Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the developed world. Although women generally have a lower prevalence, they have unique factors placing them at risk for CVD compared to their male counterparts. Studies show that prevention, early detection, and treatment can reduce downstream sequelae of CVD. However, sex and gender-specific recommendations are lagging and not always optimally disseminated to patients and providers. This article will explore sex and gender-based differences in cardiovascular burden of disease, risk factors, presentation, and natural history to aid in early identification and intervention.
Key points
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Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in women.
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Sex/gender disparities exist in the diagnosis, treatment, and long-term management of traditional CVD risk factors including hypertension, diabetes, obesity, dyslipidemia, tobacco use, and physical activity.
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Emerging literature shows unique CVD contributors across a woman’s lifespan such as polycystic ovary syndrome, menopause, breast cancer, depression, hypertensive disorders of pregnancy, and gestational diabetes mellitus.
| AHA | American Heart Association |
| cHTN | chronic hypertension |
| CVD | cardiovascular disease |
| DM | diabetes mellitus |
| GDM | gestational diabetes mellitus |
| HTN | hypertension |
| LDL | low-density lipoprotein |
| PAD | peripheral arterial disease |
| PCOS | polycystic ovary syndrome |
| T2DM | type 2 diabetes mellitus |
| WHO | World Health Organization |
Introduction
In this article, we use the terms “women” and “men” to refer to female and male sex assigned at birth ( Table 1 ). We use the term gender to refer to self-reported identity and acknowledge that gender is a complex concept not limited to the binary of men and women. The epidemiology and presentation of cardiovascular disease (CVD) in intersex and trans populations are beyond the scope of this article and deserve further in depth study.
| Risk Factor | Relative Risk | Reference |
|---|---|---|
| Pregnancy-related complications | ||
| History of preeclampsia without severe features | Relative risk (RR) of 2, P < .05 | , , |
| History of preeclampsia with severe features | RR of 5.36, P < .001 | , , |
| History of gestational diabetes | RR ranging from 1.23 (ischemic heart disease) to 3.16 (coronary artery bypass graft), P < .05 | , |
| History of preterm delivery | Cardiovascular disease (CVD) (RR 1.43), P < .05 CVD death (RR 1.78), P < .05 Coronary heart disease (RR 1.49), P < .05 Cardiac death from coronary heart disease (RR 2.10), P < .05 Stroke (1.65), P < .05 | |
| Gynecologic risk factors | ||
| Polycystic ovarian syndrome | RR 1.3, P < .05 | , |
| Early menopause prior to age 45 | RR 1.50 (1.28–1.76) for overall coronary heart disease (CHD), RR 1.11 (1.03–1.20) for fatal CHD, P < .05 | , |
The World Health Organization (WHO) defines CVD as a group of conditions affecting the heart and blood vessels. These encompass coronary heart disease, cerebrovascular disease, peripheral arterial disease (PAD), rheumatic heart disease, congenital heart disease, deep venous thrombosis, and pulmonary embolism. CVD has been the leading cause of death in the United States since 1921 with nearly 128 million Americans aged ≥20 currently living with some form of CVD or risk factor. CVD prevalence in women is 44.8% when including coronary heart disease, heart failure, stroke, and hypertension. Since 2010, there has been a nearly 20% increase in mortality attributable to atherosclerotic CVD in women suggesting significant opportunity for further exploration and intervention. Disparities abound between sexes in self-recognition of symptoms, risk factor management, referral for invasive and noninvasive testing, and in-hospital mortality. , Emerging literature suggests that consideration of traditional and unique sex-based factors across a woman’s lifespan may be key to screening, early intervention, and mitigation of downstream sequelae.
Cardiovascular disease presentation
Though women with acute coronary syndrome often report chest pain, they have lower odds of endorsing chest pain or diaphoresis when compared to their male counterparts. Additionally, while both sexes may report atypical symptoms including shortness of breath, left arm and shoulder pain, and nausea and vomiting, women are more likely to present with these symptoms. Prodromal symptoms in women are more likely to be attributed to anxiety or stress by both patients and health care providers. From a pathophysiologic perspective, increased frequency of plaque erosion has been proposed as a mechanism for the higher proportion of unstable angina and non-ST-elevation myocardial infarctions in women. , Similar sex difference trends and disparities have been observed in women with cerebral vascular disease, PAD, , and rheumatic heart disease.
