BAV is a congenital heart anomaly, and to the best of our knowledge, the literature reports exclusively genetic causes of BAV. However, other causes of BAV such as intrauterine infection or intoxication appear to be a possible cause. Moreover, the BAV phenotype is highly variable, and epigenetic modifiers and environmental factors are likely to play an important role in BAV disease event when a distinct causative genetic defect can be identified [19].

We classify the genetic causes of BAV according to frequency and mechanisms (Table 15.2). First, male predominance and familial occurrence of BAV are found in BAV, which argue for a genetic mechanism in a majority of individuals with BAV. Second, only a small fraction of individuals with BAV have chromosomal disorders. However, some chromosomal disorders, such as Turner syndrome, have BAV in up to 30%. Third, BAV may be a monogenetic disease, where autosomal dominant traits are most frequent, but where other traits, such as autosomal recessive or X-linked traits, may occur. Monogenetic BAV can occur sporadically [20].

NOTCH1, TGFBR1, and FBN1 are examples for genes, where series of patients suggest a causative relationship between gene defect and BAV phenotype. Conversely, ACTA2 and SMAD6 are examples for genes, where studies of individual patients or studies of relatives suggest such a causative relationship. In most of these genes, the pathogenic mechanism is unclear, and the association of mutation with phenotype is not firmly established. The NOTCH1, however, is a good example for a gene, where the association with BAV is well established, whereas the FBN1 gene or the DMD gene is an example, where this relationship has been questioned. In all putatively causative genes however, the BAV phenotype and the associated cardiovascular and systemic phenotype are variable.

The etiology of BAV is polygenetic, where environmental factors and unknown genetic factors seem to interact. In some instances, chromosomal aberrations or defined gene defects cause BAV.

An aortic valve may be considered “bicuspid” when we identify two cusps instead of three. However, numerous classification systems are available to further differentiate or classify BAV on the basis of anatomical criteria (Table 15.3).

First, anatomical classifications distinguish BAV from other anatomical variants of the aortic valve. These classifications include differentiation of congenital from acquired BAV and differentiation of BAV from unicuspid (UAV), quadricuspid (QAV), or pentacuspid (PAV) aortic valves according to the number of aortic valve cusps.

Second, anatomical classifications subclassify congenital BAV according to anatomical features of the aortic valve. Such classifications distinguish BAV according to patterns of valve calcification and the grade of valve calcification. However, most anatomical classifications focus on characterizing BAV according to which cusps are fused to one cusp and whether a raphe is present or absent. Unfortunately, there are many variants of such anatomical classifications, where some use the same expression to characterize different types of valves. We believe that a uniform classification system should be used. Buchner et al. distinguished BAV with raphe, where they classify BAV-RL, BAV-RN, and BAV-LN, depending on which aortic cusps, the right (R), left (L), or noncoronary (N), are fused, from BAV without raphe, where BAV-LA designated BAV with lateral orientation of the free edge of cusps and BAV-AP with anterior-posterior orientation. This classification covers all other classification systems and it is simple.

Third, we tabulate classification systems that combine the above described anatomical classification of BAV with other features of BAV disease, such as valvular function or aortic shape. However, such classifications may yield >20 subtypes, which are complicated to use without offering the reward of improving clinical management. Moreover, these combi-classifications are only in use to describe all possible combination of BAV anatomy with additional BAV disease features rather than that they establish new disease entities (such as a typical aortopathy in LR-BAV), and hence they do not provide additional insight into BAV disease.

Congenital BAV must be distinguished from acquired BAV. Congenital aortic valve malformations differ by number of cusps, ranging from one to five. BAV cusps can be subclassified according to patterns of calcification, severity of calcification, presence of a raphe, and fusion of cusps. Combi-classifications, where anatomical subtypes of BAV are combined with additional features of BAV disease, may be too complex for routine clinical use.

We classify BAV into four categories according to the presence of associated congenital heart defects (CHDs):

We tend to perceive BAV as an isolated CHD. However, we identified 20 well-defined syndromic, complex, or isolated congenital heart defects that are associated with BAV disease; some of them are apparently quite frequent.

BAV may be associated with aortic dilatation or aneurysm of the proximal aorta, the aortic arch, the descending aorta, or the abdominal aorta. Some studies classified BAV into four groups by type of aortopathy. BAV aortopathy was classified:

None of these classifications have been applied prospectively in large cohorts of unselected individuals with BAV, and hence their overlap and comprehensiveness cannot be estimated properly. However, all classifications provide useful means to describe subtypes of BAV aortopathy for future assessment of prognosis (Table 15.5).

Patients with BAV may exhibit additional factors that may increase diameter of the aorta and increase the risk of aortic aneurysm formation, aortic dissection, and rupture. We distinguish risk that may arise from three types of risk factors:

The evidence for increased risk for aortic complications is not equally strong for all factors in BAV (Table 15.6).

Biomarkers should provide information of the development and evolution of BAV aortopathy. Aortic diameters clearly provide the single most important information on presence and risk of BAV aortopathy. Therefore, guidelines base their recommendations of timing for elective surgery of the aortic root predominantly on diameters [176–178]. Nonetheless, aortic size has to be judged differently depending on sex, body size, body surface, and the individual tissue stability of the aortic wall [179]. Additional biomarkers may be helpful to further stratify the risk of acute aortic events in BAV aortopathy.