DOI 10.1007/s00246-007-9113-z
ORIGINAL ARTICLE
Abstract
Background By the age of 20 years, almost all patients with
Duchennes or Beckers muscular dystrophy have experienced dilated cardiomyopathy (DCM), a condition that
contributes significantly to their morbidity and mortality.
Although studies have shown carvedilol to be an effective
therapy for patients with other forms of DCM, few data exist
concerning its safety and efficacy for patients with muscular
dystrophy. This study aimed to evaluate the safety and efficacy of carvedilol for patients with DCM.
Methods A clinical trial at an outpatient clinic investigated 22 muscular dystrophy patients, ages 14 to 46 years,
with DCM and left ventricular ejection fraction (LVEF)
less than 50%. Carvedilol up-titrated over 8 weeks then
was administered at the maximum or highest tolerated dose
for 6 months. Baseline and posttreatment cardiac magnetic
resonance imaging (CMR), echocardiography, and Holter
monitoring were recorded.
Results Carvedilol therapy was associated with a modest
but statistically significant improvement in CMR-derived
ejection fraction (41% 8.3% to 43% 8%; p \ 0.02).
Carvedilol also was associated with significant improvements
in both the mean rate of pressure rise (dP/dt) during isovolumetric contraction (804 216 to 951 282 mmHg/s;
p \ 0.05) and the myocardial performance index (0.55 0.18
to 0.42 0.15; p \ 0.01). A trend toward improved
J. Rhodes (&) R. Margossian S. D. Colan
K. J. Jenkins T. Geva A. J. Powell
Department of Cardiology, Childrens Hospital Boston,
300 Longwood Avenue, Boston, MA 02115, USA
e-mail: jonathan.rhodes@cardio.chboston.org
B. T. Darras
Department of Neurology, Childrens Hospital Boston,
300 Longwood Avenue, Boston, MA 02115, USA
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Study Protocol
This study was a prospective, single-arm, unblinded,
medication trial. The research protocol was approved by
the Scientific Review Committee of the Cardiology
Department and the Committee on Clinical Investigation at
Childrens Hospital Boston. Informed consent and, when
applicable, assent were obtained from all subjects, their
guardians, or both.
The records of all patients older than 10 years followed
at Childrens Hospital Boston and affiliated institutions
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CMR Protocol
All CMR examinations were performed on a 1.5-Tesla
magnetic resonance scanner with a cardiac phased-array
surface coil. Ventricular volumes and function were measured using a segmented k-space steady-state free precession
cine pulse sequence with retrospective electrocardiographic
gating, prescribed in two- and four-chamber planes followed
by a stack of 12 contiguous short-axis slices extending from
Pediatr Cardiol
Table 1 Exclusion criteria
1. Structural congenital heart disease
2. History of sustained or symptomatic ventricular dysrhythmias uncontrolled by drug therapy or the use of an implantable defibrillator
3. History or screening Holter evidence of Mobitz type 2 second- or third-degree atrioventricular block or sinus node dysfunction in the absence
of a functioning pacemaker
4. Sitting systolic pressure of 85 mmHg or lower or resting heart rate 60 bpm or slower on screening physical
5. Coexistent fixed obstructive pulmonary disease or reactive airway disease (e.g., asthma) requiring therapy, or evidence of significant wheezing
on screening physical
6. Concurrent terminal illness or other severe disease
7. Endocrine disorders such as primary aldosteronism, pheochromocytoma, hyper- or hypothyroidism, or insulin-dependent diabetes mellitus
8. Unwillingness or inability to cooperate
9. Use of an investigational drug within 30 days of enrollment in the study or within 5 half-lives of carvedilol
10. History of drug sensitivity to alpha- or beta-blockers
11. Use of any of the following agents within 2 weeks of enrollment:
Monamine oxidase inhibitors
Calcium entry blockers
Alpha-blockers
Disopyramide, flecainide, encanide, moricizine, propafenone, or sotalol
Beta adrenergic agonists
Intravenous anticongestive medications (e.g., digoxin, diuretics)
12. Treatment with beta-receptor antagonists within the 2 months before study enrollment
13. Major surgical procedure (e.g., scoliosis surgery) planned within 6 months after study enrollment
Echocardiogram Protocol
Echocardiograms were performed using a Philips Sonos
5500 or 7500 ultrasound machine (Philips Medical
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Statistical Analysis
Students paired t test was used to compare continuous
variables at baseline and after 6 months of full-dose carvedilol therapy. The sign test was used to analyze the
questionnaire data. Fishers exact test was used to analyze
categorical data. A p value less than 0.05 was considered
significant.
