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Isolated mitral valve prolapse is an independent
predictor of aortic root size in a general
population
Jose
´R. Matos-Souza1†, Mariana E. Fernandes-Santos1†, Eduardo L. Hoehne2,
Kleber G. Franchini1, and Wilson Nadruz Jr1*
1
Department of Internal Medicine, School of Medicine, University of Campinas, Cidade Universita
´ria ‘Zeferino Vaz’, 13081-970 Campinas, SP, Brazil; and
2
Department of Preventive
Medicine, School of Medicine, University of Campinas, Brazil
Received 30 September 2009; accepted after revision 24 November 2009; online publish-ahead-of-print 17 December 2009
Aims Mitral valve prolapse (MVP) is associated with aortic root (AoR) enlargement in patients with inherited connective
tissue disorders. This report evaluated whether MVP is related to AoR dimension in a large population with other-
wise normal echocardiographic parameters.
Methods
and results
We retrospectively analysed echocardiograms performed by a single echocardiographer between 2001 and 2007 for
various clinical indications. Six hundred and twenty-seven subjects with isolated MVP were found and then matched
by sex, age, and body mass index to 627 individuals without MVP. The whole sample included 454 men and 800
women with an average age of 37.9 +0.3 years and a body mass index of 23.7 +0.1 kg/m
2
. MVP subjects had a
higher AoR diameter (30.4 +0.1 vs. 29.5 +0.1 cm; P,0.0001) compared with controls. Furthermore, multivariate
analyses demonstrated an independent association between MVP and AoR size (P,0.0001) in a model that included
age, gender, body mass index, body surface area, blood pressure levels, and left ventricular mass index as confounding
variables.
Conclusion Isolated MVP is an independent predictor of greater AoR size in a large population with otherwise normal echocar-
diographic parameters.
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Keywords Mitral valve prolapse †Aortic root †Echocardiography
Introduction
Mitral valve prolapse (MVP) is a common echocardiographic vari-
ation that may be detected in 2 – 4% of some populations.
1
Although MVP is most frequently a primary condition,
2,3
it has
been often associated with osteoarticular abnormalities, such
shallow chest and articular hypermobility, leading to the suggestion
that MVP might be actually a manifestation of collagen
modification.
1
In accordance with this assumption, MVP is also associated with
heritable disorders of connective tissue, such as Marfan and
Ehlers–Danlos syndromes.
4
Although subjects with such disorders
comprise ,1–2% of MVP cases,
4
they provide relevant
information regarding the potential phenotypic spectrum related
to MVP. In this context, several lines of evidence demonstrated
that aortic root (AoR) dilatation is usually seen along with MVP
in subjects with heritable disorders of connective tissue,
5–7
indicat-
ing that abnormalities in mitral valve and AoR structures may rep-
resent a phenotypic continuum. Nevertheless data available to date
have failed to detect significant changes in AoR diameter in sub-
jects with primary MVP.
6,8 – 11
It is noteworthy, however, that
these aforementioned studies included a small number of subjects,
which probably limited the statistical power of such analyses. Thus,
the aim of the present report was to evaluate whether the pres-
ence of MVP influences AoR dimension in a large sample of sub-
jects with normal AoR size and normal cardiac parameters.
†Both authors contributed equally to this study.
*Corresponding author. Tel: þ55 19 3521 7836, Fax: þ55 19 3521 7836, Email: wilnj@fcm.unicamp.br
Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2009. For permissions please email: journals.permissions@oxford journals.org.
European Journal of Echocardiography (2010) 11, 302–305
doi:10.1093/ejechocard/jep219
by guest on November 29, 2016Downloaded from
Methods
Study population
We performed a retrospective analysis of echocardiogramsperformed by a
single echocardiographer (Dr Matos-Souza) between January 2001 and
March 2007 for various clinical indications at a single cardiology/echocardio-
graphy centre. Inclusion criteria were age over 18 years and normal left ven-
tricular and left atrial (LA) dimensions according to the A mericanSociety o f
Echocardiography.
