**Unicuspid Aortic Valve**

Venkata Thota and Farouk Mookadam *Mayo Clinic College of Medicine, Scottsdale, AZ USA* 

## **1. Introduction**

Unicuspid aortic valve was first described more than half a century ago (Edwards, 1958). Although reported infrequently, the natural history of unicuspid aortic valve is poorly understood. Developmental abnormalities of aortic valve cusps in decreasing order of frequency include bicuspid (0.9%-1.3%), unicuspid (0.02%), quadricuspid (0.008%- 0.043%), and pentacupsid aortic valves (Cemri, 2000). Decreasing cusp number in the congenitally abnormal aortic valve has shown increasing male predilection, earlier valve failure and aggressive pathological changes compared to normal tricuspid aortic valve (Collins MJ, 2008).

## **2. Embryology**

The normal aortic valve consists of three valve cusps, sinuses and coaptations (Angelini, 1989). During the embryological development, the bulbous cordis elongates and forms the proximal conus and distal truncus arteriosus. This initial single channel bifurcates into two separate trunks, namely, the aortic and pulmonary trunks by two spiral truncoconal ridges, derived from neural crest mesoderm. Simultaneous to this, cardiac mesoderm and cranial neural crest derivatives grow into the two separate lumens forming 3 leaflets for each trunk. These three leaflet structures will constitute the future aortic and pulmonary valves (Carlson, 1999). Abnormalities in the growth of this mesoderm into the lumen to form leaflets are believed to result congenital aortic valvular abnormalities. During the same time, out of the many buds which arise from the coronary sinuses of the aorta, generally only two buds establish a connection with the epicardial tree to form future coronary arteries. These developmental spatial associations can explain the frequent concurrence of abnormalities between the aortic valve and coronary arteries.

Two sub-types of UAV have been described. One is the pinhole shaped acommissural UAV and the second being the slit shaped unicommissural UAV. While the pinhole-shaped UAV presents early in infancy with severe aortic stenosis, the slit-shaped UAV presents relatively later in adults with a less aggressive course. Theoretically, if the leaflet mesoderm grows in circumferentially from annulus it results in pin-hole shaped UAV and if it grows in with two coaptation points, it results in the slit-shaped unicommisural UAV. (Fig. 1)

The association of UAV with various coronary artery anomalies, patent ductus arteriosus, aortic aneurysms and coarctation of aorta suggests a common abnormal embryological development. Temporal association of the aortic leaflet evolution with coronary artery development from sinuses of valsalva implies similar embryological derangements.

Unicuspid Aortic Valve 271

The presenting features and associated anomalies/complications of UAV differ significantly

In the pediatric age group, the most common presentation included symptoms of left heart failure secondary to aortic stenosis. Pin hole shaped UAV is generally associated with a severe degree of stenosis compared to unicommissural UAV and tends to be symptomatic early in life. In the adults, reported symptoms in descending order of frequency include dyspnea, angina, dizziness and syncope. Most common aortic valve lesion included isolated

Associated anomalies in children included most commonly coarctation of aorta followed by ventricular septal defect and patent ductus arteriosus. However in adults, aortic aneurysm/dilatation was most common finding followed by aortic dissection, aortic

mycotic aneurysm, coronary artery anomalies and ventricular septal defect.

Mean age 14 months 42 years

thrive

Aortic stenosis Common Common Aortic regurgitation Uncommon Fairly common Aortic dilation Very rare Common Coarctation of Aorta Common Rare Ventricular septal defect Common Rare Patent ductus arteriosus Infrequent Rare

Symptoms Left heart failure, failure to

Table 2. Clinical presentation of adult UAV and pediatric UAV

aortic stenosis followed by combined AS with AR and isolated AR.

Fig. 2. Unicommissural AS-AI (1984, 2-630-422, Sawley 39F)

Pediatric Age<15yrs Adult >15yrs

Dyspnea,angina, syncope

**4. Clinical presentation** 

in children as compared to adults.

Fig. 1. Slit-shaped and pinhole shaped unicuspid aortic valves


Table 1. Associated anomalies/complications of unicuspid aortic valve (Mookadam, 2010a and 2010b)

## **3. Epidemiology**

While the more common bicuspid aortic valve has an incidence of 0.9-1.36% among the general population compared to unicuspid aortic valve which is about 50 fold less common with an incidence of 0.02% (Lewin, 2005; Mookadam, 2010a). Unicuspid aortic valve is more common in males with gender ratio of 4:1 in males:females (Mookadam, 2010a). It is relatively uncommon in adults when compared to neonates. Although an autosomal dominant pattern of inheritance with incomplete penetrance has been suggested for BAV, no familial cases of UAV have been reported in the literature to date.

Fig. 1. Slit-shaped and pinhole shaped unicuspid aortic valves

Patent ductus arteriosus Coarctation of aorta Aortic dissection

Anomalous coronary artery Ventricular septal defect Mycotic aneurysm of aorta

and 2010b)

**3. Epidemiology** 

Dilatation or aneurysm of aortic annulus/aortic root/ascending aorta

Table 1. Associated anomalies/complications of unicuspid aortic valve (Mookadam, 2010a

While the more common bicuspid aortic valve has an incidence of 0.9-1.36% among the general population compared to unicuspid aortic valve which is about 50 fold less common with an incidence of 0.02% (Lewin, 2005; Mookadam, 2010a). Unicuspid aortic valve is more common in males with gender ratio of 4:1 in males:females (Mookadam, 2010a). It is relatively uncommon in adults when compared to neonates. Although an autosomal dominant pattern of inheritance with incomplete penetrance has been suggested for BAV,

no familial cases of UAV have been reported in the literature to date.

## **4. Clinical presentation**

The presenting features and associated anomalies/complications of UAV differ significantly in children as compared to adults.


Table 2. Clinical presentation of adult UAV and pediatric UAV

In the pediatric age group, the most common presentation included symptoms of left heart failure secondary to aortic stenosis. Pin hole shaped UAV is generally associated with a severe degree of stenosis compared to unicommissural UAV and tends to be symptomatic early in life. In the adults, reported symptoms in descending order of frequency include dyspnea, angina, dizziness and syncope. Most common aortic valve lesion included isolated aortic stenosis followed by combined AS with AR and isolated AR.

Fig. 2. Unicommissural AS-AI (1984, 2-630-422, Sawley 39F)

Associated anomalies in children included most commonly coarctation of aorta followed by ventricular septal defect and patent ductus arteriosus. However in adults, aortic aneurysm/dilatation was most common finding followed by aortic dissection, aortic mycotic aneurysm, coronary artery anomalies and ventricular septal defect.

Unicuspid Aortic Valve 273

Given the association, early progression and aggressive presentation between aortopathy

The treatment approach differs significantly between adults and children. In children, treatment choices included aortic balloon valvoplasty, surgical valvotomy, and commissurotomy (Mookadam, 2010b). Repair of the aortic coarctation is also frequent among children, which was the most common associated anomaly. However, replacement

In adults, most common treatment modality was aortic valve replacement associated with replacement of aortic annulus/aortic root/ascending aorta. Other treatment modalities included bicuspidization of UAV, Bentall's operation, aortic valvotomy and Ross procedure. Also in UAV, aortic valve replacement (AVR) was about 10-20 years earlier than BAV, and 20-30 years earlier than normal TAV. The current management approach of UAV is to follow valve sparing techniques in children and delaying AVR to allow aorta to grow to

Agnihotri AK, Desai SC, Lai YQ, et al. Two distinct clinical presentations in adult unicuspid

Angelini A, Ho SY, Anderson RH, et al. The morphology of the normal aortic valve as

Carlson BM. Human Embryology and Developmental Biology. 2nd edition. St. Louis, MO:

compared with the aortic valve having two leaflets. *J Thorac Cardiovasc Surg* 1989;

aortic valve. *J Thorac Cardiovasc Surg* 2006; 131:1169-1170

Mosby, 1999; pp. 422-424. ISBN-10: 0815114583

and UAV, it is prudent to follow these patients regularly for timely intervention.

Fig. 3. Unicommissural AS (1983, 2-283-534, Eaton 42M), with x-ray

of aortic root is uncommon in the pediatric age group.

**7. Management** 

adult size.

**8. References** 

98:362-367

UAV is more frequent among patients presenting to surgery with AS; approximately about 5% of patients presenting to surgery for pure AS will have UAV.

