Download Bicuspid Aortic Valve Associated With Aortic Dilatation A Community

Bicuspid Aortic Valve Associated With Aortic Dilatation
A Community-Based Study
Vuyisile T. Nkomo, Maurice Enriquez-Sarano, Naser M. Ammash, L. Joseph Melton III,
Kent R. Bailey, Valerie Desjardins, Robin A. Horn, A. Jamil Tajik
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Objective—This study was undertaken to examine the association between bicuspid aortic valve (BAV) and aortic
dilatation in the community. The association between BAV and aortic dilatation has been reported predominantly in
retrospective studies in patients mostly with valvular dysfunction or selected surgical patients from tertiary referral
centers. An independent association of BAV and aortic dilatation in a community-based study has not been
demonstrated.
Methods and Results—In a geographically defined population of Olmsted County, Minnesota, residents with BAV (n⫽44,
age 35⫾13 years) without hemodynamically significant obstruction or regurgitation and matched controls with normal
tricuspid aortic valves were identified by transthoracic echocardiography. The two groups were compared with respect
to measurements of the aorta. The BAV and control groups differed with respect to size of the aortic anulus (23.2⫾2.4
versus 21.6⫾2.4 mm; P⫽0.002), aortic sinus (33.5⫾4.6 versus 30.3⫾4.1 mm; P⫽0.0001), and proximal ascending
aorta (33.3⫾6.5 versus 27.9⫾3.6 mm; P⫽0.0001). There was no difference in the size of the aortic arch (24.2⫾3.6
versus 25.3⫾3.4 mm; P⫽0.16). These differences were maintained when the groups were stratified by sex and blood
pressure. The relationship between bicuspid aortic valve and aortic dilatation was maintained when adjusting for factors
related to fluid mechanics and hemodynamics such as systolic blood pressure, diastolic blood pressure, left ventricular
ejection time, and peak aortic valve velocity.
Conclusions—In a community-based study, BAV is associated with an alteration of aortic dimensions even in the absence
of hemodynamically significant aortic valve stenosis or regurgitation. (Arterioscler Thromb Vasc Biol. 2003;23:351356.)
Key Words: bicuspid aortic valve 䡲 aorta 䡲 dilatation 䡲 epidemiology 䡲 population-based study
B
icuspid aortic valve (BAV) disease is the most frequent
congenital anomaly of the heart or great vessels.1 A
congenital BAV may lead to premature development of
significant aortic valve disease, such as aortic valve stenosis
or regurgitation and endocarditis.1–3 Abnormalities of the
aorta, such as aortic dilatation or dissection, have also been
described in association with BAV. Previously, this association had been described largely in necropsy series in individuals with significant aortic stenosis or regurgitation or in
individuals who had aortic coarctation or concomitant hypertension, a known risk factor for aortic dilatation and dissection.1,4 – 8 Moreover, other large necropsy series of aortic
dissection found no association with BAV in the patients
studied.9 Nonetheless, the presence of BAV in patients with
fatal aortic dissections led to the speculation that BAV is a
risk factor for abnormalities of the aortic wall, independent of
concomitant valvular dysfunction, aortic coarctation, or hypertension.10,11 To this end, important antemortem echocardiographic studies12–15 as well as histological studies16,17 have
suggested an independent association between BAV and
aortic dilatation. However, some of these studies are retrospective and based on referred patients from tertiary centers
mostly with hemodynamically significant aortic valve disease
or surgical patients,12,13,16,17 raising the possibility of referral
bias where patients with BAV and known aortic dilatation or
aneurysm may have been referred for evaluation. In addition,
some of the studies included only males and therefore are not
applicable to females14 or did not measure all levels of the
aortic root.15
The present epidemiologic study was undertaken to determine whether the association between BAV and aortic
dilatation could be demonstrated by echocardiography in a
geographically defined population of males and females at
first diagnosis of BAV without significant stenosis or
regurgitation.
