**5. Congenital associated cardiovascular malformations**

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 further discussed in this chapter.

#### **5.1. Coarctation of the aorta**

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

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 first-

by distorted activities of neural crest cells [32].

**4. Genetics**

308 Calcific Aortic Valve Disease

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 MRI or echocardiographic evaluation is obligatory.

#### **5.2. Turner Syndrome**

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 dissection due to aortic root dilatation and therefore responsible for a much lower life expectancy in this subgroup of BAV disease [53, 54]. Due to the relative small body size, Turner Syndrome patients require an elective ascending aortic aneurysm replacement at a much smaller absolute size [54]. Moreover, it should be noted that the aortic size has to be properly indexed to the body surface area. Therefore, proper follow-up and evaluation of the cardiovascular lesions including imaging of the heart and the aorta for evidence of BAV disease or dilatation of the ascending aorta is mandatory. When imaging appears to be without any lesions and there are no additional risk factors for aortic dissection present, a repeated imaging should be conducted every 5 to 10 years or otherwise clinically indicat‐ ed. In contrast, when abnormal imaging is present, regular imaging at smaller intervals should be made with echocardiography or CMRI [67].

**6. Diagnosis**

**6.1. Clinical examination**

**6.2. Echocardiography**

views [figure 4] [59, 60].

Syndrome patients [39, 54].

AS or AR can present themselves with significant symptoms in patients with BAV disease during activity, stress or rest including angina, shortness of breath, syncope or dizziness. In many cases, clinical examination reveals an ejection sound during auscultation at the apex. When AS is present, an ejection click can be often heard at the S1. The S2 is often simultaneously with P2 when AS is present. A diastolic murmur can often be heard when an AR is present. Heart failure of unknown cause could also be present during clinical examination. The ejection sound in BAV patients is most likely associated with anterior movement of the dome shaped BAV, and in rare cases heart failure could also be present during clinical examination in case of rapid deterioration [55]. AS, mitral valve prolapsed, AR, and COA are several associated pathological findings which have to be considered with BAV when a murmer is present.

Bicuspid Aortic Valve

311

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

The current golden standards for diagnosing, surveilling and monitoring BAV disease are

Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) can be used in the diagnosis of BAV disease. TTE has a sensitivity of 78% to 87% and a specificity of 91% to 96% for the diagnosis of BAV disease whereas TEE has a sensitivity and specificity of 87% and 96%, respectively [56, 57, 58]. However, up to 25% of TTE have non-diagnostic

The features of BAV on a TTE include systolic doming, an eccentric closure line in the para‐ sternal long axis views, presence of a single commissural line in the diastolic phase with the occurrence of two cusps and the occurrence of two commisures in the parasternal short axis

Moreover, both preoperative echocardiography and intraoperative TEE are essential for surgical preparation. When BAV disease is present, the degree of AS and AR should be determined with the help of Doppler analysis. After determining the severity of the AR, to ascertain the indication for surgery, especially TEE is needed to clarify the mechanisms that are responsible for AR. This is required to estimate the chance of successful repair and indispensible in surgical preparation. Moreover, any associated cardiovascular abnormalities or complications should be considered. Aortic diameters should therefore also be measured at several levels including valvular insertion, sinuses of Valsalva, sino-tubular junction and the ascending aorta. It should also be noted that in order to measure the severity of the AS by echocardiography- Doppler analysis, the aortic valve area and mean gradient should be applied rather than measuring only on peak systolic gradient, sequentially to prevent overes‐ timation of the severity of the AS [39]. Also, aortic valve area should always be indexed to body surface area in order to correct for different habitus and body sizes, especially in Turner

echocardiography and cardiac magnetic resonance imaging (CMRI) [39].

findings for aortic valve morphology due to severe valvular calcification [57].


**Table 1.** Known cardiovascular abnormalities related to BAV disease.
