European Heart Journal Advance Access originally published online on January 5, 2007
European Heart Journal 2007 28(3):376-379; doi:10.1093/eurheartj/ehl457
© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Relation of aortic root dilatation and age in Marfan's syndrome
Elhadi H. Aburawi*,
and
John O'Sullivan
Department of Paediatric Cardiology, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK
Received 15 April 2006; revised 29 September 2006; accepted 7 December 2006; online publish-ahead-of-print 5 January 2007.
* Corresponding author. Tel: +46 46 17 82 61; fax: +46 46 17 81 50. E-mail address: elhadi.aburawi{at}med.lu.se
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Abstract
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Aims The main aim of this study was to describe the age at which
pathological aortic root dilation occurs in patients with Marfan's
syndrome (MFS).
Methods and results A total of 160 patients with MFS attending a regional cardiac centre were reviewed retrospectively. Dilation of the ascending aorta was diagnosed by comparing the maximum aortic sinus measurement with control data from the literature. We employed a Kaplan–Meier survival curve to estimate the age at which dilatation occurs. The mean age of the total group at presentation was 15.5 years (range 1.5–40 years). Skeletal abnormalities were present in 95%. Eye involvement was found in 18%. In the 115/160 patients with an abnormal aortic root, 78/115 (68%) developed aortic root dilatation before 19 years of age. From the Kaplan–Meier curve, it can be estimated that about 35% of the patients have aortic root dilatation already at the age of 5 years and 70% before the age of 20 years, and at least 80% by 40 years. There were 31 patients with normal aortic root when first seen but 24/31 (77%) developed aortic root dilatation before the age of 19 years and 7/31 (22.6%) after 19 years of age. Of those (seven patients) who developed new pathological aortic root dilatation after age 19 years, the age range was between 21 and 40 years with a mean of 27 years. Overall, 13 patients (8%) had surgery for aortic root replacement.
Conclusion Aortic root dilatation develops early in MFS and was present in 35% by the age of 5 years and 68% by 19 years. Even though new aortic root dilation is relatively rare, it is not possible to safely discharge patients with MFS as about one-third of the patients in our series who developed new pathological aortic root dilation did so after the age of 19 years.
Key Words: Marfan's syndrome • Aorta root • Puberty • Cohort study
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Introduction
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Marfan's syndrome (MFS) is an inherited (autosomal dominant)
disorder of connective tissue, in which the most pronounced
abnormalities occur in the musculoskeletal, cardiovascular,
and ocular systems. It is caused by mutations in the fibrillin
gene locus on chromosome 15 (fibrillin-1).
1,2 The difficulty
with precise diagnosis makes it difficult to give an accurate
population prevalence figure, but it is estimated at approximately
one in 10 000 individuals.
3 Aortic dilatation and dissection
are the major causes of morbidity and mortality and for this
reason all these patients are routinely followed-up and assessed.
If aortic root dilatation develops, more frequent follow-up
is necessary. It is not clear whether continuing follow-up is
required on children and adults whose initial scan/assessment
shows normal aortic root. The following study was undertaken
to describe the age at which aortic root dilatation was diagnosed.
We were particularly interested to observe the progress of those
patients who had normal aortic dimensions at presentation and
to see if and when aortic root dilatation occurred.
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Methods
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Data files of 300 patients who were attending the joint Paediatric
Cardiac and Genetic clinic for MFS were reviewed. A clinical
diagnosis of MFS was made in 160 patients by the clinical genetic
team using the criteria of De Paepe
et al.
4 The follow-up
period was from 1982 to 2000. Follow-up of each individual patient
is defined as the time interval between first and most recent
clinical and echocardiography assessment. Age at first visit,
age at first abnormal aortic root measurement, family history
of MFS, and skeletal abnormalities were retrieved from the notes.
The echocardiography measurements were taken from the cross-sectional image and frozen at end diastole using the parasternal long-axis view. Leading edge to leading edge was used to measure the maximum aortic sinus diameter and sino-tubular junction and these were then plotted on the appropriate body surface area chart.5 All patients who had aortic root diameter exceeding two standard deviations above the mean were started on a B-blocker.6
Statistical analysis
These measured variables were analysed by means of descriptive statistics. All curves and diagrams were performed using Stat View (SAS Inst. 5.0) as a statistical software package.7 The survival analysis technique was employed to account for both left- and right-censored data. We assumed to investigate one variable that is the occurrence of the aortic root dilatation over the whole period of follow-up. It is assessed by including all patients (n = 160) and analysing the age at which the aorta root became dilated over the period of follow-up (event time) vs. the estimated cumulative distribution of having the aortic root dilatation (endpoint). The data was analysed with SAS Lifereg procedure, which fits parametric models to failure time data that can be left, right, or interval censored. The left-censored indicates the patients who are already abnormal when included in the analysis, and the right-censored represents those in whom the event does not occur. Interval-censored indicates in what age-interval the abnormality occurred. For the interval-censored patients, we assume that the event happened in the middle of the interval. Since we used no covariates, we fitted an intercept-only model for the natural logarithm of the response variable with a Weibull distribution for the failure time. The output from the SAS Lifereg procedure is presented as a Kaplan–Meier curve. Descriptive statistics are presented as mean ± standard deviation of the mean.
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Results
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The total number of patients diagnosed as MFS, according to
Ghent criteria, over this time period was 160. It is slightly
more common in males than females (1.4 : 1) and the
age range at first clinic visit was between 1.5 and 38 years,
with a mean of 15.5 years. Family history was positive in 75%.