Methods
Subjects
Bicuspid aortic valve cases were from a study entitled Initially
Normally-Functioning Bicuspid Aortic Valve Project approved by
Received November 8, 2002; revision accepted December 23, 2002.
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn.
Correspondence to Maurice Enriquez-Sarano, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail [email protected]
© 2003 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
DOI: 10.1161/01.ATV.0000055441.28842.0A
351
352
Arterioscler Thromb Vasc Biol.
February 2003
Figure 1. Parasternal short-axis view of the aortic valve showing
bicuspid aortic valve with commissures near the 12 o’clock and
6 o’clock positions. Arrows point to right (R) and left (L) aortic
valve cusps.
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the Institutional Review Board at the Mayo Clinic, Rochester,
Minnesota, where subjects gave informed consent to participate. The
study comprises a database of subjects with bicuspid aortic valves
seen at the Mayo Clinic.
The echocardiographic laboratory at the Mayo Clinic is the only
laboratory providing echocardiographic services to the community
of Olmsted County, and patients at first diagnosis of BAV confirmed
by echocardiography were identified and included in this study.
Excluded from this analysis were patients with evidence of aortic
stenosis (aortic velocity ⬎2.5 m/s), more than trivial aortic regurgitation by color Doppler, aortic coarctation, or mitral, pulmonic, or
tricuspid valve disease, cardiomyopathy, pericardial disease, Marfan
syndrome or a family history of Marfan syndrome, or any other form
of congenital heart disease.
To each qualifying case, we matched one Olmsted County control
who underwent echocardiography and was found to have a normal
tricuspid aortic valve and a normal echocardiogram. The same
exclusion criteria were applied to the control group. Controls were
matched for age within 1 year and same sex; among potential
controls, the one chosen had the body surface area closest in value to
the case.
Echocardiographic Methods
Comprehensive 2D and Doppler echocardiographic examinations
were performed by experienced echocardiogram technologists and
reviewed by the echocardiographic laboratory physician. All echocardiograms were performed in a systematic manner by technologists
who were blinded to the study. In addition to the assessment of
cardiac chamber size and function, valve morphology, and function,
a routine comprehensive echocardiographic examination includes
measurements of the aortic dimensions. Aortic valve morphology
was assessed in the parasternal long- as well as short-axis views. The
diagnosis of bicuspid aortic valve was based on previously defined
criteria18 as the presence of only 2 cusps clearly identified in systole
and diastole in the short-axis view (Figure 1). Patients with fusion of
the commissures attributable to rheumatic disease19,20 were not
included as having BAV. Dimensions of the aortic anulus, the
sinuses of Valsalva, and the proximal ascending aorta (measured 1
cm from the sino-tubular junction) were assessed in the parasternal
long-axis view (Figure 2A). Dimensions of the aortic arch were
obtained from the suprasternal view (Figure 2B). Measurements
were made perpendicular to the long axis of the aorta using the
leading edge to leading edge method in views showing the largest
aortic dimensions. Color Doppler was used to assess the presence
and severity of aortic regurgitation,21 and aortic stenosis was
excluded by both pulsed-wave and continuous-wave Doppler. Aortic
stenosis was defined as present when the aortic peak velocity
obtained by continuous-wave Doppler was ⬎2.5 m/s.22 Left ventric-
Figure 2. A, Parasternal long-axis view showing measurement
of the dimensions of the aortic anulus (A), aortic sinus (B), and
proximal ascending aorta (C). B, Suprasternal view showing
measurement of the aortic arch (D); RPA indicates right pulmonary artery.
ular end-diastolic and end-systolic dimensions were assessed by 2D
or M-mode measurements. The ejection fraction was calculated from
the internal dimensions of the left ventricle using the method of
Quinones et al,23 and in the few cases where M-mode or 2D
measurements were unsatisfactory, a visual estimate of ejection
fraction was used.24 Two of the authors (V.T.N and M.E.S) reviewed
the echocardiograms of patients with BAV to confirm the diagnosis
of BAV and the absence of significant valvular disease.
