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 January 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 muscle cells.
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 don't 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 areas.
"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 Campbell's 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," Campbell said.
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 Campbell's 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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