Heart Disease in Women

ABSTRACT: About 60,000 more women than men die each year as a result of coronary artery disease (CAD), yet many women are unaware they are at risk. In contrast to men, who are more prone to obstructive CAD, women are more likely to have microvascular coronary disease. Risk factors are the first consideration when selecting a screening test for a patient. Data from the National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation (WISE) study show that signs and symptoms of myocardial ischemia combined with abnormalities during stress testing predict a cohort of women at elevated risk for major adverse cardiac events. The first step in the prevention of CAD is to address any modifiable risk factors, including cigarette smoking, high cholesterol levels, glucose intolerance, obesity, and physical inactivity. For all women, an emphasis should be placed on healthy lifestyle habits. The risk of heart disease is reduced by 82% in women who do not smoke and who adhere to a healthy diet, such as the Mediterranean diet; consume light to moderate amounts of alcohol; maintain a body mass index of less than 25 kg/m2; and engage in at least 30 minutes of exercise daily.
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Coronary artery disease (CAD) continues to be the leading cause of mortality and morbidity in the United States. Awareness of CAD is particularly important in women because it remains a significant and yet underrecognized source of illness and death. Each year more women than men die of cardiovascular disease. Although the incidence of myocardial infarction (MI) has been decreasing, the rate of decline has been slower among women than among men. Currently, 8 million American women have heart disease, and 6 million of these women have a history of angina, MI, or both. The burden of heart disease on women will be alleviated only when we as health care providers are fully aware of the problem and actively seek to remedy the situation. In this article, we discuss the latest diagnostic and prevention strategies for CAD in women.

WOMEN’S AWARENESS OF HEART DISEASE RISK

The scope of the problem. Many women in the United States are not even aware of their risk of heart disease. An American Heart Association study showed that in 2003 only 46% of female respondents were aware that heart disease is the number one killer of women.¹ Although this percentage increased from 30% in 1997, a disconnect remains between the facts and women’s assessments of their own risks: only 13% of women believe that heart disease is their greatest health risk. Some specific sections of the population, especially women younger than 45 years, Hispanic women, and African American women, have been found to be even less aware of their risk of cardiovascular disease.

Even when women are aware of their risks, they often have symptoms that they may not necessarily associate with CAD. Two-thirds of women knew that chest pain was a symptom of heart disease, but fewer than 10% knew that shortness of breath, indigestion, and nausea could be related to heart disease.² In fact, chest pain is the presenting symptom of MI in fewer than half of women; instead, shortness of breath, nausea, indigestion, fatigue, and shoulder pain are presenting symptoms in about half of all infarctions in women.³ Even when women report cardiac symptoms, which they do more often than men, they are less likely than men to be assessed and to undergo a workup for CAD.⁴ For all these reasons, mortality after an acute MI is higher for women than for men, even after adjustment for risk factors.⁵ About 60,000 more women than men die each year as a result of CAD. Women under the age of 65 are disproportionately affected; they have the highest relative sex-specific heart disease mortality.

Cost efficacy of screening and prevention. So what can we do to decrease CAD-related morbidity and mortality in women? Heart disease is the most costly but most preventable disease in women, yet less money is spent on evaluation and prevention compared with many other conditions, such as osteoporosis, breast cancer, and gynecological cancers. In one study that compared the cost efficacy, defined as a cost of $50,000 or less for year of life saved, of lowering cholesterol levels with statins in women with and those without heart disease with the cost efficacy of mammography, mammography had a cost of $150,000 for year of life saved in women 40 to 49 years of age and a cost of $21,400 for year of life saved in women 50 to 69 years of age.⁶ The use of statins to lower cholesterol, on the other hand, was found to cost $50,000 for year of life saved in women without heart disease and $8400 for year of life saved in women with heart disease.

TESTING FOR CAD IN WOMEN

Options for testing. The cost effectiveness of testing for CAD varies depending on which test is selected, and the choice of test should be considered on a case-by-case basis. Risk factors are the first consideration when selecting a test for a patient. Key risk factors in women that differ from those in men are:

• Diabetes.
• Smoking.
• A high-density lipoprotein cholesterol level of less than 47 mg/dL. 
• A triglyceride level of greater than 125 mg/dL. 
•  Premature menopause at an age younger than 45 years.

