Great news for Guinea Pigs

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UW researchers see work as step toward regenerating human heart
University of Washington researchers have reported that transplanting human heart cells — derived from embryonic stem cells — into damaged guinea-pig hearts synchronized with and strengthened the animals' hearts and provided protection from dangerous rhythm disturbances.

By Carol M. Ostrom
Seattle Times health reporter
August 7, 2012

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Two University of Washington scientists, using expertise in stem cells, cardiology, pathology, cell biology and the electrophysiology of the heart, are a step closer to their holy grail: regenerating a damaged heart.

Human heart-muscle cells injected into the damaged heart of a guinea pig not only strengthened the heart's ability to contract, the cells synchronized with the animal's heart and protected it from arrhythmias, rhythm disturbances that can be fatal.

Regenerating a damaged heart is the "big dream, the big vision," said Dr. Charles E. Murry, a cardiovascular biologist who co-led the research published in the most recent issue of Nature.

"This is the first demonstration that human heart-muscle grafts can electrically stabilize the injured heart, and the first demonstration that they can couple and beat in sync," Murry said.

When the researchers injected the human heart cells, grown from embryonic stem cells, into the hearts of guinea pigs with damaged hearts, they saw a "profound effect," said Dr. Michael Laflamme, the senior author.

"The animals that had received these stem-cell-derived heart-muscle cells had far fewer arrhythmias," said Laflamme.

Like Murry, he is a cardiovascular biologist, pathologist and member of the UW Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine.

To tell if the new cells were beating in rhythm with their host, the researchers inserted a sensor gene that would fluoresce green when the cells contracted. The fluorescent protein was originally discovered in the Aequorea victoria jellyfish at Friday Harbor on San Juan Island.

In the last several years, medical science has made much progress in helping patients survive acute heart attacks, Murry noted.

In a way, that success has helped create an epidemic of a subsequent problem: heart failure, most often caused by the damage to heart muscle. Patients diagnosed with heart failure have an average life expectancy of less than five years, Murry said, making it a deadlier disease than breast cancer.

"Because a heart attack kills off a chunk of the heart wall, and the heart is the least regenerative organ in the body, it grows back scar tissue instead of new muscle," Murry said. "So you lose your contractile function and it causes electrical instability, too."

Arrhythmias are a leading cause of death in patients who survive heart attacks.

Existing treatments, Murry said, "dance around the root cause" — that the injured heart doesn't have enough muscle cells left to pump and keep a steady electrical rhythm.

So what's the answer? Figure out how to regenerate heart muscle.

That goal is being actively pursued by a number of research groups, with some successes. A recent trial at Cedars-Sinai Heart Institute and Johns Hopkins University showed improvement in 17 heart-attack patients who had been injected with stem cells derived from their own heart muscle.

And researchers in Israel have reported they transformed patients' own skin cells into beating heart cells.

But so far, all stem-cell therapies are still experimental.

For the UW researchers, there were a few little bumps in the road. First, about 15 years of work by Murry and a decade by Laflamme on such basics as how to coax stem cells to become heart cells.

Then, they worried that the stem cells might create tumors. About three years ago, Murry says, they put that problem to rest.

Their earlier experiments with rats and mice showed the transplanted cells improved the pumping function of damaged hearts.

But would the new cells electrically "couple" and fire in sync with their injured host heart — without creating irregular heart rhythms?

It would be bad news, Murry said, if transplanted cells created new muscle, only to cause dangerous arrhythmias.

To test that, they needed animals whose heart rate was slower, closer to the top rate they could get by stimulating the human heart cells.

Guinea pigs, with heart rates of about 240 beats a minute, would work — after the researchers learned to keep them from rejecting the new cells.

What they found was that the new cells coupled up with the majority of the damaged guinea pig hearts and actually protected them against arrhythmias. .

Dr. Glenn Fishman, a cardiologist at the New York University Langone School of Medicine not connected to this research, urged caution. In a news report in Nature, he said drawing implications for human therapy is a stretch. The area where the heart cells grafted was small, he said, and the benefits could be from a known effect in which transplanted cells secrete substances that somehow rejuvenate damaged host tissue.

Laflamme said while some of their work argued against that cause, they couldn't completely rule it out.

"We're doing experiments actively in the lab to resolve that (question)," he said.

While in the end, any action by transplanted cells that restores heart muscle is good, Murry said, "you can't rationally improve on something if you don't know how it works, so we as scientists have to figure it out."

For this research, the UW researchers worked with those at three other labs for four years, funded by the National Institutes of Health and the Geron Corp.

Murry and Laflamme are founders and equity holders in a private company, BEAT BioTherapeutics Corp.

Carol M. Ostrom: 206-464-2249 or costrom@seattletimes.com. On Twitter @costrom.