Gender Gap in CVD: The Epidemiology of Cardiovascular Disease in Postmenopausal Women-see article below
Women with HIV infection represent a growing proportion of the total HIV population. However, major prospective and retrospective studies evaluating cardiovascular disease risk and HIV therapy have included relatively few women. Pre-menopausal women are relatively protected from cardiovascular disease, in part by the influence of estrogens on lipoprotein sub-fractions. Indeed, data from the DAD study  indicate that female sex is protective against the risk of myocardial infarction. However, women taking combination antiretroviral therapy develop metabolic and body composition changes consistent with the male-type pattern classically associated with increased CVD risk. Women with HIV are now living longer and HIV-positive women may experience increased CVD risk associated with aging and menopause. Pernerstofer-Schoen et al.  prospectively evaluated male and female HIV-positive individuals starting a PI-based combination ARV drug regimen, comparing them with matched HIV-negative individuals. The authors observed that the 24-week HDL-C to LDL-C ratio fell more in HIV-infected women versus men, and that circulating levels of E-selectin, an endothelium-associated marker of inflammation and atheroclerotic risk, remained elevated in women versus men, each in comparison with the pre-treatment values. Further studies are needed to define gender-specific CVD risk factors in HIV-positive individuals. AIDS 2004
Protect Your Postmenopausal Heart
A woman's risk of heart disease increases after menopause. Here's how to keep your ticker in tip-top shape.
By The North American Menopause Society
Many women think of heart disease as a man's disease. In reality, cardiovascular disease (CVD) remains the leading cause of death for women age 65 and older and the second leading cause of death among women ages 45 to 64 in the United States and Canada. It includes many conditions, such as myocardial infarction, congestive heart failure, hypertension, stroke and valvular heart disease. More women than men die from heart disease. This may be because it is detected at later stages in women than in men as women's symptoms can be different than men's.
Menopause and CVD risk
After menopause, however, a woman's risk increases, leading some to suggest that estrogen provides cardioprotective benefits. The extent to which lowered estrogen levels may lead to an increase in CVD risk is not clear, but research continues, including investigations into whether hot flashes are related to a woman's CVD risk.
Major risk factors associated with CVD in women include:
· Age 55 or older
· Cigarette smoking
· Sedentary lifestyle
· African-American heritage
· High cholesterol
· Poor diet, obesity, metabolic syndrome
· Family history of CVD
· Premature menopause, especially if reached before age 35
Your clinician may use the Framingham Risk Score to estimate your 10-year risk for developing CVD events. Points are assigned to various levels of risk, which are then translated into the 10-year estimated risk for CVD events. Risk factors included are age, cholesterol levels, blood pressure, ongoing treatment for hypertension and cigarette smoking.
Maintaining heart health
Women with risk factors for CVD should initiate lifestyle changes to decrease their overall risk:
Don't smoke. Smokers are considerably more likely to have a heart attack than nonsmokers. But there's good news. When a woman stops smoking, no matter how long or how much she smoked, her risk of heart disease drops rapidly. There are many other good reasons not to smoke. These include increased vitality, improved appearance, and decreased risk of osteoporosis and cancer of the cervix, lungs, mouth and throat. There are numerous programs and aids available to help women quit smoking. A good place to start is smokefree.gov/.
Control blood pressure. Hypertension (high blood pressure) is defined as an arm cuff reading greater than 140/90 mm Hg. It is preferable to keep blood pressure below 120/80.Even mild elevations can double the risk of stroke or heart attack. High blood pressure becomes more common as women age. In fact, more than 50 percent of all women over age 55 are affected. Black women are especially susceptible. Regular blood pressure testing is important because high blood pressure rarely causes symptoms. High blood pressure can be controlled by eating a healthy diet, limiting salt and alcohol, exercising on a regular basis and reducing stress.
Control cholesterol. Bringing cholesterol levels to within normal limits has a significant impact on heart disease risk. Total cholesterol should be less than 200 mg/dL. Other goals include maintaining high levels of high-density lipoprotein cholesterol (HDL, the "good cholesterol") and low levels of low-density lipoprotein cholesterol (LDL, the "bad cholesterol"). Target levels for HDL are at least 50 mg/dL; for LDL, optimal levels are less than 100 mg/dL, even lower for women with heart disease risks. To lower your cholesterol, be sure to maintain a healthy weight, exercise, and make HDL fats and fiber part of your diet.
