Radiation therapy reprograms heart muscle cells to younger state
Radiotherapy repairs irregular rhythms in those with life-threatening
heart arrhythmia

Date:
September 24, 2021
Source:
Washington University School of Medicine
Summary:
New research suggests that radiation therapy can reprogram heart
muscle cells to what appears to be a younger state, fixing
electrical problems that cause a life-threatening arrhythmia
without the need for a long- used, invasive procedure.



FULL STORY ==========================================================================
New research from Washington University School of Medicine in St. Louis suggests that radiation therapy can reprogram heart muscle cells to
what appears to be a younger state, fixing electrical problems that
cause a life- threatening arrhythmia without the need for a long-used,
invasive procedure.


==========================================================================
In that invasive procedure -- catheter ablation -- a catheter is threaded
into the heart, and the tissue that triggers the life-threatening
irregular heart rhythm -- ventricular tachycardia -- is burned, creating
scars that block the errant signals. The new study, however, shows that noninvasive radiation therapy normally used to treat cancer can reprogram
the heart muscle cells to a younger and perhaps healthier state, fixing
the electrical problem in the cells themselves without needing scar
tissue to block the overactive circuits. The study also suggests 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.

The study appears Sept. 24 in the journal Nature Communications.

Physician-scientists at Washington University showed in 2017 that
radiation therapy typically reserved for cancer treatment could be
directed at the heart to treat ventricular tachycardia.

In theory, radiation therapy could reproduce the scar tissue usually
created through catheter ablation but with a much shorter and totally noninvasive procedure, making the treatment available to more severely
ill patients.

Surprisingly, the doctors found that patients experienced large
improvements in their arrhythmias a few days to weeks after radiation
therapy, much quicker than the months it can take scar tissue to form
after radiation therapy, suggesting that a single dose of radiation
reduces the arrhythmia without forming scar tissue. The data indicated
that radiation treatment worked just as well, if not better, than
catheter ablation for certain patients with ventricular tachycardia but
in a different and unknown way.

"Traditionally, catheter ablation creates scar tissue to block
the electrical circuits that are causing ventricular tachycardia,"
said senior author and cardiologist Stacey L. Rentschler, MD, PhD,
an associate professor of medicine, of developmental biology and of
biomedical engineering. "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. 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 forming 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 activates
Notch signaling, leading to a long-term increase in sodium ion channels
in the heart muscle, a key physiologic change that can reduce arrhythmias.

"Arrhythmias are associated with slow electrical conduction speeds,"
Rentschler said. "Radiation therapy seems to kick up the speed faster
by activating early developmental pathways that revert the heart tissue
back into a healthier state." The researchers studied these effects
in mice and in donated human hearts. In the human heart samples, the researchers found that 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. "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 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. 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.

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." This work was supported by
the National Institutes of Health (NIH), grant numbers T32 HL134635,
T32 GM07200, R01 HL130212, UH3 HL141800 and S10 OD020136.

This study received seed funding from the Department of Radiation
Oncology, Cancer Biology Division, at Washington University. Schwarz
holds a Female Investigator Award from AACR-Bristol Meyers Squibb and
funding from the Radiological Society of North America. Rentschler holds
a Career Award for Medical Scientists from the Burroughs Wellcome Fund
and funding from The Foundation for Barnes-Jewish Hospital that directly supported this work.

Washington University co-authors Clifford Robinson, MD, and Phillip
Cuculich, MD, have filed two institution-owned patents: Noninvasive
Imaging and Treatment System for Cardiac Arrhythmias that relates to
overall methods for delivery of cardiac radiation in patient; and System
and Method for Determining Segments for Ablation that relates to use
of cardiac segments for cardiac radiation targeting. They also provide consulting services to Varian, which produces linear accelerators for
radiation treatment delivery.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhang, D.M., Navara, R., Yin, T. et al. Cardiac radiotherapy induces
electrical conduction reprogramming in the absence of transmural
fibrosis. Nat Commun, 2021 DOI: 10.1038/s41467-021-25730-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210924104055.htm

--- up 3 weeks, 1 day, 8 hours, 25 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)