Scientists at the University of California San Diego have discovered a path between the brain and the immune system that could potentially lead to new ways to ease heart attacks. They showed that disabling specific parts of that circuit could profoundly improve outcomes in mice with experimentally induced heart attacks.
"The injury almost disappears," says UCSD neuroscientist Vineet Augustine, who led the new study appearing Tuesday in the journal Cell.
While it may not seem obvious how neuroimmune crosstalk relates to heart disease, links between the nervous and immune systems have captivated researchers for decades. Some researchers have focused on the vagus nerve, a huge bundle of fibers that carries signals between the brain and other organs to control breathing, blood pressure, digestion and other involuntary functions.
A key discovery came in 2000 when researchers at the Feinstein Institutes for Medical Research on Long Island, New York, showed that electrically stimulating the vagus nerve in rats curbed production of an immune protein that drives inflammation.
Last July, an implantable vagus nerve stimulator developed by SetPoint Medical — a company co-founded by Dr. Kevin Tracey, president of the Feinstein Institutes — earned FDA approval as a treatment for people with rheumatoid arthritis, an autoimmune disease.
Earlier research had also found striking links between the cardiovascular system and the nervous and immune systems. On the day of the devastating 1994 Northridge earthquake, the number of sudden cardiac deaths in Los Angeles County rose more than fivefold. Similar spikes occur with high-stakes sporting events. During stressful moments, the heart rate shoots up to protect us.
"The brain says, hey, get up and run, you're going to die," says Dr. Kalyanam Shivkumar, a UCLA cardiac electrophysiologist.
While such fight-or-flight signals help during emergencies, in the long term, they trigger harmful inflammation. "And then the heart swells up. You get arrhythmias and heart failure," says Shivkumar, who's leading an effort to create a new anatomical atlas of the heart.
The current research from UCSD uses state-of-the-art tools from genetics and neuroscience to gain a more precise understanding of how the brain communicates with the heart and its role in heart attacks.
It shows how the vagus nerve carries signals between the brain and the heart. Augustine says he found that during a heart attack in mice, certain vagal neurons (TRPV1 expressing neurons) "literally wrap around the injury site." His team wondered if blocking communication through those nerve cells could help slow or even prevent heart attacks in the lab animals.
It was a bold idea — one that some scientists told Augustine was "unreal" when he spoke about the project in its early stages four or five years ago.
The experiments were technically demanding and required multiple researchers to work long hours together — one performing heart surgery on the mice, another targeting specific cells in the brain, and others taking physiological measurements and conducting echocardiography to image the heart in real-time.
"Minor errors at any step could have compromised the entire experiment," Saurabh Yadav, a postdoc in Augustine's lab and one of the paper's first authors, said via email. "There were moments when I wondered whether I had taken on too much or if this was simply too big a leap."
Then came an "incredibly encouraging" moment, Yadav told NPR. The team turned off this small group of TRPV1 nerve cells and saw striking improvements in pumping efficiency and electrical signals associated with heart contraction. And that was just the first victory.
The TRPV1 neurons carry signals from the heart to the hypothalamus — a deep-brain structure that regulates body temperature, thirst, hunger and sleep. Other cells in the hypothalamus receive those signals and relay them to a different cluster of nerve cells that project back to the heart and unleash an immune protein that drives inflammation. Blocking any of the three junctures of the heart-brain-immune loop relieved heart attack complications in the mice, the UCSD team reports in Cell.
"The findings in this paper are quite impressive," says Cameron McAlpine, a neuroimmunologist at Icahn School of Medicine at Mount Sinai who was not involved in the new research.
While he and others have long known that heart attacks trigger major changes in the immune and nervous systems, McAlpine says, it's only in the last five or six years that researchers have developed "tools and technologies that allow us to study this at a really deep level" — such as some of the genetic approaches for precisely manipulating the activity in specific groups of nerve cells.
For years, research in this area stalled because of a conceptual divide — the idea that the brain is the command center, sending signals to the rest of the body, Augustine says. Clinicians "focused on the organ itself, whereas the nervous system was kind of ignored," he adds. "That created a lot of silos."
Now, interest in the nervous and immune systems is surging. These systems "affect practically everything in your body," he says. "The field is really exploding."
While the mouse findings are still years from entering human trials, it's possible that the approved vagus nerve stimulator could prove useful for heart attacks after further study, says Asya Rolls, a neuroimmunologist at Tel Aviv University in Israel. Her team has shown that the brain's reward networks can regulate inflammation in mice in various settings including bacterial infections and cancer as well as heart attacks.
In future experiments, Augustine says his team will flesh out the heart-brain-immune circuit by investigating, for example, what exactly the nerve cells are sensing and how they communicate with the heart cells.
In a 2024 paper, McAlpine and colleagues report that heart attacks send immune cells into the brain to promote deep sleep.
The growing body of research illustrates how brain-immune connections can manifest differently across conditions — and "it's likely much more complex" than the specific pathways identified by each research team, Rolls told NPR via email. Each manipulation likely affects many other pathways such as blood flow, vascularization and metabolism. A National Institutes of Health program called Stimulating Peripheral Activity to Relieve Conditions (SPARC) is funding research on stimulating neural circuits to relieve disease.
Shivkumar sees an emerging theme. "The message people should get is, oh my God, these scientists are doing something very exciting. But literally we are building on ancient knowledge," he says. Research on stimulating the vagus nerve supports "what the Buddha said: meditate. I call it Zen cardiology."
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