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Abstract

Heart disease is the leading cause of death in women. Unique risk factors have been recognized, including pre-eclampsia, eclampsia and autoimmune diseases. Diabetes and hypertension (HTN) also play a unique role in women. Women with diabetes have a higher risk for coronary heart disease and microvascular disease compared with males. Additionally, older women have a high prevalence of uncontrolled HTN and women tend to have more treatment resistant HTN, increasing risk for cardiovascular events and mortality. The outcomes of cardiovascular disease have shown an increase in the number of heart attacks in younger women, though there is decreasing mortality. Treatment with coronary artery bypass graft surgery and percutaneous intervention has also shown to have poorer outcomes in women.

Keywords

cardiovascular disease diabetes hypertension risk profile women

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/whe; (4) view/print certificate.

RELEASE DATE: 22nd June 2015; EXPIRATION DATE: 22nd June 2016

LEARNING OBJECTIVES

Upon completion of this activity, participants will be able to:

Distinguish criteria for ideal cardiovascular health among women

Assess how diabetes affects cardiovascular risk among women

Assess how hypertension affects cardiovascular risk among women

Evaluate the presentation of coronary heart disease among women

Financial & competing interests disclosure

Editor: Laura Dormer, Future Science Group, London, UK.

Disclosure: Laura Dormer has disclosed no relevant financial relationships.

CME author: Charles P Vega, MD, Clinical Professor of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed the following financial relationships: Served as an advisor or consultant for: Lundbeck, Inc.; McNeil Pharmaceuticals; Takeda Pharmaceuticals North America, Inc.

Author & credentials: Jacqueline Kurth, BA, Department of Medicine, University of California, Irvine, California, USA

Disclosure: J Kurth has disclosed no relevant financial relationships.

Shaista Malik, MD, PhD, MPH, Division of Cardiology, Department of Medicine, University of California, Irvine, Orange, California, USA

Disclosure: S Malik has disclosed no relevant financial relationships.

No writing assistance was utilized in the production of this manuscript.

Women's cardiovascular health is a major health concern with many important and increasingly recognized sex-specific differences in risk factors, presentation and outcomes related to cardiovascular disease (CVD). Heart disease is the number one cause of death in women in the USA and stroke is the third, making the reduction of women's risk of CVD a crucial determinant in reducing mortality [1]. Major efforts have been made by various national campaigns to increase awareness of heart disease among women. In addition, national guidelines have been published addressing both the prevention and diagnosis of CVD [2]. Although awareness and recognition of issues specific to women when it comes to preventing, diagnosing and managing CVD in women have improved in recent years, much is unknown about sex differences in the etiology and management of CVD.

CVD Prevention

The most recent Guidelines for the Prevention of Cardiovascular Disease in Women put out by the American Heart Association (AHA) in 2011 expanded upon the 2004 and 2007 recommendations for female-specific recommendations for CVD prevention for women in the USA. These guidelines emphasized unique risk factors for women, including pregnancy-related complications, which, even after being resolved after the pregnancy, follow women as an increased risk factor later in life. In addition to adding pregnancy-related risk factors, these guidelines recognized the role of autoimmune disease, predisposing women to higher risk of CVD. Finally, these guidelines emphasized a lower cut point for women considered high risk using the Framingham risk score.

These guidelines support a risk classification algorithm that stratifies women into three groups: ideal cardiovascular health, at risk and high risk. The ideal cardiovascular risk group applies to women who are at the lowest level of risk, based on seven measurable criteria. It would stand to reason that if women can achieve these seven standards of ideal cardiovascular health, they would reduce their risk for CVD. In order to be classified as being in ideal cardiovascular health, women must meet all of the following criteria: fasting blood glucose <100 mg/dl untreated, blood pressure <120/80 mmHg untreated, untreated total cholesterol <200 mg/dl, BMI <25 kg/m², in addition to the healthy behaviors of smoking abstinence, participation in physical activity for at least 150 min per week at moderate intensity and at least 75 min per week at vigorous activity, and adherence to a Dietary Approaches to Stop Hypertension-like diet (DASH diet) [3]. While many factors of CVD can be controlled and even avoided through lifestyle, others require medical intervention to help maintain a healthy heart. Diabetes, hypertension (HTN) and cholesterol can be modified by both lifestyle choices and medical treatment, but recent studies have shed light on important sex differences in presentation, pathogenicity and consequent treatment. Recognizing how common risk factors can affect women in the USA differently is crucial to ensuring women receive accurate diagnosis and gender-appropriate treatment.