12
Echocardiographic exclusion criteria were: (i) valvular
disease, except MVP or minimal mitral regurgitation; (ii) left ventricular
hypertrophy, defined as left ventricular mass index .110 g/m
2
for
women and .125 g/m
2
for men;
13
(iii) signs of left ventricular diastolic, sys-
tolic, or segmental dysfunction; (iv) signs of pulmonary hypertension; (v)
congenital heart disease; and (vi) AoR dilatation. The study was approved
by the Ethics Committee of the University of Campinas.
Six hundred and twenty-seven subjects with isolated MVP fulfilled the
inclusion criteria for the study. A similar number of individuals without
MVP matched by sex, age, and body size were then randomly selected
as controls from the database. Clinical evaluated variables were
extracted from patient records and included age, sex, height, weight,
and blood pressure levels. Body mass index was calculated as body
weight divided by height squared (kg/m
2
), while body surface area was
calculated according to the Dubois formula. Blood pressure was
measured using mercury sphygmomanometers with the subjects in
the sitting position before the echocardiographic examination.
Echocardiography
Echocardiography studies were performed on each subject at rest in
the left lateral decubitus position using a Vivid 3 apparatus (General
Electric) equipped with a 2.5 MHz transducer as previously
described.
14
AoR and LA diameters as well as left ventricular mass
were assessed according to the American Society of Echocardiography
recommendations.
12
AoR diameter was measured at the level of Val-
salva’s sinuses by M-mode tracings under two-dimensional control as
the maximal distance between the two leading edges of the anterior
and posterior AoR walls, while LA maximal diameter was measured
in the anteroposterior position. The reproducibility of measuring
AoR and LA diameters and left ventricular mass as well as diagnosing
MVP was determined in recordings obtained from 20 healthy subjects
(10 with MVP). Intraobserver left ventricular mass, LA diameter, and
AoR diameter variabilities were ,6, ,4, and ,3% respectively,
whereas interobserver variabilities of these parameters were ,10,
,7, and ,5% respectively. Intraobserver and interobserver corre-
lations for echocardiographic MVP diagnosis was .0.90.
The echocardiographic criterion for the diagnosis of MVP was based
on that reported by Freed et al.
15
Briefly, subjects were classified as
having MVP if displacement of mitral leaflets exceeded 2 mm. AoR
was considered normal when its diameter was equal to or smaller
than 36 mm in women and 39 mm in men. These cut-off points
were below the 98th percentile values in a group of 356 normotensive,
non-obese (body mass index between 20 and 25 kg/m
2
), apparently
normal adults (196 women and 160 men; mean age 56.0 +0.6
years) evaluated in the same unit for a cardiovascular check-up in
the previous 3 years.
16
The thickness of the mitral leaflets during dia-
stasis was measured from the leading to the trailing edge of the thickest
area of the midportion of the leaflet, excluding focal areas of thickness
and chordae.
15
Statistical analysis
Descriptive statistical results are given as the mean+standard error.
x
2
test and unpaired t-test were used to compare categorical and con-
tinuous variables, respectively. Univariate correlations between vari-
ables were assessed by Pearson’s or Spearman’s methods. Multiple
linear regression analysis with stepwise forward method was used to
assess the independent relationships between AoR and studied par-
ameters. A P-value of ,0.01 was considered significant.
Results
Clinical and echocardiographic features of the studied sample are
shown in Table 1. Although no differences in age, sex, anthropo-
metric measurements, blood pressure levels, and left ventricular
mass index were detected, subjects with MVP presented higher
AoR diameter, AoR/body surface area, as well as a lower LA diam-
eter in comparison to controls. Among subjects with MVP, 55%
(n¼345) presented mitral valve leaflets thickening 5 mm.
However, no differences in clinical and echocardiographic features
were detected between MVP individuals with thickened leaflets
...............................................................................................................................................................................
