Download Safety and Efficacy of Carvedilol Therapy for Patients with Dilated

Pediatr Cardiol
DOI 10.1007/s00246-007-9113-z
ORIGINAL ARTICLE
Safety and Efficacy of Carvedilol Therapy for Patients with
Dilated Cardiomyopathy Secondary to Muscular Dystrophy
J. Rhodes Æ R. Margossian Æ B. T. Darras Æ S. D. Colan Æ
K. J. Jenkins Æ T. Geva Æ A. J. Powell
Received: 14 June 2007 / Accepted: 10 July 2007
Springer Science+Business Media, LLC 2007
Abstract
Background By the age of 20 years, almost all patients with
Duchenne’s or Becker’s 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, Children’s Hospital Boston,
300 Longwood Avenue, Boston, MA 02115, USA
e-mail: [email protected]
B. T. Darras
Department of Neurology, Children’s Hospital Boston,
300 Longwood Avenue, Boston, MA 02115, USA
shortening fraction, E/E’ ratio, and isovolumetric relaxation
time also was observed. Two patients had runs of nonsustained ventricular tachycardia exceeding 140 beats per
minute (bpm) before carvedilol administration. Ventricular
tachycardia exceeding 140 bpm was not observed after
carvedilol therapy. Carvedilol was well tolerated, and no
serious adverse events were identified.
Conclusions Carvedilol therapy appears to be safe for
patients with DCM secondary to muscular dystrophy and
produces a modest improvement in systolic and diastolic
function.
Keywords Cardiac magnetic resonance imaging Carvedilol Dilated cardiomyopathy Muscular dystrophy Ventricular function
Beginning insidiously during the first decade of life, dilated
cardiomyopathy (DCM) ultimately afflicts almost all
patients with Duchenne’s muscular dystrophy (DMD).
Clinical evidence of cardiomyopathy is present in one-third
of patients by the age of 14 years, and in almost all patients
older than 18 years. Conduction abnormalities and arrhythmias also are quite common. Up to 57% of DMD
patients older than 18 years have symptoms related to their
cardiac disease. This percentage undoubtedly underestimates the significance of this problem because most of
these patients are wheelchair-bound secondary to their
skeletal muscle weakness.
Cardiac failure, arrhythmias, or both are the second most
common cause of death among these patients and probably
contribute to the respiratory failure that ultimately claims
the majority of these patients in the third decade of life [3,
9, 13]. It is also quite common to encounter DCM among
patients with Becker’s muscular dystrophy (BMD), at an
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Pediatr Cardiol
incidence and severity almost equaling those encountered
among DMD patients [3, 13, 25].
Patients with DCM often have elevated levels of circulating
catecholamines,
presumably
reflecting
overactivity of the sympathetic nervous system [5]. This
condition is thought to exacerbate their left ventricular
(LV) dysfunction and forms the basis for the rationale
supporting the use of beta-blocker therapy for patients with
DCM. Over the past decade, treatment with beta-receptor
blockade has become a mainstay in the management of
adult patients with DCM. Findings have shown carvedilol,
a beta-blocker with unique vasodilator and antioxidant
properties, to be the most effective pharmacologic agent in
this class. Studies have found that carvedilol therapy
improves the ventricular function, quality of life, and life
expectancy of adults with DCM [6].
It is likely that overactivity of the sympathetic nervous
system also plays a role in the pathophysiology of the
DCM associated with DMD and BMD, and that carvedilol
therapy would be beneficial for DCM patients with these
conditions as well. However, the literature contains scant
and conflicting data concerning the efficacy of carvedilol or
other beta-blockers for patients with DCM secondary to
muscular dystrophy and almost no details concerning the
safety of this therapy [2, 8, 10–12, 21, 24]. Furthermore,
the almost exclusive reliance of past studies on echocardiographic assessments of ventricular function represents a
significant shortcoming because patients with muscular
dystrophy often have poor acoustic windows, making data
quality suspect. In addition, the validity of many echocardiographic indices of ventricular function is dependent on
assumptions regarding ventricular geometry and symmetric
wall motion, which may not be valid in patients with DCM
secondary to muscular dystrophy. This study therefore
aimed to use cardiac magnetic resonance imaging (CMR),
together with echocardiography and other methods, to
evaluate the safety and efficacy of carvedilol therapy for
this unique group of patients.