Increased relative risk for CVD from diabetes

It is well known that there is considerable overlap among men and women when it comes to traditional risk factors that predict CVD. Diabetes is an important risk factor for CVD, and in women, diabetes is not only a risk factor for heart disease and stroke but it is also the seventh leading cause of death [1]. Furthermore, it has been shown that women with diabetes have a higher relative risk (RR) for coronary heart disease (CHD) compared with males with diabetes [4]. The severe implications of diabetes on women's health make early diagnosis of the disease critical.

Detection of diabetes in women has been shown to differ from detection of diabetes in men in significant ways that may contribute to a longer latent period in women. The Rancho Bernardo study documented important gender differences in the levels of fasting blood glucose and impaired glucose tolerance. Furthermore, a higher proportion of women were diagnosed with diabetes mellitus only when an oral glucose tolerance test was used [5]. Additionally, evidence from the study suggested that the effect of changing levels of hormones, notably in postmenopausal women, mediated changes in fasting plasma glucose levels and glucose tolerance. The hormone testosterone was also found to influence risk for diabetes mellitus. Diabetes risk was found to be increased in men whose levels of bioavailable testosterone were in the lowest quartile and in women whose levels of bioavailable testosterone were in the highest quartile [6,7].

In addition, the study also showed a linear relationship in men between fasting blood glucose levels and the risk of mortality from heart disease. However, in women they found that increased glucose dysregulation is required for mortality from CHD to be affected. Association between fasting blood glucose levels and mortality as a result of CHD in women existed only after the fasting blood glucose level reached 5.55 mmol/l [5]. Furthermore, prediabetes is associated with a more adverse cardiometabolic profile, and is a condition that can go undiagnosed for years and leads to delays in important disease diagnosis, control and prevention. Randomized controlled trials have shown that the duration of prediabetes and diabetes mellitus are critical factors in influencing cardiovascular health [7]. Individuals with a high risk of developing diabetes mellitus, such as those with prediabetes, can decrease the rate of disease onset with various interventions, such as lifestyle modifications and pharmacologic agents, but sex-specific delays in diagnosis of diabetes can result in later disparities in treatment and control of cardiovascular risk factors [7]. Consequently, early diagnosis and treatment of prediabetes and diabetes mellitus in women are critical to reduce women's cardiovascular risk.

In a recent study, Peters and colleagues show that diabetes mellitus has distinct implications on cardiovascular health in women. The authors performed a meta-analysis of 64 cohorts that analyzed asymptomatic individuals who went on to experience fatal and nonfatal stroke events. The pooled adjusted RR of stroke was 2.28 (95% CI: 1.93–2.69) in women with diabetes mellitus compared with women without diabetes [8]. However, in men the RR was 1.83 (95% CI: 1.93–2.69) in those with diabetes mellitus compared with men without diabetes mellitus. Women with diabetes mellitus had a 27% excess risk of stroke compared with men who had diabetes mellitus. In addition, the authors analyzed systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, BMI and waist circumference data from four cohort studies (the Scottish Heart Health Extended Cohort study, the National Health And Nutrition Examinations Survey III [NHANES III], the Asia Pacific Cohort Studies Collaboration and the Atherosclerosis Risk in Communities study) to examine the interactions between sex and cardiovascular risk factors. No statistically significant difference was found between individuals with and without diabetes mellitus when looking at systolic blood pressures, total cholesterol and HDL cholesterol, and thus the authors concluded that the gender differences in cardiovascular risk factors did not account for the observed increased risk of stroke related to diabetes mellitus in women. There were, however, significant differences in BMI and waist circumference between men and women with diabetes mellitus, implicating adiposity as a potential cause of sex differences in the RR of stroke as related to diabetes mellitus. Abdominal adiposity is not only thought to increase the risk of developing diabetes mellitus, but it is implicated in other important markers of CVD, such as endothelial dysfunction, increased platelet activation and atherosclerosis [9].

