Supravalvar aortic stenosis

INTRODUCTION — Left ventricular outflow tract (LVOT) obstructive lesions account for approximately 6 percent of cases of congenital heart disease in children; in one series, the incidence was estimated to be 6 in 10,000 live births [1,2]. Obstruction can occur at valvar (by far the most common), subvalvar, and supravalvar levels.

Supravalvar aortic stenosis will be reviewed here. Valvar and subvalvar aortic stenosis are discussed separately. (See "Valvar aortic stenosis in children" and "Subvalvar aortic stenosis (subaortic stenosis)".)

SUPRAVALVAR AORTIC STENOSIS — Supravalvar aortic stenosis (AS) is the least common form of left ventricular outflow tract (LVOT) obstruction. Among children with congenital AS, supravalvar AS has accounted for 8 to 14 percent of cases [2,3].

Anatomy — There are at least two anatomic forms of supravalvar AS. The majority of patients (60 to 75 percent) have an hourglass deformity, consisting of a discrete constriction of a thickened ascending aorta at the superior aspect of the sinuses of Valsalva (image 1) [4,5]. More diffuse narrowing for a variable distance along the ascending aorta is seen in 25 to 40 percent. There are also rare reports of a discrete membranous stenosis, which may be a variant of the hourglass deformity [6].

The major histologic features of the ascending aorta in supravalvar AS are a thickened and dysplastic media with an increased number of hypertrophied smooth muscle cells, increased collagen content, and a paucity of elastic tissue with disorganized elastin fibers [7,8]. Further support for an abnormality in elastin is the high frequency of supravalvar AS in patients with Williams syndrome, which is due to a mutation in the elastin gene (see 'Etiology' below). Supravalvar AS in these patients has been characterized as one manifestation of an elastin arteriopathy.

Supravalvar AS is associated with several other cardiovascular anomalies:

●The aortic valve leaflets may be thickened, redundant, and have reduced mobility [9,10]. In one report, the aortic valve leaflets were partially adherent to the stenosing supravalvar ridge in more than one-half of patients [9].

●Coronary artery stenosis can occur due to focal or diffuse coronary narrowing or due to obstruction by redundant, dysplastic aortic valve leaflets [9,11].

●Coarctation of the aorta and ostial stenoses of the carotid, renal, iliac, and other peripheral arteries are seen in some patients [7,8].

●Pulmonary artery stenoses, either of the main pulmonary artery or of branch pulmonary arteries, are common, occurring in approximately one-half of patients [12,13]. In contrast to the systemic arterial stenoses described above, pulmonary artery stenoses typically decrease in severity over time [13,14].

The mitral valve is usually normal.

In our experience at Children's Hospital Boston (1988 to 2002), supravalvar AS (134 patients) was associated with aortic regurgitation (AR) in 41 percent and with subvalvar AS in 10 percent, and only one patient had a bicommissural aortic valve.

Physiology — The physiology of supravalvar AS is similar to that of valvar and subvalvar stenosis. Significant obstruction is associated with a hyperdynamic, hypertrophied left ventricle. Elevated systolic pressure in the aortic root may be responsible for the associated coronary artery enlargement and dilatation of the sinuses of Valsalva that are often seen [9]. As noted above, coronary artery stenosis can occur, and subendocardial ischemic changes may be seen even without coronary narrowing [15,16].

Supravalvar AS creates a systolic jet that tends to hug the aortic wall and transfer kinetic energy into the right innominate artery [6]. This phenomenon, known as the Coanda effect, is the mechanism that explains higher blood pressure in the right than left arm in most patients with this disorder [17].

Etiology — Supravalvar AS occurs in four settings:

●As a feature of Williams syndrome, which is also characterized by unusual "elfin" facial features, intellectual disability, short stature, and hypercalcemia [12,18,19]. In a report from a multicenter consortium for children with Williams syndrome and cardiovascular lesions who underwent cardiac catheterization and/or operation, supravalvar AS was the most common lesion, diagnosed in 70 percent, followed by pulmonary stenosis (54 percent) and coarctation or aortic arch hypoplasia (13 percent) [19]. Approximately 40 percent of patients had more than one lesion (most commonly supravalvar AS plus pulmonary stenosis).

