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Coronary Artery Disease: What's Different for Women?
by Arline Kaplan
Geriatric Times March/April 2004 Vol. V Issue 2
Although heart disease afflicts one in four women age 65 and older and one in 12 age 45 to 64, "coronary disease in women has gone relatively unrecognized," warned physician educator Ken Grauer, M.D.
Several surveys have documented the need for increased awareness of coronary disease in women. For example, in a 1995 Gallup Survey of 300 primary care physicians, one out of three respondents did not know that coronary artery disease (CAD) is the leading cause of death in women. In a recent random sample survey conducted by the American Heart Association (AHA), only 46% of the 1,024 female respondents were aware that heart disease is the leading cause of death among women, and only 38% said their physicians had ever discussed heart disease with them (Mosca et al., 2004b).
Part of the problem lies in a misperception that coronary disease is not a woman's disease, Grauer told attendees on Oct. 2, 2003, at the American Academy of Family Physicians (AAFP) conference in New Orleans. While the fallacy is being corrected, it is still believed by many health care providers and their patients.
"This misperception potentially undermines all facets of management, including the workup of chest pain in women, diagnostic testing and treatment recommendations," said Grauer, who is professor in the department of community health and family medicine and assistant director of the Family Practice Residency Program at the University of Florida, Gainesville.
The mistaken belief came about, Grauer said, because up until age 85, more men die from CAD than women. Women as a group develop heart disease 10 to 20 years later than men, and after undergoing cardiac catheterization, fewer women are found to have heart disease.
Of patients presenting with typical angina who undergo cardiac catheterization, 80% of men, but only 60% of women, are found to have coronary disease. Among patients with atypical angina who undergo cardiac catheterization, 70% of men but less than 40% of women will have CAD.
A point not to miss, Grauer said, is that while fewer women than men are found to have heart disease when catheterized, that does not mean women do not have heart disease.
Differences in Symptoms
In a 1995 Gallup Survey, 88% of the 300 physicians surveyed thought that the signs and symptoms of heart disease were the same for women and men (American Medical Women's Association, undated). Yet Grauer delineated several differences. While both men and women often present with chest pain, women are more likely than men to have chest pain at rest and at night, as well as other non-coronary syndromes that produce chest pain. In addition, women with coronary disease are more likely to be five to 10 years older at the time of presentation.
Grauer noted that data from the Framingham Heart Study revealed that for women, the initial manifestation of CAD is usually stable angina (47% in women compared to 26% in men) (for more information on Framingham, please visit <www.framingham.com/heart/>). Conversely, men are more likely to present with myocardial infarction (MI) (43% compared to 29% in women). As a first manifestation of coronary disease, sudden death is more likely to occur in men than in women (10% compared to 7% in women). With regard to unstable angina, there is no significant difference in terms of frequency of presentation.
Comorbidities in women with angina tend to be quite different from those in men, Grauer explained. Women with chest pain from angina have a much more significant incidence of underlying diabetes, hypertension and heart failure than do men.
In women who do present with an acute MI, the symptoms are likely to be different from those of men. Women are more likely to have symptoms such as nausea, instead of chest, jaw, back or neck pain, and palpitations. Also, mortality after acute MI is higher in women than in men, even after adjustments for comorbidity, age or previous angina (Marrugat et al., 1998).
There is no large difference in mortality between men and women if they are age 70 or older, Grauer said. But if you look at women age 60 and younger, there is a significantly greater mortality rate from the first MI, and this is especially true if the woman with acute MI is under age 50 (Vaccarino et al., 1999).
In general, women with acute MIs have more serious presentations and more complications. They have more heart blockage and are less likely to undergo cardiac catheterization or receive thrombolytic therapy than men.
Why the Difference?
Gender differences exist in cardiovascular structure and function, according to Grauer. Women develop more left ventricular hypertrophy with age and in response to hypertension, aortic stenosis and obesity. On average, women have vessels 10% smaller than men's. Until age 50 or menopause, women tend to have somewhat better endothelial function and less aortic stiffness than men. It is uncertain how many of these differences are related to estrogen versus other factors, such as smoking, lipids, exercise and obesity, Grauer added.