Finally, although there have been challenges to diabetes being considered a risk equivalent in men, in women there is building evidence that diabetes may be a CHD equivalent. In a second study performed by Peters and colleges, they show that diabetes is a significant determinant of CHD risk in women. They performed a meta-analysis of 64 cohorts from around the world that analyzed the sex-specific RR for incident CHD associated with diabetes. Notably, the study included 30 cohorts from Asia (55% of the individuals), 13 from Europe (23%), 11 from Australia, New Zealand or Pacific (12%) and ten from the USA (10%), consequently providing cultural inclusivity. They found that the pooled RR in women for incident CHD associated with diabetes compared with women with no diabetes was 2.82 (95% CI: 2.35, 3.38) as compared with 2.16 (95% CI: 1.82, 2.56) in men. The multiple-adjusted relative risk ratio (RRR) for incident CHD was 44% greater in women with diabetes than it was in men with diabetes (RRR: 1.44 [95% CI: 1.27, 1.63]) [10]. Based on these findings they concluded that women with diabetes have more than a 40% greater risk of incident CHD compared with men with diabetes.

In addition, it has been shown that women with diabetes have unique forms of vascular dysfunction. Women with Type 2 diabetes are more likely to have coronary microvascular disease than men with diabetes [11,12]. Furthermore, studies have shown that women with prediabetes have greater endothelial dysfunction than men, in addition to higher blood pressure and more fibrinolysis and thrombosis [13]. The RUTH trial showed that diabetic women have a similar level of risk for fatal coronary disease when compared with women with CHD. They found that even though the overall risk of CHD and CVD was lower in diabetic women compared with women with CHD, the risk of fatal CHD, fatal CVD and all-cause mortality was similar [14]. Though this is a single study finding and the subject warrants additional investigation, it provides additional evidence to the growing body of work that is pointing toward diabetes being a CVD equivalent in women.

It appears that women with diabetes possess a greater RR for CVD and stroke, and that diabetes causes a number of important cardiometabolic effects in women that place them at an increased RR for heart disease. This excess risk in women is likely due to a combination of factors, though a discussed above, the observation that women with diabetes have greater impaired glucose tolerance at the time of diabetes diagnosis coupled with potential delays in detection of diabetes result in a longer period of disease burden compared with men. Increasing screening for prediabetes in all women, and in particular those at high risk, such as those with a family history of diabetes or who were diagnose with gestational diabetes, could have a substantial impact on the prevention of CHD in women.

Increased RR for CVD from HTN

In addition to the sex-specific risk of increased CVD that diabetes imparts to women, high blood pressure is another important risk factor with unique implications for women. An estimated 77.9 million adults over the age of 20 have high blood pressure, and while the overall prevalence of HTN is considered to be similar among men and women, there are differences when age ranges are considered [15]. In those under 45 years of age, more men than women tend to have HTN, whereas those over age 65 years, more women than men have HTN. [15] Furthermore, among US adults over the age of 65, women have a slightly higher prevalence of HTN compared with men, but a significantly lower rate of control of their HTN. Data from a study of nearly 100,000 postmenopausal women from across the USA between 1994 an 1998 indicates that while the prevalence of HTN ranged from 27% in women aged 50–59, to 41% in women 60–69 years, to 53% in women 70–79 years, the rate of treatment of HTN were similar across all age groups. Despite similar rates of treatment, control of HTN in women is particularly poor in the oldest age group, with only 29% of women age 70–79 having clinical blood pressures under 140/99 mmHg, compared with 41% controlled in women age 50–59 and only 37% controlled in women age 60–69 [15]. High prevalence of HTN in older women coupled with decreased control of HTN, makes education and adequate treatment in women an important part of reducing women's risk of CVD as women age. Recent investigations of HTN in women have begun to shed light on a phenomenon known as treatment resistant HTN, which has important implications in the fight to reduce cardiovascular risk factors in women.

