**1. Introduction**

Bicuspid aortic valve (BAV) represents the most common cardiac congenital malformation in the adult age, with strong male predominance. It may occur in isolation, or in association with other congenital heart diseases. The BAV is seen in 1% to 2% of the population and may be complicated by aortic stenosis or aortic insufficiency and infective endocarditis. It may be associated with abnormalities of the aortic wall such as coarctation of the aorta, aort‐ ic dissection, and aortic aneurysm. Most patients with a BAV develop some complications during life [1,2].

Congenital coronary anomalies, coronary atherosclerosis, and calcification have been descri‐ bed in association with BAV[3].

BAV has been identified at a prevalence of 4.6 cas-es per 1000 live births. The prevalence of BAV according to sex has been found to be 7.1 cases per 1000 among male neonates, and 1.9 per 1000 among female neonates.

The congenitally BAV may function normally throughout life, may develop progressive cal‐ cification and stenosis or may develop regurgitation with or without infection. Aortic root dilatation is common in BAV, even when the valve is haemodynamically normal, and conse‐ quently aortic dissection usually occurs in previously asymptomatic patients [4,5].

Aortic stenosis and regurgitation, infective endocarditis and aortic dissection are the most common complications. Left coronary artery dominance is more common in patients with a BAV (29-56.8%) and in 90% of cases, the left main coronary artery is less than 5 mm in length [6-8]. The ignorance of these associations may cause an inadequate myocardial pres‐ ervation and an increased risk of myocardial infarction[9,10].

© 2013 Demir; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Accordingly, associated congenital cardiovascular anomalies have been reported in as many as 25% of patients. Patent ductus arteriosus and ventricular septal defect are the most fre‐ quent heart defects associated with BAVdisease [11].

spatial orientation of the two cusps. When the orientation of the cusps is anteroposterior, the coronary arteries originate from the anterior sinus or if cusps laterlateral oriented the right

The Bicuspid Aortic Valve http://dx.doi.org/10.5772/52567 337

A recent study has demonstrated that BAVs with fused right and noncoronary leaflets and those with fused right and left leaflets are different etiological entities. BAVs with fused right and noncoronary leaflets result from a morphogenetic defect that occurs before cardiac outflow tract septation on the basis of an exacerbated nitric oxide-dependent epithelialtomesenchymal transformation. On the other hand, BAVs with fused right and left leaflets re‐ sult from anomalous septation of the proximal portion of the cardiac outflow tract, caused

The pulmonary valve can also be bicuspid, although this is much rarer and is most com‐ monly associated with congenital heart disease such as Tetralogy of Fallot. There have been less than 10 cases reported in the literature of an isolated bicuspid pulmonary valve [22].

Deficient fibrillin-1 content in the vasculature of BAV patients may trigger matrix metallo‐ proteinase production, thereby leading to matrix disruption and dilation. It has been noted that the fibrillin-1 content was remarkably reduced in the aorta of BAV patients, compared with that of patients with a tricuspid aortic valve. Aortic elasticity measurements of BAV pa‐

The bicuspid valve is composed of two leaflets, of which one is usually larger (due to fusion of two cusps leading to one larger cusp), and unequal cusp size the presence of a central raphe (usually in the center of the larger of the two cusps). The raphe or fibrous ridge is the site of con‐ genital fusion of the two components of the conjoined cusps and does not contain valve tissue (Figure 1) Three morphologies are identified: type 1, fusion of right coronary cusp and left cor‐ onary cusp; type 2, fusion of right coronary cusp and noncoronary cusp; and type 3, fusion of left coronary cusp and noncoronary cusp. The most common is type 1 (70% to 85%), followed

**Figure 1.** Transesophageal short-axis view of a BAV. There is fusion of the right and left cusps. The arrow points to the

tients suggest that diminished aortic elasticity is at least part of its causation [23-25].

by type 2 (10% to 30%) and most rare type 3 (1% ) [13,19,26] (Figure 2).

coronary artery originate from the common trunk and right Valsava's sinus [20].

by dysfunctional neural crest cells [21].

**1.2. Anatomy**

raphe.

