(ECG) is a painless test in which
leads, pasted on the chest, transmit
information about heart rhythms to
stress technician Lee Pillow tests
Jarrod Holly, 13, who has Duchenne
MD, at University Medical Center,
in Tucson, Ariz. Photos by Jeff Smith
On Nov. 1, there appeared in Circulation, the journal of
the American Heart Association, a somewhat unusual article. Unlike most
reports in Circulation, which address common cardiovascular problems like
heart attacks, strokes and cholesterol control, it focused on treating
cardiac disease associated with Duchenne and Becker muscular
It’s been estimated that 95 percent of boys with DMD and
at least 90 percent with BMD develop cardiac involvement. And 10 percent
to 15 percent of DMD-affected young men die of cardiac failure.
In December, the American Academy of Pediatrics published
recommendations for cardiovascular care in Duchenne and Becker muscular
dystrophy in its journal, Pediatrics (see “Recommendations”).
The study team, led by pediatric cardiologist Linda Cripe at Cincinnati
Children’s Hospital Medical Center, emphasized to doctors that cardiac
issues must be given serious consideration in the care of patients with
DMD and BMD and carriers of these dystrophies — very soon after the person
receives a diagnosis.
Death Sentences Got Old
In the Circulation paper, researchers at various Houston
medical institutions, coordinated by pediatric cardiologist Jeffrey Towbin
at Baylor College of Medicine and Texas Children’s Hospital, reported
their data on 62 boys with DMD and seven with BMD who had been referred
from the MDA clinic in Houston to the cardiovascular clinic for
evaluation, at Towbin’s request, whether or not they had any symptoms of
Of the 62 boys, 31 ultimately developed heart
abnormalities, seen on an echocardiogram (ultrasound imaging study of the
heart). The average age at which these appeared was 15, although some
children were as young as 10.
Data were missing on two patients, but Towbin and his
colleagues were able to report in 2005 that 27 of 29 (93 percent) of the
boys showed improvement of their cardiac muscle disease (cardiomyopathy),
and that the other two of the 29 showed no deterioration during the time
they were studied — an average of about three years. Nineteen of the boys
(16 with DMD and three with BMD) had a normal heart size, function or both
at the end of the study.
Unlike most children with muscular dystrophy, the Houston
patients had been referred to a cardiologist before they
developed symptoms of heart disease, such as shortness of breath or
sweating in a cool environment.
As soon as their hearts showed signs of cardiomyopathy,
they were treated with a type of medication known as an angiotensin-converting enzyme (ACE) inhibitor. Those who didn’t
improve in three months were given an additional medication, a beta
blocker. These are the same treatments given to people with
cardiomyopathy who don’t have muscular dystrophy.
cardiologist Jeffrey Towbin at Texas Children's
Hospital says children with MD need regular
checkups before they have cardiac symptoms.
Both medications are designed to reduce the work that the
damaged heart has to do. ACE inhibitors interrupt the actions of angiotensin, which raises blood pressure and leads to fluid
retention. Beta blockers block signals from the nervous system that land
on beta receptors, which increase the heart rate.
Towbin was gratified at the results. Just a few years ago,
he says, things were very different.
When he joined the faculty at Baylor in 1989, neurologists
in the Houston area were sending him patients with DMD, BMD and
occasionally other muscular dystrophies for cardiac evaluations. The
pa-tients were generally 16 to 19 years old and had ominous symptoms of
end-stage heart disease.
“I found myself being asked to see patients who were sent
for an echocardiogram because they were sweating and had shortness of
breath,” he says. “I would get called to come look at a patient’s heart,
and I would confirm that it looked terrible and then try to take care of
the patient. But there wasn’t much to do. After a while, it gets old
telling people they’re going to die.”
Monitoring and Medicating
Up north, at the University of Chicago, Elizabeth McNally
has seen a similar evolution in care. As an adult cardiologist, she sees
more people with limb-girdle, myotonic and Emery-Dreifuss MD than with DMD
or BMD, but, she says, the principles are the same.
“I treat cardiomyopathy with MD in the same way I treat
cardiomyopathy without MD,” McNally says. “I don’t see any reason why
cardiomyopathy associated with muscular dystrophy is any different, other
than that you want to make sure there’s a good pulmonologist involved,
which is less of an issue with other cardiomyopathy patients.
