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SCREENING SERIES

Cardiovascular Disease in Women: Prevention and Screening

Justine Wu, MD; Jeffrey P. Levine, MD, MPH


Cardiovascular disease (CVD) is the leading cause of mortality in US women.1 Indeed, more than half a million female lives per year are lost to CVD—more than the next seven causes of death combined (Figure 1).1 A woman's lifetime risk for CVD (one in three)2 is almost three times greater than her lifetime risk for breast cancer (one in eight).3 Yet, despite these staggering figures, women continue to underestimate their risk of developing CVD. A 2003 study conducted by the American Heart Association (AHA) of 1,024 US women revealed that only 13% of women identified heart disease and stroke as their greatest health concern,4 although this reflects an improvement in awareness from an earlier study.5 The level of awareness was lowest for black and Hispanic women—ie, the groups at highest risk for cardiac disease. In these surveys, women consistently identify cancer, specifically breast cancer, as their greatest cause for worry.6,7 Increased media attention, identification of breast cancer as a "female" problem,5 and the threatening nature of cancer as a disease7 have also been suggested as factors contributing to the overestimation of breast cancer risk by women.

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 Figure 1. Leading Causes of Death for All Men and Women United States: 20011


HISTORICAL CONSIDERATIONS

While patient factors may be barriers to optimal preventive cardiac care, traditional physician biases about women and CVD must also be addressed. Historically, women have largely been excluded from major cardiovascular research trials on prevention, diagnosis, and treatment. The dearth of data on women with respect to CVD is alarming, considering that women have a worse prognosis and higher morbidity after cardiovascular events than men. This includes a higher rate of death after myocardial infarction (MI),8-10 particularly in younger women even after adjustment for prognostic factors.11 To explore why women have poorer outcomes than men after cardiac events, consideration must be given to multiple variables. To start, women have been shown to delay seeking care for ischemic symptoms, particularly those at highest risk such as the elderly.12 When women do present for care, they are more likely than men to experience non-chest-pain symptoms such as nausea, vomiting, dyspepsia or jaw pain. Atypical presentations may contribute to a lack of recognition of early cardiac symptoms by both patients and physicians.13,14 There is also evidence that women are referred less often than men for cardiac catheterization or bypass surgery, even after controlling for risk factors.15-17 In contrast, other studies have failed to identify an independent gender bias in referral patterns for interventional procedures.18,19 When women do undergo bypass surgery or percutaneous coronary intervention, they have greater rates of complications and operative mortality compared with their male counterparts, although it has been suggested that factors such as older age and more severe disease may be responsible for these differences.18,19

Although the exact causes are unclear, women undoubtedly have a worse prognosis, greater prevalence of comorbid disease and disability, and increased mortality after cardiovascular events than men. The population of older adults is growing rapidly in the United States, and the percentage of elderly women at highest risk for CVD will also increase—underscoring the need for physicians to detect, prevent, and treat CVD early in women.


PREVENTION AND SCREENING

At every preventive health visit, women should receive age-appropriate screening for CVD and targeted risk-factor counseling. This article reviews primary preventive strategies and screening for CVD in otherwise healthy, asymptomatic women, and highlights special considerations for women. Screening recommendations of the US Preventive Services Task Force (USPSTF) and other relevant organizations are presented for each major risk factor, along with a brief discussion of cardiac screening tests and the role of novel biochemical markers. For any of the following recommended life-style modifications, health care providers should assess patient readiness for change, individualize a plan of behavioral and (if necessary) pharmacologic intervention, and schedule follow-up visits to address maintenance and relapses.