Results
Patient Population
A total of 39 potential subjects with DMD or BMD were
identified from the review of patient records. Of these, 5
fulfilled one or more of the exclusion criteria, 11 declined
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Table 2 Effect of carvedilol on indices of left ventricular function
Before
After
LVEDV (ml)
183 76
195 77
LVESV (ml)
113 62
115 61
EF (%)
41.0 8.3
%Change
p Value
+6.6
20
\0.01
+1.8
20
NS
43.2 8.3
+5.4
20
\0.02
70 18
80 22
+14.3
20
\0.0001
MPI
0.54 0.16
0.43 0.15
20.4
18
\0.01
dP/dt (mmHg/s)
804 216
947 276
+17.8
21
\0.05
E/E ratio
10.1 6.3
8.8 4.1
12.9
13
NS
IRT (ms)
115 35
106 38
7.8
18
NS
SF
0.21 0.08
0.23 0.08
+9.5
16
NS
SV (ml)
Before, before initiation of carvedilol; After, 6-month follow-up value; n, number of patients who completed pre- and posttreatment studies;
LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; NS, not significant; EF, ejection fraction; SV,
stroke volume; MPI, myocardial performance index; dP/dt, mean change in left ventricular pressure during isovolumetric contraction; IRT,
isovolumetric relaxation time; SF, shortening fraction
Questionnaire Data
Fig. 1 Change in magnetic resonance imaging (MRI)-derived ejection fraction and mean dP/dtic after 6 months of treatment with fulldose carvedilol. Carvedilol therapy was associated with statistically
significant improvements in these indices of left ventricular function.
Patients with the most severe dysfunction had the best response to
carvedilol therapy. The response of patients with milder degrees of
dysfunction was less consistent. mean dP/dt, mean rate of ventricular
pressure rise during isovolumetric contraction
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Table 3 Effect of carvedilol on heart rate
Before
After
%Change
p Value
Min (bpm)
63 11
53 7
13
22
\0.0001
Mean (bpm)
93 13
80 11
14
22
\0.0001
Max (bpm)
137 16
117 13
15
22
\0.0001
Rest (bpm)
90 14
76 26
16
22
\0.0001
After
%Change
p Value
FVC (% predicted)
50 27
47 30
6.0
16
NS
FEV1 (% predicted)
51 28
46 31
9.8
16
NS
Discussion
This study demonstrated that carvedilol therapy can be
initiated safely for patients with DMD and BMD, and
appears to be well tolerated. Although mild hypotension
was seen occasionally during the up-titration phase of the
study, symptomatic hypotension was never encountered.
Transient reductions in ACEI therapy were sometimes
necessary, but reinstitution of ACEI therapy at prestudy
levels was possible for all except one patient, who required
a slight reduction. The absence of orthostatic hypotension
(or any other significant symptom) probably was related to
the gradual up-titration protocol used for this study, and to
the fact that all but two patients were nonambulatory.
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Pediatr Cardiol
Carvedilol therapy was associated with a small, statistically insignificant deterioration in the spirometric
measurements. No patient required a permanent increase in
the level of ventilatory support, however, and it is unclear
whether the observed deterioration exceeded what would
be expected solely from the progression of the patients
muscular dystrophy during the more than 8 months that
separated the two assessments of pulmonary function [14].