In adults, pathology of resected UAVs is characterized by heavy calcification implying early degeneration from hemodynamic stress. However, calcification is a very rare phenomenon in the pediatric age group. An important clinical implication of calcific UAV is the presence of calcification that extends into the interventricular septum, with possible damage to the conduction system during debridement at the time of surgery in preparation for replacement of the aortic valve.

## **5. UAV and aortopathy**

Aortopathy is an important associated complication of UAV. Also a bimodal distribution of UAV has been described in the literature older UAV patients presenting without any pathological aortic dilatation and younger UAV patients with aggressive form of pathological aortic dilatation (Agnihotri, 2006). The UAV is also associated with pathological aortic dilatation over time which is thought to be secondary to hemodynamic stress and congenitally inherited weakness of aortic media. This congenitally inherited weakness in BAV is believed to be secondary to apoptosis of neural crest derivatives thereby predisposing to premature cystic medial necrosis. It is not known whether UAV shares similar pathological features of BAV. Aortic dissection also occurs at an increased rate in UAV patients compared to general population. And whenever it occurs, aortic dissection also presents at an earlier age in UAV patients compared to BAV and TAV.

## **6. Diagnosis**

Clinically patients present with the usual and expected symptoms of syncope, chest pain, dyspnea and heart failure. As with any other etiology of aortic stensosi, however the age at presentation should alert the clinician as to the likely etiology as being unicuspid or bicuspid. Furhermore the aortopathy implies either unicupid or bicuspid abnormalities of the aortic valve. The presence of associated congenital heart abnormalities would suggest acommissural unicuspid aortic valve especially in the very young. Auscultation is significant for a third heart sound, systolic and diastolic murmurs depending on the predominant lesion. With at least moderate AS and concomitant moderate or higher degree of AR, the murmur may be confused for a coronocameral fistula, the machinery like murmur of PDA or mixed valve diseases. This difficulty can be reflected from the fact that approximately 60% of the adult UAV cases are diagnosed at autopsy/surgical resection, while only 20% are diagnosed by TTE and TEE. (Mookadam 2010a)

Transthoracic echocardiographic imaging remains the most common modality deployed for diagnosing UAVs preoperatively. Echocardiographic imaging allows satisfactory assessment of valve morphology, valve orifice, annular attachment zone and severity of aortic stenosis and regurgitation.

In addition the ascending aorta, left ventricular changes in response to the hemodynamic load, other valvualr structures and associated congenital anomalies (Table 2), can be identified. Other ancillary modalities including transesopahgeal echocardiography (TEE), real time 3-Dimensional echocardiographic imaging, cardiac computed tomography (CT) and magnetic resonance imaging (MRI) can also be used for better evaluation. All these ancillary imaging modalities have the capability to diagnose and identify preoperatively any associated anomalies.

UAV is more frequent among patients presenting to surgery with AS; approximately about

In adults, pathology of resected UAVs is characterized by heavy calcification implying early degeneration from hemodynamic stress. However, calcification is a very rare phenomenon in the pediatric age group. An important clinical implication of calcific UAV is the presence of calcification that extends into the interventricular septum, with possible damage to the conduction system during debridement at the time of surgery in preparation for

Aortopathy is an important associated complication of UAV. Also a bimodal distribution of UAV has been described in the literature older UAV patients presenting without any pathological aortic dilatation and younger UAV patients with aggressive form of pathological aortic dilatation (Agnihotri, 2006). The UAV is also associated with pathological aortic dilatation over time which is thought to be secondary to hemodynamic stress and congenitally inherited weakness of aortic media. This congenitally inherited weakness in BAV is believed to be secondary to apoptosis of neural crest derivatives thereby predisposing to premature cystic medial necrosis. It is not known whether UAV shares similar pathological features of BAV. Aortic dissection also occurs at an increased rate in UAV patients compared to general population. And whenever it occurs, aortic dissection

Clinically patients present with the usual and expected symptoms of syncope, chest pain, dyspnea and heart failure. As with any other etiology of aortic stensosi, however the age at presentation should alert the clinician as to the likely etiology as being unicuspid or bicuspid. Furhermore the aortopathy implies either unicupid or bicuspid abnormalities of the aortic valve. The presence of associated congenital heart abnormalities would suggest acommissural unicuspid aortic valve especially in the very young. Auscultation is significant for a third heart sound, systolic and diastolic murmurs depending on the predominant lesion. With at least moderate AS and concomitant moderate or higher degree of AR, the murmur may be confused for a coronocameral fistula, the machinery like murmur of PDA or mixed valve diseases. This difficulty can be reflected from the fact that approximately 60% of the adult UAV cases are diagnosed at autopsy/surgical resection,

Transthoracic echocardiographic imaging remains the most common modality deployed for diagnosing UAVs preoperatively. Echocardiographic imaging allows satisfactory assessment of valve morphology, valve orifice, annular attachment zone and severity of

In addition the ascending aorta, left ventricular changes in response to the hemodynamic load, other valvualr structures and associated congenital anomalies (Table 2), can be identified. Other ancillary modalities including transesopahgeal echocardiography (TEE), real time 3-Dimensional echocardiographic imaging, cardiac computed tomography (CT) and magnetic resonance imaging (MRI) can also be used for better evaluation. All these ancillary imaging modalities have the capability to diagnose and identify preoperatively any

also presents at an earlier age in UAV patients compared to BAV and TAV.

while only 20% are diagnosed by TTE and TEE. (Mookadam 2010a)

5% of patients presenting to surgery for pure AS will have UAV.

replacement of the aortic valve.

**5. UAV and aortopathy** 

**6. Diagnosis** 

aortic stenosis and regurgitation.

associated anomalies.

Given the association, early progression and aggressive presentation between aortopathy and UAV, it is prudent to follow these patients regularly for timely intervention.

Fig. 3. Unicommissural AS (1983, 2-283-534, Eaton 42M), with x-ray

## **7. Management**

The treatment approach differs significantly between adults and children. In children, treatment choices included aortic balloon valvoplasty, surgical valvotomy, and commissurotomy (Mookadam, 2010b). Repair of the aortic coarctation is also frequent among children, which was the most common associated anomaly. However, replacement of aortic root is uncommon in the pediatric age group.

In adults, most common treatment modality was aortic valve replacement associated with replacement of aortic annulus/aortic root/ascending aorta. Other treatment modalities included bicuspidization of UAV, Bentall's operation, aortic valvotomy and Ross procedure. Also in UAV, aortic valve replacement (AVR) was about 10-20 years earlier than BAV, and 20-30 years earlier than normal TAV. The current management approach of UAV is to follow valve sparing techniques in children and delaying AVR to allow aorta to grow to adult size.

## **8. References**


**15** 

*Republic of Kosovo* 

**Bicuspid Aortic Valve** 

Blerim Berisha, Xhevdet Krasniqi,

Dardan Kocinaj, Ejup Pllana and Masar Gashi

*Cardiology Department, Internal Clinic, University Clinical Centre of Kosovo* 

Bicuspid aortic valve (BAV) disease is the most common congenital cardiovascular malformation with prevalence of 1-2% in the human population (Hoffman, 1990; Hoffman & Kaplan, 2002). Current clinical and scientific studies reveal that bicuspid aortic disease is not a simple valve condition. It increasingly appears to be a genetically based connective tissue disorder. It has been reported that a molecular abnormality in the extracellular matrix may lead to abnormal cell differentiation during valvulogenesis; however, the exact mechanism remains unclear (Nataatmadja et al., 2003; Eisenberg et al., 1995; Fedak et al., 2002). An important problem is that the aorta of patients with BAV is not normal in strength or size. BAV is frequently associated with other cardiovascular malformations, including aortic root dilatation, aortic stenosis, coarctation of the aorta, and ventricular defects. Although symptoms often manifest in adulthood, there is a wide spectrum of presentations ranging from severe disease detected in utero to asymptomatic disease in old age. Complications can include aortic valve stenosis or incompetence, endocarditis, aortic aneurysm formation, and aortic dissection. Two large contemporary series have demonstrated that the life expectancy in adults with normally functioning BAV is not shortened when compared with that of the general population whereas age and severity of disease were associated with primary cardiac events (Michelena et al., 2008; Tzemos et al., 2008). The risk of aortic dilatation and aortic dissection is higher in patients with BAV than in the general population. In most of patients with BAV, symptoms and physical findings often are absent for many years, whereas the clinical consequences in patients with BAV are associated with regurgitation, endocarditis, and aortic aneurism and dissection. Endocarditis is an important complication for patients with BAV. It occurs particularly in patients with regurgitant or obstructive valves, although the risk of endocarditis may also be high also in hemodynamically stable patients. Prior studies reported significant mortality in patients with infected BAV. However, the last ACC/AHA guidelines recommend that antibiotic prophylaxis is not

indicated in young patients and adolescents with BAV (Nishimura et al., 2008).

for severe valvular dysfunction, symptomatic patients, and aortic dilatation.