“From my viewpoint, if you have a sarcoglycan gene
mutation [a cause of some LGMD forms], or if you have a dystrophin
mutation [the cause of DMD and BMD], you’re at risk for cardiomyopathy.
And you want to be monitored closely. Any signs of an enlarging heart or
decreasing function, you want to be on medication.”
McNally also prescribes ACE inhibitors, followed by beta
blockers, in her MD patients.
She sometimes adds other drugs, such as spironolactone, which combats fluid retention, and she’s become
increasingly impressed with the positive effects of the implantable
electronic devices that have become available in recent years.
Among the many factors McNally has considered in treating
her MD patients who have cardiac disease is the considerable overlap
between MD-related and non-MD-related cardiomyopathy that molecular
biology has revealed over the last several years.
McNally, who has had MDA research support since 1997 to
study molecular and cellular aspects of muscular dystrophy, says she’s
been interested in hearts and muscles since she was an undergraduate at
Barnard College in New York in 1981.
Back then, she was part of a group that was studying myosins to see whether genetic flaws in these muscle proteins
could cause muscular dystrophy. It turned out that they didn’t cause MD,
but many genetic flaws in various myosins have since been found to cause
Other proteins can lead to either disorder. For instance,
the proteins myotilin and titin, when flawed, can cause
limb-girdle MD, but they’ve also been found in people with cardiomyopathy
cardiologist Elizabeth McNally at the
University of Chicago says MD-associated
cardiomyopathy should be treated the same
as cardiomyopathy not associated with
In recent years, investigations of the dystrophin gene, which, when flawed, leads to DMD or BMD, have uncovered cases of
cardiomyopathy alone — with no skeletal muscle involvement — that were
caused by dystrophin gene mutations. An infectious type of cardiomyopathy,
in which a Coxsackie virus invades the heart, is due to the virus’s
disruption of the dystrophin protein.
Since 1999, scientists have found that many cases of
cardiomyopathy and other cardiac problems are caused by mutations in the
gene for the lamin A and lamin C proteins (it’s the same
gene, known as lamin A/C). Lamin A/C mutations can cause heart
disease alone or in conjunction with Emery-Dreifuss or limb-girdle
The take-home message was that you didn’t have to have
weak skeletal muscles or even weak respiratory muscles to develop an
abnormal heartbeat or cardiomyopathy. These disorders could result from a
mutation in a heart muscle protein alone. The new findings began to change
doctors’ views of MD-associated heart disease.
“When I was training,” Jeffrey Towbin says, “the concept
was that the cardiac features of muscular dystrophy were probably mostly
secondary to the diaphragm abnormalities and the breathing problems. With
the age of molecular genetics, it became quite clear that the heart is
also a player in all of this, that problems can be caused by abnormalities
of the heart itself. That has changed some attitudes.”
Holter monitor records heart rhythms for
24 to 48 hours during a person’s
normal activities. Leads pasted on Jarrod’s
chest transmit information to a very small
Towbin’s research, in addition to showing that standard
cardiomyopathy treatments help DMD and BMD patients, also suggests (though
it doesn’t yet prove) that certain mutations in the dystrophin gene are
more likely than others to lead to heart problems.
The researchers found that mutations affecting the
area of the dystrophin gene known as exons 12 and
exons 14 to 17, as well as mutations in exons 31
to 42, seem to be particularly associated with heart
disease. Boys with mutations in exons 51 or 52 had
a lower risk of cardiac involvement with their MD.
Concerns About Carriers
Towbin and other cardiologists are worried about the high
incidence of heart disease in female carriers of X-linked forms of
muscular dystrophies. X-linked MDs, which include Duchenne, Becker and one
type of Emery-Dreifuss MD, are those that arise from defects in X
Unlike most genes, which come in pairs in both sexes and
stay active throughout life, X chromosome genes come in pairs in females
and exist on only one X chromosome in males. Females generally don’t get
X-linked diseases, at least not in their severest forms, because their
second X chromosome generally protects them from any mutations on the
But there’s something about X chromosome behavior that’s
very different from that of other chromosomes. In each cell, only one X is
active. In a process usually called X inactivation, one of the Xs
is randomly inactivated.
