Targeting flight-or-fight hormone response to combat heart failure

June 24, 2010, University of Rochester Medical Center

We've all experienced the strong heartbeat that accompanies emotions such as fear and rage. But can the body's natural response to these emotions be used to combat heart failure? Results of a study published online today in the journal Circulation Research present a strong case.

In the study, scientists from the University of Rochester Medical Center found that two experimental drugs have the potential to restore pumping strength to failing hearts in part by harnessing the fight-or-flight response that makes hearts beat stronger.

At the center of this finding is the hormone adrenalin, which normally maintains the heart's pumping strength and makes the with greater force during crisis. The newly identified drugs ensure that adrenalin's ability to drive heartbeat strength is maintained, and not thwarted, as it typically is in heart failure patients. The two therapies, when tested in human-like mouse models of heart failure, were found to slow, and in some cases halt, the progression of the disease.

"Considering the limited efficacy of current drug therapies for heart failure, this discovery is both exciting and promising," said Burns C. Blaxall, Ph.D., associate professor within the Aab Cardiovascular Research Institute at the Medical Center, and senior author of the study. "We are now taking a closer look at how these compounds compare to standard heart failure therapies, such as , to further determine their efficacy in treating the disease."

When the heart stops pumping as effectively as it should, the body responds by sending more adrenalin to give the heart a pick-me-up. While increased adrenalin initially restores the heart's vitality, over time heart muscle cells become less and less responsive to high levels of adrenalin, triggering the body to pump even more of the hormone to the heart. Elevated adrenalin is a hallmark of heart failure, and a recent study linked anxiety - which increases adrenalin - in teens and young adults to a higher risk of heart disease or heart attack later in life.

Blaxall's lab is part of a nationwide effort that has linked adrenalin's ability to propel heartbeat strength to a key protein, the beta adrenergic receptor. When adrenalin combines with this receptor it orders to contract with greater speed and force. The problem in heart failure patients is that these receptors are chronically desensitized - they no longer respond to adrenalin, so the heart grows weak and does not pump as forcefully as it should.

"While adrenalin desensitization has been studied extensively, this is the first report of compounds that effectively target this specific process to reduce heart failure," said Blaxall. The desensitization is caused in large part by elevated levels of a particular enzyme (G-protein-coupled receptor kinase 2 or GRK2) when it interacts with G-proteins.

This research was conducted in collaboration with Alan Smrcka, Ph.D., professor in the Department of Pharmacology & Physiology at the Medical Center whose laboratory discovered compounds that could block GRK2 regulation by G proteins. Smrcka's research team conducted extensive screening and testing to identify these experimental compounds. Two such compounds, M119 and Gallein, were identified and put to the test.

"In this study we took an entirely new pharmacological approach by altering signaling pathways after the beta adrenergic receptor rather than altering the receptor itself. In this way the actions of adrenalin are modified rather than blocked as with other therapies, such as beta blockers," said Smrcka. "This novel approach is applicable in heart failure and may be useful in other conditions as well."

Blaxall's team found that Gallein not only slowed, but halted heart failure progression when delivered to mice with pre-existing heart failure. Similarly, M119 reduced two characteristics of the disease - strain-related thickening of muscle tissue (hypertrophy) and scar tissue formation (fibrosis). Both compounds partially normalized the force of heart muscle contraction by making sure the beta adrenergic receptors became and remained responsive to adrenalin. This was done by both decreasing overall levels of GRK2 in the heart and by limiting its effectiveness.

M119 and Gallein have been used in a similar way in the past to target the receptor desensitization process that occurs in other conditions, such as chronic pain. For example, Smrcka and his collaborator Jean Bidlack, Ph.D., professor of Pharmacology and Physiology at the Medical Center, have shown M119 can reverse the desensitization of opiate receptors, which in turn increases the efficacy of painkillers such as morphine. M119 and Gallein are not known drugs; they are compounds that act as dyes, or stains, and were previously not known to have any therapeutic activity.

This research addresses a health problem that affects nearly 6 million Americans. The result of underlying problems like coronary artery disease, high blood pressure or heart attack damage, heart failure is the gradual loss of the heart's ability to pump with enough force to meet the body's need for blood. Half of patients will not live five years past the day they are diagnosed. The best treatment for a severe patient is a transplant, but with just over 2,000 transplants done each year and more than 3,000 people on the waiting list at any given time, research like this is needed to find new options for patients.

Related Stories

Recommended for you

Scientists produce human intestinal lining that re-creates living tissue inside organ-chip

February 16, 2018
Investigators have demonstrated how cells of a human intestinal lining created outside an individual's body mirror living tissue when placed inside microengineered Intestine-Chips, opening the door to personalized testing ...

Data wave hits health care

February 16, 2018
Technology used by Facebook, Google and Amazon to turn spoken language into text, recognize faces and target advertising could help doctors fight one of the deadliest infections in American hospitals.

Researcher explains how statistics, neuroscience improve anesthesiology

February 16, 2018
It's intuitive that anesthesia operates in the brain, but the standard protocol among anesthesiologists when monitoring and dosing patients during surgery is to rely on indirect signs of arousal like movement, and changes ...

Team reports progress in pursuit of sickle cell cure

February 16, 2018
Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao.

Appetite-controlling molecule could prevent 'rebound' weight gain after dieting

February 15, 2018
Scientists have revealed how mice control their appetite when under stress such as cold temperatures and starvation, according to a new study by Monash University and St Vincent's Institute in Melbourne. The results shed ...

First study of radiation exposure in human gut Organ Chip device offers hope for better radioprotective drugs

February 14, 2018
Chernobyl. Three Mile Island. Fukushima. Accidents at nuclear power plants can potentially cause massive destruction and expose workers and civilians to dangerous levels of radiation that lead to cancerous genetic mutations ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.