**2. Genetic and inheritance**

#### **2.1. Associated with genetic syndrome**

Although most of the BAV patients are sporadic or familial, some may have the symptoms knowngenetic syndromes as Trisomy 18, Williams syndrome, and Turner syndrome. The highest penetrance of BAV (>30%) occurs in woman with Turner syndrome caused by partial or complete absence of one X chromosome [3]. In the general population, BAV is more prevalent in men than women, suggesting that the loss of genes on the X chromosome may predispose to BAV phenotype [3, 4].

ascending aorta aneurysm and BAV [8, 9, 16]. Although the FBN1 gene mutation frequently accompanies Marfan syndrome, its association with BAV and ascending aorta dilatation has been shown in a recent study [17]. The pathologic hallmark of aortic aneurysm is medial degeneration. Disruption of the smooth muscle cells' (SMC) contractility due to mutations may lead to aortic aneurysm. Mutations in the MYH11 and ACTA2 genes are associated with

**Candidate genes Chromosomal regions**

Bicuspid Aortic Valve

101

http://dx.doi.org/10.5772/intechopen.76643

TGFBR2 (Transforming growth factor, beta receptor II) 3p24.1 NKX2.5 (NK2 Homeobox 5) 5q35.1 NOTCH1 (Translocation-associated notch protein TAN-1) 9q34.3 ACTA2 (Actin, alpha 2) 10q23.31 MYH6 (Myosin heavy chain 6) 14q11.2 MYH7 (Myosin heavy chain 7, cardiac muscle, beta) 14q11.2 FBN1 (Fibrillin 1) 15q21.1 ENG (Endoglin) 9q34.11 AXIN1 (Axin 1) 16p13.3 KCNJ2 (Potassium channel, inwardly rectifying subfamily J, member 2) 17q24.3 GATA5 (GATA binding protein 5) 20q13.33 PDIA2 (Protein disulfide isomerase family A, member 2) 16p13.3 TGFBR 1 (Transforming growth factor, beta receptor I) 9q22.33

Consequently, BAV and aortopathy are complex multifactorial and multigenetic pathologies. Genetic, epigenetic, and environmental modifiers may be responsible for the variable pen-

Cardiac and valve morphogenesis occur in early fetal life. Actually the abnormal valvulogenesis of BAV has not been clearly understood. Earlier theories proposed that abnormal blood flow across the developing valves would result in the failure of cusp separation. Current theories suggest that cell migration, signaling pathway, and genetic susceptibility are the main

The embryonic heart and aorta are developed from three precursor cells: proepicardial cells, cardiogenic mesodermal cells (contribute to first and second heart fields [SHfs]), and neural crest cells. Second heart field (SHF) and the cardiac neural crest (CNC) contribute to the

the familial thoracic aortic aneurysms [18].

**Table 1.** Genes with association with bicuspid aortic valve.

etrance and phenotypic expression [4].

factors in the development of BAV disease.

**3.1. Embryology of aortic root**

**3. Aortic root**

#### **2.2. Familial inheritance and genetic etiologies**

The heritability of BAV is now well established; however, the genes linked to the defect remain largely unknown. Autosomal dominant, X-linked, and familial modes of inheritance have been reported. BAV heritage revealed a high incidence of familial clustering. The study performed in the Canadian population revealed that 11 of 30 families (36%) had at least 1 additional member with BAV, and the recurrence rate in first-degree relatives was 9% [5]. Another study reported that 100 out of 448 subjects in a Mediterranean population had BAVs, 348 of which were first-degree relatives. In this study, the BAV recurrence rate in the firstdegree relatives was 4.6%. This value was clearly lower than that in the Canadian population. The populations or geographic areas may affect the prevalence of BAVs [6].

Epidemiologic studies have demonstrated that BAV is heritable and follows an autosomal dominant mode of transmission with reduced penetrance and variable expressivity [7, 8]. Through the linkage analysis of BAV pedigrees, investigators have found multiple genetic loci and chromosomes associated with BAV disease [7–16]. The most significantly associated genes and the chromosomes they are located on are shown in **Table 1**. However, some of these gene mutations have been found to be related with aortopathies. Several mouse studies have showed that the NOTCH1 gene mutation plays an important role in the development of


**Table 1.** Genes with association with bicuspid aortic valve.

ascending aorta aneurysm and BAV [8, 9, 16]. Although the FBN1 gene mutation frequently accompanies Marfan syndrome, its association with BAV and ascending aorta dilatation has been shown in a recent study [17]. The pathologic hallmark of aortic aneurysm is medial degeneration. Disruption of the smooth muscle cells' (SMC) contractility due to mutations may lead to aortic aneurysm. Mutations in the MYH11 and ACTA2 genes are associated with the familial thoracic aortic aneurysms [18].

