CHAPTER 108: WOMEN AND ISCHEMIC HEART DISEASE: AN EVOLVING SAGA

Throughout the 20th century, coronary heart disease (CHD) was viewed as predominantly a problem of middle-aged men, and little information was available regarding its impact on women. Recent decades have witnessed an emerging interest in CHD in women, with consequent performance of research studies and the acquisition of data specific to women. There now exists a burgeoning evidence base on sex differences in the presentation, diagnostic evaluation, management, and clinical outcomes for women as compared with men with suspected and known ischemic heart disease (IHD).^{1,2,3,4,5,6,7,8} This evidence base has evolved rapidly over the past several decades, but remains incomplete with regard to understanding the biologic basis for sex differences, distinct pathophysiologic alterations, and variability in treatment effectiveness, which contribute to the largely elevated risk for morbid and fatal outcomes related to cardiovascular disease (CVD) among women as compared to men.

Historic evidence is replete with documentation of under-referral, -testing, and -treatment of women.^9,10 For women, outcomes are further impacted by delays in seeking care.¹¹ The ensuing impact of reduced financial means and other socioeconomic factors contribute to higher risk status for women. Although recent improvements have been reported, the lack of public awareness has resulted in an insufficient knowledge regarding CVD in women.¹² The gamut of cultural, social, and financial differences among women profoundly impact prompt diagnosis, clinical management, and outcomes of at-risk women. These factors result in women presenting older, with a greater risk factor burden and more comorbidity, and often with more frequent and untreated symptom burden. Much of the earlier sex bias data¹³ are highly relevant to the practices of care for women today. This early evidence prompted more recent explorations regarding biologic and clinical differences between women and men, revealing insight into varying pathophysiologic mechanisms between the sexes. Explorations as to varying pathophysiology, particularly in atherosclerosis development and the clinical sequelae of IHD, remain a focus of ongoing research activities.

This chapter will highlight recent research findings on IHD diagnosis, management, and clinical outcomes for women with stable and acute IHD. Women have greater CVD mortality and report more disability and decreased quality of life. They present later and with more comorbid conditions, yet receive fewer medical therapies and fewer interventions than men, contributing to sex-specific gaps in outcomes. These differences probably reflect both lingering diagnostic and treatment disparities and underlying biological differences. The underuse of guideline-based preventive and therapeutic strategies for women is a substantial contributor to their less favorable coronary outcomes, but the spectrum of sex differences likely reflects a combination of biology and bias.

The term IHD will be used in this chapter to identify myocardial ischemia as the culprit for symptom burden among women. The term IHD is advantageous for women because of their lower prevalence of anatomic obstructive coronary artery disease (CAD), despite greater myocardial ischemia and associated mortality when compared to men.^14,15,16 Although obstructive atherosclerotic disease of the epicardial coronary arteries remains the major cause of acute myocardial infarction (MI) for women, symptomatic females with myocardial ischemia remain at risk even with no or minimal epicardial CAD.¹⁷ Sex differences in nonobstructive CAD are an area of active investigation. Plaque characteristics also differ for women, with recent data suggesting a greater role of microvascular disease and nonobstructive CAD in the pathophysiology of coronary events in women.¹⁸ Other contributors to myocardial ischemia include coronary vasospasm, microvascular disease, endothelial dysfunction, and intramural coronary atherosclerosis, (ie, atherosclerotic plaque in the luminal wall with external remodeling).^4,19,20,21 The paradox of acute coronary events in women is that despite older age and a greater risk factor and anginal symptom burden with consequent morbidity and mortality, women have less severe obstructive CAD at angiography.¹⁸ A paradigm shift must occur from the consideration of anatomic obstructive CAD to IHD. Earlier risk detection must resolve the less intensive patterns of care that are more often common among women than men, which likely contributes to the sex-based mortality gap.²²

Sex differences are biologic differences, such as genetic and hormonal differences, increasingly acknowledged to exist even at the cellular level.^6,23,24,25 Sex differences are all encompassing in IHD, including anatomic (eg, smaller coronary blood vessels), physiologic (eg, higher resting coronary blood flow), age/hormonal, comorbid, and other varied risk factors uniquely impacting women. For definitional purposes, the term gender relates to self-identification, behavior, and its interaction with societal expectations and roles that impact all facets of IHD detection, risk, and treatment, which also uniquely influence women when compared to men.

IHD is the leading cause of morbidity, mortality, and disability in US women.²⁶ Only 18% of patients with MI had antecedent angina, with this feature being more common in women than in men.²⁷ Chronic stable angina affects 7.8 million patients in the United States, with over half of the patients being women.²⁸ Women have a higher age-adjusted prevalence of angina, the main symptom of IHD. Approximately 15.5 million Americans live with CAD, a disease that affects over 5% of adult women and nearly 8% of adult men. In addition to substantial morbidity and mortality, there is a heavy economic burden associated with IHD.²⁹ At all ages, even among elderly individuals, women have a lesser prevalence of CAD. However, once clinical manifestations of IHD develop, women have a less favorable outcome than their male peers in the setting of stable IHD, acute coronary syndromes (ACS), and coronary revascularization.

Importantly, over the past decade, mortality from CVD has declined nearly 30% (Fig. 108–1).^{30, 31} During this time, mortality has also declined for women, in large part due to increased awareness from public health campaigns, focused clinical research on sex-related differences, and the application of guideline-directed strategies of care.³² CVD is the leading cause of death for nearly one in every four women.³³ However, declines for women, across all ages, are far less than those reported for men (Fig. 108–2).⁸ From the National Inpatient Sample, declines in fatal MI were observed for women, yet mortality remained higher for women aged < 55 years as compared to similarly aged men.³⁴ Moreover, a recent population survey noted an increasing MI prevalence among midlife women, whereas declines were observed among men.³⁵ Hospitalization rates for MI in women aged ≤ 55 years increased and their excess 30-day mortality persisted, in contrast to the overall MI hospitalization rate and 30-day mortality, which significantly declined in women in general and in men.^36A More than one-quarter of a million women are hospitalized each year for an ACS.³⁰ For women hospitalized with acute MI, reports document longer length of stays, elevated in-hospital mortality, higher readmission rates, and persistently higher death rates through 5 to 10 years of follow-up when compared to men.^{36B,37,38,39,40,41} From an analysis of international, randomized trials in ACS, 30-day mortality was higher among women with ST-segment elevation MI (STEMI), but lower for women presenting with unstable angina or non–ST-segment elevation MI (NSTEMI).⁴² Moreover, MI hospitalization rates remain lower,⁴³ whereas rates of undocumented MI⁴⁴ are higher, for women than for men. Sex differences for in-hospital outcomes related to ACS have been attributed to variability in comorbidities, clinical presentation, and the severity and extent of CAD, yet these observed patterns persist over decades of treatment advances.⁴²

The burden of de novo and persistent chest pain among women impacts heavily on the clinical evaluation of IHD. There are varying symptom characteristics unique to women, including less typical, exertional chest pain than is reported for men.⁴⁵ This confounds and complicates the index evaluation, which may contribute to the reported high rates of persistent symptoms among women—a rate two-fold higher than that of men.^46,47,48,49 Men and women do share common qualities of their symptom profile, including more angina that is stress related; with men, angina is often related to physical exertion, whereas women more often have emotional provocation.⁴⁵ Today, the typical symptom profile among women includes more frequent symptoms often occurring at rest, more persistent angina, reduced physical work capacity, and reduced quality of life.

Sex-related differences in morbid and fatal outcomes have persisted over the past several decades, despite advances in treatment and guideline-directed management of IHD.⁴³ The evidence consistently reports that progressive declines in CVD risk are documented for women, yet females remain at high risk and, in many instances, with elevated event rates when compared to men. A synthesis of this data remains challenging, as older data may be less relevant to contemporary CVD practice. Of note, more recent evidence supports that black women consistently have a high prevalence of risk factors and are at particularly high risk of CVD events when compared to white women.^15,34,50,51 These disparities in detection and treatment of CVD impact large sectors of our female population who are now characterized as a targeted priority population for appropriate care consistent with guideline-directed strategies.⁵¹ Expanding on disparities of care, there is an extensive literature on reduced use of risk-factor modifying and anti-ischemic treatments, less noninvasive and invasive procedural use, less coronary revascularization, and reduced referral to cardiac rehabilitation and other lifestyle recommendations.^{10,12,13,47,52,53,54} This less intensive pattern of care for women has an unknown, but sizeable, impact on not only their quality of care, but also worsening clinical outcomes. In this chapter, we will highlight contemporary data on sex-related differences in IHD and synthesize variable patterns in the published literature related to women as compared to men with stable or acute IHD.

Pathologic data have revealed varied atherosclerotic plaque characteristics as precursors for a fatal cardiac event, including plaque rupture, erosion, and calcified nodules, findings that were also confirmed with invasive methods.^55,56,57 This evidence supports common mechanisms for acute events uniquely different for women and men. For men, plaque rupture is common and is defined within the culprit lesion as a thin fibrous cap with a large thrombogenic lipid-rich necrotic core, expansive remodeling, and extensive plaque burden.^{56,57,58,59,60,61,62,63} Although plaque rupture explains 76% of fatal coronary events among men, only half of events in women were due to plaque rupture.⁶⁴ By comparison, plaque erosion is more common in women and is defined as being more fibrous (P < .001), with a smaller plaque burden (P = .003) and reduced positive remodeling (P = .003).^{58,65,66,67,68,69,70} These data support sex-specific differences in atherosclerotic plaque, which may underlie the varying presentation and clinical outcome differences that are commonly observed in ACS registries and treatment trials. Moreover, the varying plaque features may also require future development of sex-specific targeted treatment strategies that have yet to be elucidated in current stable or acute IHD trials.