Statistical Analysis
Continuous and categorical variables were compared between the
BAV cases and their matched controls. Differences were assessed
using the paired Student’s t test for continuous variables and the
McNemar’s test for binary variables. A 2-tailed probability value of
⬍0.05 was considered to be statistically significant. Multiple regression analysis was performed to assess the independent association of
hemodynamic parameters (systolic blood pressure, diastolic blood
pressure, left ventricular ejection time, and aortic valve peak velocity) and presence of BAV with aortic dimensions.
Results
Baseline Characteristics
Forty-four BAV cases met the eligibility criteria. They were
matched to an equal number of controls of the same age
(mean, 35⫾13 years), sex (65% male), and body surface area
(1.9⫾0.2 m2). Some of the baseline characteristics of cases
and controls are shown in Table 1. There were differences in
indication for echocardiography regarding murmurs or clicks
between cases and controls. Sixteen BAV cases versus 20
controls (P⫽0.32) complained of palpitations or atypical
chest pain before echocardiography. No case or control had a
history of diabetes, myocardial infarction, stroke, aortic
dissection, or endocarditis. Four cases compared with 6
controls had been diagnosed with hypertension, but their
systolic (122⫾17 versus 123⫾16 mm Hg; P⫽0.67) and
diastolic (77⫾10 versus 72⫾8 mm Hg; P⫽0.08) blood pressures did not differ significantly. Likewise, there was no
difference in the history of current (7 versus 2; P⫽0.41) or
previous (6 versus 5; P⫽0.41) cigarette use. Four patients
with BAV were known to have a family member with BAV
compared with none in the control group (P⫽0.13), but no
case or control had a family history of Marfan syndrome. Ten
Nkomo et al
TABLE 1. Clinical Characteristics of Olmsted County, MN
Residents With BAV and Their Age- and Sex-Matched Controls
Age, mean⫾SD, y
Men, %
Body surface area, m2
Control
(n⫽44)
P
BAV
35⫾13
35⫾13
1.00
N
61
61
1.00
Aortic anulus, mm
1.93⫾0.23
1.91⫾0.23
0.09
Aortic sinus, mm
Proximal ascending aorta, mm
Aortic arch, mm
Systolic murmur
5
2
䡠䡠䡠
353
TABLE 2. Aortic Dimensions by Sex Among Olmsted County, MN
Residents With BAV and Their Age- and Sex-Matched Controls
BAV
(n⫽44)
Indications for echocardiogram, n
Click
Bicuspid Aortic Valve
Control
P
44
44
23.2⫾2.4
21.6⫾2.4
䡠䡠䡠
0.002
33.5⫾4.6
30.3⫾4.1
0.0001
33.3⫾6.5
27.9⫾3.6
0.0001
24.2⫾3.6
25.3⫾3.4
0.16
Both sexes combined
19
13
䡠䡠䡠
Men
LV function
1
9
䡠䡠䡠
N
28
28
Endocarditis
0
0
䡠䡠䡠
Aortic anulus, mm
23.9⫾2.3
22.8⫾1.9
䡠䡠䡠
0.06
Rule out dissection
0
0
䡠䡠䡠
Aortic sinus, mm
35.6⫾3.6
32.3⫾3.4
0.003
Other
19
20
Proximal ascending aorta, mm
34.0⫾6.4
29.1⫾3.1
0.003
Murmur/click vs all others
䡠䡠䡠
40
䡠䡠䡠
40
䡠䡠䡠
0.02
Aortic arch, mm
25.0⫾3.6
26.5⫾3.4
0.16
Ejection click
17
Systolic ejection murmur
33
Physical examination before echo, n
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1.00
Women
3
0.002
N
16
16
14
0.001
Aortic anulus, mm
22.0⫾2.3
19.6⫾1.6
䡠䡠䡠
0.01
Aortic sinus, mm
29.9⫾4.0
26.8⫾2.7
0.03
Proximal ascending aorta, mm
31.7⫾6.8
24.8⫾2.7
0.01
Aortic arch, mm
23.2⫾3.4
23.6⫾2.8
0.68
cases compared with 2 controls (P⫽0.01) had a family
history of coronary artery disease. There was no difference in
laboratory data with regard to serum creatinine (1.0⫾0.2
versus 1.0⫾0.2 mg/dL; P⫽0.63), total cholesterol (211⫾66
versus 184⫾42 mg/dL; P⫽0.11), high-density lipoprotein
(47⫾7 versus 43⫾12 mg/dL; P⫽0.47), or triglycerides
(128⫾98 versus 128⫾117 mg/dL; P⫽0.99), except for
slightly higher serum calcium levels in the cases (9.5⫾0.3
versus 9.3⫾0.4 mg/dL; P⫽0.03).
