Abnormalities of the left ventricular outflow tract may occur at the subvalvar level, valvar, supravalvar, or a combination thereof. These abnormalities commonly co-exist with other left-sided lesions, such as aortic coarctation or anomalies of the mitral valve, as well as forming an important component of the pathophysiology of more complex lesions, such as atrioventricular septal defect with common atrioventricular junction, or discordant ventriculo-arterial connections. The latter lesions will be discussed in detail in the relevant chapters, while in this chapter we will deal predominantly with anomalies of the left ventricular outflow tract as seen in the setting of concordant connections.
Within the whole overall group, three-quarters of patients have valvar stenosis, just under one-quarter have discrete subaortic stenosis, and the remaining small proportion have isolated supravalvar obstruction. Congenital aortic valvar stenosis itself accounts for 5% of all cardiac abnormalities. 1 If all those with bifoliate aortic valves are included, then this may be the commonest of all congenital abnormalities. 2,3 It is difficult to know the true incidence, however, as congenitally abnormal aortic valves may not be recognised in childhood. Isolated stenosis as a presenting feature is more common than regurgitation, albeit that mixed lesions tend to occur over time, providing a challenge in management for the cardiologist.
MORPHOLOGY
The Normal Aortic Root
To understand the mechanisms of obstruction at any level within the left ventricular outflow tract, it is necessary first to understand the normal arrangement. Most accounts remain based on the concept of an aortic annulus, albeit this enigmatic feature is rarely described in consistent and satisfactory fashion. 4 An annulus, if defined literally, is no more than a little ring. There are several rings within the normal aortic root, but none of them support the leaflets of the aortic valve. The essence of normality is that the leaflets are hinged within the arterial root in semilunar fashion ( Fig. 44-1 ). The root itself is formed by interlocking of the aortic valvar sinuses and the supporting ventricular structures. Because of the interlocking, there is a marked discrepancy between the locus of the haemodynamic as opposed to the anatomic ventriculo-arterial junctions. 5 The anatomical ventriculo-arterial junction is the line over which the fibroelastic walls of the aortic sinuses are supported by the base of the left ventricle. This line does form a ring, with parts supported by the musculature of the ventricular septum and the parietal left ventricular wall and the remainder integrated within the fibrous curtain formed by the continuity between the leaflets of the aortic valve and the aortic, or anterior, leaflet of the mitral valve. The rightward extent of this area of fibrous continuity also incorporates the membranous part of the ventricular septum (see Fig. 44-1 ). The haemodynamic junction is marked by the semilunar lines of attachment of the aortic valvar leaflets (see Fig. 44-1 ). These semilunar hinges cross the ring at six points. As a result, three crescents of ventricular tissue, two muscular and one fibrous, are incorporated into the bases of the three aortic sinuses of Valsalva, while three fibrous triangles are incorporated at the distal extent of the ventricular outflow tract ( Fig. 44-2 ).
The triangles extend distally to the level of the most distal attachment of the leaflets at the sinutubular junction. This structure is also an obvious ring, marking the line over which the expanded aortic sinuses become continuous with the tubular aorta. It marks the distal extent of the aortic root. Since it is unequivocally part of the root, and valvar competence depends on its integrity, it is somewhat illogical to describe stenosis at this level as being supravalvar. It is also illogical to consider only the peripheral attachment of the valvar leaflets to the sinutubular junction as the commissures, as is currently the usual practise. Defined literally, a commissure is a zone of apposition. The zones of apposition between the normal valvar leaflets extend from the centre to the periphery of the valve ( Fig. 44-3 ). All parts of these zones need to open without hindrance if the valve is to function properly. There is then one further ring within the outflow tract. This ring is constructed by joining together the most proximal attachments of the three valvar leaflets within the left ventricle. This third ring, therefore, is a virtual structure (see Fig. 44-2 ), whereas the sinutubular junction and the anatomic ventriculo-arterial junctions are true anatomic entities. The entirety of the root, considered in three dimensions, takes the form of a crown ( Fig. 44-4 ).
