Gender-based differences in the prevalence, presentation, and treatment for coronary heart disease (CHD) defines an important area of controversy and research. Gender-based differences include age at onset of CHD, typical presentation of CHD symptoms, relative importance of coronary risk factors, and the potential relationship of ovarian function and estrogen status to the development of CHD. The American Heart Association (AHA) reported in 1998 that the leading cause of death for American women is cardiovascular disease, with CHD responsible for the majority of total deaths. 1 This is true for Hispanic, black, Asian/Pacific Islander, American Indian/Alaskan native, and white women. The percentage of total deaths in each of these groups is 34%, 41.6%, 36.1%, 28.4%, and 44.9% respectively. 1 Unquestionably, women are at great risk for death and disability from CHD.
Interesting and challenging statistics show that 44% of women compared with 27% of men will die in the first year after an acute myocardial infarction (MI), with 31% of women versus 23% of men suffering a second heart attack within 6 years. 1 The Framingham study's 36-year follow-up showed that MI is more often fatal in women compared with men (39% vs 31%). In addition, 47% of women present with angina as the first symptom of CHD with 46% of men presenting with acute MI as their first symptom. 2 When women did present with acute MI as their initial symptom, half went unrecognized compared with only one-third of men. 2 An additional important health risk for women is stroke. Mortality data from Framingham in 1985 showed that 61% of deaths from stroke occurred in women, with black women suffering disproportionately compared with white women (39.6% vs 23.1%). 1
The risks for both men and women of developing CHD and stroke are closely related to well-known cardiovascular risk factors, 3,4 including hypertension, cigarette smoking, dyslipidemia, diabetes, physical inactivity, poor nutrition, and obesity. This article discusses specific issues related to dyslipidemia and women. The article focuses on the identification and treatment of women with abnormal lipids and includes a discussion of the role of hormone replacement therapy (HRT) (Figures 1 and 2 and the box).
IDENTIFICATION OF WOMEN AT RISK
Ninety-seven million American adults have a total cholesterol level >200 mg/dL, with 38 million having levels >240 mg/dL. Women share the presence of this risk factor with men. Non-Hispanic white females and non-Hispanic black females, however, are at greater risk at for having cholesterol levels >240 mg/dL when compared with their male counterparts. 1 Most of the clinical trial data supporting the safety and efficacy of lipid lowering comes from studies of men, and as a result, the case for women is not as strong. Despite this lack of data, there is consensus among medical experts that elevated lipoprotein level is an important cardiovascular risk factor for women. Maintaining ideal levels is likely to prevent initial and recurrent coronary events in both men and women.
Women appear to be protected from the development of CHD based on ovarian function. The development of premenopausal CHD is uncommon, occurring mostly in women with diabetes. 5,6 Observational studies in American women who have chosen to take HRT after menopause suggest a significantly reduced risk of developing CHD. This reduction includes women who have ever taken HRT as well as those who are current users. 7 The average reduction in risk related to HRT usage is nearly 50%. This observation has stimulated much research regarding potential mechanisms of protection. As a result of the apparent premenopausal protection, women generally develop signs and symptoms of CHD at age 65-about 10-15 years later than men. This fact may account for a diminished overall sense of perceived risk for the development of CHD among women. Pilote and Hlatky 8 showed that in a group of Stanford graduates who were over 50 years of age, breast cancer was thought to be their biggest risk for death and illness. In 1995, cardiovascular diseases (CVD) resulted in 50% more deaths in women than all forms of cancer combined. 1 The knowledge that women carry this misconception has led to important public education efforts by the AHA and other organizations.
Although premenopausal hormones appear to protect women from CVD, the Framingham Study has provided evidence that certain risk factors in women diminish this apparent "protection." These factors include
- Age; the male-female gap in incidence closes with advancing age
- Menopause: risk escalates two- to three-fold, with more MI and death after menopause
- High total-to-HDL cholesterol ratio ≥7.5: a high ratio eliminates the female advantage
- Diabetes: twice the effect on risk in women, virtually canceling the female advantage
- Electrocardiographic evidence of left ventricular hypertrophy: greater effect on risk in women
- High triglyceride-to-HDL ratio: correlates with dyslipidemic hypertension 9
These observations from Framingham were instrumental in generating more research evaluating the influences of female hormones, diabetes, and subfractions of lipoproteins such as HDL cholesterol and triglycerides on the female risk of CVD.
