Cardiovascular Disease in Women

Cardiovascular Disease in Women Eveline Oestreicher Stock, MD, and Rita Redberg, MD, MSc Abstract: Gender-specific data focused on cardiovascular disease (CVD) are becoming increasingly available. This is of great importance, given that CVD has become the number 1 killer of women, and unlike for men, mortality rates do not seem to be declining. Many factors are cited as the causes of sex-based differences, including delays in recognizing symptoms, underutilization of diagnostic tests and treatments, as well as anatomic, physiological, and genetic factors. Evidence of fundamental biological differences in vascular function and the underlying pathologic processes is only beginning to elucidated, motivated by growing evidence of differences in clinical presentations and outcomes between men and women. The good news is that we are starting to see improvements in outcomes for women, such as after coronary revascularization; decrease in complication rates with the advent of new techniques, such as radial access for cardiac catheterizations; as well as increased participation of women in clinical trials. The underlying mechanisms of ischemic heart disease remain to be elucidated, and will help guide therapy and ultimately may explain the higher prevalence of : subendocardial myocardial infarctions, spontaneous arterial dissections, plaque erosion, increased vasospastic disorders, such as coronary microvascular disease, and pulmonary hypertension in women compared with men. We have made great progress in understanding gender-related differences in CVDs, but much remains to be done to optimize the Dr E.O.S. is supported by National Institutes of Health (NIH)/NCRR UCSF-CTSI grant Number UL1 RR024131. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Curr Probl Cardiol 2012;37:450-526. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2012.07.001

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prevention of CVD for both men and women. (Curr Probl Cardiol 2012;37:450-526.) ardiovascular disease (CVD) is the number 1 killer of women in the United States. Long thought of as a disease primarily affecting men, it is now estimated that 1 of 2 women will die of heart disease or stroke in the United States, compared with 1 in 25 women who will die of breast cancer.

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Bairey Merz: Federal breast cancer research is approximately $700 million per year, whereas CVD spending proportionate to women is approximately $420 million, or about half what is spent on breast cancer research, even though cardiovascular kills 12 times more women than breast cancer (500,000 vs 39,000 annual deaths) http://report.nih.gov/rcdc/categories/.

Two of every 3 women have at least one of the classic risk factors for heart disease: age ⬎55 years, family history of premature heart disease, cigarette smoking, high blood pressure, dyslipidemia, obesity, and diabetes. Mortality rates for heart disease differ between men and women, and the gap appears to be widening; although deaths from heart disease have been steadily declining since the 1980’s for men, the disease continues to grow among women. Current statistics show that cardiovascular deaths for women currently exceeded those for men.1 Recently, we have witnessed an increase in coronary death rates among young adults of both genders, but the increase is substantially more prominent among young women.2 This increase in coronary deaths among young adults has closely correlated or tracked with the steady increases of a spectrum of unfavorable coronary risk factors, mainly related to increases in obesity rates within the population,3 including diabetes, hypertension (HTN), and metabolic syndrome. Obesity is now recognized as an epidemic, a public health problem that continues to grow within the United States and the world. Ford called this “the leading edge of a brewing storm,” portending further unfavorable mortality trends as our population ages.

Bairey Merz: Cigarette smoking is increasingly more prevalent in young adult women who often cite “weight-management” as a reason for smoking. Newer fourth-generation contraceptive hormone therapy likely is not as safe from a CVD standpoint as the third generation.

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Recent statistics show significant differences between men and women in survival after a heart attack; an absolute greater number of women die from ischemic heart disease (IHD) than men (455,000 vs 410,000 annually).4 Furthermore, a greater proportion of women die before hospital arrival (52% of women vs 42% of men),5 and the ominous prognosis extends beyond that, with 42% of women who have heart attacks dying within 1 year compared with 24% of men. The reasons for these differences are not well understood. We know that women tend to get heart disease about 10 years later in life than men, and this makes it more likely to have coexisting chronic conditions at the time of presentation. Research also has shown that women may not be diagnosed or treated as aggressively as men, and their symptoms may be differ from those of men who are having a heart attack. Bairey Merz: Although the mean age of onset for CVD is older in women than men, case-fatality rates are higher in younger (⬍55 years) women compared with age-matched men. Younger women are more likely to be undiagnosed and untreated.

Over the past decades, we have acquired insight and improved our awareness on the multiple factors that need to be considered when evaluating and treating women of all ages.

Anatomy Coronary disease presents differently between men and women, raising the possibility that the pathologic process leading to ischemia, the pathogenesis of the disease, is different in men versus women. At time of presentation, the anatomy of the lesions is different; although men classically present with mostly obstructive epicardial lesions, women tend to have less anatomical obstructive coronary artery disease (CAD) and relatively preserved left ventricular (LV) function. However, despite the apparently more benign lesion burden, women have greater rates of myocardial ischemia and mortality compared with similarly aged males.6 Accordingly, we and others agree that the term IHD be used rather than coronary disease for discussion of the disease pertaining to women. IHD in women presents a unique and complex challenge to clinicians as a result of larger symptom burden, higher rate of functional impairment, a lower prevalence of obstructive CAD by coronary angiography, greater cost to the health care system, and poorer outcomes compared with men.7 This societal burden of the disease is further intensified by a lack of public awareness on the part of patients and clinicians alike. 452

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The incidence and severity of CVD among premenopausal women is lower than among men of comparable age, even after correction for various risk factors.8 Cardiovascular risk increases with age in both sexes. Data show that once a woman is affected by IHD, they have a worse prognosis than their male counterparts. Bairey Merz: Age-adjusted rates are never as high in women as in men, so the above statement is not accurate. Also, careful evaluation of age-related CVD curves demonstrates no change with regard to the menopause in women, unlike the breast cancer where there is a clear difference in curves pre- and postmenopause.

The cause for these differences is not clear. Estrogen appeared as the obvious candidate to explain these differences, but over the past decade, abundant studies have been unable to prove a direct causal effect; new mechanisms to explain this differential age effect are being proposed, but so far differences in serum total cholesterol level, body mass index (BMI), and diabetes prevalence explain at best 50% of the age and sex-related differences in cardiovascular morbidity and mortality.9 Women are more likely than men to be hospitalized for unexplained chest pain. Data show that in 2006, there were 477,000 admissions of women to USA hospitals for unspecified chest pain—feeling of pressure, burning, or numbness— compared with 379,000 admissions for men. See HCUP Facts and Figures 2006, online at http://www.hcup-us.ahrq.gov/ reports/factsandfigures.jsp Chest pain was among 3 of the most common conditions for uninsured hospital stays that increased between 1997 and 2008: mood disorders (44% increase), nonspecific chest pain (73% increase), and skin and subcutaneous tissue infections (138% increase). Women may present with a wide range of symptoms, making the diagnosis of coronary disease in women challenging. The 2003 National Institutes of Health (NIH) study, titled “Women’s Early Warning Symptoms of AMI,”10 was one of the first to investigate women’s experience with heart attacks and how this experience differs from men’s. Among the 515 women studied, 95% said they knew their symptoms were new or different a month or more before experiencing their heart attack, or acute myocardial infarction. The symptoms most commonly reported were unusual fatigue (70.6%), sleep disturbance (47.8%), and shortness of breath (42.1%). Many women never had chest pains; ⬍30% reported having chest pain or discomfort before their heart attacks, and 43% reported having no chest pain during any phase of the attack. Curr Probl Cardiol, November 2012

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Women’s major symptoms before a heart attack include: ● ● ● ● ●

Unusual fatigue–70% Sleep disturbance– 48% Shortness of breath– 42% Indigestion–39% Anxiety–35% Most frequent symptoms during the heart attack include:

● ● ● ● ●

Shortness of breath–58% Weakness–55% Unusual fatigue– 43% Cold sweat–39% Dizziness–39%

Women are more likely than men to experience delays in emergency care for cardiac symptoms. Researchers examined time-to-treatment for 5887 individuals with suspected cardiac symptoms who made a 911 call in 2004. They found that, on average, women arrived at the hospital 2.3 minutes later than men. Factors increasing the likelihood of delay included evening rush hour travel, bypassing a local hospital, and living in a densely populated neighborhood. Even after adjustments were made for these factors, women were significantly more likely than men to be delayed.11 Bairey Merz: Women have a greater somatic awareness in standardized testing compared with men, thus likely report feeling symptoms longer when asked, thus it is not clear if these time differences are real, yet they likely contribute to the lower frequency of thrombolysis and percutaneous coronary intervention (PCI) use in women.

Association Between Heart Disease and Previous Use of Chemotherapeutic Agents for Treatment of Breast Cancer A study that followed nearly 20,000 women with breast cancer for 16 years showed that women who received chemotherapy that included anthracycline had a higher incidence of congestive heart failure (CHF), cardiomyopathy, and dysrhythmia than women who received other kinds of chemotherapy or no chemotherapy. For example, the probability of experiencing CHF in year 10 was 32% for women who received anthracycline, compared with 26% for women who received other types of chemotherapy and 27% for those who received no chemotherapy.12 454

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Awareness of Coronary Risk in Women Despite being the leading killer of women at all ages, CVD has been slow to be recognized by patients and physicians as the leading cause of death. National educational programs, such as the Heart Truth and Red Dress Educational campaigns by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute, among others, have been instrumental in increasing public awareness. Since 1997, awareness of women recognizing heart disease as the leading cause of death has mildly increased from 37% to 54% in 2009,13 clearly more needs to be done. Awareness needs to increase further, especially among racial and ethnic minorities who happen to be the highest-risk populations.14 Equally of concern are the results from a recent national survey by the AHA, which revealed that only 53% of women interviewed would call 911 for symptoms of myocardial infarction (MI).15 Awareness of CVD risks has already resulted in implementation of preventative measures. Studies, such as those by the Women’s Ischemic Syndrome Evaluation (WISE) study, have improved our understanding of the gender differences and ultimately improved the care and outcomes of women with IHD.

Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women The guidelines for prevention of CVD have been most recently updated in 201116; a major difference from previous guidelines is that the recommendations are now not limited to evidence that documents efficacy (benefits observed in clinical research), but have been broadened to include effective preventive therapies (benefits and risks observed in clinical practice), thus the change from “evidence-based” to “effectiveness-based” guidelines. The updated guidelines include therapies with sufficient evidence of clinical benefit for improving CVD outcomes. Some interventions, such as screening for depression, were recognized to lack sufficient data on direct CVD outcomes, but were included in an algorithm for evaluation of CVD risk in women because they may indirectly impact CVD risk (Fig 1). The guidelines continue to prioritize lifestyle approaches to the prevention of CVD, likely the most costeffective strategy.

Risk Factors for IHD in Women Two-thirds of women who die suddenly from IHD had no previous symptoms (compared with half of men). This suggests that primary prevention—risk factor modifications in patients who do not have clinical Curr Probl Cardiol, November 2012

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FIG 1. Flow diagram for cardiovascular disease CVD preventive care in women. CVD, cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ACS, acute coronary syndrome. Reprinted with permission from Mosca et al.16

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evidence of IHD—must be a key strategy to reduce the burden of IHD in women. There are published guidelines from the AHA, American College of Cardiology (ACC), and NIH that detail management strategies for primary prevention risk-reducing methods for men and women.17 ● IHD prevalence increases for women in their after menopausal years. Studies have suggested that the determinants of a woman’s risk for IHD at older age are largely determined by her levels of risk factors at premenopausal to early postmenopause.18 Therefore, early risk factor intervention could be instrumental in successful reduction of the risk of IHD for postmenopausal women. Gender differences in recommendations from the National Cholesterol Education Program–Adult Treatment Panel III (NCEP-ATP III).19 ● Age at risk for CAD: in women is ⱖ55 years, and for men ⱖ45 years. ● Premature coronary disease in a first-degree relative is defined as age ⬍65 years for women, and age ⬍55 years for men. ● Low high-density lipoprotein (HDL) cholesterol (HDL-C) is defined as ⬍50 mg/dL for women, and ⬍40 mg/dL for men. ● Increased waist circumference: ⬎35 inches for women, and ⬎40 inches for men. Two of 3 women in the United States have one or more major cardiac risk factor, and this percentage increases with older age. ● IHD mortality rates increases with the number of traditional cardiac risk factors. The calculated 30-year death rate increases from 1.5 to 9.1 per 10,000 person-years for women carriers of 0 versus ⬎2 risk factors.20 ● Clustering of multiple risk factors is common after menopause, with increases in the population affected by obesity, HTN, and dyslipidemia with age. The incidence of IHD was traditionally low among premenopausal women; however, recent years have seen an increasing coronary death rate in younger adults, with this increase more prominent for women than for men, likely related to the obesity epidemic.2

Bairey Merz: Emerging risk factors specific to women include pregnancyrelated complications, such as HTN, preeclampsia, and eclampsia, as well as autoimmune diseases, such as systemic lupus erythematosus and rheumaCurr Probl Cardiol, November 2012

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toid arthritis. Polycystic ovary syndrome (PCOS) is a risk factor for CVD, although not premature and typically not until after the menopause.

