Stemming the Slide
Injected into the heart, stem cells may pump new life into patients with cardiovascular disease
This article first appeared in The San Diego Union-Tribune, 4/20/05
Last August, Dr. Richard Schatz, a cardiologist and research director at Scripps Green Hospital in La Jolla, injected either bone marrow stem cells or a mere placebo of salty water - to this day even Schatz doesn't know which - into the heart muscle of a Las Vegas man with end-stage coronary artery disease.
Schatz carried out the injection nonsurgically by inserting a catheter into an artery in the man's groin, guiding it up the aorta and across the aortic valve into the heart's oxygen-starved left ventricle, plunging the catheter's needle into a small circle of ailing tissue, and finally injecting either cells or a placebo directly into cardiac muscle.
Anthony Salas, the 58-year-old patient, "was one of the sickest people I've ever met," recalled Schatz. "He had failed all conventional therapies" - bypass surgeries, stents and angioplasty - "and was maxed out on every cardiac medication he could take" - calcium channel blockers, beta blockers and nitroglycerin. Summed up Schatz, "Tony led a chair-to-bed existence."
One good thing to be said for Salas' serious condition was that it made him eligible for a clinical trial of bone marrow stem cells designed and led by Douglas Losordo, chief of cardiovascular research at Caritas St. Elizabeth's Medical Center in Boston.
Stem cells in bone marrow are referred to as "adult" to distinguish them from the "embryonic" stem cells in the early embryo. Also residing in skin, muscle, intestine, brain, eye, liver and other organs, adult stem cells make specialized cells for the tissue they occupy, in contrast to embryonic stem cells, which theoretically can make any mature cell in the body.
The bone marrow's hematopoietic (blood-forming) stem cell is the most studied adult stem cell; its ability to constantly replace mature blood cells - red and white cells and platelets - has held researchers' attention for some time.
Years of animal experiments had convinced Losordo that a different kind of stem cell in bone marrow, if delivered to a disabled heart, might contribute to the formation of valuable new blood vessels and boost blood flow throughout the body. Approved by the FDA, the study began in February 2004, one of the world's first randomized double-blinded trials of its kind.
The trial's treatment phase, executed at three medical sites, ended last month. Of the 24 desperately ill patients enrolled, 18 received the real thing - bone marrow stem cells - and six, a placebo, with none of the 24 privy to the contents of their injection.
Bone marrow cells were collected from all the patients, so the 18 treated with cells got their own cells back, removing the risk of an immune-system rejection.
For many months following his procedure, Tony Salas hadn't felt any better. To simply walk to his mailbox, he still had to hook up to oxygen or else face the unpleasant consequence of angina, debilitating pain due to poor blood supply.
"But in December, it turned like a switch," he said. "One day I walked out to my mailbox without oxygen and had no pain at all."
Now eight months post-procedure, he says he feels better than he has since his arteries started blocking in 2002. Even though his out-of-shape legs bother him, he goes on fast-paced walks with the mayor of Las Vegas and generally feels good enough to be running for city council. His last episode of angina was in December.
Salas is one of three patients under Richard Schatz's care enrolled in Losordo's bone-marrow trial. It's too early to know how patient No. 3 is doing. But like Salas, patient No. 2 - also eight months from treatment - has returned to a normal lifestyle, according to Schatz.
Should a patient in the trial not do well, a thoughtful provision in Losordo's protocol allows for unblinding the patient - revealing whether he or she got stem cells or placebo - ahead of time, and, if that person was a placebo recipient, then providing the real thing, their own bone marrow stem cells. Patients otherwise won't learn the contents of their injection, said Losordo.
"We don't know about these patients yet. This all could be a placebo effect," acknowledged Schatz. "But I'm pretty excited because I've been around long enough to know that this late clinical response would be a very unusual presentation for placebo. Treated with placebo, patients usually get better early on, and then, within two to four weeks, get worse."