Patients with moderate valvular dysfunction and normal left ventricular dimensions should be systematically monitored using echocardiography. In adition hypertension should be carefully followed by a cardiologist or cardiac surgeon with specific interest in this valve

Adequate oral hygiene and antibiotic prophylaxis during dental procedures or when a poor cardiac condition is present are important for preventing endocarditis. Surgery is indicated

**1. Introduction** 

pathology.



## **Bicuspid Aortic Valve**

Blerim Berisha, Xhevdet Krasniqi,

Dardan Kocinaj, Ejup Pllana and Masar Gashi *Cardiology Department, Internal Clinic, University Clinical Centre of Kosovo Republic of Kosovo* 

#### **1. Introduction**

274 Aortic Valve

Cemri M, Cengel A, Timurkaynak T. Pentacuspid aortic valve diagnosed by

Collins MJ, Butany J, Borger MA, Strauss BH, David TE. Implications of a congenitally

Edwards JE. Pathologic aspects of cardiac valvular insufficiencies. *AMA Arch Surg* 1958;

Lewin MB, Otto CM. The bicuspid aortic valve: Adverse outcomes from infancy to old age.

Mookadam F, Thota VR, Garcia-Lopez AM, et al. Unicuspid aortic valve in adults:

Mookadam F, Thota VR, Garcia-Lopez AM, et al. Unicuspid aortic valve in children: A systematic review spanning four decades. *J Heart Valve Dis* 2010; 19:678-683.

abnormal valve: a study of 1025 consecutively excised aortic valves. *J Clin Pathol*.

transoesophageal echocardiography. *Heart* 2000; 84:E9

A systematic review. *J Heart Valve Dis* 2010; 19:79-85

2008 Apr; 61(4):530-6

*Circulation* 2005; 111:832-834

77:634-649

Bicuspid aortic valve (BAV) disease is the most common congenital cardiovascular malformation with prevalence of 1-2% in the human population (Hoffman, 1990; Hoffman & Kaplan, 2002). Current clinical and scientific studies reveal that bicuspid aortic disease is not a simple valve condition. It increasingly appears to be a genetically based connective tissue disorder. It has been reported that a molecular abnormality in the extracellular matrix may lead to abnormal cell differentiation during valvulogenesis; however, the exact mechanism remains unclear (Nataatmadja et al., 2003; Eisenberg et al., 1995; Fedak et al., 2002). An important problem is that the aorta of patients with BAV is not normal in strength or size. BAV is frequently associated with other cardiovascular malformations, including aortic root dilatation, aortic stenosis, coarctation of the aorta, and ventricular defects. Although symptoms often manifest in adulthood, there is a wide spectrum of presentations ranging from severe disease detected in utero to asymptomatic disease in old age. Complications can include aortic valve stenosis or incompetence, endocarditis, aortic aneurysm formation, and aortic dissection. Two large contemporary series have demonstrated that the life expectancy in adults with normally functioning BAV is not shortened when compared with that of the general population whereas age and severity of disease were associated with primary cardiac events (Michelena et al., 2008; Tzemos et al., 2008). The risk of aortic dilatation and aortic dissection is higher in patients with BAV than in the general population. In most of patients with BAV, symptoms and physical findings often are absent for many years, whereas the clinical consequences in patients with BAV are associated with regurgitation, endocarditis, and aortic aneurism and dissection. Endocarditis is an important complication for patients with BAV. It occurs particularly in patients with regurgitant or obstructive valves, although the risk of endocarditis may also be high also in hemodynamically stable patients. Prior studies reported significant mortality in patients with infected BAV. However, the last ACC/AHA guidelines recommend that antibiotic prophylaxis is not indicated in young patients and adolescents with BAV (Nishimura et al., 2008).

Patients with moderate valvular dysfunction and normal left ventricular dimensions should be systematically monitored using echocardiography. In adition hypertension should be carefully followed by a cardiologist or cardiac surgeon with specific interest in this valve pathology.

Adequate oral hygiene and antibiotic prophylaxis during dental procedures or when a poor cardiac condition is present are important for preventing endocarditis. Surgery is indicated for severe valvular dysfunction, symptomatic patients, and aortic dilatation.

Bicuspid Aortic Valve 277

BAV is a complex congenital disease; therefore, its etiology remains unclear, but genetic factors have been proposed. Most BAV s occur as an isolated congenital defect; however, a study on 41 families with a family member having surgically corrected BAV reported the prevalence of BAV to be at least 14.6% (Emanuel et al., 1978). A much more recent study in 50 probands with BAV concluded that the heritability (h) of BAV was 89%, and suggested that in this population, BAV is almost entirely genetic (Cripe et al., 2004). Two studies have identified genomic regions responsible for cardiovascular congenital disease associated with BAV. The first genetic cause of BAV is Anderson syndrome, which is reported to be a result of mutations in the KCNJ2 gene, whereas it clinically presents as ventricular arrhythmias, periodic paralysis, and scoliosis (Andelfinger et al., 2002). Another study in a large family with autosomal-dominant aortic valve disease diagnosed using genome-wide linkage analysis suggests that NOTCH1 gene mutations mapped to chromosome 9q-34 are responsible for the early developmental defect in the aortic valve (Garg et al., 2005). These studies are very important for understanding the complex etiology of congenital valvular disease, and they may help us to develop novel therapeutic strategies for preventing and treating BAV.

**4. Congenital cardiovascular syndromes associated with bicuspid aortic** 

It has been reported that BAV is presented in > 50 % of patients with coarctation of the aorta (COA) (Duran et al., 1995). Patients with COA and BAV are reported to have more severe disease associated with aortic stenosis, aortic regurgitation, and aortic aneurysm. The risk of dissection of the aorta and death is greater when COA and BAV are comorbid (Abbott, 1928). Microfibrilar proteins such us fibrillin -1 may be deficient during valvulogenesis, which could reduce the structural integrity both in the aortic valve and aorta. Aortic dysregulation is associated with increased activity of metalloproteinases, which may have

Turner syndrome characterized by a defect in or the absence of one X chromosome. Except for gonadal dysgenesis, cardiovascular defects are commonly present in this group of patients. Clinical research on patients with Turner Syndrome reports that BAV is present in 30% of cases, that over 95% of BAV s result from fusion of the right and left coronary leaflets, and that aortic ascending diameters are significantly greater in this group of

Patent ductus arteriosus is usually obliterated during the first month of life (Mitchell, 1957; Reller et al., 1988; Mandorla et al., 1990; Lim et al., 1992). Patent ductus arteriosus is usually present in pediatric patients with BAV and may be associated with hand anomalies (Gelb et

Williams Syndrome is arteriopathy characterized by supravalvular aortic stenosis which may be associated with COA, renal artery stenosis, and arterial hypertension. Williams

**3. Genetics of the bicuspid aortic valve** 

**valve** 

**4.1 Coarctation of the aorta** 

**4.2 Turner syndrome** 

**4.3 Patent ductus arteriosus** 

**4.4 Williams syndrome** 

al., 1999).

impact on fibrillin-1 (McMillan ,et al., 1997).

patients (Miller et al., 1983; Sachdev et al., 2008).

This article addresses the embryology, genetic, pathophysiology, clinical presentation, diagnostic procedures, and therapeutic strategies for BAV. In this chapter we will present some cases with BAV with different prognoses from our clinic.

## **2. Embryology**

The cardiac structure is evident from the second week of gestation, whereas separation of the heart into four chambers is completed during the sixth and seventh weeks of gestation, resulting in separated systemic and pulmonary circulation. The process of aortic valve morphogenesis begins from the cardiac cushions located in the ventricular outflow tract of the primary heart tube. The pathogenesis of BAV is still unclear. Studies in a Syrian hamster model with a high prevalence of BAV reported that fusion of the right and the left valve cushions is a key factor in the formation of BAV s (Sans-Coma et al., 2006). A previous study suggested that BAV is a consequence of the anomalous behavior of cells derived from the neural crest because BAV often is associated with congenital aortic arch malformations and other neural crest-derived systems (Kappetein et al., 1991). Other studies suggest that extracellular matrix proteins may affect the initiation of cell differentiation during valvulogenesis, while a molecular abnormality in this process may lead to the formation of abnormal cusps (Eisenberg et al., 1995; Fedak et al., 2002).