Score Predictors in Women Use of traditional risk factors and scoring system, such as the Framingham risk score (FRS), is recognized to underestimate IHD risk in women. ● FRS is calculated by summing point scores for age, blood pressure, cholesterol, diabetes, and cigarette smoking. It is used to classify patients’ at 10-year risk of CAD death or MI to determine the appropriate level of therapeutic intervention for of risk factors, such as low-density lipoprotein (LDL) cholesterol (LDL-C) and HTN. However, the FRS classifies ⬎90% of women as low risk, with few assigned a high-risk status before the age of 70,21 likely owing to its focus on intermediate-term (10-year) risk and its reliance on end points of MI and coronary death. Consideration of family history is not included. As a result, even women with evidence of subclinical atherosclerosis are often classified as at low risk by the FRS. ● Reynolds risk score is a sex-specific tool devised from large derivation (n ⫽ 24,588) and validation (n ⫽ 8158) cohorts of women.22 It incorporates high-sensitivity C-reactive protein (CRP) into the equation. When compared with the FRS, the Reynold’s score reclassified 40% of intermediate FRS women. ● Biomarkers have also been reported to improve IHD risk assessment in women.23-25 Because we need to gain more in-depth understanding of the sex-specific pathophysiology of IHD in women, further investigation into the optimal usage of novel risk factors for IHD risk stratification in women is needed. The 2011 updated Effectiveness-Based Guidelines from the AHA for the Prevention of Cardiovascular Disease in Women,16 classified women as “high risk,” “at risk,” or at “ideal cardiovascular health” (Table 1). ● Identification of “high-risk” women: presence of clinically manifest CVD, cerebrovascular, or peripheral arterial disease (PAD), abdominal aortic aneurysm, end-stage or chronic kidney disease, and diabetes mellitus (DM). ● Women “at risk”: the presence of ⱖ1 major risk factor defines this population, includes autoimmune diseases and pregnancy-related complications addressed below. 458

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TABLE 1. Classification of CVD risk in women Risk status

Criteria

High risk (ⱖ1 high-risk Clinically manifest CHD states) Clinically manifest cerebrovascular disease Clinically manifest peripheral arterial disease Abdominal aortic aneurysm End-stage or chronic kidney disease Diabetes mellitus 10-year predicted CVD risk ⱖ10% At risk (ⱖ1 major risk Cigarette smoking factors) SBP ⱖ120 mm Hg, DBP ⱖ80 mm Hg, or treated hypertension Total cholesterol ⱖ200 mg/dL, HDL-C ⬍50 mg/dL, or treated for dyslipidemia Obesity, particularly central adiposity Poor diet Physical inactivity Family history of premature CVD occurring in first-degree relatives in men ⬍55 years of age or in women ⬍65 years of age Metabolic syndrome Evidence of advanced subclinical atherosclerosis (eg, coronary calcification, carotid plaque, or thickened IMT) Poor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise Systemic autoimmune collagen-vascular disease (eg, lupus or rheumatoid arthritis) History of pre-eclampsia, gestational diabetes, or pregnancyinduced hypertension Ideal cardiovascular Total cholesterol ⬍200 mg/dL (untreated) health (all of these) BP ⬍120/⬍80 mm Hg (untreated) Fasting blood glucose ⬍100 mg/dL (untreated) Body mass index ⬍25 kg/m2 Abstinence from smoking Physical activity at goal for adults ⬎20 years of age: ⱖ150 min/wk moderate intensity, ⱖ75 min/wk vigorous intensity, or combination Healthy (DASH-like) diet Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women— 2011 Update. CVD, cardiovascular disease; CHD, coronary heart disease; SBP, systolic blood pressure; DBP ⫽ diastolic blood pressure; HDL-C ⫽ high-density lipoprotein cholesterol; IMT ⫽ intima-media thickness; BP ⫽ blood pressure; DASH ⫽ Dietary Approaches To Stop Hypertension. Reprinted with permission from Mosca et al.16

● “Ideal cardiovascular health”: this relatively new concept encompasses the following: absence of clinical CVD and ideal cholesterol, ideal blood pressure, and fasting glucose levels, coupled with adherence to heart-healthy behaviors, lean BMI, smoking abstinence, participation in physical activity at recommended goals, and a heart-healthy diet. Curr Probl Cardiol, November 2012

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Bairey Merz: The new guidelines appropriately indicate that a large majority of women are “at risk” for CVD in their lifetime.

Smoking. Tobacco use is the leading preventable cause of IHD in women especially in those who are 50 years of age and younger. Cigarette smoking triples the risk of MI for women, yet smoking cessation has been less prominent and less effective among women than men. There appears to be a dose-dependent relationship between total tar consumption per day and risk of MI, but as few as 1-4 cigarettes per day increases a patient’s risk of fatal or nonfatal MI by as much as 2-3 fold. There is also a well-established synergistic relative risk (RR) for women who smoke and also use oral contraceptives, including an elevated risk of thrombosis and cardiovascular complications. Aggressive public health campaigns put forth over the past decades have resulted in declining smoking rates for both women and men. Based on the 2008 National Health Interview Survey, since 1965, smoking prevalence for women in the United States has decreased from 33.9% to 18.3%.26 ● Smoking cessation decreases CVD morbidity and mortality; 1 year after cessation, the risk of MI decreases by 50%, and after 10 years, the CVD rate approaches that of nonsmokers.27 ● The effects of smoking on heart disease in women compared with men were reported in a systematic review and meta-analysis of prospective cohort studies. After a selection of 86 prospective trials stratified by sex, with measures of RR, and associated variability for CHD and current smoking, the investigators concluded that compared with nonsmokers, women who smoke have a 25% greater RR of CHD than male smokers, independent of other CVD risk factors. ● It is unclear whether the mechanisms underlying the gender differences are biological or related to difference in smoking behavior between men and women. Given the present trends in female smoking, smoking cessation programs and policies to address female smoking are going to be crucial from a public health perspective.28 Physical Inactivity. Physical inactivity (PA) is the most prevalent risk factor for women, and almost 2 of 3 USA women are currently overweight or obese. A recent prospective study in Taiwan29 in a population of 416,175 healthy individuals, age 20 or older, followed for a mean of 8.05 years (52% females), suggested that as little as 15 minutes a day or 90 minutes 460

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a week of moderate-intensity exercise has significant health benefits, compared with individuals in the inactive group; at age 30 years, life expectancy for individuals in the low-volume activity group was 2.55 years longer for men and 3.10 years longer for women. This study showed that in Taiwan, if inactive individuals engage in low-volume daily exercise, 1 in 6 all-cause deaths could be postponed—mortality reductions of similar magnitude have been estimated for a successful tobacco control program in the general population.30 Furthermore, every additional 15 minutes of daily exercise beyond the minimum amount of 15 minutes a day further reduced all-cause mortality by 4% (95% confidence interval [CI]: 2.5-7.0). These benefits were applicable to all age-groups and both sexes. A recent aggregate meta-analysis of epidemiologic studies investigating PA and primary prevention of CHD evaluated dose-response estimates for exercise31 suggested that high level of leisure time PA reduces the risk of CVD in a range of about 20%-30%, compared with the risk of those with low level of PA at leisure time, whereas moderate leisure time PA decreases the risk by about 10%-20%, indicating an obvious doseresponse relationship. The effects and patterns were similar for men and women. These effects were found to be independent of the impact of major cardiovascular risk factors, which were considered as confounders.32 The fact that a minimum amount of exercise can reduce mortality from heart disease, diabetes, and cancer is encouraging and raises the need for physicians to consider physical activity a major player in the global war to improve the overall health of the population, while reducing medical costs and health disparities. Diabetes. Compared with men, diabetes is a far more impressive risk factor for MI and stroke in women. ● Compared with nondiabetics, diabetic women have a 3- to 7-fold increased CV risk in diabetic in contrast to an only 2- to 4-fold increase in risk for diabetic men. ● Diabetic women have significantly increased IHD mortality rate compared with diabetic men. In numerous population-based studies, diabetic women have a 3- to several- fold increase in IHD death when compared with a 2- to 3-fold increase in death for diabetic men.27 ● The past 30-year trends show marked reduction in CVD mortality for diabetic men but not for diabetic women.33 ● A key to effective blood glucose control is optimal weight control as well as maintenance of physical fitness. Curr Probl Cardiol, November 2012

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Bairey Merz: Diabetes is associated with anovulatory menstrual cycling estrogen deficiency in younger premenopausal women. PCOS is also associated with diabetes; however, much of the associated premature CVD risk is because of the diabetes rather than PCOS.

● For women, a BMI⬎30 is associated with an increased risk for diabetes, HTN, heart failure, as well as other major adverse cardiac events. In both men and women, visceral adiposity and waist circumference are strong risk factors for progression to type-2 DM.34 In individuals with impaired fasting glucose, the effect of increase in waist circumference appears to be a better predictor of progression to diabetes type 2 (odds ratio [OR]: 2.40; 95% CI: 1.63-3.52) in leaner subjects, with BMI of ⬍25 kg/m2 compared with those whose BMI was 25 kg/m2 or more at baseline (OR: 1.66; 95% CI: 1.28-2.16). Waist circumference is thought to reflect visceral fat more accurately in leaner subjects, and individuals with impaired fasting glucose who are prone to develop overt diabetes may gain visceral fat more selectively than subcutaneous fat, compared with those who do not develop diabetes.35

Bairey Merz: Obesity is a marker most often of physical inactivity and lack of fitness. In overweight and obese women who are physically active and fit, body weight per se does not increase CVD risk.

Hypertension. Nearly 1 in 3 adults in the United States has HTN, defined as systolic blood pressure ⬎140 mm Hg and/or diastolic pressure ⬎90 mm Hg. Hypertension is a major risk factor for IHD. Hypertension increases with age and presents earlier in men. In populations younger than 45 years of age, a higher percentage of men than women have HTN; from ages 45-54, the percentage of women is slightly higher, but almost 80% of women age ⬎75 years have HTN, particularly isolated systolic HTN, exceeding the rates of males in the same age-group. ● In addition to the traditional risk factors associated with HTN, such as dyslipidemia, obesity, and diabetes, other factors, such as autonomic mechanisms and hemodynamic and metabolic disorders, are also implicated in the high prevalence of HTN and CVD in older women.36 ● For women, HTN leading to diastolic dysfunction is a major cause of CHF, noted to be up to 60% of heart failure in elderly women. 462

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● HTN also increases a patient’s risk of stroke as well as IHD: the prognostic implications of LV hypertrophy caused by HTN appear to be more profound in women than in men.37 Initial steps to control HTN include weight control and dietary changes, including lowering of sodium intake and reduction of alcohol consumption, as well as increasing fruit and vegetable consumption. ● Optimal blood pressure targets in patients at high risk for IHD, such as those with diabetes, remain controversial. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure38 recommended a blood pressure goal of ⬍130/80 mm Hg in patients with diabetes, but this recommendation was not based on evidence from randomized, controlled trials. Lipids. Compared with men, women reach higher blood cholesterol levels than men after their 5th decade of life and decrease their levels of HDL-C after menopause. The rationale for treating hypercholesterolemia for primary prevention is based on epidemiologic data documenting a continuous graded relationship between the total plasma cholesterol concentration and CVD events and mortality.39,40 Cholesterol management guidelines have been published by the NCEPATP III41 and recommend the following: ● In high-risk patients, defined as those with known CHD or equivalent, or with 10-year risk ⬎20%: X Lowering LDL-C levels to a target of ⬍100 mg/dL. X Instead of explicitly recommending clinicians lower LDL-C in high-risk patients to levels ⬍70 mg/dL, the ATP III report left the door open for future evidence. ● In moderate-risk patients, those with 2 or more risk factors for CHD (10%-20% risk of CHD within 10 years), the NCEP target remains LDL-C ⬍130 mg/dL but gives clinicians a new therapeutic option to treat to ⬍100 mg/dL. ● In low-risk patients, those with 0-1 risk factor, the target LDL-C is less than 160 mg/dL, with option to implement lipid-lowering therapy if not meeting this target despite adequate therapeutic lifestyle changes. Bairey Merz: New NCEP guidelines are expected that will summarize risk and treatment data with regard to important populations, such as women.

High-Density Lipoprotein. HDL-C levels appear to have a stronger association with heart disease in women than men.42 It is estimated that Curr Probl Cardiol, November 2012

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a 1 mg/dL increase in HDL-C reduces the risk of heart disease by 3% in women compared with 2% in men.43 Low–HDL-C levels remain a significant risk factor for CAD even when the level of LDL is appropriately lowered.44,45 The Framingham Heart study showed women in the lowest quintile of HDL-C to have a RR of IHD 3 times higher than those in the highest quintile.46 ● In ATP III, the definition for low HDL was revised to ⬍50 mg/dL (1.29 mmol/L) for women; low HDL for men was changed to ⬍40 mg/dL (1.04 mmol/L), up from ⬍35 mg/dL (0.91 mmol/L) used in the first 2 ATP reports. ATP III does not explicitly specify a goal for raising HDL. However, the current body of literature is limited with regard to HDL-C-raising therapies specifically for women. First-line therapy for low HDL should be therapeutic lifestyle changes, including exercise, weight control, and smoking cessation. Among drug therapies, niacin continues to be the most effective. Niacin should be used cautiously in patients with diabetes, as niacin may decrease insulin sensitivity and elevate glucose levels. ● Fibrates often have some ability to increase HDL, partly because of the reduction in triglyceride levels. ● Statins tend to have some effect on HDL levels, but it is usually modest. ● Although estrogen raises HDL, there is no role for its use to reduce cardiovascular risk in postmenopausal women. ● Lifestyle alterations that include dietary changes, smoking cessation, and aerobic exercise must be used concomitantly with pharmacotherapy. ● New modalities currently being investigated to further increase HDL-C levels include cholesteryl ester transfer protein inhibitors, exogenous HDL mimetics, and ABCA1 upregulators, have not shown to improve CVD outcomes, and some have had deleterious effects. Bairey Merz: The recent clinical trial AIM-HIGH that aimed at raising HDL in combination with statin therapy has failed to demonstrate CVD benefit in women and men.

Triglycerides. Elevated triglyceride levels appear to be a stronger risk factor for IHD in women than in men.47,48 There is now abundant 464

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epidemiologic evidence that remnants of very low-density lipoprotein and chylomicrons are atherogenic particles, and are present in human plaques.49,50 Oxidative stress is increased in the presence of hypertriglyceridemia, and endothelial vasomotor dysfunction is frequently present. Framingham data reveal that individuals with triglyceride levels exceeding 150 mg/dL have an increased IHD risk ⬎1.551; triglyceride values that exceed 350 mg/dL are associated with a 2-fold increased IHD risk. ● ATP III defines triglycerides of 150-199 mg/dL (1.70-2.25 mmol/L) as borderline high, 200-499 mg/dL (2.26-5.64 mmol/L) as moderately high, and ⱖ500 mg/dL (5.65 mmol/L) as high. ● Depending on the severity of the hypertriglyceridemia, pancreatitis, lipemia retinalis, and eruptive xanthomas can occur. ● Management is primarily dietary. Most affected adults can maintain triglycerides at an acceptable level while eating a diet low in fat, low in simple carbohydrates, and avoiding alcohol consumption. Complex carbohydrates are allowed in moderation and maintenance of appropriate body weight should be encouraged. ● Marine omega-3 fatty acids are effective in triglyceride reduction. ● Oral estrogens should be avoided. ● When triglycerides reach 800 mg/dL, the lipoprotein lipase clearance mechanism is saturated, and the patient should avoid all fats in the diet and alcohol for 72 hours to reduce the risk of precipitating pancreatitis. Those patients may require greater restriction of total daily fat intake (15-20 g/d). ● If needed, niacin (in the absence of insulin resistance) or a fibric acid derivative will produce further reduction. ● The Action to Control Cardiovascular Risk in Diabetics lipid52 trial demonstrated that addition of fenofibrate to statin therapy did not further reduce the rate of major cardiovascular events in the majority of patients with type 2 DM who were at high risk for CVD. Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P ⫽ 0.01 for interaction), and a possible interaction according to lipid subgroups, with a possible benefit for patients with high baseline triglyceride and low baseline HDL-C levels (P ⫽ 0.057 for interaction). Interestingly, the treatment interaction according to sex for the entire Action to Control Cardiovascular Risk in Diabetics lipid cohort was not observed in the sub-subgroup of female patients with dyslipidemic profile as defined by the study (triglyceride level 204 mg/dL or Curr Probl Cardiol, November 2012

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more and HDL-C of 34 mg/dL or less). Results from this trial and others support the view that combination lipid-lowering therapy should be limited to those high-risk patients with substantial dyslipidemia.

