Bicuspid Aortic Valve in Pediatric Populations: Clinical Considerations and Management

Bicuspid aortic valve (BAV) is the most common congenital heart defect in children, adolescents, and adults. (1) It is a heterogeneous disease that affects both the aortic valve and the aorta.

It can lead to many complications, including aortic valve stenosis, regurgitation, or endocarditis. (2)(3) It can also lead to dilation of the aorta, which predisposes individuals to a significantly increased risk of aortic aneurysm and dissection. (4)

Although most people with BAV present with these long-term complications during adulthood, a considerable number of patients may also present during childhood and adolescence with early-onset disease that may require interventions in up to 12% to 15% of cases. the patients. (5)(6) Therefore, patients with BAV require lifelong follow-up and surveillance.

BAV has multiple implications in terms of sports participation and family screening, making it an important topic for primary care professionals. This article reviews the anatomy, genetics, presentation, diagnosis, and treatment of BAV in infants, children, and adolescents.

The bicuspid aortic valve was first described by Leonardo da Vinci in 1500.

The estimated incidence of BAV is 0.5% to 2% in the general population. (1) It is 3 times more common in men than in women. It may occur as an isolated lesion or in association with other simple or complex congenital heart defects. (5)

Additionally, it may also be a clinical feature of certain genetic syndromes and connective tissue disorders. The most common congenital heart defect associated with BAV is coarctation of the aorta; BAV is observed in 25% to 85% of these patients. (5)(7) The most common genetic syndrome associated with BAV is Turner syndrome; with an impact of 15% to 30%. (eleven)

A normal aortic valve consists of 3 leaflets . These cusps are named based on the respective coronary arteries arising from the corresponding sinuses, such as right, left and non-coronary valves. VAB arises from the fusion of 2 of any of these leaflets, leading to 2 functional leaflets instead of 3.

BAV can be divided into different morphological subtypes based on the fused aortic valve leaflets. The most common form of BAV is fusion of the right and left coronary leaflets, present in 71%, followed by fusion of the right and non-coronary leaflets, present in 28%; fusion of the left leaflet and the noncoronary leaflet is the rarest form, present in only 1% of patients with BAV. (5)(17)

It is imperative to determine the different types of BAV because it can provide information about prognosis and complications.

A hereditary basis is reflected in the 8% to 10% frequency for BAV or other obstructive lesions of the left ventricular outflow tract in first-degree relatives of patients with BAV. (18)(19)(20) The genetic foundations of BAV are complex and heterogeneous. They may be polygenic in individual patients.

The familial disease conforms to an autosomal dominant inheritance pattern with incomplete penetrance. (twenty-one)

BAV is also a phenotypic feature of Turner syndrome (45, XO), present in almost 15% to 30% of patients, with an incidence 30 to 60 times higher than that of healthy women (46, XX). (11) Therefore, loss of genes on the X chromosome may be a predisposing factor for BAV. (22)

Some genes (syndromes) associated with BAV include TGFBR1-2 (Loeys-Dietz syndrome), NOTCH1 , ACTA2 (familial thoracic aortic aneurysm and dissection), FBN1 (Marfan syndrome), KCNJ2 (Andersen-Tawil syndrome), GATA6 , GATA5 , EGFR , SMAD6 and ROBO4 . (22)

There are currently no specific genetic tests available for BAV. Some of these genes are included in clinical test panels for generic congenital heart disease and all can be detected in patients undergoing whole exome sequencing. However, there is currently a high-throughput genetic testing platform not specifically dedicated to BAV.

It should be noted that the presence of a genetic mutation does not necessarily confer a risk of worsening aortic stenosis. However, longitudinal studies are required to determine whether certain genes associated with BAV confer an increased risk of aortic valve dysfunction or aortic dilation.

BAV includes a spectrum of abnormalities ranging from aortic valve dysfunction to dilation of the aorta (aortopathy).

It can come in a variety of forms at different ages. The most common presentation of BAV is auscultation of a systolic murmur or click. Most children with BAV are completely asymptomatic and may be diagnosed incidentally or as a result of echocardiography performed for family screening.

Rarely, patients with BAV may be symptomatic at initial presentation. Neonates with BAV may present with critical aortic valve stenosis and may require urgent aortic valve intervention to relieve obstruction. Similarly, older children or adolescents may be symptomatic depending on the degree of aortic valve dysfunction.