A significant difference between the genders also exists in myocardial activation of Akt, a protein kinase that regulates a broad range of physiological responses including metabolism, gene transcription and cell survival. Camper-Kirby et al. (2001) found that young women possess higher levels of nuclear-localized phospho-Akt(473) relative to comparably aged men and postmenopausal women.
Grauer went on to point out gender differences in plaques (more cellular and fibrous components in women) and in hemostatic effects (higher fibrinogen and Factor VII levels in women).
Risk Factors
While the risk factors for coronary disease--obesity, reduced activity, smoking, hypertension, diabetes and adverse lipid profile--are virtually the same in men and women, Grauer noted that the impact of these risk factors is different for women than for men.
"The cards are stacked against women. For example, if you looked at what happens with obesity, beginning at puberty, absolute and relative body fat levels increase more in girls than in boys," Grauer continued.
The increasing prevalence of obesity (body mass index [BMI] ≥30 kg/m2) was described by Grauer as scary.
The annual prevalence of obesity among U.S. adults age 20 and older has increased from 19.4% in 1997 to 23.9% in 2002 (Centers for Disease Control and Prevention, 2003). For the first six months of 2003, the prevalence of obesity among women was highest among non-Hispanic black women (38.7%), followed by Hispanic or Latino women (25.7%).
A sedentary lifestyle is the most common risk factor for coronary disease in women, Grauer said, and as a group, women are less active then men. However, 30 to 45 minutes of walking three times a week could reduce the risk of MI by as much as 50%.
Looking at lipids, Grauer said increased low-density lipoprotein (LDL) cholesterol seems to predict coronary risk in women who are under age 65, but it is not nearly as predictive in women who are older than 65. Increased triglycerides are more strongly associated with an increased risk of CAD in women, and this is especially true if high-density lipoprotein (HDL) cholesterol is <40 mg/dL.
Type 2 diabetes is a greater risk factor for CAD in women than in men, and smoking is the No. 1 preventable cause of coronary disease for women age 50 and under. More than half of all infarcts in women under age 50 are in smokers, Grauer said.
The risk factors are all interrelated, but the good news is that they are potentially correctable, at least in part, he added.
Yet only a minority of women in the AHA's national study were able to identify the major risk factors: 41% identified being overweight, 40% said lack of exercise, 36% said smoking, 31% cited high cholesterol, 29% identified family history, 19% said hypertension, 7% identified diabetes and 1% said high triglyceride level (Mosca et al., 2004b).
Finding Disease
Men and women are different with regard to the diagnostics, according to Grauer. The exercise treadmill test (ETT), he said, is potentially problematic in women because of the much higher incidence of false positive results, especially in women between 30 to 50 years of age.
"I don't even think about screening ETT in asymptomatic women. But you can and should do exercise treadmill tests for women who have symptoms, realizing that there may be more false positives," explained Grauer. "If I do an ETT on a 30- to 50-year-old woman who has chest discomfort and I do get an abnormal result, I will do more workup and follow-up."
Deciding which diagnostic test--ETT, myocardial perfusion imaging, stress echocardiography or cardiac catheterization--is best for a specific female patient, Grauer said, depends on several factors: the patient's age, the pre-test probability of CAD based on risk factors and symptoms, the treating physician's specialty, who is paying for the test, and gender-specific factors.
Grauer generally starts with treadmill testing in the office, assuming that his female patient has no significant electrocardiogram abnormalities and is able to exercise adequately. If the ETT is abnormal, he orders further tests. For hospitalized patients, he orders one of the other tests without the ETT.
With regard to myocardial perfusion imaging, Grauer said the use of the newer, high-energy isotopes (e.g., technetium 99m-sestamibi) has greatly reduced thallium scan errors from breast attenuation. For detection of wall motion abnormalities, Grauer favors stress echocardiography, based upon his reading of the medical literature.
Some new technologies that Grauer occasionally uses on selected patients are electron-beam computerized tomography (EBCT) and high-sensitivity C-reactive protein (hs-CRP).
Coronary artery calcium (CAC) is a specific marker of atherosclerosis, and EBCT picks up calcium in a vessel. Grauer said that EBCT has facilitated the creation of a calcium score for each patient, which is derived from the presence of coronary artery calcification, the number of arteries with calcification and the total "mass" of coronary calcification.