●A familial form without features of Williams syndrome. It is inherited in an autosomal dominant pattern [18,20,21].

●In sporadic patients without a family history [4].

●In patients with homozygous familial hypercholesterolemia (FH), a rare autosomal dominant disorder in which supravalvar AS occurs in as many as 44 percent of cases [22-24]. Supravalvar AS also is seen less frequently in heterozygotes (4 percent in one series) [24]. This disorder typically affects adults and rarely is seen in children. It is not clear whether the lesion is solely a manifestation of aortic atherosclerosis or whether an underlying structural abnormality is present.

In a 1983 series of 25 patients with supravalvar AS age 1 to 49 years, the distribution of Williams syndrome, the familial form, and the sporadic form was 28, 20, and 52 percent, respectively [4]. It is not apparent whether the authors looked for FH.

Genetics — Genetic studies have also demonstrated that the non-FH forms of supravalvar AS are caused either by mutations in or, in Williams syndrome, deletion of the elastin gene located on chromosome 7q11.23 [18,25-30]. The deletion in Williams syndrome includes genes other than the elastin gene that are responsible for the other manifestations of the disease [27,31]. As an example, loss of one allele of the LIM-kinase gene is thought to be responsible for the defects in visuospatial cognition [32,33]. The gene deletions responsible for other manifestations of this syndrome are not known [31]. (See "Williams syndrome", section on 'Genetic testing'.)

Clinical features — The clinical features of patients with supravalvar AS vary depending on whether or not the child also has Williams syndrome.

●Williams syndrome is associated with a number of abnormalities in addition to supravalvar AS and defects in visuospatial cognition. These include intellectual disability, hypercalcemia, renovascular hypertension, facial abnormalities, and short stature [34,35]. (See "Williams syndrome".)

Patients with Williams syndrome have an increased risk of sudden cardiac death, particularly those with biventricular outflow tract obstruction, although sudden cardiac death may occur even in the absence of outflow tract obstruction. Some deaths have been attributed to undiagnosed coronary artery ostial obstruction. Cardiac repolarization abnormalities with prolongation of the QT interval by electrocardiogram (ECG) may play a role as well; prolonged QTc occurs in approximately 14 percent of Williams syndrome patients [36].

●In contrast, supravalvar AS is usually the only abnormality in patients with familial or sporadic disease [4,18,20], although peripheral pulmonary stenosis has been described in at least one family [21]. In contrast to patients with Williams syndrome, prolonged QTc does not appear to occur in those with nonsyndromic supravalvar AS [37].

Clinical manifestations related to the supravalvar disease include those due to the LVOT obstruction and possible coronary ischemia [9,15,16]. The following reports illustrate the range of cardiac symptoms that have been described:

●In one series of 44 patients with Williams syndrome and a structural heart defect, 35 (80 percent) had symptoms at birth, including 34 with failure to thrive, 4 with heart failure, 2 with cyanosis, and 1 with absent femoral pulses [12].

●In two reports including 174 patients (5 days to 27 years of age) undergoing surgical correction of supravalvar AS not due to Williams syndrome, the New York Heart Association functional class prior to surgery was I in 11 percent, II in 57 percent, III in 26 percent, and IV in 6 percent (table 1) [38,39].

Physical examination — Supravalvar AS often is detected by the findings on cardiac auscultation (table 2) [17]. Affected patients typically have a loud systolic ejection murmur best heard at the first right intercostal space; there is no associated ejection click or diastolic murmur of AR, findings that are common in valvar AS. In the series of 44 patients described above, 28 had a murmur detected during the newborn period [12].

The aortic component of the second heart sound may be accentuated due to elevated pressure in the aorta proximal to the stenosis. A thrill at the first right intercostal space is common.