Exercise regularly. A sedentary lifestyle is almost as great a risk factor for heart disease as smoking because of diminished circulation and weight gain. Regular physical activity promotes heart health and has been shown to reduce the risk of heart attacks in women. For heart health, all women should aim for at least 30 to 60 minutes of moderate intensity aerobic exercise (brisk walking, for example) most days—provided that this amount is first approved by their healthcare provider.
Improve nutrition. Choose a diet that includes:
· A variety of fruits and vegetables
· Whole grains
· Low- or nonfat dairy products, soy food products
· Sources of protein low in saturated and trans fat (such as poultry, lean meats, and plant sources like beans, seeds and nuts)
Avoid foods that have:
· A high amount of cholesterol
· A high amount of saturated and trans fat
· A high amount of salt (limiting salt may help control high blood pressure)
Additionally, alcohol consumption should not exceed one or two drinks a day, and no more than seven per week.
Don't use hormone therapy to prevent heart disease.Previously, hormone therapy (HT) was thought to reduce the risk of heart disease, primarily because of its beneficial effects on cholesterol. However, more recent studies have shown that some types of HT increase the risk of heart disease, blood clots, and stroke. Recently, there has been debate on whether the age at which a woman begins HT makes a difference, as some studies show heart benefits when starting HT closer to menopause. It appears in some studies that only when a woman with a risk of heart disease starts HT after menopause that problems could arise. Current government recommendations are cautious, stating that estrogen should not be used to prevent heart disease. Also, a woman with heart disease should not begin HT without careful consideration of the risks.
Reducing Heart Disease Risk Naturally Post-Menopause
ScienceDaily (Mar. 18, 2008) — Aerobic exercise significantly decreased the chemical imbalances that can lead to heart disease and stroke in postmenopausal women according to a study in the spring issue of the Journal of Women and Aging.
Estrogen is known to reduce the chemical imbalances that can lead to cardiovascular diseases such as coronary heart disease and stroke in postmenopausal women. However, recent studies have reported detrimental effects of long-term use of hormone replacement therapy (HRT) or estrogen replacement therapy, including an increased risk of stroke, heart attack and breast cancer. Faced with these potential consequences, more women are turning to exercise as a natural way to combat postmenopausal effects.
The study found that HRT users and non-HRT users benefited equally from the exercise.
"Given the controversy with HRT, postmenopausal women can now use aerobic exercise training to lower chemical stress levels, thus reducing another risk factor for chronic disease," said Michael D. Brown, Ph.D., a co-author and associate professor of kinesiology at Temple University's College of Health Professions.
The chemical imbalance or stress — called oxidative stress — occurs when oxidants, harmful chemicals that damage tissue and cells, outnumber antioxidants in the body. Antioxidants protect cells and tissues against oxidants. Postmenopausal women have higher levels of oxidative stress.
A single bout of intense exercise acutely raises oxidative stress by increasing the production of oxidants. Conversely, regular exercise of moderate intensity appears to reduce oxidative stress through an adaptive process that increases antioxidant activity.
"Regardless of your hormone replacement therapy status, regular physical activity is a good way to not only decrease postmenopausal symptoms, but also to reduce the risk of cardiovascular disease, the leading cause of death of American women," said study co-author Nicola Fenty-Stewart, Ph.D., also with Temple's College of Health Professions.
"The similar response of the two groups suggests that aerobic exercise training is a powerful therapy that can potentially serve as a way for women to observe the beneficial effects of exercise," she said.
The study followed 48 sedentary postmenopausal women (21 on HRT and 27 not on HRT) through an exercise program consisting of three supervised sessions of aerobic exercise per week for 24 weeks. Participants were between 50 and 75 years of age and were postmenopausal for at least two years.
Since changes in habitual dietary intake could influence oxidative stress levels, qualified subjects were stabilized for six weeks on the American Heart Association Step I diet, which is low in saturated and trans fat, and rich in fruits, vegetables, whole grains and fat-free and low-fat dairy products, Brown said.
Weight loss was limited to 5 percent or less of the women's initial body weight in order to determine the independent effects of aerobic exercise training on oxidative stress, not the effect of exercise and weight loss on oxidative stress.