#### **1.1. Embryology and pathogenesis**

The definitive fetal cardiac structure is evident from the second week of gestation, whereas separation of the heart into four chambers is completed during the sixth and seventh weeks of gestation resulting in separated systemic and pulmonary circulation[12]. The process of aortic valve morphogenesis begins from the cardiac cushions located in the ventricular out‐ flow tract of the primary heart tube. In the outflow tract, the truncal cushion swellings con‐ tribute to form three leaflet valves of the aorta and pulmonary artery.The initial endocardial cushions, which will contribute to all four cardiac valves, are formed by the thickening of the extracellular matrix in the region of the atrioventricular and outflow tract.This process is initiated by the secretion of extracellular matrix proteins such as fibronectin and transferrin across the cardiac jelly to the adjacent endocardium. The endocardium then secretes trans‐ forming growth factor beta family members, which act synergistically with bone morphoge‐ netic protein-2 secreted by the myocardium, to increase mesenchyme formation and proliferation, which results in the growth of the endothelial cushions. The myocardial cells then invade the margins of the cellular endothelial cushions [13].

The semilunar valves form the division of the truncus arteriosus into two separate channels which form the aortic and pulmonary trunks..The channels are created by the fusion of two truncal ridges across the lumen. In each channel a third swelling occurs opposite the first two which will form the 3rd leaflet. In the normal aortic valve the left and right leaflets of the adult valve are formed from the respective swellings while the posterior leaflet is formed from a swelling in the aortic trunk.

The pathogenesis of BAV is not yet fully understood. There is certainly a genetic compo‐ nent, especially given the association of BAV with other congenital abnormalities. However, fusion of the right and left valve cushions at the beginning ofvalvulogenesis appears to be a key factor in BAV formation [14].

A previous study suggested that BAV is a consequence of the anomalous behavior of cells derived from the neural crest because BAV often is associated with congenital aortic arch malformations and other neural crest-derived systems [15]. Other studies suggest that ex‐ tracellular matrix proteins may affect the initiation of cell differentiation during valvulogen‐ esis, while a molecular abnormality in this process may lead to the formation of abnormal cusps [16,17]. Some researchers suggest that a molecular abnormality in the extracellular matrix may lead to abnormal valvulogenesis, becouse matrix proteins help direct cell differ‐ entiation and cusp formation during valvulogenesis [16-18]. This could also explain why BAVis often linked to other cardiovascular anomalies.

These abnormalities cause the fusion of two cusps and lead to one larger cusp; therefore, the BAV usually includes two unequally sized cusps, the presence of a central raphe, and smooth cusp margin. A previous studies showed that raphal position was between the right and left cusp in 86% of cases [19]. An anomalous origin of coronary arteries depends on the spatial orientation of the two cusps. When the orientation of the cusps is anteroposterior, the coronary arteries originate from the anterior sinus or if cusps laterlateral oriented the right coronary artery originate from the common trunk and right Valsava's sinus [20].

A recent study has demonstrated that BAVs with fused right and noncoronary leaflets and those with fused right and left leaflets are different etiological entities. BAVs with fused right and noncoronary leaflets result from a morphogenetic defect that occurs before cardiac outflow tract septation on the basis of an exacerbated nitric oxide-dependent epithelialtomesenchymal transformation. On the other hand, BAVs with fused right and left leaflets re‐ sult from anomalous septation of the proximal portion of the cardiac outflow tract, caused by dysfunctional neural crest cells [21].

The pulmonary valve can also be bicuspid, although this is much rarer and is most com‐ monly associated with congenital heart disease such as Tetralogy of Fallot. There have been less than 10 cases reported in the literature of an isolated bicuspid pulmonary valve [22].

Deficient fibrillin-1 content in the vasculature of BAV patients may trigger matrix metallo‐ proteinase production, thereby leading to matrix disruption and dilation. It has been noted that the fibrillin-1 content was remarkably reduced in the aorta of BAV patients, compared with that of patients with a tricuspid aortic valve. Aortic elasticity measurements of BAV pa‐ tients suggest that diminished aortic elasticity is at least part of its causation [23-25].

#### **1.2. Anatomy**

Accordingly, associated congenital cardiovascular anomalies have been reported in as many as 25% of patients. Patent ductus arteriosus and ventricular septal defect are the most fre‐

The definitive fetal cardiac structure is evident from the second week of gestation, whereas separation of the heart into four chambers is completed during the sixth and seventh weeks of gestation resulting in separated systemic and pulmonary circulation[12]. The process of aortic valve morphogenesis begins from the cardiac cushions located in the ventricular out‐ flow tract of the primary heart tube. In the outflow tract, the truncal cushion swellings con‐ tribute to form three leaflet valves of the aorta and pulmonary artery.The initial endocardial cushions, which will contribute to all four cardiac valves, are formed by the thickening of the extracellular matrix in the region of the atrioventricular and outflow tract.This process is initiated by the secretion of extracellular matrix proteins such as fibronectin and transferrin across the cardiac jelly to the adjacent endocardium. The endocardium then secretes trans‐ forming growth factor beta family members, which act synergistically with bone morphoge‐ netic protein-2 secreted by the myocardium, to increase mesenchyme formation and proliferation, which results in the growth of the endothelial cushions. The myocardial cells

