CARDIOMYOPATHY IN MUSCULAR DYSTROPHY

Tucson, Ariz., September 2003

by Margaret Wahl
MDA Medical/Science Editor

Some 50 clinicians and scientists, many of whom hold MDA research grants, met in Tucson Sept. 28-30 to discuss cardiomyopathy. This cardiac muscle deterioration, seen in several forms of muscular dystrophy, has become a crucial issue for quality of life and longevity, as assisted ventilation and corticosteroids have made it possible for those with even the most severe forms of MD to live longer and attain educational and occupational goals.

THE SCOPE OF THE PROBLEM
Almost all the muscular dystrophies can affect the heart, because, after all, the heart is a muscle. There are, however, differences between heart and skeletal muscle tissue on the cellular and molecular levels, and the functions of the heart muscle are certainly different from those of skeletal muscle.

Also, the degree of skeletal muscle involvement, which determines how active a person with MD can be, affects heart muscle function.

Cardiac effects differ among the various forms of MD. (This conference focused on muscular dystrophy and didn’t include discussion of the non-MD forms of neuromuscular disease.)

For basic information on cardiomyopathy, see “The Heart Is a Muscle, Too,” part 1. For basic information on conduction defects, see “The Heart Is a Muscle, Too,” part 2.

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MDA grantee Jeffrey Towbin, co-chair of the meeting and a professor in the Department of Pediatrics, Cardiology Division, at Baylor College of Medicine in Houston, summarized the major diseases and gene defects associated with dilated cardiomyopathy, a serious condition in which the heart’s muscle layer thins and relaxes, interfering with its pumping ability. (Towbin’s MDA grant is to study exactly how dilated cardiomyopathy occurs in muscular dystrophy.)

This type of cardiomyopathy is often seen in Duchenne and Becker dystrophies, which are both related to defects in the gene for dystrophin, a protein that normally sits near the muscle cell membrane and attaches to proteins in the membrane and proteins inside the cell.

By some estimates, about 95 percent of boys with Duchenne MD develop cardiomyopathy, and between 10 percent and 30 percent die from it. It’s been estimated that cardiomyopathy develops in more than 90 percent of people with Becker MD, and it can also occur in DMD and BMD carriers.

Dilated cardiomyopathy is also seen in type 2F limb-girdle MD, which results from defects in the gene for delta-sarcoglycan, a protein that normally sits in the muscle cell membrane.

Elizabeth McNally, who co-chaired the meeting with Towbin, presented her recent findings on the cardiac aspects of the sarcoglycan-deficient forms of limb-girdle MD. (McNally, director of Cardiovascular Research at the University of Chicago, is an MDA grantee studying the potential of bone marrow stem cells to become muscle cells.) Her recent findings, which confirm those of other investigators, suggest that some cardiac abnormalities can be found in all forms of sarcoglycan-deficient LGMD (forms 2C, 2D, 2E and 2F).

In type 1 myotonic dystrophy, which results from a chromosome 19 genetic defect, a different type of cardiac problem, called conduction defect (meaning an abnormality in the way impulses controlling the heartbeat are transmitted through the heart), predominates, although cardiomyopathy can also be seen, especially late in the disease.

MDA research grantee William Groh at the Krannert Institute of Cardiology at Indiana University is studying heart rhythm disturbances and their associated risks in myotonic dystrophy and presented his extensive work in this field. Groh and colleagues have been studying some 400 patients with MMD at 23 U.S. centers since 1996.

They’ve found that cardiomyopathy may be more common than has been generally believed in this group, although conduction abnormalities are also common. Twenty percent of the patients had hypertrophic cardiomyopathy, a type of cardiomyopathy in which the heart muscle layer is thickened, interfering with the heart’s blood-holding capacity; and 18 percent had dilated cardiomyopathy.

They’ve found that patients often don’t have any symptoms, despite having significant and even life-threatening heart disease.

Patients with Emery-Dreifuss MD are at very high risk for heart disease. People with X-linked EDMD, resulting from mutations in the gene for the emerin protein, are highly likely to have conduction defects, with possible late development of cardiomyopathy and scarring of the myocardium (cardiac muscle layer).