So, in a carrier of DMD, for instance, random chance may
have inactivated the majority of dystrophin-producing X chromosomes,
leaving muscle cells with a high number of Xs that don’t produce
Some DMD or BMD carriers have mild to serious dystrophin
deficiency and sometimes even have true muscular dystrophy. X-linked
Emery-Dreifuss carriers can likewise have a lot of X chromosomes that
can’t make normal emerin, a protein needed by the heart and
The heart, doctors have begun to notice, is particularly
hard hit in X-linked MD carriers. The reasons aren’t completely
understood, but one good explanation has to do with differences in the
anatomy of cardiac and skeletal muscles cells.
Skeletal muscle cells are long fibers containing several
nuclei. (They start out as single cells and then fuse to form the fibers.)
So, if half or even fewer than half of the fiber’s nuclei make dystrophin
or emerin, that’s probably enough for the skeletal muscle to function.
But heart muscle cells aren’t long fibers. They’re short,
with one nucleus each. If only about 50 percent of the heart’s nuclei can
make dystrophin or emerin, that means some 50 percent of the heart’s cells
have a missing or abnormal protein. Add to that the heart’s need for
constant contraction, and you have a recipe for heart disease in a
“The age of onset is much later in women than in the
boys,” Towbin says, “and the progression of the disease and the severity
of the disease is less than in the boys. But if you’re a carrier, you need
to know whether you have it.
“People get confused between the aging process and heart
disease, particularly if they’re unaware of the likelihood that they would
have a problem,” he says. “They can be short of breath or get fatigued
when they go to the mall, or they just feel blah.
“What typically occurs is that a carrier mother is, let’s
say, 53 years of age, and she starts getting tired and short of breath
with stair climbing. She says, ‘Well, I’m 53. I’m gettin’ old.’ Well —
wrong. They could have real disease.”
Towbin and others recommend regular cardiac examinations
and, if necessary, treatment, for carriers of X-linked MDs.
Who Needs a Defibrillator?
When doctors think about heart disease in muscular
dystrophy, they generally think first of cardiomyopathy, or cardiac muscle
disease. If they’re experts, they may also think of dilated cardiomyopathy, the form most common in MD.
Dilated cardiomyopathy describes what happens when the
heart’s muscle layer, particularly in the left ventricle (lower
chamber) degenerates and sags, so that it looks larger (dilated) but is
weaker and less effective as a pump than a heart of normal size.
The other main type of cardiomyopathy is called hypertrophic. This term describes a condition in which the muscle
layer hypertrophies (gets larger), probably as a coping mechanism, but
becomes so thickened that it prevents sufficient blood from entering the
But cardiomyopathy isn’t the only effect that MD can have
on the heart. Some MDs, such as myotonic and Emery-Dreifuss, cause more
heartbeat irregularities than they do muscle weakness, although they can
The heart’s contractions, or “beats,” are regulated by
electricity-like signals that move through specialized conducting tissue.
The normal path for this flow is from a specific spot in the upper right
chamber (right atrium) through a specific spot where the upper
chambers (atria) join the lower chambers
But in myotonic MD (in the chromosome 19 type and
sometimes in the chromosome 3 type) and in EDMD (the X-linked and the
lamin A/C-related form), the specialized conducting tissue is specifically
The result can be a conduction defect, meaning
that some or all signals don’t get through from the atria to the
ventricles the way they should; or an arrhythmia, meaning that
the heartbeat is too fast, too slow or erratic.
Elizabeth McNally sees a lot of patients with lamin
disorders and heart disease. Sometimes, she says, the only difference in
their outward appearance is the presence of joint contractures, which are
characteristic of Emery-Dreifuss MD, in some; or an absence of
contractures, which is more characteristic of LGMD, in others.
Fortunately, she says, the last few years have seen the
development of many new types of electronic devices, beyond standard
pacemakers. Some, called PCDs, for pacingcardiac
defibrillators, combine a pacemaker, which keeps the hearts up to
speed, with a defibrillator, which converts a runaway fast heart rhythm
down to a normal one.
