1-s2.0-S000291490602073X-main

Effect of Beta-Blockade on Ascending Aortic Dilatation in Children
With the Marfan Syndrome
Magalie Ladouceur, MD
a
, Christophe Fermanian, PhD
b
, Jean-Marc Lupoglazoff, MD
c
,
Thomas Edouard, MD
d
, Yves Dulac, MD
e
, Philippe Acar, MD
e
, Suzel Magnier, MD
c
, and
Guillaume Jondeau, MD, PhD
a,f,
*
Aortic root dilatation is the principal life-threatening complication in Marfan syndrome,
leading to aortic regurgitation, dissection, and rupture. Beta blockade slows aortic dilata-
tion in adults, but there has been no definitive evidence in children. Therefore, the evolution
of aortic diameter at the level of the sinuses of Valsalva in 155 children (82 males, 73
females) aged <12 years who had been diagnosed with Marfan syndrome according to
international criteria was retrospectively studied. Affected children treated by ␤blockade
>1 time during their lives (n ⴝ77, mean age at diagnosis 6.1 ⴞ3.2 years) were compared
with affected children who had never received ␤blockers (n ⴝ78; 42 males, mean age 7.4 ⴞ
5.2 years). A mean delay of 1.3 years was observed between diagnosis and the initiation of
␤blockade in the treated group (mean age at initiation 7.5 years). At the time of diagnosis,
aortic diameters were similar in the 2 groups, but after 1.3 years, aortic diameters were
greater in the group of children in whom ␤blockers had been initiated. On univariate
analysis, aortic diameter was related to age and height, but not gender or familial history
of aortic dissection. On multivariate analysis, treatment and age remained significant
determinants of aortic diameter. Beta blockade significantly decreased the rate of aortic
dilatation at the level of the sinuses of Valsalva by a mean of 0.16 mm/year (p <0.05), an
effect that increased with treatment duration. A trend toward lower cardiac mortality,
decreased need for preventive aortic surgery, and less dissection was observed. In conclu-
sion, ␤blockade appears to limit aortic dilatation during childhood in patients affected by
Marfan syndrome. Therefore, this treatment should be recommended as soon as the diagnosis
is made. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:406 – 409)
In a prospective, randomized study of 70 patients with
Marfan syndrome (MS) aged ⬎12 years, ␤ blockers were
shown to slow aortic root dilatation, with an associated
trend toward decreased cardiovascular morbidity and mor-
tality.
1
No such randomized trials have been performed in
children, but benefits were reported in 2 small retrospective
studies that were not limited to patients aged ⬍12 years.
2,3
We therefore studied the impact of ␤ -blocker therapy on the
evolution of aortic diameter in a large group of children
aged ⬍12 years affected by MS to evaluate potential ben-
efits from introducing therapy earlier during the evolution of
the disease.
Methods
Patients: The study population included 155 children
with MS according to international criteria
4
evaluated at 1
of 3 centers with MS outpatient clinics in France (Hôpital
Ambroise Paré, Boulogne; Hôpital Robert Debré, Paris; and
Hôpital des Enfants, Toulouse). Only patients aged ⬍12
years at diagnosis, without neonatal MS, were considered.
Children aged ⬎12 years old when taking
␤ blockers for the
first time were excluded, as were children receiving angio-
tensin-converting enzyme inhibitors.
Clinical evaluation: All patients underwent complete
clinical evaluations, including anthropometrics measure-
ments, split-lamp examinations, and echocardiography.
Measurement of aortic diameter: Aortic dilatation was
defined as an aortic diameter greater than the mean ⫹2SD
according to Roman’s nomograms based on age and body size
5
or by the ratio of the diameters at the sinuses of Valsalva and
at the annulus of 1.45.
6
Aortic diameters were measured every
year using echocardiography in a standardized fashion and
generally by a single investigator at each center. Measurements
of the aortic root were made in 2-dimensional, parasternal, and
long-axis views at end-diastole using the leading edge-to-lead-
ing edge technique. Aortic diameter at 4 levels, including the
annulus (diameter 1), the sinuses of Valsalva (diameter 2), the
sinotubular junction (diameter 3), and the proximal ascending
aorta (diameter 4), were recorded. The ratio of the diameter at
a
Consultation Marfan, Hôpital Ambroise Paré Assistance-Publique Ho-
pitaux de Paris;
b
Unité de Recherche Clinique, Hôpital Ambroise Paré,
Boulogne Billancourt;
c
Service de Cardiologie, Hôpital Robert Debré,
Paris;
d
Service d’Endocrinologie Pédiatrique and
e
Service de Cardiologie
Pédiatrique, Hôpital des Enfants, Toulouse; and
f
Faculté de Médecine Paris
Ile de France Ouest, Universite de Versailles Saint-Quentin, Garches,
France. Manuscript received June 1, 2006; revised manuscript received and
accepted August 22, 2006.