Traditional cardiovascular risk factors
Hypertension
High blood pressure poses a significant risk for coronary heart disease, heart failure, and stroke in both men and women. While a higher percentage of males have hypertension (HTN) up to age 64, for those ≥65 years of age, the percentage of females with HTN is higher. Proposed mechanisms for this difference include hypertensive disorders in pregnancy, interactions between the renin-angiotensin-aldosterone axis and sex hormones, and socioeconomic disparities. One study found that women were less likely to receive HTN medication despite having similar blood pressure values compared to their male counterparts. A separate meta-analysis found that women were 15% less likely to be prescribed angiotensin-converting enzyme inhibitors and 30% more likely to receive diuretics. Despite these differences and many published guidelines, no major societies have recommended sex-specific thresholds for blood pressure control.
Diabetes Mellitus
Diabetes mellitus (DM) has been linked to coronary heart disease, heart failure, PAD, and stroke. Overall, men have a higher prevalence of type 2 DM, but women have a higher prevalence of undiagnosed DM after age 60 and overall DM prevalence after age 70. Men are diagnosed at a younger age and lower body mass index, whereas women have higher rates of excess weight and HTN at the time of diagnosis. Women with DM have myocardial infarctions younger, lower rates of revascularization, higher risk of developing heart failure, and worse outcomes for PAD compared to their male counterparts. Moreover, men have a greater net benefit with lifestyle modifications and pharmacotherapy compared to women. Changes in insulin resistance, body fat distribution, sex hormones, pregnancy, and psychosocial factors have all been linked to disparities in diabetes prevalence, diagnosis, management, morbidity, and mortality in women.
Obesity
The 2024 American Heart Association (AHA) reports increased prevalence for obesity in females from 33.4% in 1999 to 2000 to 41.9% in 2017 to 2018. Obesity disproportionately contributes to coronary artery disease risk in women (64%) compared to men (46%). Explanations for these differences include differing fat distribution, sex hormone changes, genetic susceptibility, and gut microbiome make-up. Females are more likely to both be offered and to pursue lifestyle changes, be prescribed weight loss medications, and undergo bariatric surgery. In contrast to other risk factors, it appears that management of obesity is lagging in men compared to women. However, it is important to note the disparate role that sociocultural norms play. For example, the perceived link between physical attractiveness and thinness in western societies and greater body dissatisfaction in women compared to men contributing to higher rates of depression and eating disorders in the former.
Tobacco Use
Tobacco use is an independent risk factor for CVD and a major contributor to dyslipidemia, HTN, and DM. Prevalence estimates show that among adults 18 years of age or older, 13.1% of males and 10.1% of females reported cigarette use every day or some days. Additionally, 6.9% of females who gave birth in 2017 reported cigarette use during pregnancy, with greater prevalence in those aged 20 to 24. In those who concurrently use oral contraceptives and tobacco products, there is a 10-fold increase in myocardial infarction risk and 3-fold increase in stroke risk. When looking at CVD specifically, one meta-analysis found a 25% increase in risk of coronary artery disease in women compared to men. Despite greater attempts to stop smoking, women experience disparate challenges with cessation. , The literature emphasizes the importance of addressing gendered experiences including trauma and violence, imbalances with caregiver roles, income disparities, and second-hand exposure to increase cessation success. ,
Physical Activity
Physical inactivity is a major risk factor for CVD. Overall, women are less likely to meet the aerobic physical activity (PA) guidelines (≥150 min/wk of moderate PA, ≥75 min/wk of vigorous PA, or an equivalent combination) recommended by the AHA compared to their male counterparts. Interestingly, one study found a greater all-cause mortality benefit in women compared to men with both aerobic exercise and strength training. Moreover, women had a peak benefit in all-cause mortality at lower duration of moderate to vigorous exercise (140 min/wk in women compared to 300 min/wk in men) and higher duration of exercise before seeing plateau of these benefits (300 min/wk in women compared to 110 min/wk in men) compared to men.
Dyslipidemia
Cholesterol has been classified as a causal risk factor for atherosclerosis and CVD. While females compared to males are more likely to have a high protective high-density lipoprotein greater than 40, they are also more likely to have a total cholesterol greater than 200 and just as likely to have low-density lipoprotein (LDL) greater than 130, increasing CVD risk. A myriad of mechanisms contribute to sex differences in dyslipidemia including sex hormone-driven lipoprotein metabolism, lipid profile type across the lifespan (ie, menstrual cycle, menopause, pregnancy, contraception use), and unique comorbidities like polycystic ovarian syndrome (PCOS). Moreover, data show that women are less likely to have LDL assessed, receive recommended lipid-lowering therapy, and reach target LDL goals, contributing to disparities in CVD prevention.
Gender/sex-specific cardiovascular disease risk factors
The following section outlines unique gender/sex-specific risk factors.
