HomeCirculationVol. 96, No. 7Cardiovascular Disease in Women Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBCardiovascular Disease in Women A Statement for Healthcare Professionals From the American Heart Association , Lori Mosca, JoAnn E. Manson, Susan E. Sutherland, Robert D. Langer, Teri Manolio and Elizabeth Barrett-Connor , Lori MoscaLori Mosca , JoAnn E. MansonJoAnn E. Manson , Susan E. SutherlandSusan E. Sutherland , Robert D. LangerRobert D. Langer , Teri ManolioTeri Manolio and Elizabeth Barrett-ConnorElizabeth Barrett-Connor and Writing Group Originally published7 Oct 1997https://doi.org/10.1161/01.CIR.96.7.2468Circulation. 1997;96:2468–2482Despite an overall reduction in the death rate due to cardiovascular disease (CVD) in the United States over the last several decades, the rate of decline is less for women than men and less for African-American women than white women.1 Due to an aging population, the absolute number of deaths due to CVD in women is actually increasing (Fig 1).2 In the year 2000 nearly 50 million American women will be older than 50 years. Because the risk of CVD increases with age, there is a need for an increased awareness of the importance of CVD as a major public health issue for older women. The estimated direct and indirect costs of CVD and stroke in men and women combined will exceed $250 billion in 1997.2 CVD ranks first among all disease categories in hospital discharges for women. The sheer magnitude of the epidemic in women necessitates a strong emphasis on prevention to reduce the burden of CVD in our society.CVD, particularly coronary heart disease (CHD) and stroke, remains the leading killer of women in America and most developed countries. In 1994, the last year for which statistics are available, CVD claimed the lives of more than one half million women and accounted for 45.2% of all deaths in women, more than all forms of cancer combined.2 CVD is a particularly important problem among minority women. The death rate due to CVD is 69% higher in black women than white women. Misperceptions still exist that CVD is not a real problem for women, although it is estimated that 1 in 2 women will eventually die of heart disease or stroke, compared with 1 in 25 who will eventually die of breast cancer.2 This report discusses recent advances in knowledge of the occurrence, determinants, and treatment of atherosclerotic CVD in women, including CHD, hypertension, stroke, and peripheral arterial disease. Since the last scientific statement on this topic in 1993,3 much attention has been directed toward a better appreciation of the influence of gender on cardiovascular risk and management, but important gaps in knowledge remain. Recent developments in cardiovascular research undoubtedly will have a significant impact on prevention, clinical care, and outcomes of women and will provide direction for future work.Coronary Heart DiseaseEpidemiologyThere is a significantly lower age-specific risk of CHD in women than men. Risk of death due to CHD in women is roughly similar to that of men 10 years younger. Despite their marked advantage in age-specific risk of CHD death, the greater likelihood of survival of women to advanced ages produces nearly equal numbers of actual deaths due to CHD in men and women. In 1993 CHD claimed the lives of 239 701 women (48.9% of all CVD deaths) and 250 362 men (51.1% of all CVD deaths).2In the Cardiovascular Health Study, the prevalence of myocardial infarction (MI) in older women was 9.7% for those aged 65 through 69 years and 17.9% for those 85 years and older. Of particular concern is that nearly two thirds of sudden deaths due to CHD in women in the Framingham Heart Study occurred in those with no previous symptoms of disease compared with about half the sudden deaths in men.2 Treatment efforts in women may be less likely to be effective in reducing the death rate because the majority of cases may never reach a hospital. For these women, primary prevention is likely to be the only practical solution.Substantial ethnic differences in CHD deaths in women exist, although data are sparse for minorities other than blacks. CHD death rates are 34% higher for black women than white women, compared with a 5% higher rate for black men compared with white men. Declines in CHD death rates also show gender and ethnic variations. Death rates in men declined more steeply in the 1980s and 1990s, and rates in white women declined more rapidly than those in black women during the same period.2 The reasons for these differences remain unclear but may be related to differences in reporting, access to care, detection biases, and competing risks. In addition, higher prevalence of certain risk factors in black women (particularly diabetes and obesity) may explain their increased risk of CHD.Ethnic differences in CHD are even more perplexing for Hispanics. Death rates for CVD and CHD have been reported to be