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Previous Volume 329:247-256 July 22, 1993 Number 4 Next

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Each year approximately 2.5 million U.S. women are hospitalized for cardiovascular illness, which also claims the lives of 500,000 women annually; half these deaths are due to coronary heart disease¹. Despite the magnitude of this problem and its adverse repercussions on the national public health, we have insufficient information about preventive strategies, diagnostic testing, responses to medical and surgical therapies, and other aspects of cardiovascular illness in women. This lack of information is compounded by the less frequent participation of women in research studies; the difference has been due in part to the exclusion of women of childbearing age and in part to the exclusion of elderly women because of their frequent coexisting illnesses^2,3,4. Characteristics of patients and physicians that limit the participation of women in clinical trials and sex-specific psychosocial or economic factors remain largely unexplored.

There is increasing evidence that women undergo intensive or invasive evaluations and treatments for cardiac diseases substantially less frequently than do men with symptoms of similar or lesser severity; this is particularly true for the evaluation of chest pain^5,6,7. The contributions to the differences in the use of procedures of physicians' attitudes toward women patients and their symptoms, different choices made by women themselves, and cultural or social attitudes about sex differences must be assessed, but of pivotal importance is the relation between the use of procedures for women and the clinical outcomes of cardiovascular illness.

In January 1992, the National Heart, Lung, and Blood Institute convened an invitational conference, "Cardiovascular Health and Disease in Women," to highlight new information derived from epidemiologic and clinical research that was appropriate for clinical application and that required wider dissemination and to identify gaps in contemporary knowledge that impeded the delivery of optimal cardiovascular care to women⁸. In addition to addressing general issues of the cardiovascular health of women, this article summarizes the recommendations of the conference.

Recommendations for Clinical Practice

Coronary Heart Disease in Women: Prevention, Diagnosis, Management, and Prognosis

Coronary heart disease is the most frequent cause of death among U.S. women,¹ for whom it entails a worse prognosis than for men with both medical and surgical therapies. The rate of early death after myocardial infarction is higher among women than among men,^9,10,11,12 even when coronary thrombolytic therapy is used, and the in-hospital mortality rate among women who undergo coronary angioplasty, coronary atherectomy, and coronary bypass surgery is substantially higher than that among men^13,14,15,16. It is uncertain whether this excess mortality reflects the older age, smaller body size, or more frequent and severe coexisting illnesses of women when symptomatic coronary disease occurs, or whether it results from suboptimal or delayed care.

Education is needed to heighten awareness on the part of both health professionals and women that the misperception of angina pectoris as a benign problem in women may lead to bias in the evaluation of women with chest pain^17,18. In women, as in men, chest pain compatible with angina pectoris warrants evaluation for coronary heart disease. Preliminary estimation of the risk of coronary heart disease, derived from a careful clinical history that differentiates typical angina from other causes of chest pain and from the assessment of coronary risk factors, is equally important for women and men^19,20,21; corrections for the prevalence of coronary disease (pretest likelihood) and other variables contributing to false positive exercise tests in women result in comparable diagnostic accuracy of exercise-based tests for men and for women^19,20. Electrocardiographic exercise testing is recommended for women who give a history typical of angina pectoris if the resting electrocardiogram is normal^19,22. Because of the low prevalence of coronary disease among young and middle-aged women, a normal (negative) adequate-intensity exercise electrocardiogram has high specificity for excluding this diagnosis, comparable to that among men^19,22. When the resting electrocardiogram is abnormal and the history suggests probable or atypical angina, thallium or other perfusion imaging improves the specificity of exercise testing in women^{20,23,24,25,26}. Exercise testing with thallium scanning is preferable to exercise wall-motion studies such as multigated acquisition scans, which are not as accurate for detecting coronary disease in women as in men^27,28,29. The peak ejection fraction during exercise has been suggested as a better indicator,^30,31 but further validation is needed. Exercise and dipyridamole echocardiography, which demonstrate the development of new wall-motion abnormalities with myocardial ischemia, are reported to retain predictive accuracy in single-vessel coronary disease, a common finding in women^32,33. Pharmacologic stress testing may be undertaken to evaluate chest pain in women who are unable to exercise³³. Referral for coronary arteriography should be considered when the results of the exercise test are abnormal^21,34,35. Neither exercise testing nor any other single test is of value for large-scale screening for coronary heart disease in truly asymptomatic patients (either men or women), even when coronary risk factors are present.

