CONTACT: JENNIFER BROWN
Iowa City IA 52242
(319) 335-9917; fax(319) 335-8034
Release: Jan. 12, 2001
(NOTE TO EDITORS: Dr. Campbell will be available from Jan.12 on.)
UI researchers publish study on heart damage and muscular dystrophy
IOWA CITY, Iowa -- Cardiomyopathy, damage to heart muscles, is one devastating
consequence of muscular dystrophy. Following up on clues uncovered by previous
research, and using mouse models of a particular kind of muscular dystrophy,
University of Iowa researchers have discovered a potential preventative treatment
for some forms of cardiomyopathy caused by muscular dystrophy. They also have
found potential for applying a method commonly used to assess heart damage
in heart attack cases to screen for heart damage in patients with cardiomyopathy
associated with muscular dystrophy. The study results appear in the Jan. 15
issue of the Journal of Clinical Investigation.
Muscular dystrophy, one of the most common genetic diseases, affects one
in 4,000 boys, although it is much less common in girls. Rather than being
a single well-defined condition, muscular dystrophy is actually a complicated
set of diseases caused by genetic mutations that affect various protein components
of the so-called dystrophin-glycoprotein complex. This large complex of protein
parts provides an essential bridge between structures inside and outside of
The UI researchers, led by Kevin Campbell, Ph.D., Roy J. Carver Chair of
Physiology and Biophysics, and professor of neurology, used genetically modified
mice as models of limb-girdle muscular dystrophy (LGMD), a certain type of
muscular dystrophy found in humans. The team found that long-term treatment
with the drug verapamil could prevent heart muscle damage in the mice without
serious side effects. Verapamil prevents constrictions of the blood vessels
and has been shown to be beneficial in treating hypertension, cardiac arrhythmias
and other human and animal models of cardiomyopathies.
"Most importantly, this work illustrates the success of our approach
to studying muscular dystrophy," said Campbell, who also is a Howard
Hughes Medical Institute Investigator and a UI Foundation Distinguished Professor.
"Our goal is to try and understand the pathogenic mechanism of the disease.
We know what the genetic defect is, but at the cellular level we dont
know what causes the muscle cells to die. By gaining that understanding we
think we should be able to develop therapeutic strategies."
Earlier studies have suggested that interruptions in oxygen supply to the
heart muscles are a cause of cardiomyopathy. Oxygen is carried to tissues
in the blood, and it seemed that a defect in the vascular smooth muscle, the
muscle cells surrounding the blood vessels, caused constrictions of the blood
vessels supplying the heart muscle. These constrictions intermittently cut
off the oxygen supply to the heart muscle and initiated the damage.
The genetic defect in the mouse models of human limb-girdle muscular dystrophy
caused the loss of parts of the dystrophin-glycoprotein complex in the animals
vascular smooth muscle. The researchers observed focused areas of damage to
the heart muscle, as if blood flow was being cut off from those particular
"In smooth muscle, we saw that the complex was disrupted. Then we started
using techniques that allowed us to look at defects in the blood vessels of
these mice," Campbell said. "We found there were constrictions in
the blood vessels in this animal model."
Even though the scientists did not have a complete picture of the molecular
events underlying the disease process, their new understanding of how the
damage developed suggested that using a drug to prevent the constrictions
would alleviate the cardiomyopathy. The drug chosen for the study was verapamil.
"It is one of the first studies, at least in the field of muscular
dystrophy, in which an understanding of the pathogenesis (disease process)
has led to a drug treatment in an animal model, which may have potential as
a therapy for humans," Campbell commented.
As long as the genetically altered mice were taking the verapamil, they
did not show any signs of cardiomyopathy and their blood vessels appeared
normal despite the disruption of the protein complex. However, if the mice
were taken off the drug treatment, the damage to the heart muscle started
immediately. The researchers hope that their results will allow them to initiate
studies in humans with limb-girdle muscular dystrophy.
A more immediately applicable clinical development stemming from this study
may be a new, more sensitive way to diagnose cardiomyopathy in muscular dystrophy
patients. The research showed that the levels of a molecule called cardiac
troponin I (cTnI) in the mouse models was a highly specific indicator of heart
muscle damage. Levels of cTnI are currently measured in patients suspected
of having a heart attack. The UI study suggests that measuring cTnI levels
would also be an excellent way to detect otherwise unnoticed heart damage
in patients with muscular dystrophy. Indeed, improved early diagnosis of the
onset of cardiomyopathy coupled with the drug intervention proposed in this
study, could mean treatment before the cardiac damage is too severe.
Ronald Cohn, M.D., UI postdoctoral fellow in Campbells laboratory,
and lead author of the study, is a physician who works with muscular dystrophy
patients. He said the possibility of having a drug that can prevent the onset
of cardiomyopathy in some of his patients is very exciting.
Campbell is also excited about the prospects of this study and indicated
that this kind of work would be impossible without the use of genetically
well-defined animal models of human disease.
"It is difficult to take multiple muscle biopsies from a patient who
is already losing muscle to a disease," Campbell said.
The animal models give researchers a way to mimic human diseases and allow
them to closely investigate the physiological causes and mechanisms of disease
processes. This type of work has great potential to lead to treatment for
diseases like muscular dystrophy.
"One of the exciting aspects of our study is that there may be pharmacological
approaches to treat complications arising in patients with muscular dystrophy,"
In addition to Campbell and Cohn, Steven A. Moore, M.D., Ph.D., UI professor
of pathology, played a key role in this study. He used a variety of techniques
to closely examine changes to the muscle cells in the genetically modified
mice. Other UI investigators from Campbells lab who were involved in
the research are Madeleine Durbeej, Ph.D., Ramon Coral-Vazquez, Ph.D., and
Sally Prouty. This work was supported by the Muscular Dystrophy Association.
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