markedly lower for Mexican-American men compared with white men, but this advantage has not been demonstrated for Mexican-American women.4 Prevalence of ECG-defined MI shows similar trends with comparable rates among women in the two ethnic groups but higher rates in non-Hispanic white men compared with Hispanic men. More recent data from the Corpus Christi Heart Project demonstrate higher hospitalization rates for heart attacks and incident MI in Mexican-Americans compared with non-Hispanic whites for both men and women. This same study demonstrated a higher case-fatality after MI in Mexican-Americans and women compared with non-Hispanic whites and men, respectively.5Risk Factors and Primary PreventionThe major risk factors for CHD in women are cigarette smoking, hypertension (including isolated systolic hypertension), dyslipidemia, diabetes mellitus, obesity, sedentary lifestyle, and poor nutrition. Although most risk factors for CHD are similar in men and women, gender differences have been documented, particularly diabetes and dyslipidemia. The prevalence, magnitude of effect, and gender differences in identified risk factors for CHD are summarized below.Cigarette smoking remains the leading preventable cause of CHD in women, with more than 50% of MIs among middle-aged women attributable to tobacco.6 The magnitude of excess risk, a twofold to fourfold elevation, is similar in women and men.7 Risk of CHD begins to decline within months of smoking cessation and reaches the level of persons who have never smoked within 3 to 5 years.8 Although the prevalence of smoking among US women declined from 34% in 1965 to 24% in 1991, smoking cessation rates have declined more slowly among women than men.9 On the basis of current trends, it is estimated that by the year 2000 smoking rates will be higher in women (23%) than in men (20%).10 These changing demographics of smoking, particularly the unfavorable smoking patterns among younger women, may contribute substantially to the future burden of CHD on women, as well as other smoking-related illnesses.Epidemiological studies document a strong association between high levels of both systolic and diastolic blood pressure (BP) and risk of CHD in both women and men.11 Among US adults older than 45 years, 60% of white women and 79% of African-American women were classified as having hypertension (defined as either taking antihypertensive medication or having systolic BP≥140 mm Hg or diastolic BP >90 mm Hg). In the most recent National Health and Nutrition Examination Survey (NHANES III, 1988-1991), approximately one half of identified hypertensive subjects were receiving treatment with antihypertensive medication, but only about 21% had hypertension that was well controlled (BP <140/90).11 Of particular concern for older women is isolated systolic hypertension, which is estimated to affect 30% of women older than 65.12In the Systolic Hypertension in the Elderly Program (SHEP), in which women constituted 57% of the study population, antihypertensive therapy resulted in a 25% reduction in CHD and a 36% reduction in stroke in both sexes combined.13 For severe diastolic hypertension (diastolic BP ≥110), the benefits of medication are large and obvious for both sexes. For mild to moderate hypertension (diastolic BP = 90 to 109 mm Hg), a meta- analysis of randomized drug-treatment trials found reductions of 14% in nonfatal CHD, 42% in stroke, and 21% in vascular mortality in both sexes combined.14 A recent subgroup meta-analysis based on the database of seven trials from the Individual Analysis of Antihypertensive Intervention Trials (INDANA), in which primarily β-blockers and thiazide diuretics were used, shows a significant effect for stroke and major CVD events in women. The relative risk reduction did not differ between men and women.15 Weight reduction and dietary interventions also have important roles in prevention and treatment of hypertension.11Increased total serum cholesterol and low-density lipoprotein (LDL) cholesterol are risk factors for CHD in both women and men. From 1980 to 1991 more than 50% of women older than 55 years had serum cholesterol levels that were considered high (>240 mg/dL).16 In a recent meta-analysis, these lipids predicted CHD mortality in women younger than 65 but not in older women.17 A low level of high-density lipoprotein (HDL) cholesterol, however, was a risk factor for CHD in both younger and older women and was a stronger predictor of CHD mortality in women than in men. The role of triglycerides in CHD risk remains controversial, but observational studies suggest they may be a particularly important risk factor in women and the elderly, the majority of whom are women.18Limited data are available from randomized trials of lipid-lowering therapy for primary prevention of CHD in women. In an overview of three such trials that included women (two using dietary therapy and one using medication), no