**3. Morphologenesis**

also known as the latero-lateral cusps position which is seen in 70-86% of the BAV cases, whereas the fusion of the right and noncoronary cusps (R-N BAV; antero-posterior cusps position) are observed in 12-28% and the left and noncoronary cusps (L-N BAV) in 0.5-3% of the cases [7-11] [Figure 1]. R-N BAVs and asymmetrical sized cusps are relative risk factors that seem to accelerate the stenosis with 27 mm Hg per decade and are therefore more often associated with AS [12]. BAV with equal cusps and absence of raphé have also been reported [6, 7]. In some cases, the raphé can have a quite deep indentation, which could give a false echocardiographic image of a normal tricuspid aortic valve [13]. Calcium depositions are often confined to the raphé and the base of the cusps [7]. AS tend to develop in BAVs which contain no redundant cusp tissue whereas AR tend to develop in BAVs due to the different dimensions of the two cusps, valve prolapse or redundancy of one cusp [14-16]. Histological examination demonstrates that the raphé does not contain fibrous valve tissue but rather include elastin fibers [17]. BAV should also be distinguished from unicommisural valves that tend to calcify and degenerate even earlier in life. Unicommissural valves includes one commissure with normal height and two raphe's that are much lower height, while there is one large cusp, more or less moving like a bicuspid valve. Up to 90% of the individuals with normal tricuspid valve have right coronary artery dominance whereas 29% to 57% of the patients with BAV disease present with left coronary artery dominance. The average length of the left main stem for individuals with BAV and tricuspid valve is less than 5 mm (90% of the cases) and 10 mm in length, respectively. Recognition of these associations with BAV is mandatory due to the increased risk of perioperative myocardial infarction and a potential risk of insufficient myocardial preservation at the time of aortic valve replacement (AVR) [18, 19, 20]. L-R BAVs are often associated with right coronary artery taking its origin from the right sinus of Valsalva, while in the R-N BAVs, both coronary arteries derive from the anterior sinus [21]. The vast

306 Calcific Aortic Valve Disease

majority of the patients with COA present with a L-R BAV (66-90%) [9, 135, 136].

**Figure 1.** Schematic illustration of the anatomic variations of BAV. (A) normal tricuspid aortic valve. (B) Bicuspid aortic valve, fusion of the left and right coronary cusps. (C) Bicuspid aortic valve, fusion of the right and noncoronary cusps.

(D) Bicuspid aortic valve, fusion of the left and noncoronary cusps.

The embryogenesis of BAV is still not fully understood. It seems that both genetic predispo‐ sition and environmental factors, which could influence the valve morphogenesis, play an important role in the pathogenesis of BAV disease. Initially, the major factor in the formation of BAV is the fusion of the two cusps at the early foundation of the valvulogenesis [22]. The valve morphogenesis occurs in the early stage of foetal development. The heart is one of the first organs to develop through the specification and migration of the anterior lateral plate mesoderm cells which later forms the cardiac crescent [23]. At 3 weeks of gestation in humans, the cardiac progenitors migrate along the ventral midline where they fuse and form a linear heart tube. This beating heart tube is composed of an inner endocardial cell layer which is separated by the extracellular matrix (ECM). Cardiac looping occurs at 4 to 5 weeks of gestation which brings the atrial region of the linear tube into the posterior position of the common ventricles. This is followed by the increase of ECM production which causes the tissue to swell at several areas of the primitive heart, which leads to the formation of the endocardial cushions at the outflow tract (OFT) and atrioventricular (AV) canal. The inner endocardial cells transform into mesenchymal cells, also known as the epithelial-to-mesenchymal transforma‐ tion (EMT). EMT initiates the formation of the aortic valve in the OFT. Afterwards, the cushions undergo massive cell proliferation, as a result growing towards each other with cushion fusion being the outcome. Subsequently, the endocardial cushions develop into thin protruding leaflets that are composed of endocardial cells and ECM which remodels the valves. This complex development is reliant on apoptosis, ECM remodeling and cell differentiation. The main contributors for the aortic valve in the OFT are the mesenchymal cells that reach the OFT cushions in association with the endocardial derived mesenchymal cells [24, 25]. Therefore, any disorder in the endocardial cushion development could lead to potential valve disorder including BAV. A disturbance in the neural crest migration which could lead to the fusion of the aortic valve cushions is thought to be a possible embryological explanation for the pathogenesis of BAV disease [22, 26-28]. Several aneurysms which originate from the neural crest including intracranial aneurysms, aortic aneurysms, and cervicocephalic aneurysm have also been observed in patients with BAV disease [29, 30]. Endothelial nitric oxide synthase is a vital protein for valve formation during embryogenesis. Knockout mice lacking this protein showed a high predisposition for BAV due to the fact that malformation in this protein could lead to disturbance of the intricate cell signals which are essential for valvulogenesis [31]. Moreover, it seems that L-R BAV and R-N BAV have different etiological attributes and genotypes. The pathogenesis of R-N BAV is most likely the result of morphogenetic defect which occurs before the OFT septation and is dependent on an aggravated nitric oxide– dependent epithelial-to-mesenchymal transformation. In contrast, L-R BAV is most probably the outcome from the anomalous septation of the proximal portion of the OFT which is caused by distorted activities of neural crest cells [32].

degree family members of BAV patients to receive an echocardiographic screening to exclude any potential congenital heart disease including thoracic aortic aneurysms [39, 67, 68].