BAV may also be diagnosed indirectly during evaluation of other congenital heart defects, including coarctation of the aorta, hypoplastic left heart syndrome, or Shone complex (a combination of multiple obstructive left heart defects, such as supravalvular mitral annulus, parachute mitral valve, subaortic stenosis, BAV and coarctation of the aorta). (17)(23)

Similarly, BAV can be found during screening echocardiography performed in certain genetic syndromes and connective tissue disorders that are strongly associated with BAV, such as Turner, Williams, Loeys-Dietz, Marfan, or Ehlers-Danlos syndromes. (17)

Most patients with BAV are clinically asymptomatic. Clinical suspicion of BAV in an asymptomatic individual is based on family history and abnormal auscultatory findings on physical examination. Children with BAV may have multiple auscultatory findings depending on the status of valve function.

to. BAV with normal function : These patients may have only a systolic ejection click, which is an additional heart sound after S1 that is best heard at the apex. The ejection click can be differentiated from an S1 split (normal variant) by the lack of variability with respiration and better auscultation at the vertex. They may also have a soft ejection systolic murmur. (24)

b. Stenotic BAV : These patients may have a louder crescendo-decrescendo systolic ejection murmur at the right upper sternal border radiating toward the sternal notch and carotids, the intensity of which varies with the degree of stenosis. A systolic ejection click may precede the murmur, but is absent in severe aortic stenosis. Patients may also have systolic thrill and increased apical impulse.

c. Regurgitant BAV : These patients may have an early high-pitched decrescendo diastolic murmur radiating from the right upper chest to the left lower sternal border. In older children, the murmur can be heard better by asking the patient to sit up and lean forward with the breath held in full expiration. The murmur is accentuated by maneuvers that increase afterload, such as the handgrip maneuver. Patients with severe aortic regurgitation may have bounding pulses and wide pulse pressure.

Rarely, children with BAV may be symptomatic. The symptoms of BAV are a manifestation of its complications and are generally evident only in severe illness. Patients with significant aortic valve stenosis or regurgitation may present clinically with growth retardation, fatigue, dyspnea, and chest pain with exertion depending on their age. Clinical findings by age in symptomatic infants, children, and adolescents are listed in Table 1.

For patients with suspected BAV, it is important to look for associated findings of congenital cardiac lesions and genetic syndromes. For example, BAV is commonly associated with  coarctation of the aorta . Coarctation of the aorta produces upper extremity hypertension, delayed femoral pulses, or a systolic murmur heard prominently in the left interscapular region. Similarly, Turner syndrome is strongly associated with BAV and coarctation of the aorta.

In women with BAV and coarctation of the aorta, it is important to identify any physical manifestations of Turner syndrome , such as short stature, primary amenorrhea, wide chest, wide and spaced nipples, and cubitus valgus. It has been proposed that karyotyping for Turner syndrome should be performed in all girls with coarctation of the aorta due to its high prevalence (5.3%-12.6%) and the absence of classic findings in mosaicism. (25)(26)

The diagnosis of BAV is confirmed by transthoracic echocardiography (TTE) with sensitivity and specificity of 92% and 96%, respectively. (27)(28)(29) The parasternal short-axis view is used to visualize the aortic valve cusps and fusion morphology.

TTE can also quantify aortic valve dysfunction in terms of degree of stenosis or regurgitation. Additionally, the wall thickness and chamber size of the left ventricle can be determined, which can progressively enlarge in patients with aortic stenosis and aortic regurgitation. Additionally, TTE is used to evaluate the diameter of the aorta and the degree of aortic dilation at various levels.

The degree of aortic dilation in the pediatric and adolescent population is determined based on the Z score formatted to body surface area. Cross-sectional imaging by tomographic angiography and magnetic resonance angiography can provide incremental information in patients when there is concern that an intervention may be warranted.

Once fully grown, adolescents should have alternative imaging, such as tomographic angiography or preferably magnetic resonance angiography (due to the absence of radiation) to evaluate the entire aorta and compare it with TTE measurements.

BAV disease includes a spectrum ranging from a normally functioning aortic valve and normal aortic dimensions to significant valve dysfunction and aortic aneurysm formation.

BAV can cause 3 major complications: aortic valve disease (stenosis or regurgitation), aortopathy/dilation of the aorta, and valve endocarditis. (30)

The clinical findings of the various complications are listed in Table 1. The incidence of primary cardiac events in children and adolescents with BAV due to these complications is very low. (30)(31) Most interventions for patients with BAV are performed for valvular stenosis and include balloon angioplasty, surgical repair, or valve replacement. (6)

Primary aortic dissection is an extremely rare event in children and is usually associated with other predisposing factors. A detailed description of the complications of BAV is provided below.