evidence for reduction in CHD or total mortality was observed in the treated groups.19 In contrast, secondary prevention trials of lipid-lowering therapy in women with CHD suggest substantial benefit of treatment and significant undertreatment of postmenopausal women with CHD (discussed elsewhere in this statement).Obesity and sedentary lifestyle are parallel, interrelated epidemics in the United States that contribute to increased risk of CHD. The prevalence of obesity has increased among both men and women in the United States in the past decade; currently about one third of adult women (or 34 million) are classified as obese.20 Moreover, 60% of both men and women have no regular physical activity.21 Obesity, particularly abdominal adiposity, is an important risk factor for CHD in women.2223 Although most of the epidemiological studies of exercise and CHD have been conducted in men, most studies in women suggest a comparable 50% risk reduction among active women compared with sedentary women.24 Recent evidence suggests that even moderate-intensity activity, including brisk walking, is associated with substantial reduction in CHD risk.25 These findings support the 1995 federal exercise guidelines endorsing 30 minutes of moderately intense physical activity most days of the week,26 a program that should be feasible and safe for most of the population.Regular exercise and maintenance of healthy weight should also help reduce insulin resistance and the risk of non–insulin-dependent diabetes mellitus, which appears to be an even stronger risk factor for CHD in women than in men.27 Diabetes is associated with a threefold to sevenfold elevation in CHD risk among women, compared with a twofold to threefold elevation among men; this gender-based difference may be due to a particularly deleterious effect of diabetes on lipids and blood pressure in women.27 Diabetes is the fourth leading cause of death among black women and third among Hispanic women aged 45 to 74 years and American-Indian women aged 65 to 74 years. It is also the second leading cause of death in Pima Indian women. Approximately half of all deaths in persons with non–insulin dependent diabetes mellitus are due to heart disease, the majority of which is ischemic heart disease.28Increasing research and knowledge related to nutrition have led to identification of several dietary factors that influence CHD risk. The epidemiological evidence is compelling: diets low in saturated fat and high in fruits, vegetables, whole grains, and fiber are associated with a reduced risk of CHD.29Trans fatty acids have recently been linked to adverse lipid profiles and an increased risk of CHD.30 The role of other fatty acids, including monounsaturated, polyunsaturated, and marine omega-3 fatty acids, remains controversial. Moderate intake of alcohol is related to reduction of CHD but may raise blood pressure and increase risk of breast cancer. 31Genetic factors are also important determinants of CHD risk in both men and women, but they are not modifiable and thus are not further addressed here. Recently identified thrombotic, hemostatic, and inflammatory markers for CHD have promising roles in predicting risk of vascular events, but their clinical usefulness in the general population remains largely unknown.Pharmacological interventions, including antiplatelet therapy and postmenopausal hormone replacement therapy, are appropriate in selected patients. In primary prevention the balance of benefits and risks of aspirin prophylaxis among women remains unknown and awaits the results of the ongoing Women's Health Study, the only randomized trial of aspirin in usual-risk women. Antioxidant vitamin supplements, particularly vitamin E and homocysteine-lowering agents such as folate and B6, have promising roles in prevention of CHD, but conclusive evidence awaits the results of several ongoing randomized clinical trials.32 Early surgical menopause is linked to increased risk of CHD, which appears to be negated by the use of estrogen therapy.33 The role of postmenopausal hormone therapy in prevention and treatment of CHD is discussed in detail elsewhere in this report.In summary, epidemiological studies and randomized clinical trials provide compelling evidence that CHD is largely preventable.8 Pharmacological intervention has a role in primary prevention for selected patients. However, a major emphasis should be placed on lifestyle modifications, including smoking cessation, regular physical activity, maintenance of healthy weight, and consumption of a diet low in saturated fat and high in fruits and vegetables. Further studies on the potential benefits of stress reduction and psychosocial interventions are indicated.Identification and Management of Women With Coronary Heart DiseaseDiagnosisThe diagnosis of CHD presents a greater challenge in women compared with men. Gender differences in the clinical presentation of ischemic