The frequency and consequences of silent myocardial ischemia in women are largely unknown, despite the more frequent occurrence of silent or unrecognized myocardial infarction in women than in men³⁶. Variant (Prinzmetal) angina with angiographically normal coronary arteries, which is more common among women than among men, has a favorable prognosis^37,38. Myocardial ischemia with angiographically normal coronary arteries, which may represent microvascular angina,³⁹ also occurs more frequently among women than among men, but the data about prognosis conflict; although survival is excellent, left ventricular dysfunction develops in some patients⁴⁰. Chest-pain syndromes have characteristics both typical and atypical of myocardial ischemia. Some patients with this syndrome appear to have abnormal patterns of pain perception.

Information from a number of sources has identified differences in the frequency of use of invasive cardiovascular procedures between women and men^5,6,7,41; women undergo fewer invasive procedures, raising the question whether the rate of use is inappropriately low among women or excessively high among men, or whether procedures are appropriately used for both men and women. Although functional limitation due to chest pain appears to be greater in women than men,⁷ fewer symptomatic women than men undergo diagnostic coronary arteriography and therapeutic coronary angioplasty or coronary bypass surgery. After coronary arteriography, the use of revascularization procedures does not appear to be related to sex^6,7,42. Nonetheless, women who undergo coronary bypass surgery are typically sicker than men, more often require emergency surgery, and appear to have been referred for revascularization at a later, more symptomatic, stage of illness^{13,14,15,43,44,45,46}. Until outcome data are available to clarify whether these differences in referral patterns and use of procedures are appropriate or inappropriate, decisions about the evaluation of chest pain in women should be reviewed with this possible bias in mind. Physicians and their female patients may delay or defer necessary procedures because of concern about the increased likelihood of complications among women; because of this delay, women may be at even higher risk when they ultimately undergo the procedure.

Few data are available on the efficacy of specific medical and revascularization therapies for coronary heart disease in women. Thrombolytic therapy for acute myocardial infarction has equal benefit in terms of survival among both women and men, despite more frequent serious bleeding complications in women⁴⁷. Women are less likely than men to be eligible for thrombolytic therapy, however, because of their later presentation after the onset of symptoms of myocardial infarction, their increased likelihood of having comorbid conditions, and their more advanced age⁴⁸. Women should be encouraged to respond promptly to symptoms suggestive of myocardial infarction; such earlier response might increase their eligibility for coronary thrombolysis.

Data regarding sex differences, if there are any, in the response to most other pharmacologic therapies are sparse⁴. Aspirin and beta-blocking drugs have comparable efficacy in women and men in the prevention of reinfarction after myocardial infarction^49,50. Both coronary angioplasty⁵¹ and coronary bypass surgery¹³ confer a comparable long-term survival benefit on women and men who survive the hospital stay; however, women have higher operative mortality rates and an excess of periprocedural complications with coronary bypass surgery,¹³ and they are twice as likely as men to have continued symptoms four years after coronary angioplasty^51,52. Differences in base-line characteristics and severity of disease between women and men are important contributors to the higher rates of mortality and morbidity among women who undergo myocardial revascularization; the smaller body size and consequent smaller coronary-artery size of many women may also be disadvantageous^13,16.

Because of the underrepresentation of women in previous clinical trials of secondary prevention, few comparisons of the long-term outcomes of women and men with coronary heart disease have been made³. Physicians refer fewer women than men with coronary disease for exercise rehabilitation, despite the fact that the functional benefit of such therapy is comparable in women and men⁵³. However, even women referred to cardiac rehabilitation programs have poorer adherence and attendance because of their more frequent coexisting illnesses, family responsibilities, and possibly other psychosocial factors^53,54.

Reduction in the risk of coronary heart disease is important for women of all ages, notably by means of changes in the diet for weight control and fat restriction,⁵⁵ regular physical activity,⁵⁶ and smoking prevention and cessation. Because risk factors for coronary heart disease are highly prevalent among women, physicians should educate their women patients that coronary risk factors can be prevented or altered by behavioral strategies. Physicians should serially assess risk factors that include blood pressure, body weight, waist-to-hip ratio,^57,58 dietary intake of fat, pattern of physical activity, cholesterol levels, diabetic status, and smoking status in women as well as men. On the basis of these assessments, preventive interventions should be included in office care.

