Update (Jan. 23, 2013): As of early 2013, MDA's DMD Clinical Research Network includes these five sites: University of California, Davis (UC Davis); Nemours Children's Hospital in Orlando, Fla.; Washington University in St. Louis; Nationwide Children’s Hospital in Columbus, Ohio; and Children's Medical Center in Dallas. See Help Today, Help Tomorrow is Goal of MDA's Duchenne Clinical Research Network to learn more.
Although it’s clear that people with Duchenne and Becker muscular dystrophies should be closely monitored and treated by heart specialists, doctors and researchers at a recent MDA-sponsored meeting say there still are many unanswered questions about optimal clinical care of the DMD/BMD-affected heart.
To begin to answer some of these questions, pediatric cardiologists, neurologists and other experts met for a conference on the heart in DMD and BMD at Nationwide Children’s Hospital in Columbus, Ohio, on January 21-22, 2011. The conference included more than 40 leading clinicians and researchers from the United States and Europe.
Crucial questions posed at the conference included:
“It’s incumbent on this group, and on the larger neuromuscular disease community, to sort this out,” said neurologist Valerie Cwik, MDA executive vice president for research and medical director. “It’s a great responsibility, but also a great opportunity.”
Cwik began the conference by describing the work of the MDA DMD Clinical Research Network, a network of five elite MDA clinics (including Nationwide Children’s) that was established in 2008 to conduct clinical studies aimed at improving and standardizing medical management of DMD, and to expedite clinical trials in this disorder. The network currently is conducting a natural history study of cardiomyopathy in DMD and a trial of two cardiac drugs in DMD/BMD (see below).
Neurologist Kevin Flanigan and cardiologist Hugh Allen of Nationwide Children’s Hospital co-hosted the meeting and were among the presenters, a group which included many current and former MDA grantees.
The heart in DMD/BMD
Longer life spans in DMD mean that almost all will experience heart problems at some point. Although many deaths in DMD are due to respiratory problems, DMD deaths due to cardiomyopathy are probably underreported, said conference participants.
In addition, cardiomyopathy is an extremely common feature of BMD, and may be found in carriers of DMD and BMD. About 70 percent of people with BMD develop cardiomyopathy by age 40, and an estimated half of deaths in BMD are caused by heart disease.
However, the age of onset of heart problems in DMD and BMD, as well as the severity of the problems, can vary widely from person to person — even among brothers with the same genetic mutation.
For these reasons, conference presenters recommended that all people who receive a diagnosis of DMD or BMD, or who are known to be carriers, should see a cardiologist as part of their regular treatment plan.
Several other presentations focused on how to accurately diagnose cardiomyopathy and how best to measure changes in heart function. Although MRIs (magnetic resonance images) are considered the “gold standard” of heart tests, they are expensive and (for a variety of reasons) sometimes difficult, or even impossible, to conduct on people with DMD or BMD.
Conferees agreed on the need to standardize interpretation of heart function measurements so that accurate information can be obtained and proper studies conducted.
Treating the DMD-affected heart
The best course of treatment for people with DMD-related cardiomyopathy was a major topic of discussion.
Several speakers pointed out the potential for corticosteroids (a common treatment for skeletal muscle weakness in DMD) to have a negative effect on the heart, or at the very least, put more strain on a weak heart by strengthening skeletal muscle function. Steven Lipshultz, a cardiologist at Miami Children’s Hospital in Florida, acknowledged that steroids have benefits for skeletal muscle function but could have negative effects on the heart. However, he noted that the skeletal muscle benefits may counterbalance any negative cardiac effects.
Neurologist Jerry Mendell, director of the Center for Gene Therapy at the Research Institute of Nationwide Children’s Hospital, as well as co-director of the Muscular Dystrophy Association Clinic at Nationwide, reviewed several gene-repair strategies that are showing promise in skeletal muscle, such as stop codon read-through and exon skipping.
“But preservation or replacement of skeletal muscle dystrophin threatens the unprotected heart,” he said, so researchers must be looking for ways to strengthen heart muscle at the same time as they are working to strengthen skeletal muscle.
Mendell said research by him and others has shown that gene-repair strategies as they're currently designed are unlikely to affect heart muscle. He said the best strategy for DMD-related cardiomyopathy will probably be a combination of gene replacement therapy and drugs that lessen the workload of the heart.
Drugs such as ACE (angiotensin converting enzyme) inhibitors and ARBs (angiotensin receptor blockers) have been proven safe and effective in adults with heart conditions unrelated to neuromuscular disease. These drugs also appear to improve cardiac function in children and adults with DMD and BMD, and cardiologists now routinely prescribe them to people in these groups, despite the fact that there are few studies quantifying their effects on cardiomyopathy in DMD and BMD. Some physicians also believe that another type of cardiac drug, beta blockers, should be considered to help slow down the heart.
Another important question addressed at the conference was when treatment should begin. Some doctors favored a preventative approach and argued for starting treatment before signs of cardiomyopathy appear. Others said that, since the onset of DMD-related heart disease is so variable, the side effects and potential risk factors of long-term use of these drugs, especially in children, warrants a wait-and-see approach.
Physicians who spoke about conduction disorders (problems with the electrical signals that make the heart beat) said they were reluctant to implant defibrillators in the hearts of DMD and BMD patients younger than age 18. However, they said the devices may be appropriate to use in older people with irregular heartbeats, including DMD and BMD carriers.
Physicians agreed that each person should be evaluated individually by a multidisciplinary team, and the causes of their cardiac problems clearly identified before a decision to implant a defibrillator is made.
Clinical trials and studies
In order for doctors to learn more about cardiomyopathy in DMD and BMD, several databases have been organized to collect information from people affected by these conditions.
Kevin Flanigan spoke about one that he helped organize, the United Dystrophinopathy Project (UDP), which is funded by the National Institutes of Health and is collecting data from seven centers nationwide, as well as from self-reporting through its website. UDP contains data from about 1,600 subjects and is open until March 1, 2011, after which it will be closed and the data made available to researchers to begin their analyses.
Other presentations focused on the results of preclinical (laboratory) studies and clinical trials that showed that drugs such as ACE inhibitors, diuretics and sildenafil (Revatio) appeared to have beneficial effects on cardiomyopathy in DMD.
Researchers agreed that more study is needed to determine the types, dosages and combinations of cardiac medications that are optimal for people with DMD or BMD. Studies attempting to answer some of these questions are currently under way in France, Germany and England.
In addition, the five centers of the MDA DMD Clinical Research Network are conducting a trial comparing two types of heart drugs, lisinopril (an ACE inhibitor) and losartan (an ARB). Due to narrow inclusion criteria, the MDA network trial has been hampered by low participation rates, and there was discussion of expanding the trial to several additional sites to increase the number of enrollees.
Conference organizers said the lively exchange of information that took place between cardiologists and neurologists at the meeting was an important step toward establishing consensus and standards of care for the medical management of cardiomyopathy in DMD and BMD.
The participants plan to publish a report of the proceedings in a scientific journal, and agreed to work together to reach consensus on the many issues that remain unresolved.
For more information
To read more about a recent study on the genetics underlying Becker MD, please see Cardiomyopathy in Becker MD.
For more on the losartan versus lisinopril trial, please see DMD Clinical Research Network Studying Dystrophin-Deficient Heart.
Additional information about what is known about optimal medical management of the DMD-affected heart can be found in Revising Cardiac Care in Muscular Dystrophies.