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. From Duke University Mouse Studies Reveal How Pre-Menopausal Females are Protected From Cardiac Injury
CHICAGO — 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.