“I’m not sure the patients really care whether you call
their disease limb-girdle or Emery-Dreifuss,” McNally says, “but they’re
definitely at risk. If they’re a lamin patient, they want their heart
screened on a regular basis.” (Such screening usually includes a regularly
scheduled electrocardiogram and heart rhythm monitoring
[Holter monitoring] for 24 to 48 hours at a time, to measure
conduction in the heart; and an echocardiogram, which evaluates
“We know very well that lamin mutations increase your risk
of having arrhythmias, both slow and fast. So device insertion needs to be
considered for those patients,” McNally says.
“Sometimes the arrhythmias can come before the hearts
actually look that bad. In other words, you can have a risk of sudden
death when the heart still looks pretty good. You really want to make sure
you have a good cardiologist who knows what they’re dealing with if you
have a diagnosis of a lamin mutation.”
McNally says the fine distinctions once made between
conduction disturbance that comes from damaged conducting tissue and that
from cardiomyopathy may not be so important, now that new devices can take
care of both.
“Direct damage to the specialized conduction system could
be involved,” she says of patients with EDMD, “or the signal disruption
could come from scarred areas of the heart muscle. We can’t always tell
the difference; there’s a lot of overlap. Since we now treat it with a
defibrillator, I’m not sure it makes that much difference. Really what
we’re talking about is who needs a defibrillator and who doesn’t.”
Another new development is the biventricular
pacemaker, a device designed to make sure the right and left
ventricles are working together with a lead placed in each. This kind of
cardiac therapy, called resynchronization, can be used to treat a
failing pump — heart failure — that comes from cardiomyopathy or
“Right now if you’re a heart failure doctor and you take
care of people with cardiomyopathy, you really want to have an
electrophysiologist standing next to you,” McNally says. “We manage the
Even though the root cause of most MD-related cardiac
problems is the direct effect of a lack of or an abnormality in a heart
muscle protein, respiratory function plays a role in harming or helping
the heart as well. These two systems are intertwined.
In an environment of low oxygen and high carbon dioxide,
the heart has to work harder, Towbin says. Many of his patients use
noninvasive assisted ventilation, particularly at night, and he thinks
that helps their hearts.
McNally is also enthusiastic about treating the
respiratory aspects of MD. “I’m so excited that they put out the
guidelines for that,” she says, referring to guidelines for respiratory
care in DMD published by the American Thoracic Society in 2004.
sonographer Roxanne Ross performs an echocardiogram,
a painless test in which sound waves are
transmitted to a computer and converted
to an image of Jarrod's beating heart.
“Supporting lung function with BiPAP [a form of
noninvasive ventilation] at night for as long as possible, and choosing to
be ventilated when needed, will definitely work to preserve heart
function. The right [side of the] heart is not built for working against
high pressures. It’s used to seeing low pressures and fairly quickly will
become volume-overloaded and fail.
“On top of that, in MD you’ve got an intrinsic
cardiomyopathy problem, which is that you don’t have dystrophin or the
sarcoglycans there, so you’re losing cardiac muscle cells on a regular
Towbin tells parents, “A diagnosis of muscular dystrophy
should translate into the concept that you now have a minimum of three new
doctors: the neurologist, who should be the primary person, for sure, and
who should dictate care; the pulmonologist; and the cardiologist. And
probably in that order.”
By the age of 8 or 10, he says, a child with Duchenne MD
should have seen all of them, and “it should be as a routine. Parents have
to have the concept of early follow-up, early diagnosis, early therapy, in
order to extend life and lifestyle of the patient.”