Bairey Merz: Current hypertriglyceridemia indication for marine omega-3 fatty acids is ⬎300 mg/dL.

Lipoprotein(a) (Lp[a]) Hyperlipoproteinemia. Lp(a) is a plasma lipoprotein particle made of an LDL-like particle (contains apolipoprotein B-100) and apolipoprotein(a) protein (apo[a]), a homolog of plasminogen that covalently binds to the apolipoprotein B-100 of the LDL-like particle. Lp(a) can inhibit fibrinolysis and has been demonstrated to be present in atherosclerotic plaque. Genetic studies and numerous epidemiologic studies have identified Lp(a) as an independent risk factor for CVD.53-55 Lp(a) plasma concentrations are highly heritable and mainly controlled by the apo(a) gene (LPA) located on chromosome 6q26-27. Apo(a) proteins vary in size because of a size polymorphism (KIV-2 VNTR), which is caused by a variable number of so-called “kringle” IV repeats in the LPA gene, resulting in apo(a) proteins with 10 to ⬎50 kringle IV repeats.56 These variable apo(a) sizes are known as “apo(a) isoforms.” ● Smaller apo (a) isoforms are associated with a higher circulating levels of Lp(a) and increased risk of CAD and ischemic stroke. ● The magnitude of association of Lp(a) with CVD from the “Emerging Risk Factors Collaboration” was found to be approximately onequarter that of LDL-C.52 ● Lp(a) concentrations may be affected by disease states, for example, kidney failure, but are only slightly affected by diet, exercise, and other environmental factors. ● Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Results using statin medications have been mixed in most trials; however, a recent meta-analysis suggests that atorvastatin may be of benefit.57 ● Currently, the only available treatment to lower Lp(a) is niacin, 1-3 g daily, preferably in crystalline form (lower incidence of transaminitis compared with sustained release forms). The extent of Lp(a) reduction achieved with niacin is highly variable. ● The effect of estrogen on Lp(a) levels remains unclear. Estrogen replacement therapy in postmenopausal women appears to be associated with lower Lp(a) levels. However, one large study suggested that 466

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there was a decreased association between Lp(a) levels and risk.58 At present, estrogen is not indicated for treatment of elevated Lp(a).59 Aspirin mitigates the increased risk of MI associated with Lp(a) variant (SNP). Risk for major cardiovascular event (MI, stroke, or CV death) increases ⬎2-fold in carriers compared with noncarriers of the Lp(a) variant. In the Women’s Health Study (WHS), aspirin was found to reduce the increased risk attributed to the Lp(a) variant to the level of noncarriers. For prevention of major CVD events with aspirin, the number needed to treat (NNT) was 37 in LPA carriers versus 615 in noncarriers.60 Another study on the effects of aspirin among LPA carriers also showed increased risk of CHD in LPA carries compared with LPA noncarriers, and the use of aspirin offset this risk. These observations are consistent with those reported in WHS.61,62 The European Atherosclerosis Society currently recommends that patients with a moderate or high risk of CVD have their Lp(a) levels checked.53 A patient with one or more of the following risk factors should be screened: X Premature CVD. X Familial hypercholesterolemia. X Family history of premature CVD. X Family history of elevated Lp(a). X Recurrent CVD despite statin treatment. X ⱖ3% 10-year risk of fatal CVD according to the European guidelines. X ⱖ10% 10-year risk of fatal and/or nonfatal CVD according to the United States guidelines.

Measuring Lp(a) for all comers is currently not recommended by the guidelines, as it is not clear whether lowering concentrations of Lp(a) reverses cardiovascular risk, but should be considered in individual patients. One of the difficulties in demonstrating the potential benefit of lowering Lp(a) levels is that the only agent capable of considerably reducing Lp(a) levels—niacin—also reduces LDL-C and triglycerides and increases HDL-C. Bairey Merz: There is currently insufficient evidence to support use of Lp(a) testing or treatment.

Hormonal Disturbances. Disruption of ovulatory cycling or irregular menses in premenopausal women is associated with an increased risk of Curr Probl Cardiol, November 2012

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coronary atherosclerosis and adverse CVD events.6 PCOS is present in 10%-13% of women and is linked with a clustering of risk factors, such as obesity, insulin resistance, and PA, and is associated with adverse IHD events after menopause.63 Women who have undergone premature menopause and/or oophorectomy may have accelerated atherosclerosis and increased risk for IHD. The causative link between low estrogen level and premature IHD may be confounded by other comorbid conditions. Estrogen Replacement. The role of estrogen supplementation in postmenopausal women has been the focus of most research aimed at both primary and secondary prevention of CVD risk. In a woman’s premenopausal years, estrogen levels are approximately 10 times higher than that of an older-aged woman, which is accounted for primarily by the ovarian production of estrogen. Endogenous estrogen may serve to protect a woman’s risk of IHD through higher levels of HDL-C, improved arterial compliance and coronary flow reserve, as well as improvements in global myocardial function responses to stress.27 The net benefit of estrogen or combined estrogen-progestin replacement therapy in postmenopausal women is still uncertain. Extensive observational data suggested that estrogen may be cardioprotective; however, recent prospective clinical trials have shown that estrogen therapy alone or in combination with progestin does not protect from heart disease or stroke and may even be harmful.64,65 ● In the Heart and Estrogen/Progestin Replacement Study, there was no decrease in risk of CVD with estrogen/progestin among women with known CHD. ● The outcome in healthy women was reported from the Women’s Health Initiative (WHI), wherein menopausal hormone therapy increased the risk of MI, stroke, and venous thromboembolism.62 The menopausal hormone therapy results of WHI can be summarized as follows: X For the estrogen ⫹ progestin arm of the study, reported in July 2002, combination hormone therapy increased the risk of heart attack, breast cancer, blood clots, and stroke, as well as dementia and ovarian cancer. ● There was a decrease in the risk of hip fracture, colorectal cancer, and endometrial cancer, and there was no effect on the quality of life. X The estrogen-only arm of WHI, in women who had had hysterectomy, was reported in March 2004 and showed an increased risk of 468

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stroke and of probable dementia or memory loss, a decrease in hip fracture, and no effect on breast cancer or heart disease. Most now agree that estrogen is still a reasonable therapy when used short-term for menopausal symptoms, but it should not be prescribed for either primary or secondary prevention of IHD or stroke. Bairey Merz: The ELITE and Kronos Early Estrogen Prevention Study randomized clinical trials of hormone therapy in the early menopause results are expected soon.

Risk Factors Related to Pregnancy. Complications of pregnancy and resultant CV risk pose a problem unique to women. Increasingly, pregnancy is recognized as a CV and metabolic stress.66-68 Latent vascular dysfunction and metabolic disturbances may be unveiled during pregnancy, and manifest as pre-eclampsia, gestational HTN, or gestational diabetes. ● Pre-eclampsia and gestational HTN increase coronary risk and are associated with a 2.6 time increase in fatal myocardial ischemic events, a 3-6 times increased risk of subsequent HTN, and a 3-fold increase in the risk of subsequent DM. ● Gestational diabetes is associated with 7-fold increase in the risk of subsequently developing type 2 DM. ● Postpartum cardiomyopathy and coronary artery dissection may lead to heart failure and MI in young women. In contrast, some pregnancy-related behaviors, such as breast-feeding, may reduce CVD risk: ● Data from the WHI involving 139,681 postmenopausal women69 showed that breast-feeding was protective against CVD. Total breastfeeding of ⬎12 months decreased the risk of CVD by 72% and was associated with decreased prevalence of HTN, DM, and hyperlipidemia. The longer the lactation, the lower the risk factors. ● Recent study in a prospective cohort of 3416 British women with a singleton pregnancy who participated in the Avon (UK) Longitudinal Study of Parents and Children; patients were followed up for an average of 18 years, when the average age of the women was 48.70 After accounting for various confounders, the following relationships between pregnancy complications and cardiovascular risk factors were identified: Curr Probl Cardiol, November 2012

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● Pregestational diabetes, gestational diabetes, and glycosuria were associated with increased fasting glucose, and gestational diabetes and glycosuria were associated with higher insulin and proinsulin levels. ● The hypertensive disorders of pregnancy were associated with increase in BMI, waist circumference, systolic and diastolic blood pressure, insulin, and lower levels of HDL-C. ● Having a baby who was large for gestational age was associated with increased waist circumference and fasting glucose, and having a baby who was small for gestational age was associated with higher blood pressure. ● Preterm birth was associated with higher blood pressure. ● Pre-eclampsia may be the better predictor of future CVD because it was associated with a wider range of cardiovascular risk factors. Pregnancy may be an important opportunity for early identification of women at increased risk of CVD later in life; however, longer follow-up studies are needed to determine whether the addition of information about pregnancy complications improves existing cardiovascular risk prediction scores. Inflammatory Diseases. Chronic inflammation-induced endothelial dysfunction because of underlying systemic autoimmune disorders is increasingly recognized as a nontraditional IHD risk factor. In the general population, individuals with elevated inflammatory biomarkers (eg, CRP) have increased CV events.71 Patients with rheumatoid arthritis have chronically elevated CRP and other inflammatory markers and increased CV mortality that is not explained by established cardiac risk factors. Premenopausal women with a history of lupus have 5-10 times the risk of IHD-related events compared with the background population. The reason for this increased risk of IHD is likely to be multifactorial. Additional metabolic, inflammatory, and immunologic factors, as well as therapy with agents, such as corticosteroids, are likely to have an adverse effect on cardiovascular risk in this population. The new drugs, such as tumor necrosis factor-alpha receptor blockers or interleukin-6 blockers provide an interesting opportunity to test the hypothesis that the specific reduction of inflammation will reduce IHD incidence. Obstructive Sleep Apnea (OSA). OSA is known to be associated with cardiovascular risk factors and CVD mortality in men; a recent prospective observational cohort study in Spain enrolled 1116 women with suspected OSA and followed them for a median of 72 months.72 The study found that women with no OSA (apnea-hypopnea index [AHI]: ⬍10) had a lower cardiovascular mortality rate (0.28 per 100 person470

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years) compared to women in the severe OSA (AHI: ⱖ30) group (3.71 per 100 person-years). When AHI was considered as a continuous variable, it had an independent association with increased cardiovascular mortality (heart rate [HR]: 1.18). CPAP adherence was independently associated with decreased cardiovascular mortality among patients who started CPAP treatment (HR: 0.72). ● This study suggests that the risk of CVD mortality associated with OSA is also present in women and that CPAP adherence is important to achieve mortality risk reduction. Psychosocial Risk Factors. ● Depression and other psychosocial risk factors, more common in women than in men, contribute to CVD risk in women. Women with these problems should be considered as at risk and screened for CVD risk factors.16

Noncoronary Cardiovascular Risk for Women Stroke poses a major CVD risk for women, and death due to stroke exceeds in women than in men.73 Stroke incidence is higher than MI74 in women before 75 years of age; the opposite is noted in men. Besides the classic risk factors for atherosclerosis, which are important for ischemic stroke, other risk factors affect women, such as pregnancy and hormone therapy. Also, women have a greater prevalence of HTN at older age, and have a different risk-to-benefit ratio for interventions to reduce stroke risk compared with men. The combination of migraine plus oral contraceptive use, HTN, or cigarette smoking was associated with greater than multiplicative effect for risk of stroke in a large European collaborative study.75 Alcohol. Light-to-moderate alcohol consumption might reduce stroke risk in white women; a study of ⬎80,000 women, ages 30-55 (97% white) who were enrolled in the Nurse’s Health Study and followed for an average of 26 years, found that compared with women who did not drink, the RR of stroke ranged from 0.83 for drinking ⬍5 g/d to 0.79 for those who consumed up to 15 g/d (17%-21% reduction in risk of stroke). The risk scores were adjusted for a variety of potential confounders, including age, smoking, hormone use, aspirin use, HTN, and history of atrial fibrillation (AF). The benefit was similar for ischemic or hemorrhagic stroke. Compared with abstainers, heavier alcohol consumption was associated with smoking, a history of HTN, increased physical activity, Curr Probl Cardiol, November 2012

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TABLE 2. Sex-related frequency in clinical arrhythmias78 Arrhythmia type Bradyarrhythmia Supraventricular tachyarrhythmias

Ventricular tachyarrhythmias

Male predominance Atrioventricular block Carotid sinus syndrome Premature atrial contraction Atrial fibrillation AVRT WPW syndrome Premature ventricular contraction ventricular tachycardia Sudden cardiac death SUDS Brugada syndrome

Female predominance Sinus node disease Inappropriate sinus tachycardia AVNRT

Congenital LQTS Acquired LQTS

AVNRT, atrioventricular node reentrant tachycardia; AVRT, atrioventricular reentrant tachycardia; LQTS, long QT syndrome; SUDS, sudden unexplained death syndrome; WPW, Wolff– Parkinson–White. Adapted from Linde,79 with permission from the author and Futura Publishing Company.

and a lower BMI. The heaviest drinkers—2-3 glasses a day— had an increased total and ischemic stroke risk (HR: 1.06 and 1.17, respectively) but a slight decreased risk for hemorrhagic stroke (HR: 0.97).76 These results are consistent with previous studies, and in all, suggest that lower levels of alcohol consumption may be antithrombotic and anti-atherogenic, lead to increased HDL, decreased platelet aggregation, clot formation, and increased fibrinolysis. Diet. Postmenopausal women whose diets are high in trans fats are at higher risk for ischemic stroke. Trans fats, which are typically found in processed food from partial hydrogenation of vegetable oils, are thought to raise heart disease risk by increasing cholesterol, inflammation, and endothelial dysfunction. Analysis of trans fat intake of ⬎87,000 women aged 50-79, 85% white, using a dietary database from the national project known as the WHI, showed a 39% increased risk of stroke among highest trans fat intake group. The impact of dietary trans fat appears to be modified by aspirin use; the risk of trans fat intake was reduced in women taking aspirin in this study (P ⫽ 0.43 for trend), and the risk ischemic stroke was elevated to 66% in nonaspirin users of the highest trans fat consumption (P ⬍ 0.01 for trend).77

AF and Other Arrhythmias Gender differences in the incidence of arrhythmias have been recognized; women present more frequently with inappropriate sinus tachycardia, atrioventricular node reentrant tachycardia, and sinus node disease (Table 2).78,79 Some differences in frequency of arrhythmias are related 472