Patients and Methods
with the diagnosis of DMD or BMD were reviewed for
study eligibility. Patients who had no recent (\12 months)
echocardiographic documentation of normal LV systolic
function were invited to participate in the study. Interested
subjects then underwent an initial screening evaluation that
included a detailed history, physical examination, electrocardiogram, echocardiogram, and 24-h Holter monitoring.
Patients with echocardiographic evidence of at least mild
LV dysfunction who met none of the exclusion criteria [23]
listed in Table 1 were asked to return for a CMR study.
Patients with a clinically reported CMR-derived LV ejection fraction (LVEF) less than 50% were enrolled in the
study and started on carvedilol therapy.
Before the first carvedilol dose, spirometric measurements were obtained (except for patients with a
tracheostomy and those otherwise incapable of performing
spirometry). The patients also were asked to complete a
brief questionnaire (see Appendix) regarding their quality
of life and level of cardiopulmonary symptomatology.
Carvedilol was initiated at a dose of 3.125 mg every 12
h. At subsequent biweekly clinic visits, the carvedilol dose
was doubled progressively until a daily dose of 50 mg was
achieved. Each time the dose was increased, the medication
was administered in an outpatient clinic setting, with
assessment of the patient’s pulse, blood pressure, and level
of symptoms every 15 to 30 min for 2 h.
After the initial 6- to 8-week up-titration period, the
patients were treated with carvedilol for a 6-month maintenance therapy period. If the patient was unable to tolerate
up-titration to a daily dose of 50 mg, the highest dose
achieved during the 8-week up-titration period was used
during the 6-month maintenance phase.
During the maintenance phase, all patients were evaluated every 1 to 2 months for verification that they were
receiving and tolerating the prescribed medication. At the
end of this 6 month period, the patients completed the
questionnaire again and underwent repeat CMR, echocardiogram, 24-h Holter monitoring, electrocardiogram, and
spirometry. A Data Safety Monitoring Board, composed of
a pediatric cardiologist and a pediatric intensivist not
associated with the study, was constituted to oversee the
study and evaluate all adverse event reports.
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
Children’s 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 Children’s 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
the plane of the atrioventricular valves through the cardiac
apex. Sequence parameters included a repetition time/echo
time of 3.2/1.6 ms, an in-plane voxel size of *1.8 · 1.8 mm,
a slice thickness of 6 to 8 mm, an interslice space of 0 to 2
mm, and a flip angle of 60.
Imaging parameters at baseline and follow-up studies
were matched for each patient. For patients who could
tolerate breathholding (n = 18), each slice was acquired in
a single breathhold at end expiration with one signal
average. Otherwise, a free-breathing scan was performed
with three signal averages (n = 2).
Image analysis was performed after all patients had
completed the study conducted by a single experienced
observer blinded to whether an examination was performed
at baseline or follow-up study. These measurements, instead
of the clinically reported measurements, were used for the
analyses in this study. Left and right ventricular end-diastolic
and end-systolic volumes, mass, stroke volumes, and ejection fraction were measured using commercially available
software (MASS; Medis, Leiden, The Netherlands), as previously described [1, 16]. Care was taken to ensure that the
borders demarcating the ventricles were drawn in a consistent fashion in baseline and follow-up studies.
