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

#### **4.1. Morphology of bicuspid aortic valve**

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].

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

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

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

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

tract structural abnormalities including BAV disease [11, 16, 19, 23].

**3.2. Histopathology of the aorta**

102 Structural Insufficiency Anomalies in Cardiac Valves

the elastic lamellae of the mature vessel [30].

**3.3. Pathogenesis of aortopathy**

expression.

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 arteries). However, BAV is formed of two functional leaflets. There are two types of BAV. The typical one is the most frequent and is formed of two leaflets of unequal size with complete or incomplete fusion of two cusps. Adjacent cusps fuse into a single cusp, that is generally bigger than its counterpart cusp, but these fused cusps are smaller than two normal cusps combined. In such cases, there may be one or two raphe. The term "raphe" refers to the fused area of two underdeveloped cusps turning into malformed commissure between both cusps [28, 29]. The second and less commonly encountered type of BAV is "true BAVs," which have leaflets equal in size with no raphe [28]. Morphology of the aortic valve is defined according to spatial position of cusps, fusion types, and the number of raphe. The valve morphologies, raphe number, and fusion types are shown in **Table 2**. The fusion positions between the right and left coronary cusps (RL BAV), right and non-coronary cusps (RN BAV), and true BAVs are shown in **Figure 1**. The most prevalent aortic valve morphologies are RL BAV phenotypes and second, RN BAV phenotypes, and the least common are LN BAV phenotypes [28, 29, 38, 39].

#### **4.2. Aortic phenotype**

The aorta is anatomically composed of ascending aorta, aortic arch, thoracic aorta, and abdominal aorta. The aortic root contains aortic sinuses, aortic valve, and coronary ostia. The tubular portion of the ascending aorta begins at a point distal to the aortic root (sinotubular junction) and ends at the origin of the innominate artery. The aortic arch includes the origins of innominate artery, the left common carotid artery, and the left subclavian artery [40]. **Figure 2** shows the echocardiographic images and the measurements of aortic root, tubular portion of the ascending aorta, and aortic arc. There are computerized tomography images of various aortic phenotypes in **Figure 3**.

Several classifications have been made according to the structure, diameter of aorta, and the extent of aortic dilatation. BAV aortopathies generally present with ascending aorta dilatation or root dilatation or both. The types of aortopathies are summarized in **Table 3**. The most common types of aortic dilatation which are seen are the ascending aorta and varying degrees of aortic root. This type was associated with an older age at diagnosis (>50 years), valvular stenosis, and the RL BAV fusion pattern [29, 40, 41]. Isolated dilatation of the aortic root is a rare type and associated with younger age at diagnosis (<40 years), male sex, aortic


**Figure 1.** Echocardiographic views of commissural fusion patterns of BAVs and true BAVs. In the first view: Right-left coronary cusp fusion a) closed b) opened position; in the second view: Right non coronary cusp fusion a) closed b) opened position; in the third view: true BAV anterior-posterior valve position a) closed b) opened position; in the fourth view: True BAV right-left position a) closed b) opened position. RCC: right coronary cusp, LCC: left coronary cusp,

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NCC: non coronary cusp, ANT: anterior, POST: posterior.

**Table 2.** The bicuspid aortic valve morphologies, fusion types, and raphe number.

arteries). However, BAV is formed of two functional leaflets. There are two types of BAV. The typical one is the most frequent and is formed of two leaflets of unequal size with complete or incomplete fusion of two cusps. Adjacent cusps fuse into a single cusp, that is generally bigger than its counterpart cusp, but these fused cusps are smaller than two normal cusps combined. In such cases, there may be one or two raphe. The term "raphe" refers to the fused area of two underdeveloped cusps turning into malformed commissure between both cusps [28, 29]. The second and less commonly encountered type of BAV is "true BAVs," which have leaflets equal in size with no raphe [28]. Morphology of the aortic valve is defined according to spatial position of cusps, fusion types, and the number of raphe. The valve morphologies, raphe number, and fusion types are shown in **Table 2**. The fusion positions between the right and left coronary cusps (RL BAV), right and non-coronary cusps (RN BAV), and true BAVs are shown in **Figure 1**. The most prevalent aortic valve morphologies are RL BAV phenotypes and second, RN BAV phenotypes, and the least common are LN BAV phenotypes [28, 29, 38, 39].