This study was supported by Grant PHRC AOM 0042 from Ministere
de lasaute’ and a grant from the Association Française du Syndrome de
Marfan, France.
*Corresponding author: Tel: [phone]; fax: [phone].
E-mail address: [email protected] (G. Jondeau).
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2006.08.048

the sinuses of Valsalva to height and the ratio of the diameters
at the sinuses of Valsalva and at the annulus were evaluated.
Mitral valve prolapse was systematically assessed, as well as
mitral and aortic regurgitation.
Treatment with ␤ -adrenergic blocking agents: Beta-
blocker treatment was initiated according to physician’s
practice, either as soon as the diagnosis was made or when
aortic root dilatation was documented.
Statistical analysis: When relevant, quantitative param-
eters are expressed as mean ⫾SD in the text as well as in
the tables. Quantitative variables with a normal distribution
were compared using Student’s ttest and Fisher’s exact test.
Wilcoxon’s test was used for variables with a non-normal
distribution or an inequality of variance. Differences be-
tween categorical variables were tested using chi-square
analysis. Last, to analyze the effect of ␤ blockers on aortic
diameter, 2 statistical models were defined: (1) a static
model in which the evolution of aortic diameter from diag-
nosis to last follow-up was compared in children who re-
ceived ␤ blockers ⱖ1 time with that in children who never
received ␤ blockers and (2) a dynamic model in which the
evolution of aortic diameter while children received ␤
blockers was compared with the evolution of aortic diame-
ter while children did not receive ␤ blockers. In each model,
a linear regression equation was calculated in which the
slope corresponds to the mean progression of aortic dilata-
tion at the level of the sinuses of Valsalva.
Results
Two hundred ten patients were initially considered for the
study. However, 49 children received ␤ -blocker therapy for
the first time after the age of 12 years and so were not
eligible. Seventy-eight patients were treated with ␤ blockers
before the age of 12 years, and 83 children remained un-
treated during total follow-up. One patient who stopped
␤ -blocker treatment after 1 year for no clear reason, 3
patients with asthma taking verapamil, and 2 patients taking
angiotensin-converting enzyme inhibitors were excluded
from analysis. In total, 155 patients (82 males, 73 females)
were included, with an average age at diagnosis of 6.7 ⫾4.3
years. Ninety-two patients (59.4%) reported familial histo-
ries of MS, 22.5% of whom reported familial histories of
aortic dissection or rupture. The patients were followed up
during an average 4.5 ⫾3.7 years.
Clinical characteristics of the 2 groups (77 children re-
ceiving
␤ -blocker therapy and 78 in the untreated group) are
reported in Table 1. The 2 groups were similar in terms of
age, height, weight, blood pressure, and heart rate at the
time of diagnosis. Aortic root dilatation was more frequent
in the treatment group than in the control group (83.1% vs
76.5%, p ⬍0.001). Aortic and mitral valvulopathy were of
similar incidence and gravity in the 2 groups.
The extracardiac phenotype was similar in the 2 groups
(Table 2). Familial history of MS was more frequent in the
group of patients receiving
␤ blockers.
Beta-blocker therapy was started a mean of 1.3 years after
diagnosis in the treatment group, at a mean age of 7.5 ⫾3.2
years. Atenolol was the most frequently used ␤ blocker (in
⬎70% of the children), and nadolol (17%) and propranolol
(6%) were less often used. The percentage of treated children
differed between centers (65 of 115 [57%] at Hôpital Am-
broise Paré vs 12 of 40 [30%] at the other centers, p ⫽0.015).
