About one million Americans suffer a heart attack every year. While four in ten of them die as a result, that leaves six in ten survivors fighting to recover with permanently damaged heart muscle. Even in the best-case scenarios, cardiologists are usually only able to save about 60% of cardiac muscle after a heart attack. Meanwhile, another five million people are living with heart failure, and another six million visit the emergency room every year for chest pain.

 That’s a lot of people with damaged hearts, and up until recently, there was no way to restore that lost heart function. But now, the field of stem cell therapy seems poised  to revolutionize the way cardiovascular disease is treated. After years of promising basic science research, stem cell therapy has moved from the lab to the clinic, and early clinical trials hint that stem cells may be able to regenerate damaged heart tissue in humans just as it has been shown to do in animal models.

Within the next few weeks, the National Heart, Lung and Blood Institute is expected to announce the recipients of a total of $33 million in grants to create a national Cardiovascular Cell Therapy Research Network. Five clinical centers, plus one data coordinating center, will focus on evaluating “novel cell therapy treatment strategies for individuals with cardiovascular disease.” By “cell therapy,” the NHLBI does not mean the embryonic kind. That research is, of course, largely barred from federal funding and, when it comes to cardiovascular disease, very much in its earliest phases even in the few US and foreign laboratories pursuing it.

“There are a couple of labs studying cardiogenesis using embryonic stem cell models, but practical and ethical issues have put a damper on that work,” says Eduardo Marban, MD, PhD, chief of cardiology and director of the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University, Baltimore. “Without therapeutic cloning, these cells can lead to immune rejection, and if you’re not careful and lucky they can produce benign tumors in the heart. For those reasons, embryonic stem cell therapy hasn’t been particularly promising in cardiology, at least in the short term, although if those issues are overcome, that could change.”

Several kinds of adult stem cells have already shown promise in both animal and human models of heart disease. Just how much promise, exactly how they work, and how they should be used in real-world treatment scenarios are all questions that remain to be answered.

Bred in the bone
The September 21 edition of the New England Journal of Medicine featured the results of the largest clinical study of cardiac cell therapy yet, the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. It studied the direct intracoronary infusion of bone marrow progenitor cells in patients who had been successfully treated for acute myocardial infarction. The double-blind trial found a small but definite improvement in left ventricular ejection fraction (LVEF), 5.5% vs. 3%, in the patients who received the bone marrow stem cells, and those patients had a significantly lower rate of adverse events after one year than the placebo patients. Still, the difference was small, and another trial published in the same issue, the smaller Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial, found no improvement in LVEF. Is this really so promising?

Marban thinks it is—for more than one reason. “The bottom line is what these studies tell us about delivery. It appears to be safe to deliver cells down the coronary tree, which opens up the possibility of the use of cell therapy in a big way. Almost every hospital has a cath lab,” he says. “In addition, most of the patients in the REPAIR-AMI trial had pretty normal ejection fraction, and it’s hard to improve when patients have 50% or better EF. In a subgroup analysis, patients with less than 50% EF had a higher proportional benefit. I think it’s fair to say that the studies show that the general approach of coronary delivery of cells can be safe, and the benefit from bone marrow mononuclear cells is modest, but probably genuine.”

That modest rate of recovery may be because bone marrow cells don’t actually turn into cardiomyocytes. Although scientists are still not 100% certain about precisely what happens when bone marrow progenitor cells are delivered to an injured heart, the prevailing wisdom is that they seem to be “biocatalysts to promote healing and recovery of cardiac function,” says Douglas Vaughan, MD, chief of the Division of Cardiovascular Medicine at Vanderbilt University Medical Center, Nashville, Tenn. The division has begun enrolling patients in a small phase I trial of hematopoietic CD34 -enriched bone marrow-derived cells for treatment after heart attack. The study will ultimately enroll 60 patients who must have been scheduled for coronary artery bypass and have decreased ventricular function.

“These cells are probably just small bioreactors. You put them into a certain environment, and they look at what’s going on in the environment and start producing whatever growth factors or other chemicals are required,” says Amit Patel, MD, director of cardiac stem cell therapies at The McGowan Institute for Regenerative Medicine at the University of Pittsburgh Medical Center. Patel, a pioneer in the field, famously treated Hawaiian singer Don Ho for nonischemic cardiomyopathy in Thailand last December using Ho’s own blood-derived stem cells.

“If they’re in an area where there’s enough blood supply but the muscle is weak, the cells appear to secrete substances that will recruit factors that will help the muscle work better or stronger,” he says. “If the muscle is strong but lacks adequate blood supply, they will recruit factors that cause angiogenesis. They put out the equivalent of one of those $2 million, 30-second Super Bowl ads: ‘Hey, we have this super job, we’re going to recruit everyone.’”

Both the REPAIR-AMI and ASTAMI trials were phase I, as is the Vanderbilt trial. In March, Baxter Healthcare Corporation announced it had initiated the first human phase II adult stem cell therapy trial in the US, investigating the potential of CD34 stem cells in patients with chronic myocardial ischemia (CMI), a severe form of coronary artery disease which develops in between 125,000 and 250,000 people with coronary artery disease annually. The trial will be led by Douglas Losordo, MD, chief of cardiovascular research at Caritas St. Elizabeth’s Medical Center in Boston.

Another phase II trial should be up and running by early next year, run by a small Ohio-based company called Arteriocyte spun off from Case Western Reserve University in Cleveland. “They’re using CD133 bone marrow cells, which are very similar to CD34 cells, almost like cousins. They’re both hematopoeitic, and the way you isolate them is the same,” says Patel.

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