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Protein Implicated In Decline Of Aging Hearts

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Duke Health News 919-660-1306

DURHAM, N.C. – 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.

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