Annulus , therefore, does not seem the most obvious word the arrangement of the valvar leaflets within the root. The overall anatomic arrangement should also be taken into account when measurements are made of the outflow tract. When diagrams are made to illustrate the concept of measurement of the annulus, they often show a line drawn between proximal points of attachment of the leaflets ( Fig. 44-5 ). Such diagrams must involve a degree of poetic licence on behalf of the observer, since the section illustrated can never cut the full diameter of the arterial root ( Fig. 44-6 ).
All of this normal anatomy is of relevance when considering the structure of stenotic lesions within the outflow tract, particularly the fact that so-called supravalvar stenosis involves tethering of the valvar leaflets at the level of the sinutubular junction.
Valvar Stenosis
The stenotic aortic valve is traditionally considered as showing unicuspid, bicuspid, or tricuspid patterns. Strictly speaking, a cusp is a point or elevation. Despite its popularity, it is not the ideal adjective to use when accounting for lesions of the abnormal valve. Our preference is to describe unifoliate, bifoliate, or trifoliate valves, according to the number of leaflets present. When making such descriptions, note should also be taken of the number of sinuses present, since almost always, even when the curtain of leaflet tissue is compartmented to produce less than three component parts, the curtain is still suspended within three obvious sinuses. In the presence, for example, of the so-called unifoliate and unicommissural valve ( Fig. 44-7 ), with examination from the arterial aspect showing a solitaryslit-like opening within the valvar curtain, examination from the ventricular side typically reveals three interleaflet triangles, albeit with two of them being vestigial. 6
Similarly, examination of the majority of the valves showing a bifoliate pattern of the leaflets ( Fig. 44-8 ) reveals that they are formed within a trisinuate prototype. 7,8 In the unifoliate, or unicommissural, valve, typically seen in infants with so-called critical stenosis, the keyhole opening within the valvar curtain represents the only properly developed zone of apposition (see Fig. 44-7 ). This is usually formed between the left and non-coronary aortic leaflets, and points towards the mitral valve. The other leaflets are abnormally attached in annular fashion to the ventricular wall because of the vestigial nature of the putative zones of apposition between the other leaflets ( Fig. 44-9 ). It is paradoxical, therefore, that valvar leaflets attached more closely in annular fashion are likely to be stenotic or regurgitant.
Balloon dilation of such valves can do little more than open further the solitary zone of apposition, which is often tethered to the sinutubular junction (see Fig. 44-7 ). To produce a functioning trifoliate arrangement, it is necessary to create new triangles at the sites of the vestigial zones of apposition, with appropriate extension of the rudimentary and malformed leaflets. When seen in pathological archives, such valves are usually housed in small fibroelastic left ventricles, the heart itself often fulfilling many of the anatomic criterions for inclusion within the hypoplastic left heart syndrome (see Chapter 29 ).
The bifoliate aortic valve is also often described in association with critical aortic stenosis, albeit again formed on a trisinuate prototype, 8 but is also found in asymptomatic individuals. The leaflets themselves guard markedly dissimilar parts of the valvar orifice, with the larger leaflet formed by fusion of two putative leaflets, typically with a raphe showing the line of non-separation between them (see Fig. 44-8 ). The conjoined leaflet usually represents either fusion of the two coronary leaflets, or fusion of the right and non-coronary leaflets. 7 Truly bisinuate and bifoliate valves do exist, but are rare, as are trisinuate but bifoliate valves without evidence of a raphe between the presumed conjoined leaflets. Stenosis, when it occurs, is the result of fusion of the ends of the zone of apposition between the two leaflets. Bifoliate valves can also produce problems when they become incompetent due to prolapse, or if they provide a nidus for endocarditis. This is more likely to occur in adult life, 9 and is rarely seen in childhood.
Stenosis producing problems in childhood can also be seen in the setting of a trifoliate valve, but more usually such valves are the seat of senile aortic calcification. 10 When seen in childhood, the trifoliate valve, with dysplastic leaflets, is encountered most frequently in infants. A stenotic trifoliate valve is rare in older children and adolescents unless they have undergone previous surgery.