Skeletal abnormalities were found in 95% in our group and the
eye manifestations as confirmed by ophthalmologists were present
in 29 patients (18%) (
Table 1). Mitral valve prolapse was
found in 29 patients (18%), 32 (20%) had mitral regurgitation,
and 10 patients (6.25%) had more than trivial aortic regurgitation.
Two patients had a secundum atrial septal defect.
Aortic root dilatation, related to body surface area, was found
in 115/160 (72%) and 69 (60%) of them were subsequently prescribed
beta-blockers. Of those with an abnormal aortic root, 78/115
(68%) were less than 19 years of age (
Table 2 and
Figure 1).
A normal aortic root measurement at first visit was found in
76 patients (48%), their age range between 1.5 and 36 years
and a mean of 15 years. Of these 76 patients, 45 (59%) stayed
normal and 31 patients (41%) became abnormal throughout the
period of the study. In those who subsequently became abnormal
(
n = 31), there were 24/31 patients (77.4%) who developed aortic
root dilatation before the age of 19 years and one patient (3.2%)
who developed aortic root dilatation at 5 years, and 7/31 (22.6%)
after 19 years of age. Of those 7 patients who developed new
pathological aortic root dilatation after age 19 years, the
age range was between 21 and 40 years with a mean of 27 years
(
Table 2 and
Figure 2A and
B). The age range of these
patients (
n = 31) was between 5 and 40 years with a mean of
17.6 years (SD 8.4) and the mean length of follow-up was 4.4
years. The range of the progression rate in these patients is
in between 0.06 and 0.7 cm/year with a mean 0.23 cm/year
(SD 0.17).
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Figure 2 (A) Patients (n = 31) with an initially normal aortic measurement but dilatation develops on follow-up. (B) Spaghettis graph represents age and aorta root diameter on follow-up of the same patients as in (A).
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For all patients (
n = 160), aortic root dilatation was diagnosed
in 115/160 patients (72%) over the period of follow-up, mean
6.5 with a range 1–18 years, the age and aorta root diameter
are presented as Spaghettis graph model (
Figure 3). From
the Kaplan–Meier curve (
Figure 4), it can be estimated
that about 35% of the patients have aortic root dilatation already
at the age of 5 years and about 70% before the age of 20 years.
At the age of 40, we estimated that at least 80% of the patients
have aortic root dilatation.
Overall, 13 patients (8%) had surgery for aortic root and six
presented acutely with aortic root dissection that had replacement
with either the suspension or replacement of the aortic valve.
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Discussion
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The prevalence of aortic root dilatation in our population was
72%, which is comparable with other studies. There is little
data on the age at which the aortic dilatation develops.
Table 3 shows the findings of some of the studies
8–18 that address
this. Brown
et al.
12 report a figure of 60% for a group
between 3 and 61 years of age. Kornbluth
et al.
18 showed
that patients with the MFS (age range 14–64 years, mean
30) exhibited aortic dilatation at all ages. Considerable variation
in the severity of aortic dilatation was seen at each age, with
patients as young as 20 years having severe dilatation of the
aorta. Aortic root dilatation was present in 48 of 57 (84%)
of their patients at the time of initial examination. Of these
patients, 34 had follow-up echocardiograms. van Karnebeek
et al.
17 report a prevalence of 83% for aortic root dilatation in children
before the age of 16 years. They showed that in 52 patients,
age range between 1 and 16 years when first seen, followed-up
for a mean of 7.7 years, 43/52 (83%) developed dilatation, and
they found steady decline until the age of 16 years (with a
somewhat steep phase between age 4 and 7 years), after which
only one patient developed dilatation until 25 years. We found
in the group who subsequently develop aortic root dilatation
under our follow-up, 24/31 (77.4%) did so before the age of
19 years and one can conclude therefore the risk for aortic
root dilatation is at its highest during the growth phase. MFS
patients should be monitored quite closely while going through
their growth spurt. However, 7/31 patients (22.6%) developed
aortic root dilatation after the age of 19 years and the oldest
age was to develop new dilatation 40 years after follow-up period
of 4 years.
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Table 3 Prevalence of cardiac/cardiovascular involvement in patients with MFS from literatures review and population study
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The question of how long one needs to perform echocardiographic
follow-up of the aortic root in patients with MFS is a difficult
one and will depend on many factors such as family history of
dissection. The fact that patients with virtually normal aortic
root dimensions can occasionally dissect complicates the issue.
However, our study does provide useful information, as most
patients with MFS will develop aortic root dilatation before
the age of 21 years. One must accept that aortic root dilatation
can occur late although this is a relatively rare occurrence.
Unfortunately, it is not possible to completely reassure a patient
with MFS with regard to the aortic root even if the measurement
is within the normal range at age 21 years.
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Limitations of study
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This is a retrospective study with a limited number of years
of follow-up and the groups were difficult to compare with each
other because they were not statistically designed. The study
was based in one regional cardiac centre, so there may have
been some selection bias that cannot be excluded. A further
limitation is that MRI or CT-scan for dural ectasia, as a major
criterion for diagnosis, was not performed in our population.
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Conclusion
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Aortic root dilatation developed early in MFS, 35% at 5 years
and 68% by 19 years of age in our whole population. However,
there is no age limit beyond which we can safely predict that
the aorta will stay normal and therefore long-term follow-up
is necessary in patients with MFS.
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Acknowledgement
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The authors would like to thank Dr. Anna Audin and Dr Jonas
Björk for their assistance with the statistical analysis.
Conflict of interest: none declared.
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Footnotes
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Present address: Division of Pediatric Cardiology/Department
of Pediatrics, Lund University Hospital, 221 85 Lund, Sweden
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Abstract
Introduction