Echocardiographic Results
There was no statistically significant difference between the
BAV and control groups with respect to left ventricular
ejection fraction (62⫾5% versus 62⫾4%; P⫽0.94), left
ventricular end-diastolic dimensions (51⫾5 versus
49⫾4 mm; P⫽0.06), or left ventricular end-systolic dimensions (32⫾4 versus 31⫾3 mm; P⫽0.30). The left ventricular
mass was similar in both groups (98.6⫾26 versus 92.8⫾18
g/m; P⫽0.4 or 86⫾22 versus 84⫾14 g/m2; P⫽0.9).
The peak aortic velocity was higher in the BAV patients
compared with controls (1.7⫾0.4 versus 1.2⫾0.2 m/s;
P⫽0.0002); however, no BAV case had a peak velocity ⬎2.5
m/s. Left ventricular ejection time was the same in both
groups (291⫾21 versus 291⫾28 ms; P⫽0.99).
Aortic Dimensions and Subgroup Analyses
The dimensions of the aortic root were consistently larger in
patients with BAV compared with controls (Table 2). Of the
aortic root measurements compared, the largest difference
between cases and controls was seen in the dimensions of the
proximal ascending aorta (5.4 mm), and this difference was
more pronounced when only female cases and controls were
considered (6.9 mm) compared with the difference seen
between male cases and controls (4.9 mm). The smallest
statistically significant difference between cases and controls
was in the dimensions of the aortic anulus (1.6 mm).
However, the difference in the aortic anulus dimensions did
not reach statistical significance when only males were
compared in the BAV and control groups (P⫽0.06), although
there was a trend toward a larger aortic anulus in the BAV
group. The differences in aortic root sizes persisted even
when the cases and controls were stratified by blood pressure,
except there was no statistically significant difference in the
aortic anulus in the groups with systolic blood pressure
⬎120 mm Hg (P⫽0.09) (Table 3). There was no consistent
significant difference overall between the BAV and control
groups with respect to dimensions of the aortic arch.
Some hemodynamic parameters do correlate with aortic
root dimensions (Table 4). Both systolic and diastolic blood
pressure are correlated with dimensions of the ascending
aorta and aortic arch. There is an inverse correlation between
TABLE 3. Aortic Dimensions Stratified by Systolic Blood
Pressure (SBP) Among Olmsted County, MN Residents With
BAV and Their Age-, Sex-, and BSA-Matched Controls
BAV
Control
P
17
17
Aortic anulus, mm
22.3⫾2.3
22.2⫾2.2
䡠䡠䡠
0.09
Aortic sinus, mm
34.3⫾4.1
31.6⫾3.5
0.02
Proximal ascending aorta, mm
32.9⫾5.5
29.2⫾3.2
0.03
Aortic arch, mm
24.9⫾2.6
27.1⫾2.7
0.01
SBP⬎120 mm Hg
N
SBPⱕ120 mm Hg
N
26
26
Aortic anulus, mm
23.2⫾2.6
21.1⫾2.4
䡠䡠䡠
0.007
Aortic sinus, mm
33.1⫾5.1
29.3⫾4.2
0.002
Proximal ascending aorta, mm
33.5⫾7.4
26.8⫾3.4
0.001
Aortic arch, mm
23.4⫾3.7
23.7⫾3.2
0.73
354
Arterioscler Thromb Vasc Biol.