The aorta is anatomically composed of ascending aorta, aortic arch, thoracic aorta, and abdominal aorta. The aortic root contains aortic sinuses, aortic valve, and coronary ostia. The tubular portion of the ascending aorta begins at a point distal to the aortic root (sinotubular junction) and ends at the origin of the innominate artery. The aortic arch includes the origins of innominate artery, the left common carotid artery, and the left subclavian artery [40]. **Figure 2** shows the echocardiographic images and the measurements of aortic root, tubular portion of the ascending aorta, and aortic arc. There are computerized tomography images of

Several classifications have been made according to the structure, diameter of aorta, and the extent of aortic dilatation. BAV aortopathies generally present with ascending aorta dilatation or root dilatation or both. The types of aortopathies are summarized in **Table 3**. The most common types of aortic dilatation which are seen are the ascending aorta and varying degrees of aortic root. This type was associated with an older age at diagnosis (>50 years), valvular stenosis, and the RL BAV fusion pattern [29, 40, 41]. Isolated dilatation of the aortic root is a rare type and associated with younger age at diagnosis (<40 years), male sex, aortic

Right-non-coronary cusps

Left-non-coronary cusps

fusion (LN BAV) Right–left

fusion (RN BAV) Right–left

Anterior–posterior Right–left Right–left

**Morphology of aortic valve Type 1 Type 2 Type 3**

Right–left coronary cusps

Anterior–posterior

**Table 2.** The bicuspid aortic valve morphologies, fusion types, and raphe number.

fusion (RL BAV)

Raphe number\* 1 raphe 2 raphe

**4.2. Aortic phenotype**

104 Structural Insufficiency Anomalies in Cardiac Valves

Raphe present

Raphe absent Valve opening

\*Type 0: no raphe

fusion) Valve opening

(Complete or incomplete

various aortic phenotypes in **Figure 3**.

**Figure 1.** Echocardiographic views of commissural fusion patterns of BAVs and true BAVs. In the first view: Right-left coronary cusp fusion a) closed b) opened position; in the second view: Right non coronary cusp fusion a) closed b) opened position; in the third view: true BAV anterior-posterior valve position a) closed b) opened position; in the fourth view: True BAV right-left position a) closed b) opened position. RCC: right coronary cusp, LCC: left coronary cusp, NCC: non coronary cusp, ANT: anterior, POST: posterior.

**Figure 2.** Echocardiografic images revealing the measurements of a) aortic root in the long axis view at the annular, sinus valsalva, sinotubular junction and ascending aorta levels b) aortic arc at the transverse arc, isthmus and descending aorta levels c) sinus valsalva dilatation in long axis view d) ascending aorta dilatation in which aortic root was spared in long axis view e) aortic root and ascending aorta dilatation in long axis view.

regurgitation, and aortopathy. This type was considered most likely to be related with a genetic cause [29, 40–42].

#### **4.3. Aortic dilatation**

Aortic dimensions are generally measured at the levels of annulus, sinus Valsalva, sinotubular junction (STJ), ascending aorta, aortic arch, descending aorta, and abdominal aorta, from inner edge to inner edge, at the end of diastole in the echocardiographic evaluation. **Figure 3** shows computerized tomography images of aortic root and ascending aorta. Because the aorta increases in diameter with somatic growth in children, the aortic diameter is typically corrected, mostly for body surface area (BSA), age, and gender. It is important to evaluate children under the age of 18 according to the z scores of these measurements. Aorta is accepted to have dilatation if the aortic z score is >2, aortic/expected aortic diameter is >1.15, or it is 2 SD above the mean expected diameter. Aortic dilation was defined as mild (z score > 2 and ≤ 4), moderate (z score > 4 and ≤ 6), or severe/aneurysm (z score > 6 or > 6 SD above the mean for BSA) [43]. In adults, aortic dilatation is present if the diameter of sinus Valsalva is >35 mm, ascending aorta diameter is >34–38 mm, and an aneurysm is present if the aortic/expected diameter is >1.4 or ascending aorta is >45 mm [44–47].

in BAV than in TAV patients. The most common type of dilatation of aorta in BAVs was the ascending aorta dilatation, root dilation was the second, and the least common was the root dilatation together with the ascending aorta [44, 48, 51]. Aortic aneurysms in BAVs commonly

**Figure 3.** Three dimensional computerized tomography images showing a) ascending aorta dilatation b) sinus valsalva

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and ascending aorta dilatation extended to arcus aorta c) aortic root and ascending aorta dilatation.