Echocardiogram Protocol
Echocardiograms were performed using a Philips Sonos
5500 or 7500 ultrasound machine (Philips Medical
Systems, Andover, MA) and an appropriately sized
transducer probe. Because patients with muscular dystrophy often have poor echocardiographic windows and
perhaps segmental wall motion abnormalities, we included indices of left ventricular systolic or diastolic
function that are less affected by the presence of segmental wall motion abnormalities and that may be
acquired even when the quality of two-dimensional
echocardiographic images is suboptimal. For each
patient, we therefore attempted to acquire the following
tracings: mitral valve inflow pulsed-wave Doppler, aortic
valve outflow pulsed-wave Doppler, and mitral valve
annular tissue Doppler. The myocardial performance
index (MPI) [26] was calculated as follows:
MPI ¼ ðisovolumetric contraction timeþ
isovolumetric relaxation timeÞ=ðejection timeÞ;
where ejection time was measured from the aortic valve
pulsed-wave Doppler tracing. The numerator of the
equation was calculated by subtracting the ejection time
from the ‘‘nondiastolic time’’ (the time interval on the
mitral valve pulsed-wave Doppler tracing between the
closure of the mitral valve and the subsequent opening of
the mitral valve) [19]. The mean rate of ventricular
pressure rise during isovolumetric contraction (mean dP/
dtic) [20], an index of ventricular systolic function that
approximates and closely correlates with invasive
measures of peak dP/dt, was calculated as follows:
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Pediatr Cardiol
mean dP=dtic ¼ ðdiastolic blood pressure 5Þ=
ðisovolumetric contraction timeÞ;
where brachial blood pressure was determined using an
automated blood pressure device (Dinamapp, GE Medical
Systems, Milwaukee, WI), and the isovolumetric
contraction time was determined from the pulsed-wave
Doppler tracings of the aortic and mitral valves.
Isovolumetric relaxation time, a noninvasive index of
ventricular relaxation, was calculated by subtracting the
ejection time and the isovolumetric contraction time from
the nondiastolic time. The E/E’ ratio, a diastolic index that
correlates with left atrial pressure, was measured as the
ratio of the peak early diastolic inflow wave velocity (E) on
the pulsed-wave Doppler tracing of the mitral valve to the
peak early diastolic velocity (E’) on the tissue Doppler
sample at the level of the lateral mitral valve annulus [17].
For the patients with adequate acoustic windows, twodimensional guided M-mode echocardiographic tracings of
the left ventricle also were recorded, and the shortening
fraction was measured in accordance with American
Society of Echocardiography guidelines [15].
The average of three separate measurements was used
for each echocardiographic parameter. The measurements
were performed offline by a single experienced observer
using a proprietary software package without knowledge
concerning the results of the patient’s other studies.
Questionnaire
The questionnaire was an eight-question instrument
designed to quantify overall health status as well as specific
symptoms (e.g., dyspnea, orthopnea, palpitations) related
to cardiopulmonary function.
to participate in the study, and 1 could not be contacted.
The remaining 22 patients (17 with DMD and 5 with
BMD) were enrolled in the study. They ranged in age from
14 to 46 years (mean, 21.5 ± 8.4 years). All but two study
patients (both with BMD) were nonambulatory. Four
patients had undergone tracheostomies and required
chronic mechanical ventilatory support. Three patients
received facial or nasal continuous positive airway pressure. Ten patients (5 with DMD and 5 with BMD) were
maintained on angiotensin-converting enzyme inhibitors
(ACEI), 8 on digoxin, and 4 on diuretics.
Carvedilol Therapy Tolerance
For 21 of 22 patients it was possible to increase the carvedilol dose to 50 mg/day during the up-titration phase and
to continue this dose for the 6 months of maintenance
therapy. For one cachectic patient (weighing less than 35
kg), it was decided not to increase the carvedilol dose
beyond 25 mg/day. During the up-titration phase, it was
necessary to decrease or temporarily discontinue ACEI
therapy for five patients. However, during the maintenance
phase, it was possible to reinstitute this therapy at prestudy
levels for four of these patients. For the remaining patient,
ACEI therapy was reinstituted at a dose slightly below his
prestudy level.
Carvedilol was well tolerated by all the patients.
Although mild, transient systolic hypotension (never less
than 75 mmHg) was observed occasionally during the uptitration period, no patient experienced symptomatic
hypotension during the study, and spontaneous resolution
occurred for all. Two patients were successfully treated for
pneumonia during the study. No other serious adverse
events were identified, and no patient required permanent
increases in oxygen therapy or ventilatory support.
Statistical Analysis
Student’s 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. Fisher’s 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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Effect of Carvedilol on Cardiac Function
Of the 22 patients, 20 successfully completed the pre- and
posttreatment CMR studies. Their baseline CMR-derived
LVEF was depressed, averaging 41% ± 8.3%. In addition,
pretreatment shortening fraction and mean dP/dtic were
low, and MPI was abnormally high (Table 2).