Cardiac Effects of Muscular Dystrophy
Duchenne and Becker MD (dystrophin
dilated cardiomyopathy very common; severity
Fukuyama congenital MD (fukutin
dilated cardiomyopathy can occur and can be
Female carriers of Duchenne and
Becker MD (dystrophin mutation)
at risk for cardiomyopathy
Congenital MD 1C
(fukutin-related protein mutation)
dilated cardiomyopathy common
Limb-girdle MD 1A (myotilin
not reported in LGMD, but some myotilin defects
associated with cardiomyopathy
X-linked Emery-Dreifuss MD (emerin
arrhythmias and conduction defects common;
cardiomyopathy may occur
Limb-girdle MD 1C (caveolin
Female carriers of X-Linked
Emery-Dreifuss MD (emerin mutation)
10 percent to 20 percent have arrhythmias and
dilated cardiomyopathy common in LGMD 2C, 2E and
2F; may be less severe in LGMD 2D (alpha-sarcoglycan
Myotonic dystrophy type 2
(chromosome 3 mutation)
arrhythmias in 20 percent; conduction defects can
Limb-girdle MD 2G (telethonin
Facioscapulohumeral MD (chromosome
may have slightly increased risk of arrhythmias or
Limb-girdle MD 2I (fukutin-related
dilated cardiomyopathy common
not seen so far
Limb-girdle MD 2J (titin
not reported in LGMD, but some titin defects
Titin-related distal MD
cardiomyopathy can occur
Congenital MD 1A (laminin alpha 2
dilated cardiomyopathy uncommon; mild if
ZASP-related distal MD
cardiomyopathy occasionally occurs
Ullrich congenital MD (collagen 6
Adapted from “Cardiac
Involvement in Muscular Dystrophies: Molecular Mechanisms,” by Fiona
Goodwin and Francesco Muntoni, Muscle & Nerve,
November 2005; Washington University St. Louis Neuromuscular Home
Recommendations From the
In December, the Section on
Cardiology and Cardiac Surgery of the American Academy of Pediatrics
published its recommendations for cardiac care in DMD and BMD and
carriers of those dystrophies in its journal, Pediatrics. A summary
Cardiac care of the patient with DMD or BMD should begin after confirmation of the diagnosis. The patient should be referred for evaluation to a cardiac specialist with an interest in the management of cardiac dysfunction in neuromuscular disorders.
A complete cardiac evaluation should include (but
not be limited to) a history and physical examination,
electrocardiogram and echocardiogram. Consideration should be
given to other imaging studies, such as magnetic resonance imaging
Clinicians should be aware that the typical signs
and symptoms of cardiac dysfunction may not be present because of
the patient’s mobility limitations. The development of dilated
cardiomyopathy usually precedes the development of heart failure
symptoms by years and must be identified at its earliest
Signs and symptoms of cardiac dysfunction should
be treated. Consideration should be given to the use of diuretics
(medications to increase fluid excretion), angiotensin-converting
enzyme inhibitors and/or beta blockers.
Abnormalities of cardiac rhythm should be
promptly investigated and treated. Periodic Holter monitoring
should be considered.
Respiratory abnormalities contribute to
cardiovascular dysfunction in DMD and BMD. Evaluation and
treatment of respiratory abnormalities is recommended.
Patients undergoing treatment with
corticosteroids (such as prednisone) warrant increased cardiac
surveillance with specific monitoring for weight gain and high
Complete cardiac evaluation should be undertaken
before scoliosis surgery or other major surgical procedures. Risks
and benefits of the procedure should be discussed in detail with
the patient and the family.
Cardiac monitoring should be performed in DMD or
BMD patients during major surgical procedures and should continue
in the postoperative period. Specific anesthetic techniques and
decisions about ventilation during the operation should depend on
the patient and the procedure.
Anticoagulation therapy (to prevent blood clots)
should be considered in patients with severe cardiac
Clinicians who are experienced in the care of
patients with DMD or BMD and are knowledgeable about these
diseases should be actively involved when patients are treated in
an intensive care setting.
Recommendations for DMD Patients
Patients should be routinely managed in early
childhood with a complete cardiac evaluation at least every other
Yearly complete cardiac evaluations should begin
around 10 years of age or at the onset of cardiac signs and
Recommendations for BMD Patients
Complete cardiac evaluations should begin around
10 years of age or at the onset of signs and symptoms. Evaluations
should continue at least every other year.
Recommendations for DMD and BMD Carriers
Carriers of DMD or BMD should be made aware of
the risk of developing cardiomyopathy and educated about the signs
and symptoms of heart failure.
Carriers of DMD or BMD should be referred to a
cardiac specialist with experience in the treatment of heart
failure and/or neuromuscular disorders. Patients should undergo
initial complete cardiac evaluation in late adolescence or early
adulthood or at the onset of cardiac signs and symptoms, if these
signs or symptoms appear earlier.
Carriers should be screened with a complete
cardiac evaluation at a minimum of every five years starting at 25
to 30 years of age.
Treatment of cardiac disease is similar to that
outlined for boys with DMD or BMD.
Adapted from “Cardiovascular
Health Supervision for Individuals Affected by Duchenne or Becker
Muscular Dystrophy,” Pediatrics, December