Valvular Aortic Stenosis

Definition, Morphology, and Epidemiology

For the vast majority of adults with congenital AS, the most common morphologic finding is a bicuspid aortic valve (BAV) ( Fig. 35.1 ). Less than 5% of congenitally malformed aortic valves are unicuspid, tricuspid, or quadricuspid, all of which may result in valvular stenosis.

Unicuspid aortic valves may be (1) acommissural, characterized by a single cusp, a stenotic central orifice, and rudimentary commissures that do not divide the valve or (2) unicommissural, characterized by a single cusp with a single commissural attachment to the aortic wall and an elongated orifice. Patients with an acommissural valve typically present in the neonatal period as the pinhole opening is severely obstructive. The dysfunctional unicommissural type tends to present later in life with cardiovascular symptoms either directly related to the valve dysfunction or as a consequence of complications such as infective endocarditis or aortic dissection. Roberts and Ko examined 932 aortic valves excised predominately for AS over an 11-year period. Patients with rheumatic valvular disease were excluded. More than half of patients (54%) were found to have a congenitally malformed valve. BAVs were the most common morphologic finding and accounted for 54% of all aortic valves excised. Tricuspid aortic valves were the second most common finding (45%), and unicuspid aortic valves accounted for 5% of all valves excised. Patients with unicuspid valves typically present 10 to 20 years before bicuspid patients. In a retrospective study of patients undergoing unicuspid valve excision, the mean age of surgical intervention was 44 ± 12 years.

BAVs are the most common congenital cardiac anomaly, with an incidence of 1% to 2% in the general adult population. In an echocardiographic study of neonates, the overall prevalence of BAV was 4.6 per 1000 live births (7.1 per 1000 in male neonates and 1.9 per 1000 in female neonates). BAVs are the most common cause of isolated valvular AS in adults and the most frequent finding in aortic valve replacement (AVR) for AS up to 70 years of age.

Inherently stenotic dysplastic tricuspid aortic valves are often associated with a hypoplastic aortic annulus and usually present in infancy as a rare cause of valvular AS.

Isolated quadricuspid aortic valves ( Fig. 35.2 ) are rare. Quadricuspid aortic valve classification is dependent upon the relative size of the cusps or the position of the accessory cusp. Aortic regurgitation is the most frequent pathologic development; nevertheless, cases of severe AS have been reported. A retrospective review of 19,722 patient undergoing aortic valve surgeries identified 31 cases of dysfunctional quadricuspid aortic valves (0.0016%). The mean age at surgical intervention was 58 ± 18 years. Twenty-one patients (68% of quadricuspid valves identified) presented with isolated aortic regurgitation, five patients demonstrated AS, four patients presented with a combination of both, and one patient with a functional quadricuspid valve required excision of fibroelastoma.

Associated Lesions

In approximately 30% of individuals with a BAV, a further congenital aortic or cardiac abnormality is found. Most frequently the BAV is associated with an aortopathy, which may present with progressive dilation of the aortic root and/or the ascending aorta. Analogous to bicuspid valves, aortopathies are common in patients with unicuspid and quadricuspid aortic valves. In 149 patients with unicuspid valves undergoing aortic valve repair or replacement, 91 patients (61%) required a combined valve and aortic repair operation ; 23% of patients needing repair or replacement of a quadricuspid valve also required ascending aorta repair at surgery.

BAV disease is frequently found in association with coarctation of the aorta and less frequently with interruption of the aorta and isolated ventricular septal defect. Other associated abnormalities include a left dominant coronary artery system, subvalvular AS, parachute mitral valve, atrial septal defects, patent ductus arteriosus, bicuspid pulmonary valve, Ebstein anomaly, and hypoplastic left heart syndrome. The combined presence of multiple levels of left-sided heart obstructions (eg, subvalvular AS, BAV stenosis, aortic coarctation, parachute mitral valve, or supramitral ring) is termed Shone syndrome.

Unicuspid valves have been reported in association with patent ductus arteriosus, coarctation of the aorta, coronary artery anomalies, and great vessel anomalies.

Anomalous origins of the coronary arteries are associated with quadricuspid aortic valves.

Genetics and Molecular Biology

The genetic and molecular bases of bicuspid valves are much better understood than the rarer quadricuspid and unicuspid valves; however, a considerable number of questions remain unanswered. Studies have demonstrated substantial genetic heterogeneity in the pathogenesis of the bicuspid valve and many types of genetic variations exists from common single nucleotide polymorphisms to rare copy number variants and chromosomal abnormalities. The bicuspid valve and its associations are likely to represent the final common pathway for a wide variety of altered molecular events, genetic defects, and environmental modifiers. No single gene model clearly explains bicuspid valve inheritance.

