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Renovating the Heart

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Science  09 Apr 2004:
Vol. 304, Issue 5668, pp. 192-194
DOI: 10.1126/science.304.5668.192

Inspired by reports that cell infusions can heal animal hearts, cardiologists are rapidly moving to test the idea in humans. Even believers can't explain how or why it might work

Cardiologist Richard Schatz is tired of watching his patients die. They face daily anguish—as do millions of other people—because their hearts are pocked with dead muscle, undersupplied by blood, and gradually losing strength. Heart transplants can save a fraction of these patients, about 2000 in the United States each year. The rest get along on an imperfect mix of drugs, dietary restriction, and exercise. Some respond; many do not, joining a toll that makes heart disease the number one killer in developed countries.

But Schatz does not accept this as inevitable. Based at the Scripps Clinic in La Jolla, California, he's one of a growing number of cardiologists embracing an experimental approach to attacking heart disease, called cell therapy. It involves taking cells, usually from the patient's own body, and delivering them to the ailing heart. Interest is soaring, with more than a dozen clinical studies under way worldwide.

The trials, which got started in 2000 in France and 2001 in Germany, include a hodgepodge of techniques, cell types, and patients. In some, doctors shoot cells straight into the heart; in others, they administer potentially risky drugs that force bone marrow to churn stem cells out into the bloodstream. The results so far have been mixed and hard to interpret, but clinicians say they're seeing benefits. They can't explain why, however: Cardiologists began cell therapy thinking that transplanted cells would grow new heart muscle, but this early notion does not appear to be panning out.

Some researchers—particularly in the United States—worry about what could transpire if these trials outpace our understanding of the biology. Their worst nightmare is to repeat the errors of gene therapy, such as a trial in which an 18-year-old died after receiving an infusion of viruses carrying “repair genes.” It was a punishing setback for the field.

“We all would like to think that [cell therapy] can't be dangerous,” says Timothy Kamp, a cardiologist at the University of Wisconsin, Madison, studying embryonic stem cells. But, he adds, “there clearly can be unanticipated results.”

No potential showstoppers have come to light yet. But there have been warning signs. Four subjects in a French cell-therapy trial developed serious arrhythmias, a common problem among patients with heart failure, and Korean volunteers suffered a renarrowing of repaired arteries, forcing an early end to one study.

Physicians, researchers, and regulators are now wrestling with how fast to push cell therapy forward and how to design trials with the best shot at success. Last month, the U.S. Food and Drug Administration (FDA) invited experts from around the world to discuss the technique's promises and pitfalls. The agency, which so far has allowed only a handful of U.S. trials, is holding the reins tightly. Some researchers grumble that this is leaving them behind as their counterparts in Europe and Asia surge ahead.

Stalling to let knowledge of biology catch up to medical technology, some point out, could also have serious consequences. “If we wait 5 years, we will have lost the chance to treat hundreds of thousands of patients,” says John Martin of University College London. Many of his colleagues on both sides of the Atlantic agree. But there's no denying that the hoped-for gains will come with new risks. “This is a chance to potentially make leaps and bounds in medical therapy,” says Samuel Dudley, a cardiologist at Emory University in Atlanta. “On the other hand, there are a huge number of questions that we've left behind, because it's so easy to see the possibility” of saving lives.

Stem cell buzz

Hints that failing hearts might benefit from new cells emerged from the excitement sparked by isolating highly versatile stem cells from embryos. Cardiac trials have not yet used embryonic stem cells, nor have they attempted transplanting cells from one patient to another. But efforts to exploit the versatility of a patient's own cells got a boost from tantalizing—although still disputed—reports that immature blood cells could become brain cells and that bone marrow cells could form liver (Science, 8 June 2001, p. 1820).

As these headline-grabbing reports were appearing, a team of scientists led by Donald Orlic at the National Human Genome Research Institute in Bethesda, Maryland, published a surprising observation: When the researchers injected bone marrow cells into the hearts of mice that had suffered induced heart attacks, the marrow cells, rich in stem cells, apparently multiplied and helped repair damaged heart muscle. Other studies in mice and rats suggested that giving the animals a cocktail of bone marrow cells improved heart function.

Heart specialists were among the first to try to adapt these discoveries to the clinic, perhaps because of their tradition of bold experimentation and a remarkable array of surgical tools. “Cardiologists are just animals—extremely aggressive, inquisitive, [with] no rules,” says Schatz. “They want to do everything yesterday and not today.”

A different beat?

Immature muscle cells taken from the thigh seem to bolster injured hearts, but they might also trigger dangerous arrhythmias.

CREDIT: PHILIPPE MENASCHÉ

Inspired in part by reports from Orlic and others, Bodo Eckhard Strauer and his colleagues at the University of Düsseldorf in Germany sought permission from the university's ethics review board to infuse bone marrow cells into heart patients. On 25 March 2001, a 46-year-old heart attack survivor signed on to become the team's first subject. Doctors had already used a catheter to unclog the blocked vessel in his heart, inserted a metal stent, and stabilized his heart with standard drugs. But his prognosis was bleak: Nearly a third of his heart had been starved of oxygen, and the organ was unlikely to recover more than a small percentage of its lost pumping capacity.