Other common findings are suprasternal notch thrills, unequal carotid pulsations due to ostial stenosis, and a higher blood pressure in the right compared with the left arm due to the high pressure jet in the ascending aorta (the Coanda effect) [4,17]. A blood pressure difference between the two arms of more than 10 mmHg has been noted in approximately two-thirds of patients [4].

Diagnosis — The diagnosis of supravalvar AS is confirmed by echocardiography. Echocardiography also can assess left ventricle function and hypertrophy and estimate the gradient across the obstruction. In practice, an accurate Doppler measurement of the aortic gradient frequently is sufficient to determine which patients are candidates for surgical correction of isolated lesions [40]. Magnetic resonance imaging (MRI) with angiography also provides excellent anatomic detail of supravalvar aortic obstruction, together with associated aortic branch vessel disease, if present [41]. MRI is used when acoustic windows are poor, or when physical examination or other findings suggest associated lesions of the vascular tree (eg, branch vessel involvement).

The chest radiograph typically is normal, although some patients have mild to moderate cardiomegaly. The ECG shows left ventricular hypertrophy in many older patients, which may be accompanied by a strain pattern. In addition, the ECG may show right ventricular hypertrophy in patients with significant pulmonary artery obstruction due to peripheral pulmonary artery stenosis [21].

Cardiac catheterization provides precise hemodynamic and angiographic evaluation but is not routinely necessary (image 1). It may be performed when additional lesions are suspected, such as coronary, carotid, renal, or pulmonary artery stenoses. Pulmonary artery stenoses often are amenable to balloon dilation. When bilateral outflow obstruction is present and significant, catheterization may be extremely hazardous.

MANAGEMENT

Surgical repair — Definitive therapy for supravalvar aortic stenosis (AS), whether discrete or diffuse, consists of surgical correction of the obstruction. Stent placement has been reported in a few patients, with mixed results.

Surgery in supravalvar AS usually is performed at gradient levels that are lower than in valvar AS to avoid the progressive obstruction that occurs in some patients [5,42]. The likelihood of progression varies with the initial gradient. This was illustrated in a study of 45 patients with supravalvar AS diagnosed in infancy and followed for 13 years: 32 patients with a pressure gradient less than 20 mmHg had no evidence of progression during the first two decades of life, while 13 patients with a gradient exceeding 20 mmHg had progression of the mean gradient from 35 to 53 mmHg, with 8 requiring surgical intervention [43]. The risk of progression of supravalvar AS in adult patients is considerably lower than in childhood; one multicenter study of 113 adults with supravalvar AS (55 percent of whom had Williams syndrome) followed for a median of six years showed that progression of supravalvar AS was rare [44]. In this cohort, cardiac operation was performed in 13 percent of patients, but the majority of those were valve repair or replacements.

The indications for surgery are uncertain because experience is limited. Since surgery is usually curative for the discrete form (in contrast to valvar AS), we recommend operation for symptomatic disease and for patients with a measured gradient at catheterization of more than 30 mmHg [45].

Flap plasty techniques usually are successful in alleviating the discrete type of stenosis, which, as noted above, accounts for 60 to 75 percent of cases [39,42,45]. Techniques include simple single patch enlargement into the sinotubular junction just above the aortic root, bifurcated patches extended into two sinuses, and separate three sinus patch enlargement methods [45]. In one report of 75 patients, the mortality rate was less, need for reoperation was reduced, and hemodynamics were improved by multiple sinus reconstructions compared with single sinus patch enlargement [42].

Relief of diffuse obstruction is more complex; surgical options include extensive endarterectomy with patch aortoplasty or resection of the stenotic segment with end-to-end anastomosis to the distal ascending aorta, with or without insertion of a pulmonary autograft (the Ross procedure) [10,39]. Transcatheter stent placement is an effective alternative or adjunctive therapy in some patients, particularly in those with involvement of smaller aortic branch vessels.

Outcome — Outcomes after surgical correction of supravalvar AS depend upon the nature of the stenosis and the presence of associated lesions. A few studies with long-term follow-up have been reported. The results generally have been similar, with variability due to different patient populations, indications for surgery, and perhaps surgical technique [39,42,46-48]:

●The operative mortality ranged from 1 to 9 percent.