Only 2 children of the 77 who started
␤ -blocker therapy
stopped the treatment during the course of the study. Once
␤ -blocker therapy was started, treatment was taken 98% of the
time. When comparing the 2 groups 1.3 years after diagnosis
(i.e., at the time of introduction of
␤ blockers in the treated
Table 1
Baseline characteristics of the patients: cardiac features
Variable Total Control Treatment p Value
(n ⫽155) (n ⫽78) (n ⫽77)
Male/female 82/73 42/36 40/37 NS
Age (yrs) 7.4 ⫾5.2 6.1 ⫾3.2 NS
Height (cm) 131.6 ⫾27.7 131.3 ⫾34.6 132.9 ⫾20.2 NS
Weight (kg) 27.4 ⫾16.8 26.8 ⫾23.0 28.1 ⫾10.5 NS
Aortic diameter (mm)
Annulus 18.3 ⫾3.4 18.3 ⫾3.8 18.2 ⫾2.9 NS
Valsalva 27.8 ⫾5.3 27.2 ⫾5.7 28.4 ⫾4.8 NS
Supra-aortic ridge 21.7 ⫾4.0 21.4 ⫾4.6 21.3 ⫾3.2 NS
Ascending aorta 20.1 ⫾4.4 19.9 ⫾4.7 20.8 ⫾3.3 NS
Supra-aortic ridge/Valsalva 1.49 ⫾0.16 1.55 ⫾0.17 ⬍0.05
Diameter/height 0.21 ⫾0.05 0.22 ⫾0.03 ⬍0.05
Aortic regurgitation
0 127 (90%) 88% (66/75) 92.5% (61/66) NS
1⫹14 (9.9%) 12% (9/75) 8% (5/66) NS
⬎1⫹0 (0%) 0 0 NS
Mitral valve prolapse 77 (53.5%) 54.7% (41/75) 52.2% (36/69) NS
Mitral regurgitation
0 86 (60.1%) 56.6% (43/76) 64.2% (43/67) NS
1⫹56 (39.2%) 43% (33/76) 34% (23/67) NS
2⫹1 (0.7%) 0 1.5% (1/67) NS
⬎2⫹0 (0%) 0 0 NS
407Congenital Heart Disease/Beta Blockers in Children With MS

children and after a similar delay in the control group), aortic
diameters were significantly larger in the children treated with
␤ blockers than in the control group at the level of the annulus
(19.3 vs 17.6 mm, p ⫽0.04) and at the level of the sinuses of
Valsalva (29.7 vs 27.3 mm, p ⫽0.03). These differences could
not be explained by height or age (which were not significantly
different) and did not reach significance at the level of the
sinotubular junction and above.
At the end of the study, at a mean age of 11.1 ⫾5.0
years, aortic diameters were similar in the control group
and the treatment group at all levels (annulus: 20.8 ⫾4.0
vs 21.6 ⫾3.5 mm; sinuses of Valsalva: 31.7 ⫾7.9 vs
33.1 ⫾5.8 mm; supra-aortic ridge: 24.4 ⫾4.9 vs 24.7 ⫾
4.5 mm; ascending aorta: 22.3 ⫾5.1 vs 23.2 ⫾3.6 mm),
as were the ratio of the diameters at the sinuses of
Valsalva and at the annulus (1.47 ⫾0.19 vs 1.53 ⫾0.16)
and the ratio of the diameter at the sinus of Valsalva to
height (0.20 ⫾0.03 vs 0.20 ⫾0.03).
Determinants of aortic diameter: On univariate analy-
sis, aortic diameter was related to age and height: mean
aortic diameter was larger for a given age in the group of
children given
␤ blockers. However, ␤ -blocker therapy was
associated with significantly slower aortic root dilatation at
level of the sinuses of Valsalva: the rate of aortic root
dilatation was 1.05 mm/year in children who received
␤ -blocker treatment ⱖ1 time, compared with 1.15 mm/year
in children who did not receive ␤ -blocker therapy (static
model p ⫽0.0001; Figure 1). The dynamic model led to
similar results (aortic dilatation rate 0.97 mm/year in chil-
dren who received ␤ -blocker treatment vs 1.09 mm/year in
the control group, p ⫽0.0234; Figure 1). Although aortic
diameters were larger in patients on
␤ -blocker treatment at
the time of the initiation of therapy, they were identical to
those in the control group by the age of 18 years.
On multivariate analysis,
␤ -blocker treatment taken ⱖ1
time was associated with a decrease in the rate of aortic
dilatation by a mean of 0.16 mm/year at the level of the sinuses
of Valsalva (p ⫽0.0383). The limitation in aortic dilatation
was more pronounced when the treatment duration was longer
in the dynamic model. However, no reverse aortic dilatation
was observed in children receiving
␤ -blocker therapy.
Figure 1. Impact of ␤ blockers on aortic root diameter. The regression
curves of diameter 2 (sinuses of Valsalva) according to age in the static
(top) and dynamic (bottom) models are shown. Dotted line, treated group,
solid line, untreated group.