Bicuspid Aortic Valve

309

http://dx.doi.org/10.5772/55325

Although the vast majority of BAV disease are isolated cases, patients with BAV could also present with additional congenital cardiovascular malformations [40-43]. BAV associated anomalies are illustrated in Table 1. Whereas most associated anomalies need treatment early in life, BAV often contributes to morbidity at an older age. COA and Turner Syndrome will be

COA is a commonly seen congenital abnormality with an incidence of 50 of 100.000 births, whereby the aorta is narrowed in the region where the ductus arteriosus enters [figure 3]. COA can present itself as a simple or complex COA with simple COA referring to COA being an isolated defect and complex COA referring to a combination of COA with other cardiac defects. Congenital BAV is present in around 57% of the COA cases [44]. In the vast majority of the cases, COA in combination with BAV is observed with the fusion of left and right coronary cusps [9]. Patients with both BAV and COA have an increased risk for developing several aortic complications including aortic dissection, AS, AR, and aortic aneurysms [16, 44, 46, 49]. The overwhelming majority of BAV patients present with a L-R BAV (66-90%) [9, 135, 136].

Patients with both BAV and COA receive surgical intervention at a relative young age. Surgical options, mostly depending of the type of lesion include bypass of the coarcta‐ tion, patch aortoplasty, aneurysm replacement, arch and descending aorta replacement, subclavian artery patch aortoplasty, tube graft replacement, ascending aorta–to– descend‐ ing aorta bypass or 2-stage combined BAV surgery [69]. Endovascular balloon dilatation and stent placement are currently becoming successful novel interventional options to conventional open surgical treatment [70]. Around 11% to 14% of the patients require a reoperation somewhere in the adulthood [50]. A large cohort study showed that up to 41% of the patients who had a COA required a valve related re-operation [9]. Thus, long-term follow-up in (all) patients with COA including the evaluation of the function of the aortic valve, but also to trace re-coarctation and dilatation of the ascending aorta with routine

Turner Syndrome is a gonadal dysgenesis with complete or partial absence of one of the X chromosome. Cardiovascular defects are frequently observed in Turner Syndrome patients. Turner Syndrome is characterized as neck webbing, short stature, low hairline, and a shield-like chest. BAV disease is the most frequently seen cardiovascular abnormali‐ ty in Turner Syndrome patients [51, 52]. In Turner Syndrome patients, cardiovascular abnormalities are often the primary cause of mortality including the increase risk of aortic

**5. Congenital associated cardiovascular malformations**

further discussed in this chapter.

MRI or echocardiographic evaluation is obligatory.

**5.2. Turner Syndrome**

**5.1. Coarctation of the aorta**

### **4. Genetics**

Genetic burden also seem to contribute to the pathogenesis of BAV disease. It appears that BAV disease has a male-to-female ratio of roughly 3:1 [1-4]. Although some anatomical risk factors have been described, little is known about BAV disease with respect to the genetic insight of calcification process and why patients with BAV disease develop aortic valve calcification including stenosis at an earlier age compared with degenerative tricuspid valve. Chromosomal linkage with BAV disease has been discovered in chromosomal regions 5q, 13q and 18q [36]. Genetic mutations in the *NOTCH 1* gene, which is situated at chromosome 9q seems to be one of the major genetic contributors in the pathogenesis of BAV disease. *NOTCH 1* gene contributes to the pathogenesis of BAV disease through the pathological acceleration of aortic valvular calcium deposition by the increase of the osteogenesis due to the abnormal‐ ities in the signalling pathways [37]. Also, genetic mutations in the *ACTA2* gene which is located at chromosome 10q, is associated not only with BAV disease, but also with familial thoracic aortic aneurysms [38]. *ACTA2* gene encodes for the smooth muscle protein α-actin which is an important element of the contractile apparatus. Several familial clusters associated with BAV disease with an estimated prevalence of 24% of aortic valve disorder were found in relatives with more than one member with aortic valve disorder [33]. Additionally, an estimated BAV disease prevalence of up to 9% in first-degree family members of patients with BAV disease has been reported [34, 35]. Based on this known data, it is advisable for firstdegree family members of BAV patients to receive an echocardiographic screening to exclude any potential congenital heart disease including thoracic aortic aneurysms [39, 67, 68].
