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Duke Study Suggests New Pathway to Preserve Heart Function after Attack

Duke Study Suggests New Pathway to Preserve Heart Function  after Attack
Duke Study Suggests New Pathway to Preserve Heart Function  after Attack


Duke Health News Duke Health News

DURHAM, N.C. - Using an experimental method that breaks from
conventional wisdom about how to treat heart failure,
scientists at Duke University Medical Center have shown in
rabbits that blocking a key enzyme pathway can prevent the
onset of heart failure.

The scientists found that blocking an enzyme called
þ-adrenergic receptor kinase (þARK) directly after a heart
attack can preserve heart function. The results, reported in
the April 25 issue of the Proceedings of the National Academy of
provide a promising new avenue for treating and
perhaps preventing heart failure, they say. They explain why
their new method works, despite conventional wisdom, in a
second paper, published in the April 11 issue of the journal

The research was supported by grants from the National
Institutes of Health and the American Heart Association.

"Rather than harming the heart, as some theories predict,
blocking þARK actually helps protect the heart from
overstimulation that can lead to heart failure," said Walter
Koch, the study's lead author.

The experiments are a first step in developing a new type of
treatment for congestive heart failure, a debilitating and
deadly condition in which heart muscle loses its ability to
stretch and contract, due to clogged arteries caused by
coronary artery disease. The disease is often accelerated after
a heart attack.

If the results of the animal experiments can be confirmed in
people, Koch says þARK inhibitors might be used during a heart
attack to prevent or delay heart failure, much as aspirin or
other blood thinners are now given to reduce the risk of stroke
or new heart blockage.

Koch, an associate professor of experimental surgery, and
his colleagues have been working for several years to find ways
to boost heart function.

In earlier experiments, conducted in the laboratory of Dr.
Robert J. Lefkowitz, a Howard Hughes Medical Institute
investigator at Duke, the scientists showed that two key
proteins in heart cells work together to regulate heart

In diseased hearts, the body releases the hormone
norepinephrine, the "fight-or-flight" hormone, directly into
the heart, causing it to work up to five times harder than
normal. Norepinephrine stimulates beta adrenergic receptors
(þARs) present on heart cells. This stimulation initially
allows the heart to increase the power of its contractions, but
in heart failure it quickly becomes self-defeating: the
receptors become desensitized, meaning they no longer are able
to respond to hormone stimulation.

Desensitization is caused by the actions of þARK, which in
healthy hearts helps restore heart contractions to normal after
norepinephrine stimulation. Studies subsequently showed that
þARK is elevated in failing human heart tissue.

The researchers wanted to know whether halting the abnormal
increase in þARK could prevent heart failure in its initial
stages. The idea seemed to make sense based on the researchers
experiments, but it contradicted other observations that
doctors have made about the changes that occur in the heart
during heart failure.

For example, when doctors tried to reverse heart failure by
treating patients with medicine that increases the activity of
þARs (which is one of the therapeutic goals of blocking þARK),
patients usually became worse over time. That finding led many
doctors to believe that decreasing þARs is the body's way of
protecting itself from overstimulation by norepinephrine and
other stimulatory hormones. As a consequence, few scientists
have tried to restore heart function using this pathway.

But Koch and his colleagues, Lefkowitz, David White,
Jonathan Hata, Ashish Shah and Dr. Donald Glower, were
confident that if they could intervene early enough in the
process, they could stop the downward spiral that leads to
heart failure.

In the April 11 issue of Circulation, Koch, Lefkowitz and
Howard Rockman, also of Duke, explain why they believe þARK
inhibitors may make a good therapy for heart failure. þARK
inhibitors, they explain, act to restore equilibrium to the
hormone signaling pathways in the heart. They believe elevated
þARK and decreased þAR function that occurs in heart failure is
not protective, as is now thought, but rather escalates the
decline in heart function that eventually leads to death.

To support their claim, the researchers point to þ blockers,
a class of drugs that have only recently been shown to be
effective in treating symptoms of heart failure. þ blockers
work by interrupting the cycle of increased hormone leading to
decreased þAR signaling. By blocking the ability of þARs to
"see" norepinephrine hormones, they are no longer
overstimulated and thereby þARK is no longer needed to
desensitize them. So, indirectly, þ blockers also reduce þARK,
which may explain why they work, the researchers say.

Koch and his colleagues see þARK inhibitors as a new
approach to treating heart failure, one that may be
complementary to þ blockers. They argue that while þ blockers
help reduce the toxic effects of too much norepinephrine, þARK
inhibitors may help preserve the ability of þARs to react to
hormone signaling during exercise or when under stress.

To test their theory, they inserted a gene that codes for a
protein molecule that blocks þARK into a modified form of the
adenovirus, the same virus that causes the common cold.

The researchers then injected the virus into a living
rabbit's heart just after it experienced a surgically induced
heart attack. The researchers used a new surgical method to
ensure that the adenovirus spread throughout the heart. In this
method, they injected the virus into the left ventricle of live
rabbits while the aorta was clamped for a few seconds. This
technique allowed the virus enough time to spread through all
the coronary vessels. Clamping the aorta is sometimes used in
human heart surgery, Koch said, making this gene delivery
method feasible in people. Then the scientists measured the
pumping action of the heart. The heart function of the animals
that were treated with the þARK inhibitor was normal, while the
untreated animals showed markedly decreased heart function,
which is expected after a heart attack.

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