The HRT users and non-users both experienced an 11 to 18 percent drop in plasma thiobarbituric acid reactive substances, an indicator of oxidative stress.
There were also decreases in body mass index and total body fat, and a significant increase in VO2 max (maximal oxygen uptake or aerobic capacity) in both HRT users and non-users after the exercise intervention, Brown said.
"Exercise was able to reduce oxidative stress levels in these women regardless of whether or not they were using estrogen replacement. In addition, the women did not lose large amounts of body weight or fat," Brown said.
"No one is too old to begin an exercise program, but it is imperative to consult your physician before taking part in any exercise program. It is important to start off slow and build your program to your comfort level. Exercising is not difficult. You just have to want to do it," Brown added.
Other authors are: Selasi Attipoe, B.S., University of Maryland; Joon-Young Park, Ph.D., University of Maryland; and Dana Phares, Ph.D., University of Maryland. Funding was provided by the National Institutes of Health.
The Epidemiology of Cardiovascular Disease in Postmenopausal Women
The Journal of Clinical Endocrinology & Metabolism June 1, 1999
CARDIOVASCULAR disease (CVD) is the leading cause of death in the United States for all women (1, 2), and in 1993 was responsible for twice as many deaths (500,387) in females as all forms of cancer combined (250,529 deaths) (1). Rates of CVD mortality increase sharply with age in both men and women, with higher rates in men than women at all ages. Although the death rates from coronary heart disease for females declined 27.6% from 1984 to 1994, heart attack remains the single largest cause of death for US females, and death rates were 34.3% higher in black than in white women in 1993 (1).
"Gender gap" in CVD risk
An examination of age-specific graphs of CVD mortality rates shows an apparently large gender difference at younger ages, narrowing after the age of menopause. The largest apparent increase in coronary mortality in women occurs around age 50, coinciding with the time of menopause (3). This has led to speculation that declining estrogen levels associated with menopause result in an increased risk of CVD (2). However, evidence from vital statistics data does not support the theory that menopause apart from chronological aging increases risk of CVD in women (4). The narrowing of the gender gap appears to be due in part to declining incidence rates in men rather than to increases in women (3). Moreover, as several investigators have pointed out, if one plots the rates on the log scale to measure the slope, or rate of increase, there is no sharp increase, or "bump," in the CVD mortality rate for women at the age of menopause (3, 4, 5). In contrast, rates of breast cancer do show a menopausal effect, with nonparallel rates of increase for the 50-69 and 40-49 age groups (3). Autopsy findings also suggest that changes such as atherosclerosis occur steadily with age, with no steep increase at the age of menopause (3). CVD mortality rates differ markedly by country, and the sex advantage in CVD mortality rates appears to be lower or nonexistent in populations that have a generally low level of risk, as in Japan (6). This indicates that behavioral and environmental risk factors may play a larger role in explaining CVD mortality in women than differences in endogenous estrogen (7). Studies based on population statistics are limited in that menopausal status cannot be related to CVD risk on an individual level.
CVD risk after natural menopause
Past studies of menopause-associated changes in CVD morbidity, mortality, and risk factors are difficult to interpret in part because of inadequate adjustment for important confounding factors such as chronologic age, cigarette smoking, and obesity that are associated both with occurrence of menopause and heart disease (3, 4). Other methodological problems include misclassification of menopause status and unstable estimates due to small numbers of women with major coronary disease (3).
Perhaps the best information to date comes from large prospective studies. One such study, the Framingham Heart Study, reported that women aged 50-59 yr who had experienced natural menopause had 4 times the 10-yr incidence of coronary heart disease as premenopausal women in the same age range, but results were not adjusted for age or smoking (8). The largest of the prospective studies to date, the Nurses' Health Study, found a somewhat higher risk of coronary heart disease in women with a natural menopause compared to the risk among premenopausal women when adjusting for age in 5-yr intervals (RR = 1.7, 95% CI: 1.1-2.8) (9). However, controlling for age in 1-yr intervals reduced the relative risk to 1.2, 95% CI: 0.8-1.9. A further risk reduction occurred after controlling for cigarette smoking (RR = 1.0, 95% CI: 0.8-1.3) (9).
