Bicuspid Aortic Valve in Infants, Children, and Adolescents: A Review for Primary Care Providers.

Abstract

Bicuspid aortic valve is the most common congenital heart defect in children, adolescents, and adults. Primary care providers play an important role in screening, referral, and follow-up of these patients and should be aware of the family screening guidelines, sports participation recommendations, and periodic follow-up requirements for adequate surveillance of the complications that arise from bicuspid aortic valve.After reading this article, readers should be able to: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 also can lead to dilation of the aorta, predisposing individuals to a significantly higher risk of aortic aneurysm and dissection. (4) Although most individuals 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 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 subject for primary care providers. This article reviews the anatomy, genetics, presentation, diagnosis, and management of BAV in infants, children, and adolescents.BAV was first described by Leonardo da Vinci in Anatomica Physiologica in 1500. The estimated incidence of BAV is 0.5% to 2% in the general population. (1) It is 3 times more prevalent in males than in females. It can occur as an isolated lesion or in association with other simple or complex congenital heart defects (Table). (5) Moreover, it also can be a clinical feature of certain genetic syndromes and connective tissue disorders (Table). The most common congenital heart defect associated with BAV is coarctation of the aorta; BAV occurs in 25% to 85% patients with coarctation of the aorta. (5)(7) The most common genetic syndrome associated with BAV is Turner syndrome; 15% to 30% patients with Turner syndrome are affected by BAV. (11)A normal aortic valve consists of 3 cusps. These cusps are named on the basis of the respective coronary arteries that arise from the corresponding sinuses, as right, left, and noncoronary cusps (Fig 1A). BAV arises from the fusion of any of these 2 cusps, leading to 2 functional cusps instead of 3 (Fig 1B). BAV can be divided into different morphologic subtypes based on the aortic valve cusps that are fused. The most common form of BAV is right and left coronary cusp fusion, present in 71%, followed by right and noncoronary cusp fusion, present in 28%; left and noncoronary cusp fusion is the rarest form, present in only 1% of the patients with BAV. (5)(17) It is imperative to determine the different types of BAV because it may provide insight into the prognosis and complications.A heritable basis for BAV is reflected by the 8% to 10% frequency of BAV or other left ventricular outflow tract obstructive lesions in first-degree relatives of patients with BAV. (18)(19)(20) The genetic underpinnings of BAV are complex and heterogeneous. They can be polygenic in individual patients. Familial disease fits an autosomal dominant inheritance pattern with incomplete penetrance. (21) BAV is also a phenotypic feature of Turner syndrome (45,XO), present in almost 15% to 30% of patients, an incidence 30 to 60 times greater than that in healthy females (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) Currently there is no specific genetic testing available for BAV. Some of these genes are included on clinical testing panels for generic congenital heart disease and all can be screened for in patients who undergo whole exome sequencing. However, no dedicated, high-yield genetic testing platform is currently available specifically for BAV. Currently, presence of a genetic mutation does not necessarily confer a risk of worsening aortic stenosis. However, longitudinal outcome studies are required to determine whether certain BAV-associated genes confer increased risk of aortic valve dysfunction or dilation of the aorta.BAV includes a spectrum of abnormalities ranging from aortic valve dysfunction to dilation of the aorta (aortopathy). It can present in a variety of ways at different ages (Fig 2). The most common presentation of BAV is auscultation of a murmur or a systolic 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 the obstruction. Similarly, older children or adolescents can be symptomatic depending on the degree of aortic valve dysfunction. BAV also can be diagnosed indirectly during evaluation for other congenital heart defects, including coarctation of the aorta, hypoplastic left heart syndrome, or Shone complex (a combination of multiple left-sided heart obstructive defects, such as supravalvar mitral ring, 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, including 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 usually on the basis of family history and abnormal auscultatory findings on the physical examination. Children with BAV can have multiple auscultatory findings depending on the status of their valve function.Rarely, children with BAV can be symptomatic. Symptoms of BAV are a manifestation of its complications and usually are evident only in severe disease. Patients with clinically significant aortic valve stenosis or regurgitation may present with failure to thrive, fatigue, dyspnea, and chest pain on exertion depending on their age. Clinical findings in symptomatic infants, children, and adolescents according to age are listed in Figure 3.For patients suspected of having BAV, it is important to look for findings of associated congenital heart lesions and genetic syndromes. For instance, BAV commonly is associated with coarctation of the aorta. Coarctation of the aorta results in upper extremity hypertension, delayed femoral pulses or a systolic murmur heard prominently at the left interscapular region. Similarly, Turner syndrome is strongly associated with BAV and coarctation of the aorta. In females with BAV and coarctation of the aorta it is important to identify any physical manifestation of Turner syndrome, such as short stature, primary amenorrhea, a broad chest, wide-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 absence of classic findings in mosaicism. (25)(26)Diagnosis of BAV is confirmed by transthoracic echocardiography (TTE) with high sensitivity and specificity of 92% and 96%, respectively. (27)(28)(29) The parasternal short-axis view is used for visualization of the aortic valve cusps and the morphology of fusion (Fig 4 and Video 1). TTE also can quantitate aortic valve dysfunction in terms of degree of stenosis or regurgitation (Video 2). Moreover, left ventricular wall thickness and chamber size can be determined, and both can progressively enlarge in patients with aortic stenosis and aortic regurgitation. In addition, TTE is used to assess the diameter of the aorta and the degree of aortic dilatation at various levels. The degree of aortic dilatation in the pediatric and adolescent population is determined based on the Z score formatted to body surface area. Cross-sectional imaging with computed tomographic angiography and magnetic resonance angiography can provide incremental information in patients when there is a concern that intervention may be warranted (Fig 5). Once fully grown, adolescents should have alternate imaging such as computed tomographic angiography or preferably magnetic resonance angiography (due to lack of radiation) to assess the entire aorta and compare it with the TTE measurements.BAV disease is a spectrum ranging from a normally functioning aortic valve with normal dimensions of the aorta to significant valve dysfunction and aortic aneurysm formation (Fig 6). BAV can lead to 3 major complications: aortic valve disease (stenosis or regurgitation), aortopathy/dilation of the aorta, and endocarditis of the valve. (30) Clinical findings of the various complications are listed in Figure 3. 