Given that MI in the absence of obstructive CAD is more common among younger ages and among women,^42,71 the rarity of plaque rupture in premenopausal women has been proposed to suggest a protective effect of estrogen.⁷² From 7% to 32% of women with documented ACS have no angiographically obstructive CAD, such that their MI may be a result of plaque rupture and ulceration, plaque erosion, vasospasm, and embolism.^42,73 Despite the high prevalence of nonobstructive CAD, plaque disruption is evident in almost 40% of women with ACS.²⁹ In a recent report addressing mechanisms of MI among women without obstructive CAD, there was evidence of plaque erosion with distal embolization of atherosclerotic debris and/or vasospasm as potentially etiologic. Plaque rupture and ulceration were common in women with MI in the absence of obstructive CAD.⁷³

Contemporary in vivo invasive imaging of atherosclerotic plaque has similarly compiled evidence on sex-specific patterns that are concordant with previously described pathologic findings.^61,74 Culprit plaques identified using intravascular ultrasound (IVUS) include those with features of echolucency (ie, with a lipid-rich necrotic core), large plaque burden, and positive remodeling.^59,61,75,76 The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) registry included 697 patients (n = 168 women) who underwent three-vessel IVUS and were followed for approximately 3 years for documentation of major CAD events.⁷⁷ From PROSPECT, culprit lesions more often had a higher plaque burden (≥ 70% of the cross-sectional area), smaller minimal luminal area, and thin cap fibroatheroma (all P < .001).⁷⁷ In a secondary analysis from PROSPECT, women less often had documented plaque rupture (P = .002).⁵⁵ These data are consistent with prior pathologic data supporting varying atherosclerotic plaque features in women as compared with men, although the evidence base is limited and less defined as to the role of arterial size, physiologic impairment, and other factors that may further contribute to sex-specific outcome differences.

The American Heart Association’s (AHA) CVD prevention guidelines for women, updated in 2011,⁵³ highlighted that substantially different approaches were needed to assure adequate preventive interventions for women. This relates both to nontraditional atherosclerotic CVD risk factors that are unique to, or predominant in, women and to the fact that traditional atherosclerotic CVD risk factors impart differential risk for women and men. The importance of prevention is highlighted by the information that two of three US women have at least one major coronary risk factor, with that percentage increasing with age.⁹ Additionally, for women aged 35 to 54 years, in contrast to the total population of women, CHD mortality has increased, reversing the favorable trend of the past four decades. In this population, increasing Framingham risk scores over the past two decades are likely the result of the epidemic of obesity and sedentary lifestyle.^35,78 These characteristics support the importance of providing preventive CVD screening for women.

Although women represent 46% of the US population with CHD, they constituted only 25% of participants in CHD prevention trials, with sex-specific data cited in only 31% of primary trial publications.⁷⁹ It must be appreciated that women are not a homogeneous group. Almost half of African American women have some form of CVD, with a 44% prevalence of hypertension (which is earlier in onset), an increase in metabolic syndrome, higher CVD rates, and higher mortality than their white counterparts, and in all studies, they receive less guideline-directed therapies. Black women have the greatest risk factor burden at hospitalization for an acute MI.³⁴ By contrast, Hispanic women have double the occurrence of diabetes compared with non-Hispanic white women (12.6% vs 6.5%), yet have the paradox of lower mortality and increased life expectancy compared with non-Hispanic white women.^80,81,82

Risk Factors Unique to, or Predominant in, Women

Pregnancy Complications

Pregnancy complications, including preeclampsia, gestational diabetes, pregnancy-induced hypertension, preterm delivery, and small for gestational age at birth, are early indicators of increased CVD risk. Preterm delivery (< 34 weeks of gestation) appears as an independent risk factor for subsequent long-term CVD morbidity and hospitalizations.^83A This mandates a detailed pregnancy history as an integral component of risk assessment for all women. It has been suggested that pregnancy is the first “stress test” a woman undergoes, in that the CVD and metabolic stresses of pregnancy have the potential for early prediction of future CVD risk. It is likely that shared risk factors for preeclampsia and CVD are unmasked by the pregnancy, rather than risk being specifically caused by the preeclampsia. Preeclampsia and gestational hypertension increase by three- to six-fold the risk for subsequent hypertension and double the risk for subsequent CVD events, including stroke. Pre-hypertension during a normotensive pregnancy appears as an independent risk factor for predicting postpartum metabolic syndrome.^83B An increased later risk of cardiomyopathy has also been reported in women with hypertensive disorders of pregnancy.^84A Further, gestational diabetes increases by seven-fold the risk of subsequent development of type 2 diabetes.^{53,84B,85,86,87}

Oral Contraceptive Therapy

Although there is no apparent increase in CVD risk for healthy women with no risk factors receiving oral contraceptive therapy, smoking increases their risk by seven-fold, and there may be an increase in blood pressure for hypertensive women.^88,89,90,91 There is also a nearly two-fold increase in stroke risk, which increases with older age at oral contraceptive therapy use. There are differences among the oral contraceptives, with earlier forms, particularly levonorgestrel, increasing MI risk, and more recent oral contraceptives associated with a lesser increase in blood pressure or even a decrease, but all carry an elevated risk of venous thromboembolism. The recommendations are for precise risk factor ascertainment and control in women using oral contraceptive preparations.^88,89,90,91

Hormonal Fertility Therapy

A new area of risk is hormonal fertility therapy, best delineated in a Canadian population cohort from 1993 to 2010.⁹² These women had a decreased risk of all-cause mortality, stroke, thromboembolism, and heart failure with successful fertility therapy that was evident across age and income subsets. However, unsuccessful fertility therapy in the same cohort was associated with an increase in adverse CVD events.⁹³

Menopausal Hormone Therapy

Menopausal hormone therapy is an area where clinical trial data have dramatically altered clinical recommendations and practice. Based on data from the Women’s Health Initiative (in healthy women) and the Heart and Estrogen/Progestin Replacement Study (in women with CHD), menopausal hormone therapy is not recommended for the primary or secondary prevention of CVD. The US Preventive Services Task Force recommendations state that menopausal hormone therapy should not be recommended for the primary prevention of chronic conditions.^{94,95,96,97,98}

Systemic Autoimmune Disorders

Systemic autoimmune disorders are highly prevalent among women and have adverse consequences, increasing the risk of CHD and stroke. CHD is a leading cause of both morbidity and mortality in women with systemic lupus erythematosus. There is a two- to three-fold increase in MI and CVD mortality among women with rheumatoid arthritis, and increased CVD risk has also been reported among women with psoriasis.^53,99,100 The recommendation is that precise screening for CVD risk factors and risk intervention is warranted for women with systemic autoimmune disorders.

Traditional Cardiovascular Disease Risk Factors

Misperception among physicians of lower CVD risk status for women correlates with suboptimal application of CVD risk interventions for women.

Hypertension

Hypertension is the leading cause of CVD worldwide, with a doubled population-adjusted risk for CVD mortality in women compared with men (29.0% vs 14.9%). Hypertension is more strongly associated with MI in women than men.¹⁰¹ Although women are less likely than men to have hypertension before 45 years of age, hypertension predominates among women compared with men after the age of 65 years. Of concern is that 80% of US women aged 75 years and older have hypertension. Importantly, only 29% of elderly women in the United States have adequate control of their blood pressure compared with 41% of men.^{81,101,102,103,104} Important is the impressive correlation of body mass index and elevated systolic blood pressure in women, indicating another potential intervention to control hypertension.

Controversy remains as to blood pressure targets, with recommendations varying from 150/90 to 140/90 mm Hg. In the Systolic Blood Pressure Intervention Trial (SPRINT), a systolic blood pressure of < 120 mm Hg compared with < 140 mm Hg resulted in a 25% lower risk of fatal and nonfatal major CVD events and deaths from any cause.¹⁰⁵ However, women were underrepresented in this trial and the age range of 50 to 80 years excluded young as well as elderly women with hypertension; in addition, by the trial design, diabetic patients were excluded.¹⁰⁶

Cigarette Smoking

Smoking is the most important preventable cause of MI in women.¹⁰⁷ Although cigarette smoking rates have decreased globally, the decline is less for women than men; in fact, the number of female smokers is increasing, particularly in developing countries. Nearly one in five women in the United States smoke cigarettes, with smoking among younger women more common than in younger men. The CVD risk for female smokers is 25% higher than for male smokers, with cigarette smoking tripling the MI risk for women. Moreover, smoking in association with oral contraceptive use increases the risk of acute MI, stroke, and venous thromboembolism.¹⁰⁸ Smoking cessation is the most cost-effective risk-modifying program.^81,109

Diabetes Mellitus

Diabetes confers greater risk for CVD death in women compared with men, and the rate of diabetes in Hispanic women is more than double that of non-Hispanic white women. Women with diabetes have a three-fold excess risk of CAD mortality as compared with nondiabetic women, and a higher adjusted hazard for CAD death when compared to men. A meta-analysis of 850,000 individuals showed that the relative risk of CVD was 44% greater in diabetic women than diabetic men.¹¹⁰ Diabetic women have a more adverse CVD risk factor status than their male peers, including impaired endothelium-dependent vasodilation, a hypercoagulable state, dyslipidemia, and the metabolic syndrome.¹¹¹

The 2015 AHA Scientific Statement on Sex Differences in the CVD Consequences of Diabetes Mellitus noted that the prevalence of diabetes is increasing rapidly in the United States, with 9.3% of the population being diabetic.¹¹¹ Overall, the prevalence of type 2 diabetes is similar for women and men, with about 12.6 million women over the age of 20 years estimated to have type 2 diabetes. At hospitalization for acute MI, women are more likely than men to have diabetes mellitus (25.5% vs 16.2%). CVD is the leading cause of morbidity and mortality among type 2 diabetics, accounting for more than 75% of the hospitalizations and 50% of all deaths.¹¹² Although nondiabetic women have fewer CVD events than comparably aged nondiabetic men, this sex-specific advantage is lost once type 2 diabetes develops.^113,114 Diabetes confers a greater CVD risk for women than men (19.1% vs 10.1%). Diabetic women have a 40-fold increase in the risk of incident CHD and a 25-fold increase in the risk of stroke.