As discussed below, natural menopause is associated with some changes in CVD risk factors. The lack of any abrupt change in CVD morbidity or mortality around the age of menopause may result from a relatively wide age range for the occurrence of a woman's final menstrual period, and from the gradual decline in estrogen levels over time. In addition, any menopause-related changes in CVD risk factors may appear slowly in morbidity and mortality. Thus the occurrence of natural menopause may indicate that a woman is entering a period of increased risk for CVD, due to both chronologic aging and lower levels of estrogen (3).
CVD risk after surgical menopause
The evidence for a relationship between changes in CVD morbidity/mortality and menopause is much stronger for women who undergo a hysterectomy with bilateral oophorectomy (3, 4). A bilateral oophorectomy causes an abrupt drop in estrogen levels unlike the gradual decline associated with natural menopause. Fairly convincing evidence for estrogen as a factor comes from the Nurses' Health Study (9), which showed a significantly increased risk (RR = 2.2, 95% CI: 1.2-4.2) of coronary heart disease in women who had undergone bilateral oophorectomy and hysterectomy and who had not taken exogenous estrogens. The risk was not increased for women who used estrogens after a similar procedure. Whether or not hysterectomy alone increased CVD risk is controversial, but hysterectomy may lead to subsequent ovarian failure (3).
Menopause and coronary heart disease risk factors
Cohort studies have demonstrated that risk factors for CVD morbidity and mortality are similar between men and women. These include older age, smoking, glucose intolerance, elevated blood pressure, an unfavorable lipid profile [elevated total or low density lipoprotein (LDL) cholesterol levels, decreased high density lipoprotein (HDL) levels, elevated triglyceride levels], sedentary lifestyle, and obesity (10). Several of these factors, such as low levels of HDL, diabetes, and hypertriglyceridemia, may be stronger predictors of CVD in women than in men (4, 10).
Lipids and lipoproteins. Of all the CVD risk factors, the evidence for a link with estrogen appears to be the strongest for lipids and lipoproteins (11). Results from both cross-sectional and longitudinal studies have reported a worse lipid profile in postmenopausal than in pre- or perimenopausal women (12, 13, 14), although not all have adjusted for age and smoking status, both of which are strongly related to menopause status and levels of lipids and lipoproteins. In the Healthy Women's Study, a 5-yr prospective study of over 500 initially healthy premenopausal women, natural menopause was associated with unfavorable changes in HDL and LDL, even after adjustment for age and smoking (14).
Whether or not the unfavorable lipid changes are directly associated with declining estrogen levels is still in question. Kuller et al. (15) did not find an association with endogenous estrone and lipid levels in postmenopausal women from the Healthy Women's Study. Women in the top quintile of estradiol levels had a more favorable lipid profile than did women with lower levels of estradiol, but in longitudinal analyses there was no consistent association between changes in estrone or estradiol and changes in lipoproteins, either for women who transitioned from peri- to postmenopause or for women who were postmenopausal throughout (15). Results from the Massachusetts Women's Health Study, a longitudinal population-based study of women traversing the menopause, are consistent. In pre- and perimenopausal women, Longcope et al. (16) found no strong or consistent relationships between lipids and concurrent reproductive hormone levels. Longcope at et al. (17) also found no association between changes in endogenous estrogen levels and changes in lipid levels. Although exogenous estrogens do result in favorable changes in lipids and lipoprotein levels (18, 19) because of the suppression of hepatic lipase activity (20), estrogens at endogenous levels may not have much impact on lipids or lipoproteins. This is consistent with findings that exogenous estrogen administered in ways that bypass the liver have little impact on lipids (16).
Glucose and insulin. Diabetes appears to be a strong prognostic factor for CVD in men and women, and in some studies it has a greater association with CVD in women (2, 7, 10). Diabetes is related to atherosclerosis and hence an increased risk of acute coronary ischemia, particularly in women (21). The age-adjusted relative risk for CVD is 2:3 in men and 3:7 in women (22).
Data regarding menopause status or estrogen levels and glucose and insulin levels are somewhat limited (11). Studies of natural menopause suggest no impact on either plasma glucose or insulin concentrations (14), while others have found that menopause is associated with an increase in fasting insulin concentration (23). Exogenous estrogen may reduce plasma glucose and insulin levels (24), possibly by improving carbohydrate metabolism (11). Several studies, however, found that 2-hr insulin secretion in postmenopausal women was not different in estrogen users and nonusers (19, 25).