These abnormalities cause the fusion of two cusps and lead to one larger cusp; therefore, the BAV usually includes two unequally sized cusps, the presence of a central raphe, and smooth cusp margin (Figure 1). A previous clinicopathologic study of a large group surgically excised congenital BAVs showed that raphal position was between the right and left cusp in 86% of cases (Sabet et al., 1999). An anomalous origin of coronary arteries depends on the spatial orientation of the two cusps. When the orientation of the cusps is anteroposterior, the coronary arteries originate from the anterior sinus or if cusps laterlateral oriented the right coronary artery originate from the common trunk and right Valsava's sinus (Schang et al., 1975). An anomalous origin of coronary arteries may be associated with myocardial hypoperfusion and angina pectoris.

Fig. 1. The morphologic pattern of BAV. (a): Fusion of the right-coronary and left-coronary leaflets. (b): Fusion of the right-coronary and non-coronary leaflets. (c): Fusion of the leftcoronary and non-coronary leaflet. RCA, right coronary artery. LCA, left coronary artery. The red dotted line indicate the raphal position

This article addresses the embryology, genetic, pathophysiology, clinical presentation, diagnostic procedures, and therapeutic strategies for BAV. In this chapter we will present

The cardiac structure is evident from the second week of gestation, whereas separation of the heart into four chambers is completed during the sixth and seventh weeks of gestation, resulting in separated systemic and pulmonary circulation. The process of aortic valve morphogenesis begins from the cardiac cushions located in the ventricular outflow tract of the primary heart tube. The pathogenesis of BAV is still unclear. Studies in a Syrian hamster model with a high prevalence of BAV reported that fusion of the right and the left valve cushions is a key factor in the formation of BAV s (Sans-Coma et al., 2006). A previous study suggested that BAV is a consequence of the anomalous behavior of cells derived from the neural crest because BAV often is associated with congenital aortic arch malformations and other neural crest-derived systems (Kappetein et al., 1991). Other studies suggest that extracellular matrix proteins may affect the initiation of cell differentiation during valvulogenesis, while a molecular abnormality in this process may lead to the formation of

These abnormalities cause the fusion of two cusps and lead to one larger cusp; therefore, the BAV usually includes two unequally sized cusps, the presence of a central raphe, and smooth cusp margin (Figure 1). A previous clinicopathologic study of a large group surgically excised congenital BAVs showed that raphal position was between the right and left cusp in 86% of cases (Sabet et al., 1999). An anomalous origin of coronary arteries depends on the spatial orientation of the two cusps. When the orientation of the cusps is anteroposterior, the coronary arteries originate from the anterior sinus or if cusps laterlateral oriented the right coronary artery originate from the common trunk and right Valsava's sinus (Schang et al., 1975). An anomalous origin of coronary arteries may be

 **RCA LCA RCA LCA RCA LCA** 

Fig. 1. The morphologic pattern of BAV. (a): Fusion of the right-coronary and left-coronary leaflets. (b): Fusion of the right-coronary and non-coronary leaflets. (c): Fusion of the leftcoronary and non-coronary leaflet. RCA, right coronary artery. LCA, left coronary artery.

(a) (86%) (b) (12%) (c) (3%)

some cases with BAV with different prognoses from our clinic.

abnormal cusps (Eisenberg et al., 1995; Fedak et al., 2002).

associated with myocardial hypoperfusion and angina pectoris.

The red dotted line indicate the raphal position

**2. Embryology** 

## **3. Genetics of the bicuspid aortic valve**

BAV is a complex congenital disease; therefore, its etiology remains unclear, but genetic factors have been proposed. Most BAV s occur as an isolated congenital defect; however, a study on 41 families with a family member having surgically corrected BAV reported the prevalence of BAV to be at least 14.6% (Emanuel et al., 1978). A much more recent study in 50 probands with BAV concluded that the heritability (h) of BAV was 89%, and suggested that in this population, BAV is almost entirely genetic (Cripe et al., 2004). Two studies have identified genomic regions responsible for cardiovascular congenital disease associated with BAV. The first genetic cause of BAV is Anderson syndrome, which is reported to be a result of mutations in the KCNJ2 gene, whereas it clinically presents as ventricular arrhythmias, periodic paralysis, and scoliosis (Andelfinger et al., 2002). Another study in a large family with autosomal-dominant aortic valve disease diagnosed using genome-wide linkage analysis suggests that NOTCH1 gene mutations mapped to chromosome 9q-34 are responsible for the early developmental defect in the aortic valve (Garg et al., 2005). These studies are very important for understanding the complex etiology of congenital valvular disease, and they may help us to develop novel therapeutic strategies for preventing and treating BAV.

## **4. Congenital cardiovascular syndromes associated with bicuspid aortic valve**

#### **4.1 Coarctation of the aorta**

It has been reported that BAV is presented in > 50 % of patients with coarctation of the aorta (COA) (Duran et al., 1995). Patients with COA and BAV are reported to have more severe disease associated with aortic stenosis, aortic regurgitation, and aortic aneurysm. The risk of dissection of the aorta and death is greater when COA and BAV are comorbid (Abbott, 1928). Microfibrilar proteins such us fibrillin -1 may be deficient during valvulogenesis, which could reduce the structural integrity both in the aortic valve and aorta. Aortic dysregulation is associated with increased activity of metalloproteinases, which may have impact on fibrillin-1 (McMillan ,et al., 1997).

#### **4.2 Turner syndrome**

Turner syndrome characterized by a defect in or the absence of one X chromosome. Except for gonadal dysgenesis, cardiovascular defects are commonly present in this group of patients. Clinical research on patients with Turner Syndrome reports that BAV is present in 30% of cases, that over 95% of BAV s result from fusion of the right and left coronary leaflets, and that aortic ascending diameters are significantly greater in this group of patients (Miller et al., 1983; Sachdev et al., 2008).

#### **4.3 Patent ductus arteriosus**

Patent ductus arteriosus is usually obliterated during the first month of life (Mitchell, 1957; Reller et al., 1988; Mandorla et al., 1990; Lim et al., 1992). Patent ductus arteriosus is usually present in pediatric patients with BAV and may be associated with hand anomalies (Gelb et al., 1999).

#### **4.4 Williams syndrome**

Williams Syndrome is arteriopathy characterized by supravalvular aortic stenosis which may be associated with COA, renal artery stenosis, and arterial hypertension. Williams

Bicuspid Aortic Valve 279

The clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve disease in old age. Disease is more severe and has poor clinical outcomes in infants with BAV comorbid with aortic stenosis (Hastreiter et al., 1963; Moller

Symptoms are a result of valvular stenosis, regurgitation, endocarditis, and aortic complications such as dilatation and dissection. Symptoms associated with aortic stenosis are angina pectoris, syncope, and congestive heart failure. Stenosis is more rapid if the aortic cusps are asymmetrical or anteroposteriorly oriented (Ward, 2008). Angina pectoris occurs in patients with severe aortic stenosis and in those who do not have coronary artery disease;

Syncope is another common symptom in patients with BAV. Syncope reflects the cerebral hypoperfusion caused by the inability to increase stroke volume during physical activity. The most common complication of aortic stenosis is congestive heart failure symptomatically presented with dyspnea, which is a result of combined diastolic and systolic dysfunction

Aortic regurgitation reported to be more common in young patients and caused by prolapse of the greater cusp, which may associated with aortic root dilatation. Although young patients with BAV often are asymptomatic, echocardiographic studies show that 47% of this group of patients have some degree of incompetence (Michelena et al., 2008). Aortic regurgitation in patients with BAV carries an increased risk of endocarditis. If a patient with BAV complians of fever, weakness, and chest pain, endocarditis may be present. Endocarditis occurs in 10-30% of patients with BAV and can lead to valve perforation or

Aortic dilatation and dissection can be echocardiographcally diagnosed in patients with minimal valvular dysfunction even when they are asymptomatic; therefore, the risk of aortic dissection in patients with BAV may be higher than clinical presentation. Aortic dilatation may be progressive and often requires surgical correction (Duran et al., 1990; Sabet et al.,

The clinical presentation in patients with BAV and presence of other cardiac congenital defects depends from structural complexity of the heart. In patients with COA, the presence of hypertension increases the risk of aortic dissection, considering that congenital abnormalities of the aortic wall are also involved. Patient may complain of chest pain, hoarseness, and respiratory difficulties. In adult patients with interventricular septal defects, the clinical presentation depends on the size of the defect area and the grade of aortic stenosis. If the interventricular defect is small, the patient may be asymptomatic, but when the interventricular defect is large, cardiac output will decrease and Eisenmenger syndrome will develop. Eisenmenger syndrome clinically presents with central cyanosis and shortness of breath during physical activity. However, during that the BAV becomes thicker, more fibrotic, and more calcified, and if is not surgically corrected cardiac output will decrease

Two large recent series reported that clinical course of unoperated patients with BAV depends on age, stenosis, and aortic incompetence (Michelena et al., 2008; Tzemos et al., 2008). The severe aortic stenosis, and severe aortic incompetence in older patients increases the risk of primary cardiac events including cardiac death. Both these studies suggest that intervention on the basis of early symptoms or incipient cardiac dysfunction may decreases

**6. Clinical presentation** 

destruction (Ward, 2008).

