Cell transplants may someday cure heart failure
Most of us can recall the emotions of a failed romance, when we felt our heart was bruised if not broken. Luckily, fewer people know what it's like to have a heart that's truly damaged.
In the medical condition known as heart failure, or congestive heart failure, the heart is unable to beat as strongly as the body requires. Eventually, people with heart failure are unable to walk or breathe normally. This condition results from the organ's unsuccessful attempt to cope with inherited malformations or from damage caused by infections or severe heart attacks. In response to such problems, the heart's walls thin and weaken, while the entire organ enlarges until it can no longer contract effectively.
About 4.6 million people in the United States live with congestive heart failure. Most men live about 1.7 years after receiving that diagnosis, and women live an average of 3.2 years afterwards.
Romantic stereotypes to the contrary, the adult human heart is about the shape—and size—of a large artichoke. The heart is made primarily of muscle, but unlike other muscles in the body, it can't seem to repair itself.
People with congestive heart failure are treated with drugs, mechanical pumps, and heart transplants. All these therapies have flaws.
About a decade ago, researchers began speculating that failing hearts might be aided by fresh muscle cells. In the first experiments, scientists took cells from muscles in other parts of the body and injected them into damaged hearts of animals. The approach seemed to work, and researchers recently implanted cells into the hearts of two patients. The transplant technique seems to be safe, but it's not clear yet whether it's beneficial.
To maximize their chance of success, researchers are now comparing transplants of cells from a variety of sources.
"A few years ago, we thought there was no way to improve heart function other than through drugs," says Rose Marie Robertson of Vanderbilt University Medical Center in Nashville and president of the American Heart Association (AHA). "Though it is early days yet for these techniques, the fact that they are being done at all is very exciting."
Some of the excitement comes from a report last November at the AHA meeting in New Orleans. After almost a decade of experiments on animals, a team of French researchers implanted cells in a person's damaged heart. The researchers took cells from a 72-year-old man's thigh, isolated the ones that could give rise to new muscle, grew them in a laboratory for 2 weeks, and injected them into his heart.
The researchers performed the cell transplant during the man's scheduled heart-bypass surgery last June. They included the experimental procedure to test its safety. So far, there are no signs of ill effects from the introduced cells, says Philippe Menasche of the Hospital Bichat in Paris.
A month after the procedure, the patient's heart pumped more effectively than before it, Menasche reported at the meeting. The improvement was small, and the man's heart was still significantly less efficient than a healthy person's. Bypass surgery, which boosts blood flow to the heart muscle, improves heart function, so the patient's slight improvement can't be definitively attributed to the transplant, says Menasche.
Nevertheless, the researcher says that after 5 months, noninvasive scans indicating heart metabolism show that the transplanted muscle cells are alive. Ultrasound images also indicate that the area damaged by the heart attack and where the muscle cells were introduced is contracting and thickening as the heart beats. "The scar tissue is no longer completely dead," says Menasche. "This is admittedly based on indirect assumptions, but it is encouraging."
However, other researchers at the AHA meeting cautioned that Menasche doesn't know that the cells that appear active in the scans are the ones he transplanted. It's also possible that the area isn't initiating contractions but just responding to nearby movement.
This past September, a group in Philadelphia followed the French work with another transplant of muscle cells into a person. With up to eight more such surgeries planned, the team hopes to address the question of whether the transplanted cells survive.
Howard Eisen of Temple University in Philadelphia and his colleagues there and at the Charlestown, Mass.-based biotech company Diacrin have transplanted chemically tagged muscle cells from a patient's thigh.
The researchers select volunteers for the study from patients on waiting lists for heart transplants. In Eisen's protocol, the cells are introduced during surgery to implant a pump, known as a left-ventricular-assist device, to sustain the patient until a heart becomes available.
After each patient receives a heart transplant, the researchers plan to look for the transplanted cells in the ailing heart that was removed. They will also look for specialized connections, called gap junctions, between the original and the transplanted cells. Gap junctions are tight linkages that, in the heart, enable electrical impulses to pass through rapidly enough to instigate a normal beat.
So far, the researchers have injected cells into just one volunteer's heart. The patient is faring well, Eisen reports, but has not yet received a heart transplant.
"This is the very first step of a long process," says Eisen. "We're looking to see if the cells will survive before we make radical claims that we are improving things."
Transplanting skeletal muscle
Nearly a decade of work on mice, rats, and pigs has encouraged researchers to try cell transplants in the clinic. The research has shown clearly that after a heart attack, an animal fares better if it has received a cell transplant. However, it's less clear whether the new cells make the damaged area function as effectively as it did before the heart attack.
The earliest animal studies and both the human cell transplants have used a type of cell known as skeletal muscle. This muscle is usually attached to the skeleton and works under a person's conscious control. Connected skeletal muscle cells, unlike heart cells, don't beat continuously or work in unison. Therefore, they typically don't contain the same kinds of gap junctions as heart muscle cells do.
One question that's at the heart of the matter: Do the transplanted skeletal muscle cells function like undamaged heart muscle? If they don't, transplantation wouldn't be expected to cure heart failure.
Few animal studies have demonstrated that skeletal muscle cells moved into the heart begin to produce the gap junctions and connect to normal heart cells, says Loren J. Field of Indiana University School of Medicine in Indianapolis. Although scientists want to know whether the transplanted cells in animal experiments help damaged regions of the heart contract, but these cells are difficult to observe directly.
