A gene-based therapy reduced atrial fibrillation in animal models of disease, according to a Northwestern Medicine study published in Circulation.
Treatments for atrial fibrillation (AFib), the most common heart rhythm disorder, are effective in only about half of patients, but this new therapy targets the mechanisms behind disease — a much more promising strategy, according to Rishi Arora, MD, professor of Medicine in the Division of Cardiology and senior author of the study.
“This is something that has therapeutic value because if this gene was injected into human hearts, it could potentially reverse much of the electrical remodeling that is otherwise so hard to treat,” Arora said. “This approach could potentially help people that currently cannot be helped by drugs or ablation.”
AFib is an irregular and often rapid heartbeat that occurs when the two upper chambers of the heart experience inconsistent electrical stimulation. “Extra” heart beats that arise in the pulmonary veins — the veins that bring oxygenated blood from the lungs into the heart — cause initial elevated heart rates that can lead to AFib. Once AFib begins, it tends to “perpetuate” itself, beginning a vicious cycle that eventually becomes difficult to treat with drugs or surgical procedures such as ablation.
“It’s a self-fulfilling prophecy where the longer the heart stays in AFib, the harder it is to get the heart out of AFib,” Arora said. “This is part of why the treatments are not yet where they need to be.”
Previous studies had made incremental discoveries about the mechanistic links between elevated heart rate and AFib — some pointing to oxidative stress — but none had firmly connected the dots, according to Arora.
In the current study, Arora and his collaborators examined animal models of oxidative stress. They discovered that a particular ion channel in the heart called IKH was extraordinarily sensitive to oxidative injury, vastly increasing its activity in the presence of oxidative stress.
“It was much more sensitive than any other ion channel that we looked at,” Arora said.
Increased IKH activity caused aberrant electrical stimulation in the heart, leading to mistimed and rapid heartbeats, which went on to lead to AFib.
Next, the group developed a targeted genetic therapy: NOX2 shRNA. This therapy silences NOX2, a major regulator of oxidative stress. The investigators administered this therapy to one group of animal models, with another untreated group serving as a control.
Using rapid atrial pacing to induce AFib, the control group developed the condition after just three or four weeks. On the other hand, the group treated with the therapy never experienced AFib. Further, the experimental group’s refractory period — the amount of time between heartbeats — remained nearly constant, where the control group (like patients with AFib) experienced increasingly short refractory periods.
IKH channels are found in human patients with AFib, and Arora believes this strategy could break the cycle of rapid heartbeats leading to AFib — something that current treatments are unable to do.
“We think we’ve discovered a key mechanism,” Arora said. “Basically, we could inject the gene and hopefully reverse the electrical remodeling by attacking this mechanism.”
Shin Yoo, PhD, research assistant professor of Medicine in the Division of Cardiology and Anna Pfenniger, MD, PhD, a fellow in clinical cardiac electrophysiology in the Division of Cardiology, were joint first authors of the study.
This work was supported by National Institutes of Health (NIH) grants R01 HL093490 and R01 HL140061, the American Heart Association Strategically Focused Research Networks AF Center grant and the NIH Center for Accelerated Innovations at Cleveland Clinic (NCAI-CC).