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Researchers say nerve activity bursts may linked to heart failure. Bryan Steffy/Getty Images
  • Researchers from the University of Auckland in New Zealand report that in male rats with heart failure, the carotid body (an oxygen-sensing organ) produced sudden bursts of nerve activity that were linked to breathing problems.
  • They also found that the P2X3 receptor played a role in producing these bursts of nerve activity.
  • When researchers blocked the receptor using a drug, the bursts of nerve activity stopped and breathing and heart function improved.

Heart failure is a condition in which the heart’s muscle gets injured from something like a heart attack or high blood pressure and gradually loses its ability to pump enough blood to supply the body’s needs.

This leads to retention of extra fluid in the body, or “congestion.”

According to the Heart Failure Society of America, heart failure affects more than 6 million people in the United States over the age of 20. It also accounts for more than 8% of all heart disease deaths in the country.

Although there is currently no cure for heart failure, research has contributed to a better understanding of the condition.

Studies have shown that certain parts of the body called peripheral chemoreceptors, which typically regulate breathing, can be hyperactive in people with heart failure, leading to worsening heart failure and problems such as sleep apnea (a condition in which breathing stops and restarts multiple times during sleep).

One of these peripheral chemoreceptors is the carotid body, a cluster of sensors near the carotid artery in the throat. In response to reduced blood flow and oxygen circulation, the sensors trigger rapid breathing and increased blood pressure by activating the sympathetic (“fight-or-flight”) nervous system.

Julian F.R. Paton, PhD, a professor of translational physiology at the University of Auckland (Waipapa Taumata Rau), New Zealand, explained to Medical News Today that these sympathetic nerve signals “are good when you need to accelerate your heart rate and escape from a threatening situation, but they are deleterious in heart failure, reducing blood flow to the heart and thicken and stiffen heart muscle, [thus] worsening its performance as a pump.”

Researchers have found that ablating or removing carotid bodies can improve heart function and survival in rats and humans with heart failure. However, this approach may have risks and could disrupt important bodily functions.

In a new study published in Nature Communications, Paton and his fellow researchers looked at a way to reduce the damaging sympathetic activity of the carotid bodies by using a drug instead of removing them.

The researchers induced heart failure in juvenile (4 weeks old) male Wistar rats.

They then examined petrosal neurons in heart failure rats and other rats. A petrosal neuron is a type of nerve cell that acts as a “wire” between the carotid body and the central nervous system.

The researchers reported that these neurons had more P2X3 receptors in the rats with heart failure than in the rats without heart failure.

They also observed spontaneous bursts of nerve activity in the carotid sinus nerve that were associated with breathing problems and increased heart rate.

Based on their observations, the researchers deduced that these bursts of nerve activity occurred when the carotid body released the chemical transmitter adenosine triphosphate, which then acted on the P2X3 receptors.

Since “the P2X3 receptor [is] over expressed and highly activated in heart failure, and stimulates the production of sympathetic activity”, Paton’s team concluded it could be “a new drugable target”.

The researchers gave the rats a drug called AF-130, which blocks the P2X3 receptors and stops the bursts of nerve activity.

Prior to treatment, rats with heart failure had fast and irregular breathing patterns and experienced apnea (which means that they sometimes stopped breathing altogether). AF-130 treatment restored normal breathing patterns in rats with heart failure and lowered the number of apnea episodes.

AF-130 also improved heart function in rats with heart failure. Compared to rats who didn’t receive the drug, the rats who received the drug had a higher ejection fraction, higher stroke volume, reduced cardiac hypertrophy (thickening of heart muscle), and reduced pulmonary edema (excess fluid in the lungs). Additionally, AF-130 treatment reduced levels of a protein called N-terminal pro-B-type natriuretic peptide, which is a marker of heart failure.

The researchers also observed that, in rats with heart failure, there was an increase in natural killer cells (a type of immune cell) with the progression of heart failure. Treatment with AF-130 prevented this increase.

AF-130 also reduced levels of the inflammatory cytokine interleukin (IL)-1β, suggesting that the drug has the potential to reduce inflammation.

Researchers reported that AF-130 reduces sympathetic activity levels, which improves the contractility of cardiac muscle.

Paton noted it also reduces inflammation, which also improves heart muscle contractility and blood flow to the heart.

Further, he said it stops breathing instability, which can reduce oxygen levels in the heart and expedites the progression of heart failure.

When asked if he anticipates that AF-130 will change the way heart failure is treated, Paton replied that, “Following the next trial, we believe it will provide an additional and much-needed new weapon in the armory to treat heart failure. It attacks a mechanism that worsens heart failure that current drugs do not treat.”

Given its ability to prevent both the progression of heart failure and sleep apnea, Paton said that AF-130 “will improve exercise tolerance and reduce breathlessness.”

Dr. Douglas L. Mann, a professor in cardiology at Washington University School of Medicine in St. Louis who was not involved in the study, said “the study is well done” and “the results make sense.”

However, he told Medical News Today that “there is a lot of work to be done before this concept could be advanced into clinical trials for [heart failure].”

“The biggest limitation is that the authors did not use a cohort of rats that received beta-blockers (mainstay of HF therapy and post-MI [myocardial infarction] management) and compare that to the P2X3 antagonist alone and a P2X3 antagonist + beta-blocker,” Mann said. “It may be that beta-blockers achieve the same outcome through a different mechanism, in which case P2X3 antagonists would be redundant and would never evolve as a therapy.”

For AF-130 to become a new heart failure therapy, it would have to perform better than beta-blockers, Mann explained.

Tassos Lymperopoulos, PhD, an associate professor of pharmacology at Nova Southeastern University in Florida who also not involved in the study, told Medical News Today that it remains to be seen whether the results in rats will translate to heart failure in humans, but he wondered whether AF-130 could potentially be superior to beta-blockers.

“If the benefits of the drug reported in the study hold up in humans, then the drug may have a huge potential in treating human heart failure, since it can protect the heart against excess sympathetic nervous system stimulation but, unlike the beta-blockers and other drugs currently used for chronic heart failure in humans, can also stimulate breathing at the same time,” he explained. “Beta-blockers reduce breathing and can increase the risk of lungs contracting or even closing (that’s why they are contraindicated in asthma & COPD).

“Since systemic inflammation goes down with AF-130 and the drug’s cytokine profile seems favorable, it would be interesting to see if the drug also has anti-atherosclerotic effects,” Lymperopoulos added. “If that’s the case, its therapeutic value in post-heart attack heart failure treatment will increase exponentially,” he said.

Both Mann and Lymperopoulos noted that AF-130 could have effects in other tissues outside the heart where P2X3 receptors are present.

This could have “contributed to the improvements seen in the animals” according to Lymperopoulos.

Mann commented that these “dose-limiting side effects might be an issue in clinical trials.”