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By Mary Carmichael
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A million lonely ballads notwithstanding, with time, the human heart can recover from an emotional wound. In medicine, however, the prognosis is often bleaker, and time only makes a physical injury worse. If starved for oxygen, heart cells die, their places usurped not by fresh replacements but by scarring. Burdened with useless tissue, with no hope of new reinforcements, the remaining muscle cells in the heart take on more responsibility, working harder to pump the blood. The heart grows larger with the strain but rarely regains its original strength. Despite doctors' efforts to save them with drugs, catheters, stents and surgery, 5 million Americans currently suffer from heart failure. Half will die within five years of diagnosis. Their hearts are, in effect, permanently broken.
But the emotional heart does not yield easily to the idea that the physical heart can be defeated. So cardiologists have started pursuing an unorthodox strategy--shoring up the dying hearts with stem cells, the body's self-renewing jacks-of-all-trades, immature cells that can be coaxed into transforming into many different types. Cardiologists who have performed the procedure in Europe, South America and Japan using adult human stem cells have reported Lazarus-like improvements in their patients, some of whom have even returned from near-permanent hospitalization to their previous, normal lives. In the last year the therapy has caught on in the United States, too, with similar early results. The Food and Drug Administration, at first wary, has started approving more trials (mostly using stem cells from patients' own bodies rather than controversial embryonic stem cells). In the next few years several hundred American patients who have run out of conventional options will enroll, their hopes renewed.
Here's the problem: no one can explain exactly why the therapy works. The stem cells reach the heart, but no one knows exactly what they do after that--how they rejuvenate the tissue, or what the dangers might be. For critics, that means the risks outweigh the benefits. The treatment's supporters counter that the sickest patients will gladly accept those risks rather than face certain death. Now cardiologists must answer for themselves and their patients a question that lies at the heart of all human trials: when should you let medicine outpace the science that underlies it?
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The idea of infusing stem cells into patients' hearts has moved from the lab to the operating room with astonishing rapidity. Five years ago it was almost unthinkable; scientists had little to suggest that stem cells could repair cardiac tissue. In 2001, Donald Orlic, a molecular biologist at the National Human Genome Research Institute, published some of the first evidence. After inducing heart attacks in mice, he injected them with bone-marrow, rich in stem cells, which proliferated and appeared to be repairing the injured heart muscle.
Orlic's reports fell sweetly on the ears of German doctors at the University of Dusseldorf. In March of that year, a team extracted a few tablespoons of marrow from a 46-year-old man's hip. Then it aimed it, via catheter, toward his heart, which had been partially damaged by cardiac arrest. Ten weeks later the heart was less frail and was pumping more blood. Encouraged, the doctors scheduled more than 60 patients --for the procedure. By fall other German teams were following their lead, and in November Japanese researchers took it up, too, reporting that three of five patients with blocked coronary arteries had better blood flow after bone marrow was infused into their weak hearts.
It is not unusual for doctors to latch excitedly onto a radical medical treatment--particularly in cardiology, and particularly abroad, where many regulatory agencies are not as strict as the FDA. But breakthroughs in humans are usually based on years' worth of data from animal tests demonstrating safety and efficacy. When the German team set about its work, it had proof of neither. The therapy had not even been tested in large animals. There was one precedent in humans, and it was not encouraging. The previous year, French doctors had treated 10 heart patients using stem cells from patients' thigh muscles rather than their bone marrow. After treatment, four of the patients' hearts unexpectedly started beating dangerously off tempo, and at the time no one could say why.
That was the safety issue. As for efficacy, most of the patients in the early trials conducted abroad did seem to be getting better. But why? Almost immediately, despite the encouraging results in patients, scientists started to dispute claims that the stem cells were transforming into new cardiac muscle. Despite the many studies performed since then, they are still no closer to a consensus. The therapy's biggest boosters now argue that ultimately, it doesn't matter--the cells don't have to become muscle to give the heart another chance. They may reinvigorate old cells, act as beacons for growth factors or serve as midwives to the birth of new blood vessels. "They're probably doing a thousand different things," says Johns Hopkins cardiologist Joshua Hare, one of the field's pioneers.
Some of those things, of course, might be dangerous. That uncertainty is the reason so many scientists have serious reservations about the therapy. Most cardiologists were stunned when the procedure was performed in Europe and Japan with relatively little animal data available--and with the therapy now on the fast track in humans, many of them are even more surprised. Given how little scientists know about the biology of the treatments, unexpected problems could arise, as they did in the French trials.
What is clear, however, is that the therapy is making inroads in America, where heart disease is the No. 1 killer of both men and women. U.S. cardiologists --have reported extraordinary recoveries among their patients. Within the next few years, they should have gathered enough data to start making conclusive statements about whether stem cells really can fix a broken heart.
Of the therapies currently on offer in the States, infusions from the bone marrow are the most thoroughly tested. Amit Patel, a heart surgeon at the University of Pittsburgh who has performed the procedure in more than 100 patients abroad, started a U.S. trial in May. He sees patients with a variety of maladies and has prescribed stem cells for about 20 percent of them, usually those with low "ejection fractions," or measures of how much blood the heart can pump. Their ejection fractions have increased significantly, remaining comparatively high six months after treatment. (Patients given a placebo version of the treatment have also improved, but far less impressively.) As for safety, Patel says, there have been "no tumors, no arrhythmias, no strokes, nothing like that. I'm a little surprised. We thought, 'There has to be something bad about this.' But thus far, there's been nothing."