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MAJOR RISK FACTORS

Tobacco Use

Cigarette smoking is the leading preventable cause of CVD. The risk of CVD is two to six times higher in women who are heavy smokers than in women who do not smoke.20 National statistics from the American Lung Association reveal that smoking is no longer predominately a male habit. Over the past 25 years, the gap between the percentage of male and female smokers has narrowed, reflecting a larger decline in male smokers than female smokers.21 The benefits of smoking cessation have been documented in women, such that the risk of CVD declines to that of a nonsmoker within 3 to 5 years after quitting.22 The USPSTF strongly recommends that clinicians routinely screen all adults for tobacco use and provide smoking cessation intervention as needed,23 as evidence supports that physician discussion alone can modestly improve smoking cessation rates.24 Special considerations in counseling female smokers include dispelling myths that "light" cigarette brands do not increase one's risk of heart disease, and that smoking cessation cannot be accomplished without weight gain. A smoking cessation plan should include a quit date, behavioral strategies, and (if necessary) selection of a nicotine replacement system and referral to support groups (see Resources).24

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Resources

Obesity

There is a direct positive association between obesity, particularly central obesity, and the risk of coronary heart disease (CHD) in women.25 Rates of overweight and obesity have reached epidemic proportions. Among women 20 years of age and older, 57.3% of whites, 71.9% of Mexican-Americans, and 77.3% of blacks are either overweight or obese.26 Because body mass index (BMI) and central obesity are direct predictors of CVD risk and other comorbid complications, the USPSTF and the National Heart, Lung and Blood Institute (NHLBI) recommend that all adult patients be assessed for BMI and/or waist circumference (Table 1).23,27 The USPSTF also acknowledges that there is good evidence to support intensive counseling and behavioral interventions in those patients identified as obese. Though it is less clear whether such interventions are effective in patients who are overweight but not obese, it seems reasonable to discuss weight loss strategies in these patients as well. Successful weight loss is a complex process requiring life-style changes, diet modification, and psychological adjustments. Pharmacotherapy with medications such as orlistat or sibutramine can produce modest weight loss, but the long-term effects are unknown. Surgery should be reserved for those patients at highest risk (BMI of more than 40, or BMI of more than 35 to 40 with at least one obesity-related comorbidity), for whom traditional therapies have failed.23

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Table 1. Classification of BMI and Waist Circumference


Physical Activity

Lack of physical activity is an independent risk factor for CVD in women. Women who are physically active have a risk of CHD that is 60% to 75% lower than inactive women.28 Almost 36% of women report no regular physical activity, with higher rates of sedentary life-style among blacks and Hispanics.26 While the USPSTF could not find sufficient evidence to determine whether counseling patients in primary care settings actually promotes sustained increases in physical activity,23 it is prudent to encourage engaging in routine physical activity in those patients who can safely do so. A simple, step-wise approach to introducing physical activity into daily life should be explored, with an optimal goal of 30 minutes of moderate-intensity activity on most or all days of the week.29

Hypertension

Hypertension is a well-documented risk factor for CVD in women. A large, prospective, cohort study that included more than 11,000 women revealed that combined systolic-diastolic, as well as isolated systolic, blood pressure is an important predictor of death from CVD and stroke.30 With each 20-mm Hg increase in systolic blood pressure (SBP) and 10-mm Hg increase in diastolic blood pressure (DBP), the risk of developing CVD doubles, starting at a blood pressure of 115/75 mm Hg.31 By the age of 75 years, 84.1% of women will have high blood pressure.26 The USPSTF recommends that all adults aged 18 years and older be screened for high blood pressure.23 Changes to the classification system for hypertension set forth in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) should be noted (Table 2). A new category of "prehypertension" has been designated for an SBP of 120 to 139 mm Hg and/or a DBP of 80 to 89 mm Hg, highlighting the increased risk for progression to hypertension in these individuals. All patients identified with high blood pressure should be advised of life-style modifications, including weight reduction, adapting a Dietary Approaches to Stopping Hypertension (DASH) eating plan,31 regular aerobic physical activity. and moderate alcohol consumption. Use of antihypertensive therapy has been associated with reductions in stroke incidence, MI, and heart failure in women.32 Treatment of hypertension should include a goal blood pressure of less than 140/90 mm Hg, or less than 130/80 mm Hg in patients with diabetes or renal disease.31

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Table 2. Classification of Blood Pressure


Hyperlipidemia

High cholesterol, specifically an elevated level of low-density lipoprotein cholesterol (LDL-C), is associated with an increased risk of CHD in women. Low levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride (TG) values appear to be a more significant risk factor in women than in men.33 Menopause has an adverse impact on lipoprotein levels, with higher total cholesterol (TC), LDL-C, and TG levels, as well as lower HDL-C values. Among women aged 20 years and older, 53.6% of white women have a TC level over 200 mg/dL, and 43.7% have a LDL-C level over 130 mg/dL.26 Primary prevention trials that have included women indicate that the treatment of hyperlipidemia appears to be as effective for women as for men, including those without a history of CVD and average cholesterol levels.34 The Heart Protection Study35 evaluated the effects of statin therapy on mortality in high-risk women with and without CVD, and reported a 27% reduction in the incidence of nonfatal MI or coronary death.