Calcification of the aortic valve can develop from the third decade in all patients with mildly stenotic or bifoliate valves. It may start as early as the second decade, particularly if the valves are dysplastic and myxomatous. Most patients, however, present in later life with severe calcific aortic stenosis in what was initially no more than a mildly stenosed valve, or a valve with leaflets initially of markedly dissimilar size. 10 The changes are more common in males than females. Patients with familial hypocholesterolaemia, progeria, and rickets develop calcification earlier, even if the aortic valve is only mildly abnormal. Patients with bifoliate valves producing minimal stenosis usually do not develop calcific stenosis until the sixth or seventh decade, but presence of moderate or severe stenosis in childhood can lead to quite heavy calcification in the third and fourth decades.
Subvalvar Stenosis
A variety of lesions can obstruct the subaortic outflow tract, with or without a co-existing ventricular septal defect. When there is an interventricular communication, then postero-caudal deviation of the muscular outlet septum is usually the most important lesion. 11 We discuss this lesion in the chapters devoted to ventricular septal defect and interruption of the aortic arch. Obstruction can also be produced by hypertrophy of the ventricular septum, as seen in hypertrophic cardiomyopathy (see Chapter 54A , Chapter 54B ), by anomalous tissue tags derived from the membranous septum or the leaflets of the atrioventricular valves, or by anomalous attachment of the tension apparatus of the left atrioventricular valve ( Fig. 44-10 ). The last two lesions are also more likely to be found when there is a ventricular septal defect, or in the setting of common atrioventricular junction and deficient atrioventricular septation.
When the ventricular septum is intact, the most significant lesion is the subvalvar fibrous ridge, or diaphragm ( Fig. 44-11 ). This lesion has been described in many ways. Although often termed membranous , almost always the lesion is a firm fibrous shelf that encircles the outflow tract, often extending to be attached also to the aortic valvar leaflets. The septal component of the obstructive lesion overlies the left bundle branch as it crosses the ventricular septum. A discrete plane of cleavage almost always exists between the shelf and the musculature. Because of this, it can readily be stripped away by surgery ( Fig. 44-12 ). Since the lesion is acquired, there is always the likelihood of recurrence. The position can vary with regard to its proximity to the valvar leaflets. If extensive, it can produce so-called tunnel stenosis. In florid cases, there is a marked abnormality in the alignment between the plane of the aortic root and the ventricular septum. This has been promoted as a potential cause of the malformation. 11
Supravalvar Aortic Stenosis
Supravalvar stenosis accounts for only 1% to 2% of cases of aortic stenosis seen in childhood. The condition may be familial, or may be associated with disorders of calcium metabolism, the so-called Williams syndrome. 12 The original description included failure to thrive, gastrointestinal upset, and mental retardation. 13 The stenosis typically lies above the aortic sinuses and the coronary orifices, but incorporates the sinutubular junction ( Fig. 44-13 ). The aortic sinuses themselves are enlarged and bulge laterally, while the aortic leaflets are often slightly thickened, and are disproportionately long in relation to the portion of sinutubular junction to which they are related. The coronary arteries, which take origin below the obstruction, are typically dilated, thick walled and ectatic. The possibility of orificial stenosis must be considered in these patients, nonetheless, as hoods, entrapment by leaflet tissue, and slit-like orificies may all lead to myocardial ischaemia. The nature of the narrowing is variable. 14 The most common form is the hourglass variety with dilation of the distal aorta (see Fig. 44-13 ). There are also diffuse or tubular varieties, and, very rarely, a diaphragmatic or localised form. Irrespective of the type, the ascending aorta is usually grossly abnormal, with a thickened wall and disorganisation of the media. The narrowing and scarring are not exclusive to the aorta, and may be found in the iliac arteries, and in the abdominal and renal vessels. Stenosis of the origin of the carotid and subclavian arteries, and less frequently the renal and mesenteric arteries, occurs in up to half the patients. The pulmonary circulation is also affected. In one-fifth of patients, there are multiple pulmonary arterial stenoses. These are mostly peripheral, being seen where the major vessels enter the lung. Consequently, supravalvar aortic stenosis in most, but not all, patients is part of a more widespread abnormality of the cardiovascular system involving the major conducting arteries. Histological findings away from the site of the obstruction in the aorta show irregular thickening and branching of medial elastic fibres. This appearance has been dubbed a mosaic pattern, 9 or higgledy-piggledy arteriopathy. 15
Aortic Regurgitation
The stenotic aortic valve can also be regurgitant if the lesions producing stenosis also prevent the valvar leaflets coapting snugly during ventricular diastole. Isolated aortic regurgitation is much rarer than stenosis. If seen as an isolated finding in the neonatal period, then reflux through an aorto–left ventricular tunnel should be excluded. In this entity, one of the valvar leaflets is suspended across the ventriculo-arterial junction, so that blood is able to flow around the part that should be attached within the aortic root ( Fig. 44-14 ). Regurgitation can also be produced by abnormalities of the leaflets, such as perforations produced by infectious endocarditis, or iatrogenic damage subsequent to balloon dilation. Dilation of the sinutubular junction will also prevent the valvar leaflets coapting, but this is an acquired rather than a congenital malformation ( Fig. 44-15 ).