The decline in smoking in the United States during the past 25 years has been greater among men than among women⁵⁹. The prevalence of smoking among adolescent girls has exceeded that among boys for the past decade⁶⁰. In particular, smoking has increased among young and disadvantaged women, groups often specifically targeted by cigarette advertising; cigarette advertising is further targeted to women's greater use of cigarettes for weight control. Women also appear to smoke more of the highly publicized "low-yield" brands, despite research evidence that the risk of myocardial infarction of such women is similar to that of women who smoke "high-yield" brands. Women should be made aware both of these findings and of the importance of smoking cessation to their cardiovascular health⁶¹. Smoking cessation improves survival both for healthy women⁶² and for women who have recovered from myocardial infarction⁶¹. By providing advice and health-education materials, physicians can influence their patients to stop smoking. Weight reduction should be targeted to subgroups of women at highest risk and to periods of life when weight gain is most likely^63,64. Nonpharmacologic interventions, including weight loss and regular physical exercise,^65,66 are important in the treatment of mild-to-moderate hypertension in women. Improvements in risk factors have a cascading effect, leading to improvement in other risk characteristics; for example, weight loss leads to improvements in blood-pressure levels and glucose tolerance⁶⁷. Because childhood risk factors persist into adult life, clinicians caring for children should implement family-based treatments, which can be more effective than those instituted later in life.

Hormone-Replacement Therapy, Oral Contraceptive Agents, and Coronary Heart Disease

Hormone-replacement therapy after menopause is a promising approach to the primary and secondary prevention of coronary heart disease among women. Observational studies suggest a reduction of approximately 50 percent in the risk of coronary heart disease among healthy postmenopausal women taking oral estrogen, with an even more substantial benefit among women with documented coronary heart disease^68,69,70. Hypertension, diabetes, and a history of stroke are not contraindications to estrogen therapy. Women with hypertriglyceridemia who are given estrogen therapy require surveillance to ensure that the use of estrogen does not further increase their serum triglyceride levels. Combination hormone-replacement therapy (with progestin added to estrogen) appears prudent for women who have not undergone hysterectomy, because of the risk of endometrial hyperplasia and endometrial cancer with unopposed estrogen therapy; however, the effect of progestational agents on the favorable effects of estrogen therapy on lipids and its potential cardiovascular benefits is uncertain. Recent observational data suggest a more favorable lipid and coagulation profile (lower levels of triglycerides, factor VII, and protein C) with estrogen plus progestin than with estrogen alone⁷¹. Information is also lacking about the cardiovascular effect of hormone therapy that is initiated or reinstituted at an older age, many years after menopause. Whether the long-term use of estrogen or estrogen plus progestin increases the incidence of breast cancer is uncertain, but many women fear breast cancer more than they do coronary heart disease. Unwanted uterine bleeding is a less ominous adverse effect of hormone therapy. Pending the results of large, ongoing clinical trials, clinicians and their patients must make decisions about the use of postmenopausal hormone therapy on the basis of the relative risks of coronary disease, osteoporosis, and breast and uterine cancer and the severity of menopausal symptoms.

The rate of coronary heart disease is very low among women in the childbearing years, with annual incidence rates averaging 1 per 1000 among women 35 through 44 years of age and 4 per 1000 among those 45 through 54⁷². There is no evidence that the use of low-dose oral contraceptive hormones increases the risk of coronary disease among women under the age of 30 or among nonsmoking women without other coronary risk factors who are 30 to 50 years old^73,74.

Behavioral and Psychosocial Aspects of Cardiovascular Disease in Women

Chest pain and tachycardia can be the presenting features of depression and anxiety disorders in some women. Physicians should be skilled in assessing these symptoms and not ascribe a psychogenic origin to them without a thorough diagnostic evaluation for heart disease. Depression and panic disorders,^75,76,77 which also occur in women with heart disease, can have adverse effects in terms of morbidity and mortality. Physicians must be knowledgeable about the cardiac side effects of psychotropic drugs and the psychiatric effects of cardiac medications.

Since health care should enhance the quality as well as the quantity of life, psychosocial evaluation, including the assessment of the quality of life and of health-related behavior, should be included in all clinical evaluations. In addition, the design of treatment plans for women with heart disease must consider their often overlapping social roles as caretakers of children, aging sick parents, and sometimes older ill husbands, in addition to their work responsibilities.

Cardiovascular Disease and Pregnanc

            The Recognition and Management of Hypertensive Disease

Blood pressure should be measured during pregnancy with use of the phase 5 Korotkoff sound (i.e., the disappearance of the Korotkoff sounds) for diastolic pressure⁷⁸. The use of low-dose aspirin⁷⁹ to decrease the risk of preeclampsia and fetal growth retardation is promising, but recommendations must await the results of large ongoing clinical trials. The efficacy of calcium supplementation to prevent preeclampsia also remains to be proved in clinical trials.