HRT for postmenopausal women is a subject receiving much recent attention. The observed lipid and lipoprotein benefits of HRT include a reduction in lipoprotein (a) [Lp(a)] and LDL cholesterol levels. Lp(a) is a modified type of LDL cholesterol formed by apolipoprotein (a) binding to the LDL particle. This particle has similar properties to plasminogen and thereby interferes with fibrinolysis and enhances thrombosis. Lp(a) is also associated with increased deposition of LDL cholesterol in the arterial wall and increases oxidation of the LDL particle. HRT also raises HDL cholesterol, a lipoprotein particle known to protect against the development of atherosclerosis. These relationships between HRT and the lipoprotein subfractions, in addition to other benefits to the vascular system, appear to decrease the atherosclerotic process. 10-12 Additional intriguing data suggest that estrogen alone has a beneficial influence on endothelial function. In the absence of estrogen, a woman's arteries tend to constrict and decrease the flow of blood. 7,11 Estrogen has been shown to help arteries relax and dilate in a normal fashion, similar to the effect of nitric oxide. 11 There is also interest in the relationship of postmenopausal estrogen use on various physiologic functions including memory and cognition. 7,13 Clinical research is underway at this time evaluating the role of estrogen and neurologic function. The box lists additional risks and benefits of HRT.
It is important to remember that the use of HRT is associated with a probable increased risk of breast cancer and a small, but definite, increased risk of deep vein thrombosis and pulmonary embolism. 14,16 In addition, gallbladder disease and elevations in triglyceride levels are seen in women on postmenopausal HRT. 3 Women reporting a history of breast cancer, uterine or cervical cancer, deep vein thrombosis or pulmonary embolism, active gall bladder disease, high triglyceride levels, or abnormal liver function are generally not appropriate candidates for HRT. Pelvic examination, pap smear, vaginal ultrasound and endometrial biopsy (as indicated), mammogram, blood chemistries, and a careful history for breast cancer and thromboembolic risk are recommended before and as annual evaluations for women placed on HRT. The type, dosage, and duration of estrogen therapy needed to provide maximum benefit to the lipoprotein profile with the least risk for cancer and other negative side effects are unknown. To further complicate the issue, women with an intact uterus must be given an additional hormone, progestin, to protect the uterus from endometrial cancer secondary to hyperplasia. Endometrial hyperplasia results from the use of unopposed estrogen therapy and therefore is not generally recommended. 17 Data also suggest that progestins may blunt the beneficial effects of estrogen on the lipoprotein profile. 17
An important clinical trial was recently published regarding the use of postmenopausal HRT in women with known CHD. 18 The Heart and Estrogen-Progestin Replacement Study (HERS) asked the question: "Does HRT (estrogen and progestin) prevent heart-related death and acute MI in women with heart disease?" This nationwide study included 2,763 women with CHD who were younger than 80 years of age and had an intact uterus. The study was blinded to both participants and the investigators. The women were randomly assigned to placebo or estrogen plus progestin and were followed for an average of 4.1 years. The HERS study found no difference in fatal MI and heart disease-related death between women randomized to estrogen plus progestin and those randomized to placebo. These results, although surprising, have important implications for those who care for postmenopausal women with CHD. In addition to no difference in overall MI and CHD between the groups, there was an early (in the first 8 months of treatment) increased risk of death from acute MI and other CHD events in women randomized to estrogen and progestin compared with women on placebo. This early increased risk was balanced with a later (in years 3 and 4) decreased risk of these same endpoints. In addition, a small but definite increased risk of thromboembolic events (deep vein thrombosis and pulmonary embolism) as well as gall bladder disease was also found. Increased risk of gallbladder disease, deep vein thrombosis, and pulmonary embolism has been found in other studies of postmenopausal women taking HRT.
More questions than answers remain regarding HRT as a protection against the development of CHD or as a treatment for women with CHD. The Women's Health Initiative (WHI) is a 12-year prospective, randomized, controlled study of 164,500 postmenopausal women (64,500 have been randomized into a variety of interventions with 100,000 being followed in an observational arm). It is scheduled to be completed in 2010. WHI is asking three important questions: (1) How does HRT influence CHD, osteoporosis, and breast and uterine cancer in postmenopausal women? (2) Does a diet low in fat and cholesterol and high in fruit, vegetables, and fiber influence the rate of CHD and breast and bowel cancer in women? (3) Does calcium replacement affect rates of bone fracture and colorectal cancer in women? WHI has randomized eligible women into three clinical programs: (1) estrogen plus progestin or estrogen only versus placebo; (2) dietary modification of 20% total calories from fat and <7% total calories from saturated fat, five or more servings of fruits and vegetables per day, and six or more servings of grains and grain products per day versus usual care; and (3) 1,000 mg calcium and 400 mg vitamin D daily versus placebo. The Women's Health Initiative should help answer many of the questions concerning the risks and benefits of CHD therapies for women.
