Heart attacks are often thought of as a plumbing issue, the result of a blockage preventing blood from flowing through one of the heart’s major thoroughfares. But scientists studying the heart’s connection to the brain have devised a new model for the common injury—one where panicked neurons respond to the clogged artery with an inflammatory cascade that makes a bad situation much worse.
By intervening at three key nodes in the heart-brain connection in mice, researchers were able to soothe heart attack symptoms and reveal promising new targets for next-generation cardiac medicines.
These three nodes in the heart-brain loop—a bundle of neurons in the heart, a region of the brain’s hypothalamus and a cluster of nerves in the neck—were all known to be implicated in heart attacks, Olujimi Ajijola, M.D., Ph.D., a cardiologist at the University of California, Los Angeles’ (UCLA's) David Geffen School of Medicine who wasn’t involved with the new study, told Fierce Biotech.
“The real advance of this paper is really connecting multiple dots” to trace a whole circuit, Ajijola said, “and doing so with rigor.”
The study was published in Cell on Jan. 27.
“It's a different way to look at heart attacks and then trying to reframe it as a neuroimmune problem,” Vineet Augustine, Ph.D., a neurobiologist at UC San Diego and leader of the study, told Fierce.
Augustine started his career unraveling thirst under Yuki Oka, Ph.D., at the California Institute of Technology. He found that even though it takes 15 to 20 minutes for water to dilute the blood after drinking, the brain knows to turn off the sensation of thirst right away by sensing the swallowing motions of throat muscles and the presence of water in the stomach.
Once he started his own research group under 2021 Nobel Laureate Ardem Patapoutian, Ph.D., Augustine expanded his interest in how the internal organs act as sensory systems to the heart, an area his mentor had already probed to award-winning effect. Most research of the heart’s nervous system had focused on how the brain talks to the heart, Augustine said, not the other way around.
“When I started my lab, the only defined cardiac sensory neurons were the Piezo neurons,” Augustine explained. Those neurons were described by Patapoutian’s team in 2010 and respond to pressure. In the heart, they help regulate blood pressure. Augustine wondered whether other sensory systems, besides Piezo neurons, were present in the heart, and how they may be involved in the world’s leading killer—heart attacks.
Augustine’s team induced heart attacks in mice by pinching the coronary artery and scrutinized the outcome on a cellular level, watching how the rodents’ hearts and brains responded to the injury. They first noticed that branches of a major nerve called the vagus seemed to go haywire due to the blockage.
“They literally wrap around the injured area after a heart attack, and then they really increase in numbers as well,” Augustine said. “That was very surprising for us.”
The researchers found these proliferating neurons expressed receptors called TRPV1; normally, TRPV1 neurons respond to infections, but, for some reason they were acting up after a heart attack even with no pathogen present. Blocking these neurons in the heart restored the organ’s function almost to normal levels, even though the artery was still clogged.
Ajijola has also studied the role of TRPV1 neurons in heart attacks and launched a startup called NeuFera to develop drugs targeting the errant cells.
“The poor heart got injured and is trying to recover, but the maladaptive processes happening within the nervous system continue to make the heart worse over time,” Ajijola said. “We understand very little of the process.”
Fight or flight
The TRPV1 vagus neurons are the first node of the brain-heart loop, sending signals up to the brain’s stress center, the paraventricular nucleus within the hypothalamus. The researchers found that the neurons receiving the alarm signal from the heart express a receptor called angiotensin II receptor type 1; blocking these cells in the loop’s second node also mitigated the effects of the heart attack.
Once the brain’s stress center is activated, the signal runs down to the third node—the superior cervical ganglion, near the base of the skull in the upper neck. Here, Augustine said, “the typical fight-or-flight response” is activated, and the immune system begins pumping out inflammatory cytokines, especially interleukin 1beta (IL-1beta).
When the scientists injected an anti-IL-1beta antibody into the third node in mice, heart attack symptoms were again ameliorated.
“At any of these nodes, you can literally make heart attacks better,” Augustine said.
There are approved IL-1beta antibodies on the market, such as Novartis’ Ilaris (canakinumab), which is used to treat autoimmune diseases. IL-1beta antibodies could be reworked to treat heart attacks, Ajijola said, but would need to be specifically targeted to avoid unwanted effects in other parts of the body.
Augustine sees these three nodes as opportunities to treat heart attacks, and potentially other cardiac conditions, across different time scales. Medicines that block IL-1beta or TRPV1 neurons could be given immediately after a heart attack, or chronic brain stimulation could be used to quell the angiotensin-expressing neurons in the hypothalamus in patients at high risk of a cardiac event.
“It's not like a single target, but different avenues of modern prospective therapeutics,” Augustine said. “You can have an immune blocker, you can have brain manipulation, you can have vagal nerve stimulation.”
For both Augustine and Ajijola, the new study highlights the surging interest in interoception, the brain’s ability to sense the internal organs and assess the body’s current needs, like hunger and thirst. Augustine is interested in looking at the gut next, while continuing to explore the mysteries of the heart-brain connection.
Ajijola has seen how starkly the internal organs can influence the brain personally. He specializes in a surgical procedure to remove nerves from a part of the nervous system called the stellate ganglion, which sits just below the superior cervical ganglion, in order to treat heart conditions that don’t respond to other therapies. He’s found that patients who get the procedure tend to have lower levels of anxiety afterward, even beyond what would be expected from the patient experiencing the surgery’s benefits.
“There's something very important about that pathway enabling the heart to influence anxiety,” Ajijola said, supporting the idea “that the working of the visceral organs actually influences our mood and our thinking.”