With a needle, doctors extracted a few tablespoons of bone marrow from the man's hip. The next morning, Strauer and his colleagues snaked a catheter to the patient's heart and inflated a balloon at its tip for 4 to 5 minutes—blocking the blood flow in the damaged area long enough to give infused bone marrow cells a chance to adhere to the injured tissue. During the historic 25-minute experiment, the patient was awake and chatting with his doctors, Strauer says. Ten weeks later, the weakened area in the patient's heart had shrunk by a third and the organ's pumping capacity had improved by a few percent, although it was still far from normal. Strauer and his colleagues went on to treat more than 60 patients with stem cells.

By the fall of 2001, two more German teams were testing similar techniques. A group led by Andreas Zeiher at the University of Frankfurt treated 34 patients in an initial trial. And at the University of Hannover, Helmut Drexler launched a trial comparing 30 patients who received bone marrow stem cells with 30 who received standard care.

The German experiments exhibited clinical prowess but dismayed some U.S. researchers, who saw them as dangerously premature. The therapies had not been tested beforehand in large animals, such as pigs. “I was shocked,” says Piero Anversa, who directs the cardiovascular research institute at New York Medical College in Valhalla. He had assumed that clinical trials were 5 to 10 years away. Still, Anversa and others concede that German aggressiveness advanced the field dramatically. Early results suggested that patients treated with stem cells recovered between 5% and 30% of their lost pumping capacity. And none of the teams reported any serious complications.

The road has been rockier for a second cell-therapy strategy, which transfers a patient's immature thigh muscle cells into the heart. On 15 June 2000, Philippe Menasché and his colleagues at the Hôpital Européen Georges Pompidou in Paris were among the first to test it—on a 76-year-old man undergoing bypass surgery. While his chest was open, they injected muscle cells collected earlier from the man's thigh into damaged regions of the heart. Menasché says that preclinical work in rats, mice, and sheep had suggested that the technique held promise.

But initial excitement gave way to anxiety. One after another, four of Menasché's 10 subjects developed arrhythmia, a potentially fatal condition in which the heart fails to beat evenly. Some observers suspect that the thigh muscle cells, with their own electric rhythms, couldn't pulse in concert with their new neighbors. More than a decade of animal research had failed to predict this unsettling effect. All four patients underwent additional surgery to implant defibrillators, which stave off arrhythmia.

Exuberance

Cardiologists familiar with the European results remain enthralled by the possibilities of cell therapy. But some, such as Menasché, caution against premature exuberance: “We cannot make any reliable conclusion” about cell therapy's effectiveness without a placebo group, he says. He's busy recruiting patients for such a trial right now. Menasché also points out that controls are needed as much to rule out harm as to prove effectiveness. For example, the arrhythmias he saw may have been unrelated to the therapy, because such patients are already at risk for them. But without an untreated control group, he can't prove it.

Still, individual case reports are having an impact. Emerson Perin, a cardiologist at the Texas Heart Institute in Houston, recently conducted an autopsy on a man from a Brazilian cell-therapy trial he ran. The patient died of a stroke apparently unrelated to the bone marrow stem cells he'd received 11 months earlier, and Perin notes that “we are seeing angiogenesis and myogenesis”: the growth of both new blood vessels and heart muscle.

Even wary cardiologists agree that newly infused cells seem to be helping the heart. But how? “To be honest, we don't even know if they beat,” says Chuck Murry, a cardiovascular pathologist at the University of Washington, Seattle. The attitude of many clinicians, he says, is that “if function's improved and [patients] can climb a flight of stairs, who cares?”

Experts disagree on how much they need to know about the cells before they're transplanted. “There are too many people jumping in and trying to do clinical trials without understanding what the mechanism of their particular cells are,” says Silviu Itescu, director of transplantation immunology at Columbia University in New York City.

One reason for doubt is that the rationale for cell therapy keeps shifting. Early studies persuaded many that bone marrow stem cells would form new heart muscle cells, called cardiomyocytes. That theory has not been borne out in more detailed animal experiments. Last month, two independent groups reported in Nature that studies of mice with diseased hearts found no new myocytes produced from bone marrow stem cells. Some clinicians are increasingly skeptical that current cell-therapy methods are building new muscle mass: “I don't believe we are generating a large number of new cardiomyocytes,” says Drexler.

Pumped up.

After stem cell therapy to treat an induced heart attack, a pig's heart appears healthy (right) compared to that of a control.

CREDIT: BRADLEY MARTIN/OSIRIS THERAPEUTICS

Paradigm shift

As evidence for myocyte formation fails to materialize, a number of scientists are suggesting that transplanted cells may not have to morph into muscle for cell therapy to work. Many now say that patients could benefit because the cells support existing heart muscle, by either boosting the growth of new blood vessels or churning out growth factors that encourage cell proliferation and survival.