            Venous Thromboembolic Disorders

The objective diagnosis of venous thromboembolism is mandatory before anticoagulant therapy is instituted in pregnant and postpartum women^80,81,82,83. Noninvasive diagnostic tests such as impedance plethysmography, duplex sonography, magnetic resonance imaging, and ventilation-perfusion scanning are not contraindicated for pregnant women with suspected venous thromboembolism. Inconclusive results require definitive evaluation by contrast venography and pulmonary angiography; the risk of thromboembolism to the patient far outweighs the theoretical risk to the fetus from exposure to diagnostic radiation^84,85.

            Cardiac Disease

At least 300,000 U.S. women, most in the childbearing years, have a congenital cardiovascular malformation⁸⁶. Among these patients, maternal and fetal outcomes of pregnancy are good,⁸⁷ except for Eisenmenger's syndrome, which is associated with a 30 percent maternal mortality rate; primary pulmonary hypertension or moderately-severe-to-severe secondary pulmonary hypertension; symptomatic lesions obstructing outflow, such as aortic stenosis; lesions associated with serious left ventricular dysfunction or congestive heart failure before pregnancy; and aneurysm or dilatation of the aorta or pulmonary arteries, as in Marfan's syndrome. Prior pulmonary embolism is also associated with a less favorable outcome. Pregnancy is well tolerated by women with repaired tetralogy of Fallot, atrial and ventricular septal defects, and mild valvular defects, including pulmonary and aortic stenosis.

Fetal outcome is normal in the absence of maternal hypoxemia and high-resistance pulmonary hypertension⁸⁸. When the mother has an isolated cardiovascular malformation (without diabetes or other risk factors), the risk of a cardiovascular malformation in the child is low^89,90. In contrast to isolated cardiac defects, cardiac malformations that are part of a syndrome or are associated with multisystem congenital defects carry higher risks for the fetus⁹¹ and should be identified before pregnancy occurs. Optimal management includes careful cardiac assessment before pregnancy; specific diagnosis and identification of maternal and fetal risk factors; and management of risk factors such as polycythemia, hypoxemia, volume overload, and arrhythmias. Fetal echocardiography is indicated at about 18 to 20 weeks. Mothers with complex cardiovascular malformations and those whose fetuses have abnormal hearts require tertiary care from an obstetric-cardiac team.

Despite an overall decline in rheumatic heart disease in the United States in recent years, this disease is now actually increasing in prevalence^92,93 owing to outbreaks of rheumatic fever in areas where socioeconomic conditions are poor, and particularly to established disease encountered in large immigrant populations from countries where rheumatic heart disease is common. Careful individualized assessment is needed for women with prosthetic heart valves who are receiving anticoagulant therapy,^94,95,96 those with implanted tissue valves,⁹⁷ and those with poor ventricular systolic function.

            Peripartum Cardiomyopathy

Because of the rarity of peripartum cardiomyopathy and the high maternal mortality rate (50 to 85 percent), the diagnostic criteria for this condition must be precise: cardiac failure occurring in the last month of pregnancy or within five months of delivery, in the absence of an identifiable cause of heart failure and without demonstrable preexisting or concurrent heart disease^98,99. Findings compatible with peripartum cardiomyopathy include a cardiothoracic ratio above 0.55, a left ventricular ejection fraction of less than 50 percent, and a diastolic dimension above the 95th percentile for age and body-surface area. Patients over 40 years of age require coronary arteriography, which should also be performed when there is a history of angina, an abnormal exercise-test result, or segmental wall-motion abnormalities on echocardiography. The indications for myocardial biopsy are controversial, given the failure of biopsy-based immunosuppressive therapy to benefit nonpregnant patients with cardiomyopathy. However, several observational series suggest a high incidence of biopsy-diagnosed myocarditis in patients with peripartum cardiomyopathy, as well as substantial improvement with immunosuppressive therapy^{98,100,101,102}.

The prognosis appears most closely related to the persistence of cardiomegaly. Patients with transient cardiomegaly may do well in subsequent pregnancies, especially if cardiomegaly resolves within six months of delivery. Patients with persistent cardiomegaly should be counseled not to become pregnant again.

Noncoronary Cardiovascular Disease in Women

As with coronary heart disease, the prevalence of noncoronary cardiovascular disease increases among women as the population ages. Disorders that commonly affect women at older ages include aortic stenosis, hypertension, and stroke. Congestive heart failure¹⁰³ and peripheral vascular disease¹⁰⁴ occur less frequently among women than among men at all ages.