But Salas and patient No. 2 only began getting better after several months. Aside from the Las Vegan's new-found energy and vanished angina, Schatz is particularly impressed by the results of SPECT nuclear imaging, scans that render blood flow visible in tissues.
"Before, it looked as though a gigantic part of Tony's heart was dead, like he had a big hole in his heart," described Schatz. "At his six-month follow-up, it was all filled in," indicating new working blood vessels. "A nuclear scan is unbiased - it can't be faked," he noted.
Researchers in several countries are exploring this radical new idea that, just possibly, transplanted cells can come to the rescue of patients with narrowed, blocked arteries and weakened cardiac muscle.
"It's showing promise, although few of the studies up to this point have been randomized and blinded," said Michael Schneider, research cardiologist at Baylor College of Medicine in Houston. "It would be premature for people to run out and request it as a proven standard of care from their physicians."
So far, fewer than a dozen human studies have utilized bone marrow cells for heart treatment. Reportedly only one of these bore negative results. However, the theme apparent at a crowded NIH-sponsored symposium last September was that while bone marrow may be the major source of progenitor stem cells, other sources are being investigated as well. (Propenitor cells, a tad more specialized than stem cells, similarly make specialized cells.)
Under scrutiny are stem cells from adipose, or fat, tissue and skeletal muscle tissue, along with stem and progenitor cells recently identified in the mammalian heart itself. The appearance of these rare heart cells - identified by teams including Michael Schneider's at Baylor and Kenneth Chien's at UCSD - strengthens the notion that the heart has more regenerative oomph than once perceived and that it might heal itself if lent a helping hand.
Employing cells as heart medicines may be worth every effort. When it comes to coronary artery disease and damaged heart tissue, "We don't really have good therapy available," acknowledged Emerson Perin of the Texas Heart Institute at last fall's symposium. As a result, in 2002 as many as 70 million Americans lived with one or more forms of cardiovascular disease, according to the American Heart Association.
Since cardiac disease ravages primarily myocytes (heart-muscle cells) and blood vessels, the merit of cell-based therapies will rest on their ability to generate either new myocytes, or blood vessels, or both.
It might come to pass, said Michael Schneider at Baylor, that one or another patient scenario would dictate which type of cell to administer.
For instance, immediately following a heart attack, it might be expedient to send in a certain type that would secrete proteins to protect neighboring tissue from damage. Several months after a heart attack, a different cell type might be called for, one meant to generate new myocytes for the sake of replacing scar tissue with healthy contractible tissue.
"These are two very different clinical situations. Cardiologists and internists see both kinds of patients, and one would like to have improved therapy in both circumstances," said Schneider.
The bone marrow stem cells his research revolves around, said Losordo, appear to play a role in restoring very small blood vessels in blood-starved tissue. The loss of these microscopic vessels plays a central role in coronary vascular disease.
Bone marrow has been thought to house at least two versions of adult stem cells: hematopoietic, which give rise to mature blood cells, and mesenchymal, which give rise to mature bone, cartilage and fat cells.
Now enters Losordo's newly discovered cell, which he refers to as an endothelial progenitor since it makes new blood vessels and their endothelial lining.
Other researchers are examining the controversial claim - first made from mouse studies in 2001 - that bone marrow stem cells can also yield new heart muscle cells. If valid, this phenomenon might be a way of reinstating new tissue alongside dead tissue after a heart attack.
But many questions remain. It's not clear, for instance, which type of bone marrow stem cell is specializing into myocytes. Researchers aren't even certain that bone marrow cells actually cross lineages to become heart cells. Rather, the transplanted cells might secrete proteins that spur the division of existing heart stem cells - or perhaps recruit stem cells from elsewhere. Distinguishing one type of cell from another in any tissue is still terribly difficult for scientists, as is tracking where cells and their differentiating progeny wind up.
"Welcome to the world of bone marrow stem cells," said Losordo, "where there is lots of confusion, lots of debate, lots of rancor, but not a lot of definition, frankly - which is why there's so much debate."