LDL AND HDL CHOLESTEROL
Baseline 1988 data from the HERS Study showed that of the 2,763 women (all with known CHD) enrolled, 63% failed to reach the NCEP I goals for LDL cholesterol. This failure occurred even though 41% of the women were on lipid-lowering therapy at baseline evaluation. This finding demonstrates a greater need for more aggressive lipid management in women with CHD. 19 High LDL cholesterol is an established and significant CHD risk factor for women as well as for men. 1 Eating a diet low in saturated fat and cholesterol and high in fruits, vegetables, and grains and grain products; maintaining an ideal body weight; and participating in regular physical activity are the best protections against high LDL cholesterol levels. Data from the lifestyle and lipid-lowering trials demonstrate that LDL lowering in women with CHD provides protection from recurrent MI, death, and clinical CVD events similar to that seen in previous trials of men only. 3,20-22 There is compelling evidence to support the theory that LDL lowering with pharmacologic therapies is equally safe and effective for women and should be strongly considered after an adequate trial of lifestyle modification has been undertaken. 3,20,23 Recent data in men and women with modestly elevated lipids and without baseline CHD indicate that lipid lowering through the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor drugs resulted in reductions in morbidity and mortality from CHD. 24-26 Some of these studies included persons without significant CHD risk factors at baseline. In these apparently lower risk men and women, similar benefits in clinical CVD risk reduction as well as reductions in overall CVD mortality were seen.
Low HDL cholesterol (<35 mg/dL) appears to be a significant risk factor for women. 21 Following the lifestyle recommendations for lowering LDL and triglyceride levels and quitting smoking will help to increase levels of HDL cholesterol. Estrogen has been shown to be especially helpful in raising HDL cholesterol in women and may be an important consideration for women with low HDL cholesterol levels (<35 mg/dL). In some women, however, estrogen will increase levels of triglycerides. 3,17,21 This result can be particularly problematic in women with baseline elevations in serum triglyceride levels. Fibrates and niacin are also effective pharmacologic therapies for low HDL cholesterol and elevated triglyceride levels.
Target goals for total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels are the same for women and men. The National Cholesterol Education Program: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP II) and the American Heart Association guidelines for the treatment of dyslipidemia and CHD recommend that lipid-lowering drugs as well as HRT be considered as a therapy for postmenopausal women. 27-29 The HERS results, which were published subsequent to these guidelines, challenge the use of HRT as a general recommendation for postmenopausal women with existing CHD (Table 1). 18
To achieve the recommended lipoprotein treatment goals, many women will need to take cholesterol-lowering medications in addition to making lifestyle changes. Fortunately, there are a number of safe and effective medications to help reach and maintain target LDL, HDL, and triglyceride level goals. There are no data to suggest that the fibrates, resins, HMG-CoA reductase inhibitors, or niacin work differently in women compared with men. (See the article by Gylys elsewhere in this issue for a discussion of these therapies.) The use of pharmacologic therapies must be based on a woman's overall risk for the development of CHD, comorbid conditions (ie, the presence of diabetes or a history of DVT), and her baseline lipid levels.
Triglyceride metabolism is a complex process. Studies of risk associated with elevations in triglyceride levels are greatly confounded by levels of total and HDL cholesterol. There is a strong inverse relationship between triglyceride level and HDL cholesterol. This relationship has made it difficult to establish whether triglyceride is an independent risk factor for CHD. However, some evidence does support an independent risk. The Lipid Research Clinics, in their observational study of women followed for 8.5 years, reported that women in the highest quartile for triglyceride level had a relative risk of 6.6 compared with those in the lowest quartile. 30 This finding is supported by other population-based evidence of the importance of elevations in triglyceride levels and an increased risk for CHD. The relationship between triglyceride levels and HDL cholesterol remains an important component of treatment for both men and women. Low HDL cholesterol is associated with an increased risk for the development of CHD and other vascular diseases. 31 Effective treatments for triglyceride elevation include weight loss, regular exercise, and specific dietary reductions in carbohydrate, calorie, and saturated fat intake. This diet (also appropriate for prediabetic women and women with diagnosed non-insulin-dependent diabetes mellitus [NIDDM]) can require complex changes and is best administered and followed by a registered nutritionist or a certified diabetes educator whenever possible. Pharmacotherapies are important adjuncts to lifestyle changes in the treatment of elevated triglyceride levels. Niacin, fibrates, and HMG-CoA reductase inhibitors are effective treatments for elevated triglyceride levels. All pharmacotherapies work more effectively when added to a comprehensive lifestyle program.