Options for testing include stress electrocardiography, stress echocardiography, stress nuclear tests (perfusion imaging), coronary angiography, and cardiac calcium CT scanning. Components of exercise stress electrocardiography and noninvasive stress testing are useful for risk stratification and to guide therapeutic strategies.⁷ Data from the National Heart, Lung, and Blood Institute– sponsored Women’s Ischemia Syndrome Evaluation (WISE) study have demonstrated that persistent signs and symptoms of myocardial ischemia combined with abnormalities during stress testing predict a cohort of women at elevated risk for major adverse cardiac events.²

However, in many women with exertional angina who have abnormal perfusion study results, coronary angiography does not show obstructive CAD.⁸ These women previously received a diagnosis of cardiac syndrome X, which is now thought to result from a disordered function of the smaller coronary vessels. Further specialized testing of these women often shows abnormal coronary flow reserve and elevated left ventricular diastolic pressure. In addition, intravascular ultrasonography often reveals diffuse atherosclerosis that does not obstruct the vascular lumen. Women more frequently present with this microvascular coronary disease, whereas men are more prone to obstructive CAD.⁹ The goals of treatment of microvascular coronary disease are similar to those of obstructive CAD. Patients require aggressive risk factor management with aspirin, b-blockers, statins, angiotensin-converting enzyme inhibitors, tricyclic antidepressants, and exercise as needed. The antianginal drug ranolazine is also effective for symptomatic relief.

Newer imaging studies. Possible alternative methods of evaluating CAD are currently being investigated. Cardiac CT for calcium scoring is one of these new technologies. This procedure is noninvasive, and results are easily interpreted; scores over 100 predict a 1% per year chance of heart disease, and scores over 400 predict a 2% per year chance. However, no cost-benefit data are currently available to determine whether using this test for screening will result in fewer adverse outcomes, thus outweighing the risk from radiation exposure. Even CT angiography, a related and more frequently used test, does not yet have outcome data, and radiation deaths are expected to outnumber the cases of CAD detected. Carotid intima-media thickness (IMT), an ultrasound measurement of the thickness of the artery walls that is used to detect atherosclerotic disease, is a promising technique forevaluation of cardiovascular disease. Carotid IMT works well in women, avoids radiation exposure, and is useful not only for delineating atherosclerosis but for tracking any progression as well.¹⁰ Cardiac MRI is another promising modality.

PREVENTION OF HEART DISEASE IN WOMEN
Modifiable risk factors. The first step is to address any modifiable risk factors. These include cigarette smoking, high cholesterol levels, glucose intolerance, obesity, and physical inactivity. Some studies have shown a rise in coronary heart disease mortality among women aged 35 to 44 years despite an increase in the use of thrombolysis, percutaneous coronary intervention, statins, and antithrombotics.¹¹ This rise in mortality is thought to result from adverse trends in nutrition, smoking, physical activity, and obesity. Teaching women about the appropriate management of these risk factors can help prevent, modify, or halt disease progression.

Smoking. Cigarette smoking is a leading preventable cause of cardiovascular morbidity and mortality. Despite the widespread dissemination of knowledge about the risks of cigarettes, young adults in the current generation are more likely to start smoking than their parents were. They often start while they are away at college. Many young women begin smoking as a weight management strategy, and they are reluctant to quit because they fear weight gain. Sudden cardiac death rates have climbed 38%, which parallels this increase in the prevalence of smoking.¹¹

A newer potential smoking cessation medication is varenicline. This drug is a nicotine acetylcholine receptor that can alleviate nicotine cravings and withdrawal symptoms as well as reduce the nicotine reinforcement associated with smoking. Among long-term smokers, treatment with varenicline was associated with a higher rate of smoking cessation than treatment with bupropion or placebo with nicotine replacement in the form of patches or gum. Both varenicline and bupropion carry a black box warning because of the risk of behavioral changes, depression, and suicidal thoughts and behaviors; appropriate prescribing and monitoring are important.

Dyslipidemia. Another modifiable risk factor is dyslipidemia. The results of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials show that aggressive lipid lowering to a low-density lipoprotein cholesterol level of less than 70 mg/dL results in significantly greater atherosclerosis reduction and fewer cardiovascular events in women who are at high cardiovascular risk.¹² Currently, statins are usually recommended for any patient with elevated cholesterol levels; however, one study demonstrated that women are less likely than men to receive statin therapy.¹³ The Framingham Heart Study found yet another sex difference in cardiovascular disease: elevated triglyceride levels appear to be a risk factor for CAD in women but not in men.¹⁴