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 valve stenosis and include balloon angioplasty, surgical valve repair, or replacement. (6) Primary aortic dissection is an extremely rare event in children and usually is associated with other predisposing factors. A detailed description of BAV complications is provided later herein.Fusion of the aortic valve cusps in BAV can lead to abnormal valve opening and a decrease in the effective valve orifice, causing aortic stenosis. It can be present at birth or develop progressively over time. Critical congenital aortic stenosis presents in a neonate or in early infancy with symptoms of acute-onset heart failure, leading to cardiogenic shock, usually after spontaneous closure of the patent ductus arteriosus. These infants require urgent aortic valve interventions with either catheter-based balloon valvuloplasty (described later herein) 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 can lead to left ventricular hypertrophy, and these patients may require intervention before adulthood. (6)Abnormal coaptation of the aortic valve cusps may lead to primary aortic valve regurgitation. Moreover, regurgitation also can develop progressively secondary to previous aortic valve interventions, including balloon valvuloplasty and surgical valvotomy. Significant aortic valve regurgitation can lead to left ventricular dilation and decline in the ejection fraction over time, causing exercise intolerance and symptoms of heart failure. Symptoms of exercise intolerance or heart failure are indications for intervention.It is important to console families that most interventions in neonates and small children should be considered palliative. In almost all cases, these patients will require a more definitive valve procedure(s) later in life.Balloon valvuloplasty is a percutaneous intervention performed in the cardiac catheterization laboratory for relieving aortic stenosis. It is performed by inserting a balloon-tipped catheter, usually via the femoral artery and advancing it to cross the aortic valve followed by inflation of the balloon, leading to improved opening of the valve. In neonates it may 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 into the ascending aorta. Carotid artery access to the aortic valve may be used in select 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)Various surgical interventions are available for patients with BAV. Surgical valvotomy or repair is performed in infants and children using a short incision at the fused commissure of the valve to improve the mobility of the leaflets. Other patients may be better served with the Ross procedure, in which the patient's native pulmonary valve is used as a neo-aortic autograft and a homograft is inserted into the pulmonary valve position. A benefit of the Ross procedure is that it avoids anticoagulation with warfarin and the need for frequent upsizing of the autograft. The Ross procedure is also commonly used in neonates and infants with critical or severe aortic valve disease, but the outcomes in critically ill neonates and infants are not as durable as in older children. (33) However, the Ross procedure creates “2-valve disease” in patients who were born with only aortic valve disease. In addition, the homograft in the pulmonary position will require upsizing or percutaneous valve insertion at some point. In older adolescents approaching adulthood, aortic valve replacement with a bioprosthetic or mechanical aortic valve may be performed. Mechanical aortic valve prostheses are more durable than bioprosthetic valves and theoretically need fewer repeated operations, but mechanical valves require lifelong anticoagulation and restriction from contact sports. Therefore, valve replacement needs to be individualized for each patient. An alternate approach to the Ross procedure or primary aortic valve replacement with prosthesis may be the Ozaki operation. The Ozaki operation involves excision of the diseased native aortic cusps and creation of new cusps from autologous pericardium. (34)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 sheer wall stress on the aorta from abnormal hemodynamic flow patterns of blood across 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, type IV Ehlers-Danlos syndrome, 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 evaluated regularly, 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.Medical management of aortic dilation in patients with BAV may include β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Currently there is no evidence regarding the role of these medications in patients with BAV, and data have been extrapolated from patients with Marfan syndrome and dilated aortas. (35) Therefore, a significant variation in practice exists among pediatric cardiologists, and medical management is individualized to every patient based on the benefits, tolerance, and adverse effects of these medications. However, hypertension in patients with BAV should be aggressively treated because hypertension 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 to be approximately 0.16% per year in unoperated children and adolescents, but it can lead to significant morbidity and mortality. (36) Patients with BAV are at higher risk for infective endocarditis of the native aortic valve than are individuals with normal 3-cusp aortic valve. (37) Patients who have had previous aortic valve surgery (particularly valve replacement) are at even higher risk for endocarditis than patients with native aortic valve without intervention. (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 procedures of the respiratory tract. (39) However, patients with BAV 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 must 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 disease course depending on the clinical suspicion.We thank Dr David J. Driscoll, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, for reviewing this manuscript and making valuable suggestions for its improvement.