After 6 months of maintenance therapy, a modest but
statistically significant improvement in MRI-derived LVEF
was observed (Table 2, Fig. 1). In 14 patients, LVEF
increased, and in 6 patients, it declined. The improvement
in LVEF was due to an increase in the LV end-diastolic
volume with no concomitant change in LV end-systolic
volume. Stroke volume increased 14%, from 70 ± 18 to
80 ± 22 ml/beat (p \ 0.0001), and resting heart rate
Pediatr Cardiol
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
n
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
declined from 90 ± 14 to 76 ± 26 beats per minute (bpm)
(p \ 0.0001). Consequently, cardiac output (i.e., the
product of stroke volume and heart rate) did not change.
Carvedilol also was associated with statistically significant improvements in the MPI and the mean dP/dtic. A
trend toward improved shortening fraction, E/E’ ratio, and
isovolumetric relaxation time also was observed, but these
changes did not achieve statistical significance (Table 2).
An improvement in LVEF was observed in all six
patients with a baseline LVEF less than 41%. Among the
14 patients with an LVEF exceeding 41%, the response to
carvedilol therapy was less consistent (Fig. 1). Similarly,
all patients with a mean dP/dt less than 760 mmHg, an MPI
exceeding 0.61, or an E’/E ratio higher than 12 experienced
improvements in these parameters after carvedilol therapy.
Contingency table analysis (Fisher’s exact test) showed
that patients with an LVEF or a mean dP/dt below the
aforementioned values had a significantly superior
response to carvedilol than patients with higher values
(p \ 0.05).
The 24-h Holter recordings showed that carvedilol
caused the patients’ maximum, mean, and minimum heart
rates to fall (Table 3). Two patients had runs of nonsustained ventricular tachycardia exceeding 140 bpm before
carvedilol administration. Ventricular tachycardia exceeding 140 bpm was not observed after carvedilol therapy.
Pulmonary Function Tests
For the patients capable of performing spirometry, carvedilol was associated with small, statistically insignificant
declines in spirometric measurements (Table 4). However,
no patient required a permanent increase in the level of his
ventilatory support.
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
On the posttreatment questionnaire, seven patients reported
fewer palpitations after carvedilol treatment. No patient
reported more frequent palpitations (p \ 0.02). Similarly,
five patients reported less dyspnea on the posttreatment
questionnaire than they had reported on the pretreatment
questionnaire, whereas only one patient reported more
dyspnea. The remaining patients reported similar amounts
of dyspnea. Eight subjects felt their overall health had
improved over the course of the study, whereas 12 felt it
was unchanged, and 2 felt that their health had deteriorated
slightly. The changes in these domains did not achieve
statistical significance.
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Pediatr Cardiol
Table 3 Effect of carvedilol on heart rate
Before
After
%Change
n
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
Before, before initiation of carvedilol; After, 6-month follow-up
value; n, number of patients who completed pre- and posttreatment
studies; Min, minimum heart rate on 24-h Holter monitoring; Mean,
mean heart rate on 24-h Holter monitoring; Max, maximal heart rate
on 24-h Holter monitoring; Rest, resting heart rate at time of magnetic
resonance imaging
Table 4 Effect of carvedilol on spirometric measurements
Before
After
%Change
n
p Value
FVC (% predicted)
50 ± 27
47 ± 30
–6.0
16
NS
FEV1 (% predicted)
51 ± 28
46 ± 31
–9.8
16
NS
Before, before initiation of carvedilol; After, 6-month follow-up
value; n, number of patients who completed pre- and posttreatment
studies; FVC, forced vital capacity; NS, not significant; FEV1, volume exhaled during first second of forced exhalation
Interaction With ACEI Therapy
Before the initiation of carvedilol, the LVEF and shortening
fraction of the patients receiving ACEI therapy were lower
than those of patients not receiving this therapy (35.7 ± 8.3
vs 46.2 ± 3.9 and 0.24 ± 0.06 vs 0.16 ± 0.06, respectively;
both p \ 0.01). The ACEI-treated patients also tended to be
older, and their other indices of ventricular function tended
to be worse, but these differences did not achieve statistical
significance. Changes in ventricular function indices after
the initiation of carvedilol were similar between the patients
who did and those who did not receive ACEI therapy.
Similarly, the concurrent use of digoxin did not influence
the response to carvedilol therapy.
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.