            Stroke

Although the prevalence of established essential hypertension, defined as a systolic pressure between 140 and 160 mm Hg and a diastolic pressure greater than 90 mm Hg, is higher among men than among women, the risk of cardiovascular morbidity and mortality increases in proportion to the elevations of these pressures and the sex gap diminishes with age¹⁰⁵. Systolic hypertension by itself is a risk factor for stroke and myocardial infarction among older women. Control of isolated systolic hypertension, often readily accomplished with simple diuretic therapy, effectively reduces that risk¹⁰⁶. The risk of stroke and other cardiovascular disease posed by glucose intolerance and diabetes is greater for women than for men. Smoking and atrial fibrillation are independent risk factors for stroke^107,108.

Postmenopausal estrogen-replacement therapy does not increase the risk of heart disease or stroke, even among women with a prior cerebrovascular accident or transient ischemic attack or among women with hypertension. Secondary prevention is important, particularly the use of aspirin to reduce the risk of recurrent stroke^109,110. Other drugs such as ticlopidine do not offer an advantage over aspirin. Anticoagulation reduces the risk of stroke when atrial fibrillation is present¹¹¹.

Carotid bruits are more frequent among women than among men,¹¹² although women have less severe carotid stenosis; however, restenosis after carotid endarterectomy is more common among women than among men^113,114.

            Valvular Heart Disease

Evaluation of elderly women for aortic stenosis typically occurs later in life than evaluation of men, with more frequent and higher-risk emergency surgical procedures resulting (Cohn LH: personal communication). Aortic balloon valvuloplasty has limited usefulness because of the high rate of restenosis and post-hospitalization mortality^115,116. Echocardiography can help select patients for cardiac catheterization, and elective surgery is associated with lower surgical risk than emergency surgery^117,118. Comorbidity, particularly associated coronary heart disease, requires evaluation since concomitant coronary artery-bypass surgery adds to the operative risk¹¹⁹. Most reports of aortic-valve replacement in elderly patients do not provide sex-specific outcomes, however.

The number of women in the childbearing years with rheumatic heart disease in the United States is increasing; this increase is due predominantly to the high prevalence of rheumatic heart disease in immigrant populations from areas where rheumatic heart disease is common, such as Southeast Asia, South America, and Central America¹²⁰. The need for surgical intervention for rheumatic heart disease during the childbearing years necessitates a critical evaluation of the surgical procedure for mitral stenosis (valvuloplasty vs. valve replacement) and the choice of prosthetic valve (tissue vs. mechanical), because of the risks of anticoagulation during pregnancy.

            Peripheral Vascular Disease

Peripheral vascular disease so predominates in men that many reports of surgical treatment do not indicate the number of women included or provide sex-specific outcomes. Peripheral vascular disease rarely occurs in younger women, or in the absence of cigarette smoking or diabetes mellitus^121,122,123. A vigorous antismoking campaign is needed to heighten awareness about the relation between cigarette smoking and peripheral vascular disease in women¹²¹. Although aortic aneurysm is far more frequent among men than among women, aortic aneurysm is, on average, discovered later in women (chiefly after age 65), generally has a familial pattern, and is more likely to be ruptured at the time of diagnosis than is the case among men¹²⁴.

            Congestive Heart Failure

In the Studies of Left Ventricular Dysfunction (SOLVD) trial, women with heart failure were older than men and less frequently had coronary disease as the cause of their ventricular dysfunction¹²⁵. Women had a higher mortality rate than their male counterparts, which was not attributable either to older age or to the cause of heart failure. Favorable treatment outcomes, reduced mortality, and fewer hospitalizations occurred in both sexes with enalapril treatment in SOLVD (and are assumed to occur with all angiotensin-converting-enzyme inhibitors), although the effect appeared greater among men¹²⁵. However, the effect of treatment in reducing the rate of myocardial infarction was greater among women. Despite these favorable effects, mortality from congestive heart failure remained high, since the reductions in mortality were small.

The number of women in the Survival and Ventricular Enlargement (SAVE) trial¹²⁶ was so small that it appears inappropriate to draw conclusions either from the similarity between women and men in rates of death and morbidity due to cardiovascular disease in the placebo group or from the difference between the sexes in the reduction in risk in the captopril-treated group. A substantially larger number of women than men who had had infarctions were ineligible for inclusion in the trial because of a lack of cardiac-catheterization data; the decision about whether the patients should undergo catheterization was made by the treating physician.