Inheritances in familial clusters and sporadic cases have both been described. Studies of familial clusters are consistent with autosomal dominant inheritance with variable penetrance. Screening studies of index cases with BAV demonstrate an 8% to 10% prevalence of BAVs in asymptomatic first-degree relatives. First-degree relatives of patients with various types of left ventricular outflow tract obstruction are also at an increased risk of BAV. Turner syndrome demonstrates the highest syndromic penetration of bicuspid valve; 30% of affected individuals have a bicuspid valve. A bicuspid valve is also found in approximately 20% of patients with Loeys-Dietz syndrome. In addition to genetic syndromes, the BAV is associated with some congenital heart disorders, such as hypoplastic left heart syndrome, although again, the genetic basis remains unclear.

Investigators have uncovered multiple genetic loci for BAV through linkage analysis of BAV pedigrees. The most significant genetic loci identified are on chromosomes 3p22, 5q15-21, 9q22.33, 9q34-35 (NOTCH1), 10q23.3 (ACTA2), 13q33qter, 15q25-q26.1, 17q24 and 18q. Mutations in the signaling and transcriptional regulator NOTCH1 result in developmental aortic valve abnormalities and severe valve calcification in affected families. NOTCH1 remains the only gene identified through linkage analysis and positional cloning in isolated bicuspid valve. Mutations in the smooth muscle ACTA2 gene, which encodes vascular smooth muscle cells α-actin, are associated with familial thoracic aortic aneurysms and BAVs alongside premature coronary artery disease and cerebrovascular disease. Other potential candidate genes include endothelium-derived nitric oxide and the ubiquitin fusion degradation 1-like gene.

A genetic basis for the unicuspid valve may be extrapolated from the association with Turner syndrome, discovery in siblings and the finding of altered gene expression in patients with unicuspid valves.

The BAV arises from abnormal valvulogenesis and cusp formation, resulting in adjacent cusp fusion. Formations of two cusps of unequal size are found in the vast majority, and often the fibrous raphe is visible between the conjoined cusps. These valves tend to have three identifiable sinus of Valsalva, and the most common morphologic finding is fusion of the right and left coronary cusps. Truly bicuspid valves are rare and are identified as an absence of raphe associated with two identifiable sinuses of Valsalva.

The aortopathy associated with BAV disease is, in all probability, due to a combination of genetic inheritance resulting in intrinsic structural abnormalities of the aortic wall, abnormal postvalve hemodynamics, and the influence of traditional cardiovascular risk factors. The associated aortopathy can be markedly heterogenic with phenotypic expression encompassing, alternatively, the entire ascending aorta, the sinuses of Valsalva, or the tubular aorta as described in the literature.

The inherent aortic wall defects in patients with BAVs (including those valves which function normally by echocardiographic definition) may be mediated by coexisting defects in the aortic media. Potential defects identified include fragmentation of elastin, loss of smooth muscle cells, and an increase in collagen. These abnormalities may in part be due to increased release of matrix metalloproteinase-2 from microfibrils secondary to deficient expression of matrix protein fibrillin-1 (inhibitor). The increased activity of the matrix metalloproteinase leads to apoptosis and degeneration of the aortic wall with the eventual progression of aortic dilation. Inadequate fibrillin-1 has also been linked to deficiencies in valvulogenesis which may result in a BAV.

Increased tensile and shear stresses have also been shown to play a role in the pathogenesis of valvular disease and aortopathy. Distensibility of the aortic root permits a normal closed tricuspid aortic valve to open as a triangle and then a circle without causing flexion deformity of cuspal tissue. In contrast, even a “normally functioning” BAV is characterized by abnormal folding and creasing throughout the cardiac cycle, extended areas of valve contact, turbulent flow, and subclinical stenosis. The outlined stresses lead to valve damage, scarring, and calcification, possibly through activation of molecular pathways. Imaging studies have confirmed these “functionally normal” bicuspid valves (based on traditional echocardiographic criteria) demonstrate abnormal flow patterns and elevated aortic wall shear stress.

Turbulent flow into the ascending aorta, when added to the aforementioned intrinsic medial abnormalities, contributes to progressive dilation and increases the likelihood of rupture or dissection. Dilation of the root, ascending, and, occasionally, descending aorta can be found in association with the congenitally abnormal aortic valve although aortic arch involvement is rare. Traditional risk factors for atherosclerosis are also likely to play a role. The pathogenesis of progressive BAV disease and the associated aortopathy is complex and further work is required to fully understand the genetics and molecular development of the disease process.

