Keywords

1 Introduction

Bicuspid aortic valve (BAV) may simply be viewed as “an aortic valve that has two cusps instead of three,” and BAV aortopathy may simply be considered as “post-stenotic dilatation of the ascending aorta.”

More than 500 years ago, Leonardo da Vinci explained and depicted BAV for the first time. Paget recalled in 1844 the tendency of the BAV to develop disease, Peacock mentioned the tendency of these valves to develop obstructions or regurgitation early, Osler described the predilection of these valves to infective endocarditis, and Victor Babes (1891), in Germany, and 3 decades later Maude Abbott, in North America (1927), commented on an association between congenital BAV and aortic aneurysm, dissection, and rupture, and since Abbott described aortopathy in BAV [1]. Since then, the literature on BAV disease has grown into complex field on detailed and conflicting knowledge.

2 Frequency of BAV and BAV Aortopathy

Besides mitral valve prolapse, BAV is the most frequent congenital heart defect in the general population. Autopsy studies and echocardiographic screening studies yield strikingly similar results on the frequency of BAV in the general population. The prevalence ranges from 0.5 to 1.39% at autopsy and between 0.5 and 0.9% on echocardiographic screening. Autopsy studies and a clinical register of aortic dissection assess the prevalence of BAV in individuals with aortic dissection. Both types of studies report BAV in 7.5–11.2% and 3.5–11.8% of aortic dissections. Nistri et al. found aortic dilatation, which they defined with diameters >2 standard deviation above normal, in 68.9% of young Italian conscripts with BAV at echocardiographic screening [2]. The widely cited 2% prevalence of BAV appears to stem from a single autopsy study published in 1923 [3]. Cohort studies that register aortic events in BAV report on 0.5–0.8% incidence of aortic dissection with various difference of intervals of follow-up, treatment standards, reasons for inclusion, and ages at inclusion into the cohort. Hence, the accurate prevalence and natural history of BAV aortopathy are difficult to interpret in these studies (Table 15.1).

Table 15.1 Frequency of BAV and BAV aortopathy
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3 Classification of BAV: Etiology

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].

Table 15.2 Classification of BAV according to etiology
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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.

4 Classification of BAV: Valve Anatomy

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).

Table 15.3 Classification systems of BAV valve anatomy
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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.

5 Classification of BAV: Associated Congenital Heart Defect (CHD)

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

  1. 1.

    Smaller series report on the presence of BAV in syndromic or complex CHD, such as Ebstein’s anomaly, Shone’s complex, hypoplastic left heart syndrome, double-outlet right ventricle, tetralogy of Fallot, or complete transposition of the great arteries.

  2. 2.

    BAV frequently associates with one typical additional CHD, where coarctation of the aorta (COA), patent ductus arteriosus (PDA), ventricular septal defect (VSD), and atrial septal defect (ASD) are the most common associates of BAV.

  3. 3.

    Coronary arterial anomaly, bicuspid pulmonary valve (BPV), and mitral valve anomalies are rare in BAV, but their association with BAV is well established.

  4. 4.

    There are only sparse or conflicting data on the potential association of BAV with CHD or vascular malformation such as myocardial abnormalities, familial aorto-cervicocephalic arterial dissections, intracranial aneurysms, and various arterial or venous vascular anomalies (Table 15.4).

    Table 15.4 Classification of BAV according to associated congenital heart defect (CHD)
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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.

6 Classification of BAV: Aortopathy

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:

  1. 1.

    Type and presence of aortic valve dysfunction

  2. 2.

    Geometrical configuration of the proximal part of the aorta

  3. 3.

    Involvement of the aortic arch

  4. 4.

    According to presence of coarctation of the aorta (COA)

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).

Table 15.5 Classifications of BAV according to aortopathy
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7 Classification of BAV Aortopathy: Risk Factors

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:

  1. 1.

    From aortic valve characteristics, such as BAV morphotype, BAV stenosis, and BAV regurgitation

  2. 2.

    From comorbidities of BAV, such as arterial hypertension (HTN), atherosclerosis, and coarctation of the aorta (BAV-COA), or from sleep apnea, comprising obstructive (OSA) and central sleep apnea (CSA)

  3. 3.

    From behavioral factors including pregnancy, sports, high-performance aviation with G-force exposure, and drug abuse comprising cocaine, methamphetamine, and sildenafil

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

Table 15.6 Risk factors and predictors of BAV aortopathy
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8 Classification of BAV Aortopathy: Candidate Biomarkers

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.

Candidates for biomarkers of BAV aortopathy comprise a family history with dissection or death at younger age, increased aortic growth rates, proximal aortic shape, biomarkers of aortic stiffness and aortic elasticity markers, biomarkers of aortic wall shear stress (AWASS), biomarkers of endothelial dysfunction, and serological biomarkers (Table 15.7).

Table 15.7 Candidate biomarkers of BAV aortopathy
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No single candidate biomarker of BAV aortopathy has currently accumulated evidence enough for introduction into clinical routine. However, many of the candidate biomarkers exhibit promising data. Some of these markers are likely to improve future management of BAV disease.