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Right arrow Congenital - acyanotic

Eur J Cardiothorac Surg 2001;19:195-202
© 2001 Elsevier Science NL

Review

Congenital supravalvar aortic stenosis: a simple lesion?

Christof Stamma, Ingeborg Friehsa, Siew Yen Hob, Adrian M. Moranc, Richard A. Jonasa, Pedro J. del Nidoa

a Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
b Department of Pediatrics, Imperial College School of Medicine, National Heart and Lung Institute, London, UK
c Department of Cardiology, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA

Received 14 July 2000; received in revised form 30 October 2000; accepted 4 December 2000.

Corresponding author. Tel.: +1-617-355-6894; fax: +1-617-734-6595
e-mail: stamm_c{at}hub.tch.harvard.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
The underlying cause of congenital supravalvular aortic stenosis (SVAS) has recently been identified as a loss-of function mutation of the elastin gene on chromosome 7q11.23, resulting in an obstructive arteriopathy of varying severity, which is most prominent at the aortic sinutubular junction. The generalized nature of the disease explains the frequent association with stenoses of systemic and pulmonary arteries. Furthermore, localization of the supravalvular stenosis at the level of the commissures of the aortic valve has important implications for both aortic valve function and coronary circulation. This review summarizes the recent advances with regard to the pathogenesis of SVAS and describes the multitude of clinically relevant pathologic features other that the mere ‘supra-aortic’ narrowing that have important implications for surgical therapy.

Key Words: Aortic valve stenosis • Williams syndrome • Elastin • Thoracic surgery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
Congenital supravalvar aortic stenosis (SVAS) is the rarest obstructive lesion of the left ventricular outflow tract. The defining feature of the malformation is an aortic narrowing at the level of the sinotubular junction (Fig. 1), but in some cases there is narrowing of the entire ascending aorta and arch branches (Fig. 2A). Clinical experience with SVAS is limited, and general treatment strategies have not been defined. Increasingly complex surgical techniques for repair of SVAS have evolved, but the superiority of recent modifications over the simpler initial techniques regarding long-term preservation of aortic valve function remains to be determined. Recently, significant progress has been made linking the occurrence of both inherited and sporadic SVAS with chromosomal microdeletions including the elastin gene. In order to describe the complexity of this apparently simple lesion, we will (1) consider the role of elastin gene mutations in the pathogenesis of SVAS, (2) discuss the impact of the supra-aortic narrowing on structure and function of the aortic valve, and (3) review the incidence of systemic and pulmonary artery stenoses as well as abnormalities of the coronary circulation in association with SVAS, and discuss the implications for surgical therapy.



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  		Fig. 1. Angiogram of a 4-year-old patient with supravalvar aortic stenosis and Williams syndrome. Note the typical hourglass-shaped narrowing of the ascending aorta. The arrows indicate proximal stenoses of both left and right coronary artery. The patient subsequently underwent a three-sinus reconstruction of the aortic root and patch angioplasty of both ostial stenoses.

 


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  		Fig. 2. Aortic root angiogram in a 3-year-old patient with elastin arteriopathy as part of Williams syndrome. Note the diffuse narrowing of the ascending aorta and the discrete stenoses of the proximal left coronary and left subclavian artery. The pullback pressure gradient was measured as 120 mmHg. (B) Pulmonary angiogram of the same patient with severe central and peripheral pulmonary artery stenosis in elastin arteriopathy. Right ventricular pressure was 110 mmHg.

 

   2. Elastin arteriopathy
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
Interest in this rare malformation increased in the 1960’s after Williams et al. [1] first reported its association with mental retardation and distinctive facial features. Shortly after this report, Beuren and coworkers added peripheral pulmonary artery stenosis to the symptom complex today known as Williams–Beuren syndrome [2,3]. The main histologic feature of the ascending aorta in SVAS is the diseased media with an increased number of hypertrophied smooth muscle cells, increased collagen content, and reduced elastic tissue in the form of broken and disorganized elastin fibers [4,5] (Fig. 3). Since infantile hypercalcemia and abnormal vitamin D metabolism are also found in conjunction with Williams syndrome, earlier reports suggested that neonatal hypercalcemia may cause premature arteriosclerosis resulting in SVAS [6,7], but this concept was abandoned when the role of elastin in SVAS became apparent. Besides its association with Williams syndrome, SVAS occurs in an inherited, autosomal dominant familial form without the non-vascular features of Williams syndrome, and as sporadic cases of ‘isolated’ SVAS. Histologic studies first indicated a mutual underlying pathology for all three forms of SVAS [8]. It is now established that in patients with Williams syndrome the elastin gene is deleted or disrupted together with a number of neighboring genes that probably are important for the other features of the syndrome [9,10], whereas in patients with familial, non-Williams SVAS the elastin gene only was subjected to a loss-of-function translocation or point mutation [11–14]. Patients with ‘sporadic’ SVAS are either members of a family carrying an elastin gene mutation with subclinical phenotype, or carry the elastin gene defect as a new mutation [15].