Consequently, BAV and aortopathy are complex multifactorial and multigenetic pathologies. Genetic, epigenetic, and environmental modifiers may be responsible for the variable penetrance and phenotypic expression [4].

### **3. Aortic root**

dysfunctions, endocarditis, and dissection. In the patients presenting with valvular dysfunction earlier in life, aortic regurgitation (AR) is more common, whereas aortic stenosis (AS) is more prevalent later in life, after the fourth decade. Valve phenotypes, genetic, and hemodynamic factors have been proposed as underlying mechanisms of aortopathy. Ascending aortic aneurysm is generally due to aortopathy and hemodynamics; however, the aortic root aneurysm is considered to be a consequence of aortopathy rather than hemodynamics, especially in younger patients. The asymptomatic BAV patients with normal valvular function require surgical treatment less frequently than those with valvular dysfunction and aortopathy dur-

Moreover, BAV may be associated with several genetic disorders with cardiovascular manifestations such as hypoplastic left-heart syndrome, congenital left-sided obstructive lesions (coarctation of aorta, Shone complex), ventricular septal defect, and syndromic conditions

Although most of the BAV patients are sporadic or familial, some may have the symptoms knowngenetic syndromes as Trisomy 18, Williams syndrome, and Turner syndrome. The highest penetrance of BAV (>30%) occurs in woman with Turner syndrome caused by partial or complete absence of one X chromosome [3]. In the general population, BAV is more prevalent in men than women, suggesting that the loss of genes on the X chromosome may

The heritability of BAV is now well established; however, the genes linked to the defect remain largely unknown. Autosomal dominant, X-linked, and familial modes of inheritance have been reported. BAV heritage revealed a high incidence of familial clustering. The study performed in the Canadian population revealed that 11 of 30 families (36%) had at least 1 additional member with BAV, and the recurrence rate in first-degree relatives was 9% [5]. Another study reported that 100 out of 448 subjects in a Mediterranean population had BAVs, 348 of which were first-degree relatives. In this study, the BAV recurrence rate in the firstdegree relatives was 4.6%. This value was clearly lower than that in the Canadian population.

Epidemiologic studies have demonstrated that BAV is heritable and follows an autosomal dominant mode of transmission with reduced penetrance and variable expressivity [7, 8]. Through the linkage analysis of BAV pedigrees, investigators have found multiple genetic loci and chromosomes associated with BAV disease [7–16]. The most significantly associated genes and the chromosomes they are located on are shown in **Table 1**. However, some of these gene mutations have been found to be related with aortopathies. Several mouse studies have showed that the NOTCH1 gene mutation plays an important role in the development of

The populations or geographic areas may affect the prevalence of BAVs [6].

(Turner, Loeys Dietz). This chapter enrolls only the isolated bicuspid aortic valves.

ing their lives.

**2. Genetic and inheritance**

100 Structural Insufficiency Anomalies in Cardiac Valves

**2.1. Associated with genetic syndrome**

predispose to BAV phenotype [3, 4].

**2.2. Familial inheritance and genetic etiologies**

#### **3.1. Embryology of aortic root**

Cardiac and valve morphogenesis occur in early fetal life. Actually the abnormal valvulogenesis of BAV has not been clearly understood. Earlier theories proposed that abnormal blood flow across the developing valves would result in the failure of cusp separation. Current theories suggest that cell migration, signaling pathway, and genetic susceptibility are the main factors in the development of BAV disease.

The embryonic heart and aorta are developed from three precursor cells: proepicardial cells, cardiogenic mesodermal cells (contribute to first and second heart fields [SHfs]), and neural crest cells. Second heart field (SHF) and the cardiac neural crest (CNC) contribute to the development of aortic root, ascending aorta, and aortic arc. Paraxial mesoderm plays role in the development of descending aorta [19, 20]. First heart field (FHF) forms the early embryonic heart tube that contributes to the left ventricle and a portion of the right ventricle and atria. SHF contributes to the myocardium of the outflow tract to form the truncus arteriosus. Mesenchymal cells originating from the migrating cardiac neural crest cells reach the outflow tract cushions and contribute to the formation of the aortic and pulmonary valves together with the endocardially derived mesenchymal cells. Abnormal migration of neural crest cells has been postulated as a common pathway that results in BAV and aortopathy [21–24].