February 2003
TABLE 4. Pearson Correlations of Aortic Anulus, Aortic Sinus,
Proximal Ascending Aorta, and Aortic Arch With Age, SBP,
DBP, PV, and ET
Age
SBP
DBP
PV
ET
⫺0.05
0.03
⫺0.04
⫺0.67*
⫺0.07
0.10
0.12
0.26
⫺0.20
⫺0.34*
Case
0.41*
0.08
0.18
⫺0.24
0.31
Control
0.47*
0.29
0.21
⫺0.18
⫺0.25
Case
0.51* ⫺0.04
⫺0.04
⫺0.05
0.20
Control
0.54*
0.35*
0.34* ⫺0.16
Case
0.63*
0.26
0.36*
Control
0.27
0.33*
0.25
Aortic anulus
Case
Control
Aortic sinus
Proximal ascending aorta
⫺0.33*
Aortic arch
0.56*
0.37
⫺0.002
⫺0.10
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SBP indicates systolic blood pressure; DBP, diastolic blood pressure; PV,
peak velocity across the aortic valve; ET, left ventricular ejection time.
*P⬍0.05.
peak velocity and aortic anular dimensions in cases, and
ejection time is inversely correlated with dimensions of the
anulus and proximal ascending aorta in the control group. In
multiple regression analysis with factors related to fluid
mechanics as independent variables (systolic blood pressure,
diastolic blood pressure, peak velocity, and left ventricular
ejection time), the presence of a bicuspid aortic valve remained a statistically significant independent predictor of
aortic dimensions (aortic anulus, P⬍0.0001; aortic sinus,
P⫽0.0002; proximal ascending aorta, P⬍0.0001; aortic arch,
P⫽NS). Peak velocity was inversely related to dimensions of
the aortic anulus (P⫽0.0009) and proximal ascending aortic
dimensions (P⫽0.02). Systolic blood pressure, diastolic
blood pressure, and ejection time were not associated with
aortic dimensions in multiple regression analyses.
Discussion
The present epidemiologic community-based echocardiographic study shows that patients with a bicuspid aortic valve
without hemodynamically significant stenosis or regurgitation have a larger aortic anulus, aortic sinus, and proximal
ascending aorta compared with controls with normal tricuspid
aortic valves. The two groups were matched with respect to
age, sex, and body surface area to eliminate confounding,
because these variables do influence aortic dimensions.25,26 In
addition, none of the BAV cases or controls had Marfan
syndrome or a family history of Marfan syndrome, and the
prevalence of hypertension in each group was low. Both cases
and controls are from a geographically defined population of
Olmsted County, Minnesota, which helps eliminate geographic variation and reduce referral bias inherent in studies
from tertiary medical centers. Importantly, none of the BAV
patients were referred to the echocardiography laboratory
because of aortic dilatation.
There is biologic rationale and data to support the idea of
intrinsic aortic disease in the presence of BAV. The left
ventricular outflow tract, aortic cusps, arterial media of the
ascending aorta, and aortic arch and its branches are embryologically linked and originate from the neural crest.27–29
Disorders of the neural crest have been implicated in the
development of cervicocephalic arterial dissections,30 and a
familial cluster of aorto-cervicocephalic arterial dissection
and BAV has also been described,29 raising the possibility of
an underlying neural crest defect in the development of both
conditions. Experimental mice deficient in endothelial NO
synthase, which synthesizes endothelium-derived NO, were
found to have a significantly high incidence of BAV (42%)
compared with the control wild-type mice (0%).31 Endothelium-derived NO plays a role in cell growth and apoptosis as
well as postdevelopmental vascular remodeling, angiogenesis, and limb vascular formation during embryogenesis.32,33
These data suggest that the genetic determinants of BAV are
linked to the genetic determinants of arterial abnormalities. In
addition, noninflammatory and nonatherosclerotic premature
medial layer smooth muscle cell apoptosis was found and
proposed to be a mechanism responsible for aortopathy in
patients with BAV (mean age, 42⫾17 years) with or without
aortic dilatation.16 Recently, various degrees of medial abnormalities of the ascending aorta determined by light and
electron microscopy were found to be common in patients
with BAV compared with controls with tricuspid aortic
valves in a study of great arterial walls in congenital heart
disease.17
The peak aortic velocity was higher in the BAV patients
compared with controls (1.7⫾0.4 versus 1.2⫾0.2 m/s;
P⫽0.0002), raising the possibility of altered hemodynamic
factors, such as high-frequency vibrations, as the mechanism
for altered aortic dimensions in the BAV group.34 Turbulent
flow is known to cause disturbances in vascular endothelial
cells that eventually lead to apoptosis for the initiation of
atherosclerosis.35 Demonstration of whether turbulent flow is
important in initiating noninflammatory and nonatherosclerotic medial layer smooth muscle cell apoptosis is beyond the
scope and design of the current study.16 In multiple regression
analysis adjusting for factors related to fluid mechanics,
however, the presence of a bicuspid aortic valve remained a
statistically significant independent predictor of aortic
dimensions.
