Transplanted Skeletal Muscle Mimics Heart Muscle; Helps Failing Heart Pump, Duke Researchers Say
DURHAM, N.C. -– Immature muscle cells transplanted from the leg of an animal to its heart apparently can "learn" to act like heart muscle, significantly boosting the ability of damaged hearts to contract, Duke researchers have found.
The researchers say it is a promising first step toward a simple transplant procedure that could augment current treatment for damaged hearts.
The experiments, reported in the August issue of the journal Nature Medicine, show that a tiny plug of muscle taken from an animal's leg and injected into the same animal's severely damaged heart muscle can boost contraction between 34 percent and 100 percent compared to non-treated animals.
"We were excited to see that in many of our test animals, contractions began to approach that of a normal animal," said Duke molecular biologist and heart researcher Doris Taylor. "In addition, when we examined the hearts of the treated animals, we found that their heart tissue was less stiff than if we had not treated the animals, meaning the heart could stretch better. The treated heart was not as rigid as a failing heart."
Taylor said her research team, which also included surgeons Dr. Donald Glower and Dr. Zane Atkins, cardiologist Dr. Willam Kraus, and researchers Pinata Hungspreugs, Thomas Jones, Mary Reedy, and Kelley Hutcheson, hopes to test the therapy by next year in patients with severe heart failure who are awaiting heart transplants. The research was funded in part by the American Heart Association and a grant from the National Science Foundation Engineering Research Center.
The researchers said they hope eventually to combine their treatment with existing therapies to prevent heart failure. They envision that when a patient comes to the emergency room with a heart attack, doctors would remove a small plug of cells from the leg and grow them in the laboratory for about two weeks, long enough to assess damage to the heart and for the immune system to return to normal. Then the cells would be delivered with a catheter, a device now commonly used to clear blocked arteries. "Even if the cells only boosted contraction by 10 or 15 percent, that could mean a significant difference in a patient's quality of life," Taylor said.
Taylor began her experiments several years ago with the hope of providing some way to prevent hearts that were damaged by severe heart attacks from progressing to heart failure. Currently there is no way to reverse damage done to the heart during an extended period of low oxygen, as occurs in a severe heart attack. Although the remaining heart muscle cells grow larger to compensate, that only makes the heart more inefficient. Cardiologists rely on quickly removing blockages in arteries with clot busting agents. But in cases where the heart is damaged, it can't repair itself. The result can be congestive heart failure, a chronic condition that kills more than 41,000 people annually in the United States and Europe.
"Treatments for severe heart failure are currently limited to making the remaining heart work better or heart transplantation," Taylor said. "You are born with all the heart cells you'll ever have. Once you damage the heart muscle, it's gone forever."
Yet as any body builder knows, if you strain your biceps pumping iron they respond by building new muscle. In a deceptively simple idea, Taylor decided to try to recruit the services of individual skeletal muscle cells, called myoblasts, to actually regenerate dead heart muscle.
"Our hope is that, as a first step to treating patients, transplanted cells may boost the heart's ability to contract, at least long enough for a new heart to become available. When the failed heart is removed, we will be able to see if the engrafted cells performed as in our preliminary tests."
The technique is different from any other that has been tried for treating heart failure. For example, another new experimental procedure, called cardiomyoplasty, uses skeletal muscles taken from a patient's back or abdomen to wrap around an ailing heart. The muscle is stimulated by a device similar to a pacemaker to augment weak heart muscle. But, Taylor said, the skeletal muscle isn't really hooked up to the heart. It acts more like a mechanical assist device.
"Our idea is similar to earlier experiments by researchers at other universities who are trying to implant fetal muscle cells into hearts to stimulate growth," Taylor said. But, she added, that idea is not practical because there is no ready supply of fetal tissue and it could cause an immune reaction. The advantage of using muscle cells from each patient is that it's their own tissue, which won't be rejected by the immune system.
The Duke research team is testing the idea using rabbits, which have hearts very similar to a human heart. "Unlike some animals, rabbits have heart attacks just like people," Taylor said.
The researchers injected the damaged hearts of 12 rabbits with 10 million muscle cells. In seven of the 12, the cells took up residence and began stretching and contracting. In addition, when the researchers examined the hearts three to six weeks later, the skeletal muscle cells had organized themselves in a pattern resembling heart muscle cells, suggesting that the skeletal muscle had somehow "learned" how to act like heart muscle.
"We were very encouraged to see that the engrafted cells appear to adapt to their local environment and mimic heart muscle," Taylor said. "We had been concerned that the skeletal muscle could induce an arrhythmia if it did not respond to the electrical signals of the heart, but that doesn't appear to be happening."
In the remaining five rabbits, immune system inflammatory cells appear to have destroyed the injected muscle cells. Taylor said this is a natural response. The body sends immune system cells to the heart to clear out dead heart cells, and in this case they also cleared out the injected cells. She says that in the future, they will wait longer, until the body's normal inflammatory response subsides after the initial heart attack, before injecting the skeletal muscle cells. When the procedure is tried on people, doctors may also use anti-inflammatory agents to help give the skeletal muscle time to engraft, she said.
The researchers also plan to combine their work with findings reported in February by Dr. Thomas-Joseph Stegmann and his colleagues of Fulda Medical Center in Fulda, Germany. These researchers were able to induce damaged heart muscle to regenerate new blood vessels using a human growth factor called fibroblast growth factor 1 (FGF 1) that they produced with genetic engineering techniques.