Clotting and coagulation. As with glucose and insulin, there is little data regarding the relationship between estrogen and coagulation. Plasma levels of plasminogen activator inhibitor (PAI-1), an essential antagonist of fibrinolysis in humans, increase in women after menopause, and high levels have been associated with increased CVD risk (26). Decreased PAI-1 levels and enhancement of fibrinolytic activity has recently been demonstrated after estrogen replacement therapy, but the effect of menopause per se on PAI-1 is not yet known (26).
Circulation and vessel walls. Estrogen appears to have a favorable impact on the circulation through direct effects on vessel wall physiology and on mechanisms controlling blood flow (24). Estrogen receptors are found in the myocardium, coronary arteries, vascular smooth muscle tissues, and endothelium (27). Estrogen may act on endothelial cells to increase the relaxation response to acetylcholine, or it may act directly on vascular smooth muscle (28). In animals, estrogen administration alters the constrictor response of atherosclerotic coronary arteries (29). Estrogen also may have an impact on arterial wall mechanisms involved in formation of atherosclerotic plaques and may affect the release of vasoactive neurotransmitters involved in the control of vasomotor tone (28).
Deficiency of or changes in endogenous estrogen levels are associated with conditions related to circulation, including vaginal dryness, migraine headaches, and hot flashes (28).
Exogenous estrogen appears to have a beneficial impact on blood flow (11, 30, 31). In postmenopausal women and estrogen-deficient animals, administration of estrogen increases coronary artery vascular reactivity (30, 32) and prevents acetylcholine-induced coronary vasoconstriction (30). Administration of estradiol also has a acute beneficial effect on treadmill performance in women with coronary artery disease (31). In other animal studies, administration of estradiol has led to vasodilatation, increased cardiac output, and lower systemic vascular resistance (28).
Blood pressure. Both elevated systolic and elevated diastolic blood pressures are risk factors for CVD in women, and lowering the diastolic blood pressure is associated with reductions in acute coronary events (33). Studies of natural menopause, however, have found no relationship between the menopausal transition and changes in blood pressure (14). There is also little evidence for a reduction in blood pressure after the use of estrogen estrogen replacement therapy (18).
Weight and body composition. It has been estimated that 70% of CVD in obese women and 40% in all women is due to excess weight (34). Obesity itself, however, is not an independent risk factor for CVD, but is related to CVD through other risk factors such as hypertension, elevated cholesterol, and diabetes (2). In contrast, centralized body fat, indicated by the waist-to-hip ratio, appears to be a strong predictor of incidence of CVD for both men and women (2), independent of other risk factors (35).
As with blood pressure, there appears to be little association between natural menopause and body weight per se (14, 36, 37). The menopause transition may, however, be associated with a change in body composition, with an increased waist-to-hip ratio occurring at the time of the menopause (36).
Behavioral factors. Key behavioral factors affecting CVD risk in women are cigarette smoking and physical activity (2, 10). There is a strong positive, dose-response relationship between cigarette smoking and the risk of fatal CVD, and smoking may modify the effect of other risk factors, such as diabetes, high blood pressure, and adverse lipid profiles (38). Smoking is also associated with an earlier age at menopause (39).
The impact of exercise on CVD is less well-established in women than in men (2). Recently, a 7-yr follow-up of women from the Iowa Women's Health Study found an inverse association between higher physical activity levels and mortality, most strongly for CVD mortality (40).
Ongoing studies of CVD and menopause
Currently in progress are two large prospective studies that may provide some answers to the magnitude of the impact of the menopause on CVD risk. These are The Women's Health Initiative, which is studying the impacts of factors such as HRT and diet in very large groups of women who are already postmenopausal, and The Study of Women's Health Across the Nation (SWAN), which is recruiting and following somewhat younger women, who are initially premenopausal or still early in the perimenopausal transition. These women will be closely followed as they transition through menopause, and their levels of estrogen, lipids, glucose, and clotting factors will be measured longitudinally to assess the impact of the menopausal transitions and the decline in estrogen levels.