1999).

it may be a result of ventricular hypertrophy.

dramatically and may lead to cardiac death.

the mortality of patients with BAV.

caused by elevated afterload and increased filling pressures.

et al., 1966).

syndrome has also been associated with complete atrioventricular septal defect (Nakamoto et al., 2003), and is reported to be commonly present in patients with BAV (Sugayama et al., 2003; Hallidie-Smith & Karas, 1988).

#### **4.5 Ventricular septal defect**

Ventricular architecture may be characterized by complex malformation during embryogenesis involving both septation and valve formation. Ventricular septal defects are often associated with BAV and other complex congenital malformations (Oppenheimer-Dekker et al., 1985) . BAV is reported to be present in up to 30 % of adult patients with small ventricular septal defects (Neumayer et al., 1988). However, BAV may also be associated with large ventricular septal defects and poor clinical outcome (Berisha et al., 2009).

## **5. Pathophysiology**

Valve leaflet morphology and orientation are competent for pathophysiology of left heart. Adhesions of commissures and cusp calcifications predisposes to eventual stenosis, hemodynamically presented by different pressures between left ventricle (LV) and the ascending aorta during the systolic and diastolic period. Aortic stenosis is the most common complication of BAV, whereas aortic regurgitation is reported to be present in 13% of cases (Sabet et al., 1999). Turbulent flow along the abnormal structure of the BAV leads to fibrotic changes and stenotic progression. The pressure differences in stenotic patients with BAV are important because deviation from normal flow can cause important changes, in both the LV and the ascending aorta. High LV pressure in BAV increases wall stress, which results in the generation of concentric ventricle hypertrophy. Previous studies suggest that mechanical stimuli of myocytes can induce ventricular hypertrophy by specific gene expression, possibly via protein kinase C activation (Komuro et al., 1991, 1999). Progressively over time, the LV becomes more hypertrophic and less compliant, which contributes to a reduction of LV function. At this point, reduced stroke volume and cardiac output may lead to congestive heart failure. Post-stenotic dilatation may be a result of prolonged and severe aortic stenosis. Abnormal flow along the wall of the aorta can vibrate the vessel wall at different frequencies (Boughner & Roach, 1971), and may directly modulate elastin, whereas histopathological findings in congenital cardiac syndromes show medial degeneration and decreased fibrillin-1 in the aortic wall (Nataatmadja et al., 2003); however, the exact mechanism causing aortic dilatation in patients with BAV is unclear.

BAV may be associated with abnormal coronary arteries or the coronary ostium may be stenotic (Roberts, 1970), while angina pectoris is reported to be present in patients with severe aortic stenosis and without coronary disease (Julius et al., 1997) .Wall stress during systole and diastole, and impaired LV relaxation in severe aortic stenosis, reduces the coronary flow reserve and causes subendocardial underperfusion; however, the exact mechanisms of angina pectoris in BAV are not very clear.

Aortic regurgitation in patients with BAV is a result of cusp prolapse, fibrotic retraction, or dilatation of the sinotubular junction. BAV tends to become progressively more stenotic or regurgitant over time, and the valve becomes the site of infective endocarditis. Endocarditis is a result of turbulent flow, which induces chronic abrasion and abscess formation. Endocarditis can cause valve destruction and lead to severe aortic incompetence associated with a poor clinical outcome.

syndrome has also been associated with complete atrioventricular septal defect (Nakamoto et al., 2003), and is reported to be commonly present in patients with BAV (Sugayama et al.,

Ventricular architecture may be characterized by complex malformation during embryogenesis involving both septation and valve formation. Ventricular septal defects are often associated with BAV and other complex congenital malformations (Oppenheimer-Dekker et al., 1985) . BAV is reported to be present in up to 30 % of adult patients with small ventricular septal defects (Neumayer et al., 1988). However, BAV may also be associated

Valve leaflet morphology and orientation are competent for pathophysiology of left heart. Adhesions of commissures and cusp calcifications predisposes to eventual stenosis, hemodynamically presented by different pressures between left ventricle (LV) and the ascending aorta during the systolic and diastolic period. Aortic stenosis is the most common complication of BAV, whereas aortic regurgitation is reported to be present in 13% of cases (Sabet et al., 1999). Turbulent flow along the abnormal structure of the BAV leads to fibrotic changes and stenotic progression. The pressure differences in stenotic patients with BAV are important because deviation from normal flow can cause important changes, in both the LV and the ascending aorta. High LV pressure in BAV increases wall stress, which results in the generation of concentric ventricle hypertrophy. Previous studies suggest that mechanical stimuli of myocytes can induce ventricular hypertrophy by specific gene expression, possibly via protein kinase C activation (Komuro et al., 1991, 1999). Progressively over time, the LV becomes more hypertrophic and less compliant, which contributes to a reduction of LV function. At this point, reduced stroke volume and cardiac output may lead to congestive heart failure. Post-stenotic dilatation may be a result of prolonged and severe aortic stenosis. Abnormal flow along the wall of the aorta can vibrate the vessel wall at different frequencies (Boughner & Roach, 1971), and may directly modulate elastin, whereas histopathological findings in congenital cardiac syndromes show medial degeneration and decreased fibrillin-1 in the aortic wall (Nataatmadja et al., 2003); however, the exact

BAV may be associated with abnormal coronary arteries or the coronary ostium may be stenotic (Roberts, 1970), while angina pectoris is reported to be present in patients with severe aortic stenosis and without coronary disease (Julius et al., 1997) .Wall stress during systole and diastole, and impaired LV relaxation in severe aortic stenosis, reduces the coronary flow reserve and causes subendocardial underperfusion; however, the exact

Aortic regurgitation in patients with BAV is a result of cusp prolapse, fibrotic retraction, or dilatation of the sinotubular junction. BAV tends to become progressively more stenotic or regurgitant over time, and the valve becomes the site of infective endocarditis. Endocarditis is a result of turbulent flow, which induces chronic abrasion and abscess formation. Endocarditis can cause valve destruction and lead to severe aortic incompetence associated

with large ventricular septal defects and poor clinical outcome (Berisha et al., 2009).

mechanism causing aortic dilatation in patients with BAV is unclear.

mechanisms of angina pectoris in BAV are not very clear.

with a poor clinical outcome.

2003; Hallidie-Smith & Karas, 1988).

**4.5 Ventricular septal defect** 

**5. Pathophysiology** 

## **6. Clinical presentation**

The clinical presentation of patients with BAV can vary from severe valve disease in infancy to asymptomatic valve disease in old age. Disease is more severe and has poor clinical outcomes in infants with BAV comorbid with aortic stenosis (Hastreiter et al., 1963; Moller et al., 1966).

Symptoms are a result of valvular stenosis, regurgitation, endocarditis, and aortic complications such as dilatation and dissection. Symptoms associated with aortic stenosis are angina pectoris, syncope, and congestive heart failure. Stenosis is more rapid if the aortic cusps are asymmetrical or anteroposteriorly oriented (Ward, 2008). Angina pectoris occurs in patients with severe aortic stenosis and in those who do not have coronary artery disease; it may be a result of ventricular hypertrophy.

Syncope is another common symptom in patients with BAV. Syncope reflects the cerebral hypoperfusion caused by the inability to increase stroke volume during physical activity.

