Researchers at the University of Utah Health in the US corrected abnormal heart rhythms in mice by restoring healthy levels of a protein needed by heart cells to make connections to each other. This protein, called GJA1-20k, is underproduced in people with a genetic condition called arrhythmogenic cardiomyopathy, one of the leading causes of sudden cardiac arrest in athletes under 35.
The discovery, reported in the scientific journal Circulation Research, suggests a new strategy for treating abnormal heart rhythms caused by arrhythmogenic cardiomyopathy. The findings may also have implications for the treatment of dangerous arrhythmias associated with more common conditions, such as those that can develop soon after a heart attack.
Heart disease causing sudden cardiac arrest in young athletes
People with arrhythmogenic cardiomyopathy are born with a normal heart but begin to develop an irregular heartbeat in their 20s or 30s. These arrhythmias can raise the heart rate to dangerous levels, which is why some people with the condition experience sudden cardiac arrest during exercise.
Patients diagnosed with arrhythmogenic cardiomyopathy are advised to limit exercise. They may also benefit from an implantable defibrillator to control their heart rhythm. As the disease progresses, the heart muscle becomes fatty and fibrous. This prevents the heart from pumping blood efficiently and eventually patients need a heart transplant.
Gene therapy could restore the right protein levels
The research team studied the heart tissue of patients with arrhythmogenic cardiomyopathy who had undergone a transplant and discovered a problem with a protein called Connexin 43. In healthy hearts, Connexin 43 forms channels between adjacent cells, facilitating Communication. Diseased hearts produced normal amounts of Connexin 43, but not in the right place at the cellular level. This, according to the study authors, likely because there was a lack of a protein called GJA1-20ka. Researchers knew from previous experiments that without it, heart cells couldn’t get Connexin 43 to the right place.
To determine if they could restore normal heart rhythm, the scientists turned to mice that show similarities to people with arrhythmogenic cardiomyopathy. They both have low levels of GJA1-20k and develop arrhythmias. They used low doses of gene therapy to bring the GJA1-20k trafficking protein back to normal levels. This, they confirmed, allowed heart muscle cells to transport Connexin 43 to its proper locations.
“It’s a new paradigm for the treatment of cardiac arrhythmias”
More importantly, it gave the rodents a more normal heartbeat. However, although the arrhythmia improved, the animals still had heart scarring, a symptom of a different underlying condition. This suggests that arrhythmia and heart scarring can occur independently and that it might be possible to treat abnormal heart rhythms even when the heart is severely scarred. “This is truly a new paradigm for the treatment of heart rhythm disorders”said study first author Joseph Palatinus, a researcher at Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), in a communiqué.
The success of the treatment in mice suggests that increasing GJA1-20k levels might also restore normal heart rhythms in patients with arrhythmogenic cardiomyopathy. For the latter, Joseph Palatinus asserted, it might be possible to deliver the therapeutic protein directly to the heart. Further research will still be needed to develop the treatment for clinical use.