Can a genetic fix replace the pacemaker?
There may soon be a biological alternative to keep the heart beating steadily. Yi-Di Ng reports.
After more than a decade of experiments, scientists in the US have taken the first steps to developing a new form of pacemaker made not from artificial materials but from natural heart cells. Eduardo Marbán and his team at the Cedars-Sinai Heart Institute in Los Angeles have found that by genetically modifying normal pig heart cells they can effectively turn them into the cells that control heartbeat.
The heart owes its steady beat to electrical signals originating from a group of cells known, fittingly, as pacemaker cells. These are grouped in a part of the heart called the sinoatrial node, which works like a metronome to maintain a regular heartbeat. But if the signal is disrupted the heart loses its rhythm causing fatigue, dizziness and even cardiac arrest.
Artificial pacemakers, which are implanted in a patient’s chest, are designed to take over when the heart’s natural pacemaker fails. But as sometimes happens with machines, they don’t always work perfectly.
“An artificial pacemaker is still a piece of hardware,” says Edward Barin, director of the pacemaker and implanted devices clinic at the Royal North Shore Hospital in Sydney. “Pacemakers can break or malfunction, and have to be replaced every few years. Being foreign bodies, they can sometimes get infected, which is rare but life-threatening.” Patients with implanted pacemakers also cannot undergo magnetic resonance imaging (MRI), he adds. “That’s a pretty big disadvantage.”
Enter Marbán and his team. For the past 12 years they have been experimenting with a biological alternative to artificial pacemakers. As reported in the journal Science Translational Medicine, they may now have succeeded. By injecting a gene called T-box 18 (TBX18) into living pig hearts, Marbán and his colleagues have turned ordinary heart cells into specialised pacemaker cells.
“It’s a remarkable achievement that they have done this in a large living animal, and not just in mice or a test tube,” says Barin.
Even if the biological approach offers only a short-term fix, it could be extremely useful for patients whose electronic pacemakers become infected.
The gene, TBX18, of which pigs and humans each have a version, plays a role in telling embryonic cells what type of cells they will become. Previous studies by Marbán also confirmed that the gene is active in the sinoatrial node of the heart, suggesting it may play a role in building the heart’s natural pacemaker.
Marbán and team tested TBX18's effects on living pigs with a complete heart block, a condition where the electrical signals generated by pacemaker cells fail to reach the rest of the heart. To deliver TBX18 the researchers inserted the gene into a virus and then injected the virus directly into the right ventricle of the heart, a region where pacemaker cells are not normally found.
Within 48 hours, not only had the heartbeats of the TBX18-injected pigs returned to normal, but the animals could also sustain their own heart rates. The TBX18-treated hearts also behaved very much like a natural heart, beating faster with physical exercise and slowing during rest. After the experiment, the researchers discovered that a peppercorn-sized region of cells had been converted into impulse-generating pacemaker cells.
“In essence, we created a new sinoatrial node,” says Marbán. “We have been able, for the first time, to create a biological pacemaker using minimally-invasive methods and show that the new pacemaker suffices to support the demands of daily life,” he says.
Marbán does note, however, that the activity of these induced pacemaker cells began to fade at the end of the two-week experiment, probably because the pigs' immune systems spotted the virus used to transfer TBX18 and began to attack the infected cells. The team is now testing how the converted cells perform in the long term and expects to trial the procedure in humans within three years.
Even if the biological approach offers only a short-term fix, it could be extremely useful for patients whose electronic pacemakers become infected and must be removed while the infection clears.
So, does Barin see himself carrying out this procedure on his own patients in the future? “I hope so,” he says. “There are definite niches where a biological pacemaker is needed if an implanted device isn’t an option.”
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