Patel is one of just three American doctors the FDA has allowed thus far to perform cardiac therapy with bone-marrow cells, and he is the only surgeon--the other two deliver the cells by catheter, without surgery, as the German team did in 2001. This less-invasive approach may carry fewer risks than surgery. At the Texas Heart Institute, Emerson Perin is treating 30 patients with advanced heart failure. Although he has yet to publish the results of this trial, he does have data from another he conducted four years ago on 14 patients in Rio de Janeiro. Thirteen improved dramatically. Five needed heart transplants, but within months four of those were healthy enough to come off the list; another, who could barely breathe before the trial, took up jogging afterward.
Douglas Losordo, chief of cardiovascular research at Caritas St. Elizabeth's Medical Center in Boston, is the third in this group of cardiological crusaders. His patients wear "life vests" that constantly monitor and record their heartbeats for months after the procedure. If arrhythmias arise, the vests can electrically tamp them down. Because the vests are on duty 24/7, they also provide an exact count of how many arrhythmias the patients have suffered. So far: none. Moreover, Losordo's patients, like Patel's and Perin's, appear to be rejuvenated by the procedure. He is planning new studies, including an FDA-approved trial with patients who have blocked blood vessels in their legs, scheduled to start in December.
Bone marrow is a popular source of stem cells, but it is not the only one. Several scientists are pursuing skeletal-muscle precursor cells, which docs can obtain by removing a grape-size piece of muscle from a patient's thigh, as an alternative. Unfortunately, arrhythmias like those in the first French trial continue to plague their attempts. In two recent trials conducted abroad, arrhythmias affected 11 of 18 patients, one of whom needed cardiac resuscitation. In June, a Johns Hopkins team shed some light on why. Implanted stem cells from muscles fail to produce a key protein called Connexin 43 that would normally allow them to properly conduct electrical impulses, as heart-muscle cells must do. However, Eduardo Marban, who led the Johns Hopkins team, has genetically engineered versions that do produce the protein, at least in the lab--which might make the skeletal-muscle strategy more viable in the long run.
Another source for stem cells might be the patients' own hearts. When Marban, a molecular cardiobiologist, is not working with skeletal-muscle cells, he focuses on stem cells that originate within the heart. Scientists have known of their existence only for the last two years. "Presumably, they're there to help the heart heal itself from normal wear and tear. There aren't enough to help it in a catastrophic injury," he says. "But we can grow millions of them in a lab in a matter of weeks." Stem cells from the heart are probably the most likely to actually turn into heart muscle in the body. Marban is gearing up for human trials, which he hopes will start in about 18 months.
All these strategies, of course, rely on using stem cells from the patients themselves. There's a flaw with that approach, though: older patients' stem cells are not as robust and active as younger patients', but it's often the older patients who need the treatment the most. Losordo wants to combine his stem-cell procedure with gene therapy, removing the cells from the bone marrow, modifying them and then putting them back in. Although the idea is still extremely sketchy--for starters, it's unclear which genes would have to be modified--he is in early negotiations to start a trial.
Alternatively, doctors could try implanting stem cells from a young, healthy donor, an approach closer to traditional transplant therapies. Because stem cells "grow like crazy" in a culture, says Dr. Hare, one donation might ultimately yield enough cells to treat as many as 1,000 patients. Hare has previously cured pigs of heart-attack injuries by injecting them with bone-marrow stem cells from other, healthy pigs. This summer he moved on to humans. He is scheduled to treat 48 heart-attack patients with stem cells cultured from a single donor. The approach resembles traditional transplant surgery, with one crucial, and surprising, exception: there may be little risk of rejection. Hare says that his cultured stem cells lack the protein markers that would otherwise cause the immune system to recognize them as foreign. What that means, says Hare, is that, just like a drug, "the cells could be ready in a blood bank when a patient rolls in"--an advantage crucial in emergencies.
And then there are the youngest donors, and the most controversial--embryos, which generate the most versatile and valuable stem cells. Until this summer, no one had used them in cardiac patients, which meant the field was free of that particular ethics controversy. But in June, Valavanur Subramanian, a surgeon at Lenox Hill Hospital in New York, injected fetal-derived stem cells into 10 patients' hearts in Ecuador. A month after the procedure, the formerly sluggish patients were suddenly more active; their hearts pumped 40 percent more blood than they had before. A sample size of 10, of course, can't provide definitive conclusions. But embryonic research is also yielding promising results in other countries. Last year scientists at the Technion-Israel Institute of Technology and Rambam Medical Center reported that heart cells grown from embryos could mesh with mature heart tissue and regulate its beat. They might, the scientists suggested, someday replace mechanical pacemakers, meaning stem-cell treatment could benefit not just heart-failure sufferers but also an entirely new category of patients. The thought of that future makes many doctors--and patients--take heart.
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