When a patient’s heart beats too rapidly, too slowly or erratically, and if the usual heart medicines fail to properly regulate the heart rhythm, then the patient’s cardiologist may prescribe the implantation of an electronic pacemaker to regulate the heart rhythm. Even though implanted pacemakers are widely used, their installation requires an invasive surgery, they carry some risk of infection, and they also set off metal detectors during airport security checks. However, gene therapy might soon join the electronic pacemaker as a treatment for a poorly-regulated heart. It runs out that inserting a specific gene into heart-muscle cells can allow researchers to restore a normal heart rhythm in pigs, albeit temporarily.
Electronic pacemakers restore regular function to hearts by sending small electrical currents to the heart muscle in order to stimulate a heartbeat. This function is usually donned by the sinoatrial node, which is a cluster of a few thousand cardiac cells in the upper part of the right atrium that signals the heart to initiate a heartbeat and, therefore, sets the heart rate.
A research team led by Eduardo Marbán, who is a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California, attempted to engineer heart cells outside the sinoatrial node to act as the pacemaker of the heart. The findings from Marbán’s laboratory were reported in the journal Science Translational Medicine.
Marbán and his colleagues used 12 laboratory pigs for their laboratory experiments. In these animals, Marbán and others induced a fatal heart condition in which electrical activity that originates from the sinoatrial node cannot spread through the heart. This forces other, less capable parts of the heart to take over and act as a pacemaker. Then, Marbán’s group used high-frequency radiowaves to destroy the sinoatrial nodes in the pigs’ hearts. This caused the animals’ average heart rate to slow to about 50 beats per minute (compared to the normal rate of 100 or more beats per minute). Such animals, if they were a human, would require an electronic pacemaker.
Next, Marbán and other injected the pigs’ hearts with a genetically modified virus that carried a pig gene called Tbx18, which is involved in heart development. Within one day, infected heart cells infected with the virus began to express those genes usually found in sinoatrial node cells. These cells acted as the pacemaker and began to direct the pumping the heart at a normal rate. The animals maintained this steady beating for the two-week study period, whether resting, moving or sleeping.
In an interview, Marbán said that his method is simpler than other biological approaches to restore a normal heart rhythm to hearts. These other approaches include inducing cardiac muscle cells to a pluripotent state, then coaxing them to differentiate into pacemaker cells. However, Marbán cautioned that the effects of gene therapy might be temporary. Over time, the body’s immune system would probably recognize the virus used to deliver Tbx18 to the heart and attack and destroy the infected cells. Marbán’s team is presently monitoring pigs that have received the gene-therapy treatment for several months to measure the persistence of this pacemaker effect.
However, even if the treatment’s effects are limited, it could still prove useful, according to Marbán. For example, if a pacemaker patient suffers from an infection as a result of the pacemaker, that pacemaker must be temporarily removed. This patient could then receive a biological pacemaker that could keep the heart pumping steadily until the infection clears and a new device is implanted. The gene-therapy approach could also help unborn children with heart defects, or even children who quickly outgrow implanted pacemakers or people for whom surgery is simply too risky.
“I think it’s a truly creative idea,” says Ira Cohen, a cardiac electrophysiologist at Stony Brook University Medical Center in New York. He would like to see the therapy tested in dogs, whose average heart rate is 60-100 beats per minute, which is more similar to that of a human.
Marbán is presently in talks with the US Food and Drug Administration about developing a human trial, which he says could be just two to three years away.