Mark B. Lewin, MD
Catherine M. Otto, MD
From the Division of Cardiology, Department of
Pediatrics (M.B.L.), and the Division of Cardiology,
Department of Medicine (C.M.O.), University of
Washington School of Medicine, Seattle.
The population frequency
of a bicuspid aortic valve is ≈0.9% to 1.36%,
with a 2:1 male:female ratio. It is likely that the presence of
a bicuspid aortic valve has a genetic basis, with the pattern of
transmission in some families suggesting an autosomal dominant
pattern of inheritance.
Epidemiological data from the Baltimore-Washington Infant Study
demonstrated the familial clustering of left heart obstructive
lesions (including coarctation of the aorta, aortic valve
stenosis, and hypoplastic left heart syndrome).
More recently, the increased risk of identifying a bicuspid
aortic valve in the parent or sibling of the proband with any
form of left heart obstructive lesion was described.
By inference, this also suggests the potential identification of
a congenitally malformed aortic valve in the presence a family
member with a more complex congenital heart lesion. In addition,
a bicuspid aortic valve is present in >50% of patients with
aortic coarctation
and in 10% to 12% of women with Turner syndrome The specific genetic locus and protein abnormality in patients
with a bicuspid aortic valve have not yet been identified,
however.
The tissue abnormality
in patients with a bicuspid aortic valve is not confined to the
valve leaflets; these patients are at increased risk of aortic
aneurysm and dissection. At the tissue level, the aorta shows
cystic medial necrosis, loss of elastic fibers, increased
apoptosis, and altered smooth muscle cell alignment.
When compared with patients with a trileaflet valve, patients
with a bicuspid valve have larger aortic root dimensions and an
increased rate of aortic dilation over time, with the degree of
aortic dilation independent of valve hemodynamics.
The risk of aortic dissection in patients with a bicuspid valve
is 5 to 9 times higher than in the general population, although
some investigators hypothesize that this increased risk is
limited to a subset of bicuspid valve patients.
Even after valve replacement, surgery for a bicuspid valve is a
strong risk factor for subsequent aortic dissection. The
association of bicuspid aortic valve with aortic aneurysm and
dissection suggests the possibility that a bicuspid valve, at
least in some patients, is only the most identifiable
manifestation of a systemic connective tissue disorder.
Most patients with a
bicuspid aortic valve are unaware of the diagnosis until late in
life because symptoms and physical findings often are absent for
many years. Unless echocardiography is requested for other
indications, the diagnosis often is made only at the time of an
adverse cardiovascular outcome. On echocardiography, aortic
valve anatomy can be reliably determined in a short-axis view,
although care is needed to visualize the opening of all 3
leaflets in systole. Diastolic images can be misleading because
the raphe in the larger leaflet of a bicuspid valve may simulate
a trileaflet valve in the closed position .
If images are suboptimal, then transesophageal imaging may be
helpful for the accurate evaluation of valve anatomy.
Transthoracic
echocardiographic parasternal short-axis view of a
bicuspid aortic valve. In diastole (left), the prominent
raphe (arrow) in the larger anterior leaflet of the
bicuspid valve results in an echocardiographic
appearance similar to a trileaflet valve. In systole
(right), the opening of only 2 leaflets with 2
commissures is clearly seen.
Nearly all patients with
a bicuspid aortic valve will require valve surgery during their
lifetime. The clinical outcomes in patients with a bicuspid
valve include significant valve regurgitation, endocarditis,
aortic aneurysm and dissection, and in the majority of these
patients, severe stenosis resulting from superimposed calcific
changes. A small subset of patients with unicuspid or severely
deformed bicuspid valves require intervention in childhood or
adolescence. The vast majority of “hemodynamically significant”
aortic valve disease in infancy and young children results from
aortic stenosis of the bicuspid valve. In the current era, these
children receive intervention via balloon aortic valvuloplasty
rather than via surgery. Later in childhood and into
adolescence, identification of aortic regurgitation is more
frequent, often slowly evolving in the patient who previously
received intervention in the cardiac catheterization laboratory.
These children may eventually require valve repair or
replacement, the latter group divided among the allograft, the
autograft (Ross procedure), and the mechanical valve.
Another important issue
in any discussion of the bicuspid aortic valve is that of the
relative risk for the development of endocarditis. Although the
population risk of endocarditis in the presence of an isolated,
nonobstructive or regurgitant aortic valve may be as high as 3%,
the exact prevalence remains controversial. Outcomes in children
with an infected bicuspid aortic valve are poorer than they are
in children with other types of congenital heart disease.
About 15% to 20% of
bicuspid valve patients have incomplete valve closure and
present at age 20 to 40 years with an asymptomatic diastolic
murmur, cardiomegaly, or symptoms resulting from aortic
regurgitation. Once significant regurgitation is present, the
natural history is determined by the left ventricular response
to chronic volume overload. In these patients, aortic valve
surgery often is needed because of the onset of symptoms at the
rate of ≈6% per year or progressive left ventricular dilation in
3% to 4% per year.
Some of these patients remain asymptomatic with normal left
ventricular function, however, and they will subsequently
develop valve stenosis.