In the chromosome 1 form of EDMD, which results from a defect in the gene for lamin A/C, there’s often a mixture of serious conduction defects and cardiomyopathy. Lamin A and C are made from the same gene and are located in the membrane that surrounds each cell nucleus. The emerin protein interacts with the lamin proteins near this membrane.

Mutations in lamin A/C also underlie the LGMD type 1B, and this disorder also leads to conduction defects and cardiomyopathy. Patients with LGMD2I, which stems from flaws in the gene for fukutin-related protein, can also have cardiomyopathy.

FINDING TARGETS FOR THERAPY
Several molecular biologists and physician-investigators working to understand the molecular basis of cardiomyopathy presented their findings.

Understanding these molecular mechanisms and those that underlie heart failure (the heart’s inability to pump an adequate amount of blood for the body’s needs), the most severe consequence of cardiomyopathy, may provide the research community with targets at which to aim experimental treatments.

The muscle cell membrane, which is very similar in cardiac and skeletal muscle cells, is the site of many defects underlying muscular dystrophy. MDA grantee Robert Bloch, a professor in the Physiology Department of the University of Maryland, showed how the muscle cell membrane is connected by filaments to the “contractile apparatus” in muscle cells. When the membrane is disrupted, the contractile apparatus probably is, too.

The membrane is clearly more fragile in mouse models of Duchenne dystrophy, as demonstrated in some impressive videotapes of moving cells under mechanical stress shown by Joseph Metzger, a professor in the Physiology Department at the University of Michigan.

Judy Anderson, a professor in the Department of Human Anatomy & Cell Science at the University of Manitoba (Canada) in Winnipeg, discussed the possible role of nitric oxide and nitric oxide synthase (necessary to make nitric oxide) in the development of cardiomyopathy. Anderson, who has MDA support to study the nitric oxide in a mouse model of DMD, discussed how one form of nitric oxide synthase (nNOS) is missing from its usual place in mice that lack dystrophin. This, she believes, may be part of the reason that cardiomyopathy develops in these mice and in patients, and it could be a target for intervention.

Elizabeth McNally’s experiments showed that there may be an interaction between vascular damage and cardiac muscle damage in the sarcoglycan-deficient forms of LGMD, with each abnormality increasing the other. Vascular spasms, which could be related to contractions of sarcoglycan-deficient muscle inside blood vessels in some forms of the disease, can certainly damage cardiac muscle tissue. But McNally also suggested that cardiac muscle damage could, in turn, cause vascular damage. This vascular aspect of cardiomyopathy could also be a therapeutic target.

Jill Rafael-Fortney, assistant professor in the Department of Molecular and Cellular Biochemistry at Ohio State University in Columbus, has identified protein abnormalities that stem from the loss of dystrophin in mice with DMD. One of these proteins has to do with cell-to-cell connections.

A protein called p300 seems to be needed for hearts to develop hypertrophic cardiomyopathy, reported Nanette Bishopric, an associate professor in the Departments of Pharmacology, Medicine and Pediatrics at the University of Miami. Her studies in mice have shown that p300 may underlie the transition between hypertrophy (excessive growth of cells) and heart failure, at least in mice. She’s undertaking some human studies now.

Another potential target for therapy is a protein called phospholamban. Kenneth Chien, a professor at the Institute of Molecular Medicine at the University of California at San Diego, told the group that this protein may be “pivotal” in the control of how cardiac cells handle calcium. When his research group blocked phospholamban in human cells taken from failing hearts, their contractile function improved.

Understanding how lamins and emerin interact could also lead to clues about human disease and the best treatment pathways.

Further information on how each mutation affects the behavior of the lamins and of emerin, which seems to need lamins to localize properly in the cell, would improve understanding of cardiac abnormalities in people with EDMD and the lamin-related form of LGMD.

MDA Medical Advisory Committee member Howard Worman, associate professor in the Department of Anatomy & Cell Biology at Columbia University in New York, described his MDA-supported research on the lamins, as did Matthew Taylor, director of Adult Clinical Genetics at the University of Colorado Health Sciences Center.

