Mar. 24, 1998 DURHAM, N.C. - It's a cruel irony that the body's most crucial components are also the most vulnerable. Snap your spine and you're paralyzed because nerve cells can't regenerate. Damage your heart muscle in a heart attack and it can't mend itself.
"You are born with all the heart cells you'll ever have," says Duke molecular biologist and heart researcher Doris Taylor. "Once you damage the heart muscle, it's gone forever. The heart can't regenerate new muscle."
Yet as any bodybuilder 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 to actually regenerate dead heart muscle.
"Skeletal muscles, the muscles we use to get around, get damaged all the time when we strain them by overuse," Taylor said. "The skeletal muscles have specialized cells called myoblasts that can reproduce to fix damaged muscles."
Taylor reasoned that she might be able to recruit myoblasts taken from a tiny plug of a patient's arm or leg muscle to boost the contraction of a failing heart.
"Right now treatment options to prevent progression to heart failure after a severe heart attack are severely limited," Taylor said.
During a heart attack clogged arteries in the heart suffocate the heart muscle, depriving it of oxygen and nutrients long enough to kill muscle that keeps the heart pumping. When enough heart muscle is damaged, it can no longer pump efficiently. The remaining heart muscle cells grow larger to compensate, but that only makes the heart more inefficient. The result is congestive heart failure, a chronic condition that kills more than 41,000 annually in the United States and Europe.
For severe heart failure, heart surgeons can implant a mechanical pump that assists the heart until a suitable donor heart can be found for transplantation. A 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 is their own tissue, which won't be rejected by the immune system.
She is testing her idea using rabbits, which have hearts very similar to human hearts. Unlike some animals, rabbits have heart attacks just like people, Taylor said.
Her early studies, published in the May 1997 issue of the Proceedings of the Association of American Physicians, show that it is possible to isolate myoblasts from arm or leg muscle, grow them in a laboratory dish for a few days and then inject them into the heart where they take up residence in the existing heart muscle.
In that study, Taylor and cardiologists William Kraus and Brian Annex, heart surgeons Dr. R. Eric Lilly, Dr. Scott Silvestry and Dr. Donald Glower, all of Duke, and pathologist Dr. Sanford Bishop of the University of Alabama at Birmingham, tried two ways of getting myoblasts into the heart. They injected the cells directly into the heart muscle using a needle and syringe, and found that in using this method, the myoblasts took up residence in an area around the injection site. And they learned that if they injected too much fluid, the heart rhythm became unstable and the rabbits died. In a second method they used a catheter, similar to those used to clear blocked arteries in balloon angioplasty, to infuse the cells into the heart. In this experiment the cells became much more broadly distributed across the damaged section of heart and integrated into the heart muscle.
Based on these findings, Taylor and her collaborators are now studying how well the introduced cells work to boost contraction.
"Usually, if 30 to 40 percent of the left ventricle is damaged it can lead to congestive heart failure," Taylor said. "We found we can deliver 10 million cells, enough to replace up to 75 percent of the damaged tissue."
New research, done in conjunction with surgeon Zane Atkins and a team of medical students, will test how well the cells actually work to boost contraction. Preliminary findings suggest the cells are indeed contracting in otherwise dead tissue and improve the function of the heart, Taylor said. Since myoblasts are skeletal muscle, which by its nature contracts when stretched, Taylor explained, the cells likely respond by contracting when they are stretched as the heart's chambers fill with blood. But it is too soon to say precisely how much they are contracting, she added.
Investigators at other institutions are trying similar strategies by implanting genetically engineered animal cells into damaged hearts, but Taylor said she believes her group can accomplish the same goal without using cells from animals or cells that have been engineered.
"We think we can use skeletal muscle and get nature to do the engineering for us," Taylor said. "I like the idea of treating patients using their own cells."
However, Taylor also plans to combine her 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.
"If we could combine new blood vessel formation with new muscle formation, we could for the first time, regenerate living heart muscle where there was only dead tissue," said Taylor.
She and the research team next plan to extend their early work into larger animals such as pigs, and to see how long they can maintain active pumping in the introduced cells. If the experiments go well, the researchers plan to try the procedure in patients with end-stage heart failure by 1999.
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