The majority of
patients with a bicuspid valve have relatively normal valve
function and remain undiagnosed until late in adulthood, when
stenosis develops because of superimposed leaflet calcification.
The cellular and molecular mechanisms involved in the
calcification of a bicuspid aortic valve appear to be similar to
the process in a trileaflet valve.
Aortic leaflet calcification starts as a focal area on the
aortic side of the leaflet with subendothelial accumulation of
lipoproteins and an inflammatory cell infiltrate. There is
lipoprotein oxidation with infiltration of macrophages and T
lymphocytes and local production of proteins associated with
inflammation and tissue calcification, including bone matrix
proteins such as osteopontin and osteocalcin, tenascin-C,
upregulation of matrix metalloproteinases, and active tissue
angiotensin-converting enzyme. Microscopic calcification in the
subendothelium and adjacent fibrosa is seen early in the disease
process, with marked calcification and even cartilage and bone
formation as the disease progresses. The accumulation of calcium
and lipid along with tissue fibrosis eventually leads to
increased leaflet stiffness with a reduction in systolic valve
opening. When patients present with symptoms resulting from
valve obstruction, the treatment is valve replacement.
In this issue of
Circulation, Roberts and Ko
report that the prevalence of bicuspid aortic valve was 53% in a
consecutive series of 933 patients undergoing valve replacement
for isolated aortic stenosis. In addition, 4% had unicommissural
valves. The authors intentionally excluded patients with a
previous aortic valvulotomy; thus the prevalence of congenitally
malformed aortic valves may be underestimated. Although we have
long recognized that the 3 most common causes of aortic stenosis
are a bicuspid valve, rheumatic disease, and calcification of a
trileaflet valve, previous reports of the prevalence of a
bicuspid valve were based on surgical series that likely
included patients with rheumatic disease. In addition, both
echocardiographic and surgical evaluation of valve anatomy can
be misleading unless care is taken to distinguish a congenital
raphe from inflammatory commissural fusion. The study by Roberts
and Ko is the first that was restricted to nonrheumatic aortic
stenosis with rigorous examination of the pathology of the
explanted valve leaflets.
The study demonstrates
a marked difference in the age distribution at the time of valve
surgery, according to valve anatomy. Only 7% of the total valve
surgeries were performed in patients ≤50 years old; of these
patients, about one third had a unicuspid valve and two thirds
had a bicuspid valve. About 40% of valve surgeries were
performed when the patient was between 50 and 70 years old, with
about two thirds of these patients having a bicuspid valve and
one third having a trileaflet valve, and rare cases having a
unicuspid valve. More than 50% of valve surgeries were performed
in patients >70 years old, with ≈60% of these patients having a
trileaflet valve and 40% having a bicuspid valve. Thus, these
data demonstrate that increasing calcification results in severe
valve obstruction before an individual is 50 years old for most
unicuspid valves and before 80 years old for most bicuspid
valves, whereas stenosis of a trileaflet valve may occur as
early as 50 years old but typically presents in the 70- to
90-years-old range. This pattern of presentation is consistent
with the hypothesis that abnormal mechanical and shear stresses,
as expected with unicuspid and bicuspid valves, are associated
with earlier leaflet calcification.
These data have
important clinical implications. The ≈50% incidence of a
congenitally malformed aortic valve in adults requiring aortic
valve replacement suggests a significant issue of which both the
public and the health professional should be aware. Clearly, an
effective therapy to prevent calcific aortic valve
stenosis - focusing on patients with a bicuspid aortic valve - would
have a major impact on the number of older adults requiring
valve replacement. The study by Roberts and Ko study highlights
another issue, that of the ongoing concern about the risk of
developing aortic dilation and dissection in the presence of a
bicuspid aortic valve.
Dr Roberts truly is a
student of the aortic valve, and this study builds on his
innumerable contributions to our understanding of aortic valve
disease. As with Dr Roberts’s other pioneering articles, it is
hoped that the present data will stimulate other investigators
to find answers to the many questions remaining about the
bicuspid aortic valve: What is the genetic basis of a bicuspid
aortic valve? Is this a single phenotype or have we included
more than one condition in the designation “bicuspid aortic
valve”? Should relatives of a patient with a bicuspid valve
undergo screening for valve disease? Why do some patients
develop regurgitation and others stenosis? What recommendations
should we make to a young patient with a bicuspid aortic valve?
Can we prevent calcific stenosis of a bicuspid valve? Which
patients are at risk of aortic dissection?
Although definitive
answers to these questions may take years, a prudent approach to
the patient with a normally functioning bicuspid valve is to
educate the patient about the expected long-term prognosis,
emphasize dental hygiene and endocarditis prophylaxis, evaluate
and treat standard cardiovascular risk factors on the basis of
evidence-based guidelines, and follow valve function with
periodic echocardiography. When regurgitation or stenosis is
detected, guidelines for evaluation and treatment of those
conditions should be followed. Given the increased risk of
identifying a bicuspid aortic valve in first-degree relatives
having the same diagnosis, screening of this at-risk population
should be considered. Echocardiographers should take particular
care to identify bicuspid aortic valves in young patients
because of the important long-term clinical consequences of this
condition.
