A woman's heart: a mystery of science

Rita Baron-Faust

July 28, 2000

"Since I am a man, my heart is three or four times less sensitive, because I have three or four times as much power of reason and experience of the world a thing which you women call hard-heartedness... " Stendhal

 

Stendhal may have been more astute than even he knew. Poets, politicians, and psychologists have often argued that women's hearts were fundamentally different from men's, women being the more "sensitive." And while they were referring only to emotions, scientists have recently uncovered gender differences showing that women's hearts are indeed more sensitive to certain factors. Some sex-related differences can be seen on an electrocardiogram, but others are found at the cellular or genetic level.

To begin with, the female heart is somewhat smaller than a man's, about two-thirds the size. Its physiology is different, too. At puberty, the rate of repolarization or QT interval becomes longer in females and shorter in males (after age 60 those differences largely disappear). Studies show that women's mean 24-hour heart rates are more rapid than men's (possibly due to a different autonomic input into the sinus node).

Women are also at greater risk for drug-induced torsades de pointes, a sometimes fatal ventricular arrhythmia that occurs without provocation in people with long-QT syndrome. Similarly, women with long-QT syndrome suffer a higher rate of sudden cardiac death than men with the syndrome. Women are also more likely to have adverse reactions to anti-arrhythmic therapy and to medications that lengthen QT intervals.

Researchers now know that this is due to gender-related differences in the biology of the ion channels in the heart the tiny "pores" in cell membranes that allow charged molecules to flow in and out of cells which affect the duration of cardiac repolarization.

"We all went to medical school and were taught that all hearts are the same, it's just a muscle. But, in fact, it's a hormonally sensitive muscle," remarks Raymond L Woosley MD PhD, chairman of pharmacology at Georgetown University. "Sex hormones interact with one of the most primitive signaling mechanisms in the body, potassium channels, and this has direct consequences in terms of heart rhythm."

Tuning in to the K channel

Certain repolarizing currents carried by potassium appear to be less strong in the female ventricle, leading to a longer period of repolarization, observes Michael R Rosen MD, director of the Center for Molecular Therapeutics at the Columbia University College of Physicians and Surgeons.

"Work that we have done shows that there is a different characteristic to the calcium current, which carries inward current. The more inward current you have during repolarization, again the longer the duration of repolarization would be," explains Rosen. "Some of these repolarization differences relate to gender, and others are directly affected by gonadal steroids."

One area where these differences show up dramatically is in the cardiac response to medications that prolong the QT interval on ECG, a familiar measure of repolarization.

"In animal studies, the males seem to be protected by testosterone against prolonged repolarization from QT-prolonging drugs. Males' hearts are less sensitive to drug effects in this sense. But the risk factors in females are not just related to estrogen, they are far more complicated than that," says Rosen. "There is gender-related modulation of cellular function, likely genetically determined. These genetic determinants express themselves partly in response to gonadal steroids and partly in ways we don't understand yet."

A gene called HERG

A gene first found in animals which controls certain potassium channels, called "HERG", plays a role. The HERG potassium channel is blocked by a number of antiarrhythmics, antihistamines, antibiotics, antifungals, antidepressants, anti-psychotics, and other classes of drugs. This effect made headlines with fatal incidents of torsades de pointes in people taking both erythromycin and the non-sedating antihistamine terfenadine (Seldane), which was subsequently pulled off the market by the FDA. In a Georgetown study of Seldane, two-thirds of those with torsades were women.

Many more women than men also developed torsades while taking the anti-arrhythmics quinidine and d-sotalol; the SWORD trial testing the effects of d-sotalol on post heart attack arrhythmias was shut down in 1995 because of doubled mortality among treated patients (most deaths were women). A greater incidence of torsades in women was also seen with the anti-malarial halofantrine and the propulsant heartburn drug cisapride (Propulsid, recently withdrawn from the market), notes Rosen.

A gender-specific Rx?