The USPSTF recommends screening for lipid disorders in asymptomatic, middle-aged persons (starting at 45 years of age for women), and screening only those younger patients (20 to 45 years of age in women) with known risk factors such as hypertension or family history of early coronary disease.23 Guidelines from the Third National Cholesterol Education Program/Adult Treatment Panel (NCEP-ATP III) recommend screening asymptomatic individuals at an earlier age, such that adults aged 20 years and over be screened at least once every 5 years with a fasting lipoprotein profile.33 If screening reveals elevated lipid levels, the decision to treat should then be guided by the patient's risk factors (Table 3). Women with two or more risk factors should be further stratified into those with a 10-year risk of CHD of less than 10% (low risk), 10% to 20% (intermediate risk), or greater than 20% (high risk or CHD equivalent), using the Framingham risk scores (Table 4). The LDL-C cutoff values for when to consider life-style changes and drug therapy are shown in Table 5. Statins are considered the first-line treatment for hyperlipidemia in women in the majority of cases.33

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Table 3. Major Risk Factors (Exculsive of LDL Cholesterol) That Modify LDL Goals*

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Table 4. Estimate of 10-year Risk for Women (Framingham Point Scores)

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Table 5. LDL Cholesterol Goals and Cutpoints for Therapeutic Life-style Changes (TLC) and Drug Therapy in Different Risk Categories.


Diabetes

Patients with type 2 diabetes are considered to have the same risk of developing cardiovascular complications as patients without diabetes who have had a previous MI.36 Diabetes is a stronger risk factor for CVD and stroke in women than in men. Screening recommendations vary due to the lack of data from prospective studies on the benefits of screening. The USPSTF states that there is insufficient evidence to routinely screen asymptomatic adults, and recommends targeted screening for those with hypertension and hyperlipidemia.23 The American Diabetes Association (ADA) recommends screening all patients aged 45 years or older at 3-year intervals, particularly those with a BMI of 25 kg/m2 or greater.37 Fasting plasma glucose (FPG) is the recommended screening test. The diagnosis of diabetes is based on an FPG of 126 mg/dL or greater, with a repeat test for confirmation on a separate day. The ADA criteria for diabetes have become more stringent, such that the FPG must be below 100 mg/dL to be considered "normal," while an FPG between 100 and 125 mg/dL is designated as "impaired fasting glucose" (IFG). Patients who fall into the category of IFG are recognized as "prediabetic," indicating individuals who are at higher risk for developing diabetes as well as CVD.37 Treatment of diabetes has been proved to decrease the risk of microvascular complications, but tight glycemic control has not been shown to have any impact on macrovascular events or cardiac complications to date.37

Metabolic Syndrome

The combination of insulin resistance with risk factors for CVD has been identified as syndrome X, or metabolic syndrome. The diagnosis of metabolic syndrome requires the presence of at least three of the following risk factors: abdominal obesity (Table 1); TG levels over 150 mg/dL; HDL-C of less than 50 mg/dl in women; blood pressure over 130/85 mm Hg; and an FPG of more than 110 mg/dL.33 There is a strong association between metabolic syndrome and its constituent risk factors with the development of CVD, although the majority of large studies have been confined to men, and studies that do include women yield conflicting data.38 Nevertheless, the prevalence of metabolic syndrome in US women has risen to a staggering 23.4%, similar to the rate in men at 24%.39 Intervention for metabolic syndrome should emphasize weight reduction and increased physical activity, along with concomitant modification of nonlipid and lipid disorders.