Table 2
Baseline characteristics of the patients: extracardiac features
System Total Control Group Treatment Group p Value
Skeletal features
Pectus carinatum 22.2% (30/137) 26.1% 17.2% NS
Arm span/height ⬎1.05 18% (18/100) 16% 20% NS
Arachnodactyly 69.3% (88/127) 74.6% 62.7% NS
Scoliosis ⬎20° or spondylolisthesis 47.8% (65/136) 51.4% 45.3% NS
Ocular features
Ectopia lentis 64.1% (84/131) 57.8 70.8% NS
Severe myopia (⬍2/10) 46.8% (59/126) 55.7% 39.7% NS
Lungs
Spontaneous pneumothorax or emphysematous bulla 1.3% (2/155) 1.3% 1.4% NS
Integuments
Stretch mark or recurring hernia 15.7% (18/115) 14% 17.9% NS
Central nervous system
Dural ectasia 9.7% (3/31) 5.9% 14.3% NS
Familial history
Parent affected by MS 59.4% 49.4% 70.8% 0.001
FBNI mutation 18.7% 8% 21% —
Linkage with FBNI 1.3% 1% 1% —
408 The American Journal of Cardiology (www.AJConline.org)

During the course of the study, after a mean of 4.5 ⫾3.7
years, valvular heart diseases remained mostly unchanged:
88% in the control group and 92% in the treated group had
no aortic regurgitation at the start of the study, whereas 81%
and 88%, respectively, remained free of aortic regurgitation
at the end of the study. All aortic regurgitation was at most
1⫹, except in 2 patients in whom it was 2⫹. Aortic regur-
gitation remained stable in 1 patient in the treated group,
whereas it increased to 3⫹in 1 patient in the control group.
The incidence of mitral valve prolapse increased from
55% to 61% in the control group and from 52% to 72% in
the treatment group. Mitral regurgitation remained minimal
(ⱕ1⫹in 99% at baseline in the 2 groups and 92% at the end
of the study). One patient presented mitral regurgitation 2⫹,
which remained stable during the course of the study.
Morbidity and mortality: Very few events occurred
during follow-up. Altogether, 4 patients died (3 sudden
deaths, 1 respiratory distress), of whom 3 were in the con-
trol group. Among these children, 3 had atrial or ventricular
arrhythmias. More children underwent aortic surgery in the
control group (5 vs 2 [6.4% vs 2.6%]) at a mean age of 7.5
years. Bentall’s technique (3 vs 1) was more frequent than
valve-sparing surgery (1 vs 1). Mitral valvuloplasty (3 vs 1)
was more frequent than mitral valve prosthesis (1 control
patient). Patients in the
␤ -blocker group who proceeded to
operation received ␤ blockers for a short period of time
before surgery (about 2 years).
Discussion
This retrospective study strongly suggests that the beneficial
effect of ␤ -blocker therapy, already demonstrated in adults
with MS, is also observed in children. Aortic dilatation was
slowed by about 0.2 mm/year in children on ␤ -blocker
therapy compared with untreated patients. The beneficial
effect of ␤ -blocker therapy was initially believed to be due
to their negative inotropic properties: by decreasing dP/dt
and therefore the rate of aortic stretch during systole, the
aortic wall is preserved. This theory has not been confirmed
by acute hemodynamic studies, which showed that
␤ -blocker therapy did not significantly reduce dP/dt but did
actually result in increases in stroke volume, pulse pressure,
and therefore, aortic stretch for each systole. These obser-
vations, however, were in patients at rest who had been
operated on for major aortic dilatation 20 years ago,
7
and
aortic dilatation may influence hemodynamic parameters.
8
The beneficial effect of ␤ -blocker therapy during exercise
was not ascertained. Bradycardia is also associated with
decreased aortic stretch during life: the aorta dilates with
age in normal subjects as a result of repetitive stretches, and
bradycardia should be beneficial in this regard. Alterna-
tively, ␤ -blocker therapy may directly affect aortic wall
properties; acute and chronic studies have reported in-
creased aortic distensibility and the reduction of aortic stiff-
ness and pulse-wave velocity in patients with MS receiving
␤ -blocker therapy.
9 –11
Last, they may exert their beneficial
effect by decreasing blood pressure.