heart disease and diminished accuracy of diagnostic tools, in part due to the lower prevalence of CHD in women, may contribute to the difficulty. Elucidation of the cause of chest pain and an increased awareness of atypical symptoms of CHD in women are needed. In addition, diagnosis of unrecognized ischemia is of interest in women because of the high fatality rate associated with first MIs.Historically, chest pain has not been perceived to be of great prognostic value in women. This is based partly on follow-up reports from the Framingham study indicating that women developed chest pain more often than men, but it rarely progressed to MI.34 In the same population the predictive value of angina was increased among older subsets of women.35 In the Coronary Artery Surgery Study (CASS), half of all women undergoing arteriography for suspected CHD did not have significant obstruction.36 Refinement of the diagnosis as definite angina, probable angina, or nonspecific chest pain may improve the predictive value of symptoms. Women with classical angina pectoris had a 71% probability of angiographic evidence of disease compared with 36% of women with probable angina. Nonspecific chest pain syndromes in women have an excellent prognosis and are rarely associated with significant disease on arteriography.37Syndrome X, defined as exertional angina, a positive response to exercise testing and angiographically normal coronary arteries occurs predominantly in postmenopausal women. Although chest pain may be typical for angina, conventional antianginal therapy may not successfully treat symptoms. Long-term survival rates are not reduced in women with syndrome X.38Despite the limited prognostic value of chest pain, it remains the most common initial manifestation of CHD in women. In the Myocardial Infarction Triage and Intervention (MITI) Project,39 nearly 90% of women with MI had chest pain as a feature of initial clinical presentation, similar to that of men. In contrast, women with MI were significantly more likely than men to present with upper abdominal pain, dyspnea, nausea, and fatigue. Chest pain and possible atypical symptoms of angina should be pursued in women, given the appropriate clinical context and based on the underlying probability of disease. A recent review of the evaluation of chest pain in women suggests that it is possible to stratify patients into broad categories of low, intermediate, and high likelihood of disease on the basis of the existence of minor and major determinants of CHD to make diagnostic testing more cost-efficient and informative.40The choice and interpretation of an array of noninvasive procedures poses unique challenges in women. Factors that influence gender differences in the accuracy of diagnostic testing include a lower prevalence of CHD and multivessel disease compared with men, sex-based differences in the pathophysiology of coronary disease and its relation to risk factors, altered referral patterns for men versus women, and features intrinsic to the testing procedure itself.4142Gender-specific considerations related to diagnostic test performance may influence the choice of procedures used to evaluate chest pain syndromes in women. Electrocardiographic (ECG) stress testing in women has a lower sensitivity and specificity compared with men, not only because of gender differences in prevalence and extent of disease but also because women are less likely to achieve an adequate heart rate response and more likely to have repolarization abnormalities.43 In addition, hormone replacement therapy may induce a false-positive ST-segment depression, thereby reducing the specificity of ECG exercise testing in women.44Sensitivity and specificity of pharmacological or exercise treadmill testing is enhanced by added imaging techniques. Myocardial perfusion imaging with thallium 201 has improved sensitivity over conventional treadmill testing, but breast tissue attenuation of radioactivity may lead to a false-positive test result in women.45 Attenuation artifacts may be reduced and specificity increased with the use of newer high energy agents such as technetium 99m Sestamibi and simultaneous ECG-gated single-photon emission computed tomography (SPECT), but data are limited in women.46 Radionuclide ventriculography is of limited prognostic value in women because of a reduced left ventricular response to exercise compared with men.47 In contrast, exercise echocardiography may be a valuable diagnostic tool in women. It is more specific than exercise electrocardiography and is considered a cost-effective approach to diagnosis of CHD in women.48These data suggest gender has a significant impact on the accuracy of widely available diagnostic tests and should be a consideration in the choice and interpretation of noninvasive tests. Emerging data on electron beam computed tomography, a noninvasive screening technique that detects coronary