Indeed, Zeiher believes that the bone marrow cells he infused into patients promote existing healing processes—the kind that occur in hearts that partially recover from a heart attack. “We are simply enhancing the natural function” by injecting extra cells, he theorizes.

The search for clear answers is complicated by the assortment of techniques. Some teams are using a mixture of bone marrow cells, whereas others are attempting to isolate specific cell types. And the jumble of cells in bone marrow is poorly understood. “It's like a witch's cauldron, stirring around,” says Schatz of bone marrow. “You've got to find out which ingredient is key.”

Skeletal myoblasts, the immature muscle cells used in the French studies, also remain popular. A U.S. trial funded by Weston, Florida-based BioHeart Inc. is recruiting 15 patients with heart failure. All must already have a defibrillator in place to guard against arrhythmia.

Two more cell types are waiting in the wings: mesenchymal stem cells (MSCs), which are precursors to muscle, bone, and other connective tissue, and embryonic stem cells. Among the first to try MSCs is Joshua Hare, who heads the cardiac section in the Institute for Cell Engineering at Johns Hopkins University, using cells provided by Baltimore-based Osiris Therapeutics. He is running tests in pigs who've suffered induced heart attacks and has found that the animals' heart function returns to normal.

Embryonic stem cells might also work: In culture, they form nodes of pulsing cells, presumably immature heart muscle cells, that beat in unison. But some worry that renegade stem cells could morph into different tissues. “What we don't want,” says Columbia's Itescu, “is to develop bone in the middle of the heart.”

Risks reconsidered

FDA's effort to prepare for new clinical trials brought animal researchers and clinicians together last month in a hotel conference room in the Maryland suburbs, where they reviewed some of the risks. One veteran of the field, cardiac expert Doris Taylor of the University of Minnesota, Twin Cities, was troubled that her 15 years of work with skeletal muscle cells in animals failed to turn up the arrhythmias seen in humans. “We didn't really expect there to be safety problems,” she said.

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Scientists can't agree whether bone marrow stem cells might also carry a risk for arrhythmias. One who is reluctant to gamble is Douglas Losordo, chief of cardiology at St. Elizabeth's Medical Center in Boston and head of one of the few U.S. cell-therapy trials. He's outfitting subjects with vests that monitor heart activity and treat arrhythmias.

FDA is weighing other safety issues, mostly theoretical. Some experts worry that cells transplanted to the heart could boost blood vessel development in undetected tumors, helping them grow. And a drug called G-CSF, which a number of investigators are using to force bone marrow to churn out stem cells so they can be collected from blood and reinfused, could promote cardiac inflammation and other problems.

Concerns about G-CSF came to a head late last year in South Korea, where scientists were using the drug in a stem cell trial. Although the therapy seemed to enhance heart function, seven of the 10 people receiving G-CSF experienced a renarrowing of previously blocked arteries. All were successfully treated, but clinicians, alarmed by what they were seeing, shut the trial down.

Most trials, however, have advanced smoothly. And that is prompting researchers worldwide to press forward. Europeans are starting placebo-controlled trials involving hundreds of patients, while U.S. scientists are launching pilot studies. Competition drives them on. “We will be licked by the Germans or the Japanese if we don't keep our pace going,” says Vincent Pompili, who directs interventional cardiology at Case Western Reserve University in Cleveland, Ohio. His protocol, to use stem cells to grow new blood vessels, is one of a growing number on the desks of FDA reviewers, awaiting a green light.

So far, the agency has approved a small number of clinical trials. Losordo's stem cell trial was approved by FDA in December; Itescu has been cleared to treat intractable angina and blocked arteries; and Perin can expand on his early Brazilian work. FDA will also be weighing at least one stem cell study on patients awaiting heart transplants. That could provide invaluable data because cardiologists would be able to scrutinize cell therapy's effects in the hearts after they are removed.

Although FDA demands stringent safety data before allowing cell-therapy trials to proceed, the agency also gives scientists “lots of latitude” for speculating on why their approach might succeed, says Stephen Grant, an FDA reviewer in the cell- and gene-therapy division. Europeans, meanwhile, seem more concerned about funding. Researchers have received some government support but complain that cobbling together public funds for expensive phase II trials is nearly impossible. “Financing is a major issue,” says Drexler, who is working with University College London's Martin to raise money for a trial of their bone marrow cell-infusion technique, which will include a placebo group. “There is nothing to patent, so funding from industry is almost nonexistent,” says Drexler. If the team enrolls 400 or 500 patients, costs could easily top $5 million, he says.

The one thing no cardiologist worries about is a shortage of study subjects. Clinic waiting rooms are overflowing with potential volunteers. Kamp, the Wisconsin cardiologist, receives e-mails daily from desperate patients seeking new therapies. One recent message was just a single line. “Read about your work,” it read. “I'm willing to be a guinea pig in your clinical trial.”

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