            Sudden Death from Cardiac Causes

The assumption that most sudden deaths from cardiac causes among women are due to coronary heart disease may not be valid. It is uncertain whether the results of studies of sudden death from cardiac causes among men can be extrapolated to women. Pending further studies, women successfully resuscitated from sudden cardiac death or sustained ventricular tachycardia should undergo standard electrophysiologic testing according to the same criteria used for men. Women survivors of cardiac arrest who are known to have coronary disease are less likely than men to have inducible ventricular tachycardia,¹²⁷ but those who do are more likely to have an effective drug identified; cardioverter-defibrillators also appear more effective in women,^128,129 because of the generally lower defibrillation thresholds of women.

Recommendations for Research

Research should focus on aspects of cardiovascular disease that are unique to women, or areas in which comparisons between women and men are unavailable or inadequate. When elderly people are underrepresented in research studies, women are disproportionately excluded¹³⁰. Women should be encouraged by their physicians to participate in research studies; adequate diversity in terms of age, race, ethnic group, culture, and socioeconomic status should be present in the groups of women studied². Prerandomization stratification according to sex has been recommended for large clinical trials to permit separate evaluation of the sexes. The infrequent inclusion of women in clinical research until very recently warrants scrutiny to clarify whether women have been excluded from participation for medical reasons (such as existing illnesses) and why they have not participated in research studies for which they do qualify. Few registries from large clinical trials are available for evaluation of the outcomes of women who did not participate in the randomized trial; such information would be useful in identifying the reasons for women's nonparticipation and clarifying whether those women fared differently from the participants.

Information from existing clinical trials and registries should be analyzed to compare the features of coronary heart disease in women and men with respect to base-line characteristics, clinical manifestations, responses to treatment, and clinical outcomes. Sex, estrogen status (menopausal status and estrogen intake),^131,132 and age should be related to the incidence of chest pain, silent ischemia, and variant angina, among other conditions. For example, the relations among body size, the relative dose of thrombolytic therapy, and the incidence of hemorrhagic complications among women could be reexamined in large data bases from thrombolytic trials. A number of interesting research questions can be suggested. It is evident, for instance, that men with "low-risk" angiographically identified coronary disease -- such as single-vessel disease -- and good ventricular function do well¹³³ and that men with single-vessel disease have more complete relief of angina and better exercise-test performance after coronary angioplasty than after medical therapy (despite higher costs and higher complication rates with angioplasty)¹³⁴; is the same true for women? Why is there a later onset of coronary heart disease in women than in men, as well as a later onset of other cardiovascular disorders such as aortic stenosis, hypertension, stroke, heart failure, and peripheral vascular disease? Can it be determined why women have a higher risk of death than men after myocardial infarction and myocardial revascularization procedures?

Specific drug therapy for pregnancy-induced hypertension should be explored, along with both maternal and fetal outcomes; predictors of preeclampsia, the efficacy and mechanism of action of low-dose aspirin therapy, and the causes of fetal death should be studied. The management of chronic hypertension in women with different categories of antihypertensive agents should be evaluated for efficacy and side effects, and possible interactions with cigarette smoking should be explored.

Optimal methods to promote healthy lifestyles throughout the life span require further research, which should target groups of women at high risk for coronary disease because of health-related behavior; an example would be strategies to prevent and stop smoking by young women, including those of relatively low socioeconomic status. Risk factors that require modification are known, but effective strategies are needed to initiate and maintain behavior resulting in risk reduction. Patterns of obesity and fat deposition and their relation to cardiovascular disease in women should be investigated, with attention to differences among ethnic and racial groups. More precise and convenient methods of measuring regional body fat are needed.

More research is needed on the relations between personality and behavioral features and cardiovascular disease in women. New approaches should be developed to the study of the quality of life as it relates to women's health. Because of the puzzling association of cardiovascular disease in women with panic disorder and depressive syndromes, further scrutiny of this relation is warranted. The difference between men and women in behavior in response to symptoms and in cardiovascular responses is another fruitful area for research.

