New research by scientists at Washington University School of Medicine in St. Louis suggests that noninvasive radiotherapy, which is typically used to treat cancer, can reprogram heart muscle cells to a younger and perhaps healthier state, fixing electrical problems that cause life-threatening arrhythmias without the need to resort to the long-used invasive procedure of catheter ablation.
The study results also indicate that the same cellular reprogramming effect could be achieved with lower doses of radiation, opening the door to the possibility of wider uses for radiation therapy in different types of cardiac arrhythmias. “Arrhythmias are associated with slow electrical conduction speeds,” explained cardiologist Stacey L. Rentschler, MD, PhD, an associate professor of medicine, developmental biology, and biomedical engineering at Washington University School of Medicine. “Radiation therapy seems to kick up the speed faster by activating early developmental pathways that revert the heart tissue back into a healthier state.” Rentschler is senior author of the team’s published paper in Nature Communications, which is titled, “Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis.”
Sudden cardiac arrest can occur when there is impaired cardiac function and structural heart disease that lead to ventricular tachycardia (VT) and ventricular fibrillation, and is a leading cause of death in the world, the authors explained. Implantable cardioverter defibrillators are one option for treatment and can improve survival, but “at the cost of reduced quality of life from shocks and potential for worsening heart failure (HF),” the investigators noted. Anti-arrhythmic drugs (AAD) also have only modest efficacy and can cause considerable side effects. Radiofrequency catheter ablation (CA) can be carried out to destroy the area of the heart that is causing the abnormal rhythm. A catheter is threaded into the heart, and the tissue that triggers the life-threatening ventricular tachycardia is burned, creating scars that block the errant electrical signals. However, as the authors commented, “CA is time-consuming, technically challenging, and highly operator-dependent,” and the success rate varies, dependent on factors such as the degree of preserved ventricular function.
Radiotherapy (RT) noninvasively delivers high-dose radiation to volumes of target tissue anywhere in the body, with minimal off-target exposure. It’s a well-established treatment for different cancers. In theory, RT could reproduce the scar tissue usually created through CA, but using a much shorter and totally noninvasive procedure, which could make the treatment approach available to more severely ill patients. In 2017, physician-scientists at Washington University showed that radiation could be directed at the heart to treat ventricular tachycardia. “Hypothetically, ablative doses of radiation could noninvasively replicate effects of CA, with a fibrotic response expected over months to years,” the team reporting on the latest study in Nature Communication suggested.
“Traditionally, catheter ablation creates scar tissue to block the electrical circuits that are causing ventricular tachycardia,” said Rentschler. “To help us understand whether the same thing was happening with radiation therapy, some of the first patients to have this new treatment gave us permission to study their heart tissue—following heart transplantation or if they had passed away for another reason, for example.”
Surprisingly, through their investigations, the doctors found that patients experienced large improvements in their arrhythmias a few days to weeks after receiving RT, which was much quicker than the months it can take scar tissue to form after CA therapy. This suggested that a single dose of radiation reduces the arrhythmia without forming scar tissue. The analyses also indicated that radiation treatment worked just as well, if not better, than CA for certain patients with ventricular tachycardia, but in a different and unknown way. “Through histologic examination and MRI scans of the hearts from patients who received cardiac RT, we provide evidence from a cohort of human RT patients to show that 25 Gy transmural radiation does not create transmural scar,” the investigators reported. Rentschler added, “We saw that scar tissue alone could not explain the remarkable clinical effects, suggesting that radiation improves the arrhythmia in some other way, so we delved into the details of that.”
The scientists found that radiation treatment triggered heart muscle cells to begin expressing different genes. They measured increased activity in a signaling pathway called Notch, which is known for its vital role in early development, including in the formation of the heart’s electrical conduction system. Notch is usually switched off in adult heart muscle cells. But the researchers found that a single dose of radiation temporarily activated Notch signaling, leading to a long-term increase in sodium ion channels in the heart muscle, a key physiologic change that can reduce arrhythmias. “Through RNA-seq and transgenic approaches, we identify cardiomyocyte-specific Notch activation as one potential cell signaling mechanism that may contribute to the pro-conductive effect of radiation via upregulation of the cardiac sodium channel,” the team wrote.
The researchers studied these effects in mice and in donated human hearts. They found that in the human heart samples, these changes in heart muscle cells were only present in areas of the heart that received the targeted radiation dose. “Radiation does cause a type of injury, but it’s different from catheter ablation,” said co-author and radiation oncologist Julie K. Schwarz, MD, PhD, a professor of radiation oncology and director of the cancer biology division in the department of radiation oncology, Washington University School of Medicine. “As part of the body’s response to that injury, cells in the injured portion of the heart appear to turn on some of these early developmental programs to repair themselves. It’s important to understand how this works because, with that knowledge, we can improve the way we’re treating these patients and then apply it to other diseases.” The authors further pointed out, “Mechanistic insights such as these are expected to lead to refinements in the cardiac radiation clinical protocol and ultimately greater adoption of cardiac RT.”
The researchers also found that the beneficial effects of radiation continued for at least two years in surviving patients. And importantly, they were able to demonstrate in mice that a lower dose of the radiation produced the same effect. A lower radiation dose could minimize long-term side effects and open the door to this type of treatment in other types of heart arrhythmias. “Although the largest biological effects were seen at 25 Gy, these findings suggest that lower doses of ionizing radiation, between 15 and 20 Gy, may also be sufficient to achieve therapeutic electrophysiologic effects of RT on VT reduction,” the authors stated. And while Notch was a big player in these effects, Schwarz said it’s not the only pathway involved. The researchers are continuing to investigate how radiation triggers heart cells to revert to a healthier state.
“Our findings have direct relevance for patient care,” the authors concluded. “Most surviving patients continue to exhibit reduced VT burden 24 months after a single RT treatment.” They suggested that “… the ability to noninvasively and functionally eliminate VT circuits, by modulating cardiac electrophysiology in a localized way and without tissue destruction, may allow for safer treatments and prevention of arrhythmias for individuals with myocardial scarring … Our results demonstrate that the functional and molecular effects of RT and Notch reactivation are persistent and expected to directly translate into long-term durability of therapy.”
Added first author David M. Zhang, an MD/PhD student in Rentschler’s lab: “This was an exciting collaboration not only between basic scientists and clinicians but also cardiologists and radiation oncologists. Historically, radiation oncologists are focused on cancer and try to avoid irradiating the heart, so this study opens up a whole new area of research and collaboration between these two fields.”