BETHESDA, MARYLAND--It's been more than 6 years since the first person was injected with stem cells to rescue a failing heart. Hundreds of patients have since followed the lead of that 46-year-old German man. But experts are still divided on how well the strategy works. At a 2-day symposium on cardiovascular regenerative medicine at the National Institutes of Health here that ended today, cardiologists, surgeons, pathologists, and other researchers debated the future of cardiac cell therapy. Clinical trials and animal studies are supplying a wealth of information; so far, the treatment seems safe. But it is not at all clear which stem cells should be given, or by what method--or, most importantly, whether patients who get them are likelier to survive.
Cardiologists seized on cell therapy as a way to prevent decay of heart muscle immediately after a heart attack and restore muscle long after it had died. But three of the four largest clinical trials have failed to accomplish what they set out to do--improve a particular measure of heart function, measured as an increase the amount of blood pumped, the so-called ejection fraction. By other measures of health, however, such as regeneration of heart muscle or preventing heart attacks, the trials may have been a success, argued some of those who conducted them. "It's sad, but it's life" that the trials failed, said Philippe Menasché, a cardiac surgeon at the George Pompidou Hospital in Paris who has tried his hand at transplanting skeletal muscle cells. But "should we be discouraged? Certainly not."
One big problem, Menasché and others noted, is that the transplanted cells may be disappearing quickly rather than sticking around to do their job. Scientists have seen this happen in animals. Joshua Hare, a cardiologist at the University of Miami in Coral Gables who also directs the Interdisciplinary Stem Cell Institute, described work in pigs showing a "washout of cells" within 8 weeks of delivery. Charles Murry, a pathologist at the University of Washington, Seattle, described how he spent a frustrating 18 months trying to keep cardiac muscle cells derived from human embryonic stem cells alive in mice after an induced heart attack. It nearly drove him over the edge, he joked, showing a slide of a white pickup truck hanging over a cliff. Finally, his lab found a cocktail of factors that kept the cells alive, enabling them to engraft and preserve cardiac function in affected mice. The work appeared in the September issue of Nature Biotechnology.
A side effect could complicate how the cells are delivered. Injecting cells directly into the heart, which facilitates engraftment, may cause arrhythmias. In a sobering talk in which he chided researchers for moving quickly into human trials before conducting exhaustive studies in large animals, Menasché pointed to a study published in May in Circulation by a team in Britain, showing that rats suffered more arrhythmias if bone marrow was shot straight into the heart. (Menasché's own cell therapy trial was plagued by several cases of arrhythmias, which he now is not certain were a result of the cell therapy.)
Another hot question: Can injected cells develop in ways that ameliorate heart disease? Scientists are working with a hodgepodge of various stem cells, some better characterized than others. They include Hare's favored mesenchymal stem cells, which can become bone, muscle, and more; a cocktail of bone marrow cells used in German trials; and bone marrow cells that express a certain marker on their surface called CD34. One trial in the planning stages, based in Cedars-Sinai Medical Center in Los Angeles, California, and at Johns Hopkins University in Baltimore, Maryland, hopes to use a natural pool of cardiac stem cells, whereas groups such as Murry's are interested in coaxing embryonic stem cells into more defined but still flexible heart cells. Pinpointing what each of these cell types can accomplish in an animal isn't easy. "Right now, we're limited to throwing them on plastic" to see what they do, said David Scadden, co-director of Harvard's Stem Cell Institute in Cambridge, Massachusetts, in a talk.
Potency of stem cells is also an issue. Cardiologist Douglas Losordo of Northwestern University in Chicago, Illinois, reviewed published studies showing that certain stem cells, such as those from bone marrow, may be less potent when they come from a heart patient than from a healthy person. Menasché speculates that conditions such as diabetes or atherosclerosis can impair function of some bone marrow stem cells. Using cells from patients--most of what's been tried so far--has other downsides, such as cost and complexity. Hare described the first-ever trial in heart patients to take a different tack and use donor stem cells. Led by Hare and sponsored by Osiris Therapeutics in Baltimore, the trial enrolled 53 people who got mesenchymal stem cells within 10 days of a heart attack. In the spring, Hare reported that there were no significant safety problems, such as mesenchymal stem cells developing into other organs.
What next? One of the biggest cell therapy enthusiasts, Andreas Zeiher of the University of Frankfurt, Germany, said that "it's time to embark on a 1000 person clinical trial" to nail down once and for all whether cell therapy keeps heart patients alive and in better health--a question the trials so far have been too small to answer. The circulatory diseases targeted by cardiac cell therapy continue to expand: Losordo hopes to launch a trial in critical limb ischemia, which affects diabetes patients and others and often results in amputation and even death. Researchers are mindful, too, that cardiac patients are desperate for new treatments. Some are flocking to Thailand, where a company now offers cardiac cell therapy--at a steep cost.
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