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  		Fig. 3. Histology of the ascending aorta in a patient with elastin arteriopathy and diffuse SVAS (A), and of the normal aorta (B). Hematoxylin-eosin stain, 16x. Note the irregularity and haphazard arrangement of elastic lamellae in addition to the severe thickening of the aortic wall in SVAS.

 
A single gene on chromosome 7q11.23 encodes for the soluble elastin-precursor tropoelastin, which is expressed in smooth muscle cells during the early stages of development. Tropoelastin units polymerize and are laid down as concentric rings of fenestrated lamellae, alternating with smooth muscle cell layers. A hemizygous microdeletion on chromosome 7q11.23 has been identified in patients with Williams syndrome as well as familial and sporadic SVAS [16–18]. Affected individuals appear to express only 50% of the normal amount of tropoelastin during development, resulting in an overall reduced arterial elastin content and pathologic alignment of the elastin fibers. In contrast to small arteries in which smooth muscle cells and collagen dominate, great systemic arteries contain the largest number of elastin fibers in the media in order to absorb hydrodynamic energy during systole and release it during diastole in the form of sustained blood pressure (windkessel-effect). Reduced elasticity of great arteries may increase shear stress in the vascular wall, provoking smooth muscle hypertrophy and increased collagen deposition, and resulting in the marked media thickening in great arteries of patients with elastin arteriopathy (Fig. 3).

Direct evidence linking a mutation of the elastin gene with the development of arteriopathy was recently reported [19,20] using a transgenic mouse model carrying an elastin gene deletion. Homozygous mice die soon after birth from severe obstructive arteriopathy, but heterozygous animals survive with histologic characteristics of the great arteries that closely resemble the histology of patients with SVAS. The number of elastin lamellae in the mouse model as well as in affected humans is increased while the total amount of elastin in the aortic media is reduced, which may be interpreted as an attempted compensatory mechanism in response to an overall reduced tropoelastin expression.


   3. Supravalvar aortic stenosis
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
The first description of supravalvar aortic stenosis is often attributed to the Italian pathologist Mencarelli in 1930, although Chevers had described a typical lesion in 1842, focusing on the supravalvar narrowing as a structure separate from the aortic valve [21,22]. Denie and Verheugt first emphasized that the narrowing is located at the level of the sinutubular junction, the peripheral attachment of the commissures [4], and Morrow et al. [23] described partial adhesion of aortic valve leaflets to the sinutubular ridge. Clinical studies have documented cases of SVAS with severely thickened leaflets adherent to the narrowed sinutubular junction [24,25], and surgical reports describe abnormalities of the aortic valve leaflets in up to 50% of the patients. Important for the development of valvar lesions in SVAS is the mismatch between the free edge of the leaflets and the corresponding part of the sinutubular junction [25]. In normal hearts, the aortic root including the flexible sinutubular junction expands during systole, straightening the leaflet free edges and maintaining a constant strain in order to minimize fatigue stress [26]. An inexpandable sinutubular junction and redundant leaflets do not permit this mechanism, promoting premature degeneration of the leaflets.

The distorted geometry of the aortic root has important implications for surgical therapy. The main goal of surgery is the relief of left ventricular pressure overload, which can be achieved by simple patch enlargement of the sinutubular junction above the noncoronary sinus (Fig. 4A) [27–29]. Other techniques reconstruct the aortic root in a more physiologic fashion [30,31]. Doty's extended aortoplasty augments the sinutubular junction by placing an inverted bifurcated patch into the noncoronary and the right coronary sinus (Fig. 4B) [32]. However, the stenosis above the left coronary sinus remains unrelieved, posing a potential risk of compromised blood flow in the left coronary artery. Brom first described insertion of separate patches in all three sinuses after transection of the aorta (Fig. 4C) [33]. The same result can be achieved without any patches by tailoring the distal aortic and reanastomosing both ends directly (Fig. 4D) [34,35], but these techniques usually require extensive mobilization of ascending aorta and aortic arch. Furthermore, there is a potential risk of obstruction of the left main bronchus and left pulmonary artery. Interposition of autologous pulmonary artery between the aortic ends has also been described [36], as well as modifications of Doty's technique inserting an extra patch in the left coronary sinus [37]. One complication of a 3-sinus repair is aortic regurgitation due to oversizing of the reconstructed sinuses, but only very few cases have been reported [38]. The appropriate patch-size can be calculated based on the age-normalized circumference of the aortic root, but in most cases it is sufficient to use the circumference of the distal aortic end as a guideline.