The calcium score is adjusted for age and sex. For example, a calcium score of 30 in a 40-year-old man is probably normal, Grauer said. However, the same score in a 40-year-old woman is probably abnormal, indicating potentially significant plaque burden.
"Keep in mind that EBCT will not find the vulnerable plaque, but it may help to find the vulnerable patient," Grauer warned.
Inflammation is believed to have a role in the pathogenesis of cardiovascular events. Therefore, the measurement of inflammation markers has been proposed as a method to improve the prediction of the risk of these events. One of the newest markers for coronary artery disease risk is hs-CRP (Ridker et al., 2000), and Grauer believes "it is a keeper."
"At least one-third of all our patients with CAD do not have the standard risk factors, and a significant percentage of the other patients have only slight risk factors. So consider high-sensitivity CRP in such patients to help assess risk," Grauer said.
The level of hs-CRP is a significant predictor of risk, even in the subgroup of women with LDL cholesterol <130 mg/dL (3.4 mmol/L), the target for primary prevention established by the National Cholesterol Education Program (Ridker et al., 2000).
Hormone Therapy
In the final section of his presentation, Grauer discussed hormone replacement therapy (HRT) and coronary disease, describing the issue as a moving target.
Fortunately, he said, the picture started becoming more clear with the Heart and Estrogen/progestin Replacement Study (HERS) trial (Hulley et al., 1998) and the HERS II trial (Grady et al., 2002). These trials sought to determine if estrogen plus progestin therapy alters the risk of CAD in postmenopausal women with established coronary disease. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with coronary disease (Grady et al., 2002). The Women's Health Initiative, which looked at risks and benefits of estrogen plus progestin in healthy postmenopausal women, concluded that the regimen should not be initiated or continued for the primary prevention of coronary heart disease (Rossouw et al., 2002).
In February, the AHA noted in its evidence-based guidelines for cardiovascular disease prevention in women that combined estrogen plus progestin hormone therapy should not be initiated or continued to prevent cardiovascular disease in postmenopausal women, and other forms of menopausal hormone therapy (e.g., unopposed estrogen) should not be initiated or continued to prevent cardiovascular disease in postmenopausal women, pending the results of ongoing trials (Mosca et al., 2004a).
The decision to continue or stop HRT in women with cardiovascular disease who have been undergoing long-term HRT should be based on established noncoronary benefits, risks and patient preference, Grauer said. If a woman develops an acute cardiovascular event or is immobilized while on HRT, it is prudent to consider discontinuing the HRT or implementing prophylaxis to minimize the risk of a venous thromboembolic event associated with immobilization. Reinstitution of HRT should be based on established non-coronary risks and benefits, as well as patient preference.
References
American Medical Women's Association (undated), Coronary heart disease. Available at: www.amwadoc.
org/Education/gallup.htm. Accessed Feb. 9, 2004.
Camper-Kirby D, Welch S, Walker A et al. (2001), Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 88(10):1020-1027 [see comment].
Centers for Disease Control and Prevention (2003), Early release of selected estimates based on data from the January-June 2003 National Health Interview Survey. Available at: www.cdc.gov/nchs/about/major/nhis/released200312.htm. Accessed Feb. 12, 2004.
Grady D, Herrington D, Bittner V et al. (2002), Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). [Published erratum JAMA 288(9):1064.] JAMA 288(1):49-57 [see comments].
Hulley S, Grady D, Bush T et al. (1998), Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280(7):605-613 [see comments].
Marrugat J, Sala J, Masia R et al. (1998), Mortality differences between men and women following first myocardial infarction. RESCATE Investigators. Recursos Empleados en el Sindrome Coronario Agudo y Tiempo de Espera. JAMA 280(16):1405-1409 [see comments].
Mosca L, Appel LJ, Benjamin EJ et al. (2004a), Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 109(5):672-693.
Mosca L, Ferris A, Fabunmi R, Robertson RM (2004b), Tracking women's awareness of heart disease. An American Heart Association national study. Circulation 109(5):573-579.
Ridker PM, Hennekens CH, Buring JE, Rifai N (2000), C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342(12):836-843.
Rossouw JE, Anderson GL, Prentice RL et al. (2002), Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333 [see comments].
Vaccarino V, Parsons L, Every NR et al. (1999), Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 341(4):217-225 [see comments].
