Molecular Key To Heart Failure Development

June 09, 1998

CHAPEL HILL, N.C. -- A new study has identified a molecular key to the development of heart failure, the most common form of cardiac disease.

Researchers led by Dr. Howard A. Rockman, associate professor of medicine and pharmacology at the University of North Carolina at Chapel Hill School of Medicine, prevented heart failure in a strain of mice genetically engineered to develop the disease. They were able to do so by blocking an enzyme known to be elevated in failing human hearts.

In a report in the June 9 issue of the Proceedings of the National Academy of Sciences, the authors characterize the findings as "dramatic" and say they may point the way toward new drugs to prevent and treat heart failure in people.

"Our goal is to understand the molecular mechanisms of heart failure--to understand what molecules or pathways are involved in the formation of heart failure and why the heart progressively fails until it can no longer function," Rockman says. xvThe UNC cardiologist and co-authors from Duke University and the University of California at San Diego focused on the beta-adrenergic receptor on the surface of cardiac tissue cells. These bind with the neurotransmitters epinephrine(adrenaline) and norepinephrine which increase the force and speed of the heart's beat, thus enabling the body to deal with stress, anxiety and exercise.

"It turns out that the beta-adrenergic receptor system is very abnormal in heart failure," Rockman explains, noting that studies conducted in the 1980s showed the system functions at "half the normal level in heart failure patients." Studies subsequently established that an enzyme called beta-adrenergic receptor kinase (BARK) is elevated in failing human heart tissue. This enzyme uncouples or "turns off" cardiac beta-adrenergic receptors, making less of them available for neurotransmitter binding.

In the new study, through genetic manipulation, Rockman and Drs. Walter Koch and Robert Lefkowitz at Duke created two strains of mice having different beta-adrenergic receptor system function. One group of these "transgenic" mice had more than one hundred times the number of beta-adrenergic receptors on their cardiac cells. In the other group, BARK activity was genetically inhibited. The researchers then mated these animals with mice genetically bred to develop heart failure, so-called MLP mice.

In terms of heart failure development, the outcome was striking. Only the offspring of MLP mice and mice that inhibit BARK were free of characteristics typical of heart failure, such as heart enlargement and diminished contraction.

"Essentially, we totally prevented heart failure," Rockman says. "Whether they're young animals or old animals--age 6 months or one year--we prevented it. The heart failure mice which also contain BARK-inhibitor are normal and remain normal over time."

According to the UNC cardiologist, the outcomes demonstrate that a fundamental abnormality in the beta-adrenergic receptor can be at the root of causing heart failure. "You want to take the receptors that are there and make them behave normally by blocking an enzyme that inactivates them." The new findings suggest a tantalizing question: "Is this curing heart failure that has already developed or is it really preventing the development of heart failure?" asks Rockman. "We're actually involved in studies to determine if it is possible to reverse heart failure in mice after it has already developed by turning on this [enzyme] inhibitor later in life."

Rockman says if it is shown that such an outcome is possible, "then, in fact, it could lead to a treatment for people with established heart failure ... a drug that would hopefully prevent further impairment."

University of North Carolina Health Care

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