calcium, suggest minimal gender differences in diagnostic and prognostic usefulness.49 Recent advances in development of three-dimensional imaging with magnetic resonance or positron emission tomography hold promise for women because they may overcome some of the inherent test-related limitations described above; however, these are still considered experimental.50 As new techniques are developed to help detect CHD, gender-specific information about test efficacy will need to be provided to clinicians. Follow-up evaluation and management should be based on both pretest and posttest probability of disease in women.Prognosis and RevascularizationSeveral reports have documented a worse prognosis for women with CHD than for men with CHD, which likely reflects increased severity of illness at presentation, increased age, and comorbidity in women. In the Framingham study the initial case fatality rate for MI was greater in women compared with men, and within 1 year after infarction, 44% of women died, compared with 27% of men.51 In addition, the proportion of first events occurring as sudden death rose more sharply with age in women than in men in this cohort. Data from the more recent Multicenter Investigation of the Limitation of Infarct Size (MILIS) study has also documented a more adverse prognosis in women after MI compared with their male counterparts, even after adjustment for differences in risk.52 In-hospital mortality was 13% for women versus 7% for men. Cumulative mortality at 48 months was 36% for women versus 21% for men, with the poor prognosis among women largely due to a high mortality rate in black women (48%).Observations from placebo control groups of large-scale clinical trials, such as the International Study of Infarct Survival (ISIS-1) trial of atenolol, confirm a greater 1-week mortality for women compared with men (7.5% versus 3.7%).53 ISIS-4, which compared captopril with placebo in patients receiving thrombolytic agents after MI, also suggested an increased short- and long-term mortality in women.54 The 30-day mortality rate in women was double that of men in the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) study of tissue type plasminogen activator.55 Women were shown to have a 60% greater mortality than men 35 days after presentation to the hospital with acute MI in the Fibrinolytic Therapy Trialists study meta-analysis.56 In contrast, the outcome of women and men with unstable angina and non–Q-wave MI was found to be similar in the Thrombolysis in Myocardial Ischemia (TIMI) III B Registry despite less extensive disease and better left ventricular function.57 However, older age and more comorbidity among women may have attenuated these benefits.Reported differences in mortality rates among studies may reflect differences in the baseline characteristics of the populations studied as well as methodological considerations related to whether short-term, long-term, or cumulative mortality is examined. Furthermore, gender differences in mortality in the postthrombolytic era may potentially reflect gender differences in utilization and responsiveness to cardiovascular revascularization and aggressiveness of postinfarction risk reduction.Use of diagnostic and therapeutic cardiovascular modalities may be related to gender differences in morbidity and mortality. Data from the Myocardial Infarction Triage and Intervention (MITI) registry suggest that the gender gap in mortality due to acute MI is associated with a lower likelihood of women receiving acute cardiovascular interventions.39 In this community hospital trial, women had twice the in-hospital mortality of men and were half as likely to undergo acute catheterization, angioplasty, thrombolysis, or coronary bypass surgery. In contrast, women with unstable angina or non–Q-wave MI in the TIMI III Registry had similar risk for an adverse event at 6 weeks compared with men despite being less likely to undergo revascularization.58 In area hospitals participating in the Atherosclerosis Risk in Communities (ARIC) study, women hospitalized for an MI were less likely to have coronary angiography, bypass graft surgery, and thrombolytic therapy than men, even after adjusting for several clinical and demographic variables.59 This may not necessarily represent underuse in women, because evidence for a gender difference in the appropriateness of use of cardiovascular procedures has not been clearly demonstrated.60 Recently, women in New York state have had a higher rate of bypass surgery when compared with women in Ontario, but it is unclear if this translates into a survival benefit.61Gender differences in the efficacy of myocardial revascularization procedures could also explain a more adverse prognosis in women, but data are limited due to a lack of randomized clinical trials that include large numbers of women. The mortality benefit of thrombolytic therapy in men and women was found to be equivalent