It has been estimated that 8.9% of people with HTN and 12.8% of people taking antihypertensive medication have resistant HTN, which is defined as HTN requiring four or more antihypertensive agents [16 –18]. Compared to nonresistant HTN, resistant HTN is associated with increased risk for major cardiovascular events and mortality [19,20]. It also increases the risk of major adverse cardiovascular outcomes in patients with HTN and established coronary artery disease [21]. Several recent studies have shown that the resistant HTN population has a greater ratio of females to males than the nonresistant HTN population, and that female sex appears to be an independent predictor of resistant HTN [21,22]. This increased RR of resistant HTN in the female population puts women at a unique risk for CVD.

There appears to be a conundrum regarding the ultimate effect of HTN and resistant HTN in women. In general, women with HTN have a lower risk of mortality compared with age-matched men with HTN [23]. Though HTN is an important risk factor for CVD in women, it appears that women are less likely to have adverse cardiovascular events compared with men, but, importantly, they are more likely to develop treatment resistant HTN, which confers an increased risk for major cardiovascular events and mortality. Smith and colleagues recently investigated the long-term risk of adverse outcomes associated with resistant HTN, specifically in women with signs and symptoms of cardiac ischemia. They found that women with treatment resistant HTN had a higher occurrence of nonfatal stroke, nonfatal MI, hospitalization for angina or heart failure and mortality compared with those women who had nonresistant HTN or who were normotensive [24]. In addition, the all cause mortality in women with treatment resistant HTN was higher at least 10 years from the initial determination of resistant status. While the ultimate goal of CVD risk reduction is to avoid these events, the reality is that many women will have one in her lifetime, and the recognition of treatment resistant HTN in women can improve outcomes of CVD.

The danger of treatment resistant HTN in women in compounded by the fact that there is neither a definitive understanding of the pathophysiology of the disease, nor a clear-cut algorithm for treatment. Studies have identified predictors for treatment resistant HTN, including age, obesity, higher baseline blood pressure, excessive salt ingestion, diabetes, chronic kidney disease, left ventricular hypertrophy, Black race and residence in the southeastern USA [17]. The issue of chronic kidney disease is a compounding factor for CVD. It has been shown that both men and women face increased risk of all-cause mortality, cardiovascular mortality and end-stage renal disease with lower glomerular filtrations rates and albuminuria [25,26]. The backbone of diagnosis and treatment of women with treatment resistant HTN, much like the prevention of many other risk factors for CVD, is lifestyle modification and use of an effective multidrug regimen established by a physician [17,27]. Blood pressure monitoring is important in women with risk factors for CVD and those with diagnosed HTN, in conjunction with a good diet and exercise regimen.

Lifestyle effects on CVD

A healthy lifestyle that reduces a woman's risk of CVD involves maintaining a BMI <25 kg/m², smoking abstinence and participation in physical activity for at least 150 min per week at moderate intensity and at least 75 min per week of vigorous activity. Physical activity can pose a problem for those who might have limited mobility, or for those who have busy schedules. Studies have shown that walking for 30 min a day five times a week is associated with a 19% reduction in CHD and that walking shows a dose-dependent reduction in CVD risk [28 –30]. Simple changes in one's daily routine, such as taking the stairs, walking to work, or walking during lunch breaks can quickly add up to the goal of 150 min of moderate intensity exercise. It is estimated that adherence to physical activity guidelines for aerobic and muscle strengthening activities were associated with 27% lower mortality in adults without existing chronic conditions like DM, cancer, MI, angina, CVD, stroke or respiratory disease, and 46% lower mortality in people with chronic comorbidities [15]. In addition to increased mortality in those with chronic comorbidities, inactivity was higher among women than men (31.0 vs 28.6%, age adjusted) and increased with age [15]. Increasing physical activity not only has profound effects upon a woman's cholesterol, diabetes and HTN risk factors, but engagement in physical activity is also required for a woman to be considered in ideal cardiovascular health.

Not only does physical activity help reduce CVD risk, it also helps to control BMI. Maintaining a BMI <25 kg/m² is considered one of the goals to maintain ideal cardiac health. A study by Canoy and colleges showed that women with a BMI <25 kg/m² and a waist circumference <70 cm had the lowest risk of CHD and women with BMI ≥30 kg/m² and waist circumference ≥80 cm had the highest risk [31]. Many other studies correlate increased BMI, waist–hip ratios and increased weight circumference in women with increased risk of CHD, and as such it is critical for women to maintain an appropriate weight [32 –34].