Depression

Depression is a prospective risk factor for the development of CVD and cardiac mortality for women.40,41 Women have higher rates of depression than men of the same age group. Whether treating depression has an impact on cardiac outcomes remains to be proved. In a recent large randomized controlled trial (RCT), treating post-MI patients for depression with antidepressants and cognitive behavioral therapy had no impact on mortality or reinfarction.42 Nonetheless, adult patients should be screened and treated for depression during routine visits, given its significant impact on disability and quality of life.33 Screening for depression should occur ideally in clinic practice settings that have the ability to provide accurate diagnosis, effective treatment, and follow-up.23

Other Preventive Measures

The role of aspirin in the primary prevention of CVD is controversial. Major studies on primary prevention have been confined to men.43 The Women's Health Study, a large-scale RCT, is currently investigating the effect of aspirin as primary prevention in apparently healthy women. The USPSTF recommends that clinicians discuss aspirin therapy for patients with risk factors (postmenopausal women, younger women with cardiac risk factors) for primary prevention of CVD, with consideration given to the individual risk factors and potential harms, including gastrointestinal and intracranial bleeding.23

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ADDITIONAL SCREENING

Electrocardiography/ Exercise Stress Testing

The USPSTF states there is insufficient evidence to support the routine use of electrocardiography (ECG) or exercise stress testing for primary cardiac screening in otherwise low-risk, asymptomatic patients. Data are lacking on improved outcomes, and there is the potential harm of false-positive results (ie, unnecessary invasive testing).23

Coronary Calcium

Coronary artery calcification is associated with the pathologic process of atherosclerosis, and has been proposed as a surrogate maker for the development of CVD. There has been recent interest in the use of electron-beam computed tomography (EBCT) as a screening tool to detect subclinical CVD in asymptomatic individuals, as well as obstructive coronary artery disease in symptomatic patients. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines currently do not recommend EBCT for diagnosing obstructive coronary disease because of its low specificity. In addition, for otherwise asymptomatic patients, the use of EBCT has not proved to have an added predictive benefit over the use of conventional risk-factor assessment.44 Finally, the importance of coronary calcium must be further examined with respect to its role in CVD in women, as the prevalence of calcification in women is half that of men until age 60 years. The ACC/AHA44 and USPSTF23 have concluded that there is insufficient data to support recommending EBCT to asymptomatic patients as a primary cardiac screening test.


SPECIAL CONSIDERATIONS FOR WOMEN

Hormone Replacement

The hormone replacement therapy (HT) arm of the Women's Health Initiative (WHI) study was the first large study designed to investigate the role of HT in the primary prevention of cardiovascular disease.45 The HT arm was terminated prematurely due to the finding that the overall health risks (observed increases in CVD, venous thromboembolism [VTE], and breast cancer) outweigh its benefits (observed decreases in osteoporotic fractures and colon cancer). Specifically, there were seven more cardiovascular events per 10,000 women over 1 year.45 While the absolute risk is small, the risk may be more significant over a period of years. The estrogen replacement therapy (ET) arm of the WHI, which examined the effect of estrogen only on postmenopausal women with prior hysterectomy, was also terminated prematurely. The primary findings of this arm included an increased risk of stroke, decreased risk of fracture, a possible reduction in breast cancer, and no effect on the incidence of CVD.46 While there are certain limitations to the WHI trial, its findings nevertheless emphasize the fact that estrogen or estrogen with progestin products should not be used for primary prevention of heart disease. The only indications approved by the US Food and Drug Administration (FDA) at this time for HT/ET products include treatment of vasomotor symptoms and/or vulvar and vaginal atrophy, and prevention of postmenopausal osteoporosis. Ultimately, the decision to use HT/ET in postmenopausal women must be based on discussions with patients that appropriately balance benefits and potential risks.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common condition occurring in 4% to 7% of reproductive-aged women, characterized by hyperandrogenism and chronic anovulation. The etiology of PCOS is likely related to insulin resistance. Patients with PCOS have an increased risk of hypertension, impaired glucose tolerance, and hyperlipidemia. Hence, it is not surprising that women with PCOS are at higher risk for CVD, given the higher prevalence of risk factors.47 The condition is further compounded by obesity, which is a common finding in patients with PCOS. Patients diagnosed with PCOS should be screened and treated for hypertension, lipid disorders, and glucose intolerance. Weight loss should be emphasized, as this intervention alone can decrease insulin resistance and often restore normal ovulatory function.