Table 1 Characteristics of studied subjects
Variable All (n51254) MVP (n5627) Controls (n5627) P
Age, years 37.9 +0.3 37.9 +0.5 37.9 +0.4 NS
Sex, male/female 454/800 227/400 227/400 NS
Height, cm 166.9 +0.3 167.5 +0.4 166.4 +0.5 NS
Weight, kg 66.2 +0.4 66.3 +0.5 66.2 +0.5 NS
Body mass index, kg/m
2
23.7 +0.1 23.6 +0.1 23.9 +0.1 NS
Body surface area, m
2
1.75 +0.01 1.76 +0.01 1.75 +0.01 NS
Systolic blood pressure, mmHg 125.0 +0.6 124.7 +0.7 125.3 +0.8 NS
Diastolic blood pressure, mmHg 79.8 +0.3 79.5 +0.4 80.1 +0.4 NS
Left atrium diameter, mm 31.8 +0.1 31.3 +0.1 32.2 +0.1 ,0.0001
AoR diameter, mm 30.0 +0.1 30.4 +0.1 29.5 +0.1 ,0.0001
AoR/body surface area, mm/m
2
17.06 +0.06 17.27 +0.08 16.86 +0.08 ,0.0001
Left ventricular mass index, g/m
2
89.1 +0.5 89.2 +0.6 89.1 +0.6 NS
AoR, aortic root; MVP, mitral valve prolapse. NS, non-significant. P-values are related to the comparison between MVP vs. controls.
Mitral prolapse and aortic root size 303
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and MVP subjects with valve leaflets thickening ,5 mm (data not
shown).
Univariate regression analyses were performed in order to
evaluate relationships between AoR diameter and clinical/echocar-
diographic variables (Table 2). AoR diameter exhibited a direct cor-
relation with MVP in the whole sample (r¼0.13; P,0.0001),
while age, male gender, height, weight, body mass index, body
surface area, blood pressure levels, and left ventricular mass
index displayed significant correlation coefficients with AoR diam-
eter in the whole sample as well as in both studied subgroups (r
0.20–0.60; all P,0.0001).
A stepwise regression model was constructed to evaluate the
independent contribution of different factors to AoR size
(Table 3). This model included age, gender, body mass index,
body surface area, systolic blood pressure, diastolic blood
pressure, left ventricular mass index, and the presence of MVP
as independent variables. Male gender and age were found to be
the foremost predictors of AoR diameter, while left ventricular
mass index and MVP contributed to explain its variance to a
lesser extent.
Discussion
MVP and enlarged AoR frequently coexist in patients with inher-
ited connective tissue disorders, indicating that these echocardio-
graphic alterations may represent a phenotypic continuum.
5–7
Previous studies have also investigated whether AoR diameter is
increased in individuals with primary MVP.
6,8 – 11
Nevertheless,
they failed to find significant differences in AoR diameter according
to the presence or not of MVP. Noticeably, these latter reports
enrolled a small number of subjects with isolated MVP, which
varied from 10 to 100 individuals per study. Such feature probably
limited the statistical power of the analysis. In the present report
we evaluated a much larger sample (627 subjects with isolated
MVP) and detected higher average AoR diameter and AoR/body
surface area compared with measurements obtained from a
similar number of individuals without MVP. In addition, results of
multivariate analysis revealed that MVP was an independent predic-
tor of greater AoR diameter in the whole sample. Overall, these
data support the notion that alterations in mitral valve and AoR
structure may indeed comprise a phenotypic continuum even in
individuals with isolated MVP. In accordance with this hypothesis,
previous studies have also described decreased elastic properties
in the aorta of subjects with MVP.
17,18
One potential limitation to the assumption that greater AoR size
is related to isolated MVP was that we did not know whether the
enrolled individuals had diagnoses of inherited connective tissue
disorders, since there were a variety of reasons for examination
referral. Thus, inclusion of subjects with such diseases in the
MVP group could have contributed to increase the average AoR
diameter in this population.
