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The pacemaker of the future might be made of heart cells

The pacemaker of the future might be made of heart cells


A new technique uses gene therapy to create "biological pacemakers" in pigs

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Cardiologists in Los Angeles have developed a gene-therapy technique that allows them to transform working heart-muscle cells into cells that regulate a pigs’ heartbeat. This procedure, described today in the Science Translational Medicine, restored normal heart rates for two weeks in pigs that usually rely on mechanical pacemakers. The experiment, researchers say, could lead to lifesaving therapies for people who suffer infections following the implantation of a mechanical pacemaker.

the biological pacemaker supports "the demands of daily life."

"We have been able for the first time to create a biological pacemaker using minimally invasive methods and to show that the new pacemaker suffices to support the demands of daily life," Eduardo Marbán, a cardiologist at the Cedars-Sinai Heart Institute and lead author of the study, told the press yesterday. The approach is practical, added Eugenio Cingolani, a cardiogeneticist also at Cedars-Sinai and a co-author of the study, because "no open-heart surgery is required to inject this gene."

In the study, researchers injected a gene called Tbx18 into the pigs’ hearts. This gene, which is also found in humans, reprogrammed a small number of heart-muscle cells into cells that emit electrical impulses and drive the beating of the heart. The area in which this change occurred — about the size of a peppercorn — doesn't normally initiate heartbeats. "We were able to get the biological pacemaker to turn on within 48 hours," Marbán said. To get the gene to the heart, the researchers sent a modified virus into the right ventricle through a catheter. The viral vector isn’t harmful, the researchers said, because the virus they employed was engineered to be "replication deficient" — meaning that it will not reproduce and spread beyond the heart.

Overall, the results of the study demonstrate that the pigs who received the gene therapy experienced an increase in heart rate that allowed them to be much less dependent on backup pacemakers. In contrast, the backup pacemakers were responsible for more than 40 percent of the beats in pigs who didn’t receive the gene therapy, but still underwent surgery.

Two weeks isn't "a magic cap."

Unfortunately, it appears that the increased heart rates of the treated pigs tapered off toward the end of the two-week period. This, the researchers say, doesn't mean that the therapy couldn't last longer. "Based on the data showing in the paper or the unpublished results," Marbán said, "we don’t have any reason to believe... that the two weeks is somehow a magic cap."

"The study’s novel since it was done in a large animal. It’s also a really clever approach," says Ira Cohen, a cardiac electrophysiologist at Stony Brook University in New York who did not participate in the study. Cohen explains that this study is different from previous attempts at producing "biological pacemakers" because the scientists didn’t use stem cells.

The study also differs from previous efforts because instead of being aimed at permanently replacing mechanical pacemakers, it offers temporary support for people with infections while doctors wait to replace their devices. "Currently, a temporary pacemaker is placed for this indication, but implantation of additional hardware isn't an ideal solution given the high likelihood for reinfection," researchers at UT Southwestern Medical Center explained in an accompanying article published in Science today. This means that this type of gene therapy could curb the need for a temporary device, and reduce the likelihood of reinfection.

Two percent of people with pacemakers in the US experience infection

An estimated 2 percent of people with pacemakers in the US experience an infection at some point, Marbán explained. "And some sizeable fraction of those 2 percent would go on to need revision of the system, and presumably this kind of bridge from one device to another." Marbán also thinks the therapy might help doctors treat congenital heart block in fetuses, because surgeons can’t implant pacemakers in the womb. "Even though it’s rare," Marbán said, "we offer this as a potentially life-saving procedure in those babies in which there’s no other therapeutic option."

But there might be an "enormous surgical effect."

But Cohen also raised questions about certain aspects of the study. For one, the researchers didn’t report the pigs’ initial heart rates. This makes it hard to evaluate the effectiveness of the therapy, he says, because the pigs who weren’t treated with Tbx18 also experienced an increase in heart rate over the two-week period. "Either there’s an enormous surgical effect," or the pigs’ heart rates were very high to begin with, Cohen says, which means it might not be the best model of human health.

Cohen also thinks the study would have been more convincing if the pigs were experiencing infections at the time of the intervention. "Why wouldn’t you create an animal model that’s infected if you want to replace an infected site?" he asks. Still, "I give [the researchers] enormous credit for looking for short-term solutions, and enormous credit for the advancement to actually differentiate these cells into pacemaker cells."

"Why wouldn’t you create an animal model that’s infected if you want to replace an infected site?"

The researchers hope to try the therapy on humans within the next three years. But the scientists couldn't estimate what the therapy might eventually cost, because "we’re developing it in the initial incidence for very narrow niche indications for which there’s no comparable therapy," Marbán said, adding that he hopes to expand the uses of the work to the entire population of people with pacemakers. "If you look at the natural history of other first-in-class treatments for heart-rhythm disorders, they start with the most arcane and difficult cases, and then ultimately they become generalized to be able to treat hundreds of thousands of patients," he said. "We wouldn’t be surprised if that’s the path that this takes."

A lot is riding on the success of this approach

From a medical research standpoint, a lot is riding on the success of this approach, Cohen says. "There has been a lot of promise and a lot of hype surrounding regenerative medicine, but there have been very few successes." So, even if the resulting application ends up being a relatively small success, given the small population it might serve, "this would basically be saying that we are doing something with the dollars that have been invested." That’s why Cohen, who considers himself a competitor, thinks it’s "incredibly important" that something in this field makes it to clinical trials. "It could be the core that allows people who are on medical review boards to point to the fact that we do, indeed, have a therapy."