Stem Cells Help Rat Hearts Recover After Attack

SEATTLE, Aug. 27 -- Human embryonic stem cells can improve heart function after an infarction -- at least in rats, researchers said here.
The finding is a proof-of-concept for the idea that stem cell grafts might one day form the core of therapy for people after heart attacks, according to Charles Murry, M.D., Ph.D., of the University of Washington, and colleagues.
Earlier research had shown that cardiac muscle cells derived from human embryonic stem cells could form new heart muscle in rats with uninjured organs, the researchers noted online in Nature Biotechnology.
But when they had tried the same thing in rats with induced heart attacks, the grafts failed for two reasons, they said -- it's hard to get stem cells to generate enough heart muscle cells and the cells that were transplanted didn't survive.
"Past attempts at treating infarcted hearts with stem cells have shown promise, but they have really been hampered by these challenges," Dr. Murry said in a statement.
To overcome the first challenge, the researchers treated single layers of stem cells with two compounds, activin A and bone morphogenetic protein 4, which greatly increased the proportion of stem cells that generated heart muscle cells.
An earlier method induced less than 1% heart muscle cells, while the new treatment increased that to more than 30%.
Adding a centrifuge step, the researchers obtained cultures that were 82.6% heart cells, Dr. Murray and colleagues said.
But simply injecting the cells into damaged hearts had little effect, they found, implying that the cells were simply dying, probably as a result of several factors, including ischemia, apoptosis, and inflammation.
To prevent that, the researchers developed a "pro-survival cocktail" aimed at blocking the various death pathways.
Experiment showed that 100% of rat hearts showed successful tissue grafts with the cocktail, compared to only 18% without, Dr. Murry and colleagues said.
"This is one of the most successful attempts so far using cells to repair solid tissues -- every one of the treated hearts had a well-developed tissue graft," he said.
Moreover, the animals who got the treated cells also had better heart function 28 days after their experimental heart attack, compared to several types of controls, the researchers said.
For instance, at day 28, left-ventricular systolic function, measured by fractional shortening, had fallen significantly (P<0.05) in all the control animals, compared with their values two days after the experimental heart attack.
But treatment with cardiac cells and the pro-survival cocktail "completely prevented the decline in fractional shortening," the researchers found.
Magnetic resonance imaging showed that four weeks after the heart attack, left-ventricle chamber dimensions were significantly increased and ejection fraction significantly reduced (P<0.01) in all the control animals, compared with rats that hadn't had a heart attack.
Again, in animals that got the heart cells and pro-survival cocktail, the damage was attenuated.
For instance, the researchers noted, in the treated animals the left-ventricle wall thickened by an average of 27.5%, compared with between 8.8% and 11.5% in the control groups. (The differences were significant at P<0.01.)
Overall, they said, the treatment slowed the progression of heart disease, improved global function, and increased regional wall motion compared with controls.
"We found that the grafts didn't just survive in the rat hearts -- they also helped improve the function of the damaged heart," lead author Michael Laflamme, M.D., of the University of Washington, said.
"That's very important, because one of the major problems for people suffering a myocardial infarction is that the heart is damaged and doesn't pump blood nearly as well," he said. "This sort of treatment could help the heart rebound from an infarction and retain more of its function afterwards."
This study was supported by Geron Corp. and by the NIH. The authors cited potential conflicts.Primary source: Nature BiotechnologySource reference: Laflamme MA et al. "Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infracted rat hearts." Nature Biotechnology 2007; doi:10.1038/nbt1327.