**2. BAV syndrome pathology and pathophysiology**

The bicuspid aortic valve morphology has been characterized by raphe number and the position of cusps and raphes [8]. This morphology includes complete or partial leaflet fusion. The most common morphology in BAV patients is fusion of left and right coronary cusps. The next most common morphology in BAV patients is fusion of right coronary cusp with noncoronary cusp [8, 9]. The morphology of the bicuspid aortic valve has been described by various classification systems, most notably the Sievers classification [8–10]. Sievers Type 0 BAV has an incidence of 7% in the original Sievers and Schmidtke series and a BAV valve geometry of no raphe and 2 valve cusps [8, 11]. Sievers Type 1 BAV morphology is the most common and has an incidence of 88% in the original series with a BAV valve geometry of a single raphe and 2 valve cusps [8, 11]. Sievers Type 2 BAV has an incidence of 5% in the original series and is the rarest morphology of the three types in this classification with a BAV valve geometry of 2 raphe and 2 valve cusps [8, 11].

Patients with BAV are known to have high rates of various valvular pathologies in adult life [7], particularly aortic stenosis (especially in males) [12], aortic regurgitation [13], and infective endocarditis involving the aortic valve [14]. BAV is three to four times more frequent in men than in women. Approximately, 50–75% of patients with BAV will require aortic valve replacement procedure during their lifetime and up to 25% may require an aortic procedure often concurrent with their valve replacement [15].

BAV syndrome pathophysiology is associated with dilation of the aorta [2]. BAV may be associated with an ascending aortic aneurysm phenotype in around 26–50% patients or a root phenotype in up to 20–32% of patients [2, 3, 16]. These distinct phenotypes have been stratified into three categories. Type 1 is dilation of ascending *Bicuspid Aortic Valve: Current Therapeutic Strategies DOI: http://dx.doi.org/10.5772/intechopen.113315*

aorta along its convexity and can involve root dilation. Type 2 is arch dilation and ascending aortic dilation with sparing of the root. Type 3 involves an isolated root phenotype and has been associated with a genetic causality [16–18]. BAV associated with aortic dilation increases the risk of dissection as the aorta dilates further. In BAV patients, aortic dissection has been observed to occur almost 5–10 times more commonly than trileaflet aortic valve population [19].

Aortic dilatation and aneurysm formation in BAV patients has been attributed to two different mechanisms: hemodynamic stress and the inherent aortic wall tissue abnormality. Hemodynamically, shear stress on the aortic wall due to blood flowing through a stenotic valve has been hypothesized to cause early dilatation of the aorta [20]. Abnormal flow patterns have been noted due to the configuration of the BAV even in absence of stenosis [21].

Dysregulation of the aortic wall can also contribute to aneurysmal dilation. Human and animal studies have identified that extracellular matrix dysregulation along with dysfunctional signaling pathways can contribute to hemodynamic effects observed in calcific aortic valve disease and regurgitation [22]. A recent study demonstrated newborns with BAV having aortopathy and dilated aorta even in the presence of relatively normal velocities across the valve [23] and this suggests inherent aortic tissue dysregulation as a factor which may impact the population of patients with BAV.

#### **3. Embryology and genetics of BAV and associated aortic aneurysm**

The aortic valve develops from endocardial cushions within the maturing heart tube and begins to form around the fifth week of embryonic development. In normal cardiac development, these cushions later divide into three distinct aortic valve leaflets. In patients with BAV disease, the cushions either fail to divide or fuse leading to the characteristic bicuspid morphology. It has been postulated that multifactorial variables including genetic/embryologic factors impact the formation of the bicuspid aortic valve.

There is a recognized genetic component to bicuspid aortic valve disease. It may occur sporadically or as an autosomal dominant disorder with variable penetrance [24]. And, it has been noted that some family members of BAV patients may present with isolated BAV, some with associated aortic (ascending/root) aneurysms and some may be carriers with no manifest disease. The spatial and anatomical sequences in development of congenital heart disease (CHD) continues to be defined. Outflow tract defects specifically those involving the aortic valve have been difficult to categorize as they appear to be multifactorial in origin with many signaling and transcriptional gene anomalies possible for the outcome. Autosomal dominant inheritance pattern has been described for BAV specifically involving the NOTCH1 gene pathway however, this is not exclusive [25].

The genetic mechanism for a majority of BAV cases remains unknown. Although these cases may seem 'sporadic' there is still a 10% increase in risk of having BAV in siblings and offspring based on epidemiological studies [26]. There is a similar rate of incidence of aortic aneurysms in family members with or without BAV demonstrating some role of shared environmental or genetic causes [27]. High number of genetic variants, associated with structural variation and mixed inheritance patterns of the disease have complicated the discovery of the BAV-associated genes [28]. Chromosomal mutations involving 9q have been linked to BAV disease [29]. Mutations at various loci on chromosomes 5, 15, and 18 are linked to familial BAV and aortic syndromes [24].