Polycystic Ovarian Syndrome
PCOS is a sex-specific syndrome defined by the presence of 2 of 3 criteria, including anovulation and/or oligomenorrhea; excess androgen production; and characteristic imaging findings of many small ovarian cysts on pelvic ultrasound. Women with PCOS have insulin resistance (50%–70%) and increased risk of metabolic syndrome. One study found that women with PCOS have increased risk of HTN, DM, higher concentration of total cholesterol, and increased risk of nonfatal cerebrovascular disease compared to women without PCOS. Though data regarding the relationship between PCOS and CVD remain controversial, one meta-analysis found a small but statistically significant increase in risk of coronary heart disease, with a relative risk of 1.3 to develop CVD and 1.44 for coronary heart disease.
Menopause
Women develop CVD several years later than men, often coinciding with the transition to menopause. Symptoms of menopause including hot flashes, sleep difficulties, and depression have been associated with CVD and its risk factors. One study found that women with higher total cholesterol and blood pressure were more likely to develop menopause earlier. Additionally, a first cardiovascular event before age 35 was linked to a 2-fold increased risk of early menopause. In numerous other studies, women who reached menopause at younger ages had increased risk of coronary heart disease and heart failure. Overall, the relationship between changes in sex hormone, body fat distribution, lipid profile, and menopause have been well documented and represent a critical stage for close monitoring and intervention.
Breast cancer treatment
The strongest risk factor for breast cancer is female gender with roughly 99% of cases occurring in women. Existing literature supports a link between breast cancer and cardiovascular health. CVD (namely heart failure and myocardial infarction) and CVD risk factors (ie, dyslipidemia, obesity, HTN) are increased in breast cancer survivors. Breast cancer treatments including chemotherapeutic agents and radiation therapy have been associated with cardiotoxicity. This underscores the importance of monitoring patients with breast cancer for CVD risks and therapy-related cardiac effects.
Depression
According to the WHO, depression is 50% more common in women compared to men. Women with depression have a 30% to 50% higher risk of CVD compared to men. One study found that in women with CVD, depression is a predictor of death and all-cause mortality even after adjusting for demographic factors and CVD risk factors. Moreover, women with depression are more likely to experience recurrent ischemia, cardiogenic shock, cardiac arrest, and in-hospital mortality. Mechanistically speaking, persistent low-grade pro-inflammatory states influenced by variations in sex hormones across the lifespan contribute to both depression and CVD in women.
Pregnancy-related risk factors
Multiple studies have found correlations between common complications of pregnancy and both cardiovascular risk and future all-cause mortality. Hypertensive disorders of pregnancy, gestational diabetes, and preterm birth have also been associated with increased all-cause mortality decades later, with CVD being the predominant cause of death. In shorter time frames, complications of pregnancy are repeatedly associated with higher risk scores on established cardiovascular risk calculators, implying greater CVD risk later in life. , Despite these findings, many women with complications of pregnancy are unaware of their risk. One study found that up to 96% of women were unaware of the relationship between preeclampsia and CVD.
Hypertensive disorders in pregnancy: chronic hypertension, gestational hypertension, and pre-eclampsia
Hypertensive disorders of pregnancy include a continuum of syndromes ranging from chronic hypertension (cHTN) (blood pressure >140/90 mm Hg prior to 20 weeks gestation) to gestational hypertension (new-onset blood pressure >140/90 mm Hg after 20 weeks gestation), pre-eclampsia (new onset blood pressure >140/90 mm Hg after 20 weeks gestation with proteinuria and/or signs of end-organ damage), and cHTN with superimposed PEC (preeclampsia). According to the Centers for Disease Control and Prevention (CDC), between 2017 and 2019 prevalence of hypertensive disorders in pregnancy increased from 13.3% to 15.9% with the highest prevalence among women aged 35 to 44 (18%) and 44 to 55 (31%) and those who identified as Black (20.9%). Hypertensive disorders of pregnancy both predispose individuals to other CVD risk factors and act as independent CVD risk factors themselves. Literature shows an increased risk of future maternal myocardial infarction, heart failure, cHTN, and stroke with history of hypertensive disorders of pregnancy. One study of 4273 women found that hypertensive disorders of pregnancy conferred an almost 2-fold risk of progressing to an elevated risk for CVD, based on Framingham 30 criteria, 2 to 7 years after delivery. Early identification of women at risk for CVD based on reproductive history of hypertensive disorders of pregnancy may help reduce associated morbidity and mortality.
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) is most commonly diagnosed based on 2 or more abnormal values on a 3-hour oral glucose tolerance test, often following an abnormal 1 hour screening test between 24 and 28 weeks of gestation. Women with GDM have an increased risk of developing hypertensive disorders of pregnancy and type 2 diabetes mellitus (T2DM) later in life, both CVD risk factors. One study with 90,000 women found a 43% increased risk of CVD (myocardial infarction or stroke) in women with a history of GDM with a median follow-up of nearly 26 years. In addition to increasing the risk of T2DM, GDM has been associated with early atherosclerosis and endothelial dysfunction further contributing to downstream CVD risk. In conjunction with managing GDM, providers should prioritize postpartum counseling to mitigate the CVD risk that persists for decades after this diagnosis.