in the GUSTO-I trial; however, women had a higher stroke rate.62 Reinfarction and reocclusion of an initially patent infarct-related artery tended to be more common in women but were not statistically different from men.63 With respect to percutaneous transluminal coronary angioplasty (PTCA), women have an excellent long-term prognosis after a successful procedure, similar to that observed in men.646566 However, procedural morbidity and mortality for PTCA is three times higher for women.67 Newer revascularization procedures such as atherectomy and stents have been less well studied in women and men.CASS68 demonstrated a similar rate of bypass grafting for men and women. The 15-year survival rate approached 50% for men and women with initial medical treatment. A greater survival rate was associated with surgical treatment for men (52%) versus women (48%), which was attributable to differences in operative mortality. Differences in functional class, age, and size of coronary arteries as well as a greater likelihood of emergent surgery have explained a gender differential in operative mortality in some studies but not others.697071 Women have been sicker at the time of bypass surgery but show similar patterns of recovery and improvements in psychosocial and physical functioning after bypass surgery.7273It has been suggested that gender differences in mortality related to CHD no longer exist after adjustment for differences in age, risk factors, and interventions.7475767778 Although this may be important from an explanatory point of view, from the perspective of public health the fact remains that women have a worse prognosis and die more often than men after a heart attack or bypass surgery.Adjunctive Drug Therapy and Secondary PreventionThe role of pharmacological therapy on the outcome of acute MI was recently reviewed.798081 Conclusions related to gender differences in treatment efficacy are limited because the number of women in many postinfarction intervention trials has been small, probably because of upper age restrictions (as low as 65 years) where prevalence of CHD increases in women.82 Clinicians may refer to the ACC/AHA guidelines for the acute management of patients with MI, including drug therapy, that were published in 1996.83 Treatment with β-blockers is associated with a 21% reduction in mortality, a 30% decrease in sudden death, and a 25% lower reinfarction rate,8485 with reportedly similar benefits in women and men in some studies.37The Survival and Ventricular Enlargement (SAVE) study demonstrated that long-term therapy with an angiotensin-converting enzyme (ACE) inhibitor decreased mortality and morbidity among MI survivors with left ventricular dysfunction (ejection fraction ≤40%)86 and found the beneficial effect of β-blockers was additive in these patients who often are not prescribed β-blockers.8187 ACE inhibitor therapy was associated with a decreased rate of reinfarction in both the SAVE trial and Studies of Left Ventricular Function (SOLVD), suggesting potential antiatherogenic qualities of ACE inhibitors.888990 Short-term ACE inhibitor therapy (<3 months) should be considered for patients with no contraindications, and treatment may be continued up to 3 years in patients with left ventricular dysfunction.79Calcium channel blockers, antiarrhythmic drugs, or intravenous magnesium are not recommended as standard therapy during or after an acute MI because they have not demonstrated a conclusive reduction in mortality in randomized trials.79 Nitrates may be considered for symptomatic relief of ischemic chest pain during or after MI. Few data are available to examine gender differences in quality of life or potential adverse side effects of many of these medications, and future research should address this issue.In high-risk women with prior occlusive vascular events, lifestyle modifications and therapeutic interventions (discussed in the section on primary prevention) are applicable and of heightened importance. Women at high baseline risk of CHD have the most to gain from using the risk-reduction strategies above. For some interventions, such as aspirin therapy and cholesterol-lowering medications, the evidence for benefit in secondary prevention among women is much stronger than the evidence for primary prevention. A meta-analysis of randomized trials of aspirin documented that among both men and women with prior vascular disease, aspirin treatment reduced risk of subsequent cardiovascular events by about 25%.91Lipid-lowering therapy also appears to provide substantial benefit in secondary prevention in women.18 Although data are limited (six trials have included women with CHD and hyperlipidemia), these studies suggest a >50% reduction in CHD mortality among the treated women.18 In the Cholesterol and Recurrent Events study, the one trial of patients with CHD and "normal" cholesterol levels, pravastatin therapy was associated with