Thus, it still isn't clear exactly how transplanted skeletal cells have exerted their beneficial effect, Field says. It's possible that transplanted muscle cells don't participate in the beat but simply take the place of dead or dying cells. This might strengthen the tissue enough to help the heart function.
Working with stem cells
When researchers first began looking at cell transplants, skeletal muscle seemed an obvious choice. If patients receive transplants of cells from their own arm or leg, they wouldn't need the immune-suppressing drugs required by people given tissue transplanted from another person.
Mature skeletal muscle cells wouldn't work for transplants because they're already specialized and couldn't repopulate a damaged area. But skeletal muscle contains so-called stem cells that can grow into new muscle cells after an injury. When transplanted into the heart, these stem cells reproduce, mature, and may make connections. As far as scientists know, heart muscle doesn't naturally contain such stem cells.
Stem cells lie at forks in the developmental path. There are many different types of stem cells. Those in muscle typically develop into more-specialized muscle cells. However, embryonic stem cells can grow into almost any type of cell in a mammal's body.
Until recently, stem cells in adults have been thought to be relatively specialized. For example, a stem cell from bone marrow could turn into bone or blood, but nothing else. Over the past few years, however, research has shown that adult stem cells can be coaxed along a wider variety of developmental pathways (SN: 1/23/99, p. 54; 7/1/00, p. 7; 9/2/00, p. 155; 12/2/00, p. 360).
Some researchers now contend that stem cells from adult bone marrow—called bone marrow stromal cells—can turn into heart muscle cells. A Canadian group transplanted cells from a rat's bone marrow into normal hearts of genetically identical rats.
Four weeks after injection, the transplanted cells had survived, and most appeared to have become normal heart tissue, says Ray C.J. Chiu of McGill University Health Centre in Montreal. Descendants of the injected cells, for instance, formed two proteins that make up the gap junctions normally found in the heart, and the new cells connected with the healthy tissue surrounding them, he reports.
However, not all the bone marrow stem cells differentiated into heart-muscle cells. In the small region that had been slightly injured by the needle, the stem cells turned into cells resembling cartilage and scar tissue, Chiu notes. This suggests that bone marrow stem cells may not successfully transform into heart cells in damaged areas, he says, so researchers may need to develop ways of turning stromal cells into heart muscle cells before they are transplanted. Such methods are already in development, he reports.
But do even bone marrow stromal cells injected into an animal's heart turn into heart muscle or do they develop into cells that resemble heart tissue only in some respects?
Chiu and other researchers argue that the resulting cells are in essence heart tissue. Field says no one can answer the question, yet. He and his colleagues have been unable to get stromal cells to express several proteins characteristic of the nucleus of heart cells.
Now, Field's team is turning to embryonic stem cells as a potential source of heart muscle cells in animal experiments. These cells are most likely to form functional gap junctions with heart tissue, Field says.
Replacing heart cells with exact replicas, "may be a goal that's not particularly important," says Terrence Yau of the University of Toronto. At the AHA meeting, his colleagues presented data suggesting that--at least in animal models of heart attack damage--cell transplants using embryonic stem cells, skeletal muscle, or bone marrow stem cells are about equally effective in preventing the heart wall from thinning and in maintaining the heart's ability to contract.
The differences may be more important when it comes to forming gap junctions between transplanted and original heart muscle, says Chiu.
Pros and cons
Each cell type that is a candidate for transplant into damaged hearts has its pros and cons. Sturdy skeletal muscle cells are much more successful at growing in damaged heart tissue than are bone-morrow-derived cells, which require more energy and a better blood supply, says Hans Reinecke of the University of Washington in Seattle. At the AHA meeting, he and his colleagues showed that in pigs and rats, about 50 percent of injected skeletal muscle cells would grow in damaged tissue, compared with less than 10 percent of transplanted stromal cells.
Besides any benefits of more closely resembling heart cells, bone marrow stem cells may offer a separate advantage over skeletal muscle stem cells. At the meeting, several groups reported that in pigs, bone marrow stem cells can turn into cells that line local blood vessel walls and encourage the formation of new blood vessels. Since increasing blood flow to a damaged heart is also important, this could be an additional benefit of using bone marrow stromal cells, says Shinji Tomita of the National Cardiovascular Center Research Institute in Osaka, Japan.
Regardless of the type of cell employed, transplants will probably be used along with, not instead of, medication. So-called ACE inhibitors, which make it easier for the heart to pump, are often prescribed for people with heart failure. So, when Menasche and his colleagues recently induced heart attacks in 100 rats, they treated them all with these drugs and also gave half of them cell transplants. "If you add transplants to ACE inhibitors you further improve [heart] function," he reported at the meeting.
Yau says that transplants "may ultimately improve a person's quality of life and affect a sizable percentage of patients."
Making predictions for the future impact of research is always a risky business, cautions Field. "But the advantage of [cell transplantation], if it works, is that it could be curative-and nothing else out there is."
Ray C.J. Chiu
Montreal General Hospital
1650 Cedar Ave.
Montreal, Quebec H3G 1A4
Howard J. Eisen
Temple University Cardiac Transplant Program
3401 N. Broad St. Ste. 920
Philadelphia PA 19104
2, Rue Ambroise-Pare
75475 Paris, 45267 0558
E520 Health Sciences
University of Washington
Seattle, WA 98195
Terrence M. Yau
Toronto General Hospital
University Health Network
200 Elizabeth St.
Toronto, Ontario M5G 2C4