123
Carvedilol therapy also was associated with modest
improvement in ventricular function. Significant improvements were detected in the left ventricular ejection fraction
(secondary to an increase in left ventricular end-diastolic
volume with no change in end-systolic volume), mean dP/
dtic, and MPI. These changes were not accompanied by a
significant increase in the E/E’ ratio (indeed, this ratio
actually fell slightly). This observation suggests that the
improvements in the indices of ventricular function were
not associated with a rise in left atrial pressure. It is
therefore unlikely that these changes were attributable
merely to increased preload secondary to beta-blockerinduced bradycardia.
Furthermore, carvedilol therapy was associated with a
trend toward an abbreviated isovolumic relaxation time,
despite the fall in heart rate. This observation implies that
carvedilol therapy may have been associated with an
enhancement of left ventricular diastolic (as well as systolic) function, a finding consistent with past studies
investigating the effect of carvedilol on ventricular function in patients with DCM [18].
It also is important to note that the DCM associated with
DMD and BMD is a relentless, progressive disorder [3, 9,
13]. Consequently, the modest improvements in ventricular
function observed in this study after treatment with carvedilol are more remarkable given that more than an 8month interval separated the baseline and posttreatment
assessments of ventricular function.
Patients with more severe LV dysfunction appeared to
have the best response to carvedilol therapy. All patients
with an LVEF less than 41%, a mean dP/dt less than 760
mmHg, an MPI exceeding 0.62, or an E’/E ratio higher
than 12 experienced improvements in these parameters
after carvedilol therapy. Improvements in ventricular
function parameters were not consistently observed
among patients with milder degrees of LV dysfunction.
This finding is similar to that observed among patients
with dilated cardiomyopathy secondary to other disorders
[22].
Carvedilol also had a favorable effect on the patients’
rhythm problems. Ventricular tachycardia exceeding 140
bpm was observed in the 24-h Holter monitoring studies of
two patients before carvedilol therapy, but was not seen in
any patient’s posttreatment study. Pro-arrhythmic effects
were not detected in any of the Holter studies.
Carvedilol therapy also was associated with significant
improvements in the patients’ symptoms of palpitations.
We believe this finding probably corresponds to the
decrease in heart rate/sinus tachycardia associated with
carvedilol therapy. There were trends toward improvement
shown in other domains of the questionnaire that did not
achieve statistical significance, and may have been related
to a placebo effect rather than the effect of the drug itself.
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, 3.125–6.25 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, 10–12, 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.
Do you ever become short of breath or have trouble
breathing?
a. No, never
b. Yes, but not every day
123
Pediatr Cardiol
c. Yes, about once every day
d. Yes, many times a day
2.
Do
a.
b.
c.
you have trouble breathing when you lie flat?
No, not at all
Yes, and I therefore usually lie on a pillow
Yes, and I therefore usually lie on more than one
pillow
d. Yes, and I therefore avoid lying down.
3.
Have you ever had pneumonia?
a. No, never
b. Yes, but not in the past 6 months
c. Yes, and once within the past 6 months
d. Yes, and more than once in the past 6 months
4.
Do
a.
b.
c.
d.
e.
5.
Do you ever feel that your heart is beating abnormally
or irregularly?
a. No, never
b. Yes, but less than once a month
c. Yes, about 1 to 3 times a month
d. Yes, at least once a week but not every day
e. Yes, at least once a day
6.
Do
a.
b.
c.
d.
e.
f.
7.
Do
a.
b.
c.
8.
Compared with 6 months ago, would you say your
overall health status is
a. About the same
b. A little better
c. A lot better
d. A little worse
e. A lot worse
you ever have chest pain?
No, never
Yes, but less than once a month
Yes, about 1 to 3 times a month
Yes, at least once a week but not every day
Yes, at least once a day
you ever use supplemental oxygen?
No, never
Yes, but less than once a month
Yes, about 1 to 3 times a month
Yes, at least once a week but not every day
Yes, every day, but not all day
Yes, all the time
you use mechanical support for your breathing?
No, and I do not have headaches in the morning
No, but I do have headaches in the morning
Yes, I use facial continuous positive airway
pressure (CPAP) or biphasic positive airway
pressure (BIPAP)
d. Yes, I use mechanical ventilation at night
e. Yes, I use mechanical ventilation almost all the
time.
123
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