The semilunar valves form the division of the truncus arteriosus into two separate channels which form the aortic and pulmonary trunks..The channels are created by the fusion of two truncal ridges across the lumen. In each channel a third swelling occurs opposite the first two which will form the 3rd leaflet. In the normal aortic valve the left and right leaflets of the adult valve are formed from the respective swellings while the posterior leaflet is

The pathogenesis of BAV is not yet fully understood. There is certainly a genetic compo‐ nent, especially given the association of BAV with other congenital abnormalities. However, fusion of the right and left valve cushions at the beginning ofvalvulogenesis appears to be a

A previous study suggested that BAV is a consequence of the anomalous behavior of cells derived from the neural crest because BAV often is associated with congenital aortic arch malformations and other neural crest-derived systems [15]. Other studies suggest that ex‐ tracellular matrix proteins may affect the initiation of cell differentiation during valvulogen‐ esis, while a molecular abnormality in this process may lead to the formation of abnormal cusps [16,17]. Some researchers suggest that a molecular abnormality in the extracellular matrix may lead to abnormal valvulogenesis, becouse matrix proteins help direct cell differ‐ entiation and cusp formation during valvulogenesis [16-18]. This could also explain why

These abnormalities cause the fusion of two cusps and lead to one larger cusp; therefore, the BAV usually includes two unequally sized cusps, the presence of a central raphe, and smooth cusp margin. A previous studies showed that raphal position was between the right and left cusp in 86% of cases [19]. An anomalous origin of coronary arteries depends on the

quent heart defects associated with BAVdisease [11].

then invade the margins of the cellular endothelial cushions [13].

formed from a swelling in the aortic trunk.

BAVis often linked to other cardiovascular anomalies.

key factor in BAV formation [14].

**1.1. Embryology and pathogenesis**

336 Calcific Aortic Valve Disease

The bicuspid valve is composed of two leaflets, of which one is usually larger (due to fusion of two cusps leading to one larger cusp), and unequal cusp size the presence of a central raphe (usually in the center of the larger of the two cusps). The raphe or fibrous ridge is the site of con‐ genital fusion of the two components of the conjoined cusps and does not contain valve tissue (Figure 1) Three morphologies are identified: type 1, fusion of right coronary cusp and left cor‐ onary cusp; type 2, fusion of right coronary cusp and noncoronary cusp; and type 3, fusion of left coronary cusp and noncoronary cusp. The most common is type 1 (70% to 85%), followed by type 2 (10% to 30%) and most rare type 3 (1% ) [13,19,26] (Figure 2).

which encodes for smooth muscle alpha-actin (ACTA2), and mutation in this gene can result in thoracic aneurysm and, in some instances, BAV [40]. Also the ubiquitin fusion degrada‐ tion 1–like gene UFD1L (chromosome 22q11.2) expressed in the outflow tract during em‐ bryogenesis is down-regulated in BAV tissue when compared with trileaflet valve tissue [41]. The UFD1L gene encodesa component of a multi-enzyme complex involved in the deg‐ radation of ubiquitin fusion proteins, and is highly expressed during embryogenesis in cer‐ tain tissues. It seems to play a key role in the development of ectoderm-derived structures, including neural crest cells.Downregulation of the UFD1L gene, hypothetically resulting from an anomalous behavior of neural crest cells, may lead to reduced degradation activi‐ ties, and may finally lead to fusion of valve cushions, a key factor in the development of congenital BAV[42]. Recent American College of Cardiology (ACC)/American Heart Associ‐ ation (AHA) adult congenital heart disease guidelines suggest echocardiographic screening

The Bicuspid Aortic Valve http://dx.doi.org/10.5772/52567 339

Although these valves are more common in males than females by a factor of 2:1 in the gen‐ eral population, the prevalance was equal in males and females in families having more

Clinical findings are usually limited to auscultation with most patients having an ejection systolic murmur heard loudest at the apex [47]. The S1 usually is normal but sometimes may be associated with ejection click. The S2 is soft, and when aortic stenosis is present, S2 occurs simultaneously with P2. In aortic stenosis, an ejection systolic murmur is heard in the left second intercostal space but may also be transmitted to the carotid arteries. If aortic incom‐

The electrocardiogram is usually normal; and ECG changes are not specific in patients with BAV: left ventricular hypertrophy, atrial enlargement, and arrhythmias may be present.

