September 15,
2003
Experimental Cancer Drugs May Halt
Events That Lead To Cardiac Hypertrophy and Heart Failure
(Philadelphia, PA) - The events that
lead to cardiac hypertrophy, the enlargement of heart
muscle cells, may be stopped by histone deacetylase
(HDAC) inhibitors, a class of therapeutic agents currently
under development as cancer drugs, according to researchers
at the University of Pennsylvania School of Medicine.
Cardiac hypertrophy is one of the leading causes of
congestive heart failure, the most common diagnosis
given for discharged hospital patients in the United
States.
In the September issue of Journal of Clinical Investigation,
the Penn researchers suggest novel genetic causes for
- and new therapeutic agents against - cardiac hypertrophy
and heart failure. Furthermore, the researchers demonstrate
that anti-HDAC drugs can block the development of hypertrophy
in animal models.
"In our studies, we determined that valproic acid,
an HDAC inhibitor used to treat seizure disorders, is
effective in preventing heart muscle cells from enlarging,"
said Jonathan A. Epstein, MD, Associate Professor
in the division of Cardiovascular Medicine within Penn's
Department of Medicine. "In recent years, drug companies
have also begun developing more advanced HDAC inhibitors
to treat cancer. These HDAC inhibitors may be among
the first known medications to prevent cardiac hypertrophy."
Cardiac hypertrophy can be a healthy physiological
response to events, such as aerobic exercise, where
heart cells grow larger like any other well-conditioned
muscle. Pathological hypertrophy, however, may result
from genetic mutation or, most commonly, from the consequences
of an unhealthy cardiovascular system.
"The exertion of pushing blood against high resistance
in the setting of high blood pressure or overcompensation
for heart muscle lost during a heart attack can cause
heart muscle cells to enlarge," said Epstein. "While
it might be helpful at first, hypertrophy can increase
the stress placed on the heart and begin a downward
spiral of events that ultimately leads to heart failure.
Despite the fact that this is a common every-day problem
for clinicians and patients, we have very few, if any,
medications that are directed at halting the cellular
events responsible for this deterioration. That's why
our present studies are so encouraging."
Unlike most cells, cardiac muscle cells largely stop
dividing after birth and only then grow larger through
hypertrophy. The disease form of hypertrophy is associated
with the re-activation of a genetic program that normally
stops soon after birth. "Mature heart cells are naturally
programmed to be anti-hypertophic, but mutation or the
cumulative effects of cellular stress seems to restart
a program of events that we've only seen in developing
fetuses, " said Epstein.
Epstein and his colleagues previously linked fetal
cardiac development to a protein called Hop, which is
thought to control heart cell growth. Hop is abundant
in fetuses and newborns, but less so in adults, where
it seems that the over-production of Hop overrides the
cell's normal genetic programming. Hop does so by recruiting
HDAC, which blocks a set of genes that normally protect
the heart from hypertrophy. In effect, HDAC unlocks
genes that have been kept hidden since birth.
"This genetic control of cell growth is why HDAC inhibitors
also make for promising anti-cancer drugs," said Epstein.
"Although we do not know for certain what this genetic
program entails, it clearly results in severe cardiac
hypertrophy and premature death in animal models."
The elucidation of these chemical pathways and genetic
programs will offer more new targets for the treatment
of congestive heart failure, Epstein believes. The Penn
researchers hope to continue to study HDAC inhibitors
and their possible therapeutic roles in clinical trials
to prevent hypertrophy in at-risk patients.
Contributing Penn researchers include Hyun Kook, John
Lepore, Aaron D. Gitler, Min Min Lu, and Victor Ferrari
from the Division of Cardiovascular Medicine and Rong
Zhou from the Department of Radiology. Other contributing
researchers include Wendy Wing-Man Yung and Joel Mackay
from the University of Sydney and Peter Gruber from
The Children's Hospital of Philadelphia.
Funding for this research was provided through grants
from the National Institutes of Health.
For
a printer friendly version of this release, click
here.
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