The relationship between the aortic valve structure and dilatation has been investigated in several studies. It was reported that RL BAV phenotype was usually associated with aortic root and/or sinus Valsalva and/or proximal aortic dilatation [28, 29, 44, 49, 52–55]. RN BAV phenotype was more commonly associated with ascending aorta dilatation and LN BAV phenotypes with aortic root dilatation [29, 56]. In addition, the RN BAV phenotype was associated with a more rapid growth of the ascending aorta [43]. On the contrary, a relationship between the RL BAV phenotypes and increased risk of rapid aortic dilatation in BAV patients has been reported [57]. Clinical variation of the BAV patients may be related to different etiological entities of cusp phenotypes. Recently preclinical studies have shown that RN and RL cusps' fusion have different pathogenesis [58, 59]. In contrast to these studies, only minor differences in aortic shape can be demonstrated in different BAV phenotypes. Aortic dilatation was primarily caused by intrinsic mechanisms of the aortic wall regardless of valve type [48].

involve aortic root, ascending aorta, and aortic arch [42].

Aortic dilatation may begin early in life and progress with age. It is three times more common in BAV patients than in TAVs [48]. In total, 40% of patients in referral centers were reported to have BAV-associated aortopathy [49]. BAV patients have significantly larger proximal aorta than those with TAV, even in the absence of significant valvular hemodynamic disturbance. Children with BAV have larger sinus Valsalva and ascending aorta, which increase in size at a higher rate than TAVs [48, 50]. Studies showed that aortic aneurysm also was more common

**Figure 3.** Three dimensional computerized tomography images showing a) ascending aorta dilatation b) sinus valsalva and ascending aorta dilatation extended to arcus aorta c) aortic root and ascending aorta dilatation.

regurgitation, and aortopathy. This type was considered most likely to be related with a

**Figure 2.** Echocardiografic images revealing the measurements of a) aortic root in the long axis view at the annular, sinus valsalva, sinotubular junction and ascending aorta levels b) aortic arc at the transverse arc, isthmus and descending aorta levels c) sinus valsalva dilatation in long axis view d) ascending aorta dilatation in which aortic root was spared in long

Aortic dimensions are generally measured at the levels of annulus, sinus Valsalva, sinotubular junction (STJ), ascending aorta, aortic arch, descending aorta, and abdominal aorta, from inner edge to inner edge, at the end of diastole in the echocardiographic evaluation. **Figure 3** shows computerized tomography images of aortic root and ascending aorta. Because the aorta increases in diameter with somatic growth in children, the aortic diameter is typically corrected, mostly for body surface area (BSA), age, and gender. It is important to evaluate children under the age of 18 according to the z scores of these measurements. Aorta is accepted to have dilatation if the aortic z score is >2, aortic/expected aortic diameter is >1.15, or it is 2 SD above the mean expected diameter. Aortic dilation was defined as mild (z score > 2 and ≤ 4), moderate (z score > 4 and ≤ 6), or severe/aneurysm (z score > 6 or > 6 SD above the mean for BSA) [43]. In adults, aortic dilatation is present if the diameter of sinus Valsalva is >35 mm, ascending aorta diameter is >34–38 mm, and an aneurysm is present if the aortic/expected

Aortic dilatation may begin early in life and progress with age. It is three times more common in BAV patients than in TAVs [48]. In total, 40% of patients in referral centers were reported to have BAV-associated aortopathy [49]. BAV patients have significantly larger proximal aorta than those with TAV, even in the absence of significant valvular hemodynamic disturbance. Children with BAV have larger sinus Valsalva and ascending aorta, which increase in size at a higher rate than TAVs [48, 50]. Studies showed that aortic aneurysm also was more common

genetic cause [29, 40–42].

106 Structural Insufficiency Anomalies in Cardiac Valves

diameter is >1.4 or ascending aorta is >45 mm [44–47].

axis view e) aortic root and ascending aorta dilatation in long axis view.