VALVAR AORTIC STENOSIS
Genetics
A bicuspid or bifoliate aortic valve occurs with a frequency of 1% to 2%, with a ratio of two males to each female. Familial clustering is recognised, as well as a common association with other left-sided obstructive lesions, such as aortic coarctation. Studies assessing first-degree relatives by echocardiography have demonstrated an incidence of associated bicuspid or bifoliate aortic valve from 4.7% to 24%, with a higher incidence of other left-sided lesions in these families. 15–19
Critical Stenosis in the Neonate and Young Infant
Aortic stenosis is an important cause of heart failure in the neonate and young infant. It is being identified more frequently in the prenatal period and indeed, intervention has now been attempted in a group of fetuses with the lesion, with varying degrees of success. 20,21 The main issue at this stage, as well as for those presenting in the newborn period, relates to the adequacy of the left ventricle to support the systemic circulation. Although many attempts have been made to address this problem, it still remains controversial as to when a left ventricle is too small, such that a biventricular repair is abandoned in favor of the Norwood protocol or cardiac transplantation. 22,23 The problem is magnified by the fact that many patients have associated endocardial fibro-elastosis, mitral valvar abnormalities, or coarctation of the aorta in addition to the stenosis of the aortic valve. Hypoplasia of the aortic root and ascending aorta may also be seen, usually in those patients having borderline left ventricles. The pathogenesis is still poorly understood, but it most likely involves a primary left-sided insult, with secondary failure of growth of the left ventricle. This theory is supported by observation that left ventricular growth is seen following relief of the obstruction, even in those with borderline left ventricular volume at the time of first presentation. 21 What is also clear is that the associated left-sided lesions have an ongoing impact on morbidity, even in those patients undergoing adequate relief of the obstruction. 21
Pathophysiology in the Newborn Period
Why do neonates and young infants with critical aortic valve stenosis present in heart failure? In those patients with a left ventricle having borderline volume, there is associated right ventricular hypertension in addition to left ventricular failure. The right ventricular dilation associated with the pulmonary hypertension has a further negative effect on left ventricular output, due to interactions between the ventricles. The ventricular septum bows into the left ventricle, further reducing its volume, and compounding the underlying problem. Tricuspid valvar regurgitation, if present, may also result in further dilation of the right ventricle. In other cases, where the left ventricular volume is adequate, failure is most likely due to a sudden increase in left ventricular afterload after birth as a result of reduced mass necessary to normalise mural myocardial stress.