11
There was a trend toward less aortic root replacement for
the children who received long-term ␤ -blocker therapy, but the
young age of patients, the low event rate, and the relatively
limited follow-up (⬍5 years) precluded calculating a signifi-
cant improvement in prognosis. This trend, however, is impor-
tant considering the risks of anticoagulation associated with
valve replacement, difficulties with prosthesis sizes in growing
children, and the attraction of valve-sparing operations in chil-
dren, as in adults.
12,13
Our study had some limitations. Retrospective analyses
are always subjects to bias, and patients who received
␤ -blocker therapy appeared to be more severely affected at
treatment initiation. However, the demonstration of a lower
rate of increase in aortic diameter despite more severe
disease reinforced the results. Aortic diameters were mea-
sured using 2-dimensional echocardiography on parasternal
long-axis views at end-diastole using the leading-edge tech-
nique. Echocardiographic quality is highly operator depen-
dent, and the reproducibility of aortic measures may be
improved using 3-dimensional echocardiography
14
or com-
puted tomography or magnetic resonance, which are less
operator dependant and allow good visualization of the
aorta despite thoracic deformation. However, the increased
background noise due to the lower reproducibility of the
measure with 2-dimensional echocardiography could only
decrease the ability to detect an existing effect.
1. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic
dilatation and the benefit of long-term beta-adrenergic blockade in
Marfan’s syndrome. N Engl J Med 1994;330:1335–1341.
2. Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH,
O’Loughlin JE, Davis JG, Devereux RB. Phenotypic features and
impact of beta blocker or calcium antagonist therapy on aortic lumen
size in the Marfan syndrome. Am J Cardiol 1999;83:1364 –1368.
3. Salim MA, Alpert BS, Ward JC, Pyeritz RE. Effect of beta-adrenergic
blockade on aortic root rate of dilation in the Marfan syndrome. Am J
Cardiol 1994;74:629 – 633.
4. De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE.
Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet
1996;62:417– 426.
5. Roman MJ, Devereux RB, Kramer-Fox R, O’Loughlin J. Two-dimen-
sional echocardiographic aortic root dimensions in normal children
and adults. Am J Cardiol 1989;64:507–512.
6. Mart CR, Khan SA, Smith FC, Kavey RE. A new on-line method for
predicting aortic root dilatation during two-dimensional echocardiog-
raphy in pediatric patients with Marfan syndrome using the sinus of
Valsalva to annulus ratio. Pediatr Cardiol 2003;24:118 –121.
7. Yin FC, Brin KP, Ting CT, Pyeritz RE. Arterial hemodynamic indexes
in Marfan’s syndrome. Circulation 1989;79:854 – 862.
8. Jondeau G, Boutouyrie P, Lacolley P, Laloux B, Dubourg O, Bourdarias
JP, Laurent S. Central pulse pressure is a major determinant of ascending
aorta dilation in Marfan syndrome. Circulation 1999;99:2677–2681.
9. Rios AS, Silber EN, Bavishi N, Varga P, Burton BK, Clark WA,
Denes P. Effect of long-term beta-blockade on aortic root compliance
in patients with Marfan syndrome. Am Heart J 1999;137:1057–1061.
10. Haouzi A, Berglund H, Pelikan PC, Maurer G, Siegel RJ. Heteroge-
neous aortic response to acute beta-adrenergic blockade in Marfan
syndrome. Am Heart J 1997;133:60 – 63.
11. Groenink M, de Roos A, Mulder BJ, Spaan JA, van der Wall EE.
Changes in aortic distensibility and pulse wave velocity assessed with
magnetic resonance imaging following beta-blocker therapy in the
Marfan syndrome. Am J Cardiol 1998;82:203–208.
12. David TE, Ivanov J, Armstrong S, Feindel CM, Webb GD. Aortic
valve-sparing operations in patients with aneurysms of the aortic root
or ascending aorta. Ann Thorac Surg 2002;74:S1758 –S1761.
13. Cattaneo SM, Bethea BT, Alejo DE, Spevak PJ, Clauss SB, Dietz HC,
Gott VL, Cameron DE. Surgery for aortic root aneurysm in children: a
21-year experience in 50 patients. Ann Thorac Surg 2004;77:168 –176.
14. Dulac Y, Taktak A, Acar P, Abadir S, Chilon T, Edouard T, Julia S,
Tauber M, Hovnanian A. 3D echocardiography of the ascending aorta
in Marfan’s syndrome. Arch Mal Coeur Vaiss 2005;98:538 –541.
409Congenital Heart Disease/Beta Blockers in Children With MS