Mice without lamins show the same symptoms as do patients with EDMD, including conduction abnormalities in their hearts.

Some mutations in the lamin A/C gene affect lamin A, some lamin C, and others both protein forms; and some defects cause both dilated cardiomyopathy and a conduction defect, while others seem to cause only a conduction defect.

Viruses that affect the heart may play a role in worsening the cardiomyopathy seen in DMD and BMD, reported Kirk Knowlton of the Department of Cardiology at the University of California at San Diego. Knowlton presented his research showing that an enzyme made by the Coxsackie virus cuts the dystrophin protein at a specific point and that this protein cleavage underlies much of the heart damage caused by this virus.

More recent evidence presented by Knowlton shows that dystrophin deficiency, such as that seen in DMD and BMD, allows the virus easier access to cardiac muscle cells and, once there, easier exit from them as the virus replicates and moves into neighboring cells. Knowlton suggested that Coxsackie viruses and perhaps other viruses could worsen MD-related cardiomyopathy and that dystrophin deficiency probably makes people more susceptible to the effects of this infection.

AVAILABLE TREATMENTS & RECOMMENDATIONS FROM EUROPE
Reducing the workload of the heart may improve or stabilize cardiomyopathy and, it’s hoped, prevent it from progressing to irrevocable heart failure.

Jeffrey Towbin presented evidence from non-MD forms of cardiomyopathy showing that extreme resting of the heart with a mechanical ventricular assist device actually caused reversal of some aspects of the cardiomyopathy.

In animal experiments, Towbin said, cardiac drugs called beta blockers showed benefits similar to those of the ventricular assist devices, though they were less dramatic. He cautioned, however, that these results have not been confirmed in humans.

Resting the cardiomyopathic heart with angiotensin-converting enzyme (ACE) inhibitors and beta blockers is commonly done in non-MD forms of this disorder, several of the cardiologists noted, but specific studies in muscular dystrophy are lacking. Studies on the relative benefits and risks of various forms of exercise are also needed, they said.

The steroid drug deflazacort (similar to the U.S. drug prednisone) seems to increase production of the needed form of nitric oxide synthase, said Judy Anderson, and it significantly improved the appearance of the heart muscle in mice with DMD.

Implantable pacemakers and defibrillators may reduce the risk of stroke or sudden death in patients with irregular heart rhythms or heart rates that are too slow or too fast. William Groh’s research is directed at determining which patients with myotonic dystrophy would most benefit from having a pacemaker. In Europe, he noted, these devices are used in MMD quite often.

Paula Clemens, who has MDA funding to study gene transfer in mice with DMD, is also planning a trial of coenzyme Q10 and prednisone in older, wheelchair-using young men with DMD.

Coenzyme Q10 has been used to treat other diseases, including congestive heart failure and cardiomyopathy related to high blood pressure. It increases cellular energy production, acts as an antioxidant (tying up harmful compounds called free radicals), and interferes with a cell death pathway.

Prednisone has long been known to have benefit in skeletal muscle in DMD, and there’s some preliminary evidence that its close relative deflazacort may have some benefits for cardiopulmonary function.

If viruses turn out to be a major contributor to MD-related cardiomyopathy, antiviral agents could have a role in treatment. In addition, the concern about viral exposure, if it proves valid, may dampen enthusiasm for using immunosuppressants to combat inflammation in MD.

Kate Bushby, a professor at the Institute of Human Genetics of the International Centre for Life in Newcastle upon Tyne, United Kingdom, presented the findings of the 107th European Neuromuscular Centre Workshop on the management of cardiac involvement in muscular dystrophy that took place June 7-9, 2002, in Naarden, the Netherlands.

The full report is published in the February 2003 issue of the journal Neuromuscular Disorders.