> Aortic stenosis. Fusion of the aortic valve cusps in BAV can lead to abnormal opening of the valve and a decrease in the effective valve orifice, causing aortic stenosis. It may be present at birth or develop progressively over time. Critical congenital aortic stenosis presents in a neonate or infant with symptoms of acute-onset heart failure leading to cardiogenic shock, usually after spontaneous closure of the patent ductus arteriosus. These children require urgent interventions on the aortic valve through balloon catheter valvuloplasty (described later) or surgical intervention. The choice of intervention is influenced by valve morphology, severity of left ventricular dysfunction, and institutional preference. Older infants and children may develop progressive aortic valve stenosis, which may lead to left ventricular hypertrophy, and these patients may require intervention before adulthood. (6)

> Aortic regurgitation. Abnormal coaptation of the aortic valve cusps can cause primary aortic valve regurgitation. In addition, regurgitation may also develop progressively secondary to previous interventions on the aortic valve, including balloon valvuloplasty and surgical valvotomy. Significant aortic valve regurgitation can cause left ventricular dilation and decreased ejection fraction over time, leading to exercise intolerance and symptoms of heart failure. These symptoms are indications for intervention.

> Management. It is important to support families since most interventions in neonates and young children should be considered palliative. In almost all cases, these patients will require a more definitive valve procedure later in life.

• Percutaneous balloon valvuloplasty : Balloon valvuloplasty is a percutaneous intervention performed for the relief of aortic stenosis. It is performed by inserting a balloon-tipped catheter, usually through the femoral artery, and advancing it to cross the aortic valve followed by inflation of the balloon, leading to improved valve opening. In neonates it can be performed from the femoral venous approach, and access to the aortic valve is provided in a prograde manner after crossing the patent foramen ovale and advancing the catheter through the left atrium and left ventricle towards the ascending aorta. Access from the carotid artery to the aortic valve can be used in selected patients. Although it has excellent immediate results in relieving stenosis, balloon valvuloplasty can cause significant aortic regurgitation. Valve restenosis is a progressive problem and additional procedures are necessary in many patients. (32)

• Surgical interventions. Several surgical interventions are available for patients with BAV. Surgical repair or valvotomy is performed in infants and children by making a short incision in the fused commissure of the valve to improve the mobility of the leaflets. In other cases, the Ross procedure may be more useful, in which the patient’s native pulmonary valve is used as a neo-aortic autograft with insertion of a homograft in the position of the pulmonary valve. A benefit of the Ross procedure is that it avoids warfarin anticoagulation and the need for frequent autograft upsizing.

The Ross procedure is also commonly used in newborns and infants with critical problems or severe aortic valve disease, but the results in these types of patients are not as long-lasting as in older children. (33) However, the Ross procedure creates “2-valve disease” in patients who were born with only aortic valve disease. Additionally, the pulmonary-positioned homograft will require enlargement or insertion of a percutaneous valve at some point.

In older adolescents approaching adulthood, aortic valve replacement can be performed with a mechanical or bioprosthetic aortic valve. Mechanical aortic valve prostheses are more durable than bioprosthetic valves and theoretically require fewer repeat surgeries, but mechanical valves require lifelong anticoagulation and restriction of contact sports.

Therefore, valve replacement must be individualized for each patient. An alternative approach to the Ross procedure or replacement of the primary aortic valve with a prosthesis may be the Ozaki operation. The Ozaki operation involves excision of diseased native aortic leaflets and creation of new leaflets from autologous pericardium. (3. 4)

Aortopathy, or abnormal dilation of the aorta, is another major complication of BAV. The mechanism of this aortopathy is multifactorial, including genetic, cellular and molecular mechanisms. Cystic-medial necrosis of the aortic wall, association with connective tissue disorders, and continued stress on the aortic wall due to hemodynamically abnormal blood flow patterns through the abnormal aortic valve contribute to aortic dilation.

Although aortic dilation is common in children with BAV, it rarely causes aortic dissection during childhood or adolescence unless there are other concomitant connective tissue disorders or syndromes, such as Marfan syndrome, Ehlers-Danlos syndrome type IV, Loeys-Dietz syndrome or Turner syndrome and/or predisposing risk factors, such as hypertension or significant dilation of the aorta (> 50-55 mm).

Children with BAV who have a dilated aorta should be periodically evaluated with echocardiography performed at least every 2 to 3 years to monitor the degree and rate of aortic dilation and the status of the aortic valve.