The reasons for the sex differences are not well delineated, but likely are contributed to by inherent physiologic differences, including the impact of sex hormones, differences in CVD risk factors, and differences between the sexes in the treatment of diabetes and CVD.¹¹⁵ It remains uncertain whether differences are related to increased adiposity, increased abdominal adiposity, and/or possibly insulin resistance among diabetic women. In all studies, diabetic women receive less treatment and reduced control of their CVD risk factors than diabetic men.^{116,117,118,119,120} Women with diabetes are less likely to be appropriately treated than are men, which is contributory to worsening outcomes.¹²¹ Diabetic women are the sole group without a documented mortality reduction, based on recent population surveys. These surveys showed a decreased mortality among men with and without diabetes and women without diabetes (13%, 36%, and 27.1%, respectively). Conversely, mortality has increased in diabetic women (23%).

Hypercholesterolemia

Hypercholesterolemia imparts the highest population-adjusted risk for women (47%), with all studies showing similar statin benefit for women and men. In the US population, fewer than half of adults eligible for cholesterol medications actually took them,¹²² with women less likely to be prescribed statin therapy^123,124 and with variable compliance.¹²⁵ The 2013 American College of Cardiology (ACC)/AHA guidelines for cholesterol management promulgated significant change in the management of dyslipidemia.¹²⁶ First, the new pooled cohort risk equations were to be used, and these include sex-specific calculations.¹²⁷ Lifestyle guidelines are offered for diet and physical activity for low-density lipoprotein (LDL) lowering. Fixed-dose statin therapy for women is based on their risk categorization by the new pooled cohort risk equations, without use of target LDL cholesterol levels. Lifestyle modifications, particularly diet and exercise, are important for primary and secondary prevention of atherosclerotic CVD, with the use of pharmacologic therapy for secondary prevention being equally effective among women and men for the reduction of recurrent CAD events and mortality. Nonstatin therapies are generally not recommended. Moderate-dose statins are recommended after the age of 75 years, as a result of altered statin metabolism in the elderly.^{128,129,130,131,132} The outcome of these new guidelines will likely increase statin use for women, decrease inappropriate statin use, decrease the use of nonstatin therapies, and decrease the use of LDL-cholesterol laboratory testing. Recommendations for ezetimibe and PCSK9 inhibitors were not included in these guidelines, because the clinical trial results were not available by 2013. Ezetimibe added to statin therapy decreases LDL-cholesterol by approximately 15% and has been associated with a decrease in CVD events,¹³³ and although there are no clinical trial outcome results to date, the recently approved PCSK9 inhibitors have resulted in dramatic lowering of LDL-cholesterol.^134,135 Women appeared to have a greater likelihood than men of developing diabetes on statins.¹³⁶

Obesity/Overweight

Two out of three US women are either obese or overweight; obesity is closely associated with hypertension, dyslipidemia, physical inactivity, and insulin resistance. In the Framingham Heart Study, obesity increased CAD risk by 64% in women compared with 46% in men.¹³⁷ Obesity is a major risk factor for MI in women, increasing their risk nearly three-fold.¹³⁸ Overall, the prevalence of obesity is double in women compared with men in low-to-middle-income nations, although it is equivalent among women and men in higher income countries.^101,139 Detailed guidelines released by the ACC/AHA in 2013 are available for the management of obesity.¹³⁹

Physical Inactivity

Nearly one-third of adults in the United States are physically inactive (32.2% of women vs 29.9% of men). In the INTERHEART study (Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries), the protective effects of exercise were more prominent for women than for men. Physical inactivity is the most prevalent risk factor for women, with one-quarter of US¹⁰¹ women reporting no regular physical activity and three-quarters reporting less than the recommended amount of activity. Moreover, the development of diabetes and risk of CVD events are decreased for women who exercise regularly. For secondary prevention, exercise-based rehabilitation is a Class IA recommendation in all coronary guidelines, yet women are 55% less likely to participate than men.^{101,130,140,141} The recommended levels in the physical activity guidelines for adult Americans are at least 150 minutes per week of moderate-intensity aerobic activity, such as walking, 75 minutes per week of vigorous-intensity aerobic activity, such as jogging, or a combination of both, with muscle strength training activity recommended on 2 or more days of the week.²⁸ Higher levels of physical activity are associated with lower rates of CVD.^142,143

Psychosocial Issues: Depression and Stress

Psychosocial issues, particularly depression, preferentially disadvantage women. In the INTERHEART study, psychosocial factors increased CVD mortality more for women than men (45.2% vs 22.8%).¹⁰¹ These factors include stress at work or home, financial stress, and major life events.¹⁰¹ There is growing evidence that psychological factors and emotional stress influence the onset and clinical course of IHD, particularly for women. From the Variation in Recovery: Role of Gender on Outcomes of Young Acute MI Patients (VIRGO) registry, young women had significantly higher stress scores than young men.¹⁴⁴ Depression among women appears to be a powerful predictor of early-onset MI and, in the VIRGO registry, young women were more likely than young men to have a history of depression.¹⁴⁵

Depression is associated with a 1.6-fold increase in CVD mortality independent of the severity of the depression. In addition, increased mortality has been reported among depressed young women (< 65 years of age) with established CAD. Depression is also a risk factor for adverse outcomes with ACS.^{101,146,147,148,149,150} Likely contributors are the high-risk behaviors and nonadherence to therapies associated with depression. Depression after MI occurs with increased frequency in women, with the greatest risk in younger women.¹⁵¹ Depression may be a component of the increased CAD event risk of younger women following both MI and coronary artery bypass graft (CABG) procedures.^152,153

Aspirin Therapy

The preventive use of aspirin for CVD varies by sex. Aspirin is routinely recommended for primary prevention in men, but not in women, based on the Women’s Health Study.¹⁵⁴ In this study, 38,876 healthy low-risk women older than 45 years of age were randomized to either 100 mg of aspirin every other day or placebo. Aspirin prevented stroke, but not MI or CVD death, among those younger than 65 years of age, with a sizeable potential for gastrointestinal bleeding. In women over 65 years of age, aspirin prevented stroke, MI, and CVD death; however, an increased risk of gastrointestinal bleeding was comparable to the preventive benefits, thus mandating treatment individualization. By contrast, in the Physicians’ Health Study, in which men were randomized to the same aspirin regimen, a reduction in MI (but not stroke) was observed.¹⁵⁵ Comparable sex-specific recommendations for aspirin use are routine in all clinical practice guidelines for secondary prevention.^156,157

Class III Interventions: Not Useful/Effective and May Be Harmful for Cardiovascular Disease Prevention in Women

Menopausal Hormone Therapy

The Heart and Estrogen/Progestin Replacement Study⁹⁸ and the Women’s Health Initiative hormone trials⁹⁶ documented that menopausal hormone therapy did not prevent incident or recurrent CVD in women, but increased their risk of stroke. These trials displaced menopausal hormone therapy as the ubiquitous solution to women’s cardiovascular problems, refocusing attention on established cardiovascular preventive therapy. In summary, hormone therapy and selective estrogen receptor modulators should not be used for the primary or secondary prevention of CVD. This is emphasized in recommendations from the US Preventive Services Task Force.⁹⁴

Antioxidant Supplements and Folic Acid

The Women’s Antioxidant CVD and the Women’s Antioxidant and Folic Acid CVD studies demonstrated that vitamins E, C, and β-carotene and folic acid and B vitamin supplements, respectively, did not prevent incident or recurrent CVD in women. Antioxidant supplements (eg, vitamins E, C, and β-carotene) should not be used for the primary or secondary prevention of CVD.^158,159 In addition, folic acid, with or without vitamin B₆ and B₁₂ supplementation, should not be used for the primary or secondary prevention of CVD.¹⁶⁰

In the de novo evaluation of suspected cardiac symptoms, the clinical diagnosis of angina can be challenging for women. Population evidence supports that stable chest pain is a more prominent presenting symptom for women compared with men (who more commonly present with acute MI or sudden cardiac arrest).¹⁶¹ Higher rates of suspected cardiac symptoms (eg, angina) are reported in women.^45,162 From a meta-analysis of 13,331 women and 11,511 men, the prevalence of angina was 20% higher among women as compared to men (P < .0001).¹⁶² The evidence further supports a more variable symptom profile for women compared with men.⁴⁵ Women with angina more frequently report provocation following emotional stress that may occur at rest; this varies from the typical exertional pattern of angina as triggered during physical work that is typical of male patients.⁴⁵ Moreover, the consistent pattern among women presenting with de novo chest pain includes worsening angina frequency and stability along with reduced quality of life,¹⁶³ even for younger women (< 55 years old).¹⁶⁴ A major challenge with reported symptoms among women is that women receive less intensive anti-ischemic therapies, which leads to worsening CAD outcomes.^10,13,52,53