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  		Fig. 4. Techniques for repair of discrete SVAS. (A) Patch enlargement with incision into the non-coronary sinus; (B) ‘Extended aortoplasty’ with incision of non-coronary and right coronary sinus and implantation of an inverted Y-shaped patch; (C) Patch enlargement of all three sinuses as described by Brom [33]; (D) Three-sinus reconstruction without the use of patches. (Reprinted with permission from Stamm et al., J Thorac Cardiovasc Surg 1999;118:874-885).

 
Controversy remains whether 3-sinus reconstructions are truly superior to a simple patch enlargement of the non-coronary sinus. Comparative data of long-term results with different techniques are rare, but long-term studies indicate that the results after 1- and 2-sinus reconstructions are not optimal. Moderate pressure gradients and aortic valve regurgitation persist or recur in up to 50% of the patients (Table 1). Hazekamp et al. [38] recently reported their experience with 3-sinus reconstructions of the aortic root in SVAS compared with 1- and 2-sinus reconstructions. Although they favor Brom's technique, they did not find a significant difference in long-term gradients or need for reoperation. In our own institutional experience, time-related comparisons of survival and freedom from reoperation did not reach statistical significance, but there were no late deaths, less reoperations, and lower long-term pressure gradients in patients with 2- or 3-sinus reconstructions in contrast to patients undergoing a single-patch repair [44]. Some groups have opted for a primary Ross procedure in patients with SVAS and a bileaflet aortic valve [46]. In our experience the presence of a bicuspid aortic valve is not associated with increased need for reoperation, we hence attempt a valve-sparing operation whenever possible.


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  		Table 1. Results of surgery for SVAS (reports published after 1980)a

 

   4. Diffuse aortic/systemic artery stenosis
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
In approximately 30% of the patients with SVAS the entire ascending aorta is narrowed, sometimes including the aortic arch [47]. The most common technique for repair of a diffuse stenosis of the ascending aorta in SVAS is insertion of an elongated patch reaching past the origin of the brachiocephalic trunk, which is mostly possible on cardiopulmonary bypass. When the stenotic process reaches well into the aortic arch, deep hypothermic circulatory arrest is usually employed to facilitate insertion of a patch across the undersurface of the arch, which may be necessary to reduce the gradient without simply shifting the pressure gradient to the distal end of the patch. In many cases of diffuse SVAS the origins of the supra-aortic vessels are also stenotic, exposing the patients to a risk of cerebral ischemia. Patch enlargement of the proximal branch arteries has been described in association with augmentation of the aortic arch [48], but also complex tube graft constructions bypassing the aortic arch (ascending-descending aortic conduit), with additional grafts supplying the supra-aortic branches. In a number of patients with severe obstruction of the entire thoracic aorta, left ventricular apex-to-descending aortic conduits have been implanted [43,49,50], but this concept has largely been abandoned in favor of extensive arch augmentation. In our experience, long-term survival of patients with diffuse SVAS is somewhat surprisingly similar to that of patients with the discrete form, though the operative risk is increased [44]. A study using intravascular ultrasound demonstrated severe thickening of the arterial wall in infradiaphragmatic arteries [51], and localized stenoses of mesenteric and renal arteries have been reported in up to 30% of the patients with SVAS [52–54]. It is important to diagnose concomitant stenoses prior to surgery for SVAS, so that the consequences of peri- and postoperative hypoperfusion of abdominal organs can be minimized.


   5. Pulmonary artery stenosis
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 
Obstructions of the pulmonary vasculature have been described in up to 83% of the patients with Williams syndrome, familial elastin arteriopathy, or sporadic non-Williams SVAS [47,52]. Peripheral pulmonary artery stenosis is usually present, and central pulmonary arteries can have localized stenoses or are generally hypoplastic [54–57] (Fig. 2B). Localized supravalvar pulmonary stenosis has also been described [58,59], and some patients develop complex multi-level right ventricular outflow tract obstruction. Several reports indicate that in the natural course of the disease the severity of pulmonary artery stenoses, and thus right ventricular pressure load, decrease throughout childhood and adolescence [60]. A negative correlation between the severity of pulmonary artery stenoses and age at presentation was found [55,56,61]. Serial follow-up studies showed a tendency towards spontaneous regression of pulmonary artery stenoses with respect to right ventricular pressure overload, pulmonary artery pressure gradients, and pulmonary artery size [47,56,62]. A wait-and-see approach for isolated mild and moderate pulmonary artery stenoses may be justified, but pulmonary artery stenoses in conjunction with significant SVAS require a more aggressive approach. A number of patients with severe pulmonary artery stenosis require surgery for SVAS whilst also having significant right ventricular pressure overload, and these patients have a higher operative risk [44,56]. In our institutional experience with surgery for SVAS, 41% of patients had concomitant stenoses of the right ventricular outflow tract and/or pulmonary arteries, but the presence of a right-sided obstruction was not a risk factor for survival [44]. In the majority of patients with mild pulmonary artery stenoses, RV pressure load spontaneously decreased during follow-up [61]. However, patients having severe, generalized obstructive arteriopathy with systemic and pulmonary artery stenoses, and suprasystemic right ventricular pressure frequently required reoperations or interventions. Preoperative dilation of peripheral and central pulmonary artery stenoses decreases the RV pressure load prior to the ischemic insult of surgical repair of SVAS, and helps reduce the risk of right ventricular failure in the postoperative course [61–65]. Although interventional treatment of pulmonary artery stenosis is an important tool in the treatment of patients with elastin arteriopathy, it is not clear whether balloon angioplasty of pulmonary arteries in elastin arteriopathy is as effective as dilation of other forms of pulmonary artery stenosis. Decreased elasticity of the arteries may increase the risk of rupture, and smooth muscle proliferation in elastin arteriopathy may result in restenosis. Central pulmonary artery stenoses amenable to surgical repair should therefore be treated by patch enlargement at the time of repair of SVAS.