The mainstay of diagnosis is echocardiography (transthoracic or transoesophageal) which can provide a definitive diagnosis in the majority of patients [ 92% sensitivity and 96% spe‐ cificity) [48,49]. Transesophageal echocardiography (TEE) is also very important for evaluat‐ ing the aortic valve and thoracic aorta, whereas the sensitivity and specifity of multiplane

The parasternal short axis view allows for direct visualization of the valve cusps. In this view the normal triangular opening shape is lost, becoming more "fish mouth-"like in ap‐ pearance, more similar to the mitral valve. This is especially pronounced in systole, as in di‐ astole the raphe can appear similar to a commissure of the third cusp. Differentiating severe bicuspid aortic stenosis from severe other aortic stenosis can also be difficult. In order to es‐ tablish the diagnosis, the valve must be visualized in systole in the short-axis view. In the long-axis view, the valve often has an eccentric closure line and there is doming of the leaf‐ lets. If there is uncertainty in diagnosis, a TEE can improve visualization of the leaflets [50].

for BAV and aortopathy in first-degree relatives of patients with BAV [43,44].

petence is present, a diastolic murmur of aortic regurgitation may be heard.

technique for assessing aortic valve morphology is high [13].

than one affected individual [45,46].

**2. Diagnosis**

**Figure 2.** The classification and incidence of BAVs.

The site of cusp fusion can have effects on the prognosis of BAV [27], with the suggestion that type 1 BAVs are more likely to stenose as adults while type 2 valves will have complica‐ tions at a younger age. The fused valve leaflet in BAV is actually smaller in area. Valvular incompetence is usually caused by the redundancy of one cusp, since the two cusps usually have different dimensions [28]

The coronary anatomy can be abnormal. Most patients with BAV disease have a left dominant coronary circulation [29]. This left coronary can arise from the pulmonary artery. The left main can also be up to 50% shorter than in normal in up to 90% of cases. This is an important consid‐ eration for any aortic valve surgery. The commonest abnormality associated with BAV is dila‐ tation of the thoracic aorta, also known as aortopathy. This is thought not only to be due to the altered flow in the aorta, but also due to cellular structural abnormalities including decreased fibrillin, causing smooth muscle cell detachment, and cell death [30].

The other abnormality found in conjunction with BAV disease is coarctation of the aorta. [22,31]. The presence of coarctation and a poor result from repair can lead to more rapid fail‐ ure of the valve or aortic dissection.

#### **1.3. Genetics**

BAV is an inheritable disorder, with a family recurrence rate of approximately 35% [33]. Re‐ cent clinical studies have reported a 9% prevalence of BAV in first-degree relatives of pa‐ tients with BAV which was the estimated population prevalance of 1-2% [33-35].

BAV is likely due to mutations in different genes with dissimilar patterns of inheritance [33].

The first genetic cause of BAV is Anderson syndrome, which is reported to be a result of mutations in the potassium channel gene KCNJ2 (chromosome 17q24.3)], whereas it clinical‐ ly presents as ventricular arrhythmias, periodic paralysis, and scoliosis [36]. Another muta‐ tions in a gene called NOTCH1(gene map locus 9q34.3), a transmembrane receptor that has a role in determining cell outcome in organogenesis, were noted in two families with BAV [37]. Regions 18q, 5q, and 13q are reported to contain genes responsible for BAV and/or as‐ sociated cardiovascular malformations [38,39]. The region 10q contains the ACTA2 gene, which encodes for smooth muscle alpha-actin (ACTA2), and mutation in this gene can result in thoracic aneurysm and, in some instances, BAV [40]. Also the ubiquitin fusion degrada‐ tion 1–like gene UFD1L (chromosome 22q11.2) expressed in the outflow tract during em‐ bryogenesis is down-regulated in BAV tissue when compared with trileaflet valve tissue [41]. The UFD1L gene encodesa component of a multi-enzyme complex involved in the deg‐ radation of ubiquitin fusion proteins, and is highly expressed during embryogenesis in cer‐ tain tissues. It seems to play a key role in the development of ectoderm-derived structures, including neural crest cells.Downregulation of the UFD1L gene, hypothetically resulting from an anomalous behavior of neural crest cells, may lead to reduced degradation activi‐ ties, and may finally lead to fusion of valve cushions, a key factor in the development of congenital BAV[42]. Recent American College of Cardiology (ACC)/American Heart Associ‐ ation (AHA) adult congenital heart disease guidelines suggest echocardiographic screening for BAV and aortopathy in first-degree relatives of patients with BAV [43,44].

Although these valves are more common in males than females by a factor of 2:1 in the gen‐ eral population, the prevalance was equal in males and females in families having more than one affected individual [45,46].