Clinical Presentation and Physical Findings in the Neonate and Young Infant
The newborn or young infant presents in one of three ways. The first is with a picture similar to other forms of left-sided obstructive disease, such as aortic coarctation, interruption of the aortic arch, or hypoplastic left heart syndrome. These patients usually have a left ventricle with borderline volume, and become profoundly unwell subsequent to closure of the arterial duct. Clinically, they are in cardiac failure, or else present with cardiovascular collapse once they become acidotic. These neonates and young infants are tachypnoeic, tachycardic, and often cyanosed, due to the combination of pulmonary venous congestion and right-to-left shunting across the duct. Of note, the shunting through the oval foramen is from left to right. The physical examination reveals hepatomegaly, right ventricular enlargement, diffusely weak pulses, and frequently no murmur to suggest aortic valvar stenosis. An ejection click is uncommon. If they have right ventricular hypertension and failure, they may have a systolic murmur of tricuspid valvar regurgitation with an associated gallop. The second heart sound is invariably single. The patients are differentiated from those with aortic coarctation or interruption in that all the pulses are weak, as opposed to the right brachial and temporal pulses being palpable when the obstruction is within the aortic arch. The neonates with problems at valvar level are best described as having critical stenosis, since they are dependent on the patency of the arterial duct to sustain systemic cardiac output.
The second mode of presentation is seen in neonates or young infants with left-sided cardiac failure, but in the absence of acidosis, in other words, without ductal dependency. In this setting, the patients are tachypnoeic, have pulses that are usually low volume, and exhibit significantly less hepatomegaly. Auscultatory findings may reveal an ejection click heard along the lower left sternal border and at the apex, with a systolic ejection murmur that is heard in the same area, with radiation towards the upper right clavicular region. An associated systolic thrill is uncommon, as is the clinical detection of associated aortic regurgitation. While these patients usually have severe valvar stenosis, they are differentiated from those with the critical form by their lack of ductal dependency, and are often somewhat older at presentation. Consequently, as we will discuss, their outcomes tend to be better.
In the third situation, some patients are referred as neonates, or during the early period of infancy, for the evaluation of a systolic murmur. These patients do not have severe stenosis. They are more likely to have an ejection click, with an associated systolic murmur, but no signs of congestive cardiac failure. Of note, the pulses are usually of normal volume.
Investigations in the Newborn and Young Infant
The Electrocardiogram
The tracings at this age may look very similar to those seen in aortic coarctation or interruption, or hypoplastic left heart syndrome. There is right ventricular dominance, with upright T waves in lead V1, and a paucity of left-sided forces. Of note, there may also be diffuse changes in the S-T/T waves related to diffuse subendocardial ischaemia. In other cases with a larger left ventricle there is still right ventricular dominance, but with better left-sided forces. In those without pulmonary hypertension, there is evidence of left ventricular hypertrophy with associated strain.
Chest Radiograph
This may demonstrate cardiomegaly, with evidence of right ventricular enlargement and associated pulmonary oedema.
Echocardiography
The echocardiographer is presented with a challenge, particularly in those cases where the left ventricle is relatively hypoplastic ( Fig. 44-16 ). There is usually right ventricular dilation due to the associated pulmonary hypertension, as well as associated left ventricular dysfunction. The left atrium is dilated, and there is usually left-to-right shunting at high velocity across the oval foramen. Of note, this mean gradient can be used to obtain an indirect assessment of left atrial pressure, by adding the estimated mean right atrial pressure. Usually, if the inferior caval vein is non-pulsatile, then the mean right atrial pressure is greater than 10 mm Hg. An estimated systolic right ventricular pressure can be obtained from associated tricuspid valvar regurgitation, and the mean pulmonary arterial pressure via the arterial duct. There is usually some degree of hypoplasia of the left ventricle and aortic root. Although it is possible to measure the left ventricular volume by using the calculations in the biplane Simpson approach, this is probably an underestimation of the true volume, since the left ventricle has an abnormal shape due to the associated septal shift in cases with systemic right ventricular pressures. With newer three-dimensional echocardiographic techniques, or with magnetic resonance imaging, this limitation should be overcome. In some patients, nonetheless, the true left ventricular volume remains unknown until the stenosis is relieved.
The aortic valve is more likely to be unifoliate and unicommissural in those presenting with critical aortic valve stenosis (see Fig. 44-16 ). In some cases, the valve appears to be so dysplastic that the precise nature of the morphology of the leaflets is difficult to determine.