> Management:   Medical management of aortic dilation in patients with BAV may include beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. There is currently no evidence on the role of these medications in patients with BAV, and the data have been extrapolated from patients with Marfan syndrome and dilated aortas. (35)

Therefore, there is significant variation in practice among pediatric cardiologists, and medical treatment is individualized for each patient based on the benefits, tolerance, and adverse effects of these medications. However, hypertension in patients with BAV must be treated aggressively because it is a risk factor for aortic dilation.

Surgical management consists of replacement of the aortic root or ascending aorta with or without valve replacement. Valve-sparing aortic root replacement may be more difficult in patients with BAV than in those with a normal 3-cusp valve.

Native aortic valve endocarditis is a relatively rare entity, estimated at approximately 0.16% per year in children and adolescents, but can lead to significant morbidity and mortality. (36)

Patients with BAV have a higher risk of infective endocarditis of the native aortic valve than individuals with a normal 3-cuspid aortic valve. (37)

Patients who have had prior aortic valve surgery (particularly valve replacement) are at even higher risk of endocarditis than patients with uninterventional native aortic valve. (38)

Current endocarditis prophylaxis guidelines consider BAV as an intermediate-risk condition, and endocarditis prophylaxis is not recommended for patients with BAV before dental procedures or invasive airway procedures. (39) However, BAV patients with a previous episode of endocarditis or those who have a history of aortic valve surgery or intervention require endocarditis prophylaxis depending on the type of intervention and prosthetic material used.

Endocarditis should be excluded in any patient with BAV (including those who have had aortic valve surgery) who presents with fever of unknown origin or an embolic event.

Evaluation of these patients should include blood cultures, inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), and imaging such as echocardiography early in the course of the disease, depending on clinical suspicion.

1. Follow-up by pediatric cardiology: Patients with BAV require lifelong follow-up with a cardiologist. Most patients with a normally functioning BAV are followed periodically, every 2 to 3 years, with repeat echocardiography to monitor aortic valve function and aortic dilation. Patients with significant aortic valve stenosis, regurgitation, or marked aortic dilation may require more frequent follow-up.

2. Follow-up with the primary care professional: All patients with BAV should have an annual follow-up with their primary care doctor. Any change in murmur or new symptoms of atypical chest pain, palpitations with activity, increased fatigue, or decreased exercise tolerance should prompt expedited follow-up with the cardiologist. Blood pressure should be obtained during every health check, with special attention to hypertension. In patients with hypertension, upper and lower extremity blood pressures should be obtained because BAV is associated with coarctation of the aorta. In those with repaired coarctation, hypertension may indicate significant re-coarctation, but may also be present in patients without residual narrowing. Furthermore, hypertension is a risk factor associated with aortic dilation and should be treated aggressively. (40)(41)

3. Family screening: Echocardiographic screening is recommended by the American Heart Association (AHA) in all first-degree relatives of patients with BAV because it can occur in up to 10% of asymptomatic family members. (42) It is important to evaluate parents and older siblings because most complications of BAV usually manifest after early childhood.

4. Sports participation: The AHA and the American College of Cardiology have published guidelines for sports participation in athletes with BAV. Suggestions for sports restriction are based on the symptoms and degree of aortic valve stenosis, aortic regurgitation or dilation, and the presence of additional connective tissue disorders or syndromes. (43) Most experts suggest avoiding isometric exercises, weight lifting, and contact sports in patients with significant aortic dilation due to concern for aortic dissection. Because symptoms and complications of aortic valve disease or aortopathy are rare in children and adolescents, decisions about sports participation are complex. A shared decision is required by the patient, family, coach, school officials, and cardiologist. In those competing at an elite level, it is prudent to perform an annual evaluation with imaging and perhaps an exercise test.

5. Endocarditis prophylaxis: Although patients with BAV have a significantly higher risk of endocarditis than individuals with a normal aortic valve, it is rare to have endocarditis of the native aortic valve. Current guidelines do not recommend routine antibiotic prophylaxis before invasive respiratory tract or dental procedures. (39) However, patients with BAV who have had a previous episode of endocarditis or those after aortic valve surgery and replacement require lifelong antibiotic prophylaxis. Optimal dental hygiene is universally important in all patients with BAV. Despite its low incidence, it is important to consider endocarditis in the differential diagnosis of patients with BAV who have fever of unknown origin or any embolic phenomenon.

Table 1. Clinical presentation of symptomatic bicuspid aortic valve.