Protein implicated in decline of aging hearts

Duke University Medical Center researchers have linked elevated levels of a specific heart protein in elderly hearts to a decrease in the pumping ability of the heart.

Since levels of this protein, known as G-alpha-i, are also elevated in patients with congestive heart failure, the researchers believe that not only do they better understand why the heart’s pumping ability decreases with age, but that there may be a pharmacological approach to prevent this age-related decline.

It is known that a class of drugs known as beta-blockers can improve the symptoms of patients with congestive heart failure. Interestingly, these drugs also reduce the levels of G-alpha-i, leading the researchers to speculate that beta-blockers drugs could be potentially used in healthy patients to forestall the natural decline of the aging heart.

The results of the Duke study were published today (Oct. 4, 2003) in the Journal of Cardiovascular Pharmacology. The study was support by the National Institutes of Aging.

G-alpha-i mediates signaling through a family of G protein-coupled receptors (GPCR), which are important in cardiac function. Beta-adrenergic receptors (beta-AR), which respond to the hormones epinephrine and norepinephrine in the so-called “fight-or-flight” response to increase cardiac output, are also members of this family.

G-alpha-i is one protein that can prevent these hormones from “coupling” to beta-ARs, thereby decreasing the heart’s contractability. The mechanism of action for G-alpha-i appears to be its ability to block adenylel cyclase, an enzyme that resides within cells and is responsible for transmitting messages within the cell in response to hormonal stimulation.

“The results from our study suggest that the dampening of G-alpha-i activity in the human heart may improve the age-induced decreases in cardiac function,” said Duke pharmocologist Madan Kwatra, Ph.D., principal investigator of the study. “From what we know now, it would seem logical to consider the use of beta-blockers in a preventative role. More research, however, is needed to prove this hypothesis.”

Numerous studies in animals attempting to prove an association between elevated levels of G-alpha-i and failing hearts have been inconclusive, researchers said. However, Kwatra’s team published results last year which demonstrated that an age-induced increase in G-alpha-i occurs in rat ventricles (lower heart chambers) and was the cause of a decrease in receptor-mediated activation of adenylyl cyclase seen in aged hearts, and they wanted to see if the same held true in humans.

For their studies, the Duke team collected samples of human atria, the upper chambers of the heart, from 28 patients undergoing surgery that required the use of the heart-lung machine. In order to hook up the circulatory system to the heart-lung machine, a small “plug” of atrial appendage tissue must be removed to attach the tubing. None of the patients had congestive heart failure.

Atrial samples were then divided into two 14-patient groups based on age: mature (40-55) and elderly (71-79).

“After thorough testing the samples, we found that levels of G-alpha-i were 82 percent higher in the elderly patients when compared to the younger patients,” Kwatra continued. “Additionally, this is the first study to show that G-alpha-i can be activated through more than one GPCR.”

Kwtara concludes that blocking the effects of G-alpha-i with a targeted drug could be an effective way of protecting the heart from age-related decline.

“Beta-blockers, which have been quite effective in improving the heart function of patients with congestive heart failure, would seem to be a likely candidate,” Kwatra said. “That class of drugs is already very well understood and has very few side effects.”

By blocking the stimulatory effects of epinephrine and norepinephrine, beta-blockers reduce heart rate and blood pressure. The drugs have been used for 20 years for different ailments, but are primarily used to help treat high blood pressure, chest pain, and heartbeat irregularities.

“The obvious next step, which we are already pursuing, is to see if what we observed in human atria also occurs in ventricles, (lower heart chambers)” Kwatra said. “When we finish those experiments, we should have a much better understanding of the role of G-alpha-i in the aging heart.

Other Duke team members were Jason Kilts, Ph.D., Toshimasa Akazawa, M.D., Habib El-Moalem, Ph.D., Joseph Mathew, M.D., and Mark Newman, M.D.