Research should be directed toward understanding the basic mechanisms of action of reproductive hormones, both endogenous and exogenous. What are the mechanisms by which hormone-replacement therapy in postmenopausal women, with both estrogen alone and estrogen-progestin combinations, may alter the risk of coronary heart disease, as well as of breast cancer and uterine cancer? Does estrogen therapy delay or reverse the progression of other manifestations of atherosclerosis, including stroke and peripheral vascular disease, as it does for coronary heart disease? Is combined treatment with estrogen plus progestin as effective as unopposed estrogen in preventing coronary heart disease? The relation of estrogen status to other risk factors must be explored. Does hormone-replacement therapy have additional benefit beyond that of nonpharmacologic risk-reduction strategies, such as diet, weight control, and exercise? What is the effect of hormone-replacement therapy on the outcomes of medical therapy and strategies for myocardial revascularization, and what is the effect on women with heart failure?

For cardiovascular disease in general, and coronary heart disease in particular, why are there sex differences in access to care for invasive diagnostic and therapeutic procedures? Issues that warrant examination include patient-related factors (such as age, social circumstances, and patients' preferences), physician-related factors (including the interpretation of tests, physicians' preferences or prejudice, and the physicians' interpretation of the role of comorbid conditions as deterrents to invasive interventions), environmental factors (including social support), and factors related to insurance and reimbursement. What is the extent of difference between the sexes in the use of procedures and its effect on prognosis^135,136? Have sex differences in the outcomes of diagnostic and therapeutic procedures influenced physicians' patterns in referring women for such procedures? Data on such questions should permit the development of criteria to identify women who would benefit from diagnostic and therapeutic procedures, particularly if the use of such procedures is related to outcome measures that include not only overall survival but also event-free survival and the quality of life. Quality-of-life measures -- the ability to function at work, in the family, and socially; the level of emotional distress; sexual functioning; and physical morbidity -- must be incorporated into assessments of the efficacy of treatments^3,137,138. Research on women's quality of life should address the need for adaptation of existing assessment scales and the relevance of data on social class in the evaluation of the effectiveness of treatments and in understanding the factors that affect adherence to treatment regimens.

What behavioral and psychosocial characteristics predispose women to coronary disease and its sequelae? How do women and their physicians perceive and interpret cardiac symptoms? Do patterns of communication between women patients and their physicians have an effect? Do psychosocial constraints limit the use of timely and effective treatments in women? Techniques are needed to assess psychosocial factors and health behavior related to the cause, prevention, management, and outcome of cardiovascular disease in women.

General Considerations

New approaches are needed to bring high-quality clinical care to women who are at risk for cardiovascular disease or who have such disease already. In addition to incorporating information about the prevention and treatment of cardiovascular disease in women into the standard medical school curriculum, postgraduate training of physicians should also include information about sex-specific aspects of cardiovascular care. Educational programs about the cardiovascular health and disease of women are needed at professional meetings for physicians in family practice, internal medicine, gynecology and obstetrics, preventive medicine, and pediatric and adolescent medicine, among other fields. Also of value would be a registry of current observational and clinical cardiovascular studies, including those sponsored by the National Heart, Lung, and Blood Institute, that include women; sex-specific analyses might be encouraged and made easier by such a centralized effort. Finally, an increase in educational messages focusing on cardiovascular disease in women could promote the overall objective of enhancing the cardiovascular health of women in the United States.

We are indebted to Julia Wright and Jeanette Zahler for their assistance in the preparation of the manuscript.

Source Information

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta (N.K.W.); the Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland (L.S.); and the National Heart, Lung, and Blood Institute, Bethesda, Md. (B.P.). Based on the proceedings of the National Heart, Lung, and Blood Institute conference "Cardiovascular Health and Disease in Women: Health Promotion and Disease Prevention, Optimal Disease Recognition and Management," Bethesda, Md., January 22-24, 1992. The participants in the conference are listed in the Appendix.

Address reprint requests to Dr. Wenger at Emory University School of Medicine, 69 Butler St., SE, Atlanta, GA 30303.

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The participants in the National Heart, Lung, and Blood Institute conference "Cardiovascular Health and Disease in Women" were as follows: Conference Cochairs: N.K. Wenger, M.D., Emory University School of Medicine, and L. Speroff, M.D., Oregon Health Sciences University; Organizing Committee: S.J. Blumenthal, M.D., M.P.A., National Institute of Mental Health; T.L. Bush, Ph.D., Johns Hopkins University School of Hygiene and Public Health; C.K. Cassel, M.D., Pritzker School of Medicine, University of Chicago; K.M. Detre, M.D., Dr.P.H., University of Pittsburgh Graduate School of Public Health; J.E.G. Douglas, M.D., Case Western Reserve University School of Medicine; G.C. Friesinger, M.D., Vanderbilt Medical Center; N.F. Gant, M.D., University of Texas Southwestern Medical Center; B.J. Gersh, M.B., Ch.B., D.Phil., Mayo Medical School; S.B. Hulley, M.D., M.P.H., University of California, San Francisco, School of Medicine; A.M. Hutter, Jr., M.D., Harvard Medical School; J.C. LaRosa, M.D., George Washington University School of Medicine and Health Sciences; K.A. Matthews, Ph.D., University of Pittsburgh School of Medicine; B. Packard, M.D., Ph.D., National Heart, Lung, and Blood Institute; V.M. Parisi, M.D., M.P.H., University of Texas Medical School at Houston; L. Speroff, M.D., Oregon Health Sciences University; P.H. Stone, M.D., Harvard Medical School; and N.K. Wenger, M.D., Emory University School of Medicine.