During the chest pain evaluation, a careful history is required to assess the likelihood of CAD and to aid decision making regarding additional testing for myocardial ischemia or anatomic CAD. Preconceived bias can impact a physician’s perception of CAD risk for women.^7,165 Adequate assessment of CAD risk requires synthesis of multiple risk factors, clinical history, and a detailed assessment of activities of daily living and factors related to symptom frequency and stability.⁴⁵ McSweeney et al¹⁶⁶ have identified five prominent prodromal symptoms in women, including discomfort in jaw or teeth, unusual fatigue, arm discomfort, shortness of breath, and general chest discomfort. The relative hazard for CAD events (at 2 years of follow-up) was elevated four-fold for women reporting more than one of these symptoms.¹⁶⁶

The integration of clinical symptomatology and risk factors into an assessment of clinical risk for women is challenging. Many of the risk scores were developed several decades ago, were derived from largely male cohorts with limited representation of women, and included patients with a higher prevalence of significant and severe CAD than is observed in contemporary practice.^167,168 Current patient populations are decidedly lower risk and have less prevalent obstructive CAD, resulting in marked overestimation in risk, particularly for women.^169,170 When relying solely on the typicality of chest pain symptoms, CAD likelihood estimates will result in the majority of women being at lower risk.⁴⁵ In one recent example, low- and intermediate-risk women were, on average, 10 years older than their male counterparts and had a higher risk of death.¹⁷¹ In the 2014 AHA consensus statement on the diagnostic evaluation of IHD in women, a simplified approach to categorize risk was presented (Fig. 108–3).⁴⁵ For women with stable symptoms, risk is broadly categorized as low, intermediate, and high for women in their 50s, 60s, and 70s (or older), respectively.⁴⁵ Risk may be accentuated by one category (eg, low to intermediate risk) for those with multiple CAD risk factors, functional disability, or extensive comorbidity. Additionally, high-risk equivalent women are those with longstanding or poorly controlled diabetes or those with peripheral arterial disease. Although this approach remains imperfect, it provides a simplistic means to define risk in women and captures the prominent impact of age as driving clinical outcomes and CAD prevalence. Women allocated to low-risk status do not require prompt diagnostic testing, whereas optimal candidates for noninvasive functional or anatomic testing include women with intermediate or high CAD risk (Fig. 108–4).⁴⁵

There has long been a misperception that women have a low risk of CAD and that documented ischemic or other stress test abnormalities are associated with false-positive findings.^13,47 The result of these misperceptions is that women with abnormalities on stress testing disproportionately receive minimal to no post-test change in management. In one recent trial, less than 10% of women with abnormal stress test findings received any intensification or new anti-ischemic therapies or referral to invasive coronary angiography.⁴⁷ An evolution in thought regarding the importance of ischemia as elevating risk in women has occurred over the past decade. A landmark population registry reported that coronary mortality was significantly elevated for women with ischemic findings on noninvasive testing, particularly for those < 75 years old, in whom the relative hazard for CAD death was higher as compared to similarly aged men.¹⁷ Although issues remain on potential technical artifact relevant to ischemic abnormalities among women (eg, breast artifact in stress myocardial perfusion single-photon emission computed tomography [SPECT]), contemporary approaches to documented ischemia now include the extensive evidence on the prognostic accuracy of ischemic findings among women. Moreover, there is an expanded focus on detection of obstructive CAD, but also, more recently, an expanded understanding of risk associated with nonobstructive CAD, including high-risk atherosclerotic plaque features, as also driving risk for women with suspected IHD.^4,172

Noninvasive diagnostic testing can refine the management of symptomatic women largely as a result of their more nonspecific clinical presentation. There are currently two diagnostic approaches for the evaluation of suspected IHD: (1) noninvasive or invasive anatomic testing using coronary computed tomographic angiography (CCTA) or invasive coronary angiography and (2) stress testing using exercise electrocardiography (ECG), echocardiography, myocardial perfusion SPECT or positron emission tomography (PET), or cardiac magnetic resonance (CMR) imaging.

The mainstay of functional or stress testing has been the exercise ECG, with strong evidence on its diagnostic and prognostic accuracy for women.^45,173,174 Exercise ECG is indicated for intermediate-risk women who are capable of performing activities of daily living (or ~5 metabolic equivalents [METs] of exercise [or higher]).¹ Candidates for exercise ECG, based on the 2012 guidelines for stable IHD, are those without disabling comorbidity, including younger patients, patients without marked obesity or orthopedic limitations, and patients with no existing peripheral arterial disease or chronic obstructive pulmonary disease.¹ Additionally, women who report limitations in performing routine activities of daily living may also be categorized as those with limited physical work capacity and may not be candidates for exercise testing. Given the predominance of these factors among female patient cohorts, the candidate pool for women capable of maximal levels of exercise is limited. The commonly applied Bruce protocol may be too rigorous for many women and precipitate premature fatigue; reviews and consensus statements suggest exercise protocols with smaller incremental grades of work and lower starting MET levels as preferred for females (eg, modified asymptomatic cardiac ischemia pilot protocol).^45,175

However, for women presenting with de novo chest pain who are capable of exercising maximally, exercise ECG has a high negative predictive value for excluding obstructive CAD.⁴⁵ The high negative predictive value is based on women achieving maximal levels of exercise and heart rate until the point of volitional fatigue without ECG changes. In a younger, lower risk cohort, the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) trial revealed similar 2-year outcomes (ie, CAD death or hospitalization for heart failure or an ACS) for women randomized to exercise ECG as compared to exercise myocardial perfusion SPECT (P = .59).⁴⁷ Based on this trial, the recent AHA consensus statement introduced the concept of an exercise ECG first strategy (see Fig. 108–4), whereby selective imaging is performed in women whose index exercise ECG identifies indeterminate or positive findings. Women incapable of performing 5 or more METs of exercise are at high risk of all-cause mortality and other major CAD events.⁴⁵ Among those incapable of performing adequate levels of exercise, stress imaging should be performed with pharmacologic stress.

The diagnostic accuracy of exercise ECG is decidedly lower in women than men.^176,177 From 29 studies (n = 3392 women), the diagnostic sensitivity and specificity are 62% and 68%, respectively.¹⁷⁶ For women and men, early provocation of ST-segment changes at low workloads denotes high-risk status.¹⁷⁵ Care should be taken when no ECG abnormalities are detected in a woman failing to achieve maximal levels of exercise. However, significant ventricular arrhythmias (eg, seven or more premature ventricular contractions per minute or ventricular tachycardia/fibrillation), a drop in systolic blood pressure or blunted heart rate response with increasing physical work, a 1-minute recovery heart rate that has dropped from peak exercise by < 12 bpm, and the occurrence or worsening horizontal or downsloping ST-segment changes of ≥ 1 mm (at 60-80 ms beyond the J point) all signify high-risk findings on the exercise tolerance test for women.^175,178A Additionally, ≥ 1 mm of ST-segment elevation (at 60-80 ms after the J point) in a non–Q-wave lead is also a high-risk marker associated with transmural ischemia.¹⁷⁵ Sex-specific clinical and exercise risk scores are described to identify patients at the highest risk for all-cause mortality.^178B Documentation of significant ST-segment elevation in lead aVR is associated with a high risk of severe CAD, including proximal left anterior descending or left main involvement.¹⁷⁵ The interpretation of ST-segment changes is dependent on the quality of the ECG tracing. Use of computer-averaged electrocardiograms is not advised unless the quality of the raw tracings is reviewed for motion artifact and baseline wander.¹⁷⁵ Sex-specific clinical and exercise risk scores are described to identify patients at the highest risk for all- cause mortality.^178B

Older reports highlight the prognostic accuracy of the Duke treadmill score (Exercise Time – [5 × Max ST] – [4 × Angina Index]) in women, and care should be taken when applying absolute risk or CAD estimates in contemporary lower risk cohorts who are also more functionally disabled.^45,179 However, the categorization of low (score ≥ +5) to high (score ≤ –11) risk women based on the Duke treadmill score remains a valuable means to identify candidates for follow-up stress or anatomic imaging. Those with intermediate/high risk (score ≤ +4) are generally considered candidates for further risk assessment with noninvasive imaging and, in select high-risk cases, invasive coronary angiography. The addition of a noncontrast computed tomographic coronary artery calcium (CAC) score may provide additional information as to the presence of atherosclerosis to guide clinical management and further testing and estimate future risk of CAD events.^180,181,182 From a large symptomatic cohort, significant obstructive CAD was rarely observed in symptomatic women and men with a low-risk CAC score ≤ 10.¹⁸² In a recent trial, patients with a CAC score of 0 did not have any CAD events over 1 year of follow-up.¹⁸³

There are decades of available evidence in women indicating that stress imaging, including stress echocardiography, myocardial perfusion SPECT or PET, and CMR imaging, has an improved diagnostic and prognostic accuracy when compared to exercise ECG.^45,184,185 Candidates for stress imaging include intermediate- or high-risk women who meet the following clinical criteria: (1) functionally disabled (defined earlier); (2) an abnormal resting electrocardiogram precluding accurate assessment of exercise-induced changes (eg, left ventricular hypertrophy with repolarization changes or significant resting ST-T–wave changes); or (3) high CAD likelihood.^1,45 Additional details on the appropriate candidates for stress imaging are detailed in the ACC’s multimodality appropriate use criteria.¹⁸⁶