The occurrence of aortic aneurysm and coarctation in patients with BAV underlines a possible common genetic pathway for these disease entities. Microscopic examination of BAV associated aneurysm tissue has demonstrated non-inflammatory medial degeneration also known as cystic medial necrosis [30]. Dysregulation of the canonical (Smad2/ Smad3) TGF-B signaling genes has been implicated to be a possible common defect for BAV and aneurysm formation. TGF-B signaling plays a role in cell migration and valvulogenesis that are pivotal in proper valve formation and functioning [30]. Similarly, Loeys-Dietz syndrome (LDS) is caused by mutations in genes encoding for TGF-B receptors. BAV along with thoracic aortic aneurysms are commonly found in patients with LDS.

With these multifactorial variables that impact BAV syndrome presenting as familial clusters and variable penetrance, screening is recommended in first degree relatives of patients with BAV disease [31]. An echocardiogram is commonly utilized to monitor the bicuspid aortic valvular pathophysiology. A CTA or MRA may also be utilized for monitoring the bicuspid aortic valve aortic phenotype.

### **4. Genetic syndromes with BAV**

BAV is associated with several complex valvuloaortopathies and specific syndromes. Approximately 30–50% of patients with coarctation of the aorta have BAV [32–34].

Turner Syndrome is one of the most common genetic syndromes involving patients having a BAV phenotype [34]. The syndrome is associated with X chromosome monosomy in females. Approximately 30% of females with Turners can have a BAV [35]. The frequency of aortic aneurysms associated with BAV is also known to be higher in this group [36]. This observation along with the male predominance of BAV has led to the hypothesis that the X chromosome reduction maybe related to BAV incidence [37]. Generally short statured females with coarctation of the aorta should raise suspicion and lead to surveillance for BAV disease [38].

Loeys-Dietz Syndrome (LDS) is the second most common syndrome associated with BAV with approximately 10% of these patients manifesting the BAV phenotype [39]. TGF-B pathway gene mutations are known to be associated with the LDS. These mutations are common in non-syndromic thoracic aortic aneurysmal disease as well demonstrating a possible common pathway. Compared to non-syndromic patients, the LDS patients tend to present earlier in their life usually with symptomatic aortic regurgitation due to accelerated aortic dilation. Increased arterial tortuosity in major blood vessels and male sex have been determined to be associated with a higher risk of dissection in these patients [40].

Velocardiofacial Syndrome (DiGeorge Syndrome) is caused by deletions in gene 22; this syndrome involves cleft palate, immune deficiency, hypoparathyroidism, ventricular septal defect (VSD), and conotruncal defects of the heart (truncus arteriosus and tetralogy of Fallot). BAV and aneurysmal disease is more prevalent in this set of patients compared to the non-syndromic population [41]. The syndrome itself is a combination of genetic defects that are found in BAV disease demonstrating the multigenetic components that are involved in the BAV phenotype.

### **5. Surveillance of the aorta in BAV disease**

BAV syndrome is a heterogenous disease presenting with variable aortic and valvular pathology over a spectrum of age groups. Asymptomatic BAV may be an *Bicuspid Aortic Valve: Current Therapeutic Strategies DOI: http://dx.doi.org/10.5772/intechopen.113315*

incidental finding on imaging [32, 33, 38]. Patients with BAV syndrome require individualized treatment according to the degree of involvement of the aortic and valvular apparatus with patient comorbidities and age considerations. BAV patients should therefore undergo routine, periodic surveillance, to delineate the optimal timing of therapeutic intervention.

Surveillance for BAV syndrome patients is performed based on the pathophysiology of the aortic valve phenotype or aortic phenotype. Surveillance requires serial echocardiography for valvulopathy. The growth rate of the aorta in BAV patients can be 0.2–2.3 mm/year [16, 42, 43], and serial CTA or MRI should be performed to monitor the growth rate. For patients with ascending aortic and root dimensions within normal limits, imaging can be done every 3–5 years [35]. For dimensions ranging from 40 to 49 mm, imaging should be performed annually. For BAV patients with an aorta measuring 50–54 mm or with family history of aortic dissection or rapid growth of the aorta, imaging should be performed every 6–12 months [44].

#### **5.1 Family screening**

Current guidelines suggest family screening with echocardiography for all firstdegree relatives with BAV probands. Relatives found to have BAV should have complete evaluation and CTA or MRA imaging [45]. When multiple signs of a disorder are present, genetic testing should be conducted for BAV patients especially those in their early years of life. Other high-risk features that should lead to genetic testing are family history of dissection or sudden death, congenital heart lesions, or other aneurysmal disease. Once identified, genetic counseling plays an important role in the holistic care for BAV patients. Due to the variable expression of causative genes, parents of BAV patients may not have a bicuspid aortic valve. Lifetime follow-up and aortic surveillance is also important as the timing of incidence of valve or aortic disease may be different amongst different family members.