The most common complication of aortic stenosis is congestive heart failure symptomatically presented with dyspnea, which is a result of combined diastolic and systolic dysfunction caused by elevated afterload and increased filling pressures.

Aortic regurgitation reported to be more common in young patients and caused by prolapse of the greater cusp, which may associated with aortic root dilatation. Although young patients with BAV often are asymptomatic, echocardiographic studies show that 47% of this group of patients have some degree of incompetence (Michelena et al., 2008). Aortic regurgitation in patients with BAV carries an increased risk of endocarditis. If a patient with BAV complians of fever, weakness, and chest pain, endocarditis may be present. Endocarditis occurs in 10-30% of patients with BAV and can lead to valve perforation or destruction (Ward, 2008).

Aortic dilatation and dissection can be echocardiographcally diagnosed in patients with minimal valvular dysfunction even when they are asymptomatic; therefore, the risk of aortic dissection in patients with BAV may be higher than clinical presentation. Aortic dilatation may be progressive and often requires surgical correction (Duran et al., 1990; Sabet et al., 1999).

The clinical presentation in patients with BAV and presence of other cardiac congenital defects depends from structural complexity of the heart. In patients with COA, the presence of hypertension increases the risk of aortic dissection, considering that congenital abnormalities of the aortic wall are also involved. Patient may complain of chest pain, hoarseness, and respiratory difficulties. In adult patients with interventricular septal defects, the clinical presentation depends on the size of the defect area and the grade of aortic stenosis. If the interventricular defect is small, the patient may be asymptomatic, but when the interventricular defect is large, cardiac output will decrease and Eisenmenger syndrome will develop. Eisenmenger syndrome clinically presents with central cyanosis and shortness of breath during physical activity. However, during that the BAV becomes thicker, more fibrotic, and more calcified, and if is not surgically corrected cardiac output will decrease dramatically and may lead to cardiac death.

Two large recent series reported that clinical course of unoperated patients with BAV depends on age, stenosis, and aortic incompetence (Michelena et al., 2008; Tzemos et al., 2008). The severe aortic stenosis, and severe aortic incompetence in older patients increases the risk of primary cardiac events including cardiac death. Both these studies suggest that intervention on the basis of early symptoms or incipient cardiac dysfunction may decreases the mortality of patients with BAV.

Bicuspid Aortic Valve 281

important for evaluating the aortic valve and thoracic aorta, whereas the sensitivity and specifity of multiplane technique for assessing aortic valve morphology is high (Alegret et

In patients with poor acustic window, cardiac magnetic resonance (MR) and multidetector computed tomography (CT) are useful for measuring the aortic valve area and is an alternative method to echocardiography in selected cases (Shelton et al., 2003; Pouleur et al.,

The most common bacteria that causes the formation of perivalvular abscess is Staphylococcus aureus. Indications for antibiotic prophylaxis in patients with BAV are before procedures expected to produce bacteremia; however, new ACC/AHA guidelines recommend that antibiotic prophylaxis is no longer indicated for preventing of infective endocarditis in adolescents and young adults with native heart valve disease (Nishimura et al., 2008). This committee concluded that infective endocarditis prophylaxis for dental procedures is reasonable only for patients with cardiac conditions associated with a high risk of adverse

Manipulation of periapical region of teeth Clindamycin, Cefalexin, Cefadroxil, Cefazolin Perforation of oral mucosa Azithromycin, Clarithromycin, Clindamycin

Table 2. Recommendations for antibiotics for endocarditis prophylaxis before procedures

When to surgically treat asymptomatic patients with BAV remains controversial. Sometimes aortic stenosis correlates poorly with clinical presentation; however, if it is combined with regurgitation, symtoms might be present. The risk of sudden death in asymptomatic adult patients with severe aortic stenosis is reported to be less than 1% per year (Pellika et al., 2005). Bonow et al., (2007) and Iung B et al. (2003) reported that valve replacement is not recommend for asymptomatic patients; however, current practice guidelines recommended aortic valve replacement in patients with reduced left ventricular systolic function (EF< 50%)

2007). MR imaging is an essential method for diagnosing COA and root aneurism.

al., 2005; Espinal et al., 2000).

**7.4 Other diagnostic procedures** 

**8. Endocarditis prophylaxis** 


**9. Treatment** 

outcomes from infective endocarditis (Table 2).

Nishimura et al., (2008). *J Am Coll Cardiol* 52,676-685.

**Procedures Antibiotics** 

Dental : Amoxicillin, Ampicillin

**Prophylaxis is not recommended for patients who undergo a:** 

without other explanation even when they are asymptomatic (Table 3).

Manipulation of gingival tissue Penicillin allergic:

## **7. Diagnosis**

## **7.1 Physical examination**

A physical examination is very helpful for evaluating the complications of BAV. Munt et al. (1999) reported that the amplitude of the pulse in the carotid artery was a significant predictor of outcome in patients with valvular aortic stenosis. If stenosis is present, the arterial pulse is small or weak and rises slowly, described as "parvus et tardus". The cardiac pulse at the apex initially is normal; however, arterial pulse is delayed and reduced in amplitude if evaluated by palpation of the carotid artery. Auscultatory findings are best heard in the left second intercostal space. The S1 usually is normal but sometimes may be associated with ejection click. The S2 is soft, and when aortic stenosis is present, S2 occurs simultaneously with P2. In aortic stenosis, an ejection systolic murmur is heard in the left second intercostal space but may also be transmitted to the carotid arteries. If aortic incompetence is present, a diastolic murmur of aortic regurgitation may be heard.

## **7.2 ECG**

The ECG changes are not specific in patients with BAV: left ventricular hypertrophy, atrial enlargement, and arrhythmias may be present.

### **7.3 Echocardiography**

The most important diagnostic method for first detecting and evaluating complications in patients with BAV is echocardiography. A transthoracic echocardiogram (TTE) considered the method of choice for evaluating valvular structure, calcifications, vegetations, cardiac chamber structure, and ejection fraction. Doppler methods are the most common techniques used for evaluating valvular regurgitation. For BAV associated with stenosis, mean gradient and maximal flow velocity should be measured, but when regurgitation is present, the effective regurgitant area (ERO) and Doppler jet size should be evaluated (Quinones, et al., 2002; Zoghbi et al., 2003). Based on recommendations for evaluating the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography, aortic regurgitation is classified as mild, moderate, and severe (Zoghbi et al., 2003). In 2006, ACC/AHA published guidelines for the management of patients with valvular disease in which aortic stenosis classified as mild, moderate, or severe (Table 1). For asymptomatic patients with aortic stenosis, echocardiography is recommended for evaluating disease progression. In asymptomatic patients, TTE recommended: every year for severe aortic stenosis, ever 1-2 years for moderate aortic stenosis and every 3-5 years for mild aortic stenosis (Bonow et al., 2006). Transesophageal echocardiography (TEE) is also very


Modified from Bonow et al.,(2006). ACC/AHA Practice Guidelines. *Circulation* 114, pp. e84-e231.

Table 1. Classification of the severity of aortic stenosis

A physical examination is very helpful for evaluating the complications of BAV. Munt et al. (1999) reported that the amplitude of the pulse in the carotid artery was a significant predictor of outcome in patients with valvular aortic stenosis. If stenosis is present, the arterial pulse is small or weak and rises slowly, described as "parvus et tardus". The cardiac pulse at the apex initially is normal; however, arterial pulse is delayed and reduced in amplitude if evaluated by palpation of the carotid artery. Auscultatory findings are best heard in the left second intercostal space. The S1 usually is normal but sometimes may be associated with ejection click. The S2 is soft, and when aortic stenosis is present, S2 occurs simultaneously with P2. In aortic stenosis, an ejection systolic murmur is heard in the left second intercostal space but may also be transmitted to the carotid arteries. If aortic

incompetence is present, a diastolic murmur of aortic regurgitation may be heard.

**Indicator Mild Moderate Severe**  Jet velocity (m per second) < 3.0 3.0-4.0 > 4.0 Mean gradient (mmHg) < 25 25-40 > 40 Valve area (cm²) < 1.5 1.0-1.5 < 1.0 Valve area index (cm per m²) < 0.6

Modified from Bonow et al.,(2006). ACC/AHA Practice Guidelines. *Circulation* 114, pp. e84-e231.