Stress echocardiography is particularly useful for ruling out wall motion abnormalities with a high diagnostic accuracy (sensitivity, 79%; specificity, 83%) in women; this aim may be helpful for younger and lower risk women.^2,176 Image quality, particularly for obese women or those with lung disease, may be improved with the use of intravenous contrast.⁴⁵ Stress echocardiography has many Class I indications for testing, based on multicenter trials and large registries, that support its utility in women and men with stable IHD.¹ For women capable of exercising, no inducible wall-motion abnormality in the setting of maximal exercise identifies those at low risk of future CAD events.¹⁸⁷ Following the principles of demand ischemia, an inducible wall-motion abnormality is more likely to be elicited in the setting of more severe stenosis, and thus, a failure to document a new wall-motion abnormality may occur in a woman with single-vessel CAD.¹⁸⁸ Each test has its limitations, which will be discussed herein, but importantly, nonechocardiographic risk parameters during stress testing may improve detection of at-risk women and men. Echocardiography can also be helpful in assessing noncoronary etiologies for symptoms such as diastolic dysfunction, abnormal filling pressures, or abnormal myocardial mechanics using tissue Doppler or speckle tracking.²

There is a similarly robust evidence base as to the utility of stress myocardial perfusion SPECT in women that is reflected in the numerous Class I indications in the 2012 stable IHD clinical practice guideline.¹ Based on the systematic review from the Agency for Healthcare Research and Quality, the diagnostic sensitivity and specificity were 81% and 78%, respectively, for women; these statistics include older reports using the radioisotope thallium-201, which is associated with reduced accuracy due to breast tissue artifact in women.¹⁷⁶ Breast tissue artifact reduces diagnostic accuracy of SPECT for women who are obese and/or for those with large breasts. Significant improvements in diagnostic accuracy have been reported using validated attenuation correction algorithms or the addition of two-position supine/prone imaging.^189,190,191 Decades of evidence support the effectiveness of risk stratification using the extent and severity of rest and stress myocardial perfusion SPECT abnormalities, with moderate-to-severe ischemia defined as ≥ 10% of the myocardium.¹⁹² There is an increasing CAD event risk that is proportional to the extent and severity of rest and stress SPECT abnormalities (ie, a gradient relationship with percent abnormal myocardium). A low risk of CAD events is consistently reported for those with normal SPECT findings, and an intermediate-to-high risk of CAD events is reported for those with mild and moderate/severe findings.^188,192 Risk stratification evidence is similarly effective for women and men.^{45,188,193,194} This evidence is expansive on the prognostic utility of SPECT imaging in women undergoing exercise or pharmacologic stress, in the obese, in diabetics, and in women of diverse race and ethnicity.^50,195 One challenge with the use of stress myocardial perfusion SPECT is that the overall radiation burden is higher than for CCTA or PET imaging; rest and stress technetium-99m SPECT has an effective dose of 10 to 15 mSv.^196,197 Optimization of dose-reduction techniques is a primary goal for nuclear cardiology. For women, stress imaging should be performed first, and if findings are normal, elimination of the follow-up resting scan can reduce radiation exposure considerably (ie, stress only imaging).¹⁹⁷ Importantly, for the purposes of justification of exposure, only women with appropriate indications for testing should undergo SPECT, CCTA, or invasive coronary angiography.^1,186 There should be limited use of SPECT imaging for younger women (ie, < 50 years old), but if clinical indications warrant, they should undergo target procedures with low-dose exposure (eg, PET) or, if possible, a test without radiation exposure.

More recently, stress myocardial perfusion PET has gained increasing attention with its improved image quality translating into high diagnostic accuracy for women, particularly for the obese,¹⁹⁸ its reduced breast tissue artifact, and its ability to segment subepicardial and epicardial perfusion and quantify rest and stress absolute myocardial blood flow and coronary flow reserve (CFR).^{2, 199} Conventional cardiac PET using the perfusion tracers rubidium-82 or ¹³N-ammonia has a markedly reduced radiation exposure with effective doses of only 2 to 3 mSv.¹⁹⁶

Stress myocardial perfusion PET has a very high diagnostic accuracy when compared to SPECT (88% vs 67%; P = .009).^198,200 Risk stratification evidence based on the rest and stress percent abnormal or ischemic myocardium appears to similarly risk stratify women and men, similar to SPECT imaging.^200,201,202 One clear advantage of PET is the added contribution of CFR measures documenting the ratio of stress-to-rest absolute myocardial blood flow. An interesting finding is that approximately 20% to 40% of patients with normal or low-risk PET also have reduced CFR,^203,204,205 which signifies underlying atherosclerosis and higher CAD event risk. The evidence supports that a CFR ≤ 2 is associated with an elevated CAD event risk.^{206, 207} Additionally, an understanding of flow and ischemic abnormalities in relation to high-risk atherosclerotic plaque features may importantly improve detection of at-risk women and guide future treatment strategies.^{21,208,209,210} A reduced CFR combined with ischemia severity accelerates CAD event rates.^202,207 Reductions in CFR are proportional to stenosis severity, but in the patient with angiographically normal coronary arteries, they reflect dysfunction in the microvasculature.²¹¹ Evidence of impaired CFR can be particularly helpful in understanding abnormalities of flow for women with nonobstructive CAD in whom underlying high-risk atherosclerotic plaque (that is not obstructive) may be eliciting reduced myocardial blood flow and provoking anginal symptoms.²⁰¹ When considering women with prior stress-induced ischemia or reduced CFR, the addition of CCTA may help to document normal, mild (even diffuse), or obstructive epicardial CAD. This is an area of active investigation focusing on the utility of PET with CFR, with the addition of CCTA findings of no obstructive CAD, to define coronary microvascular dysfunction (CMD). The defining of epicardial, atherosclerotic plaque, particularly if high risk or more diffuse, but no obstructive CAD, may improve IHD risk detection and foster targeted treatment strategies for this large cohort with nonobstructive, but functionally limiting, atherosclerosis (ie, reduced CFR).⁴

Stress CMR imaging is our final functional testing modality that has evidence as to its utility in evaluating women with suspected IHD.² A meta-analysis of the combined diagnostic accuracy of stress CMR perfusion and wall-motion imaging reveals comparable sensitivity and specificity to SPECT and echocardiography in women.¹⁷⁶ The development of rapid high-resolution techniques has fostered the use of CMR perfusion imaging.² Relevant to IHD evaluation of women, a subset analysis of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) trial compared women who were randomized to a multiparametric CMR evaluation including angiography, function, perfusion, and scar imaging, versus myocardial perfusion SPECT.²¹² For CMR, the sensitivity in women was 89%, and the specificity was 84%, whereas for SPECT, the sensitivity was 51%, but the specificity was the same (84%). In this subset analysis, CMR outperformed SPECT with a higher diagnostic accuracy (P < .0001). Recently, it has been shown that CMR perfusion also effectively risk stratifies women with demonstrable ischemia, identifying females with worsening prognosis (P < .001).²¹³ Additionally, CMR techniques can measure myocardial flow reserve on vasodilator stress CMR, which may improve detection of CMD in symptomatic women; although the evidence base is minimal when compared to PET imaging. A final important consideration is the evidence as to the value of late gadolinium enhancement CMR imaging to improve detection of scarred or infarcted myocardium, which has been shown to identify women with previously undocumented MI.^214,215

Separate indications are warranted for invasive versus noninvasive angiographic procedures. Current indications for invasive coronary angiography within the diagnostic evaluation include use as a frontline procedure for women who may be categorized as high risk or for those whose symptom burden is considered unstable.¹ In addition, invasive angiography is also indicated in the setting of demonstrable ischemia by stress imaging. Indications for CCTA are similar to those of stress imaging (limited functional capacity or abnormal 12-lead ECG) for those with an intermediate pretest risk.^1,186 There are selected indications for CCTA as an index procedure that may be advantageous for the female patient with de novo chest pain.^1,186 CCTA may be preferable for women with persistent symptoms or for those with indeterminate or prior inconclusive stress test findings.

For invasive angiography and CCTA, there is a proportional increase in the risk of major CAD events with the number of vessels with obstructive CAD.^172,216,217 Women have a higher risk of major CAD events in the setting of more severe and extensive multivessel CAD, perhaps related to their advanced age or comorbidity. The role of coronary revascularization in women with obstructive CAD is detailed in a later section of this chapter. For the remainder of women undergoing invasive angiography, data have recently revealed that the presence of (normal and mild obstructive) nonobstructive CAD is associated with worsening prognosis, including in women undergoing invasive coronary angiography or CCTA.^4,18,172,193

Our current approach within the noninvasive stable IHD evaluation, particularly for women, has expanded beyond detection of obstructive CAD to understanding the prognostic significance associated with nonobstructive CAD, especially among those with evidence of high-risk atherosclerotic plaque. The anatomic approach now includes a focus for women on the importance of prognostically significant mild, but nonobstructive CAD as well as obstructive CAD. Across all female patient subsets with acute and stable IHD, there is a higher frequency of nonobstructive, CAD as compared with male patients.^4,15,218 Included in this analysis are women with mild, but obstructive, CAD with < 50% stenosis. Approximately half of women referred for angiography do not have obstructive CAD, including women with previously documented ischemia.^{4,18,172,193,201,219} For example, a report from the ACC’s CathPCI Registry (n = 375,886 [~50% women] from > 600 hospitals) reported higher rates of nonobstructive CAD for women (58%, 55%, 46%, 47%, and 51% for black, Hispanic, Native American, Asian, and white women with stable IHD, respectively) than men.¹⁵

In cohorts of symptomatic women with IHD and documented nonobstructive CAD, reports document as many as 80% of females with epicardial atherosclerosis.²¹ In the setting of no obstructive CAD, prognosis significantly worsens in the setting of diffuse segmental atherosclerosis (ie, more than four segments involved in the epicardial vessels).²²⁰ The adjusted hazard for major CAD events is increased approximately 90% for women and men with diffuse nonobstructive CAD.²¹⁸

Documented myocardial ischemia or evidence of vascular dysfunction in the setting of angiographically normal coronary arteries (ie, CMD) has been the focus of much research, in large part, because of its frequent occurrence in women. There are no diagnostic techniques that are capable of interrogating the coronary microcirculation.^208,221 Invasive and PET CFR measures flow alterations within the epicardial coronary arteries (including diffuse atherosclerosis), the impact of vessel remodeling, and impairments in flow within the microvasculature. Previous discussions focused on worsening prognosis associated with impaired CFR on PET with nonobstructive CAD.^201,210,219 There are also evolving invasive techniques for measuring microvascular resistance, such as the index of microvascular resistance or hyperemic microvascular resistance.^222,223 Limited female-specific data are available.