**4.3. Aortic dilatation**

in BAV than in TAV patients. The most common type of dilatation of aorta in BAVs was the ascending aorta dilatation, root dilation was the second, and the least common was the root dilatation together with the ascending aorta [44, 48, 51]. Aortic aneurysms in BAVs commonly involve aortic root, ascending aorta, and aortic arch [42].

The relationship between the aortic valve structure and dilatation has been investigated in several studies. It was reported that RL BAV phenotype was usually associated with aortic root and/or sinus Valsalva and/or proximal aortic dilatation [28, 29, 44, 49, 52–55]. RN BAV phenotype was more commonly associated with ascending aorta dilatation and LN BAV phenotypes with aortic root dilatation [29, 56]. In addition, the RN BAV phenotype was associated with a more rapid growth of the ascending aorta [43]. On the contrary, a relationship between the RL BAV phenotypes and increased risk of rapid aortic dilatation in BAV patients has been reported [57]. Clinical variation of the BAV patients may be related to different etiological entities of cusp phenotypes. Recently preclinical studies have shown that RN and RL cusps' fusion have different pathogenesis [58, 59]. In contrast to these studies, only minor differences in aortic shape can be demonstrated in different BAV phenotypes. Aortic dilatation was primarily caused by intrinsic mechanisms of the aortic wall regardless of valve type [48].


The increase in regional wall shear stress may explain the RL BAV phenotype with dilatation of the aortic root and asymmetric dilatation of the tubular ascending aorta. Conversely, a RN BAV phenotype may result in a flow toward the posterior aorta, with increased wall shear stress at the right posterior aspect of the aorta leading to dilatation of the aortic arch [39].

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BAV disease is strongly associated with different degrees of stenosis, regurgitation, and mixed presentations. Although most of the neonates and infants remain asymptomatic, dysfunction may present in older ages. Valve interventions may be necessary in a minority, mainly early in life, typically for aortic stenosis (AS) [66]. The progression of stenosis is probably similar to that of TAV stenosis but it becomes manifested at least 5–10 years earlier in patients with BAV [67]. AS and aortic regurgitation (AR) are equally found in TAVs and BAVs with normal aortic dimensions. If the aorta is dilated, AS is predominantly associated with BAV, whereas AR is with TAV [48].

Aortic aneurysms associated with AS have been considered to be poststenotic dilatation because of the chronic impact of the high-flow velocity turbulent transvalvular jet on the aortic wall. Aortic stenosis in BAVs may present a significant additional risk for patients with aneurysm [68]. However, not the severity of AS, but the degree of ascending aorta dilation and the presence of moderate or more AR is associated with higher aortic root and ascending aortic diameter z scores [43]. Moderate–severe AR is generally associated with larger sinus Valsalva diameters compared with normally functioning aortic valve and AS. On the other hand, moderate–severe AS is associated with a larger ascending aortic diameter compared with the normally functioning aortic valve without AR [55]. It is very confusing whether the AR causes aortic root dilatation or if the visa versa is true, so careful follow-up of these patients is important to understand which presents earlier. The root aneurysm and AR with BAV has been linked more often to a genetic/aortopathy cause, which occurs earlier in life, independent of hemodynamic factors [44]. In young adults, it has been shown that RN BAV pattern is more commonly associated with moderate or severe AS and moderate or more AR when compared with other BAV phenotypes. In addition, RN BAV phenotype is associated with progressive valve dysfunction and is strongly predictive of valve intervention when compared with RL BAV phenotype [39, 66]. Similarly, AS has been revealed to be more common in RN BAV phenotype, whereas AR is most commonly encountered in the patients with NL BAV and RL BAV phenotypes [45, 56, 69]. Consequently, despite a variety of study results, it can be concluded that RN or RL BAV phenotypes may show progression and AS or AR may

Most patients with BAV are unaware of the diagnosis until elderly because the symptoms and physical findings are usually absent for many years. Unless echocardiography is requested for other indications, the diagnosis is usually made at the time of an adverse cardiovascular

**4.5. Aortic regurgitation and stenosis**

accompany with both valve morphologies.

**5. Diagnosis**

outcome.

