A New Publication
A New Publication
Results: Circulation
(C) 2005 American Heart Association, Inc.
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Volume 111(7) 22 February 2005 pp 832-834
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The Bicuspid Aortic Valve: Adverse Outcomes From Infancy to Old Age
[Editorial]
Lewin, Mark B. MD; Otto, Catherine M. 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 opinions expressed in this article are not necessarily those of the editors
or of the American Heart Association.
Correspondence to Dr Catherine M. Otto, Division of Cardiology, Box 356522,
University of Washington, Seattle 98195. E-mail
[email protected]
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Outline
References
Graphics
Figure. Transthoraci...
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The population frequency of a bicuspid aortic valve is [almost equal to]0.9% to
1.36%,1-3 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.4,5
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).6 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.7 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 8 and in 10% to 12% of women
with Turner syndrome.9 The specific genetic locus and protein abnormality in
patients with a bicuspid aortic valve have not yet been identified, however.
See p 920
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.10 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.11,12 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.13,14 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 (Figure). If images are suboptimal, then transesophageal imaging may be
helpful for the accurate evaluation of valve anatomy.
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Figure. 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.
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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%,15 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.16
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 [almost equal to]6% per
year or progressive left ventricular dilation in 3% to 4% per year.17,18 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.19 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 20 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 70 years old, with [almost equal to]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 [almost equal to]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.
References
1. Roberts WC. Anatomically isolated aortic valvular disease: the case against
its being of rheumatic etiology. Am J Med. 1970;49:151-159. Bibliographic Links
2. Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy study
of 161 cases. Am J Cardiol. 1984;53:849-855. Bibliographic Links
3. Gray GW, Salisbury DA, Gulino AM. Echocardiographic and color flow Doppler
findings in military pilot applicants. Aviat Space Environ Med. 1995;66:32-34.
Bibliographic Links
4. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency
of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol.
1997;30:1809-1812. Bibliographic Links
5. Clementi M, Notari L, Borghi A, Tenconi R. Familial congenital bicuspid
aortic valve: a disorder of uncertain inheritance. Am J Med Genet. 1996;62:336-338.
Bibliographic Links
6. Brenner JI, Berg KA, Schneider DS, Clark EB, Boughman JA. Cardiac malformations
in relatives of infants with hypoplastic left-heart syndrome. Am J Dis Child.
1989;143:1492-1494. Bibliographic Links
7. Lewin MB, McBride KL, Pignatelli R, Fernbach S, Combes A, Menesses A, Lam W,
Bezold LI, Kaplan N, Towbin JA, Belmont JW. Echocardiographic evaluation of
asymptomatic parental and sibling cardiovascular anomalies associated with
congenital left ventricular outflow tract lesions. Pediatrics. 2004;114:691-696.
8. Roos-Hesselink JW, Scholzel BE, Heijdra RJ, Spitaels SE, Meijboom FJ, Boersma
E, Bogers AJ, Simoons ML. Aortic valve and aortic arch pathology after
coarctation repair. Heart. 2003;89:1074-1077.
9. Sybert VP. Cardiovascular malformations and complications in Turner syndrome.
Pediatrics. 1998;101:E11. Bibliographic Links
10. Fedak PW, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and
pathophysiological implications of a bicuspid aortic valve. Circulation.
2002;106:900-904. Ovid Full Text Bibliographic Links
11. Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG.
Bicuspid aortic valves are associated with aortic dilatation out of proportion
to coexistent valvular lesions. Circulation. 2000;102(suppl III):III-35-III-39.
Ovid Full Text Bibliographic Links
12. Ferencik M, Pape LA. Changes in size of ascending aorta and aortic valve
function with time in patients with congenitally bicuspid aortic valves. Am J
Cardiol. 2003;92:43-46.
13. Roberts CS, Roberts WC. Dissection of the aorta associated with congenital
malformation of the aortic valve. J Am Coll Cardiol. 1991;17:712-716. Bibliographic
Links
14. Nistri S, Sorbo MD, Marin M, Palisi M, Scognamiglio R, Thiene G. Aortic root
dilatation in young men with normally functioning bicuspid aortic valves. Heart.
1999;82:19-22. Ovid Full Text Bibliographic Links
15. Mills P, Leech G, Davies M, Leathan A. The natural history of a non-stenotic
bicuspid aortic valve. Br Heart J. 1978;40:951-957. Bibliographic Links
16. Hansen D, Schmiegelow K, Jacobsen JR. Bacterial endocarditis in children:
trends in its diagnosis, course, and prognosis. Pediatr Cardiol. 1992;13:198-203.
Bibliographic Links
17. Bonow RO, Lakatos E, Maron BJ, Epstein SE. Serial long-term assessment of
the natural history of asymptomatic patients with chronic aortic regurgitation
and normal left ventricular systolic function. Circulation. 1991;84:1625-1635.
Bibliographic Links
18. Borer JS, Hochreiter C, Herrold EM, Supino P, Aschermann M, Wencker D,
Devereux RB, Roman MJ, Szulc M, Kligfield P, Isom OW. Prediction of indications
for valve replacement among asymptomatic or minimally symptomatic patients with
chronic aortic regurgitation and normal left ventricular performance. Circulation.
1998;97:525-534. Ovid Full Text Bibliographic Links
19. Wallby L, Janerot-Sjoberg B, Steffensen T, Broqvist M. T lymphocyte
infiltration in non-rheumatic aortic stenosis: a comparative descriptive study
between tricuspid and bicuspid aortic valves. Heart. 2002;88:348-351.
20. Roberts WC, Ko JM. Frequency of unicuspid, bicuspid and tricuspid aortic
valves by decade in adults having aortic valve replacement for isolated aortic
stenosis. Circulation. 2005;111:920-925.