   6. Coronary circulation
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
7. Other associated cardiac...
 8. Conclusions
 References
 
Impaired coronary blood flow in SVAS has been reported frequently. In fact every patient with SVAS should be considered at risk of myocardial ischemia. Inflow to the coronary arteries can be restricted due to adhesion of the leaflet edge to the narrowed sinutubular junction. Even complete fusion of the entire leaflet edge with the prominent sinutubular ridge resulting in total isolation of the sinus has been reported [66]. These changes appear to affect the left coronary sinus of Valsalva most frequently [55,67]. The coronary orifice can be obstructed by the thickened aortic or sinus wall [55,68–70], especially when the coronary orifice is located close to the sinutubular junction [67]. Furthermore, the coronary arteries are subjected to the elevated prestenotic systolic pressure, resulting in dilatation and tortuosity and promoting premature arteriosclerosis [55,71]. Although the coronary arteries are primarily muscular arteries, elastic lamellae are an essential part of their normal architecture. They hence demonstrate the primary structural changes seen in elastin arteriopathy [72,73], but it is not clear to what extent the pathologic changes in coronary arteries in SVAS are primary or secondary. Finally, severe ventricular hypertrophy with increased myocardial mass as well as increased intramyocardial pressure can lead to a critical perfusion mismatch resulting in subendocardial ischemia. Chronic ischemic changes including myocyte necrosis, subendocardial fibrosis and papillary muscle calcification have been described in patients with SVAS [73], resulting in chronic left ventricular dysfunction or acute myocardial infarction and sudden death [74]. Numerous cases of procedure-related sudden death attributed to acute myocardial ischemia have been reported [44,75,76], often during procedures associated with a sudden drop in coronary perfusion pressure such as induction of anesthesia or manipulation at coronary orifices during coronary angiography.

Patch enlargement of coronary ostial stenoses in SVAS has been described, but also mammary artery bypass grafting has been performed in children with long-segment coronary artery stenosis [77–80]. Most importantly, any obstruction to coronary blood flow should be identified preoperatively and relieved at the time of surgical repair of SVAS. Furthermore, patency of both coronary arteries should be confirmed by intraoperative probing in every case.


   7. Other associated cardiac malformations
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
8. Conclusions
 References
 
Aortic coarctation, patent ductus arteriosus, atrial and ventricular septal defects, and tetralogy of Fallot have been reported in occasional patients with SVAS [47,55,56,81,82]. Mitral valve abnormalities have been described regularly [54,55,83]. Becker et al. reported three patients who had uniform thickening of the mitral valve caused by an increase in fibrous tissue [84], and the literature describes several cases of patients with SVAS who had to undergo mitral valve repair or replacement [38,39,44]. However, it remains unclear whether atrioventricular valve deformities are primary malformations caused by the elastin defect.


   8. Conclusions
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
References
 
Congenital supravalvar aortic stenosis is NOT a simple lesion. The underlying elastin arteriopathy is a generalized disease of both pulmonary and systemic arteries. Furthermore, the ‘supravalvar’ stenosis has profound effects on architecture and function of the aortic valve itself. In addition to leftventricular pressure overload, there is always a risk of myocardial ischemia due to coronary hypertension and premature arteriosclerosis, or obstruction to coronary blood flow as part of the aortic root malformation. Both medical and surgical treatment strategies must take all these features into account, so that optimal long-term outcome can be achieved.


   References
Top
 Abstract
 1. Introduction
 2. Elastin arteriopathy
 3. Supravalvar aortic stenosis
 4. Diffuse aortic/systemic...
 5. Pulmonary artery stenosis
 6. Coronary circulation
 7. Other associated cardiac...
 8. Conclusions
 References
 

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