With the introduction of noninvasive CCTA, the presence of atherosclerotic plaque, mild CAD stenosis, or obstructive CAD can be easily determined with minimal radiation exposure (average, 5-7 mSv or less).^224,225 Similar to invasive angiography, women have more nonobstructive CAD on CCTA,^{15,170,226,227} and their risk of death is accentuated in the setting of multivessel CAD.¹⁷² More careful attention to mild CAD burden and, in particular, a focus on the presence of atherosclerotic plaque have led to evolutionary approaches to understanding risk for women with suspected IHD. From a large multicenter registry of 23,854 patients with suspected IHD, the presence of nonobstructive CAD on CCTA was associated with worsening mortality.¹⁷² Similarly, death risk increased nearly three-fold for every vessel with nonobstructive plaque.^{216,228,229,230} In women with suspected IHD, nonobstructive CAD was associated with an approximate two-fold increased risk of major CAD events.^231,232

Several recent randomized trials compared CCTA versus exercise ECG for 1-year CAD outcomes and costs of care in suspected IHD patients.^183,233 In both trials, 1-year CAD outcomes were improved, angina was more often reduced, and costs of care were lower for CCTA versus exercise ECG, although no subset analysis was performed in women. Given the reduced diagnostic accuracy of exercise ECG, these data suggest that CCTA may be a favorable option. In the Computed Tomography Versus Exercise Testing in Suspected Coronary Artery Disease (CRESCENT) trial, a CAC score was initially performed, and CCTA was limited to patients with detectable plaque.¹⁸³ This approach of applying CAC scoring either as the index approach or along with exercise ECG may be one alternative to improve detection of women with underlying atherosclerosis. Importantly, in the CRESCENT trial, there were no events documented in the 40% of patients without detectable CAC.

Secondary analysis by sex was recently reported in the National Heart, Lung, and Blood Institute–sponsored Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.^234,235 From PROMISE (n = 8966), women had less documented CAD (8%) on CCTA as compared to positive stress test findings (12%, P < .001), whereas men had roughly a similar rate of positive findings on CCTA and stress testing (14%-16%, P = .046). Women with obstructive CAD on CCTA had a nearly 10-fold higher (P < .001) hazard of death, MI, or unstable angina hospitalization, whereas females with a positive stress test had only a 5-fold (P = .002) hazard for the clinical outcome, resulting in a significantly higher risk noted with CCTA versus stress testing (P = .043). These data suggest that CCTA may aid in the evaluation of symptomatic women as a result of its ability to detect risk and provide details on nonobstructive atherosclerotic plaque. One may envision a symptomatic evaluation approach that applies CCTA: (1) as a secondary test following stress testing or (2) as an index procedure with stress testing limited to individuals with at least mild CAD. Although subset analysis among women has not been published, the Scottish Computed Tomography of the Heart Trial (SCOT-HEART) randomized 4146 patients to a strategy of CCTA versus standard of care. Interestingly, the randomization occurred following the index evaluation, which largely included the use of exercise ECG (ie, in 85% of enrollees). The main findings from the SCOT-HEART trial revealed a trend toward improved 25-month CHD death or MI among patients randomized to CCTA versus the standard of care (P = .053). These data confirm prior findings that CCTA has supportive evidence as an index or follow-up diagnostic procedure.

A review of 59 studies challenged whether a classical chest pain presentation for an ACS was truly typical for either sex.²³⁶ In this review, 37% of women, as compared with 27% of men, had no chest pain or discomfort, with absent chest pain increasing with advancing age. Data from the National Registry of Myocardial Infarction (NRMI) showed that the odds ratio of older age was greater than the odds ratio of female sex for absent chest pain with MI (1.28 vs 1.06). Further, women presenting with ACS were far more likely than men to have associated symptoms (2.6 vs 1.8). In the Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond Premature ACS registry, although chest pain was the most prevalent symptom in both sexes, women were more likely to have additional symptoms and less chest pain as compared to men.²³⁷ More prominent in women were back, neck, and jaw pain; dyspnea; paroxysmal nocturnal dyspnea; nausea; indigestion; and weakness or fatigue, challenging the clinician to identify both the woman with a non–chest pain presentation and one in whom the chest pain may be overwhelmed by a multiplicity of other symptoms.²³⁸ This is often associated with misdiagnosis, delayed revascularization, and higher ACS mortality.²³⁹ Women characteristically have longer presentation delays and greater time-to-treatment delays, which exacerbate in-hospital mortality.²⁴⁰ Contributors also include the lack of awareness of risk, inaccurate symptom attribution, and other barriers to self-care.^241,242 Despite their more prevalent nonobstructive CAD, women have higher mortality, and the absence of chest pain at presentation appears more predictive of mortality in younger women than for other age groups.²⁴³

Women have different clinical profiles, presentations, and outcomes with ACS. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIb trial included 3662 women and 8480 men.²⁴⁴ At ACS presentation, women were more likely to have unstable angina than documented MI; even with documented MI, fewer women than men had an STEMI.²⁴⁵ Women with ACS tended to be older and were more likely to have diabetes, hypertension, and heart failure, typically with intact ventricular systolic function, and to have an excess of both hospital complications and bleeding complications. Women had greater delays than men in seeking emergency care. GUSTO showed a reduced use of coronary angiography among women versus men (53% vs 59%). At angiography, more women than men were described to have “clinically insignificant” obstructive CAD, with clinically insignificant indicating no lesions amenable to percutaneous coronary intervention (PCI). However, the episode was not clinically insignificant for the woman hospitalized for ACS. In an ACS and stable IHD registry from British Columbia, women with obstructive CAD had higher rates of adverse events and readmission.²⁴⁶ For the women with ACS, a greater in-hospital mortality was observed. In addition, women with NSTEMI had more complications than men, including bleeding, heart failure, shock, renal failure, reinfarction, stroke, and readmission.

Coronary artery spasm is a rare mechanism for ACS,^247,248 as is spontaneous coronary artery dissection (SCAD).²⁴⁹ SCAD is the primary cause of peripartum MI and accounts for 10-30% of MI in women under the age of 50 years. These women have an increased occurrence of fibromuscular dysplasia in the carotid, iliac and renal vessels; and genetic components remain uncertain. Women with SCAD have few traditional coronary risk factors, and describe precipitants including emotional, hormonal or other stressors, and exercise. Despite the overall low early mortality with SCAD, complications are high in PCI-treated patients, because PCI may propagate the dissection.²⁵⁰ There was a high recurrence rate (17%), as based on the Mayo Clinic SCAD registry, occurring solely in women. A high prevalence of tortuosity of the coronary vessels appears to predict recurrence. The 10-year mortality was also high, at 7.7%, and with a high incidence (47%) of major CAD events.²⁵⁰ Recommended therapy includes a single antiplatelet agent, avoidance of statins unless hypercholesterolemia is present, use of β blockade, and avoidance of systemic hormones, including oral contraceptives.

Age is a major covariate interacting with sex and impacting outcomes. In the NRMI, there was significant interaction between sex and age.¹⁵³ Among 384,878 NRMI patients aged 30 to 89 years, women had a greater mortality than their male peers to the age of 70 years, with women younger than 50 years of age having a doubled hospital mortality with MI compared with men. Women with CAD, and in particular women younger than 50 years old, have a doubled mortality after MI,¹⁵³ although the greater improvement in hospital mortality for younger women than younger men over time appears to be narrowing the sex gap.²⁵¹ The absolute reduction was three times greater in women than men younger than 55 years old, suggesting a decrease in treatment-related sex bias.

A uniform finding among studies is that women with ACS are less likely to be treated with guideline-directed medical therapies, less likely to undergo cardiac catheterization and coronary revascularization,^252,253,254 and less likely to receive timely reperfusion.^{36,255,256,257} The reduced frequency of PCI and CABG is largely related to the reduced rate of obstructive CAD. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) data challenge whether the adverse outcomes of women with ACS reflected their baseline risk, their suboptimal admission and discharge therapies, or both. In the National Cardiovascular Data Registry, women of all ethnic backgrounds were less likely to undergo PCI and CABG revascularization than their male counterparts,¹⁵ with characteristic documentation of disparities in referral rates of black women to coronary angiography and reperfusion compared with both white women and black men.