Pathophysiology and Clinical Course (Without Intervention)

Only 1 in 50 children born with bicuspid or unicuspid aortic valves will develop significant obstruction or regurgitation by adolescence. BAV disease is usually a slowly progressive disorder which can present with either stenosis or regurgitation, although patients may present acutely with associated complications such as aortic dissection or infective endocarditis. Echocardiographic surveillance studies have demonstrated similar life expectancy to the general population at up to 20 years of follow-up in bicuspid patients with absent or minimal hemodynamic abnormality. However, cardiovascular events (medical and surgical) were more frequent affecting approximately 4 in 10 patients over 20 years. Furthermore, sudden death has been shown to be more common in patients with bicuspid valve after AVR compared with AVR for tricuspid AS.

Evidence of echocardiographic valve thickening may be seen as early as the second decade, and calcification is often evident by the fourth decade. Concomitant aortic regurgitation can also accelerate progression of valvular AS.

Asymptomatic patients with AS have similar outcomes to age-matched normal adults; however, disease progression with symptom onset is common. In a longitudinal study of the long-term outcomes of 622 adults with asymptomatic but hemodynamically severe AS at study inception, most developed symptoms within 5 years. Sudden death in patients with AS is an uncommon event, estimated at less than 1% per year when patients with known AS are observed prospectively ( Fig. 35.3 ).

There is marked individual variability in the rate of hemodynamic progression and a wide variability in the degree of outflow obstruction that causes symptoms depending in part on patient size and the level of physical activity. For this reason regular clinical follow-up is mandatory in all patients with asymptomatic mild-to-moderate AS.

Eventually, symptoms of angina, syncope, or heart failure develop after a long latent period, and the outlook changes dramatically. After the onset of symptoms, average survival is 2 to 3 years, with a high risk of sudden death. It is important to emphasize that symptoms may be subtle and unless specifically and carefully sought may not be elicited when taking a routine clinical history.

In most patients with severe AS, impaired platelet function and decreased levels of von Willebrand factor can be demonstrated. The severity of the coagulation abnormality correlates with the severity of AS and resolves after valve replacement, except when the prosthetic valve area is small for patient size (<0.8 cm ² /m ² ). This acquired von Willebrand syndrome is associated with clinical bleeding, most often epistaxis or ecchymoses, in approximately 20% of patients.

The prevalence of ascending aortic dilation associated with BAV varies from 35% to 80%, subject to the criteria for aortic dilation and screening methods used. The rate of dilation of the aorta is higher in the tubular ascending aorta than the sinus of Valsalva. Prevalence increases with age, beginning in childhood and continuing throughout life. A study of the prevalence of aortic dilation in association with bicuspid valve, by age quintile, demonstrated aortic dilation in 56% of those aged younger than 30 years old and up to 88% of those aged more than 60 years old. However, ongoing progression of the dilated aorta should not always be presumed. In one study, 43% of BAV patients with aortopathy did not show further dilation over a follow-up period of 3.6 ± 1.2 years.

Aortic dissection and rupture have been described in association with BAV disease. Aortic diameter has previously been shown to be a significant predictor of dissection and rupture in a cohort of mixed etiology. The lifetime risk of aortic dissection in patients with bicuspid valves is estimated at eight times that of the general population, but the overall absolute risk remains low and considerably lower than age-matched Marfan patients. Identified risk factors for aortic dissection in this patient group include greater aortic stiffness, male gender, hypertension, aortic size, concurrent aortic valve disease, Turner syndrome, family history of aortic disease, and prior coarctation.

Physical Examination

AS is typically first suspected on finding a systolic ejection murmur on cardiac auscultation. The classic finding is of a loud (grade 4/6), late-peaking systolic murmur that radiates to the carotids. The intensity of the murmur does not correspond to the severity of the AS. The Gallavardin phenomenon occurs when the murmur is heard best at the left ventricular apex. A single or paradoxically split second heart sound and a delayed and diminished carotid upstroke confirm the presence of severe AS. The only physical examination finding that is reliable in excluding the possibility of severe AS is a normally split second heart sound ( Box 35.1 ). A fourth heart sound may be palpable and audible due to vigorous left atrial contraction. The apical impulse is not usually displaced but is often sustained due to secondary left ventricular hypertrophy.

An aortic ejection click may be heard after the first heart sound early in AS with a congenital bicuspid valve, when the cusps are stiff but still somewhat compliant and mobile. This tends to diminish as the valvular disease progresses. Unicuspid and quadricuspid aortic valves do not demonstrate the same ejection click and cannot be reliably diagnosed by physical examination only.

Investigations