In addition to exercise and weight control, abstinence from smoking is a vastly important component of reducing a woman's CVD risk. It is estimated that there are 250 million women worldwide who smoke cigarettes and millions more who use smokeless tobacco products [35]. A large meta-analysis of prospective cohort studies that reviewed data from 2.4 million participants found that compared with nonsmokers, women who smoke have a 25% greater RR of CHD compared with male smokers [36]. Furthermore, even the effects of passive smoking from encounters in public places or from smoke from family members has been shown to slightly increase one's risk for CAD [37]. The effects of smoking on CAD risk factors have also been shown to vary depending on culture. In a study by Peters and colleagues, they found that the increased risk of stroke from smoking is similar among women and men who smoke (RRR: 1.06 [95% CI: 0.99–1.13]). However, once a regional analysis was performed, it showed a more harmful effect in women than in men in western (RRR: 1.10 [1.02–1.18)] but not in Asian (RRR: 0.97 [0.87–1.09]) populations [38]. Consequently, for women in the USA, abstinence from smoking has important implications.

Diet & cholesterol effects on CVD

Diet affects multiple classic cardiovascular risk factors, as well as novel risk factors, such as inflammation, endothelial cell function and triglyceride levels [15]. Adhering to a reduced sodium diet or the DASH diet reduces HTN, and if combined they can reduce systolic blood pressure (SBP) by 7.1 mmHg in adults without HTN and by 11.5 mmHg in adults with HTN [39]. While the DASH diet might not suite all lifestyles, there are many other diets that promote weight loss and healthy lifestyle. In one study that considered the Atkins, Zone, Ornish and LEARN Diets, it was found that premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake of these diets, lost more weight and experienced more favorable overall metabolic effects after 1 year [40]. In addition, the Mediterranean diet has gathered notoriety for its health benefits. One study of the diet found that there was a −5.9 mmHg (CI: −8.7 to −3.1 mmHg) and −7.1 mmHg (CI: −10.0 to −4.1 mmHg) drop in systolic blood pressure, respectively, in addition to a −0.38 (CI: −0.55 to −0.22) and −0.26 (CI: −0.42 to −0.10) drop in the cholesterol–HDL cholesterol ratio, respectively. Furthermore, they found that the Mediterranean diet reduced C-reactive protein levels by 0.54 mg/l (CI: 1.04 to 0.03 mg/l) compared with a low-fat diet [41].

Diet also has important implications on cholesterol levels. Total cholesterol and low-density lipoprotein (LDL) cholesterol levels in men and women are relatively similar up to about 20 years of age, after which point cholesterol levels increase more in men than in women [42,43]. However, after menopause, total cholesterol and LDL levels in women rise and can exceed those of men due to the low estrogen levels of menopause [44,45]. In addition to total cholesterol and LDL levels, HDL is an important component of cardiovascular risk and is one of the parameters taken into consideration in the most recent equation for risk calculation put forth by the AHA [46]. Low HDL levels have been shown to be a risk factor for heart disease independent of serum LDL levels, and in several studies HDL and triglyceride levels were stronger predictors of cardiovascular death in women than LDL and total cholesterol [47 –49].

Multiple studies have shown that women in the lowest quintile of HDL cholesterol have a higher RR of heart disease than those in the highest quintile [50,51]. The relationship between LDL, HDL and CVD is complex, and it is important for women to monitor their total cholesterol, LDL, and HDL and to not assume that a high HDL level will mask the risk associated with a high LDL, or that a low HDL level can be compensated for by a low LDL level. The Third Adult Treatment Panel of the National Cholesterol Education Panel classified HDL cholesterol levels <40 mg/dl as low, while HDL cholesterol levels greater than 60 mg/dl were defined as protective. However, when taking gender-specific differences into consideration an HDL of 50 mg/dl was established as the cutoff for identifying women at marginal risk [52]. While LDL and total cholesterol levels are often the target of drug therapies, lifestyle modification such as smoking cessation, aerobic exercise and a healthy diet must be employed by women in order to gain the maximum benefit of cholesterol control. It has been shown that there are still sex disparities in cholesterol care among women. A study from the Department of Veterans Affairs showed that female veterans with coronary vascular disease were less likely than men to have an LDL <100 mg/dl (odds ratio = 0.56; 95% CI: 0.45–0.72) [53]. Furthermore, female veterans were less likely to receive treatment intensification (odds ratio = 0.66; 95% CI: 0.43–1.00) for elevated cholesterol levels. Raising awareness in women about the importance of not solely monitoring total cholesterol and LDL cholesterol levels, but also their HDL levels, will help to empower women to ask questions of their healthcare providers and to monitor their cholesterol risk factors in the context of female predispositions.

Similar to the effect of decreased estrogen levels in menopause on a woman's lipid profile, the pregnancy state also has unique affects on a woman's cardiovascular profile. Pre-eclampsia and eclampsia have been shown to affect a woman's future cardiovascular health. One study showed that mothers with a history of mild or moderate pre-eclampsia had an adverse metabolic and cardiovascular risk profile 11 years after delivery, including higher blood pressure and higher insulin resistance compared with mothers with severe pre-eclampsia as well as mothers without a history of pre-eclampsia [54]. In addition to pregnancy effects on cardiovascular risk, the recent AHA and American Stroke Association guidelines for stroke prevention in women highlights the important novel risk factors in women, including pre-eclampsia, gestational diabetes mellitus, oral contraceptives and hormonal replacement therapy during menopause [55]. These are novel risk factors that are just starting to be investigated and warrant further investigation and inclusion into an overall assessment of cardiovascular risk prediction in women.

Diagnosing CHD in women

A recent June 2014 consensus statement released by the AHA outlined the first set of recommendations in nearly a decade to advocate a gender-specific approach for diagnosing heart disease in women [2]. Many of the original studies of cardiovascular heath contained predominantly men, and consequently women have been diagnosed and treated according to standards developed from male dominated studies. As a result, many women who did not present with classic obstructive coronary artery disease have gone undiagnosed and inappropriately treated. The update points to the growing body of evidence that supports that women can present with different symptoms of ischemia from CHD, such as epigastric pain and nausea, radiation to the arms, neck, and between the shoulder blades, as well as shortness of breath and fatigue [2]. These different symptoms can stem from different causes of coronary vascular disease, such as endothelial damage and microvascular disease, which require unique guideline directed medical management [2,12]. The update puts a needed spotlight on the state of women's cardiovascular health and focuses on a model of diagnosis and treatment based on female-specific evidence to identify women with an elevated ischemic heart disease risk. While accurate identification and treatment of women with heart disease is vital to reducing morbidity and mortality, how do women use this gender-specific model to prevent the disease from taking hold in the first place?

In addition to reducing disparities in the diagnosis and treatment of risk factors for CVD in women, recent insights into sources of ischemia in women have been shedding light on gender differences in the predictive value of diagnostic testing. In women with signs of chest pain, it has been shown that women have higher rates of angiographic non obstructive coronary artery disease compared with men [56]. It has also been shown that women who did not have a significant obstructive stenosis of their artery upon angiography had double the risk (12.8 vs 6.7%) of adverse outcomes at 10 years compared with women with angiographically normal coronary arteries [57]. In addition, impaired coronary flow is present in roughly 50% of these women [58]. This phenomenon is known as coronary microvascular dysfunction (CMD) and it is due to disease of the small coronary artery blood vessels of the heart. The growing evidence of this disease's disproportionate presentation in women is leading to recognition of the deficiency of current diagnostic testing to identify this unique form of ischemia in women.