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to differences in presentation of underlying organic heart disease, such as the presence of ventricular arrhythmias associated with IHD. However, clinical and experimental differences in electrophysiological properties have been reported between men and women. These differences have important clinical and therapeutic implications for the management of arrhythmias in women. QT Interval. It is long recognized that compared with men, women have longer QT intervals (congenital and acquired), and the difference becomes more prominent at lower heart rates (HRs). A high incidence of torsade de pointes (TdP) in women has been described in connection with both congenital and acquired long QT syndromes.78 In the International Long QT Registry, 70% of the probands were women,80 also in a pooled analysis of 322 patients with drug-induced TdP, 70% of those affected were women,81 irrespective of underlying LV function, electrolyte abnormalities, or baseline QT intervals. ● Female sex and advanced age are known risk factors for developing TdP in hospitalized patients.82 ● A possible protective effect of natural androgens is suggested from the observation that corrected QT intervals tend to shorten in males after puberty (when androgen levels are highest).83 Atrial Fibrillation. Men are at greater risk of AF than women for all age-groups. However, because there are almost twice as many women than men who are older than 75 years in the general population, the absolute number of women with AF in older age-groups exceeds that of men. Women affected by AF are more likely than men to experience symptoms, tend to present with higher HRs during AF, and have increased rates of recurrence, which increases the risk of stroke.84 Diverse mechanisms have been proposed to explain the gender differences, including electrophysiologic differences throughout the atrial tissue and hormonal differences; AF in women may be influenced by menstrual cycle phase and age-related differences in atrial effective refractory period. The potential benefits of various treatment strategies to control HR, prevent thromboembolic complications, and conversion to and maintenance of sinus rhythm may be affected by gender. ● Risks of stroke and mortality associated with AF are significantly higher in women than men.85 ● AF is associated with a 4- to 5-fold increase in the risk of embolic stroke, and undertreatment with anticoagulants doubles the risk of recurrent stroke. Undertreatment with anticoagulants is a common problem for women. Curr Probl Cardiol, November 2012

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● The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial reported no significant sex differences to rate or rhythm control strategy in high-risk AF patients.86 ● However, the Rate Control Versus Electrical Cardioversion study revealed that women randomly assigned to rhythm control arm had 3 times higher incidence of cardiac events, including increased incidence of CHF, thromboembolic complications, and severe antiarrhythmic adverse drug events, such as proarrhythmia and bradycardia requiring pacemaker implantation.87,88 ● Because of their propensity for developing QT prolongation and TdP, caution must be used when administering antiarrhythmic agents to women. Female gender has been documented in many studies as a risk factor, with females having baseline QTc intervals that are generally 20 ms greater than that of males.89,90 ● Several drugs have been withdrawn from the United States market or have received black box warnings because of their potential to cause QT interval prolongation that leads to fatal ventricular arrhythmias and sudden cardiac death91; in these cases, the adverse effect was seen predominantly in women. ● Whether a rate or a rhythm control strategy is used, appropriate use of anticoagulation is pivotal to avoid AF-related thromboembolism. ● Interruption of anticoagulation before invasive procedures contributed to the significantly higher rate of thromboembolism observed in the Stroke Prevention Using an Oral Thrombin Inhibitor trial.92 ● Warfarin use has been associated to an increased risk of bleeding in women. The Canadian Registry of Atrial Fibrillation database reported that compared with men, women taking warfarin were 3.35 times more likely to experience major bleeding.93 ● Dabigatran, a new oral direct thrombin inhibitor, has been shown to be noninferior to warfarin in terms of thromboembolism prevention and risk for bleeding,94 but recent reports of increased serious bleeding events are being investigated by the Food and Drug Administration (FDA) to determine whether the reports of bleeding in patients taking dabigatran are occurring more commonly than expected. In addition to concerns for bleeding, the lack of a reversal agent for dabigatran has limited its widespread implementation. Ventricular Tachycardia. Male predominance in patients presenting with ventricular tachycardia and sudden cardiac death/arrest in the Framingham Study94 increased with the age of the subjects and appeared to be explained by the epidemiology of CAD. Other studies, have 474

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reported that women presenting with sudden cardiac death/arrest were younger, had better ejection fractions, lower defibrillation thresholds, were less likely to have organic heart disease, and more likely to present with ventricular fibrillation.95 After 2-year follow-up, the incidence of ventricular events necessitating device therapy was lower in women than in men (37% vs 52%). Sex-related differences in the incidence and prevalence of certain cardiac arrhythmias remain unexplained. Scant evidence available suggests 2 general mechanisms: sex steroid hormone effects on ion channels and the modulation of autonomic tone. Better understanding of the basic mechanisms of these differences will facilitate the development of more effective sex-specific methods of diagnosis and treatment. Implantable Cardioverter Defibrillators (ICDs). ICDs have not been shown to reduce all-cause mortality in women with advanced heart failure, according to a meta-analysis published by Ghanbari et al96 that raised questions about the value of using data from male-dominated trials to treat females. The study pooled data from 934 women enrolled in 5 primary prevention trials (MUSTT, MADIT II, DINAMIT, DEFINITE, and SCD-HeFT) and showed a hazard ratio of 1.01 for death (95% CI: 0.76-1.33; P ⫽ 0.95) for women. NNT to save a single life was 40 for women with ICDs versus 12 for men. The reasons for the sex differences in ICD implantation rates are not well established, but may be largely driven by the paucity of data for women in randomized clinical trials of ICD therapy. For example, 3810 men were included in the analysis; this is ⬎4⫻ the number of women that were included. There are questions as to whether the amount of data for women is sufficient to allow for the type of subgroup analysis included in the study. In contrast, MADIT-cardiac resynchronization therapy (CRT) showed no discernible difference in ICD deaths between men and women. Moreover, CRT-D was more effective in women, who had a RR reduction of 63% (HR: 0.37; 95% CI: 0.59-0.97), than in men. Males had a RR reduction of 24% (HR: 0.76; 95% CI: 0.59-0.97; P ⫽ 0.01 for interaction). Currently, ICD therapy is indicated for patients with cardiomyopathy (ischemic or nonischemic), a LV ejection fraction of 35% or less, and New York Heart Association class II-III heart failure. However, use of these devices in women has been the exception rather than the rule. Medicare data indicate that only 8.6 of every 1000 women who meet criteria for ICD for primary prevention of sudden cardiac death receive a device within a year of diagnosis. That compares with 32.3 of every 1000 men with the same diagnosis. Curr Probl Cardiol, November 2012

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Analysis of data from the National Cardiovascular Data Registry found that women have a 70% higher risk of major adverse events after ICD implantation than men. In summary, these findings highlight what is already known about women with heart failure, they have more comorbidities and are less likely to be enrolled in clinical trials of ICDs. More research is needed to determine the effects of ICD therapy for women with heart failure.

Peripheral Arterial Disease PAD is considered a CAD risk equivalent, thus aggressive screening for and treatment for this disorder is of great importance for both men and women. Although few deaths are attributed directly to PAD, patients with PAD have a 5- to 6-fold increase in risk of morbidity and death from CAD and stroke. The prevalence of CAD in PAD patients varies according to the sensitivity of the method used to detect its presence, ranging from 19% when clinical history is used to as high as 90% when angiography is used.97 The development of PAD for women, similar to the risk of CAD, lags approximately 10 years behind men, such as for ambulatory patients under age 70, PAD is more common in men than women; however, in patients over age 85, the prevalence of PAD is higher in women (39% in women vs 27% in men).98 ● Compared with men, women more often have unrecognized disease, leading to more advanced PAD at the time of diagnosis and a decreased likelihood of revascularization and overall worse prognosis.99 ● The prevalence of PAD in women increases rapidly beyond 40 years of age from 3% to 4.4% up to 15.5%-29% at the age of 80 years and older.100,101 ● Because of a lower prevalence of PAD in young women compared with older women and men, little is known about risk factors and prognostic factors of the long-term outcome in premenopausal women with PAD. Young women with PAD (⬍60 years old) are at higher risk for cardiovascular events compared with men of that age (HR: 4.9; 95% CI: 1.8-13.6), whereas no difference was found ⬎60 years of age.102 A 5-year prospective study from the Netherlands found young women with PAD smoked more often than older women with PAD (85.2% vs 47.5%; P ⬍ 0.01) and more often had previous vascular interventions (59.3% vs 30.5%; P ⬍ 0.01). Women older than 60 years more often had critical limb ischemia (57.4% vs 25.9%; P ⬍ 0.01), angina pectoris (23.4% vs 0%; P ⫽ 0.03), and an ABI ⬍0.6 (68.8% vs 476

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FIG 2. Kaplan–Meier curves stratified by age and sex. Women ⱕ60 years of age (n ⫽ 27), women ⬎60 years of age (n ⫽ 142), men ⱕ60 years of age (n ⫽ 90), and men ⬎60 years of age (n ⫽ 223). Reprinted with permission from Wisman et al.102 (Color version of figure is available online.)

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48.1%; P ⫽ 0.048). Women under 60 years of age with PAD are particularly at risk, with a 5-fold increased risk of cardiovascular complications compared with men of the same age; their prognosis was found to be as poor as patients older than 60 years with PAD (Fig 2). Gender-based differences in the development of PAD have been studied in select populations. In Taiwanese diabetic patient, older age and high systolic blood pressure were associated with PAD in men, and high uric acid levels and treatment with insulin were associated with PAD in women.103 Classic risk factors for the development of PAD are similar to traditional risk factors for CAD: smoking, diabetes, HTN, and dyslipidemia. In the general population, the prevalence of PAD doubles in patients with diabetes (9.5%)104; cigarette smoking is the strongest risk factor for development of PAD in women.105 Smoking is associated with a 5.5 OR for PAD in the National Health and Nutrition Examination Survey in persons aged 60 and older106; in young women on oral contraceptive pills (aged 18-49 years), smoking is associated with a 19.1 OR for development of PAD, according to a population study in Netherlands.107 Nontraditional risk factors that have been associated with PAD in women include elevated serum uric acid, CRP, and homocysteine levels.108,109 Women are more likely than men to present with asymptomatic disease, thus the patient’s history may not be helpful. It is estimated that physicians will miss approximately 85%-90% of PAD cases if they

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rely only on the patient’s history for the diagnosis of PAD.110 In patients with intermittent claudication, the ratio of men to women ranges between 1:1 and 2:1. ● Progression to critical limb ischemia is rare, but more common in women than in men. From population-based studies, the prevalence of critical limb ischemia is estimated to be 1.5% in women and 0.9% in men; the presence of critical limb ischemia is associated with high mortality rates, up to 25%.111 ● Long-term prognostic research in patients with PAD is scarce, and outcome determinants have mainly been studied in males. Aggressive risk factor control, such as smoking cessation, might improve the prognosis, especially for younger women. Differences in risk factors for PAD between men and women suggest gender differences in the pathophysiology of the disease and raise the need for further research to optimize management of PAD in women. In summary, a number of differences in risk-factor prevalence and outcome exist between men and women. Generally, women present later in life, and have a greater degree of co-morbidities with a larger risk-factor burden that plays important roles in clinical outcomes.

Myocardial Ischemia in Women Symptom Assessment There are substantial differences between women and men in pain perception and reporting, as well as the type, frequency, and quality of symptoms, noted during chest pain presentations. Women may perceive chest pain sooner after the onset of ischemia/MI, this may lead to “longer” estimated “ischemia onset” times in the ED, potentially leading to conclusions that “women delay seeking treatment,”112 as well as making more women “ineligible” for thrombolytic therapy. These factors may contribute to more adverse outcomes.113 Because women report generally more symptoms of chest pain, and have higher frequency of unexplained chest pain, chest pain is less specific for epicardial CAD,114 resulting in physicians having reduced confidence in pursuing testing.

Gender Differences in Symptoms As presented in Fig 3, the likelihood of significant obstructive coronary disease in women has been found to vary by age-group and with the type of chest pain symptoms at the time of presentation; the likelihood of CAD 478

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FIG 3. From the Women’s Ischemia Syndrome Evaluation (WISE) study. Graphs comparing the probability of coronary artery disease (diamond probability, shown as open bars) compared with the observed coronary artery disease prevalence in the WISE study (solid bars) in symptomatic women grouped by age: (35-45), (46-55), (56-65), 66-75) years. Open bars ⫽ diamond probability; solid bars ⫽ WISE prevalence. Reproduced with permission from Shaw et al.115

decreases as pain classification degrades from “typical angina” and “atypical angina” to “non-cardiac chest pain.”115 Typical angina is defined as having all 3 of the following characteristics: (1) substernal chest discomfort with a quality characterized by patients as “squeezing,” “grip-like,” “pressure-like,” “suffocating” or “heavy,” unchanged with position or respiration, and with duration of the pain typically lasting a few minutes (a fleeting discomfort or a dull ache lasting for hours is unlikely to be angina); (2) provoked by exertion or emotional stress; and (3) relieved by rest or nitroglycerin. Atypical angina meets 2 of the previous characteristics, whereas noncardiac chest pain meets one or none of the typical angina characteristics. Other frequently reported symptoms are diaphoresis, light headedness, shortness of breath, nausea, and vomiting; these symptoms may or may not accompany chest pain or discomfort. For elderly women, it is recognized that shortness of breath is often the initial presenting symptoms for acute MI; however, despite the reported Curr Probl Cardiol, November 2012

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gender differences, women who present acutely with the typical symptoms (chest pain or discomfort, dyspnea, diaphoresis, and arm or shoulder pain) have acute coronary syndromes (ACSs).116 Because women age, they tend to present with more typical symptoms, more similar to men (typical angina). Absence of chest pain is associated with diabetes and delayed hospital arrival, irrespective of age or sex. Patients with chest pain are more likely to have ST-segment elevation MI (STEMI) and anterior MI, whereas those without pain or discomfort were more likely to have non-STEMI, irrespective of age and sex. However, a study that reviewed medical records of 1.1 million Americans from 1994 to 2006 in the National Registry of Myocardial Infarction, the largest database of MI patients in the world, revealed higher mortality for both women and men with MI and no chest pain compared with patients presenting with chest pain; compared with men, mortality for women was higher.117 In this study, 35.4% of patients presented with no chest pain on arrival to the hospital with a MI— 42% of the women and 30.7% of the men (P ⬍ 0.001). Analysis of the data stratified by age showed that women were more likely to have no chest pain in association with an MI across all age-groups. The absence of chest pain at presentation was associated with increased mortality, especially among younger women. In-hospital mortality was higher for women compared with men (15% of the women died in the hospital, compared with 10% of men); the excess risk for women decreased with age, as the oldest women were less likely to die than men the same age presenting without chest pain. Younger women presenting without chest pain had greater in-hospital mortality compared with same age men, and these sex differences decreased or even reversed with advancing age, with adjusted OR for age younger than 45 years, 1.18 (95% CI: 1.00-1.39); 45-54 years, 1.13 (95% CI: 1.02-1.26); 55-64 years, 1.02 (95% CI: 0.96-1.09); 65-74 years, 0.91 (95% CI: 0.88-0.95); and 75 years or older, 0.81 (95% CI: 0.79-0.83). Comparison of mortality among men and women with chest pain revealed a similar pattern. Women had a higher mortality across all age-groups, but the odds versus men declined with increasing age and reversed in the oldest age-group, OR 1.18 for patients aged younger than 45 and OR 0.81 for women aged 75 and older. Patients without chest pain and discomfort tend to present later, are treated less aggressively, and have almost twice the short-term mortality compared with those presenting with more typical symptoms. 480

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When evaluated for symptoms suggestive of myocardial ischemia, women tend to perceive pain earlier than men and have lower rates of obstructive CAD at angiography. The Coronary Artery Surgical Study registry demonstrated that for any given extent of CAD (single, double, or triple vessel) found during angiography, women were more symptomatic, had more functional impairment, and more unstable symptoms than men.118 Data from the WHI document that women with nonspecific chest pain have a 2-fold greater risk for nonfatal MI,119 whereas the WISE data and the St. James “Women Take Heart Project” demonstrate increased rates of mortality in women with chest pain and no obstructive CAD,120 underscoring that prognosis in these women is not benign. Many women without epicardial CAD at coronary angiography continue to have symptoms that contribute to a poor quality of life and continuous consumption of health care resources, including repeated evaluations for myocardial ischemia and hospitalizations.

Microvascular Coronary Dysfunction (MCD) Management of patients with angina and evidence of myocardial ischemia on stress testing without obstructive CAD by angiography (previously referred to as cardiac syndrome X [CSX]) is a challenge. Patients with MCD may have persistent chest pain, evidence of angina, and ischemic-type ST-segment depression or noninvasive perfusion or wall-motion abnormality during stress testing. Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine (endotheliumindependent microvascular coronary reactivity) improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. Coronary microvessels studies are shedding new light into novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women. Data from the National Heart, Lung, and Blood Institute-WISE, the largest and most completely investigated cohort with midlife women and this syndrome, showed that up to 50% of patients may have MCD.121 MCD has been linked with adverse outcomes among women with stable IHD and nonobstructive CAD. In symptomatic women with no significant obstructive CAD, MCD is associated with the presence of atherosclerosis on intravascular coronary ultrasonography122 and has a 2.5% annual adverse cardiac event rate, including risk of MI, stroke, CHF, and sudden cardiac death. Thus, MCD appears to be a high-risk subgroup within CSX. Curr Probl Cardiol, November 2012

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Bairey Merz: Identification of the triad of persistent symptoms, abnormal stress test, and no obstructive CAD identifies an at-risk group for adverse cardiac events, recurrent hospitalization, and procedures.

There is ample evidence over supporting the crucial role that the endothelium plays in vascular homeostasis. Endothelial dysfunction is characterized by impairment of endothelium-dependent vasodilation and the presence of proinflammatory and prothrombotic factors promoting atherosclerosis, plaque progression, and occurrence of clinical events.123,124 Endothelial dysfunction is present in patients with cardiovascular risk factors and no angiographic or ultrasonography evidence of obstructive intraluminal coronary disease. The relative importance of endothelial and microvascular dysfunction has only recently been recognized and as yet insufficiently explored. An integrated understanding of mechanisms and manifestations of ischemia impacting IHD risks in women has been summarized in Fig 4.6 CMD appears to be more prevalent in women than men; likely the result of risk factor clustering, higher prevalence of vascular inflammation and remodeling, and hormonal influences. MCD is likely playing an etiologic role in the paradoxically frequent, “atypical symptoms” seen in women with no evidence of obstructive coronary disease, yet who have increased adverse outcomes. This model provides a rationale for incorporating MCD and nonobstructive atheroma into the risk stratification armamentarium to diagnose and treat IHD in women.

Approaches for Diagnosing IHD in Women Recommendations for the noninvasive workup of women presenting with stable angina are summarized in the following diagram (Fig 5).125,126

Management of Women with Chest Pain and Suspected IHD Noninvasive stress testing is recommended to assess for ischemia. Although specific exceptions are allowed, current guidelines recommend that standard exercise testing be used as the initial screening modality for females. Exercise testing provides extensive useful information regarding a person’s cardiovascular status, including exercise capacity, hemodynamic response, symptoms elicited by exercise, and electrocardiographic (ECG) response. Abnormalities in exercise capacity, blood pressure response to exercise, HR response to exercise, and occurrence of ischemic chest pain during exercise are all important 482

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FIG 4. Working model of ischemic heart disease pathophysiology in women. CAD, coronary artery disease; PCOS, polycystic ovary syndrome. (Reprinted with permission from Shaw et al.6) (Color version of figure is available online.)

FIG 5. Algorithm for noninvasive testing in women. Consensus statement from the American Society of Nuclear Cardiology. CAD, coronary artery disease; ECG, electrocardiogram; EF, ejection fraction; Ex, exercise; LV, left ventricle; METs, metabolic equivalents. (Reprinted with permission from Mieres et al.125 and with permission of the Society of Nuclear Medicine from Cacciabaudo and Hachamovitch.126) Curr Probl Cardiol, November 2012

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findings that carry diagnostic as well as prognostic significance beyond ECG interpretation.127 Therefore, in patients who are able to exercise, an exercise-based test should be preferred over pharmacologic testing, as it provides further valuable information. Exercise Stress Testing. Compared with men, use of exercise ECG stress testing for the diagnosis of coronary disease in women has some well-described challenges as follows: ● Exercise ECG testing is viewed as less specific in women than in men, for obstructive CAD; however, results from the literature have varied. The sensitivity and specificity of exercise-induced ST-segment depression in symptomatic women vary widely depending on the study, with the sensitivity generally being worse than the specificity. The sensitivity and specificity for the diagnosis of CAD in women range from 31% to 71% and 66% to 86%, respectively.128-131 A meta-analysis of exercise testing in women showed that the sensitivity and specificity for exercise-induced ST-segment depression in symptomatic intermediate-risk women were 61% and 70%, respectively.129 In a metaanalysis of predominantly male participants, the sensitivity and specificity were higher, 68% and 77%, respectively.132 In a study of symptomatic men and women undergoing exercise ECG and subsequent angiography, the positive predictive value of exerciseinduced ST-segment depression in women was significantly lower compared with men (47% vs 77%, respectively; P ⬍ 0.05). However, the negative predictive value (NPV) of ST-segment depression in symptomatic women was similar to that of men (78% vs 81%, respectively).133 X Women are more likely to have false-positive exercise ECGs; however, a negative exercise stress test is useful in effectively ruling out CAD. X Gender differences have been attributed multiple factors, including disease prevalence, non-Bayesian factors, and hormonal differences. Furthermore, compared with men, women have more frequent baseline ST- and T-wave changes that make the interpretation of ECG with exercise difficult. ● In premenopausal women, the intensity and severity of ECG-based ischemia may vary with the menstrual cycle, with lower midcycle estradiol levels associated with a greater frequency and intensity of chest pain, as well as increased inducibility of ST-segment abnormalities.115,134 484

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Bairey Merz: The lower specificity of exercise ECG for obstructive CAD in women compared with men is at least partially due microvascular ischemia because of MCD.

The evaluation of exercise capacity, HR response, HR recovery (HRR), blood pressure response, and Duke Treadmill Score (DTS) can be used to enhance the utility of exercise testing. Of all the factors noted during testing, one of the strongest predictive parameter from the treadmill test is exercise duration, a measure of fitness or exercise capacity (measured as metabolic equivalents [METs] during treadmill testing). Exercise capacity is an independent predictor of CAD in women. X In a study of 419 women and 555 men who underwent maximal exercise stress testing for symptom evaluation, maximal exercise capacity (added to ST-segment depression) improved the sensitivity and specificity of exercise stress testing. Compared with those who achieved ⬎10 METs, those who achieved ⬍7 METs were more likely to have ischemia (0.4% vs 7.1%; P ⬍ 0.001). No significant ischemia was observed in participants who achieved ⬎10 METs and had no ST-segment depression.135 X HR response: the inability to reach 85% of the maximum agepredicted HR with exercise has been associated with higher likelihood of CAD in women.136 Peak and recovery HR measures have also been shown to improve risk assessment and diagnostic accuracy for IHD in women. The measurement of HRR may be particularly important for women who have a rapid HR increase early into the test and remains elevated during recovery. Early hyperexaggerated HR response is often seen in sedentary women, associated with excessive dyspnea and premature fatigue. X Abnormal HRR, defined as the peak HR minus the HR at 1 minute into recovery of ⬍12 beats per minute, has been shown to be an independent predictor of both all-cause mortality and cardiovascular death in women.137 X An exaggerated blood pressure increase with exercise stress testing or during recovery (defined as ⱖ210 mm Hg in men or ⱖ190 mm Hg in women) has been shown to be associated with an increased risk of developing HTN in both men and women.138 ● DTS has been shown to provide information beyond clinical predictors of both coronary disease and survival in women and men. The use of the DTS in the interpretation of exercise stress testing is currently Curr Probl Cardiol, November 2012

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recommended in the ACC/AHA guidelines for exercise stress testing.139 This score was developed from data in 2842 patients (30% women), with known or possible CAD, who underwent exercise testing and subsequent diagnostic angiography; these patients had no history of previous revascularization or recent MI.140 ● The DTS score includes the following variables: exercise time (during Bruce protocol testing), maximum ST-segment depression, and the presence or absence of angina, as follows: DTS ⫽ exercise time (min) ⫺ (5 ⫻ ST-deviation) ⫺ (4 ⫻ angina score index) Exercise time is measured in minutes on the Bruce protocol. ST deviation is greatest net ST-segment deviation in any lead; the angina score index is scored from 0 to 2, where 0 is no angina, 1 is nonlimiting angina with exercise, and 2 is angina limiting exercise. ● Patients with a high-risk DTS (DTS ⱕ⫺11) were 376-fold more likely to have significant CAD than those with a low-risk DTS (DTS ⱖ⫹5). Similar results for the value of DTS as a diagnostic tool have been validated in symptomatic women. X A study by Shaw et al in men and women who underwent treadmill testing followed by cardiac catheterization showed that the DTS performed equally well in stratifying both genders into prognostic categories; however, the DTS performed better in women excluding disease, with fewer women identified as “low risk” having any significant coronary disease (1 vessel with 75% stenosis) (20% vs 47%; P ⬍ 0.001), or severe disease (3-vessel disease or 75% left main stenosis) (3.5% vs 11.4%; P ⬍ 0.001). Exercise Testing With Imaging. The AHA consensus statement recommends the addition of imaging (single-photon emission computed tomography [SPECT] or echocardiography) for the evaluation of intermediate-risk women who either have an abnormal exercise ECG or an abnormal baseline ECG that would preclude the interpretation of STsegment changes with exercise.125 Frequent difficulties with clinical evaluation of women for CAD led to propose ECG exercise treadmill test (ETT) with stress imaging as the initial method to evaluate women rather than performing isolated exercise EKG testing. However, the WOMEN trial, a prospective study in women who were able to exercise evaluated 486

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the ability of EKG alone versus EKG plus myocardial perfusion imaging (MPI) for the diagnostic evaluation in women with suspected CAD, yielded similar 2-year posttest outcomes for major adverse cardiovascular events using ETT with or without imaging.141 In this cohort of women, ETT provided significant diagnostic cost savings. ● Women were eligible to enter the trial if they (1) had typical/atypical chest pain or ischemic equivalents (eg, dyspnea); (2) had an interpretable baseline EKG (ie, no significant resting ST-segment changes ⱖ0.5 mm); (3) were aged ⱖ40 years or postmenopausal; (4) were able to achieve ⱖ5 METs on the Duke Activity Status Index questionnaire142; and (5) were at intermediate pretest CAD likelihood.139 ● ETT with selective follow-up imaging testing may be considered as the initial diagnostic strategy in symptomatic women with suspected CAD who do not meet the inclusion criteria mentioned previously. ● A normal exercise MPI study and a normal exercise echocardiography study have both been found to have high NPVs for CAD in primary and secondary cardiac events. X A meta-analysis of patients with a negative imaging study (MPI or echocardiogram) found an annualized event rate of ⬍1% (same as the general population).143 Single-Photon Emission Computed Tomography. SPECT is used to assess for myocardial ischemia by detecting regional variations in the distribution of blood flow in the myocardium. It is important to recognize the fact that global coronary vascular ischemia (eg, in severe multivessel CAD) or dysfunction (endothelial or microvascular dysfunction) may be completely missed, as in these conditions, the images may show no regional differences in the distribution of flow and will appear normal. ● SPECT has been shown to be less sensitive for detecting CAD in women; the difference correlates with heart size (smaller LV chamber size in women) compounded by the limited spatial resolution of SPECT cameras.144 ● It is important to note that during MPI, image quality may be degraded by the interference of breast tissue or subcutaneous fat and may be the cause of false-positive test results. Higher-energy 99mtechnetium radioisotopes are preferred in women to avoid these soft tissue attenuation artifacts. Further reduction in false-positive results can be obtained by attenuation corrections or prone imaging techniques. Global and regional LV wall motion, function, and wall thickness can be used to Curr Probl Cardiol, November 2012

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TABLE 3. Diagnostic accuracy of various stress testing modalities in women Exercise EKG Author, year (reference) Fleischmann et al., 1998 Kwok et al., 1999 Kohli and Gulati, 2010

Sensitivity

Specificity

Exercise echocardiography

Exercise SPECT

Sensitivity

Specificity

—

—

85%

77%

Sensitivity Specificity 87%

64%

61%

70%

86%

79%

78%

64%

31%-71%

66%-78%

80%-88%

79%-86%

78%-88%

64%-91%

SPECT, single-photon emission computed tomography. Adapted from Shaw et al.115, with permission from the author and Elsevier publishing company.

correlate reductions in regional myocardial perfusion to further evaluate reductions in tissue perfusion seen by SPECT. Cardiac Positron Emission Tomography (PET). PET is increasingly used for noninvasive assessment of myocardial perfusion and myocardial viability. Compared with conventional SPECT techniques, PET has superior spatial and temporal resolution and is a quantitative method; also, the use of PET perfusion tracers with short half-lives, such as FDA-approved 82Rb and 13 N-ammonia, allows for shorter imaging protocols. In women, the use of 82 Rb PET allows for quantification of absolute values of regional and global blood flow, which is particularly useful to assess flow reserve (to detect microvascular dysfunction). More studies are needed to further validate prognostic data and improve sex-specific reporting. Stress-Induced Wall-Motion Abnormality Assessment. Wall-motion abnormalities appear later than perfusion abnormalities during stress testing, a phenomenon known as the “ischemic cascade”; the presence of wall motion abnormalities has a higher diagnostic specificity and prognostic significance for ischemia. For the detection of wall-motion abnormalities, stress echocardiography has advantages over nuclear imaging because of its low cost, no radiation exposure, and ability to assess cardiac structure as well as function. Despite these advantages, stress echocardiography can be limited in some patients because of inability to obtain good quality imaging, for example, in obesity or lung disease (poor acoustic windows). Table 3 summarizes the diagnostic accuracy of the modalities discussed previously.13,115,129,145 488

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Cardiovascular Magnetic Resonance (cMR) Imaging Assessment. Stress cMR imaging has the capability of not only detecting myocardial ischemia useful for the diagnosis of CAD but has been also shown to be effective in the detection of subendocardial perfusion deficit consistent with small vessel disease. The detection of cMR subendocardial ischemia in women with abnormal stress tests and normal coronary angiograms has been assessed in small studies and found to be strongly correlated with abnormal coronary reactivity testing.146,147

Bairey Merz: Abnormal perfusion by cMR also predicts an adverse prognosis in women with signs and symptoms of ischemia but no obstructive CAD.

Coronary Computed Tomographic Angiography (CCTA). CCTA has been reported to have a high diagnostic accuracy for the detection of obstructive CAD in patients presenting to the emergency department with chest pain. In a series of 51 women and 52 men, the overall diagnostic sensitivity and specificity were 85% and 99% respectively148; a larger multicenter controlled trial in 291 patients (74% male) reported a specificity of 90%.149 ● The use of radiologic imaging techniques, such as nuclear imaging and CCTA, is limited by the inherent risk of cancer associated with ionizing radiation exposure. ● Women, especially younger women, have greater cumulative risk of cancer compared with men exposed to comparable amounts of radiation. One study estimated the mean number of radiation-related incident cancers and found that the projected number of incident cancers per 10,000 scans generally decreased with increasing age at exposure.150 The risk per 10,000 scans also varied according to scan type, with consistently high risks for chest or abdomen computerized tomography angiography and whole-body computerized tomography. The projected risks were generally higher in females than in males for scans that exposed the chest because of the additional risk of breast cancer and the higher lung cancer risk. ● Radiation exposure in younger women may increase lifetime cancer risks, and should be done with caution and avoided if possible. ● Test protocols emphasizing reductions in radiation exposure, including ECG-controlled tube current modulation, prospective gating, minimiCurr Probl Cardiol, November 2012

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zation of scan length, and optimization of tube current and voltage, should be optimized in medical centers for all patients. Pharmacologic Stress Testing. For patients who are unable to adequately exercise, pharmacologic stress testing (commonly performed with adenosine or dipyridamole or the newer selective A2A adenosine receptor agonist, regadenoson) is recommended by the ACC/AHA and American Society of Nuclear Cardiology guidelines.151 In summary, exercise ECG is the recommended first test of choice in the evaluation of symptomatic intermediate-risk women who are able to exercise and have a normal baseline ECG. Given the strong diagnostic and prognostic information that can be determined with exercise variables, women who are able to exercise should preferentially undergo this method of testing over pharmacologic testing. ● The Duke Activity Status Index questionnaire can be used as a screening tool to determine which women will perform adequately on an exercise stress ECG. The Duke Activity Status Index questionnaire is a self-administered 12-question form designed to provide an assessment of exercise capacity; an estimated exercise capacity of ⬍5 METs suggests that a pharmacologic stress test will be preferable to an exercise stress test because such a low exercise capacity may not be able to induce ischemia.142 ● A negative stress ECG has a high NPV, which in combination with its low cost and wide availability makes it the recommended first step in the evaluation of a symptomatic woman with chest pain. ● A positive or inconclusive exercise ECG should be followed by stress testing with imaging or angiography if the exercise ECG appears particularly high risk. Negative stress testing with imaging effectively rules out CAD in symptomatic women. ● A woman who has no ST-segment depression, good functional capacity, and low-risk DTS is unlikely to have CAD,135 and no further is testing is required. Coronary Angiography. Use of coronary angiography as a diagnostic tool may be indicated if a patient’s risk factors, medical history, and clinical presentation are consistent with an intermediate-to-high IHD probability. If a patient’s symptoms are definitive, a diagnostic angiogram will define the patient’s coronary anatomy and the amount of myocardium at risk. For high-risk women, with either a high IHD probability or with unstable symptoms (eg, increasing chest pain frequency in the proceeding 490

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6 weeks of evaluation, rest angina), the decision to perform diagnostic angiography is supported by ample evidence. ● Among symptomatic patients referred for coronary angiography, it has been shown that women are 3-5 times more likely than men to have normal coronary angiograms at the time of catheterization.152,153 Women with a positive exercise test have traditionally been less likely than men to undergo further cardiac evaluation (62% vs 38%), but over the past decade, women with abnormal noninvasive tests are more likely to be referred to coronary angiography.154 In a study of ⬎30,000 patients (33% women) who underwent exercise radionuclide imaging, referral rates for men and women were similar after imaging results were stratified by the amount of abnormally perfused myocardium detected by the nuclear scan.155 However, in the setting of severe ischemia, women were referred to catheterization more frequently than men. This higher rate appears to be clinically appropriate because women with severely abnormal scan results had a significantly higher event rate than men (17.5% vs 6.3%, P ⬍ 0.0001). This greater risk in women than in men appeared to be underappreciated because the increased rate of hard events in women with severely abnormal scan results was out of proportion to the smaller increase in their rate of referral to cardiac catheterization, suggesting that women may have been under-referred for comparable degrees of risk.

Strategies for Prevention of IHD in Women The importance of a healthy lifestyle to prevent the future evolution of cardiac risk factors is paramount. Risk scores can help to identify traditional risk factors and provide a platform for reducing a large percentage of the population-attributable risk for IHD in women. Within the available risk models, the Reynolds risk score is a more useful tool, as FRS does not take into account a patient’s family history of CVD and was derived from a homogenous, mostly male, white population. Ideal cardiovascular health, a concept well supported in the literature, was coined by the AHA 2010 Impact Goal task force.156 It has been defined as (1) the simultaneous presence of 4 favorable health behaviors: abstinence from smoking within the past year, ideal BMI, physical activity at goal, and consumption of a dietary pattern that promotes cardiovascular health; (2) the simultaneous presence of 4 favorable health factors: abstinence from smoking within the past year, untreated total Curr Probl Cardiol, November 2012

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cholesterol ⬍200 mg/dL, untreated blood pressure ⬍120/⬍80 mm Hg, and absence of DM; (3) the absence of clinical CVD, including CHD, stroke, and heart failure. Abundant evidence supports the concept of ideal cardiovascular health for promotion of longevity, disease-free survival, quality of life, and reduction in health care costs.

Gender Differences in Clinical Response to Antiplatelet Treatment Aspirin. Although it is well known that women respond differently to aspirin treatment compared with men, few comparative studies have been done that provide insights into the biology underlying sex-related differences. Women show greater propensity for bleeding, even with appropriate dosing; and have differential benefit in terms of prevention of ischemic vascular events, dedicated trials are needed to increase female representation in antiplatelet treatment. ● For men, 2 randomized controlled trials, one in the United States and the other in Great Britain, have examined the efficacy of aspirin in the primary prevention of MI; the American study (Physicians’ Health Study) that enrolled ⬎22,000 asymptomatic male physicians aged 40-84 years was stopped prematurely, after 60.2 months of follow-up, when a statistically significant 44% reduction in the incidence of total (fatal plus nonfatal) MIs was noted in the group receiving 325 mg of aspirin every other day for MI, but not for stroke. However, the study failed to show benefit in total cardiovascular mortality because the reduction in the rate of acute fatal MI was offset by an increased rate of sudden death. ● In the WHS, involving 39,876 healthy low-risk female health professionals over the age of 40, aspirin 100 mg every other day prevented stroke, but not MI or CV death before age 65 years157; after age 65, although there was slight increase in the prevention of stroke, MI, and CV death for women, the increased risk of gastrointestinal (GI) bleeding virtually denied the benefit, prompting the authors to recommend individualization of aspirin use. ● In a meta-analysis of 6 randomized primary prevention trials, aspirin therapy was associated with significant reductions in stroke risk in women, but no significant effect was shown for MI.158 In contrast, for men, no effect was seen for stroke, but there was a significant reduction in risk of MI (tests for heterogeneity of treatment effect were not reported). 492

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● The International Study of Infarct Survival-2 trial159 found aspirin to be less effective in preventing vascular mortality after acute MI in women compared with men (16% for women vs 22% reduction for men on aspirin compared with placebo; P ⬎ 0.05 for heterogeneity). ● The Antithrombotic Trialists’ Collaboration160 meta-analysis included data from 16 secondary prevention trials (17,000 individuals; 3306 CVD events), and individual participant data from 6 primary prevention trials (95,000 individuals; 3554 CVD events) noted significant reductions in major coronary events and serious vascular events with aspirin in men, but not in women, for both primary and secondary prevention (Fig 6).160 ● In addition to the Antithrombotic Trialists Collaboration meta-analysis, 3 additional major randomized trials have been reported.161-163 In all 3 trials, aspirin use failed to reduce CVD events, raising questions about the utility of aspirin for primary prevention of CVD. But, as Mora noted in a recent editorial, all 3 trials were underpowered and had lower than anticipated CVD event rates, although the participants were selected from high-risk groups, based on the presence of diabetes or PAD.164 ● A more recent meta-analysis for aspirin use updated the previous data for primary prevention of CVD by combining the 3 recent trials with those of the previous 6 (total, 102,621 participants, 4278 CVD events, and 6-year mean follow-up). Consistent with previous results, this updated pooled analysis also found a RR reduction of 10% for CVD events and again no reduction in CVD mortality. The NNT was 120 to prevent 1 CVD event for 6 years, at the cost of 1 nontrivial bleeding event for every 73 individuals treated for 6 years.165 ● Although women have been shown to have higher platelet reactivity compared with men,166 aspirin doses ⬎100 mg have not demonstrated to have any additional benefit among women.167-169 ● The U.S. Preventive Services Task Force reviewed the evidence from NIH’s WHS and other recent studies and found good evidence that aspirin decreases first heart attacks in men and first strokes in women. The task force has issued a recommendation that women between the ages of 55 and 79 should use low-dose aspirin to reduce their risk for ischemic stroke when the benefits outweigh the harms for potential GI bleeding.169,170 ● The American Stroke Association and the AHA recommend aspirin therapy for people whose 10-year cardiovascular risk is 6% or higher,171 but in the final decision to prescribe aspirin for primary prevention in patients with no previous CVD, the benefit-to-risk ratio Curr Probl Cardiol, November 2012

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FIG 6. Selected outcomes in primary and secondary prevention trials of aspirin, by sex. Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented together with the corresponding mean yearly event rate (in parentheses). Rate ratios for all trials are indicated by squares and their 99% confidence intervals by horizontal lines. Subtotals and their 95% confidence intervals are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. *Myocardial infarction, stroke (hemorrhagic or other), or vascular death. CI, confidence interval. Reprinted with permission from the Antithrombotic Trialists Collaboration.159

for aspirin should be carefully weighed because these patients are at lower absolute CVD risk than patients with known CVD, and aspirin increases the risk of bleeding (GI bleeding and, more rarely, hemorrhagic stroke). ● The data available so far argue against the routine use of aspirin for primary prevention of CVD for individuals at low absolute risk of CVD. As the current guidelines recommend, it is reasonable to 494

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consider using aspirin for primary prevention in higher-risk individuals without known CVD (above 1% CVD event rate per year) if they are deemed to have a greater benefit-to-risk ratio.172 ● Thanks to the Patient Protection and Affordable Care Act and the aim to prevent 1 million MI s and strokes in the next 5 years, the Centers for Medicare & Medicaid Services has now expanded coverage of CVD prevention to include intensive behavioral counseling in addition to evaluating the individual benefit-to-risk ratio for aspirin use in primary prevention.

Bairey Merz: The US Preventive Services Task Force recommendations are the most evidenced based, recognizing that the clinical trial data did not support a “higher risk” strategy.

Aspirin for Secondary Prevention of CVD. Because clinical trials with aspirin have consistently shown reduced risk of CVD events and CV mortality for both men and women with CVD, aspirin is recommended for the secondary prevention of CVD, and hence, it should be routinely prescribed as recommended by current guidelines.160 However, among heart disease patients, women are less likely than men to use low-dose aspirin therapy— one study examined data on 1869 men and women aged 40 or older who reported heart disease before a heart attack. After adjusting for demographic, socioeconomic, and clinical characteristics, only 62% of women reported regular aspirin use, compared with 76% of men.170 Thienopyridines. Overall, clopidogrel treatment decreased the risk of CVD event (cardiac death, MI, or stroke) in patients with known risk factors for CAD, in a meta-analysis of 5 large randomized controlled trials.173 Among the 23,533 women included in the analysis, clopidogrel reduced the risk of MI (RR: 0.81; 95% CI: 0.70-0.93), but not for stroke or all-cause mortality. In contrast, in men (56,091 were evaluated), clopidogrel use was associated with significant reductions in all 3 end points. ● Randomized clinical trials of the antiplatelet agents prasugrel174 and ticagrelor175 showed greater risk reduction in primary end points in men compared with women, but the studies failed to show a significant interaction between sex and treatment assignment; these studies were underpowered to examine treatment interactions among subgroups. Curr Probl Cardiol, November 2012

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Glycoprotein (GP) IIb/IIa Inhibitors. Gender effect of GP IIb/IIIa inhibitors on cardiovascular events has been reported. In contrast to men with ACS, in whom the use of GP IIb/IIIa inhibitors has been associated with reduced incidence of death or MI at 30 days versus placebo, the use of these inhibitors in women had worse outcomes.176 The difference in outcomes has been explained by differences in clinical characteristics: women were older, had more comorbid conditions, and tended to have larger infarct size compared with men; the difference in risk disappeared when risk was stratified by troponin level. More recent studies have shown similar outcomes for men and women presenting with ACS.177 Statins. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) were shown to be effective in lowering cholesterol and have been extensively studied. The small number of women in the earlier statin trials led to questions about extrapolating results to women. A 2004 meta-analysis on lipid lowering showed no effect of lipid lowering in women without CVD on total or CHD mortality; however, some analyses were limited by too few CHD events in the available trials. For women with heart disease, lipid lowering reduced CHD mortality (RR: 0.74; 95% CI: 0.55-1.00), nonfatal MI (RR: 0.71; 95% CI: 0.58-0.87), revascularization (RR: 0.70; 95% CI: 0.55-0.89), and total CHD events (RR: 0.80; 95% CI: 0.71-0.91).178 A more recent large-scale trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) showed that for primary prevention, benefits for statins were similar in women 60 years or older and men 50 years or older, but did not show a benefit on mortality.179 A recent Cochrane Review assessing the effectiveness of statins for primary prevention of CVD found statin use associated with a reduction in overall all-cause mortality and reduction in combined fatal and nonfatal cardiovascular end points; they found no evidence of significant harm associated with statin use.180 However, there was limited evidence that primary prevention with statins was cost-effective. The review included 14 randomized controlled trials, 11 of these trials recruited patients with conditions, such as raised lipids, diabetes, or HTN, and some trials entered participants with CVD (an arbitrary threshold of ⬍10% of participants with pre-existing disease was used for inclusion of a trial in the review). The Cochrane investigators noted important limitations in the published data: power calculations in the majority of trials were based on composite outcomes, power calculations in over one-third of trials outcomes were reported selectively, and 8 trials did not report on adverse events at all. Moreover, 2 large trials were prematurely stopped because significant reductions in primary composite outcomes had been observed, 496

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and only 1 trial had been publically funded, whereas the authors of 9 trials reported having been sponsored either fully or partially by pharmaceutical companies. ● The Cochrane Review is helpful in highlighting that the available evidence does not support use of statins with ⬍1% annual all-cause mortality risk or an annual CVD event rate of ⬍2%. ● Other meta-analysis of primary prevention studies found no benefit on all-cause mortality in men or women.180 Side Effects Related to Statin Use. Adverse side effects are more common in women than men. A higher incidence of statin-related muscle symptoms (myalgia, muscle weakness) and memory problems is reported in women compared with men. ● Statin use in postmenopausal women has been associated to increased risk of DM; data from the WHI show that the risk of diabetes is higher than previously suggested, with an estimated 48% increased risk of diabetes among postmenopausal women taking statins. Women with the lowest BMI (⬍25.0 kg/m2) appeared to be at higher risk of diabetes compared with obese women, a finding the investigators speculate is related to phenotype or hormonal differences between the women.181 ● Further research is needed to define the risk-to-benefit ratio of statins for primary prevention in diverse populations of women with varying risks of CVD. In the meantime, aggressive lifestyle measures, including heart-healthy diet, increased physical activity, and smoking cessation should be integrated within well-rounded primary prevention programs to further reduce IHD risk in women. Bairey Merz: Summary analyses demonstrate that more nonfatal CVD events are avoided than cases of diabetes caused in women for primary prevention. Although we await the clinical trial fund of knowledge to recruit and test an adequate number of women for primary prevention, existing guidelines indicate that at-risk women should be treated with statins.

Management of IHD in Women There are many clinical challenges associated with treating women with IHD: ● There is an increased frequency, severity, and mortality of chronic stable angina in women compared with men.182 Curr Probl Cardiol, November 2012

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● Women with ACSs also entail an excess of complications, mortality, heart failure, stroke, and transfusion requirement compared with men.183 ● Women receive fewer evidenced-based beneficial therapies and referrals to cardiac rehabilitation after hospitalization for ACS. ● The excess mortality of younger women, specifically those age ⬍50 years, compared with men, after both MI and coronary artery bypass graft (CABG) surgery, remains unexplained.184 ● The increase in early mortality of women with ST-elevation MI appears related to the underuse of evidence-based treatments and delayed reperfusion.185 Recently, a large investigation using data from the Canadian Registry of ACS I and II, 6558 patients (4471 men and 2087 women), demonstrated sex differences in delivery of evidencebased therapies among patients with CAD.186 Female gender was also associated with underutilization of lipid-modifying agents and angiotensin-converting-enzyme (ACE) inhibitors despite adjustment for confounders; furthermore on average, women were nearly 5 years older than the men, and age was independently associated with lower use of beta blockers (OR: 0.83; P ⬍ 0.001) and lipid-lowering agents (OR: 0.80; P ⬍ 0.001) at discharge. X Only 41.8% of women underwent cardiac catheterization, compared with 49.6% of men, thought to be an indicator of physician assessment of perceived patient risk. X A multivariable analysis identified lack of catheterization as an independent predictor for underutilization of lipid-lowering agents (OR: 0.42; P ⬍ 0.001) and ACE inhibitors (OR: 0.83; P ⫽ 0.028). X These results highlight the fact that despite clear guidelines, women with ACS are still not receiving appropriate cardiac treatment, likely stemming from an erroneous belief that women are less at risk; this is a big mistake. Even if patients are not sent to the catheterization laboratory, they should receive appropriate evidence-based treatment for their ACS, including the appropriate use of beta blockers, ACE inhibitors, and lipid-lowering agents. ● A study from the Swedish Coronary Angiography and Angioplasty Register analyzed use of cardiovascular medications and diagnostic coronary angiography between 2006 and 2008 in 7195 men and 5005 women with suspected CAD after chest pain.187 X This study showed that a large proportion of women (78%) in the youngest age-group (59 years or younger) who underwent angiography had no significant CAD in comparison with only 42.3% of 498

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men (P ⬍ 0.001), and 18.2% of men were diagnosed with left main or 3-vessel disease compared with 4.2% of women (P ⬍ 0.001). This study suggests overuse of coronary angiography, especially in younger women, underscoring the difficulty faced by clinicians in diagnosing CAD in women. X Future studies need to focus on how physicians triage symptoms, risk factors, and results of noninvasive tests in selecting patients for angiography. The term CSX should be discouraged, as it is not useful.

Acute Ischemic Syndromes in Women Women who present with ACS, including unstable angina, non-STsegment elevation MI, and ST-segment elevation MI, are often older than their male counterparts and have a higher rate of comorbidities, such as HTN, diabetes, hypercholesterolemia, tobacco use, obesity, and a previous history of CHF.184,188

ST-Segment Elevation MI (STEMI) The GUSTO-II ACS study showed that fewer women than men present with STEMI (27% vs 37%), and for the remainder of patients with non-STEMI or unstable angina, approximately 37% of women had an infarction when compared with 48% in men.188 Women presenting with ACS-like chest pain syndromes have a higher incidence of no obstructive coronary disease at time of catheterization than men. Numerous clinical syndromes have been implicated in this phenomenon, including mitral valve prolapsed, vasospastic angina, microvascular endothelial dysfunction, hypothyroidism, neuromuscular disorders, and tachyarrhythmias. ● Women who present with obstructive epicardial CAD by angiography show no significant differences compared with men; they present with similar degrees of lesion severity, disease distribution, and prevalence of left main and 3-vessel disease.189 ● Women who undergo percutaneous coronary revascularization procedures often have clinical characteristics that increase the risk of major adverse events, including older age at presentation, and higher prevalence of comorbidities in comparison with men. Thus, women are also more likely to be considered suboptimal candidates for surgical revascularization. Curr Probl Cardiol, November 2012

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Cardiac Catheterization/PCIs According to the 2011 updated report from the AHA on heart disease and stroke statistics, ⬎1 million PCIs are performed each year in the United States; of these, one-third are performed in women.190 Compared with men, women present at an older age, more frequently have comorbidities (diabetes, obesity, and HTN), less frequently have a history of a previous MI or previous surgical revascularization, and differ in some angiographic characteristics, including smaller coronary artery size and extent of disease (lower SYNTAX score).191 In the early balloon angioplasty era, procedural success rates were lower and in-hospital mortality was higher for women than men192; bare metal stents improved safety and efficacy of PCI in women.193 More recently, drug-eluting stents (DES) have been shown to further reduce restenosis and repeat revascularization rates for both men and women.194 ● To date, only a few studies are available on sex-based differences in PCI using DES. A recent meta-analysis pooled individual patient data from 3 recent randomized clinical trials with unrestricted use of DES in all-comers (SIRTAX, LEADERS, and RESOLUTE-III trials) and compared clinical and angiographic outcomes between women and men during 2-year follow-up. This study showed that women undergoing PCI with DES have similar risk of cardiac death and MI as compared with men. Furthermore, their results showed comparable safety and efficacy for women and men undergoing PCI with DES in terms of stent thrombosis, repeat revascularization, and angiographic outcomes through 2-year follow-up, irrespective of the type of DES used.191 ● Other studies demonstrate similar angiographic outcomes for men and women, with similar incidence of periprocedural MI and need for emergent CABG.195,196 ● In the New Approaches to Coronary Intervention Registry,197 women undergoing percutaneous revascularization presented with higher-risk profiles, yet had similar procedural success rates; however, women experienced higher rates of periprocedural complications, such as coronary artery dissection, hypotension, need for vascular access repair, and transfusions. There were no significant sex-based difference in the rate of in-hospital death, ST-elevation MI, or emergent CABG, and sex was not found to be an independent predictor of major adverse cardiac events. At 1-year follow-up, more women than men reported an improvement in their angina symptoms (70% vs 62%), and fewer women than men required repeat revascularization (32% vs 36%). 500

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● Because of the risk of femoral access site complications and bleeding in women, many physicians are using radial access or bivalirudin as the antithrombotic of choice in women. Use of radial artery for access during cardiac catheterization has decreased the rate of insertion site complications for both men and women. However, compared with men periprocedural complication rates remain higher for women using radial artery approach.

Surgical Revascularization Advances in surgical techniques and myocardial protection have increased the availability of surgical revascularization procedures for women with ACS. Despite these advances, in-hospital mortality rates for women are often 2-3 times higher than for men. These poor outcomes are only partially explained by older age and higher risk profiles and are attributed to greater technical difficulty as well as a higher frequency of urgent or emergent procedures in females.198 In women, surgical myocardial revascularization has increasingly been performed using an off-pump (without cardiopulmonary bypass) technique. In a series of patients considered appropriate for off-pump revascularization procedures, the mortality for women was lower in comparison with men who underwent traditional surgical revascularization procedures.199 However, these favorable outcomes in women likely reflect patient selection and require further study.

Prognosis Post-MI Several studies have described worse post-MI prognosis for women compared with men; these differences that may reflect the rate of revascularization procedures used in women in comparison with men. Women have been shown to seek medical attention later than men, and once evaluated, they are less likely to receive immediate aspirin therapy and had longer times to reperfusion.200 Cardiogenic shock is a serious complication after acute MI in 5%-15% of patients. Risk factors include older age, female gender, more IHD risk factors, history of previous MI, preexisting LV dysfunction, and CABG surgery.201 The “Should we emergently revascularize Occluded Coronary arteries for Cardiogenic shocK” (SHOCK) trial was a multicenter trial that randomized 302 women presenting with acute myocardial infarction and LV dysfunction to either revascularization or medical therapy202 to assess the role of mechanical reperfusion therapies on outcomes of cardiogenic shock. There were no significant differences in 30-day mortality between Curr Probl Cardiol, November 2012

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treatment groups, but by 6 months, a survival benefit was seen in patients who underwent revascularization. Of note, patients 75 years of age or older had a worse outcomes with any revascularization procedure. Also, 1107 patients ineligible for the SHOCK trial were entered into the SHOCK registry, in which women with cardiogenic shock were found to have similar cardiogenic shock rate owing to LV dysfunction as men, but women had higher rates of cardiogenic shock because of mechanical complications, such as acute severe mitral regurgitation, ventricular septal rupture, or isolated right ventricular shock, than men.203 ● Women who present with acute ST-segment elevation MI accompanied by cardiogenic shock are often older, thus revascularization may portend worse outcomes in this subset of women.

Bleeding Risk in ACS Sex-related differences in bleeding risk have been consistently demonstrated. ● Female sex was identified as an independent predictor of in-hospital major bleeding in a multivariate risk model (OR: 1.31; 95% CI: 1.23-1.39).204 ● The CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines?) study showed that women undergoing PCI had significantly higher rates of in-hospital major bleeding compared with men (14.1% vs 5.9%; P ⬍ 0.001).205 The increased bleeding risk seen in women treated with antiplatelet therapy appeared to be in part related to inappropriate dosing; an estimated 15% of the major bleeding observed in CRUSADE was related to excess dosing of unfractionated heparin, low-molecularweight heparin, or GP IIb/IIIa inhibitors. Even after adjustment for age, weight, and renal function, women remained at higher risk of excess dosing and bleeding than men. ● A report from the Northern New England Percutaneous Coronary Intervention Registry also found that women undergoing PCI tend to have more access site bleeding and retroperitoneal bleeding,206 in part related to smaller blood vessel size than men. The Registry also found that in women, excess dosing of antiplatelet agents accounted for 72% of the increased bleeding risk, compared with only 27% of the risk in men. Bleeding has implications that extend well beyond the acute event, because patients who bleed are less likely to be prescribed antiplatelet 502

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therapies, and the reinitiating of treatment is often delayed indefinitely (until the patient is deemed “safe”). Given the higher incidence of in-hospital bleeding among women compared with men, this may have major implications for the risk of future ischemic events in women. In summary, for patients presenting with ACS, sex-based differences in clinical presentation, evaluation, treatment strategies, and outcomes have been well documented. Compared with men, women have been shown to be older, have higher-risk clinical features, and comorbid diseases at the time of presentation. Additionally, noninvasive and invasive tests often poorly diagnose the etiology of chest pain in women owing to the high chest pain prevalence in the absence of a epicardial coronary artery stenosis. Women who are found to have obstructive CAD often have more high-risk angiographic features than men. Women presenting with ACS undergo coronary revascularization with a higher risk for adverse outcomes. Recent advances in access site (radial approach), device application, adjunctive therapies, and surgical techniques suggest that coronary revascularization strategies are safe and effective to treat women in the setting of ACS’.27

Treatment Strategies for Women with Stable CAD Although revascularization by PCI or CABG has been shown by many studies to be superior to medical management in patients presenting with ACS, as well as in symptomatic patients with complex CAD, in patients with chronic stable angina, and in patients with silent ischemia, there is an ongoing debate as to the best treatment strategies for women with stable coronary disease.207 This debate has been further stimulated by the findings of 2 large randomized controlled trials, Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation (COURAGE)208 and Bypass Angioplasty Revascularization Investigation type 2 Diabetes,209 which showed that in selected patients with mild-to-moderate angina and documented obstructive CAD by coronary angiography suitable for revascularization, there was no difference in death or MI between the 2 strategies. Of note, the COURAGE trial reviewed 35,000 angiograms but only included 6% of these angiograms into their randomization; high-risk patients were excluded from the trial. Furthermore, 40% of COURAGE participants were low-risk patients presenting with mild angina or no angina symptoms (class 0 or I symptoms), these patients would not have an indication to undergo cardiac catheterization or PCI according to Curr Probl Cardiol, November 2012

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TABLE 4. Drugs used to treat patients with chronic stable CAD Medication Antithrombotic drugs (eg, aspirin) Lipid-lowering drugs (eg, statins) Beta-blocking agents Calcium channel blockers Nitrates ACE inhibitors Nicorandil Ivabradine

Indicated in all patients

Symptomatically useful

Yes

No

Yes

Yes

No

Yes

Yes No

Yes Yes

Yes (chronic stable CAD?) No

No No No No

Yes No Yes Yes

No Yes (chronic stable CAD?) Yes No

Prognostically useful

ACE, angiotensin-converting-enzyme. Reprinted with permission from Zellweger and Pfisterer207 and John Wiley & Sons publishing company.

current guidelines; these limitations of the COURAGE trial make it difficult to generalize findings to the general population presenting with chronic angina symptoms. ● It remains unclear how these findings can be used in the general population, and should not be generalized to patients with unknown coronary anatomy or to female patients that only represented 15% of the total COURAGE cohort.