Diabetes mellitus. This is also a highly significant risk factor; it confers the same risk equivalent as known CAD. Lifestyle changes, including diet and exercise, can markedly reduce glucose intolerance and modify the disease process. Only 30 minutes of walking daily, resulting in a 7- to 10-lb weight loss, was found to substantially decrease the incidence of type 2 diabetes mellitus.¹⁵

Lifestyle modification. For all women, an emphasis should be placed on healthy lifestyle habits (Table). Meals should incorporate high levels of fiber, marine omega-3 fatty acids, and folate; low levels of saturated and trans fats; and low glycemic content. Women should not smoke, although 1 drink a day is encouraged if there are no restrictions to alcohol. Body mass index should be maintained under 25 kg/m²; a woman should not weigh more than 20% over her ideal body weight. Women should also engage in at least 30 minutes of exercise daily.

Women who maintain all 5 of these healthy habits have an 82% lower risk of heart disease; unfortunately, fewer than 10% of women actually do so.¹⁶ In one study, mortality was 50% lower among 50- to 70-year old women who maintained all of these lifestyle habits.¹⁷ An excellent way for women to eat more healthfully is to follow the Mediterranean diet. This diet includes large amounts of plant-based foods, a moderate to high amount of fish, and only sparing amounts of meat. It also emphasizes olive oil as the principal source of fat; “healthy fats” make up about 25% to 35% of total daily calories. The diet includes moderate alcohol consumption— about 1 glass of wine daily for women.

Multiple studies have shown that the incidence of coronary heart disease is decreased among persons who consume a Mediterranean-style diet, even though they eat a higher amount of fats.¹⁷

Omega-3 fatty acid supplements. Although a diet high in marine omega-3 fatty acids is recommended for the prevention of cardiovascular disease, most persons in the United States do not consume the recommended amount. Studies such as Diet and Reinfarction Trial (DART) and Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico (GISSI) Prevenzione trial found a 17% to 33% reduction in mortality from coronary heart disease with the daily supplementation of 1 to 2 g of fish oil.¹⁸ Currently, only 1 FDA-approved prescription omega-3 fatty acid supplement (Lovaza) is available. It contains about 900 mg of omega-3 fatty acids and is more potent than over the counter formulations. Patients with heart disease are encouraged to take 1 g daily, while patients with triglyceride levels over 400 mg/dL should take 2 to 4 g daily. Persons of any age who are at low risk for CAD should not use these supplements because the long-term safety data are unknown and adverse effects (typically dyspepsia) occur in about 25% of those who take them. Data are still insufficient to support the daily use of fish oil supplements in patients at intermediate or high risk for cardiovascular disease.

Hormone replacement therapy. From a cardiologist’s standpoint, hormone replacement therapy (HRT) in the perimenopausal and early menopausal stages may or may not be beneficial; studies are still ongoing to answer this question. HRT in women older than 60, on the other hand, has not been shown to have an overall heart health benefit.¹⁹ If a patient has vasomotor symptoms and is at relatively low cardiovascular risk, HRT is certainly appropriate. The lowest dose possible should be used for the shortest amount of time needed. Topical and “natural” HRT products are not necessarily any safer than prescription formulations. Although there are some benefits, HRT cannot be used as a “fountain of youth” and the risks must be carefully considered.

Aspirin. Aspirin also has a role in preventing cardiovascular events in women. The Women’s Health Study found low-dose aspirin to be effective in reducing stroke rates in all women and reducing MI rates in women older than 65.²⁰ According to current guidelines, aspirin should be prescribed for all high-risk women with coronary heart disease or diabetes mellitus as well as for women aged 50 and older for ischemic stroke prevention and women aged 65 and older for MI prevention when the benefits outweigh the risks of hemorrhagic stroke and GI bleeding. If a woman at high risk cannot take aspirin, clopidogrel should be prescribed.²¹ If a woman of any age is at risk for MI, the risks and benefits of aspirin should be discussed with her. Aspirin should not be given for prevention of cardiovascular events to women who are at low risk for MI.

General guidelines for prevention. Given all of this information, what can be done to help women who are at risk for CAD? The first step is to acknowledge that women can and do have heart disease. As health care providers, it is important for us to be able to determine which women in our practice are at intermediate and high risk and refer them for testing. It is also important to be aware of the differences in symptoms of cardiac disease between men and women. Patients should be encouraged to contact either their health care provider or their closest medical center immediately when and if they have these symptoms. Once it is determined that a woman is at risk for heart disease and is having symptoms, it is cost-effective to evaluate for CAD and treat with lifestyle changes and medications that prevent or reverse the disease.