction. For example, Sievers type 1, L/R, S refers to a BAV with 1 raphe, LR cusp fusion and aortic stenosis, whereas type 0, L/R, N is a BAV with no raphe, LR fusion, and normal valve function.

It is now well recognized that BAV is associated with dilatation of the ascending aorta. Once thought to be the result of “poststenotic” dilatation, BAV-related aortic enlargement is predominantly attributed to a genetic basis. In support of a genetic underpinning, aortic dilatation can be seen early in life with BAV, without stenosis, and, in children, aortic dimensions increase at a greater rate than in matched controls with a trileaflet aortic valve.

In adults with BAV, aortic dilatation is present in approximately 50% to 60% of cases. The adult ascending aorta at all levels (annulus, sinuses, midascending) is larger in BAV subjects compared with their trileaflet valve counterparts. BAV aortic dilatation can be present in those without valvular dysfunction and can progress despite having undergone valve replacement surgery. Finally, dilated aortas are prevalent in first-degree relatives of probands with a BAV.

Although not considered the primary reason, there is evidence that altered hemodynamics contribute, perhaps in combination, to the primary BAV aortopathy. Even a normally functioning BAV wrinkles, domes, and folds during the cardiac cycle, leading to turbulent flow currents that can impose increased shear stress on the ascending aortic wall. In aortic regions enduring the most increased wall stress, greater degrees of medial matrix disruption are found. These eccentric flow patterns across a BAV will vary depending on leaflet orientation. Visualized using four-dimensional flow magnetic resonance imaging (MRI), the RL-pattern BAV directs a turbulent jet in the direction of the right anterior greater curvature (right-handed flow), whereas the RN-pattern BAV promotes flow toward the posterior aortic wall and proximal arch (left-handed flow). In small populations, these two BAV subtypes were associated with distinct patterns of aortic dilatation, midtubular dilatation, and distal ascending and arch dilatation, respectively.

Because not all BAVs will develop a dilated aorta, the hemodynamic alterations alone are insufficient to fully explain the developing aortopathy. Histologically, BAV-related aortopathy is associated with distinct intrinsic alterations of the aortic wall that reduce its structural integrity. Abnormalities in the aortic media of BAV patients are commonly identified and consist of vascular smooth muscle cell apoptosis, elastic fiber fragmentation, increased matrix metalloproteinase activity, and matrix disruption. These changes notably

differ in pattern from those seen in diseased dilated aortas of patients with trileaflet aortic valves. The degenerative medial process in the aortic wall is thought to result from an imbalance between tissue concentrations of matrix metalloproteinases and their endogenous tissue inhibitors, specifically an increase in matrix metalloproteinase 2 relative to tissue inhibitor of metalloproteinase 1. Moreover, fibrillin-1, the glycoprotein that functions abnormally in Marfan syndrome, has been found in lower amounts in BAV aortas. It has thus been speculated that abnormal signaling of transforming growth factor β may also play a role in BAV aortopathy.

As BAVs differ in morphotype, so do their dilated aortas (Fig. 3.2A-C). Although there is no widely accepted classification scheme, there are three principal patterns of aortic dilatation: