JoEllyn Moore Abraham and Ellen Mayer Sabik
EPIDEMIOLOGY/SCOPE OF PROBLEM
Cardiovascular disease (hypertension, cerebrovascular disease, and coronary artery disease [CAD]) is the leading cause of death for women in the United States, killing approximately 500,000 women annually. CAD is responsible for half of those deaths. This may in part be due to the lack of awareness among women: although ultimately 1 in 2.4 women will die from cardiovascular disease, compared to 1 in 30 women from breast cancer, many women consider breast cancer to be their greatest potential health problem. These attitudes are beginning to change as the National Health Lung and Blood Institute (NHLBI) in 2001 and the American Heart Association (AHA) in 2004 have undertaken national education campaigns to educate women and their physicians regarding women’s risk for cardiovascular disease.
One reason that heart disease has usually been thought of as a disease that primarily affects men is that clinical manifestations typically occur in women 10 years later than in men. As a consequence, historically there has been a tendency for women to be underrepresented in national trials studying risk factors, diagnosis, and treatment for CAD, heart failure, and arrhythmias. Despite this neglect, “optimal care” for treating women with these problems has been extrapolated from predominantly male patient data. More recent studies have attempted to improve the recruitment of female patients as well as to conduct separate analyses on the specific treatment effects on women, in order to identify possible differences in outcomes based on gender.
RISK FACTORS FOR CORONARY ARTERY DISEASE
The standard risk factors for CAD include diabetes, elevated cholesterol, hypertension, smoking, and a positive family history of the disease. Although risk factors for CAD are similar in men and women, the effects of the individual risk factors as well as interventions can differ dramatically based on gender. Thus, in order to appropriately diagnose and treat CAD in women, we need to understand the pertinent risk factors and determine the effects of modifying these factors on disease progression. Although these risk factors are common in women of all racial and ethnic groups in the United States, they are more prevalent among socioeconomically and educationally disadvantaged women. Data from 2008 for women ≥18 years old in the United States showed that more than a third had hypertension, more than a third had low-density lipoprotein (LDL) cholesterol ≥130 mg/dL, approximately a fifth were cigarette smokers, more than 60% were either overweight or obese, and more than two-thirds led a sedentary lifestyle.
Diabetes
Diabetes is the most powerful risk factor for CAD in women. Not only does diabetes increase the risk of CAD fivefold, the risk of myocardial infarction (MI) twofold as well as the risk for developing congestive heart failure or dying post-MI, but it also eliminates the 10-year gender gap in risk for CAD.
Hyperglycemia decreases estradiol-mediated nitric oxide production, thus causing endothelial dysfunction and platelet aggregation. Diabetes is also associated with abnormalities of platelet function and coagulation factors. Diabetics have elevated levels of fibrinogen, factor VII, and fibrinopeptide A, all markers of a hypercoagulable state. Also, women have increased platelet response and reactivity compared to men, which compounds the effects of hyperglycemia.
Elevated Cholesterol
While there is a strong association between total cholesterol and LDLs and CAD in men, there is only a very weak association in women and none at all in women ≥65 years of age. In older women, low HDL and elevated triglycerides are strong risk factors for CAD. Total cholesterol/high-density lipoprotein (HDL-C) ratio (which should be ≤4) is a more accurate predictor of CAD risk in women of all ages. The average HDL-C level in adult premenopausal women is 20% higher than in age-matched men. Although HDL-C declines following menopause, it still remains higher than in men.
Several secondary prevention studies have assessed the effect of treatment of lipid abnormalities in women. The CARE (Cholesterol and Recurrent Events) trial, which studied pravastatin as treatment in patients with average cholesterol levels and prior MI, found a 46% reduction in death or recurrent MI in treated patients (as compared with a 26% reduction in men). The 4S trial (Scandinavian Simvastatin Survival Study) investigated the use of simvastatin in patients with known CAD. The outcome was a 35% reduction in relative risk for coronary events in women (compared with a 34% reduction in men). The LIPID (Long Term Intervention with Pravastatin in Ischemic Disease) trial studied patients with prior MI or unstable angina who were treated with pravastatin and found a 24% decrease in CAD events.