in the arterial wall, so its destruction directly leads to the expansion of aorta. Moreover, some intrinsic medial degenerative differences have been identified between TAV and BAV patients. While degeneration in TAVs has been attributed to inflammation and accelerated aging, it has been attributed to the maturation defect in BAVs. Several BAV studies have revealed noninflammatory loss of vascular SMCs, less-differentiated vascular SMC, low laminin A/C, and progerin expression as the other causes of medial degeneration [27, 30, 31]. The total thickness of the aortic media is the same for BAV and TAV aortas, but the distance between the elastic lamellae is greater and the lamellae themselves are thinner and more fragmented in BAV patients [30, 32]. It was suggested that matrix disruption and SMC apoptosis were earlier in BAVs with stenosis than TAVs with respect to the dilatation of aorta [33]. The patients with ascending aorta dilatation with BAV showed lesser cystic medial necrosis (focal loss of vacsular smooth muscle cell (VSMC) nuclei in the media) than those with TAV [30]. Nondilated BAV aortas may have higher rates of vascular SMC apoptosis, particularly at the convexity, where wall stress is expectedly higher. Stress-dependent BAV matrix changes may trigger early apoptosis [33].

Bicuspid Aortic Valve

103

http://dx.doi.org/10.5772/intechopen.76643

Deficiency of fibrilin-1: Maturation defect is maintained in the dilated aortic wall in BAV patients. Fibrillin-1, which stabilizes the vascular wall, is secreted by the SMC. It is low in BAV patients because of the immaturity of SMC [21]. Deficiency of fibrillin-1 results in vascular SMC detachment, matrix disruption, and apoptosis, which ultimately result in a fragile aorta, less suited to deal with stress associated with valvular dysfunction. Decreased levels of fibrillin-1 may also lead to tinning and weakening of the aortic wall. Some studies have showed that aortic tissues in BAVs have significantly less fibrillin-1 than TAV aortas [34, 35]. Increased activity of MMPs: To date, most studies have focused on MMP-2 and MMP-9, which belong to a subclass of MMP. An increase in MMPs, enzymes that process or degrade the extracellular matrix, may lead to the weakening of the aortic wall and may be associated with the development of aortic aneurysms. In particular, MMP-2 and MMP-9, secreted from macrophages, which have infiltrated the inflammatory site, are known as powerful proteinases that degrade elastin fiber. BAV patients have dilated aortas with a higher content of MMP and a lower level of tissue inhibitor of MMP compared to TAV patients, indicating an increased collagen turnover. MMP-9 has been closely associated with the formation of abdominal aortic aneurysms [31, 36]. MMP-2 has been identified as a key molecular modulator and a circulation biomarker of aortic dilation in patients with BAV [36]. Several markers as c-Kit (a marker for differentiated vascular SMCs), pc-Kit (phosphorylated state of c-Kit, triggered by the presence of MMP9), HIF1a (influencing hypoxia-inducible-factor-1alpha), and endothelial nitric oxide synthase might play an important role in the pathogenesis of the aortopathy [31]. Increased collagen turnover and decreased collagen cross-linking may be

another factor in the formation of aneurysms in BAV cases [37].

**4. Phenotypic presentation of aortic valve and root**

Normal aortic valve is tricuspid, meaning it possesses three leaflets (or cusps: the left coronary, the right coronary, and non-coronary cusps, named after their relationship to the coronary

**4.1. Morphology of bicuspid aortic valve**

Several proteins are used to determine the positional and functional relationship of various cellular populations during embryogenesis. Conical Wnt, non-conical Wnt, TGF-β, fibroblast growth factor, bone morphogenetic protein, and Notch are some important proteins in the development of aortic valve and aorta. Errors of this pathway may result in various outflow tract structural abnormalities including BAV disease [11, 16, 19, 23].