Furthermore, the vast majority of patients reported
improved or unchanged symptoms of dyspnea after carvedilol therapy, and all but two patients felt that their
overall health status was unchanged or improved after 6
months of full-dose carvedilol therapy. Nevertheless, the
results of the spirometric studies raise concerns regarding a
possible deleterious effect of carvedilol on the patients
pulmonary function and indicate that it is important to
monitor closely the respiratory status of DMD and BMD
patients receiving carvedilol therapy.
Previous studies of carvedilol therapy for patients with
DCM secondary to muscular dystrophy have been quite
limited. Kajimoto et al. [12] reported that carvedilol therapy was associated with a small but statistically significant
improvement in the left ventricular fractional shortening of
13 patients with DCM secondary to muscular dystrophy. In
contrast, Saito et al. [21] found that carvedilol therapy had
no effect on the ventricular function of eight patients with
DCM secondary to DMD. Ishikawa et al. [10] treated 11
patients with dilated cardiomyopathy secondary to DMD
using a combination of ACEI and beta-blockers (but not
carvedilol) and found an improvement in echocardiographic indices of ventricular function, neuroendocrine
hormone levels, and symptoms and signs of heart failure.
In that study, it was not possible to differentiate between
the effects of the beta-blocker and ACEI therapies.
Similarly, Jefferies et al. [11] found improvements in
echocardiographically derived measurements of LVEF,
MPI, and the sphericity index after treatment with an ACEI
alone (13 patients) or a combination of ACEI and a betablocker (18 patients). However, their data did not permit
evaluation of the effect produced by beta-blocker therapy
alone. In addition, the dose of carvedilol used in their study
(mean dose, 4 mg; range, 3.1256.25 mg) was far below
the recommended target dose of carvedilol and significantly less than that achieved by all the patients in our
study (all but one patient received 25 mg twice a day).
Notably, Duboc et al. [4] recently presented data demonstrating that patients with DMD may benefit from the early
institution of ACEI therapy. It therefore seems possible that
the improvements detected in the study by Jefferies et al.
[11] were due primarily to the ACEI therapy rather than the
low-dose beta-blocker therapy used in their study.
None of the past studies of beta-blocker therapy for
patients with DCM secondary to muscular dystrophy
provided details regarding the patients tolerance of carvedilol therapy. In addition, all past studies relied solely on
echocardiographic measurements of ventricular function
[2, 8, 1012, 21, 24]. Echocardiographic data quality is
dependent on acoustic windows, which often are poor in
this patient population as result of chest wall deformities
and large patient size. Moreover, two-dimensional echocardiography and M-mode quantification of ventricular
size and function are limited by geometric assumptions that
are less reliable in remodeled hearts. The data and conclusions of past studies must therefore be interpreted with
some caution.
To maximize data quality, the current study used CMR
to quantify ventricular size and function because of its
consistently good image quality and avoidance of geometric assumptions. Especially for serial assessment of
cardiomyopathies, CMR is the preferred clinical imaging
method because of its excellent interstudy reproducibility,
which is superior to that of two-dimensional echocardiography [7].
The current study has therefore expanded our understanding of the safety and efficacy of carvedilol therapy for
patients with DCM secondary to DMD or BMD. However,
it must be noted that this was a small, nonrandomized,
prospective study that focused primarily on the short- and
intermediate-term effects of this medication on the
patients cardiovascular and pulmonary function. Although
the improvements in ventricular function documented in
this study are encouraging, the long-term effects of carvedilol therapy and its impact on the survival of this
complex patient population were not evaluated. Certainly,
the clinical significance of the modest improvements documented in this study remains unclear. Additional studies
are needed for optimal definition of the role played by
carvedilol in the management of patients with DCM secondary to muscular dystrophy.
Acknowledgment The authors gratefully acknowledge the skillful
clinical assistance of Elizabeth Brown, RN; Julianne Evangelista,
PNP; Shay Dillis, PNP; and Terry Saia, PNP. They also are indebted
to the patients who volunteered to participate in the study. This study
was supported by an investigator-initiated grant from GlaxoSmithKline. No other conflicts of interest exist.
Appendix
Carvedilol in Muscular Dystrophy Questionnaire
Name: Date:
1.
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