Primary prevention studies include the AFCAPS/Tex-CAPS (Air-Force/Texas Coronary Atherosclerosis Prevention Study). Patients were men and postmenopausal women with average total cholesterol and LDL-C levels but belowaverage HDL. Long-term lipid-lowering treatment decreased the incidence of a first major acute CAD event by 46% in women and by 37% in men. There are no data to support aggressive lipid lowering in premenopausal women without CAD or family history or multiple risk factors.
Hypertension
More than 50 million people in the United States have been diagnosed with hypertension, and >60% of these individuals are women. However, there is a lower prevalence of hyper tension in women until the sixth decade at which point the prevalence in women begins to exceed that in men. Hypertension is more likely to cause a cardiovascular event in women and is a risk factor for congestive heart failure in women. Nonetheless, women are more likely than men to be aware of their diagnosis, to receive treatment, and to reach target blood pressure.
Etiology
The origin of hypertension is predominantly essential. Etiologies that are seen exclusively or disproportionately in women include hypertension associated with pregnancy or use of oral contraceptives (especially older agents with higher doses of estrogens and progestins) and renovascular hypertension, which has a female:male ratio of 8:1.
Treatment
Antihypertensive treatment recommendations are generally similar for women as compared to men except in certain situations.
Pregnancy: Methyldopa is generally preferred and ACE-inhibitors and angiotensin receptor blockers are contraindicated.
Elderly: Thiazide diuretics may be helpful as they have been shown to reduce hip fracture.
The following side effects have been demonstrated to be more frequent in women:
Hyponatremia
Hypokalemia
ACE-inhibitor induced cough
Peripheral edema from calcium channel blockers
Hirsutism from minoxidil
Smoking
Cigarette smoking is the leading preventable cause of death in men and women in the United States. Women who are heavy smokers (>20 cigarettes a day) have two- to fourfold increased risk of coronary disease compared with nonsmokers. Even light smokers (1 to 4 cigarettes a day) have a two- to three-fold risk of fatal coronary heart disease (CHD) or nonfatal MI. Second-hand smoke may increase risk of CAD by 20%.
The prevalence of smoking has declined in the United States since 1965, but more men have been successful at quitting than women. There are multiple factors in women’s failure to quit, including fear of weight gain and lack of confidence.
Mechanisms by Which Smoking May Increase Risk of CAD
Chronic smokers are insulin resistant, hyperinsulinemic, and dyslipidemic compared to nonsmokers. (There is a dose–response relationship between number of cigarettes smoked and plasma cholesterol, possibly due to increased lipolysis.)
Second-hand smoke may cause intimal wall damage and accelerate atherosclerotic plaque formation. In young women, the combination of smoking and use of oral contraceptives promotes thrombogenesis.
Smoking Cessation Decreases Risk
The Nurses’ Health Study showed a 30% decrease in risk for CAD in 2 years following cessation of smoking. There is continued decline in risk over next 10 to 15 years, and then the risk is at the same level as that of a nonsmoker.
Most studies show a 30% to 50% decrease in risk for CAD in the first 2 years following cessation.
Obesity and Sedentary Lifestyle
Obesity is an independent risk factor for CAD in women. In the Framingham Heart Study, relative weight in women was positively and independently associated with the development of CAD as well as mortality from CAD and cardiovascular disease. In the Nurses’ Health Study, women with a body mass index (BMI) of 25 to 29, had an age-adjusted relative risk for CAD of 1.8, whereas those with BMI ≥ 29 had a relative risk of 3.3, compared with women of ideal BMI.
Truncal obesity correlates with increased LDL-C and decreased HDL-C and also is associated with hyperinsulinemia and hypertension. Although obesity is associated with diabetes (insulin resistance), hypertension, and hypercholesterolemia, the waist/hip ratio still correlates positively with CAD after controlling for smoking, hypertension, glucose intolerance, lipids, and BMI.
AHA 2011 GUIDELINES FOR HEART DISEASE PREVENTION IN WOMEN
The 2011 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for heart disease prevention in women are evidence based and provide individual recommendations for women (see Tables 56.1 and 56.2). In general, the recommendations differ very little from those for men.
TABLE
56.1 Guidelines for Prevention of CAD in Women: Clinical Recommendations
LVEF, left ventricular ejection fraction; BMI, body mass index; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease; CVD, cardiovascular disease; ACS, acute coronary syndrome; hsCRP, high-sensitivity C-reactive protein; HbA1c, hemoglobin A1C; MI, myocardial infarction; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Prior Stroke; and INR, international normalized ratio. Reprinted from 2011 Writing Group Members, Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:2022–2060, with permission.
TABLE
56.2 Class III Interventions (Not Useful/Effective and May Be Harmful) for CAD or MI Prevention in Women
CVD indicates cardiovascular disease; MI, myocardial infarction.
aFolic acid supplementation should be used in the childbearing years to prevent neural tube defects.
Reprinted from 2011 Writing Group Members, Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:2022–2060, with permission.
Women are grouped into high-risk (includes risk for CHD event of ≥10% over the next 10 years, women with CHD, cerebrovascular disease, diabetes mellitus, peripheral arterial disease, chronic kidney disease, or abdominal aortic aneurysm), at-risk (includes women with systemic autoimmune collagen-vascular disease, history of preeclampsia, pregnancy-induced hypertension, or gestational diabetes along with other traditional risk factors), and ideal cardiovascular health. As compared to the 2007 guidelines, the 2011 guidelines have decreased the threshold at which women are considered to be high-risk (from risk for CHD event over the next 10 years of ≥20% to ≥10%).
HISTORICAL PERSPECTIVE: ESTROGEN THERAPY FOR PREVENTION OF CARDIOVASCULAR DISEASE
Physiologic Effects of Estrogen
Benefits
Beneficial effects on lipid profile
Antioxidant effects
Reduction of serum fibrinogen
Inhibition of neointimal hyperplasia, smooth muscle cells, and collagen biosynthesis
Potentiation of endothelium-derived relaxing factor
Calcium channel blocking effect
Increases prostacyclin biosynthesis
Decreases insulin resistance
May cause favorable distribution of body fat
Risks
Breast cancer: relative risk is 1.35 with >10 years of hormone-replacement therapy (HRT).
Endometrial cancer: relative risk is 8.22 with >8 years of HRT.
Risk of deep vein thrombosis (DVT)/pulmonary embolism (PE) is doubled with HRT.
Risk of gall bladder disease is doubled with HRT.
Population Data
Observational studies (e.g., the Nurses’ Health Study) showed a significant reduction in MI or death among postmenopausal estrogen users.
Some randomized controlled trials of HRT for secondary prevention of cardiovascular disease have been undertaken. The HERS (Heart and Estrogen/progestin Replacement Study) was the first randomized controlled trial of HRT for prevention of CHD. It looked at estrogen and progestin versus placebo in postmenopausal women with prior MI, coro nary revascularization, or angiographic evidence of CAD. Results showed, over a mean follow-up period of 4.1 years, no difference in the rates of nonfatal MI and coronary death, and a 52% increase in cardiovascular events in the first year of HRT.
The ERA (Estrogen Replacement and Atherosclerosis) trial was the first randomized angiographic-endpoint trial to test the effect of estrogen replacement therapy (ERT) and HRT on the progression of atherosclerosis in postmenopausal women with documented CAD. Neither the HRT (estrogen and progestin) nor the ERT (estrogen only) showed any angiographic benefit on disease progression.
In a randomized controlled trial of HRT for the primary prevention of CHD, the Women’s Health Initiative (WHI) studied estrogen plus progestin in >16,000 postmenopausal women aged 50 to 79 years. Primary outcomes were nonfatal MI or death from CHD. Mean follow-up was 5.2 years, but the trial was stopped early because the overall risks exceeded the benefits, with a hazard ratio for CHD of 1.24. The study’s conclusions stated: “Estrogen plus progestin does NOT confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year of treatment.” The separate Estrogen Only arm of the WHI was stopped because the hormone increased the risk of CVA and did not reduce the risk of CHD.
Thus, based on the randomized, placebo-controlled trials, hormone replacement therapy (estrogen and progestin or estrogen alone) is not indicated for either primary or secondary prevention of cardiovascular disease in women and may in fact increase risk.
CLINICAL PRESENTATION OF CAD IN WOMEN
The most common presentation of CAD in women is angina pectoris (typical and atypical), in contrast to men, who present most commonly with MI or sudden cardiac death. Women who present with acute coronary syndrome (ACS) are more likely to be older and to have more comorbidities than men, including hypertension, diabetes, hyperlipidemia, and congestive heart failure. Women are less likely to have had a prior MI or revascularization. In MI, both men and women present with chest pain as the most common symptom; however, women are more likely to have atypical symptoms, including shoulder, neck, and abdominal pain. Women may also present with profound fatigue or dyspnea without pain. Atypical symptoms often contribute to delay in women seeking medical attention for acute MI.
A Women and Ischemia Syndrome Evaluation (WISE) substudy demonstrated that women with chest pain and nonobstructive CAD on coronary angiogram were likely to have atherosclerosis as assessed by intravascular ultrasound and abnormal flow reserve. Additionally, it has been demonstrated that women with persistent chest pain have an increase in cardiovascular events, even when documented to have nonobstructive CAD by coronary angiogram.
CAD TREATMENT RESULTS
During hospitalization for MI, women had more complications and higher 30-day mortality rates than men, but similar rates of reinfarction. In Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) IIb, once the data were adjusted for age and baseline characteristics, however, men and women had similar mortality rates. Complications seen more commonly in women include shock, heart failure, recurrent chest pain, cardiac rupture, and stroke.
A recent meta-analysis demonstrated that gender is an independent risk factor for complications after both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) but these differences were attenuated after adjustment for risk factors such as age, presence of diabetes and body habitus.
Thrombolytics
GUSTO I showed comparable infarct-related artery patency and significant reduction in early mortality with thrombolytic treatment in women as in men; however, unadjusted 30-day mortality for women was double that for men (13% vs. 4.8%). Multiple factors may be contributing to women’s increased mortality: later presentation and diagnosis, more comorbidities and older age, as well as more bleeding complications (including intracranial hemorrhage), due in part to lack of weight-adjusted dosing. Thrombolysis in Myocardial Infarction (TIMI) II and Gruppo Italiano per lo Studio (GISSI) also showed mortality benefits for both men and women with thrombolytics, however both showed higher 6-week and 1-year mortality rates for women. Data from the National Registry of Myocardial Infarction showed that women have greater mortality with acute MI than men, even when matched for age, both with and without thrombolysis. Women were less likely to receive thrombolytics and were more likely to have major bleeding when they did. Younger women (<70 years of age) had higher mortality rates during hospitalization than age-matched men.
Primary Angioplasty for Acute Myocardial Infarction
The possibility of a referral bias has been explored. In the GUSTO IIb trial, fewer women than men underwent coronary angiography (53% vs. 59%). Women at catheterization had less severe coronary disease than men. Although previously women with abnormal noninvasive test findings suggesting CAD were less likely to be referred for catheterization, this bias has changed so that currently men and women have comparable referral rates for angiography following abnormal nuclear stress tests. Similarly, referral rates for revascularization have been comparable between men and women based on coronary anatomy once angiography has been performed.
Similar procedural success rates have been found for men and women treated with primary angioplasty Primary percutaneous transluminal coronary angioplasty (PTCA) decreased risk of intracranial hemorrhage seen in women with thrombolytics, and improved survival. Note that women still had higher 30-day and 7-month mortality, although this is likely due to differences in baseline characteristics.
A recent meta-analysis comparing early invasive versus conservative treatment in patients presenting with unstable angina or non ST-elevation MI suggests that, unlike men and high-risk women, low-risk women (defined as myocardial necrosis biomarker negative) should be treated according to a conservative strategy. It is possible that some of this trend toward harm with early invasive therapy for low-risk women is driven by increased bleeding risk that has been seen in women with ACS.
NONINVASIVE EVALUATION OF WOMEN SUSPECTED OF HAVING CORONARY ARTERY DISEASE
The gender-specific challenges of noninvasive evaluation in women are due to the fact that women are more likely to have single-vessel disease and nonobstructive CAD than men (who have more multivessel disease or left main disease), and there is a decreased diagnostic accuracy of noninvasive testing in women, with a higher rate of false positives. Therefore it is important to determine the likelihood of disease before testing.
Data support the use of stress testing with stress electrocardiography or cardiac imaging in patients with intermediate risk for CAD, to provide the best chance of determining the presence of disease. In patients at high risk for CAD, cardiac imaging is more useful for determining prognosis and guiding therapy than determining if the disease is present. The use of testing in low-risk patients is more likely to produce a false positive and should be avoided.
Exercise electrocardiograms (ECGs) are less accurate for women than for men. Using ECG alone, sensitivity and specificity are 61% and 70% in women, compared to 72% and 77% in men. Improved accuracy can be achieved by integrating multiple other clinical parameters of the stress test, including the Duke treadmill score, heart rate recovery, and maximal exercise capacity, all of which have significant prognostic as well as diagnostic value.
Recommendations based on stress ECG include the following:
1. If the Duke treadmill score is high or high risk stress ECG indicates high risk, there is increased likelihood of obstructive disease, and the patient should be referred for cardiac catheterization.
2. If the Duke treadmill score is intermediate, further risk stratification using cardiac imaging is recommended.
3. If pretest probability is low and the Duke treadmill score is also low, no further evaluation for CAD is usually necessary. Exercise ECG in women has a high negative predictive value in women with low pretest probability.
4. Lower work capacity on exercise tests (average 5 to 7 minutes) challenges the ability of the test to provoke ischemia. Therefore, patients who are expected to perform <5 metabolic equivalents (METs) at exercise are better evaluated using pharmacologic stress imaging.
5. Women who exercise at <5 METs are at increased risk of death.
Stress echocardiography can indicate not only the presence or absence of ischemia but may also provide information on overall systolic and diastolic function, valvular structure and function, and the extent of infarct or stress-induced ischemia. Meta-analysis of stress echo studies in women found that mean sensitivity and specificity are 81% and 86%, respectively. Stress echo testing is gender neutral; there is no gender effect on diagnostic accuracy. Echo data provide incremental value over the exercise ECG and clinical variables, and may be the most cost-effective tool to diagnose CAD in women with intermediate pretest likelihood of disease. The use of dobutamine echo for patients who are unable to exercise is recommended.
Radionuclide imaging, myocardial perfusion and ventricular function imaging, have special features in women. Single photon emission computed tomography (SPECT) imaging parameters include perfusion defects, global and regional left ventricular (LV) function, and LV volumes. In women, however, a generally smaller LV cavity decreases the accuracy of the test. Breast attenuation can be improved by using a higher count isotope (technetium-99 m: 99mTc) with less attenuation, allowing gating that improves accuracy. In addition, performing studies on a combination SPECT/computed tomography (CT) scanner allows attenuation correction to be performed. This correction can also be useful when imaging obese women.
Vasodilator pharmacologic stress SPECT can be used for patients who are unable to exercise adequately. Because women with suspected CAD are typically older and have diminished exercise capacity, pharmacologic stress SPECT is useful. Vasodilator stress perfusion imaging is more accurate than exercise stress and is the test of choice in men and women with left bundle branch block.
SPECT imaging provides incremental prognostic value to clinical and exercise variables. The annual cardiac event rate for a person with a normal SPECT is <1%. The prognosis worsens as the number of vascular territories with provocable ischemia increases. Rather than a dichotomous result of positive or negative, evaluation of extent and severity of perfusion defects allows gradation of risk.
Emerging Technologies for the Evaluation of Women with Suspected Coronary Artery Disease
Limited data are now appearing on the use of CT and magnetic resonance imaging (MRI) as well as carotid intimamedia thickness (IMT—combined thickness of intima and medial layer of the carotid) in the diagnosis of CAD in women. These techniques appear promising; however, further studies, which are currently ongoing, are required to determine their differential role in diagnosis and riskassess ment in women.
Cardiac CT: Appears to be equally useful in men and women although there are no specific studies evaluating this question.
Coronary artery calcium: There is evidence that coronary artery calcium screening is equally accurate in men and women.
Cardiac MRI: Appears to be equally useful in men and women although there are no specific studies evaluating this question.
Carotid IMT: Carotid IMT is predictive of CAD and it appears to be both a more sensitive and specific risk marker for women as compared to men.
As with all tests involving radiation exposure, patients should be informed of the risks associated with radiation exposure as well as the increasing risk with increasing cumulative dose of radiation from multiple modalities of diagnostic tests.
WOMEN AND DEVICE THERAPY
Recent studies have demonstrated that implantable cardioverter defibrillators (ICDs) are less likely to be offered to women than men. The reasons for this discrepancy are not clear. According to the National Cardiovascular Data Registry, overutilization in men does not explain this gap. Also, women appear to have more in-hospital adverse events related to ICD implantation. Nonetheless, although females comprised only one-quarter of the subject pool, data from the MADIT-CRT trial suggest that female subjects benefit more from CRT as compared to male subjects.
At least two studies found that women received fewer dual-chamber (as opposed to single-chamber) pacemakers with a trend toward increased complications in women.
WOMEN AND HEART FAILURE
Risk factors for heart failure differ by gender. Hypertension and diabetes mellitus are major risk factors in women (with diabetes in younger women markedly increasing the risk of congestive heart failure), while CAD is a more important risk factor in men. Note, however, that women, especially diabetic women, have a greater risk of developing heart failure post-MI than men. There are also gender-specific causes of heart failure, such as peripartum cardiomyopathy and X-linked cardiomyopathy.
Structural responses to loading differ by gender; women, for example, are more likely to develop concentric LV hypertrophy and less likely to have cardiac dilation.
Heart failure is more prevalent in men as compared to women across all age groups and has almost twice the prevalence in men between ages 60 and 79 (9.1% vs. 4.9%)— although this gap narrows in octogenarians and older (14.7% men vs. 12.8% women). However, it is estimated that of the women with heart failure, approximately 57% will have a preserved ejection fraction.
Survival
There are discrepancies in the literature as to whether women have a better prognosis with heart failure than men. A problem is that many studies lump different etiologies of heart failure as well as systolic and diastolic heart failure (i.e., patients with impaired systolic function lumped with those with preserved left ventricular ejection fraction, LVEF). In the Framingham Heart Study (controlled for age and etiol ogy of heart failure), National Health and Nutrition Examination Survey (NHANES) I, Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), Inception cohort, and the Malmo Prevention project, women had better survival than men with congestive heart failure. These were epidemiologic studies and did not stratify by LV function. The SOLVD (Studies of Left Ventricular Dysfunction) and Cleveland Clinic cohort data showed no differences in overall survival based on gender. The patients in both of these cohorts had reduced LVEF as enrollment criteria.
Treatment
The large therapeutic trials suffer from the problem of limited numbers of women enrolled as subjects. Attempts to pool data, such as Gali et al.'s examination of the use of ACE inhibitors for patients with decreased LVEF, found no reduction of mortality or combined endpoint of all-cause mortality and heart failure hospitalizations in women. Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) looked at benefits from the addition of beta-blockers to heart failure regimens, but only 23% of the patients studied were women. A subgroup analysis did not show a mortality benefit for women. It is possible that the study was underpowered to detect benefit.
Thus, the standard treatment for women with heart failure with depressed LVEF (including ACE inhibitors, beta-blockers, spironolactone, and possibly digitalis) is based on overall population benefits shown in studies that predominantly enrolled men. Morbidity and mortality benefits have not been specifically proven for women, and further study is needed. Heart failure in women with preserved systolic function is a different entity seen mostly in older women, often women with hypertension. Only small numbers of clinical trials have addressed treatment of these patients, and thus there are no conclusive data to guide therapy. Nonetheless, at least two studies have demonstrated that women are less well managed according to recommended guidelines than men. The 2009 ACC/AHA guidelines for this patient population recommend using standard guideline-driven care for heart failure for women as well as their inclusion in ongoing clinical trials. Further study is required to optimize treatment of this patient population to improve their quality of life.
SUGGESTED READINGS
Gibbons RJ, Balady GJ, Bricker T, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1977 Exercise Testing Guidelines. J Am Coll Cardiol. 2002;40: 1531–1540.
Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndrome. N Engl J Med. 1999;341:226–232.
Johnson, BD, Shaw, LJ, Pepine, CL, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J. 2006;27:1408–1415.
Manson, JE, Hsia, J, Johnson, KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003; 349:523–534.
Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease. Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005;111:682–696.
Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update. A Guideline from the American Heart Association. Circulation. 2011: 1–22. (Published online February 16, 2011.)
Mosca l, Banca C, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. AHA Scientific Statement. Circulation. 2007;115(11):1481–1501.
O’Donoghue M, Boden WE, Braunwald E, et al. Early in vasive versus conservative strategies in women and men with un stable angina and non-ST-Elevation myocardial infarction: A meta-analysis. JAMA. 2008;300(1):71–80.
Wenger NK. Clinical characteristics of coronary heart disease in women: emphasis on gender differences. Cardiovasc Res. 2002;53:558–567.
Wenger NK. Coronary heart disease: the female heart is vulnerable. Prog Cardiovasc Dis. 2003;46(3):199–229.
Wenger NK. Women, heart failure, and heart failure therapies. Circulation. 2002;105(13):1526–1528.
QUESTIONS AND ANSWERS
Questions
1. All of the following are true regarding women with a myocardial infarction (MI) except:
a. Women are more likely to have complications such as ventricular septal defect (VSD), heart failure, cardiac rupture, and shock than men.
b. Women are more likely than men to have had a prior MI.
c. Women have unadjusted 30-day and 1-year mortality rates post-MI that are higher than those for men.
d. Primary percutaneous transluminal coronary angioplasty (PTCA) decreased the risk of intracranial hemorrhage that is seen with thrombolytics.
2. Women with hypertension are:
a. Less likely than men to be aware of their diagnosis
b. More likely than men to reach their target blood pressure
c. Less likely than men to have a cerebral vascular accident (CVA) than men with hypertension
d. Less likely than men to have renovascular hypertension
3. All of the following are true regarding diabetes as a cardiac risk factor in women except:
a. Eliminates the 10-year gender gap
b. Increases the risk of coronary artery disease (CAD) fivefold over women without diabetes
c. Increases the risk for developing congestive heart failure post-MI
d. Increases the risk of MI 10-fold over women without diabetes
4. All of the following are true regarding the use of hormone replacement therapy for prevention of CAD except:
a. Estrogen therapy increases the risk of breast and endometrial cancer.
b. Hormone replacement therapy is useful for secondary prevention of CAD in women.
c. The HERS trial showed no difference in nonfatal MI or coronary death in postmenopausal women with prior MI or revascularization or angiographic CAD who had hormone replacement therapy.
d. Hormone replacement therapy may increase risk of CAD in healthy postmenopausal women.
5. The use of thrombolytics in women who present with an MI:
a. Is associated with comparable infarct-related artery patency as seen in men
b. Is associated with fewer bleeding complications than are seen in men
c. Did not show mortality benefit as seen in men
d. Is contraindicated in menstruating women or women of reproductive age
6. The following statements are true except:
a. Women with chest pain are at an increased risk of cardiovascular events even if documented not to have obstructive CAD.
b. Women are more likely than men to have atypical symptoms of acute coronary syndrome (ACS).
c. Women are more likely to have systolic, as compared to diastolic, dysfunction.
d. In low-risk women, routine use of aspirin is not recommended for primary prevention.