5–7
However, this hypothesis seems
less probable since primary MVP is much more prevalent than sec-
ondary MVP to established connective tissue disorders.
2,3,19
In this
context, it has been estimated that no more than 1 – 2% of patients
with MVP have an associated connective tissue disorder.
4
More-
over, the presence of MVP in adults with heritable disorders of
connective tissue is usually associated with AoR dilatation,
5 – 7,20
an echocardiographic feature excluded from our analysis.
It was noteworthy that MVP subjects presented a smaller LA
diameter in comparison to controls. However, we believe that
this finding might not a represent a real reduction in LA dimension.
LA diameter was measured in the anteroposterior position
according to echocardiographic guidelines.
12
Noticeably, this
evaluation may subestimate LA dimension since expansion of the
LA can be limited by the thoracic cavity between the sternum
and the spine. In this regard, increases in the AoR diameter are
known to compress the adjacent LA, leading to a reduction in
the anteroposterior diameter of this latter chamber.
21
Given that
the MVP and control groups had a similar body size, it is possible
that the higher AoR diameter in the MVP group was responsible
for the observed lower LA size in this population. This hypothesis
is further supported by our findings showing that the average
increase in AoR diameter in MVP was of 0.9 cm, which was
quite comparable to the average decrease in LA diameter in com-
parison to controls.
....................................................
...............................................................................
Table 2 Univariate correlations of aortic root
diameter
Variable AoR diameter (r)
All
(n51254)
MVP
(n5627)
Controls
(n5627)
Age 0.27 0.26 0.30
Male gender 0.49 0.46 0.53
Height 0.45 0.38 0.51
Weight 0.50 0.43 0.59
Body mass index 0.34 0.27 0.46
Body surface area 0.52 0.45 0.60
Systolic BP 0.21 0.21 0.20
Diastolic BP 0.22 0.22 0.21
LV mass index 0.33 0.30 0.36
MVP 0.13 – –
AoR, aortic root; MVP, mitral valve prolapse; BP, blood pressure; LV, left
ventricular. All P-values were ,0.0001.
................................................................................
Table 3 Stepwise regression analysis
Step Variable R
2
change Fratio P
Aortic root size (dependent)
1 Male gender 0.241 395.9 ,0.0001
2 Age 0.087 161.9 ,0.0001
3 Body surface area 0.051 103.1 ,0.0001
4 Left ventricular mass
index
0.030 62.4 ,0.0001
5 Mitral valve prolapse 0.014 30.0 ,0.0001
Body mass index, systolic blood pressure and diastolic blood pressure did not
improve the model.
J.R. Matos-Souza et al.304
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Some potential limitations of the present study deserve further
comments. First, our data were extracted from databases, there-
fore, the examinations or the diagnoses could not be reviewed.
However, we reduced this bias by only including exams carried
out by a single echocardiographer. Moreover, intraobserver and
interobserver correlations were performed and revealed high
reproducibility in echocardiographic examinations. Second, we
had no access to clinical features such as prevalence of hyperten-
sion, smoking, and diabetes, which are acknowledged markers of
cardiovascular risk. Nevertheless, several reports have demon-
strated that these variables are not consistent determinants of
AoR size,
22 – 25
suggesting that the lack of clinical characterization
on these topics played no major influence in our results.
In conclusion, the present report demonstrated that MVP is an
independent determinant of the greater AoR size in a large popu-
lation with otherwise normal echocardiographic parameters. This
result supports the notion that alterations in the mitral valve and
AoR structures may represent a phenotypic continuum in subjects
with isolated MVP.
Conflict of interest: none declared.
Funding
This study was sponsored by grants from Fundac¸a˜o de Amparo a
`Pes-
quisa do Estado de Sa˜o Paulo (Proc. 05/56986-5) and Conselho Nacio-
nal de Desenvolvimento Cientı
´fico e Tecnolo
´gico (Proc. 304329/06-1
and 474206/07-6), Brazil.
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