Medical Therapy and Risk Factor Management for CAD Optimized medical therapy is the cornerstone of treatment in patients with chronic CAD, including patients with stable coronary disease and those undergoing revascularization. Medical treatment includes aggressive risk factor modification with lifestyle changes, diet, exercise training, treatment of diabetes, HTN and hyperlipidemia, as well as smoking cessation and weight reduction. ● Medical treatment is effective on reducing angina and improving prognosis; it is a low-risk low-cost intervention that is underused in daily practice. Current medical therapy and risk factor modification strategies should conform to updated ACC/AHA treatment guidelines as summarized in Table 4.207 Optimal management is targeted to achieve stabilization of existing atherosclerotic plaque, reduce future risk of ischemic events, and reduce symptoms. All patients with coronary disease and chest pain syndromes 504

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should receive antithrombotic therapy with aspirin. Aspirin acts via irreversible inhibition of platelet cyclooxygenase-1 and thus inhibits thromboxane production, which is usually completely achieved with chronic doses of 50-75 mg/d. The available evidence supports daily use of aspirin in the range of 75-100 mg for long-term prevention of vascular events.207 Clopidogrel, 75 mg/d, is recommended in patients with allergy or intolerance to aspirin.210 Use of dual antiplatelet therapy with clopidogrel in addition to aspirin is recommended in all patients after stent implantation or after MI, unless contraindicated. However, in patients with chronic stable CAD, there are no data to support the addition of clopidogrel to treatment with aspirin, and there are clear data of increased rate of bleeding complications. Lipid-lowering drugs and, particularly, statins improve survival in patients with acute as well as chronic CAD. Statins lower cholesterol effectively, but mechanisms other than cholesterol synthesis inhibition, such as anti-inflammatory and antithrombotic effects, may contribute to cardiovascular risk reduction. Current guidelines recommend a goal, LDL-C of ⬍100 mg/dL in patients with stable CAD. A more stringent goal of ⬍70 mg/dL is advocated, but is left to the discretion of treating clinicians. For patients with refractory angina symptoms despite optimal medical therapy and revascularization, other newer anti-ischemic drugs may provide additional symptomatic relief. ● Ranolazine is a drug with a novel mechanism of action that has been shown in several large trials to be an efficacious adjunctive agent in reducing symptoms of chronic stable angina. It is thought to work by inhibiting the late sodium current in cardiac myocytes, thereby reducing sodium and calcium overload that follows ischemia. This improves myocardial relaxation and reduces LV diastolic stiffness, which in turn enhances myocardial contractility and perfusion. The drug is generally well tolerated, and the evidence so far is encouraging.211 ● Nicorandil, a potassium channel opener, has anti-ischemic effects similar to long-acting nitrates and may be used in combination with other anti-ischemic drugs to treat chronic angina. One study revealed prognostic efficacy of nicorandil,212 and a more recent study showed that nicorandil prevents endothelial dysfunction213 its use has been limited by it causing painful mucosal ulcers in a approximately 5% of patients.214 ● Ivabradine also has anti-ischemic effects. It reduces HR at rest and during exercise by inhibiting sinus node activity. Thus, it may be an alternative drug for patients not tolerating beta-blocking agents.215 Curr Probl Cardiol, November 2012

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Coronary Angiography and Revascularization for Stable CAD In all randomized trials comparing invasive versus conservation strategies for chronic CAD, revascularization has been shown to reduce angina severity more effectively and more rapidly than medical therapy. The same was true for quality of life improvement in those studies in which this was measured.207 Recent subgroup analyses of COURAGE216 and Bypass angioplasty revascularization Investigation type 2 Diabetes217 confirmed findings from previous studies that higher-risk patients or those with complex CAD derived the most benefit from revascularization. PCI is recommended for a proximal coronary artery stenosis that jeopardizes a large myocardium area, which may result in severe inducible ischemia and also angina refractory to medical therapy. Drug-eluting stents and maturation of other catheter-based techniques have improved the procedural success rate and further reduced restenosis rate. In a report of 118,548 patients undergoing PCI, women who underwent coronary stenting had higher rates of same-admission mortality and urgent CABG when compared with men.218 On event-free survival through hospitalization, the overall therapeutic PCI benefit for women is equivalent to that of men. CABG surgery is considered the treatment of choice for patients with significant obstruction of the left main coronary artery, as well as for those with triple-vessel CAD and LV systolic dysfunction. Women who undergo CABG generally have less symptomatic relief than men. This has been related to smaller-diameter vessels and more incomplete revascularization. In conjunction with older age and greater comorbidity, women tender to have higher in-hospital mortality after CABG.219 Despite differences in near-term outcomes, female sex is not associated with late morbidity and mortality after CABG.220

Heart Failure in Women Heart failure affects 5 million Americans, and nearly 50% of these are women. Compelling sex differences have been noted regarding the underlying etiology, prognosis, response to treatment, and how the disease impacts quality of life. Although HTN and valvular disease are more likely the culprits for heart failure in women, men are more likely to have CAD as the underlying cause.221 Women often present with heart failure at an older age and have less systolic dysfunction than men. The higher prevalence of CHF despite a lower prevalence of LV systolic dysfunction 506

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(consistent with fewer previous MIs) in women contrasted with men is now a clinical entity known as heart failure with preserved ejection fraction (HFpEF),222 also known as “diastolic heart failure” or “heart failure with normal ejection fraction.” It is essentially defined as heart failure in the absence of obvious reduction of LV systolic function (commonly defined as ejection fraction [EF] ⱖ45%, which includes a proportion of patients with abnormal LV function—EF: 45%-55%). Recent reviews and guidelines estimate the incidence of HFpEF to be present from 20% to 60% of patients with CHF; the patient population under study is obviously of great importance in making this estimate. The older the patient population, the higher the incidence of HFpEF. ● Women constitute a significant majority of elderly population, and hence, they appear disproportionally affected by HFpEF—approximately two-thirds of patients affected with HFpEF are women.27 ● Hypertension is the most common comorbidity associated with HFpEF (approximately 75%); CAD is less prevalent (approximately 35%). ● Mortality of patients with HFpEF is at least as high as, if not higher, that of heart failure with systolic dysfunction.223 For both sexes, heart failure contributes to significant morbidity and mortality, but ageadjusted data reveal that women have a better survival. However, women tend to have worse quality of life than men because of more physical limitations, increased heart failure–related hospitalizations, and higher rates of depression. ● In elderly patients hospitalized with (all-cause) heart failure, female gender is an independent predictor of preserved LV systolic function. ● Among postmenopausal women with established coronary disease, women with diabetes and elevated BMI or elevated creatinine have the highest risk for developing heart failure, with annual incidence rates of 7% and 13%, respectively; women with MI appear to have a lower risk of heart failure than men.224 Indeed, evidence from experimental studies, postmortem, and observational clinical studies suggests important differences in the process of myocardial remodeling between females and males in response to different types of myocardial injury (aging, pressure overload, volume overload, and MI). Interestingly, the remodeling process appears to favor women, as they have less ventricular dilation during the remodeling process compared with men. ● Factors influencing differential myocardial response to stress in women and men8 are summarized in Table 5. These differences between men and women are postulated to be related to differences in sex hormones, such as estrogen, but the molecular effects of estrogen on ventricular cardiomyoCurr Probl Cardiol, November 2012

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TABLE 5. Factors influencing cardiovascular prognosis in men and women Women

Men

Aging cardiomyopathy Preservation of cardiac weight Reduction in cardiac weight (1 g/yr) Preservation of myocyte number Reduction in myocyte number (64 million/yr) Preservation of myocyte volume Increase in myocyte cell volume Constant mononucleate/binucleate myocytes ratio Decreased mononucleate/binucleate myocytes ratio Low apoptotic index Apoptotic index 3-fold higher than women Increased apoptotic rate Decreased apoptotic rate Myocardial response to pressure overload Earlier improvement in EF after aortic valve Later improvement in EF after aortic replacement valve replacement Greater degree of LVH Lower degree of LVH Increased LV mass Increased relative wall thickness Smaller end-diastolic and -systolic dimensions Preserved LV function Impaired LV function Later onset of impaired systolic pump performance Earlier onset of impaired systolic pump performance Greater EF Greater cardiac index Smaller end-diastolic and -systolic volumes Higher expression of myosin heavy chain Lower expression of myosin heavy chain Higher expression of ANF mRNA Lower expression of ANF mRNA Myocardial response to volume overload Smaller end-diastolic and -systolic volumes Larger end-diastolic and -systolic volumes Greater LV mass/volume ratio Lower LV mass/volume ratio Concentric hypertrophy No concentric hypertrophy No impairment of cardiac function Impairment of cardiac function Minimal ventricular dilation Significant ventricular dilation No changes in myocardial compliance Decreased ventricular compliance Myocardial response to acute myocardial ischemia Lower apoptotic rate in peri-infarct region 10-fold higher apoptotic rate in periinfarct region Lower bax expression in peri-infarct region Greater bax expression in peri-infarct region Longer duration of the cardiomyopathy Shorter duration of the cardiomyopathy Later onset of cardiac decompensation Earlier onset of cardiac decompensation Longer interval between heart failure and Shorter interval between heart failure transplantation and transplantation Earlier myocardial healing Delayed myocardial healing Lower infarct expansion index Higher infarct expansion index Three times lower mortality Greater incidence in cardiac rupture

508

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TABLE 5. Continued Women

Men

Better cardiac function Better remodeling

Worse cardiac function Maladaptive remodeling Significantly greater dilatation Myocyte hypertrophy Premature extracellular matrix degradation Higher number of neutrophils Increased activity of metalloproteinases

Cardiogenic shock Significantly lower cardiac index Higher cardiac index More frequent adverse clinical events Less frequent adverse clinical events Less frequent mechanical complications More common low cardiac output syndrome Less common low cardiac output syndrome Heart failure Preserved LV EF Smaller LV end-diastolic volume Smaller stroke volumes Higher LV end-diastolic pressure More frequent congestive symptoms Greater impairment in diastolic filling

Impaired LV EF Greater LV end-diastolic volume Greater stroke volumes Lower LV end-diastolic pressure Less frequent congestive symptoms Lower impairment in diastolic filling

ANF, atrial natriuretic factor; EF, ejection fraction; LV, left ventricle/ventricular; LVH, left ventricular hypertrophy; mRNA, messenger ribonucleic acid. Reprinted with permission from Piro et al.8 and Elsevier publishing company.

cytes are not well understood. A better understanding of the processes involved in cardiac remodeling in women will likely lead to novel treatment modalities and ultimately will benefit patients of both sexes.

Management of CHF Despite sex differences in heart failure, prospective studies on sexspecific clinical therapies are lacking; thus, to date, the management recommendations for women and men are the same; some studies suggest221 that some of the available medications may not be as effective in women, whereas other therapies, for example, beta blockers, aldosterone antagonists, and pacemakers, may be beneficial.

Device Therapy The advent of device therapy, including ICDs and CRT for heart failure, further highlights the sex-specific response to novel heart failure management strategies. Implantation of ICDs has expanded to include primary prevention Curr Probl Cardiol, November 2012

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for sudden cardiac death after the publication of randomized clinical trials establishing their efficacy.225-227 However, data supporting the efficacy of ICDs for primary prevention in women are sparse. A meta-analysis of pooled data from 5 trials (934 women) revealed no statistically significant decrease in mortality in women with heart failure who received ICDs (hazard ratio: 1.01).96 Meanwhile, recent analysis of the National Cardiovascular Data Registry found that women have a 70% higher risk of major adverse events after ICD implantation than do men.228 CRT has become a significant part of the management of patients with advanced CHF. Several large-scale studies demonstrated significant improvement in multiple end points, including survival in patients with advanced CHF.229 Sex-specific results are similarly lacking for the use of CRT devices. Studies have shown that women have received significantly fewer CRT devices, despite the facts that more women have left bundle branch block at baseline, and the prevalence of heart failure with preserved systolic function is only slightly higher in women.230 For advanced heart failure patients, Thoratec HeartMate II (Thoratec Corporation, Pleasanton, CA) is a ventricular assist device that was recently approved based on data from only 44 women, who constituted 23% of the overall study population. Among the women participants, there was a 3-fold higher incidence of stroke (18% vs 6% in men) and trends toward a higher incidence of bleeding and infection events.231 Part of the reason for the lack of sex-specific data for devices may be related to the lack of FDA guidance in this area. There is reason to be optimistic that this deficit will start to be corrected in the near future. The FDA center for Devices and Radiological Health held workshops that addressed underrepresentation of women in cardiovascular trials, barriers to enrolling women, and improperly designed trials that fail to account for the unique characteristics of women. Current FDA guidelines already suggest that sex-specific data should be reviewed with every new drug application.231,232 Our knowledge of how to treat HFpEF is limited. Common treatment approaches incorporate therapy applied to other forms of HF. In particular, diuretics are the mainstay of therapy, although the necessity of maintaining filling pressure for optimal cardiac output frequently results in a narrow window between congestion and overdiuresis, resulting in potentiation of the cardiorenal syndrome. Treatments designed to ameliorate HTN have been shown to be efficacious, and controlling blood pressure is a class 1 recommendation of the ACC/AHA heart failure guidelines.233 The renin-angiotensin-aldosterone system is involved in many of the processes associated with HFpEF. Inhibitors of this system have been of 510

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particular interest as therapeutic interventions, although multiple largescale randomized control trials failed to demonstrate effectiveness of this class of drugs in reducing mortality and cardiovascular events among patients who had heart failure with preserved EF.234-236 The effect of aldosterone antagonists is being tested in the ongoing Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial conducted by the National Heart, Lung and Blood Institute.237 The cornerstone of therapy for HFpEF remains to be treatment of the underlying disease process. This is outlined in the revised ACC/AHA guidelines for the Evaluation and Management of Chronic Heart Failure in the Adults.233 Treatment of ischemia and adequate blood pressure control is essential, as well as maintenance of fluid balance and the control of ventricular rate in patients with AF.

Call for More Sex-Specific Research Sex-specific research has uncovered important differences in the causes, symptoms, and treatment of heart disease. The rate of public awareness of CVD as the leading cause of death in women has nearly doubled between 1997 and 2005 (from 30% to 55%).238 Despite better understanding of the mechanisms and growing awareness of sex-specific differences, several issues remain to be solved. For example, much of the evidence supporting current recommendations for noninvasive diagnostic studies in women is extrapolated from studies conducted predominantly in cohorts of middleaged men; Furthermore, women are still underrepresented in clinical trials. Women constituted only 30% of the patient population in the 156 randomized clinical trials cited by the AHA’s 2007 guidelines for CVD prevention in women239; also, only about one-third of the 156 trials reported sex-specific results, whereas women accounted for at least half the deaths in the affected patient populations studied. These findings underscore the importance and urgency of having adequate representation of women in clinical trials to solidify the evidence-based practice guidelines. Further study in sex-specific areas of cardiovascular research holds great promise in the development, prevention, and treatment of CVD in the aging female population.

Bairey Merz: Women are the majority of CVD victims since 1984; clinical pathophysiological and trial work should be designed, approved, and funded only when a representative proportion of women (at least 50%) are included.

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