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Chemical ’band-aid’ prevents heart failure in mice with muscular dystrophy

18.07.2005


Could be first step for treatment of heart damage caused by MD



A common chemical used in the manufacturing and pharmaceutical industries can repair damage to cardiac muscle cell membranes and prevent heart failure in mice with the genetic mutation that causes Duchenne muscular dystrophy, according to scientists at the University of Michigan Medical School.

The mutation in the dystrophin gene causes the progressive deterioration of skeletal muscles seen in people with MD. But the mutation affects cardiac muscle, too. Many people with Duchenne muscular dystrophy die in their 20s from heart failure caused by cardiomyopathy, a gradual weakening of the heart muscle. Heart failure is the second leading cause of death in DMD.


The chemical sealant that protected hearts in dystrophic mice from damage is called poloxamer 188. According to Joseph M. Metzger, Ph.D., the U-M scientist who directed the research, poloxamer 188 can insert itself into small holes in cell membranes just like "a finger in a dike".

The U-M study will be published July 17 in Nature as an advance online publication.

The study is important because it is the first to show what happens to heart muscle cells called myocytes in the absence of dystrophin, and the first study to demonstrate a new, promising approach to repair the damage. The study’s authors emphasize, however, that several years of additional animal research will be required before the treatment could be tested in human patients.

"Most people think of the heart as a pump," explains Metzger, a professor of molecular and integrative physiology and of internal medicine in the U-M Medical School. "They say their heart is failing, because it’s not pumping hard enough. That can be true, but another major problem is poor function during the relaxation phase when the heart fills with incoming blood. In our study, we found that cardiac myocytes in dystrophin-deficient mice don’t relax and lengthen as readily as cardiac myocytes in normal mice. They are stiffer than normal heart muscle cells, and vulnerable to damage when stretched.

"That’s where poloxamer 188 comes in," Metzger adds. "It assists the heart to be more compliant during the relaxation phase – allowing more blood to flow into the heart. We demonstrated this effect at the level of individual heart muscle cells, and it turned out to be true at the organ level, also."

The key to the U-M discovery was technology developed by Soichiro Yasuda, Ph.D., a post-doctoral fellow and co-first author of the study. He created a device to allow the simultaneous measurement of force and intracellular calcium concentration in individual myocytes as they are stretched. Yasuda’s device uses microcarbon fibers stuck by electrostatic attraction to each end of a single cardiac myocyte. As the myocyte is stretched between the carbon fibers, a transmitter on one fiber measures the amount of stretch and a force transducer on the other fiber measures the contractile force of the cell in response to that stretch.

"It’s like stretching a rubber band," Yasuda says. "You can do specific controlled stretches and record the force generated by the cell. We found that myocytes from normal mice easily handled a 20 percent stretch in length, while myocytes from dystrophin-deficient or mdx mice had about 70 percent more passive tension in response to the stretch. Compared to normal myocytes, mdx myocytes were stiffer and resistant to stretching. When they were stretched repeatedly, they started shaking and eventually contracted and died."

"It’s a physiologically relevant test, because it mimics what happens in the heart muscle when myocytes must relax and stretch to make room for incoming blood filling the heart," says Metzger, who is affiliated with the U-M’s Cardiovascular Center. "This shows, for the first time, the effect of a deficit of dystrophin on individual cardiac myocytes. Our hypothesis was that stretching created small tears or holes in the myocyte membrane, which allowed calcium ions to get inside the cell. When calcium floods a cell, it triggers a hyper-contraction, which causes the cell to roll into a little ball and die."

To test for the presence of tears in myocyte membranes, U-M researchers used a special fluorescent dye, which cannot penetrate an intact cell membrane. After a 20 percent stretch, control myocytes remained stable and showed no fluorescence, while myocytes from mdx mice became unstable, started shaking and showed a steady increase in fluorescence, providing direct evidence for membrane damage.

When U-M scientists repeated the stretch test after bathing both types of cells with a solution of poloxamer 188, they found that it restored the ability of mdx myocytes to handle a 20 percent stretch without damage or increased levels of calcium. P188 had no effect on normal myocytes.

The next step was testing the ability of P188 to prevent cardiac damage in the hearts of mdx mice. They found that an intravenous infusion of P188 in mdx mice restored the volume of the heart’s main pumping chamber to the volume of normal mice – a direct effect of P188’s ability to restore normal elastic properties in individual cardiac myocytes.

To examine the effects of P188 on mdx hearts under stress, U-M researchers gave the mice a drug called dobutamine to make the heart work harder and faster for 30 minutes.

"During the stress test, 40 percent of the untreated mdx mice progressed to cardiac failure," says DeWayne Townsend, D.V.M., Ph.D., a post-doctoral fellow and co-first author of the study. "Even those that didn’t reach the threshold were doing poorly. The control mice, on the other hand, did just fine throughout the whole procedure. When we gave the mdx mice an infusion of P188 before the dobutamine, none of the mdx mice went into cardiac failure. The polyoxamer had an instant corrective effect in the mdx mice, which really surprised us."

In future research, U-M scientists want to test P188 on mice with other types of dystrophies and see if it works as well when given as injections, rather than infusions.

Metzger emphasizes that it is uncertain whether P188 will have any clinical use in patients with muscular dystrophy. The material has been used for 24 hours to 72 hours in a phase III clinical trial for patients with sickle-cell anemia, but questions about the safety of long-term use remain.

"If issues of dosing and long-term safety can be resolved, our research suggests that poloxamer 188 could be a new therapeutic agent for preventing or limiting progressive damage to the hearts of patients with muscular dystrophy," Metzger says.

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

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