The following is a summary of some of this report’s recommendations for patient care:

Duchenne MD
* echocardiogram and electrocardiogram at diagnosis
* cardiac investigations before any surgery and every two years up to age 10; every year after age 10
* assessment and treatment of respiratory dysfunction in parallel with the cardiac investigations
* treatment with angiotensin-converting enzyme (ACE) inhibitors with consideration of adding beta blockers when abnormalities start to progress

Becker MD
* echocardiogram and electrocardiogram at diagnosis
* screening for cardiomyopathy at least every five years
* treatment with ACE inhibitors and possibly beta blockers if progressive abnormalities are found
* consideration of cardiac transplantation

Female Carriers of Duchenne and Becker MD
* echocardiogram and electrocardiogram at diagnosis or after age 16 and at least every five years thereafter, with more frequent evaluations if abnormalities are found or if there are severe skeletal muscle symptoms or cardiac symptoms
* treatment with ACE inhibitors if significant abnormalities are detected, with consideration of additional medications
* consideration of cardiac transplantation

Type 1 Myotonic Dystrophy
* annual electrocardiogram starting at diagnosis
* monitoring with portable electrocardiogram recorder (Holter monitor) for 24 to 48 hours at diagnosis in adult patients
* echocardiogram at diagnosis in congenital myotonic dystrophy
* Holter monitoring if annual electrocardiogram shows increased risk of abnormally slow heart rate; consideration of invasive measurement of cardiac conduction to help decide whether pacemaker is needed
* consideration of drugs to treat overly fast heart rate in atria (upper cardiac chambers) but with recognition that these may aggravate tendency to overly slow heart rate or fast heartbeat in ventricles (lower chambers)
* pacemaker insertion when progressive rhythm abnormalities detected
* not inserting defibrillators routinely until more evidence justifies their use

Congenital MD
* echocardiogram and electrocardiogram at diagnosis
* echocardiogram prior to surgery or as symptoms suggest, except in congenital MD due to mutations in merosin gene, in which cardiomyopathy is generally not progressive

X-Linked Emery-Dreifuss MD
* electrocardiogram at diagnosis and yearly thereafter
* follow-up by a cardiologist, as electrocardiographic changes may be subtle and difficult to interpret
* 24- to 48-hour electrocardiogram (Holter monitoring) yearly, with particular attention to detecting overly fast or overly slow heart rates
* echocardiogram on a less regular basis
* permanent pacemaker implantation when electrocardiogram begins to show abnormalities of the heart’s sinoatrial node (natural cardiac pacemaker) or atrioventricular nodes (relay station from upper to lower chambers of the heart)
* in the presence of sinoatrial or atrioventricular conduction abnormalities on electrocardiogram, consideration of invasive electrophysiology testing to help determine the right type of pacemaker insertion site and mode of operation
* with frequent atrial fibrillation (uncoordinated contractions in upper chambers) or atrial standstill, consideration of anticoagulant drug warfarin to prevent clots or strokes

Female Carriers of X-Linked Emery-Dreifuss MD
* periodic electrocardiograms to detect atrial or atrioventricular conduction disease, while awaiting further study of the natural history of cardiac involvement in carriers

Chromosome 1 Emery-Dreifuss MD
* consideration of implantable defibrillator
* with frequent atrial fibrillation or atrial standstill, consideration of anticoagulant drug warfarin to prevent clots or strokes

Limb-Girdle 2C, 2D, 2E and 2F (Sarcoglycan-Deficient LGMD)
* same surveillance as for Duchenne or Becker MD for cardiomyopathy
* periodic surveillance for abnormal heart rhythms with Holter electrocardiogram or similar recording
* treatment with angiotensin-converting enzyme (ACE) inhibitors with consideration of adding beta blockers for cardiomyopathy (studies needed)
* consideration of calcium antagonist medications to reduce abnormalities of coronary artery flow, since there can be involvement of smooth muscle in coronary artery walls in sarcoglycan-deficient LGMD
* consideration of cardiac transplantation in selected patients with cardiac failure despite therapy