Combined Oral Contraceptive Pills

Although women who use combined oral contraceptive pills (COCs) have some increased risk of MI, it is estimated that 80% of these cases can be attributed to smoking, and the remaining cases occur in patients with other cardiac risk factors.48 Therefore, the use of COCs in female smokers over the age of 35 years is not recommended. However, women older than 35 years of age who do not smoke may still be suitable candidates for COCs, as there is no evidence to support an increased risk of MI in nonsmokers with no history of diabetes or hypertension.


FUTURE SCREENING TESTS

Atherogenic Lipoprotein

Atherogenic lipoprotein [Lp(a)] structurally resembles LDL-C, and has associated apoproteins that may have thrombotic properties. There is epidemiologic evidence to suggest that elevated Lp(a) levels may be an independent risk factor for atherogenic events. This association has been demonstrated in both premenopausal and postmenopausal women.49 While estrogen use in postmenopausal women has been associated with lowered Lp(a) levels in clinical trials, routine use of estrogen for treatment of elevated Lp(a) levels is not recommended.50 To date, no clinical trials have shown improvement in cardiovascular outcomes as a result of lowering Lp(a) levels or support the use of Lp(a) for primary screening in the general population.51

Homocysteine

Epidemiologic studies show that elevated levels of homocysteine are associated with the development of CVD independent of other known risk factors.52 Homocysteine levels have been shown to be lower in women than men, and lower in premenopausal than postmenopausal women.53 Supplementation with vitamin B6, vitamin B12, and folic acid has been shown in studies to lower homocysteine levels, but has yet to be proven effective in preventing cardiovascular events. The routine measurement of homocysteine levels and/or vitamin supplementation is not recommended at this time for primary screening or prevention of CVD in low-risk women.29

C-Reactive Protein

Several markers of inflammation have been studied as potential predictors of coronary events, given evidence that atherosclerosis is a chronic inflammatory process. In a study of more than 28,000 postmenopausal women, high-sensitivity C-reactive protein (hs-CRP) appeared to be the strongest predictor of CVD risk of the biochemical markers studied.54 Statin therapy has been shown to reduce the levels of hs-CRP. Whether statin therapy can have an impact on cardiac morbidity and mortality in patients with elevated hs-CRP levels and low levels of LDL-C is currently under study in the JUPITER Trial.55 There is currently no evidence to support routine measurement of hs-CRP levels in otherwise low-risk patients.56

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CONCLUSION

Major public health campaigns (eg, "Go Red for Women" by the AHA) have been launched to disseminate information about heart disease in women to the general public. Health care providers can complement these programs by integrating screening and prevention strategies into their daily routines. For busy clinical practices, a practical flowsheet such as the "Heart Healthy" Checklist (Figure 2) may help to remind staff and physicians to provide ongoing risk-factor assessment and management.

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 Figure 2. "Heart Healthy" Screening and Prevention Checklist

Patients identified as having cardiac risk factors should be counseled and treated early. Aspirin may be considered in at-risk patients after a discussion of the benefits and risks, but HT/ET should not be used for the primary prevention of CVD in women. There is insufficient evidence to support the use of ECG, exercise stress tests, or EBCT for primary cardiac screening in otherwise low-risk, asymptomatic patients. The routine measurement of Lp(a), hs-CRP, or homocysteine, or supplementation with folic acid, is not recommended at this time.


Acknowledgement

The authors wish to acknowledge William E. Chavey II, MD, MS, for his time and assistance in the preparation of this manuscript.

Justine Wu, MD, is Women's Health Fellow, Department of Family Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick. Dr Wu is now a Reproductive Health and Family Planning Fellow, University of Rochester, NY. Jeffrey P. Levine, MD, MPH, is assistant professor, Departments of Family Medicine and Obstetrics, Gynecology, and Reproductive Sciences; and director, Women's Health Fellowship Program, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick.

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