7. Which of the following is more likely in men than in women following antihypertensive therapy?
a. Hyponatremia
b. Hypokalemia
c. ACE-inhibitor induced cough
d. Peripheral edema from calcium channel blockers
e. None of the above
8. Which of the following is true about the use of pacemakers and implantable defibrillators in women?
a. Women are more likely to receive an advanced pacemaker device such as a dual chamber pacemaker than men.
b. Women are less likely to have a therapeutic response to biventricular pacemaker insertion than men.
c. Women are more likely to have complications following device insertion than men.
d. Women are more likely to be offered an implantable defibrillator than men.
9. Risk factors for CAD in older (>65 years) women are all of the following except:
a. High low-density lipoprotein (LDL)
b. Low high-density lipoprotein (HDL)
c. High triglycerides
d. Morbid obesity
e. Total cholesterol/HDL ratio > 4
10. Which of the following is true about stress testing in women?
a. False positive stress electrocardiography is less common than in men.
b. False positive stress echocardiography is more common in women than in men.
c. Women who exercise for <5 METS have little implication for adverse outcomes.
d. Women are less likely to have multivessel or left main disease than men and this in part explains the greater diagnostic challenge in noninvasive assessment of CAD in women.
Answers
1. Answer B: Women who present with an MI are less likely to have had a prior MI, and are more likely to have mechanical complications including VSD, congestive heart failure, cardiac rupture, and shock. Women also have higher 30-day and 1-year unadjusted mortality rates compared to men who present with an MI. Primary PTCA has decreased the risk of intracranial hemorrhage that is seen with thrombolytics.
2. Answer B: Women with hypertension are more likely than men to be aware of their diagnosis, to have appropriate treatment, and to reach their target blood pressure. Women with hypertension are more likely to have a stroke than men with hypertension. Women have renovascular hypertension much more commonly than men (ratio 8:1).
3. Answer D: Diabetes increases a woman’s risk of CAD fivefold and of MI twofold, not 10-fold, over nondiabetics. The other statements are all true.
4. Answer B: Hormone replacement therapy has no role in either primary or secondary prevention of CAD. It may, in fact, increase the risk of CAD in healthy postmenopausal women. HRT has certain noncardiac risks associated with it, including increased risk of breast cancer, endometrial cancer, and gallbladder disease, as well as increased risk of DVT and pulmonary embolism.
5. Answer A: The use of thrombolytics in women produces equivalent rates of infarct-related artery as when used in men, as well as mortality benefit. More bleeding complications were seen in women, but this is likely related to the uniform dosing (i.e., not weight adjusted) that was used in the early studies. These bleeding complications included intracranial hemorrhages as well as groin bleeds at the site of catheterization.
6. Answer C: Approximately 57% of women with heart failure have preserved ejection fraction.
7. Answer E: None of the above. All of the others are more common in women than in men.
8. Answer C: Women are more likely to respond positively to biventricular pacemaker insertion than men. They are less likely to be offered advanced pacemaker options and ICDs than men and are at higher risk of post device complications than men.
9. Answer A: While there is a strong association between total cholesterol and LDL and CAD in men, there is only a very weak association in women and none at all in women ≥ 65 years of age. In older women, low HDL and elevated triglycerides are strong risk factors for CAD. Total cholesterol/high-density lipoprotein (HDL-C) ratio (which should be ≤4) is a more accurate predictor of CAD risk in women of all ages. Obesity is an independent risk factor for CAD in women. In the Nurses’ Health Study, women with a body mass index (BMI) of 25 to 29, had an age-adjusted relative risk for CAD of 1.8, whereas those with BMI ≥ 29 had a relative risk of 3.3, compared with women of ideal BMI.
10. Answer D: The gender-specific challenges of noninvasive evaluation in women are due to the fact that women are more likely to have single-vessel disease and nonobstructive CAD than men (who have more multivessel disease or left main disease), and there is a decreased diagnostic accuracy of noninvasive testing in women, with a higher rate of false positives. Exercise ECGs are less accurate for women than for men. Using ECG alone, sensitivity and specificity are 61% and 70% in women, compared to 72% and 77% in men. Women who exercise at <5 METs are at increased risk of death. Stress echo testing is gender neutral; there is no gender effect on diagnostic accuracy.