#### **3.2. Histopathology of the aorta**

The normal aortic valve involves three layers. The first layer is the inner intimal layer, which consists of endothelial cells. The second layer is the thicker medial layer formed of smooth muscle cells (SMCs) and elastin. The elastin is arranged in fenestrated sheets (lamellae) between which collagen fibers, thin layers of proteoglycan-rich extra-cellular matrix (ECM), and SMCs are located. Thin elastic fibers embed lamellae into a three-dimensional network and connect them with SMCs. The third layer is the strong adventitial layer with collagen fibers wrapping the aorta [25, 26]. The relatively high collagen content of the adventitia prevents vascular rupture at extremely high pressures [27]. SMC and ECM play an important role both in the normal tissue development and in the main mechanical function of the aortic media [2, 28, 29]. SMCs are the major cell types of the aortic wall that synthesize and organize the ECM with the elastic fiber network in the arterial wall [25, 26, 30]. SCMs also provide lamellar organization, depending on the diameter and stress applied upon the vessels during embryogenesis. ECM, mainly composed of elastin and collagen, is important for the aortic strength and flexibility to withstand the arterial blood pressure [26]. The number of lamella is greater in larger vessels facing greater wall tension and it seems to remain stable after birth. In the normal aorta, SMCs have a little active role in managing wall tension; microfibrillar structure is the major passive contributor [26, 30]. As the vessel wall matures, SMCs condense down around the endothelial tube to form the circumferential layers, which will finally define the elastic lamellae of the mature vessel [30].

#### **3.3. Pathogenesis of aortopathy**

Aortopathy is very complex pathology, in which both cellular and extracellular mechanisms are involved. Possible mechanisms for aortopathy in patients with BAV include medial degeneration (elastic fiber fragmentation and smooth muscle cell apoptosis), fibrilin-1 deficiency, increased metalloproteinase (MMP), and decreased MMP tissue inhibitor expression.

Medial degeneration: Failure of the balance between the synthesis and degradation of ECMs in the aortic wall leads to aortic aneurysm. Especially elastin is the major fibrillar component in the arterial wall, so its destruction directly leads to the expansion of aorta. Moreover, some intrinsic medial degenerative differences have been identified between TAV and BAV patients. While degeneration in TAVs has been attributed to inflammation and accelerated aging, it has been attributed to the maturation defect in BAVs. Several BAV studies have revealed noninflammatory loss of vascular SMCs, less-differentiated vascular SMC, low laminin A/C, and progerin expression as the other causes of medial degeneration [27, 30, 31]. The total thickness of the aortic media is the same for BAV and TAV aortas, but the distance between the elastic lamellae is greater and the lamellae themselves are thinner and more fragmented in BAV patients [30, 32]. It was suggested that matrix disruption and SMC apoptosis were earlier in BAVs with stenosis than TAVs with respect to the dilatation of aorta [33]. The patients with ascending aorta dilatation with BAV showed lesser cystic medial necrosis (focal loss of vacsular smooth muscle cell (VSMC) nuclei in the media) than those with TAV [30]. Nondilated BAV aortas may have higher rates of vascular SMC apoptosis, particularly at the convexity, where wall stress is expectedly higher. Stress-dependent BAV matrix changes may trigger early apoptosis [33].

Deficiency of fibrilin-1: Maturation defect is maintained in the dilated aortic wall in BAV patients. Fibrillin-1, which stabilizes the vascular wall, is secreted by the SMC. It is low in BAV patients because of the immaturity of SMC [21]. Deficiency of fibrillin-1 results in vascular SMC detachment, matrix disruption, and apoptosis, which ultimately result in a fragile aorta, less suited to deal with stress associated with valvular dysfunction. Decreased levels of fibrillin-1 may also lead to tinning and weakening of the aortic wall. Some studies have showed that aortic tissues in BAVs have significantly less fibrillin-1 than TAV aortas [34, 35].

Increased activity of MMPs: To date, most studies have focused on MMP-2 and MMP-9, which belong to a subclass of MMP. An increase in MMPs, enzymes that process or degrade the extracellular matrix, may lead to the weakening of the aortic wall and may be associated with the development of aortic aneurysms. In particular, MMP-2 and MMP-9, secreted from macrophages, which have infiltrated the inflammatory site, are known as powerful proteinases that degrade elastin fiber. BAV patients have dilated aortas with a higher content of MMP and a lower level of tissue inhibitor of MMP compared to TAV patients, indicating an increased collagen turnover. MMP-9 has been closely associated with the formation of abdominal aortic aneurysms [31, 36]. MMP-2 has been identified as a key molecular modulator and a circulation biomarker of aortic dilation in patients with BAV [36]. Several markers as c-Kit (a marker for differentiated vascular SMCs), pc-Kit (phosphorylated state of c-Kit, triggered by the presence of MMP9), HIF1a (influencing hypoxia-inducible-factor-1alpha), and endothelial nitric oxide synthase might play an important role in the pathogenesis of the aortopathy [31]. Increased collagen turnover and decreased collagen cross-linking may be another factor in the formation of aneurysms in BAV cases [37].