Associated supravalvar and subvalvar stenosis is uncommon, albeit that endocardial fibroelastosis, and pathology involving the mitral valve, are common associations. When the endocardial fibroelastosis is extensive, this is seen as a bright layer covering the entire endocardium. When it is more patchy, it may be difficult to detect by echocardiography, which is not a good method for assessing the character of the insonated tissues. Assessing the severity of any associated mitral valvar pathology may also be difficult upon presentation due to poor left ventricular function, which in itself results in immobility of the leaflets ( Fig. 44-17 ). Similarly, Doppler echocardiography is of limited value in determining the severity of the stenosis in the presence of a dilated ventricle with poor function. Despite this, if there is turbulence across the valve, then it most likely represents stenosis, rather than a dilated cardiomyopathy with an associated abnormality of the aortic valve, or more commonly aortic coarctation associated with a bifoliate aortic valve. Problems are created in the patients with moderate aortic valvar stenosis, coarctation of the aorta, and poor left ventricular function. In this setting, it usual first to deal with the coarctation, followed by reassessment of the aortic valve.
Magnetic Resonance Imaging
More recently this technique has been employed by some to gain a more reliable assessment of left ventricular volume, though whether such measurements are accurate remains unclear.
Management of Critical Aortic Valvar Stenosis
In this current era, management starts in the prenatal period. There has been an interest in intervening prenatally in the fetus with aortic valvar stenosis, in an attempt to promote left ventricular growth. Although first described more than 10 years ago, more recently this approach has been extensively examined by the group working at Boston Children’s Hospital, who now have significant experience with this technique. 20,21 The procedure involves paralysing the fetus, and then either directly via the maternal abdomen, or through the exposed uterus, an attempt is made percutaneously to dilate the aortic valve with a balloon. The results have been variable, but biventricular repair has been achieved in some who previously would have been destined to undergo functionally univentricular palliation. There is, however, mortality and morbidity associated with the procedure. It remains a matter of debate as to whether the long-term outcome of the borderline biventricular repair is better than the alternative palliation culminating in conversion to the Fontan circulation.
For the neonate or young infant where the left ventricle is deemed adequate to support the systemic circulation, balloon dilation of the left ventricular outflow tract has become the mainstay of initial therapy. With follow-up it is clear that the early results are comparable to earlier surgical outcomes, though there appears to be a higher incidence of aortic regurgitation when the valve is dilated with a balloon. 24–28 In the majority of patients, such regurgitation is well tolerated, at least for the first few years of life. Interventional cardiologists are very cautious not to oversize the balloon, since this introduces a greater chance of producing substantial regurgitation, which itself then requires further intervention. Should regurgitation ensue, then a neonatal Ross procedure is the treatment of choice. 29–31 . In general, this approach has a high rate of success, with the results in the early and medium terms being encouraging.
Those patients who present during the neonatal period or early infancy without cardiac failure present another challenge. In comparison to their older counterparts, the modest gradient seen across the valve in the early phase may progress fairly rapidly during the first one to two years of life, necessitating closer follow-up in this population. 32–35 If faced with this dilemma, it is advisable to repeat the echocardiogram every 2 to 3 months, until reassured that the rise in gradient is not rapidly progressive. A similar issue arises in those cases with combined aortic valvar stenosis and coarctation of the aorta. In this setting, the downstream obstruction results in an underestimation of the severity of the valvar stenosis, even in the presence of reasonable left ventricular function. Again, close follow-up is warranted once the coarctation has been addressed.
Outlook in the Longer Term
Presentation during the neonatal period represents the severe end of the spectrum of this disease, with those presenting earliest usually having the most severe lesions. When the predominant lesion is stenosis, these children are likely to require further intervention in the future, in the form of further balloon dilation, while those with significant regurgitation will likely require replacement of the valve. Associated lesions such as endocardial fibroelastosis and mitral valvar disease, add to the morbidity in this group. The presence of significant endocardial fibroelastosis results in diastolic dysfunction and left atrial hypertension. To address this, some groups have attempted surgically to remove the thick peel of endocardial fibroelastosis, attempting to improve both left ventricular growth and diastolic function. The results of this strategy over the long term remain to be seen, and it has not yet been widely adopted.
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