Bicuspid aortic valve disease is a common congenital
cardiac disorder affecting ⬇1% to 2% of the general population,1 and its association with intrinsic aortic disease is
important given the complications of aortic dissection and
death. Prospective studies in patients with BAV are required
to determine the natural history and rate of progression of
aortic dilatation and to determine whether early intervention,
such as ␤-blocker therapy, is of any clinical and prognostic
significance.14 Management with ␤-blockers retards aortic
root dilatation and improves survival in patients with Marfan
syndrome.36,37 The present study shows that aortic root
dilatation in both males and females with BAV occurs in the
absence of hemodynamically significant aortic valve disease.
The aortic root dimensions in the BAV group, however, were
not markedly enlarged or aneurysmal, suggesting subclinical
disease. Multiple regression analyses maintain the association
between aortic root dimensions and the presence of bicuspid
aortic valve, even when factors related to fluid mechanics are
Nkomo et al
taken into consideration. We believe the demonstration of the
association between BAV and aortic dilatation in a nonsurgical community-based study population of both males and
females adds valuable data to the growing body of literature,
supporting an intrinsic abnormality of the aorta in patients
with BAV.
Limitations
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Subjects for this study were not randomly identified from
a cross-sectional sampling of the community of Olmsted
County but were identified at the time of echocardiography. However, to randomly identify the 1% to 2% of BAV
in the community and further limit it to those without
hemodynamically significant disease is impractical. The
Rochester Epidemiology Project38 allowed for capturing of
relatively unselected cases at first presentation to primary
medical care providers in a geographically defined population of Olmsted County. There was a difference in
referral for echocardiography between cases and control,
as shown in Table 1 (more clicks and systolic murmurs in
the BAV group); however, this is a reflection of the
bicuspid valve, and hemodynamically significant valve
disease was excluded in the analysis. In addition, although
referral bias (more clicks and systolic murmur in BAV
versus control) was not completely eliminated, for reasons
already mentioned, none of the BAV subjects were referred for echocardiography because of aortic dilatation,
which would bias the association under study. Loss of
statistical differences in anular dimensions in subgroup
analysis (males only or SBP ⬎120 mm Hg) could be
secondary to a smaller number of patients in the
subgroups.
Although below the value considered to define stenosis, the
peak flow velocity across the aortic valve in the BAV group
was higher compared with the control group. This raises the
issue of poststenotic dilatation as a potential mechanism of
aortic dilatation. However, in aortic valve stenosis, the
occurrence of poststenotic dilatation is inconsistent, and
aortic dilatation does not correlate well with degree of aortic
stenosis.34 In addition, multiple regression analysis confirmed
the independent association of BAV and larger aortic dimensions. Patients with trivial aortic regurgitation (n⫽15) were
included in this analysis because this degree of regurgitation
is usually considered insignificant and does not modify the
stroke volume in any significant way and therefore should not
influence aortic dimensions. The present study design, however, does not discount turbulent flow as a potential trigger or
aggravator of cellular events that ultimately manifest as aortic
dilatation in BAV.