Preterm Delivery
Preterm deliveries (<37 weeks gestational age) affect 11% of pregnancies worldwide. One systematic review and meta-analysis of 338,000 women with preterm deliveries found an increased relative risk (RR) of future maternal CVD (RR 1.43), CVD death (RR 1.78), coronary heart disease (RR 1.49), coronary heart disease death (RR 2.10), and stroke (RR 1.65). Women with a history of preterm birth have been noted to have higher atherogenic lipids and carotid arterial wall thickening predisposing them to future CVD compared to women with term births. Moreover, studies show an inverse relationship between weeks of pregnancy prior to delivery and insulin resistance and blood pressure values. Overall, health care providers should consider detailed history of prior deliveries to identify and offer interventions for CVD at risk patients.
Prevention and surveillance
Current guidelines recommend screening for 10-year atherosclerotic CVD risk in patients 40 to 75 years of age using the joint American College of Cardiology/AHA guidelines. , Adults are encouraged to prioritize a healthy diet (minimal trans fats, processed foods, refined carbohydrates, and sweetened beverages) and engage in 150 minutes per week of moderate-intensity or 75 minutes per week of vigorous-intensity exercise to reduce CVD risk. Strong evidence supports the discussion of tobacco cessation at every health care visit. Based on clinician evaluation of CVD risk, consideration is made for pharmacotherapy including antihypertensives, metformin, statins, and/or aspirin in addition to lifestyle modifications.
Women routinely undergo screening mammography, which may provide insight into cardiovascular health and an opportunity for risk stratification. Recent evidence has found the presence of breast arterial calcification, an incidental finding, to confer a 2.06 relative risk of cardiac death, with similarly elevated risk ratios for ischemic stroke, PAD, and heart failure. The updated 2011 AHA risk stratification guidelines take into account nontraditional risk factors such as autoimmune diseases and pregnancy-related complications. Moreover, the fourth trimester or postpartum period has been identified as a key stage to screen for and address CVD risks. The AHA has recently published extensive recommendations including an early postpartum visit to counsel on hypertensive disorders of pregnancy, GDM, contraception, and lactation followed by a 6-week visit for screening of other essential health parameters conferring CVD risk. From a pharmacotherapy standpoint, the AHA found “not useful/effective and maybe harmful” evidence for use of hormone replacement therapy, selective estrogen receptor modulators, antioxidant supplements, folic acid, and aspirin in women less than 65 years of age for primary CVD prevention.
Discussion
Further investigation is needed in identifying causal factors, treatments, and prevention strategies for gynecologic disease and complications of pregnancy. The identification and quantification of cardiovascular risk conferred by gynecologic syndromes or pregnancy complications have been studied in the context of existing risk assessment tools. Identifying sex-specific risks thus allows for early identification of patients who are likely to be high enough risk to merit pharmacologic intervention, perhaps years before traditional risk calculators such as the atherosclerotic cardiovascular disease (ASCVD) risk calculator.
Early capture of risk represents an opportunity for the health care system and individual patients to intervene and forestall future CVD. Moreover, the ability to enact meaningful lifestyle changes is largely determined outside of the health care system. For example, access to healthy diet and exercise is often driven largely by external circumstances such as what food sources are available, what employment opportunities exist, and the availability, affordability, and safety of facilities for physical exercise and exposure to chronic stressors. The addition of pregnancy-related risk factors further complicates the social determinants, with childcare support systems now also affecting maternal stress and ability to enact recommended behavioral changes.
Incorporating sex-based risk factors may also allow providers to have more nuanced discussions with patients around a shared decision regarding interventions, acting as a tiebreaker in cases where there is ambiguity regarding the patient’s degree of cardiovascular risk or around the risk/benefit of pharmacologic intervention.
Clinics care points
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Health care providers should take into consideration both traditional and unique sex-based factors when screening women for cardiovascular disease.
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Though there is a paucity of sex-specific guidelines, all women aged 40 to 75 should be screened for 10-year atherosclerotic CVD risk, counseled on the specifics of a healthy diet, exercise frequency, and tobacco cessation per the AHA guidelines, and offered evidence- based pharmacotherapy when indicated.
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Further research is needed to better quantify the CVD risk conferred by disorders of pregnancy and gynecologic syndromes in addition to the role of sex-specific structural determinants of health to better enact change and decrease existing disparities.
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