Attack on the marrow. Arrows point to different types of immune cells from a healthy mouse (left) and one that had an induced heart attack 3 days ago (right).

Xiaoyin Wang et al., Science Translational Medicine

Only the Best Marrow to Help Heal the Heart

About 8 years ago, heart researchers were abuzz with excitement. Studies in mice had found that infusing bone marrow into the heart after a heart attack could heal the organ and prevent subsequent heart failure. Given that there are about 500,000 new cases of heart failure each year in the United States and only 2000 heart transplants, a new therapy for failing hearts was badly needed. But when researchers tried the same approach in humans, it didn't work as well. Now scientists think they may have pinpointed one big reason why.

Researchers used to think that bone marrow contained stem cells that could transform into heart muscle; now most suspect that it secretes factors that help the heart repair itself. When scientists treated heart attacks with bone marrow in mice, the donor marrow came from young, healthy animals that were genetically identical to animals with induced heart attacks. People participating in clinical trials, on the other hand, were getting their own bone marrow back, a strategy to avoid immune reactions. The human participants tended to be middle-aged or older, and they had health problems. (And, of course, they'd just had a heart attack.)

Matthew Springer, who studies cardiovascular medicine at the University of California, San Francisco (UCSF), wondered whether this difference in where the bone marrow came from could explain divergent results in the research studies: the mice did well, but the human studies were mixed. People benefited somewhat, but their heart function didn't improve nearly as much as heart function in the mice.

To find out, Springer, UCSF cardiologist Xiaoyin Wang, and their colleagues decided to make the bone marrow donated by mice more similar to the marrow used in human studies. To start, they induced heart attacks not only in the mice that would get the treatment but also in some of those donating marrow—just as the bone marrow in human studies comes from people who recently had a heart attack. And lo and behold, the bone marrow cells that came from the mouse heart attack victims "were not as therapeutic," Springer says. For example, the results of a key test of heart function that measures how well the organ pumps blood were the same before and after the recipients received the marrow. By comparison, in mice that got cells from young, healthy animals, the measure increased about 10 percentage points, and in animals who got sham injections, it deteriorated by about 10 percentage points.

In a way, the result was surprising. The bone marrow was given just 3 days after the heart attacks. "That means that in 3 days, something has changed in the bone marrow," says Springer, whose team reports the work today in Science Translational Medicine.

The researchers already knew that heart attacks cause a massive inflammatory reaction, and they suspected that this changed the composition of the marrow. And when they gave the donor mice that had suffered heart attacks a powerful anti-inflammatory drug, the recipients of their marrow fared much better. Springer doesn't know yet which immune cells in bone marrow are key to reducing its ability to repair the heart.

The work adds insight into how we can best use these cells to help the heart, says Anthony Rosenzweig, director of cardiovascular research at Beth Israel Deaconess Medical Center in Boston. What all of this means for people is still up in the air, however, he cautions. In the past, doctors tried giving heart attack patients powerful anti-inflammatories. But the treatment didn't help and in some cases proved dangerous, appearing to weaken the heart muscle wall and cause aneurysms.

Another option, Rosenzweig says, is modifying the bone marrow before it's given back to patients. To do that, researchers would need to know which factors in the marrow matter most for repair and which are deficient after a heart attack. A handful of other studies have suggested that factors in the bone marrow may be able to help the heart heal, says Kenneth Chien, who directs the Cardiovascular Research Center at Massachusetts General Hospital in Boston. The new study hints that the immune system runs up against those factors, he says, and "suggests a way to potentially improve" the therapy.