Table 1. Classification of the severity of aortic stenosis

The ECG changes are not specific in patients with BAV: left ventricular hypertrophy, atrial

The most important diagnostic method for first detecting and evaluating complications in patients with BAV is echocardiography. A transthoracic echocardiogram (TTE) considered the method of choice for evaluating valvular structure, calcifications, vegetations, cardiac chamber structure, and ejection fraction. Doppler methods are the most common techniques used for evaluating valvular regurgitation. For BAV associated with stenosis, mean gradient and maximal flow velocity should be measured, but when regurgitation is present, the effective regurgitant area (ERO) and Doppler jet size should be evaluated (Quinones, et al., 2002; Zoghbi et al., 2003). Based on recommendations for evaluating the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography, aortic regurgitation is classified as mild, moderate, and severe (Zoghbi et al., 2003). In 2006, ACC/AHA published guidelines for the management of patients with valvular disease in which aortic stenosis classified as mild, moderate, or severe (Table 1). For asymptomatic patients with aortic stenosis, echocardiography is recommended for evaluating disease progression. In asymptomatic patients, TTE recommended: every year for severe aortic stenosis, ever 1-2 years for moderate aortic stenosis and every 3-5 years for mild aortic stenosis (Bonow et al., 2006). Transesophageal echocardiography (TEE) is also very

**7. Diagnosis** 

**7.2 ECG** 

**7.3 Echocardiography** 

**7.1 Physical examination** 

enlargement, and arrhythmias may be present.

important for evaluating the aortic valve and thoracic aorta, whereas the sensitivity and specifity of multiplane technique for assessing aortic valve morphology is high (Alegret et al., 2005; Espinal et al., 2000).

## **7.4 Other diagnostic procedures**

In patients with poor acustic window, cardiac magnetic resonance (MR) and multidetector computed tomography (CT) are useful for measuring the aortic valve area and is an alternative method to echocardiography in selected cases (Shelton et al., 2003; Pouleur et al., 2007). MR imaging is an essential method for diagnosing COA and root aneurism.

## **8. Endocarditis prophylaxis**

The most common bacteria that causes the formation of perivalvular abscess is Staphylococcus aureus. Indications for antibiotic prophylaxis in patients with BAV are before procedures expected to produce bacteremia; however, new ACC/AHA guidelines recommend that antibiotic prophylaxis is no longer indicated for preventing of infective endocarditis in adolescents and young adults with native heart valve disease (Nishimura et al., 2008). This committee concluded that infective endocarditis prophylaxis for dental procedures is reasonable only for patients with cardiac conditions associated with a high risk of adverse outcomes from infective endocarditis (Table 2).


## **Prophylaxis is not recommended for patients who undergo a:**


Table 2. Recommendations for antibiotics for endocarditis prophylaxis before procedures

## **9. Treatment**

When to surgically treat asymptomatic patients with BAV remains controversial. Sometimes aortic stenosis correlates poorly with clinical presentation; however, if it is combined with regurgitation, symtoms might be present. The risk of sudden death in asymptomatic adult patients with severe aortic stenosis is reported to be less than 1% per year (Pellika et al., 2005). Bonow et al., (2007) and Iung B et al. (2003) reported that valve replacement is not recommend for asymptomatic patients; however, current practice guidelines recommended aortic valve replacement in patients with reduced left ventricular systolic function (EF< 50%) without other explanation even when they are asymptomatic (Table 3).

Bicuspid Aortic Valve 283

Risk factor EuroSCORE Points

< 60 **0**  60-64 **1**  65-69 **2**  70-74 **3**  75-79 **4**  80-84 **5**  85-89 **6**  90-94 **7**  >95 **8** 

Female **1**  Chronic pulmonary disease **1**  Extracardiac arteriopathy **2**  Neurological dysfunction **2**  Previous cardiac surgery **3**  Serum creatinine > 200 µM/L **2**  Active endocarditis **3**  Critical preoperative state **3**  Unstable angina **2** 

LVEF 30-50% **1**  LVEF < 30% **3**  Recent MI < 90 days **2**  Pulmonary hypertension, PSAP>60mmHg **2**  Emergency **2**  Major cardiac procedure other than CABG **2**  Surgery of thoracic aorta **3**  Post- infarct septal rupture **4** 

LVEF=left ventricular ejection fraction, MI= myocardial infarction, CABG=coronary artery bypass grafting

Age (years)

Sex

LV dysfunction :

Roques et al. (1999).

Table 5. Score risk classification in the EuroScore


CABG, coronary artery bypass graft. AVR, aortic valve replacement; Bonow et al. (2006).

Table 3. Indications for aortic valve replacement in patients with aortic stenosis


CMR= cardiac magnetic resonance, CT= computed tomography. Bonow et al. (2006).

Table 4. Evaluation and Treatment of Dilated Ascending Aorta in patients with Bicuspid Aortic Valve ACC/AHA 2006 Guidelines for the management of patients with valvular heart disease

exercise

1. Asymptomatic with severe aortic stenosis and abnormal response to

2. Asymptomatic Adults with severe aortic stenosis and rapid progression

rapid progressions

3. Mild aortic stenosis, undergoing CABG,

4. Asymptomatic with extremely severe aortic stenosis (when mortality ≤1%)

preventing sudden cardiac death in patients who have non of the findings

It is reasonable to give b-adrenergic blocking agents to patients with BAV and dilated aortic roots (diameter >than 4.0 cm) who are not candidates for surgical correction and who do not have

1. AVR is not recommended for

listed in IIa and IIb

moderate to severe AR.

the ascending aorta.

CMR imaging or cardiac CT is

reasonable in patients with BAV when aortic root dilatation is detected by echocardiography to further quantify severity of dilatation and involvement of

**Class I Class II b** 

**Class II a Class III** 

CABG, coronary artery bypass graft. AVR, aortic valve replacement;

**Class I Class IIa** 

Table 3. Indications for aortic valve replacement in patients with aortic stenosis

CMR= cardiac magnetic resonance, CT= computed tomography. Bonow et al. (2006).

Table 4. Evaluation and Treatment of Dilated Ascending Aorta in patients with Bicuspid Aortic Valve ACC/AHA 2006 Guidelines for the management of patients with valvular

1. Indicated for symptomatic patients with severe aortic stenosis

undergoing CABG

other heart valves

Bonow et al. (2006).

2. Indicated for severe aortic stenosis and

3. Indicated for severe aortic stenosis and undergoing surgery on the aorta and

4. Indicated for severe aortic stenosis and LV dysfunction EF less than 0.50

1. Indicated for moderate aortic stenosis and undergoing CABG or surgery of the aorta and other heart valves

Patients with bicuspid aortic valve and dilatation of the aortic root or ascending aorta (diameter > 4.0 cm) should undergo serial evaluation of aortic root/ascending aorta size and morphology by echocardiography, CMR

BAV if the diameter of aortic root or

In patients with BAV undergoing AVR because of severe AS or AR, repair of the aortic root or replacement of the ascending is indicated if the diameter of the aortic root or ascending aorta is grater than 4.5 cm.

Surgery to repair the aortic root or replace the ascending aorta is indicated in patients with

ascending aorta is greater than 5.0 cm or if the rate of increase in diameter is 0.5 cm per year

or CT on a yearly basis.

or more.

heart disease


LVEF=left ventricular ejection fraction, MI= myocardial infarction, CABG=coronary artery bypass grafting Roques et al. (1999).

Table 5. Score risk classification in the EuroScore

Bicuspid Aortic Valve 285

(a) (b)

(a) (b)

(a) (b)

view: aortic valve area

diameter

Fig. 2. TTE: (a) Parasternal short axis view: BAV during systole, (b) Parasternal short axis

Fig. 3. TTE: (a) Normal haemodinamic parameters , (b) Parasternal long axis view: Aortic

Elective surgery in patients with severe stenosis can prevent sudden cardiac death, and irreversible cardiac damage, and decrease operative risk. Coady et al., (1997) reported that the growth rate for the ascending segment of the aorta is 0.1 to 0.15 cm per year; therefore, older patients and those who have hypertension must be carefully followed-up and should be informed about the symptoms of aortic dissection. According to the ACC/AHA guidelines, patients with a dilated aortic root or an ascending aorta > 5.0 cm, or if the rate of increase in diameter > 0.5cm per year, should undergo simultaneous AVR and ascending aortic replacement (Table 4).

AVR carries a high risk for adverse events and poor clinical outcome when associated with LV dysfunction. In patients with functional class NYHA III-IV after aortic replacement, the one year mortality increased especially in patients with aortic stenosis (Rothenburger et al., 2003). Based on factors predicting operative mortality, which have been identified form large series of patients undergoing heart-valve surgery, The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology proposed risk classification scores for this group of patients (Vahanian et al., 2007) (Table 5).