Added data regarding sex disparities in ACS are available from the CRUSADE National Quality Improvement Initiative, which addressed patients with NSTEMI.^252,258,259 CRUSADE derived data from 391 US hospitals between 2000 and 2002, representing 35,875 patients, 41% of whom were women. Women were less likely to acutely receive heparin, an angiotensin-converting enzyme (ACE) inhibitor, or glycoprotein IIb/IIIa inhibitor therapy, and were less likely to receive coronary interventions. Women had an increased risk of in-hospital death, reinfarction, heart failure, stroke, and transfusion (ie, highlighting the bleeding problem in women); at discharge, despite their high-risk status, women were less likely to be prescribed guideline-based aspirin, ACE inhibitors, and statin drugs. Women had an excess dosing of antiplatelet and antithrombin agents, which correlated with an increase in bleeding, mortality, and longer length of stay. Twenty-five percent of the increased bleeding risk among women, as compared with men, seen with glycoprotein IIb/IIIa inhibitors was secondary to excess dosing. Dosing of many of these agents relates to glomerular filtration rate, which should be the parameter used rather than simply inspection of the creatinine level.

Data from the Get with the Guidelines CAD registry encompassing 78,254 patients with acute MI in 420 hospitals between 2001 and 2006 highlighted sex differences.²⁵⁴ Women were older, more likely to have comorbidities, and less likely to have STEMI than men. Although there were no sex differences in hospital mortality, women with STEMI had higher adjusted mortality than men (10.2% vs 5.5%), with increased STEMI mortality evident very early, within the initial 24 hours. This was associated with lesser likelihood of early aspirin and early β-blocker use, a decrease in reperfusion therapy, and a decrease in timely reperfusion. Underuse of evidence-based treatment for women and delayed reperfusion represent opportunities to decrease the sex disparities in the care and outcomes of women with STEMI.²⁵⁴ Also in this registry, in a subset of 49,358 patients aged 65 years and older, women were less likely than men to receive optimal care at discharge. The authors concluded that approximately 69% of the sex disparity may potentially be reduced by providing optimal quality of care to women; however, the higher mortality in African American patients of both sexes could not be accounted for by differences in the quality of care as measured in this study.²⁶⁰ Moreover, from the VIRGO registry of women and men 18 to 55 years of age with acute MI,^261,262 women were less likely to return to work after MI than were men.²⁶³

Women with MI are more likely than men to have recurrent MI and be subsequently disabled by heart failure.²⁶⁴ The Canadian ACS registry assessed the factors influencing the underutilization of evidence-based therapies in women.²⁶⁵ Canadian women in this ACS cohort had higher death rates than men, but had lower rates of use of ACE inhibitors, β-blockers, and statins. There was apparent lower assessment of patient risk, as evidenced by the decision for not scheduling cardiac catheterization. Despite adjustment for these biasing confounders, female sex remained associated with underutilization of therapy with lipid-modifying agents and ACE inhibitors.

Cardiac rehabilitation is an essential component of comprehensive care after ACS with unquestionable morbidity and mortality benefits, with a Class IA recommendation in all coronary guidelines.²⁶⁶ Women are 55% less likely to participate in cardiac rehabilitation than men, with one contributor being the lack of referral by the treating physician.^267,268 Women particularly absent from cardiac rehabilitation include the uninsured, unmarried, socioeconomically disadvantaged, smokers, depressed, obese, sedentary, elderly, and nonwhite and also those with less education, social support, and competing family obligations. Depressive symptoms are linked to suboptimal cardiac rehabilitation attendance, despite evidence that cardiac rehabilitation exercise training improves depression in women.^269,270 Home-based cardiac rehabilitation may prove effective for women with significant barriers to attending structured outpatient programs.

Further data has been derived from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 trial evaluating ranolazine in the management of ACS.²⁷¹ A total of 6650 patients with NSTEMI were randomized to ranolazine versus placebo, which had no effect on the primary end point: CVD death, MI, or recurrent ischemia. In the subset analysis, for CVD death or MI, the hazard ratio was 0.99 (P = .87), whereas the reduction in recurrent ischemia was significant, with a hazard ratio of 0.87 (P = .03). A post hoc analysis examining the results by sex showed striking differences.²⁷² The MERLIN-TIMI 36 population was composed of 2291 women and 4269 men. Women were older and more likely to have diabetes, hypertension, heart failure, prior angina, ECG ST-segment depression, and increased brain natriuretic peptide levels. However, they had lower rates of obstructive CAD and of elevated troponin levels. Women in the MERLIN-TIMI 36 trial were more likely than men to report angina, despite less obstructive CAD. They had more ischemic episodes on continuous ECG recording during the hospitalization, with electrocardiographic ischemia predictive of an unfavorable outcome.²⁷² The primary end point was significant in women, with a P value of .03. Although there was no sex difference in CVD death and MI, ranolazine significantly reduced recurrent ischemia in women (P = .002).

Reperfusion data from the NSTEMI and STEMI guidelines^{273,274,275,276} provide no sex-specific recommendations for the utility of agents. In STEMI strategies, reperfusion with thrombolytic therapy carries a higher risk of death and bleeding complications compared with PCI. Although thrombolysis is rarely used today, the complications of thrombolysis are greater in women than in men, especially hemorrhagic stroke. In the GUSTO trial, one-third of an increase in bleeding complications and a doubled mortality related to thrombolysis were documented for women.^{273,274,275,276} Primary PCI has a lower 30-day mortality than thrombolysis and a reduced risk of intracranial bleeding, but a persistent high risk of vascular complications. Decreased major CAD events and target vessel revascularization are characteristic with stenting compared with balloon angioplasty. PCI is the preferred reperfusion strategy, but there are no sex-specific guideline recommendations. Women with STEMI undergoing CABG have an increased in-hospital mortality compared with men, but no specific guideline recommendations are offered on utility. PCI revascularization for NSTEMI reduces mortality and recurrent MI in high-risk women who should undergo an early invasive strategy.

Numerous studies document that women with NSTEMI with high-risk features benefit from an early invasive strategy. Although early invasive management of ACS is an effective treatment strategy for women, major bleeding independently predicts 30-day mortality. Women have an increased risk of procedural bleeding complications, such that an early invasive management strategy showed benefit only in the higher risk ACS women. The ACC/AHA guidelines recommend an initial conservative strategy for low-risk women with an ACS, in that an early invasive strategy for such women affords no benefit.^277,278

Regarding medical management, aspirin reduces the risk of recurrent ischemic events, and antithrombotic agents reduce the risk of thrombotic complications. However, women have an increased bleeding risk with antiplatelet and antithrombotic agents, mandating careful attention to weight and renal calculation of doses.²⁷⁸ Women with NSTEMI are recommended to receive the same pharmacologic therapy as men—aspirin, P2Y₁₂ receptor inhibitors, anticoagulants, statins, β-blockers, and ACE inhibitors, both in the ACS setting and for secondary prevention. Women with both STEMI and NSTEMI are recommended to receive aggressive behavioral interventions, including smoking cessation; referral to a comprehensive cardiac rehabilitation program that includes education on lifestyle and stress management; and appropriate weight maintenance, dietary interventions, and physical activity.^273,278

Hormone therapy with estrogen plus progestin should not be given de novo to menopausal women after ACS for secondary prevention of coronary events. Women taking estrogen plus progestin or estrogen at the time of ACS should discontinue these agents.^273,278

Although the 2014 ACC/AHA NSTEMI guidelines recommend that women with NSTEMI be treated with the same pharmacologic agents as men in both the acute care and secondary prevention setting,²⁷⁶ with consideration of weight and renal dosing of antiplatelet and anticoagulant agents because of the higher bleeding risks in women,^259,279,280 most data show that women with nonobstructive CAD and ACS are less likely to be prescribed secondary prevention medications (including antiplatelet agents and statins)²⁸¹ despite their increased rates of readmission, reinfarction, and death in the first year after MI. The 2013 ACC/AHA STEMI guidelines identify female sex as a risk factor for bleeding complications after STEMI, but provide no sex-specific recommendations for use of antiplatelet or anticoagulant therapies.²⁷⁴ In premenopausal women who are still menstruating, antiplatelet therapy may significantly increase menstrual bleeding.

Statin therapy is an effective secondary prevention intervention for both women and men, but women had no benefit for stroke or all-cause mortality.²⁸² Important for younger women who may become pregnant is that both statins and ACE inhibitors/angiotensin II receptor blockers are contraindicated during pregnancy.

Complication rates following MI are higher in women than men, despite similar success rates with treatment. Women sustain more bleeding complications, often secondary to pharmacologic therapies or invasive procedures. Mechanical complications such as acute severe mitral regurgitation, septal rupture, free wall rupture, and heart failure are more likely to occur in women, whereas ventricular arrhythmias do not differ by sex. Data from the Global Registry of Acute Coronary Events registry indicated that women had a 43% increased risk of bleeding during hospitalization.²⁸³ Women undergoing PCI also incurred more in-hospital major bleeding, including access-related complications,²⁵⁹ in part due to inappropriate dosing of antithrombotic therapies.