Seeking other sources
Meanwhile, other groups believe that stem cells derived from adipose tissue, or body fat, might help the heart.
"The irony of it - adipose cells being used for heart disease!" exclaimed John Fraser, a stem cell biologist at the placeLa Jolla biotechnology firm MacroPore Biosurgery. Its president, Marc Hedrick, was the first to identify fat-residing stem cells when he was working in UCLA's Department of Surgery.
This very same type of adult stem cell made headlines last December when surgeons in placecountry-regionGermany used it to fill in a hole in a 7-year-old girl's skull. Fraser and Hedrick were authors on the published paper.
MacroPore and UCLA scientists recently studied heart function in pigs who were injected with adipose stem cells. Six months after induced heart attacks, the pigs had significantly better heart function than animals given a placebo. While stem cells in bone marrow are quite rare, those in fat cells occur with greater frequency, said Fraser. "You could take a liter of fat from a patient" - perhaps from waist or thigh, doing the patient a service - "and get an awfully lot of stem cells out of it," he said.
"What people forget about, and it's really important," he added, "is that adipose-derived stem cells don't necessarily have to be differentiating into cardiac muscle cells to help. They also could be making growth factors that can stop myocytes from dying," after a heart attack.
Years of studying yet another cell candidate - stem cells in skeletal muscle - has left many researchers leery of using this particular cell for heart repair, despite some positive evidence in animal and human studies.
"At the experimental level, it is so totally clear from work in several labs that skeletal muscle cells rarely turn into heart muscle," said Baylor's Michael Schneider. "Electrically, these cells don't make normal connections with their neighbors," a situation that can elicit an irregular heartbeat.
In respect to two other possible sources of heart-healing cells, a staggering amount of detective work awaits. It's too early to know, for instance, to what extent the rare stem cell that lives in the human heart might be mobilized, extracted, amplified and therapeutically transferred back into the same patient.
Indeed, heart disease may occur in older patients in part because these cells are so extremely depleted in older bodies. For now "their most ready utility might be to help us understand how all the distinct myocardial lineages form" to make the heart, explained Sylvia Evans, a UCSD developmental biologist who studies how the heart develops.
Finally, some scientists are attempting to turn embryonic stem cells, nature's famously regenerative and unspecialized cell type, into cardiomyocytes. A drug discovery program under way in Mark Mercola's Burnham Institute lab in placeLa Jolla, for instance, is identifying small molecules as well as genes that can persuade embryonic stem cells to transform into heart cells.
"For replacing heart cells, embryonic stem cells are a good bet," said Mercola, especially because "it may prove an uphill battle to efficiently convert adult stem cells from non-heart sources," such as bone marrow or fat, into myocytes.
Whether non-heart adult stem cells can even make heart muscle is controversial; many consider it unlikely, said Mercola. And whether heart stem cells can be prodded to replicate for the sake of heart therapies is also unclear. On the other hand, said Mercola, "Studies have shown that embryonic stem cells - in both a dish and in animals - can become cardiomyocytes."
Waiting with optimism
The warm, cautious air of optimism that surrounds attempts to treat heart disease with cell-based therapies could abruptly blow cold next week, next month or next year.
According to Douglas Losordo, several of the severely sick in his clinical trial are noticeably better, and now the real proving ground will be whether a patient's improved health will last, and for how long.
Losordo has been criticized by various colleagues for proceeding with human trials before more is known about the effects of inserting cells into the human heart. He defends his actions by pointing to the thousands of animal studies his protocol is based on, and by stressing that his patients have run out of options and are at death's door.
"They've tried everything - they are very courageous people - and frankly it's a response to this unmet medical need that drives the whole program and forces us to take steps into the unknown," said Losordo. "To find out what's possible, sometimes you have to go a little bit into the impossible."
Tony Salas certainly isn't quibbling with that philosophy. Every day of feeling better is a gift, so much so that he has amended his license plate.
Before his illness, it reflected his occupation as a design engineer. "I Make It," it read.
Now it reads: "I Made It."