For high-risk patients to undergo conventional novel methods including aortic balloon valvulotomy or transfemoral valve implantation may be helpful. This method reduced oneyear mortality from 50.7% in the standard therapy group to 30.7% in transcatheter aorticvalve implantation group (Leon et al., 2010). A patient considered inoperable should be treated orally with angiotensin converting enzyme (ACE) inhibitors, diuretics, and digitalis. In patients with depressed LV associated with pulmonary congestion and atrial fibrillation, diuretics and digitalis may be used with the understanding that in some cases intensive hemodynamic monitoring is needed. Patients with aortic root dilatation > 4.0cm who are not candidate for surgical treatment should be given β-adrenergic blocking agents.

## **10. Case presentations**

## **Case 1**

#### **History**


#### **Physical examination**


#### **Other diagnostic procedures**


Elective surgery in patients with severe stenosis can prevent sudden cardiac death, and irreversible cardiac damage, and decrease operative risk. Coady et al., (1997) reported that the growth rate for the ascending segment of the aorta is 0.1 to 0.15 cm per year; therefore, older patients and those who have hypertension must be carefully followed-up and should be informed about the symptoms of aortic dissection. According to the ACC/AHA guidelines, patients with a dilated aortic root or an ascending aorta > 5.0 cm, or if the rate of increase in diameter > 0.5cm per year, should undergo simultaneous AVR and ascending

AVR carries a high risk for adverse events and poor clinical outcome when associated with LV dysfunction. In patients with functional class NYHA III-IV after aortic replacement, the one year mortality increased especially in patients with aortic stenosis (Rothenburger et al., 2003). Based on factors predicting operative mortality, which have been identified form large series of patients undergoing heart-valve surgery, The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology proposed risk classification

For high-risk patients to undergo conventional novel methods including aortic balloon valvulotomy or transfemoral valve implantation may be helpful. This method reduced oneyear mortality from 50.7% in the standard therapy group to 30.7% in transcatheter aorticvalve implantation group (Leon et al., 2010). A patient considered inoperable should be treated orally with angiotensin converting enzyme (ACE) inhibitors, diuretics, and digitalis. In patients with depressed LV associated with pulmonary congestion and atrial fibrillation, diuretics and digitalis may be used with the understanding that in some cases intensive hemodynamic monitoring is needed. Patients with aortic root dilatation > 4.0cm who are not




VTI: 41.9cm, Mean pressure gradient: 8 mmHg, aorta: 2.90 cm, (Figure 2 and 3). - TEE: Bicuspid aortic valve with vertical commissure, cusps are unequal, aortal

candidate for surgical treatment should be given β-adrenergic blocking agents.



scores for this group of patients (Vahanian et al., 2007) (Table 5).

aortic replacement (Table 4).

**10. Case presentations** 

**Physical examination** 

heart Gr. 4/6

**Other diagnostic procedures** 

regurgitation (Figure 4).


0.5mm in V5 and V6 with biphasic T.




**Case 1 History** 

 (a) (b) Fig. 2. TTE: (a) Parasternal short axis view: BAV during systole, (b) Parasternal short axis view: aortic valve area

Fig. 3. TTE: (a) Normal haemodinamic parameters , (b) Parasternal long axis view: Aortic diameter

Bicuspid Aortic Valve 287

(a) (b)

(c) (d)

systolic function at rest (EF> 45%).

**Comments** 

complication.

**11. References** 

Fig. 5. TTE: (a) Artificial aortic valve (parasternal short axis view), (b) Apical five chamber view, (c) and (d) Parasternal long axis view: incipient aortic dilatatation and LA enlargement



Abbott, M. (1928) Coarctation of the aorta of adult type; II. A statistical study and historical

Alegret, J., Palazon, O., Duran, I. & Vernis, J. (2005) Aortic valve morphology definition with

arch in subjects above age of two years. *Am Heart J*, 3:574-618.

skeletal muscle phenotypes. *Am J Hum Genet* 71,663–668.

retrospect of 200 recorded cases with autopsy, of stenosis or obliteration ofdescending

transthoracic combined with transesophageal echocardiography in a population with high prevalence of bicuspid aortic valve. *Int J Cardiovasc Imaging* 21, 213–217. Andelfinger, G., Tapper AR., Welch, RC.,Vanoye, CG., George, AL. & Benson, W. (2002)

KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and

(c)

Fig. 4. TEE: (a) Short axis view: BAV during systole, (b) Short axis: BAV during diastole, (c) Aortic regurgitation

## **Comments**


#### **Treatment**


### **Case 2**

#### **History**


#### **Physical examination**


### **Other diagnostic procedures**


EF: 45%, aortic valve is artificial, Vel: 1.82m/s, PG: 13.2mmHg, incipient dilatation of aorta (Figure 5).

### **Treatment**


(c) Fig. 4. TEE: (a) Short axis view: BAV during systole, (b) Short axis: BAV during diastole,





EF: 45%, aortic valve is artificial, Vel: 1.82m/s, PG: 13.2mmHg, incipient dilatation of aorta




recommended serial evaluation using echocardiography.


(c) Aortic regurgitation

**Physical examination** 

at the apex.

(Figure 5). **Treatment** 

**Other diagnostic procedures** 

is normal at rest (EF> 50)

evaluation using echocardiograpy.



**Comments** 

**Treatment** 

**Case 2 History** 

Fig. 5. TTE: (a) Artificial aortic valve (parasternal short axis view), (b) Apical five chamber view, (c) and (d) Parasternal long axis view: incipient aortic dilatatation and LA enlargement

#### **Comments**


## **11. References**


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**16** 

Mehmet Necdet Akkus

*Mersin University* 

*Turkey* 

**A Case-Control Investigation of the** 

**Relationship Between Bicuspid Aortic** 

**Valve Disease and Coronary Heart Disease** 

Bicuspid aortic valve disease is the most common congenital heart defect, affecting 1% to 2% of the general population, with a higher prevalence in males (Hoffman & Kaplan, 2002; Movahed et al., 2006). Quite often, the diagnosis of bicuspid aortic valve disease is an incidental finding during an echocardiogram. However, the disease may be associated with significant valvular dysfunction and lead to aortic stenosis (Subramanian et al., 1984; Roberts & Ko, 2005) or aortic regurgitation (Roberts et al., 1981; Olson et al., 1984) and is a risk for infective endocarditis (Lamas & Eykyn, 2000; Fenoglio et al., 1977). Aortic regurgitation is probably more common in younger patients, and aortic stenosis becomes more frequent with age (Movahed et al., 2006). In this paper we reviewed the current literature on bicuspid aortic valve disease, particularly its etiopathogenesis, and report a case-control investigation

The earliest description of a bicuspid aortic valve has been attributed to Leonardo da Vinci, who over 400 years ago sketched the bicuspid variant of the aortic valve (Mills et al., 1978, as cited in Braverman et al., 2005). In 1844, Paget brought attention to the propensity of the bicuspid aortic valve to develop disease, and in 1858, Peacock reported the tendency of these valves to develop obstructive lesions initially, with subsequent incompetence (Roberts, 1970, as cited in Braverman et al., 2005). The clinical significance of the bicuspid aortic valve was also emphasized by Osler in 1886 when he described 18 cases of bicuspid aortic valve with the predilection of these valves to develop infective endocarditis (Wauchope, 1928, as cited in Braverman et al., 2005). In the 1950s, investigators observed that the propensity to develop isolated calcific aortic stenosis occurring in the setting of bicuspid aortic valve was the result of an intrinsic property of the bicuspid aortic valve rather than the result of rheumatic disease (Campbell et al., 1953, Smith & Matthews, 1955, and Bacon & Matthews, 1959, as cited in Braverman et al., 2005). Wauchhope's autopsy studies established that the bicuspid aortic valve is the commonest congenital anomaly of the heart (Mills et al., 1978 and Wauchope, 1928, as cited in Braverman et al., 2005). Furthermore, the association of bicuspid aortic valve with diseases of aorta was first commented on by Abbott in 1927 with the description of an association between congenital bicuspid aortic valve with aortic

of the relationship between this disease and coronary heart disease.

dissection (Acierno, 1994, as cited in Braverman et al., 2005).

**1. Introduction** 

**1.1 History** 

