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Mouse Studies Reveal How Pre-Menopausal Females are Protected From Cardiac Injury

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Duke Health News 919-660-1306

CHICAGO, IL -- Despite recent reports that hormone therapy
does not offer protection for post-menopausal females against
heart disease and heart attack, researchers from Duke
University Medical Center have determined in mouse studies that
non-hormone treated pre-menopausal females are, in fact, better
protected from cardiac damage following ischemia compared to
their male counterparts. The findings suggest that research
should continue toward finding better ways to treat
post-menopausal women to maintain such cardiac protection, the
researchers said.

"While the Women's
Health Initiative
study showed quite clearly that hormone
replacement therapy (HRT) was ineffective in protecting
post-menopausal women from heart disease, our research does
show that females are protected from greater damage than males
following heart attack," said Heather R. Cross, Ph.D, of the
Duke Clinical Research Institute. "HRT may not have worked, but
females are still protected. We want to figure out why, so that
is where we are focusing our efforts."

The Women's Health
Initiative
's (WHI) HRT trial was brought to a halt earlier
this year when evidence was found to suggest that the risk of
getting breast cancer outweighed the benefits of the treatment.
Post-menopausal women being treated with HRT were thought to be
at lesser risk for heart attacks, strokes and blood clots. The
Women's Health
Initiative
(http://www.nhlbi.nih.gov/whi), conducted by the
National Institutes of Health, is among the largest studies
ever conducted on prevention of heart disease, cancer and
osteoporosis in post-menopausal women.

Cross contends that benefits might yet be available from
some form of hormone replacement therapy for women, and that
such research should not be dismissed.

"It is clear that we have not yet developed a hormone
therapy that exactly mimics the female state, and using
specific hormones in research is not the same as looking at the
overall female state," she adds.

The team's findings were prepared by Cross for presentation
today (Nov. 18, 2002) at the 75th annual scientific session of
the American Heart
Association
.

Using a mouse model, the researchers compared the
differences in myocardial ischemia-reperfusion injury between
non-hormone treated male and female hearts. To do this, they
pretreated the mouse hearts with the "adrenergic agonist"
isoproterenol (Iso) before subjecting the hearts to 20 minutes
of ischemia followed by 40 minutes of reperfusion -- the
reintroduction of oxygen-rich blood to the damaged tissue. The
process of reperfusion often causes a second wave of injury
(ischemia-reperfusion injury) to the heart tissue, but the
mechanism responsible for this is not yet well understood.
Adrenergic agonists such as isoproterenol "switch on" the
heart's fight-or-flight response, increasing heartbeat rate and
volume. Such treatment increases stress on the heart, rendering
the heart more vulnerable to ischemia.

With pretreatment, the male mice were found to be three
times more susceptible to ischemia-reperfusion injury than
females.

Cross and colleagues believe that the experimental model
they developed is among the first to clearly show such
male-female differences in cardiac injury in hearts that have
not been previously hormone-treated. "It has been very hard to
demonstrate such differences before now without use of large,
non-physiological doses of estrogen," she says. "As the WHI
indicates, we are finding it difficult to mimic the female
state by simply reintroducing female hormones. With this model
clearly defined, more people will be able to take this type of
research forward in the future."

The team's research further deciphered the role of nitric
oxide in the cardioprotection of females. Previous studies had
shown that female cardioprotection is mediated by nitric oxide
and seems to involve an effect of nitric oxide on maintenance
of calcium balance, or homeostasis, in heart cells. Such
calcium balance is critical to controlling the contraction of
heart muscle cells, and thus regulating the heart beat.

"Our findings show that calcium homeostasis is more stable
in females via some action of nitric oxide and that females can
resist the effects of adrenergic agonists," Cross says.

Adrenergic agonists -- like the Iso used in this research --
are substances that cause calcium overload in the cells of the
heart tissue, thus disrupting the homeostasis of calcium, which
regulates the heartbeat, in those cells. With the disruption of
the natural balance of calcium in the heart cells, a cascade of
negative events begin. For example, mitochondria -- the
principal energy source for those cells -- are thrown into
chaos. The cells begin to rapidly lose energy and die, leading
to the death of portions of heart tissue.

In this study the researchers used Iso, but the adrenergic
agonist dobutamine is used as a clinical test in patients who
have ischemia and adrenaline (epinephrine), the naturally
occurring form, is used for anaphylactic shock and cardiac
arrest.

Since females appear better able to resist the effects of
adrenergic agonists, the researchers believe that females may
be more resistant to cardiac injury occurring during
psychological or physical stress, drug treatment for low
cardiac output during congestive heart failure, use of drugs
designed to stimulate the heart during stress testing, use of
an adrenergic stimulator like epinephrine during treatment for
anaphylactic shock, and from calcium overload during the
cardioplegia of cardiac surgeries such as bypass or donor heart
transplantation.

"The long-term goal for this research is to determine the
key cardioprotective components of the natural female state,"
says Cross. "This would enable the development of therapies
which could be used in females to counteract the effects of
menopause without other negative outcomes."

Determining the specific protective components might also
enable such therapies to be developed for use in males without
the obvious unwanted side-effects of administering female
hormones, she added.

Cross conducted the research while she was with Duke's
pathology department. Her team of researchers included Charles
Steenbergen, M.D., of Duke and Elizabeth Murphy, Ph.D, of the
National Institute of Environmental Health Sciences. Their
research received grant funding from the National Institutes of
Health.

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