Current widely used detection tests for heart ischemia tend to look for regional lack of blood flow to the myocardium. However, in CMD, the ischemia is more homogenously spread in throughout the heart, so tests such as single photon emission computed tomography (SPECT) and stress tests that rely on perfusion differences between different coronary artery territories due to obstruction are less effective in perceiving ischemia in CMD [59]. This leads to under detection of significant CMD in women, which can lead to future adverse cardiovascular events. In addition to this under detection of heart disease in women being evaluated, women with CMD who are having active signs of chest pain and are being evaluated with angiography can go undetected. CMD often does not result in obstruction of a coronary artery, and thus finding no stenotic artery on angiography often leads women with CMD to be diagnosed as normal and they are therefore not targeted for aggressive risk factor modification. The recent iPOWER study looked at the viability of using noninvasive measurement of coronary flow reserve via Doppler to evaluate CMD and found that it was successful as a routine assessment tool in women with suspected ischemic heart disease and no obstructive coronary artery disease [59]. This study is currently being continued to evaluate the women they have identified with CMD for insight into potential ways to diagnose and treat CMD. There is no current large-scale study of interventions in women with CMD, which is an area that urgently needs to be explored and incorporated into the understanding of women's CVD risk.

CVD outcomes in women

Despite increasing awareness of CVD in women and the known danger of diabetes and HTN in increasing a woman's risk for cardiovascular events, it was recently shown that the number of younger women with acute myocardial infarction (AMI), commonly known as a heart attack, is not only not plateauing or decreasing, it's increasing [60]. This study showed that from 2001 until 2010, women under the age of 55 have had an increased number of admissions for AMI, whereas the number of AMI diagnoses in men of this age had decreased over the years. Furthermore, while younger women had a decrease in their in-hospital death rates from heart attacks, the rate of death in younger women is still higher than it is in men [60]. In contrast to this trend of increasing number of heart attacks in younger women, a study looking at rates of AMI in those over 65 and on Medicare between 2002 and 2007 found that their rates of AMI were decreasing [61].

Despite the increasing trend in AMI diagnosis in younger women, studies have shown a downward trend in in-hospital mortality from CVD in women of all ages, though there is evidence that younger women have worse outcomes after AMI, and after coronary artery bypass graft and percutaneous coronary intervention, two of the main treatments for heart attack [60,62–63]. Interestingly, it has also been noted that mortality in women declines with increasing age, once again placing younger women in a disadvantages cardiovascular profile [63]. Why would there be decreasing numbers of heart attacks in older women, but increasing numbers of heart attacks and poorer outcome in younger women? While there is no clear answer to this conundrum, there are some telling clues.

The 2001–2010 study found that not only were comorbid HTN and diabetes mellitus more prevalent in younger women compared with younger men, but the prevalence of these conditions increased in both women and men from 2001 to 2010 [60]. Similarly, the National Health and Nutrition Examination Survey found that from 1999 to 2010 there was no decreasing trend seen in the percentage of women aged 20–59 years with either uncontrolled HTN, uncontrolled LDL cholesterol, or smoking, all major risk factors for CVD. However, there was a decline in these risk factors seen in women over the age of 60, as well as in men greater than 40 [64]. While this tells us that risk burden in younger women could be playing a part in this observed increased incidence of AMI in younger women, it also raises the critical question of why the risk factor burden is not decreasing in younger women. The answer to this question requires further investigation into social and physiologic components of CVD in women, but it is also a question that we can begin to rectify through awareness of the impact of HTN and diabetes in young women.

Executive summary

Cardiovascular disease prevention

Female-specific guidelines emphasize pregnancy-related complications, including eclampsia, pre-eclampsia and gestational diabetes.

The ideal cardiovascular risk group applies to women who are at the lowest level of risk as classified by the following criteria: fasting blood glucose <100 mg/dl untreated, blood pressure <120/80 mmHg untreated, untreated total cholesterol <200 mg/dl, BMI <25 kg/m², smoking abstinence, participation in physical activity for at least 150 min per week at moderate intensity and at least 75 min per week at vigorous activity, and adherence to a Dietary Approaches to Stop Hypertension-like diet.

Increased relative risk from diabetes and hypertension

Diabetes and hypertension (HTN) result in higher relative risk for cardiovascular disease (CVD) among women compared with men.

Women with diabetes have a higher risk for coronary heart disease (CHD) compared with males with diabetes and women with Type 2 diabetes are more likely to have coronary microvascular disease than men with diabetes.

Prediabetes appears to be more prevalent in women than in men and women with prediabetes have greater endothelial dysfunction, more fibrinolysis and thrombosis, and higher blood pressure. Prediabetes is a condition that can go undiagnosed for years and leads to delays in important disease control.