●Among patients discharged from the hospital, survival ranged from 94 to 98 percent at 10 years and 77 to 97 percent at 20 years. The incidence of reoperation ranged from 14 to 19 percent.

●In different trials, the main predictors of worse survival and more frequent reoperation were the presence of diffuse as opposed to discrete stenosis [42] and the presence of associated aortic valve disease [46]. Most series have reported reduced mortality and need for reoperation with the three-patch technique [48].

●Operative risk is higher in patients with diffuse arteriopathy and biventricular outflow obstruction. These typically are patients with Williams syndrome. In a study from the Society of Thoracic Surgeons Congenital Heart Surgery Database of >400 cardiac operations in patients with Williams syndrome, major adverse cardiac events (defined as death, cardiac arrest, or requiring mechanical support) occurred in 4 percent of patients with isolated supravalvar AS, 9 percent of those with complex left ventricular outflow tract obstruction, and 21 percent of those with biventricular outflow obstruction [49].

Endocarditis prophylaxis — Antibiotic prophylaxis to prevent bacterial endocarditis is not necessary for most patients with supravalvar AS, except those with a prior history of endocarditis or with a repair that required prosthetic material or device. In the latter, antibiotic prophylaxis is recommended for the first six months after repair unless a residual defect is present, in which case prophylactic antibiotics are continued beyond the six-month period. Recommendations of endocarditis prophylaxis are reviewed in detail separately. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

SUMMARY AND RECOMMENDATIONS — Supravalvar is the least common form of left ventricular outflow tract (LVOT) obstruction, accounting for 8 to 14 percent of all cases of aortic stenosis (AS).

●In 60 to 75 percent of patients with supravalvar AS, there is a discrete constriction of a thickened ascending aorta at the superior aspect of the sinuses of Valsalva (image 1) and, in the remaining cases, there is a more diffuse narrowing along the ascending aorta. (See 'Anatomy' above.)

●Supravalvar AS is often associated with other cardiovascular anomalies, including coronary artery stenosis, coarctation of the aorta, aortic regurgitation, and pulmonary artery stenosis. (See 'Anatomy' above.)

●Supravalvar AS is one of the characteristic findings of Williams syndrome, along with unusual elfin facies, intellectual disability, and hypercalcemia. Williams syndrome is caused by a deletion of the elastin gene on chromosome 7q11.23. Other forms of supravalvar AS are also associated with mutations of the elastin gene. (See 'Genetics' above.)

●In patients with significant supravalvar AS, there is a hyperdynamic, hypertrophied left ventricle. The progression of obstruction varies and appears to depend on the initial gradient. (See 'Physiology' above.)

●The clinical findings of supravalvar AS depend on the degree of LVOT obstruction and the presence of other cardiac abnormalities, especially coronary artery stenosis. The range of cardiac findings varies from no or few symptoms to heart failure. (See 'Clinical features' above.)

●The main physical finding of supravalvar AS is a loud systolic ejection murmur heard best at the first right intercoastal space. It is not accompanied by a click or diastolic murmur, which are common physical findings of valvar AS. (See 'Physical examination' above.)

●The diagnosis of supravalvar AS is confirmed by echocardiography. Echocardiography also can assess left ventricle function and hypertrophy and estimate the pressure gradient across the obstruction. (See 'Diagnosis' above.)

●The definitive treatment of supravalvar AS is surgical correction. Indications for surgery are uncertain because of limited outcome data. At our center, we suggest surgical correction for patients with a gradient greater than 30 mmHg measured by cardiac catheterization. (See 'Surgical repair' above.)

●Endocarditis prophylaxis is not necessary for most patients with supravalvar AS, except those with a previous history of endocarditis or with a repair with prosthetic material or device. In these latter patients, prophylactic antibiotics are given only for the first six months after repair unless a residual defect is present. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

●Outcome varies following surgical repair and depends on the nature of the stenosis and presence of associated lesions. (See 'Outcome' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Keane, MD, who contributed to earlier versions of this topic review.