Participants: W.B. Applegate, M.D., University of Tennessee College of Medicine; K.M. Bass, M.D., Francis Scott Key Medical Center; M.F. Bellantoni, M.D., Johns Hopkins University School of Medicine; T.J. Benedetti, M.D., University of Washington; L. Berkman, Ph.D., Yale University School of Medicine; W.P. Castelli, M.D., Framingham Heart Study; M.A. Chesney, Ph.D., University of California, San Francisco, School of Medicine; T.B. Clarkson, D.V.M., Bowman Gray School of Medicine; L.H. Cohn, M.D., Harvard Medical School; D.M. Cosgrove, M.D., Cleveland Clinic Foundation; D.B. Cotton, M.D., Wayne State University School of Medicine; S.M. Czajkowski, Ph.D., National Heart, Lung, and Blood Institute; R.W. DeSanctis, M.D., Harvard Medical School; J.E. Dimsdale, M.D., University of California, San Diego, School of Medicine; E. Eaker, Sc.D., American Heart Association; D. Echt, M.D., Vanderbilt University School of Medicine; W.H. Frishman, M.D., Albert Einstein College of Medicine; E.D. Frohlich, M.D., Alton Ochsner Medical Foundation; J.C. Gallagher, M.D., Creighton University School of Medicine; R. J. Gibbons, M.D., Mayo Medical School; D.G. Grady, M.D., University of California, San Francisco, School of Medicine; N.E. Grunberg, Ph.D., Uniformed Services University of the Health Sciences; T.B. Harris, M.D., National Institute on Aging; W.L. Haskell, Ph.D., Stanford University School of Medicine; W.R. Hazzard, M.D., Bowman Gray School of Medicine; N.R. Hertzer, M.D., Cleveland Clinic Foundation; M.W. Higgins, M.D., D.P.H., National Heart, Lung, and Blood Institute; M. Hollenberg, M.D., University of California, San Francisco, School of Medicine; N.S. Jecker, Ph.D., University of Washington; K.M. Kent, M.D., Washington Cardiology Center; T. Killip, M.D., Mount Sinai School of Medicine; R.H. Knopp, M.D., University of Washington; R.M. Krauss, M.D., University of California, Berkeley, School of Medicine; T.W. Lowe, M.D., Sunlife OB/GYN Services; R.R. Magness, Ph.D., University of Texas Southwestern Medical Center; D.B. Mark, M.D., Ph.D., Duke University Medical Center; D.E. Meier, M.D., Mount Sinai School of Medicine and City University of New York; V.T. Miller, M.D., George Washington University School of Medicine and Health Sciences; C.A. Neill, M.D., Johns Hopkins Hospital; J.K. Ockene, Ph.D., University of Massachusetts Medical School; V.A. Ravnikar, M.D., Harvard Medical School; J.M. Roberts, M.D., University of California, San Francisco, School of Medicine; L. Rosenberg, Sc.D., Boston University School of Medicine; S.A. Shumaker, Ph.D., Bowman Gray School of Medicine; M.J. Stampfer, M.D., Harvard Medical School; M.L. Stefanick, Ph.D., Stanford University School of Medicine; R.M. Steingart, M.D., State University of New York at Stonybrook; J.M. Sullivan, M.D., University of Tennessee, Memphis; C.B. Taylor, M.D., Stanford University School of Medicine; E.J. Topol, M.D., Cleveland Clinic Foundation; C.P. Weiner, M.D., University of Iowa Hospitals and Clinics; J.T. Willerson, M.D., University of Texas Medical School; R.R. Wing, Ph.D., University of Pittsburgh School of Medicine; P.D. Wood, Ph.D., Stanford University School of Medicine; and S. Yusuf, M.B., B.S., H.R.C.P., D.Phil., National Heart, Lung, and Blood Institute.

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