Older women have a high prevalence of uncontrolled HTN and women tend to have more treatment resistant HTN, which increases risk for cardiovascular events and mortality

Adhering to a reduced sodium diet or the Dietary Approaches to Stop Hypertension-like diet reduces HTN, and if combined they can reduce SBP by 7.1 mmHg in adults without HTN and by 11.5 mmHg in adults with HTN.

Low high-density lipoprotein levels have been shown to be a risk factor for heart disease independent of serum low-density lipoprotein levels, and in several studies high-density lipoprotein and triglyceride levels were stronger predictors of cardiovascular death in women than low-density lipoprotein and total cholesterol.

Diagnosing CHD in women

Women can present with different symptoms of ischemia from CHD, such as epigastric pain and nausea, radiation to the arms, neck, and between the shoulder blades, as well as shortness of breath and fatigue.

Women have higher rates of angiographic nonobstructive coronary artery disease compared with men.

It has been shown that women who do not have a significant obstructive stenosis of their artery upon angiography have double the risk of adverse outcomes at 10 years compared with women with angiographically normal coronary arteries.

CVD outcomes in women

The number of younger women with acute myocardial infarction has been increasing from 2001 to 2010.

Comorbid HTN and diabetes mellitus are more prevalent in younger women compared with younger men.

Despite the increasing trend in acute myocardial infarction diagnosis in younger women, studies have shown a downward trend in in-hospital mortality from CVD in women of all ages.

Future perspective

The rate of awareness that CVD is the number one cause of death in this country has not changed significantly over the past 6 years.

Future approaches to educating and reducing heart disease risk in women should focus on opening up a dialog between younger women and their physicians.

The mechanisms behind diabetes, HTN, cholesterol, pre-eclampsia, eclampsia and gestational diabetes need to be further elucidated and included in a gender-specific cardiovascular risk prediction, diagnosis and treatment model.

Conclusion& future perspective

While the outcomes of CVD in women are improving and there are downward trends in mortality, there is room to improve women's awareness of how CVD can affect their lives. In a study looking at women's awareness of CVD, between 1997 and 2012, awareness of heart disease as the leading cause of death in women doubled [65]. However, when looking at the past 6 years, the rate of awareness has not changed significantly, indicating a recent stagnation in the flow of information. Furthermore, the rate of awareness that heart disease is the leading cause of death was lower among younger women ages 25–34. Younger women reported that time constraints, stress or depression and lower perceptions of risk were barriers to prevention of disease. They were also more likely to report that their doctor did not talk to them about their heart disease risk [65].

Future approaches to educating and reducing heart disease risk in women should focus on opening up a dialog between younger women and their physicians, be it their OB/GYN or their primary care physician. Young women in their reproductive years may present with gestational diabetes, pre-eclampsia and eclampsia, but the opportunity to educate them on their future risk for CVD from these events is being missed in the current system. Breaking down these barriers to information will help women to understand the impact of CVD on their lives and will hopefully help to empower women to lead healthy lives and keep CVD risk factors at bay.

Women are a unique population with specific challenges to understanding their distinct cardiovascular risk factors. Differences in the physiology of diseases with known influence on cardiovascular risk, such as diabetes, HTN and cholesterol, in addition to unique markers such as pre-eclampsia, eclampsia and gestational diabetes need to be further elucidated and included in a gender-specific cardiovascular risk prediction, diagnosis and treatment model. As the mechanisms of the underlying disease processes in women becomes more completely understood, methods for accurate diagnosis and treatment can be developed and utilized in the prevention and management of CVD in women.

Footnotes

Reducing women's cardiovascular disease risk profile

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References

Papers of special note have been highlighted as:

of interest; •• of considerable interest

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Reducing Women's Cardiovascular Disease Risk Profile

Abstract

Keywords

Financial & competing interests disclosure

CVD Prevention

Increased relative risk for CVD from diabetes

Increased RR for CVD from HTN

Lifestyle effects on CVD

Diet & cholesterol effects on CVD

Diagnosing CHD in women

CVD outcomes in women

Conclusion& future perspective

Footnotes

Reducing women's cardiovascular disease risk profile

References