Cardiologists may one day be writing gender-specific prescriptions, based on research now ongoing into potassium and calcium channel differences in male and female hearts.

At Georgetown, researchers are studying the effects of hormones on the HERG channel in male and female rabbit hearts, which have the same baseline sex differences in QT as humans and the same differences in sensitivity to K-channel blocking drugs. When the rabbits' ovaries and testes were removed, their ECGs changed and so did their drug sensitivity. "What we don't know is whether hormones change the number of potassium channels or change the type of potassium channels or how they link with calcium channels. We're trying to work out the basic mechanisms," says Woosley.

The team has also begun human studies to look at drug-induced differences in QT segments between men and women and to study the genetics of the long-QT syndrome. Patients are given a tiny dose of ibutilide (Corvert?), a K-channel blocker used to treat arrhythmias, then their ECGs are studied. Even at one third the clinical dose there was less of a response in men than in women. The researchers also found changes in response during the course of the menstrual cycle, something studies of these drugs had never looked at before.

"The overall response to ibutilide correlates nicely with progesterone levels. We don't know if it's causative, but during menses and the follicular phase, women are most sensitive and more susceptible to toxicity of K-channel blockers and in the luteal phase, they're least sensitive," observes Woosley. "Women who need these drugs should be given the lowest possible dose and monitored closely. We are working with the pharmaceutical industry to have this information mentioned in package inserts."

Woosley also hopes to recruit women undergoing in vitro fertilization. These patients are thrown into chemical menopause during the protocol, then subjected to high levels of progesterone and other hormones. Woosley wants to study their electrocardiographic changes.

He and others are also studying responses in people who seem to be very sensitive to small doses of ibutilide, to determine if they're carriers of one of the genes for long-QT syndrome. Georgetown is developing a gene chip to help predict who might develop drug-induced arrhythmias. This genetic (and gender) information will be stored in an international registry to be set up to keep tabs on patients taking drugs that affect the QT segment.

Flexing female heart muscle

Gender-related differences in the heart also seem to extend to proteins in the muscle tissue itself, notably myosin, and in the overgrowth of muscle that leads to cardiomyopathy.

A research team led by Leslie Leinwand PhD, chair of the Department of Molecular, Cellular, and Developmental Biology at the University of Colorado at Boulder, has created transgenic mice to study familial hypertrophic cardiomyopathy, FHC, an inherited disease that causes thickening of the heart muscle that hampers its ability to pump blood. The transgenic mice carry different mutant genes that predispose to FHC, a disease that sometimes causes sudden death in young athletes. Mutations in the gene which codes for myosin a key muscle protein and the molecular "motor" that creates the energy and motion for heart contractions have been shown to be a cause of FHC, Leinwand notes. Her team has already found some striking gender differences in how the disease progresses in these genetically altered mice.

"In all of the females, the hearts just keep getting bigger and bigger but continue to function as close to normal as possible, but that is not true in the males. The males' hearts enlarge initially, but when they are mature adults, they develop features of congestive heart failure and begin to die," reports Leinwand. "We're tying to find out why this is, because this mimics, to some degree, what we see in clinical populations. The obvious first question is whether or not female hormones play some sort of protective role."

The transgenic mice are being exercised on tiny treadmills under the watchful eyes of Leinwand's research team, to measure how their hearts respond to vigorous activity. "One of our cardiology fellows is altering the sex hormone status of these transgenic mice to determine the effect on the pathogenesis of the disease," she says. "It's a very simple, straightforward experiment that I think could tell us a great deal about the basis of these gender differences." Some answers may be available in 6 months to a year.

The team is also thinking about ways to screen for the condition, which is often diagnosed too late. Leinwand is already working with the pharmaceutical industry to develop drug screening targets for congestive heart failure. While much remains to be studied, "One thing is clear. We can no longer use men as a generic model for the human heart, or the human race," concludes Columbia's Rosen.

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