**Table 3.** Aortic dilatation pattern.

#### **4.4. Hemodynamic effect**

Flow abnormalities, related to turbulent and helical flow patterns, as a result of the asymmetric movement of valve leaflets, may be a major contributor to aortic dilation in BAV. Even normally functioning BAVs may have abnormal transvalvular flow patterns, resulting in regional increases in wall shear stress [60, 61]. The asymmetric opening of even "clinically normal" BAV has been demonstrated. The orifice of the open BAV has been shown to be irregular and dome shaped due to the restricted motility of conjoined leaflets. This asymmetric and morphologically stenotic orifice leads to a nonaxial, turbulent transvalvular flow jet, which propagates eccentrically toward the wall of ascending aorta [61]. Restricted systolic conjoint cusp motion may cause flow deflection even if the BAV is normofunctional on echocardiographic evaluation. Systolic flow deflection toward the right, affecting the right anterolateral-ascending wall, has been demonstrated by magnetic resonance imaging (MRI) [62]. Abnormal cusp motions of BAV, including folding or wrinkling of the valve tissue and increased cusp doming during the cardiac cycle, may result in altered flow characteristics even when the cusps are not stenotic [63].

MRI studies have shown that RL BAV phenotype is associated with rightward flow deviation (flow jet directed toward the right anterior aortic wall, which is then propagated in a right-handed helical direction) and dilatation of tubular portion of the ascending aorta. Right anteriorly oriented flow jet may also result in larger aortic root dimensions and asymmetric dilatation of midascending tract [53]. However, RN BAV phenotype has been linked to the leftward deviation (flow jet directed toward left posterior aortic wall) and diffuse dilatation of the ascending aorta extending to the arch [64, 65]. The RN BAV phenotypes have shown more severe hemodynamic flow abnormalities than the RL BAV phenotypes [65].

The increase in regional wall shear stress may explain the RL BAV phenotype with dilatation of the aortic root and asymmetric dilatation of the tubular ascending aorta. Conversely, a RN BAV phenotype may result in a flow toward the posterior aorta, with increased wall shear stress at the right posterior aspect of the aorta leading to dilatation of the aortic arch [39].

#### **4.5. Aortic regurgitation and stenosis**

BAV disease is strongly associated with different degrees of stenosis, regurgitation, and mixed presentations. Although most of the neonates and infants remain asymptomatic, dysfunction may present in older ages. Valve interventions may be necessary in a minority, mainly early in life, typically for aortic stenosis (AS) [66]. The progression of stenosis is probably similar to that of TAV stenosis but it becomes manifested at least 5–10 years earlier in patients with BAV [67]. AS and aortic regurgitation (AR) are equally found in TAVs and BAVs with normal aortic dimensions. If the aorta is dilated, AS is predominantly associated with BAV, whereas AR is with TAV [48].

Aortic aneurysms associated with AS have been considered to be poststenotic dilatation because of the chronic impact of the high-flow velocity turbulent transvalvular jet on the aortic wall. Aortic stenosis in BAVs may present a significant additional risk for patients with aneurysm [68]. However, not the severity of AS, but the degree of ascending aorta dilation and the presence of moderate or more AR is associated with higher aortic root and ascending aortic diameter z scores [43]. Moderate–severe AR is generally associated with larger sinus Valsalva diameters compared with normally functioning aortic valve and AS. On the other hand, moderate–severe AS is associated with a larger ascending aortic diameter compared with the normally functioning aortic valve without AR [55]. It is very confusing whether the AR causes aortic root dilatation or if the visa versa is true, so careful follow-up of these patients is important to understand which presents earlier. The root aneurysm and AR with BAV has been linked more often to a genetic/aortopathy cause, which occurs earlier in life, independent of hemodynamic factors [44]. In young adults, it has been shown that RN BAV pattern is more commonly associated with moderate or severe AS and moderate or more AR when compared with other BAV phenotypes. In addition, RN BAV phenotype is associated with progressive valve dysfunction and is strongly predictive of valve intervention when compared with RL BAV phenotype [39, 66]. Similarly, AS has been revealed to be more common in RN BAV phenotype, whereas AR is most commonly encountered in the patients with NL BAV and RL BAV phenotypes [45, 56, 69]. Consequently, despite a variety of study results, it can be concluded that RN or RL BAV phenotypes may show progression and AS or AR may accompany with both valve morphologies.