Limb-Girdle 2I (Fukutin-Related-Protein-Deficient)
* surveillance for cardiomyopathy as in Duchenne or Becker MD, taking into consideration that severity of cardiomyopathy may be out of proportion to that of skeletal muscle involvement
* treatment with angiotensin-converting enzyme (ACE) inhibitors with consideration of adding beta blockers for cardiomyopathy (studies needed)
* consideration of cardiac transplantation in selected patients with cardiac failure despite therapy

Limb-Girdle 1B (Lamin A/C-Related)
* consideration of implantable defibrillator
* with frequent atrial fibrillation or atrial standstill, consideration of anticoagulant drug warfarin to prevent clots or strokes

Facioscapulohumeral MD
* electrocardiogram and echocardiogram at diagnosis, with further follow-up dictated by the clinical picture; might need more testing in severe, childhood-onset patients

FUTURE THERAPIES -- REPAIR CELLS
Two speakers discussed their findings concerning cells that reside in the heart and may give rise to cardiac muscle cells when repairs are needed.

Kenneth Chien has found cells he’s called cardioblasts, which appear to be a little further along than true stem cells toward becoming cardiac muscle cells but which have some flexibility. These might be exploited in the future for their potential in cardiac repair.

Daniel Garry of the Department of Molecular Cardiology at the University of Texas Southwestern Medical Center in Dallas described a marker he’s dubbed Abcg2, for ATP binding cassette transporter, which appears on cells early in the developing mouse heart but disappears later on, only to appear again in tissue that needs repair work. These may or may not be related to the cells described by Chien.

Garry, who has had MDA funding to study stem cells that can become muscle, also suggested that the marker might in fact be a signal that recruits repair cells from elsewhere, such as the bone marrow.

In genetic disorders, stem cells would probably have to be genetically corrected or taken from healthy donors before they could be used as fully effective agents of repair, although some investigators have suggested that simply increasing their number, even without genetic correction, could be beneficial to the target tissue.

FUTURE THERAPIES -- GENE TRANSFER
Gene therapy by transferring the dystrophin gene into the heart is a highly promising strategy for the cardiomyopathy of DMD and BMD.

MDA grantee Dongsheng Duan, an assistant professor in the Department of Molecular Microbiology & Immunology at the University of Missouri in Columbia, described his extremely encouraging results with injecting a highly miniaturized dystrophin (microdystrophin) gene directly into the heart cavity in mice with DMD.

The microdystrophin gene is small enough to fit inside an adeno-associated virus (AAV), considered a safe and effective transport vehicle for genes whose target is muscle tissue. Mice lacking dystrophin that got these genes showed dystrophin protein production in their heart muscle cells for at least 10 months.

Jeffrey Chamberlain, a professor in the Neurology Department at the University of Washington in Seattle, a longtime MDA grantee who’s working closely with Duan on dystrophin gene transfer using AAV transporters, presented his work on different types of AAV. He’s found that type 6 may be the best form to use. He’s also looking at different molecular switches that turn on the transferred gene in the target tissue.

Chamberlain has found that it’s crucial to switch on the gene only in the target tissue (muscle), because turning it on elsewhere can elicit an unwanted immune response.

The best skeletal muscle switch is called CK6, he said, but it unfortunately doesn’t work in heart tissue, making it necessary to find another way to turn on the gene in the heart.

Delivering the gene to an isolated muscle, such as the heart, could be very helpful in DMD and BMD dystrophies. However, the ideal form of gene therapy would be to deliver this gene to the entire musculature via the circulation.

Hansell Stedman, an associate professor in the Department of Surgery at the University of Pennsylvania and an MDA grantee, described combination surgical-chemical procedures he’s tested in animals that might make vascular delivery to whole body regions possible.

Stedman’s colleague Charles Bridges, Chief of Cardiothoracic Surgery at the University of Pennsylvania Health System, showed how isolating the heart from the rest of the circulation could be useful for delivering genes specifically to the heart.

MDA grantee Barry Byrne, director of the Powell Gene Therapy Center at the University of Florida in Gainesville, discussed the regulatory requirements for producing viral gene transport vehicles suitable for human use in the United States.

He noted that even though more effective and perhaps safer forms of AAV are now in development, switching from the ones now approved for human use would result in a significant delay in starting human trials.