References
1. Roberts WC. The congenitally bicuspid aortic valve: a study of 85
autopsy cases. Am J Cardiol. 1970;26:72– 83.
2. Roberts WC. Living with a congenitally bicuspid aortic valve [editorial].
Am J Cardiol. 1989;64:1408 –1409.
3. Roberts WC, Morrow AG, McIntosh CL, Jones M, Epstein SE. Congenitally bicuspid aortic valve causing severe, pure aortic regurgitation
without superimposed infective endocarditis: analysis of 13 patients
requiring aortic valve replacement. Am J Cardiol. 1981;47:206 –209.
Bicuspid Aortic Valve
355
4. Edwards WD, Leaf DS, Edwards JE. Dissecting aortic aneurysm associated with congenital bicuspid aortic valve. Circulation. 1978;57:
1022–1025.
5. Anagnostopoulos CE, Prabhakar MJ, Kittle CF. Aortic dissections and
dissecting aneurysms. Am J Cardiol. 1972;30:263–273.
6. Murray CA, Edwards JE. Spontaneous laceration of ascending aorta.
Circulation. 1973;47:848 – 858.
7. Roberts WC. The hypertensive diseases: evidence that systemic hypertension is a greater risk factor to the development of other cardiovascular
diseases than previously suspected. Am J Med. 1975;59:523–532.
8. Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy
study of 161 cases. Am J Cardiol. 1984;53:849 – 855.
9. Wilson SK, Hutchins GM. Aortic dissecting aneurysms: causative factors
in 204 subjects. Arch Pathol Lab Med. 1982;106:175–180.
10. McKusick VA. Association of congenital bicuspid aortic valve and Erdheim’s cystic medial necrosis. Lancet. 1972;1:1026 –1027.
11. Lindsay J Jr. Coarctation of the aorta, bicuspid aortic valve and abnormal
ascending aortic wall. Am J Cardiol. 1988;61:182–184.
12. Hahn RT, Roman MJ, Mogtader AH, Devereux RB. Association of aortic
dilation with regurgitant, stenotic and functionally normal bicuspid aortic
valves. J Am Coll Cardiol. 1992;19:283–288.
13. 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:
III35–II39.
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.
15. Pachulski RT, Weinberg AL, Chan KL. Aortic aneurysm in patients with
functionally normal or minimally stenotic bicuspid aortic valve. Am J
Cardiol. 1991;67:781–782.
16. Bonderman D, Gharehbaghi-Schnell E, Wollenek G, Maurer G,
Baumgartner H, Lang IM. Mechanisms underlying aortic dilatation in
congenital aortic valve malformation. Circulation. 1999;99:2138 –2143.
17. Niwa K, Perloff JK, Bhuta SM, Laks H, Drinkwater DC, Child JS, Miner
PD. Structural abnormalities of great arterial walls in congenital heart
disease: light and electron microscopic analyses. Circulation. 2001;103:
393– 400.
18. Brandenburg RO Jr, Tajik AJ, Edwards WD, Reeder GS, Shub C, Seward
JB. Accuracy of 2-dimensional echocardiographic diagnosis of congenitally bicuspid aortic valve: echocardiographic-anatomic correlation in
115 patients. Am J Cardiol. 1983;51:1469 –1473.
19. Passik CS, Ackermann DM, Pluth JR, Edwards WD. Temporal changes
in the causes of aortic stenosis: a surgical pathologic study of 646 cases.
Mayo Clin Proc. 1987;62:119 –123.
20. Rose AG. Etiology of acquired valvular heart disease in adults: a survey
of 18,132 autopsies and 100 consecutive valve-replacement operations.
Arch Pathol Lab Med. 1986;110:385–388.
21. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic
insufficiency by Doppler color flow mapping. J Am Coll Cardiol. 1987;
9:952–959.
22. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association
of aortic-valve sclerosis with cardiovascular mortality and morbidity in
the elderly. N Engl J Med. 1999;341:142–147.
23. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB,
Winters WL Jr, Ribeiro LG, Miller RR. A new, simplified and accurate
method for determining ejection fraction with two-dimensional echocardiography. Circulation. 1981;64:744 –753.
24. Amico AF, Lichtenberg GS, Reisner SA, Stone CK, Schwartz RG,
Meltzer RS. Superiority of visual versus computerized echocardiographic
estimation of radionuclide left ventricular ejection fraction. Am Heart J.
1989;118:1259 –1265.
25. Roman MJ, Devereux RB, Kramer-Fox R, O’Loughlin J. Twodimensional echocardiographic aortic root dimensions in normal children
and adults. Am J Cardiol. 1989;64:507–512.
26. Vasan RS, Larson MG, Levy D. Determinants of echocardiographic
aortic root size: the Framingham Heart Study. Circulation. 1995;91:
734 –740.
27. Rosenquist TH, Beall AC, Modis L, Fishman R. Impaired elastic matrix
development in the great arteries after ablation of the cardiac neural crest.
Anat Rec. 1990;226:347–359.
28. Kappetein AP, Gittenberger-de Groot AC, Zwinderman AH, Rohmer J,
Poelmann RE, Huysmans HA. The neural crest as a possible pathogenetic
factor in coarctation of the aorta and bicuspid aortic valve. J Thorac
Cardiovasc Surg. 1991;102:830 – 836.
356
Arterioscler Thromb Vasc Biol.
February 2003
29. Schievink WI, Mokri B. Familial aorto-cervicocephalic arterial dissections and congenitally bicuspid aortic valve. Stroke. 1995;26:
1935–1940.
30. Schievink WI, Michels VV, Mokri B, Piepgras DG, Perry HO. Brief
report: a familial syndrome of arterial dissections with lentiginosis.
N Engl J Med. 1995;332:576 –579.
31. Lee TC, Zhao YD, Courtman DW, Stewart DJ. Abnormal aortic valve
development in mice lacking endothelial nitric oxide synthase. Circulation. 2000;101:2345–2348.
32. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC.
Direct evidence for the importance of endothelium-derived nitric oxide in
vascular remodeling. J Clin Invest. 1998;101:731–736.
33. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C,
Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric
oxide synthase modulates angiogenesis in response to tissue ischemia.
J Clin Invest. 1998;101:2567–2578.
34. Jarchow B, Kincaid O. Poststenotic dilatation of the ascending aorta: its
occurrence and significance as a roentgenologic sign of aortic stenosis.
Mayo Clin Proc. 1961;36:23–33.
35. Freyberg MA, Kaiser D, Graf R, Buttenbender J, Friedl P. Proatherogenic
flow conditions initiate endothelial apoptosis via thrombospondin-1 and
the integrin-associated protein. Biochem Biophys Res Commun. 2001;
286:141–149.
36. Haouzi A, Berglund H, Pelikan PC, Maurer G, Siegel RJ. Heterogeneous
aortic response to acute beta-adrenergic blockade in Marfan syndrome.
Am Heart J. 1997;133:60 – 63.
37. Silverman DI, Burton KJ, Gray J, Bosner MS, Kouchoukos NT, Roman
MJ, Boxer M, Devereux RB, Tsipouras P. Life expectancy in the Marfan
syndrome. Am J Cardiol. 1995;75:157–160.
38. Melton LJ 3rd. History of the Rochester Epidemiology Project. Mayo
Clin Proc. 1996;71:266 –274.
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Bicuspid Aortic Valve Associated With Aortic Dilatation: A Community-Based Study
Vuyisile T. Nkomo, Maurice Enriquez-Sarano, Naser M. Ammash, L. Joseph Melton III, Kent
R. Bailey, Valerie Desjardins, Robin A. Horn and A. Jamil Tajik
Arterioscler Thromb Vasc Biol. 2003;23:351-356; originally published online January 9, 2003;
doi: 10.1161/01.ATV.0000055441.28842.0A
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