Coronary Artery Bypass Graft Surgery

Women constitute 20% to 30% of the CABG surgical population, about 180,000 procedures annually. Mortality is greater for women than for men, especially among younger women. Contributing factors may be an increase in nonelective surgery or late referral, reduced use of an arterial conduit, and an excess of procedural complications. From the Society of Thoracic Surgeons (STS) registry,²⁸⁴ 28% of the 344,913 patients were women. Women were older and more likely to have diabetes, hypertension, peripheral vascular disease, and nonelective procedures. Operative mortality was 4.5% for women versus 2.6% for men. Women had increased operative mortality for every risk factor examined univariately. Data from the National CVD Network registry (n = 51,187 patients, with 30% women) also reported that women were at greater CABG risk.¹⁵² For women younger than 50 years of age, there was a 3-fold increase in hospital mortality, whereas women aged 50 to 59 years had a 2.4-fold increase, with this sex difference decreasing with advancing age.¹⁵² Women of all ages had a better left ventricular ejection fraction and a smaller number of diseased vessels at surgery. In the Northern New England CVD registry of 26,725 CABG patients, hospital mortality was 4.1% for women and 2.1% for men.²⁸⁵ The majority of excess mortality in women was related to diabetes or to an urgent/emergent presentation. Studies have shown trending improvement in 30-day CABG mortality for women from 1991 to 1994, with a steeper decrease in mortality in women than in men (5.6% to 1.9% vs 1.4% to 1.9%). This was likely due to the increased use of arterial CABGs for women.²⁸⁶ Compared with men, women younger than 50 years old had a greater burden of comorbidities and were more likely to have emergency surgery and decreased use of arterial grafts, the latter possibly explaining the excess mortality among younger women. In a case-control study of CABG, women had higher perioperative risk in all comorbidity categories compared with matched male controls.²⁸⁴ As with all other coronary presentations, women undergoing CABG have an excess of bleeding complications, and to date, it has not been elucidated whether sex differences in blood vessels or blood factors underlie the increased bleeding risk.

In another report from the STS registry, data suggested that off-pump CABG surgery reduces the sex disparity and may advantage women. Women who had on-pump CABG were older and had more comorbidity; they had an increased adjusted mortality, an increased duration of ventilation, and a longer length of stay. However, women who had off-pump CABG surgery had comparable mortality to men; in addition, the women with off-pump CABG had a reduced risk of reexploration.^287,288 Improved outcomes have also been realized with improved glucose control among diabetic patients typically treated with continuous insulin infusion postoperatively. In addition, better anemia control can improve outcomes because anemia is an independent risk factor for adverse outcome, as is the need for transfusion.^264,289

CABG for acute MI is rare, but in a review of 23 CABG studies that reported data stratified by sex,²⁹⁰ women were older and sicker at the time of CABG. Adjustment for baseline differences reduced, but did not eliminate, the increased in-hospital mortality for women. In this review, women were less likely to receive an internal mammary artery graft and had more postoperative complications including renal failure, neurologic complications, and postoperative MI.²⁹⁰

Percutaneous Coronary Interventions

Among patients undergoing PCI, women tend to be older and to have more comorbidities. However, the improvement in outcomes with the use of stenting has preferentially advantaged women,²⁹¹ with newer generation stents further improving outcomes.²⁹² In the National Heart, Lung, and Blood Institute Dynamic Registry of PCI, women were more likely to have high-risk characteristics than men, including older age, diabetes, hypertension, hypercholesterolemia, heart failure, and unstable angina.²⁹³ Sex differences in procedural outcome have diminished markedly over time, such that there are now similar PCI procedural and clinical success rates in women and men. The improved outcomes in women over time seem related to the better appreciation of pathophysiologic variables specific to women.²⁹¹ Women have a thick small chamber left ventricle, such that changes in pressure and volume are more likely to precipitate a myocardial ischemic event. In addition, the increased use of stenting and adjunctive pharmacologic agents selectively advantages women. Nonetheless, women continue to have an increased bleeding risk, transfusion requirement, and vascular complications as well as post-PCI renal failure.²⁹⁴ The latter likely reflects lack of appreciation of preprocedural chronic kidney disease and consequent therapeutic measures for renal protection. Women younger than 50 years of age have less severe angiographic CAD, but have an increased risk of target vessel and target lesion failure.²⁹⁵

Following PCI, women have more residual angina than do men. Moreover, 1-year mortality remains greater in women than men (6.5% vs 4.3%), with the combined occurrence of death, MI, and need for CABG being greater for women (18.3% vs 14.4%). A recent study examining sex-stratified outcomes following PCI linked 426,996 patients (42% women) in the ACC’s CathPCI registry to Medicare inpatient claims. Women experienced worse in-hospital outcomes compared with men.³⁸ Among female veterans undergoing coronary angiography, women had lower rates of epicardial obstructive CAD compared with men and improved 1-year mortality; this cohort differed from previous studies in that the rate of traditional risk factors was lower among female than male veterans.²⁹⁶

An important exception to adverse outcomes for women is PCI, where the application of stenting and adjunctive therapeutic agents appears to selectively benefit women; current PCI procedures result in comparable clinical and angiographic improvement for both sexes.^291,297,298 Recent pooled data show that newer generation drug-eluting stents (DES) have better safety and efficacy profiles in women compared with older DES and bare metal stents.²⁹² Although women have almost twice the rate of bleeding after PCI as men,²⁹⁹ the Study of Access Site for Enhancement of PCI for Women randomized trial showed reductions in bleeding or vascular complications with radial access.³⁰⁰

CVD accounts for 48% of all noncommunicable disease deaths, with 80% occurring in low- and middle-income countries. The global prevalence of CVD is anticipated to increase 15% to 20% from 2010 to 2020. This is related to unfavorable changes in lifestyle in developing nations including urbanization, Western diets, processed foods, and increasing rates of obesity, hypertension, dyslipidemia, and diabetes. In 2008, there were more than 9 million CVD deaths among women worldwide, representing 33% of all female deaths. From 1990 to 2020, a 120% increase is anticipated in CVD mortality among women in developing countries, contrasted with a 29% mortality increase for women within industrialized countries. In the INTERHEART study, modifiable risk factors accounted for 94% of the population-adjusted CVD mortality in women.^{101,301,302,303}

In 2012, the United Nations held a Summit on Noncommunicable Diseases, the first health summit in several decades. It highlighted sex disparities in risk and access to diagnosis and treatment and established compelling linkages with the empowerment of women and education of girls. The vulnerability of women was highlighted in this summit by the finding that 60% of the world’s poor are women and two-thirds of illiterate adults are women.³⁰⁴ Women are often a focal point of a majority of households throughout the world, with the matriarch of the family central to understanding and adapting habits of a heart-healthy lifestyle.³⁰¹ Because women often serve as role models in the lives of others, their examples of good CVD health (eg, exercising, not smoking, omitting alcohol, managing high blood pressure and diabetes, managing stress, and eating right) can not only improve their personal health, but also positively influence others to do the same, improving CVD outcomes for women and globally.³⁰⁵ Key global issues are to educate women about CVD risk factors, specifically the modifiable behavioral risk factors. Prominent among these are smoking cessation, a diet decreased in sodium and saturated fats and increased in fresh fruits and vegetables, and an increase in physical exercise.^101,301,306 This requires that women be equipped, enabled, empowered and engaged.

In 2015, the First National Policy and Science Summit on Women’s CVD Health³⁰⁷ highlighted three unanswered research questions likely to improve CVD outcomes for women:

1. What biological variables are most influential in the development and clinical outcomes of CHD, and what can be done to reduce mortality among women?

2. What are the best strategies to assess, modify, and prevent a woman’s risk of CHD?

3. What factors influence and explain disparities in CVD epidemiology and outcomes between men and women?

A woman’s CVD health is not solely a medical issue. Eradication or lessening of the burden requires a multifaceted approach and involvement from the community, government, social advocates, and others in order to support social change meeting the diverse needs of women. Both in the developing world and in developed nations, a focus on preventive care should not only target high-risk populations, but also create population programs to globally reduce the burden of CVD. Recent regulations in the United States require the reporting and tracking of targeted priority populations, including women. From the Centers for Medicaid and Medicare Services, there is a focus to report and track services by sex and race/ethnicity, but also a focus on population health. This population health focus extends beyond the traditional health care facilities to engage with community leaders and organizations to provide optimal environments for healthy living and access to quality healthcare services. This includes an environment where women can safely engage in daily exercise and have access to heart-healthy food, which requires the help of community leaders and prioritization of public regulatory officials. Increasingly important is the use of social media to create a cultural change to understand individual and societal responsibilities.^34,51

This chapter highlights the evidence on sex differences in the pathophysiology and the clinical presentations of IHD among women and identifies significant disparities in primary prevention and stable and acute management strategies resulting in the often reported high adverse outcomes for females. The greater risk factor and comorbidity burden as well as advanced age of women undergoing CVD care compound the challenges of care for women and accelerate CHD risk.^193,194 Women often present with variable symptom characteristics and with a reduced frequency of obstructive CAD that may be etiologic for sex-specific atherosclerotic plaque.^4,20 A working model of female-specific angina is detailed in Figure 108–5. The role of vascular dysfunction and flow abnormalities as they relate to CMD as driving worsening clinical outcomes has yet to be fully elucidated.⁴ Currently, guideline-directed strategies for nonobstructive CAD are not defined. However, considerable research has focused on strategies to improve the high-risk status of women referred for coronary revascularization with some success. In general, there are considerable unmet needs of women at risk for CVD, and without concentrated population health and healthcare strategies tailored for women, it remains unlikely that marked reductions in the observed high clinical adverse outcomes for women will occur. Goals for reducing CVD risk tailored to women remain underexplored, including the role of biology. Clinical and population needs of women and the socioeconomic disparities between women and men remain sizeable hurdles to effecting changes in the large population of young and older women at risk for CVD.

With appreciation to C. Jeanette Zahler and Anne O’Neal for assistance in manuscript preparation.