Premenopausal protection against CVD holds true for most women with the exception of women with diabetes. Diabetes appears to confer a gender-based risk for the development of CVD in women. It has been hypothesized that women with diabetes have had a more atherogenic pattern of risk factors before the development of clinical hyperglycemia when compared with men. 32,33 The San Antonio Heart Study found that women with NIDDM had a fourfold increased risk for the development of CHD compared with the twofold increase seen in diabetic men. Haffner and coworkers 34 postulated that women who eventually converted to NIDDM were more likely to have had a past history of increased diastolic blood pressure, an elevated fasting insulin (a marker of insulin resistance), a higher triglyceride level, and a lower HDL cholesterol level. Similar findings have also been reported by Barrett-Connor, 33 who found that women with NIDDM were at as great a risk for the development of CHD as men without diabetes. Again, the hormonally mediated protection of estrogen was not observed. Mechanisms for this increased risk were postulated to be related to higher triglyceride levels, lower HDL cholesterol, and greater abdominal pattern obesity seen in the women with NIDDM. 33 Because women with diabetes carry a disproportionate risk for the development of premature CHD, it is imperative that women with diabetes, and women with risk factors for the development of NIDDM be treated aggressively. Weight management, regular physical activity, a diet low in saturated fat (and one that addresses issues of triglyceride levels and glycemic control), interventions for dyslipidemia, control of blood pressure, and smoking cessation are critical issues for this special population.
The American Diabetes Association 35,36 recently defined new criteria for the diagnosis of diabetes. Impaired glucose tolerance has been defined by a fasting plasma glucose of ≥110 mg/dL and ≤127 mg/dL and a fasting plasma glucose of ≥127 mg/dL repeated on two different days as diabetes mellitus. With these new criteria, diabetics and those at risk for its development are more likely to receive aggressive lifestyle and medical management before the development of macrovascular and microvascular disease. National Guidelines for lipid management in persons with diabetes suggest goals similar to those in persons with diagnosed CHD. 35,36 In fact, some endocrinologists are advocating that lipid levels for persons with NIDDM and without any evidence of CHD should equal those of a person with CHD and without diabetes. 34 This more aggressive treatment of people with diabetes without symptomatic CHD supports the research that equates NIDDM with a high risk for the development of all vascular diseases.
Older age, black race, hypertension, atrial fibrillation, cigarette smoking, diabetes, pregnancy, oral contraceptive use, lack of physical activity, and possibly migraine headaches all have been linked to stroke in women. 1,37 Although lipid abnormalities have not been specifically identified as a major stroke risk factor, there is increasing interest in this area. New evidence suggests that lipid lowering results in reductions in overall rates of stroke and transient ischemic attacks. 38 Bucher and colleagues 38 evaluated stroke risk as reported in randomized controlled trials of lipid lowering since 1966. In this meta-analysis, fatal and nonfatal strokes were reduced by 24% in those trials with interventions that included HMG-CoA reductase inhibitors (statins). No difference between treatment and control was found when fibrates, resins, or dietary interventions were studied. In this report, data on women and men were not reported separately. However, it would be plausible to consider that women would experience stroke benefits similar to those experienced by men. Much more research is needed to identify the exact mechanisms of reduced stroke risk secondary to lipid lowering and statin use, as well as mechanisms specifically related to gender.
TREATMENT GUIDELINES FOR WOMEN
The American Heart Association and the American College of Cardiology have challenged health care professionals to provide aggressive risk-reduction therapies for both men and women, including the management of dyslipidemia (Table 1). The National Heart, Lung, and Blood Institute set forth guidelines describing abnormal lipid parameters as well as ideal goals for lipid management that are similar for men and women. These goals and treatment strategies are not gender based, with the exception of postmenopausal HRT recommendations. Based on the results of the HERS study, however, HRT in women with existing CHD must be carefully reconsidered. 18 A recent publication of the American Heart Association and the American College of Cardiology summarized preventive cardiology goals for women. Lifestyle factors, coronary risk factors, and pharmacologic therapies as they relate specifically to women were carefully defined and treatment recommendations were made. 39Table 2 summarizes their recommendations.
The goals of health care providers should be to identify women at highest risk of a coronary event; institute lifestyle changes known to reduce this risk; define and intervene in those who are candidates for medical and pharmacologic interventions; and provide systematic care and support of these efforts.
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Keywords:Copyright © 2000 by Aspen Publishers, Inc.
coronary heart disease; dyslipidemia; hormone replacement therapy; women