Overview of atherosclerotic cardiovascular risk factors in females

INTRODUCTION — Clinicians and patients may have gaps in their awareness of, recognition of, and preparedness to manage atherosclerotic cardiovascular disease (ASCVD) risk in females [1-3]. This topic will present an overview of ASCVD risk factors in females.

Related issues are discussed separately:

●ASCVD risk assessment in adults. These topics include discussion of sex-specific ASCVD risk assessment. (See "Overview of established risk factors for cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

●Prevention of ASCVD. (See "Overview of primary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

●The management of ASCVD, including management of coronary heart disease in women. (See "Management of coronary heart disease in women" and "Overview of secondary prevention of ischemic stroke" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

DEFINITIONS AND EPIDEMIOLOGY — Atherosclerotic cardiovascular disease (ASCVD) includes four major areas:

●Coronary heart disease (CHD) clinically manifested by myocardial infarction, angina pectoris, and coronary death. CHD is a common cause of heart failure. (See "Epidemiology of heart failure".)

●Cerebrovascular disease clinically manifested by stroke and transient ischemic attack.

●Peripheral artery disease clinically manifested by intermittent claudication.

●Aortic atherosclerosis and thoracic or abdominal aortic aneurysm.

The presence of vascular disease in one of these territories significantly increases the likelihood of disease in other vascular distributions. (See "Overview of established risk factors for cardiovascular disease", section on 'Noncoronary atherosclerotic disease'.)

ASCVD is the leading cause of death worldwide in females and males [4], accounting for 4.8 and 4.9 million deaths respectively in 2017 [5]. The CVD burden for females and males in the United States are also similar, causing 21.8 and 24.2 percent of deaths, respectively [6].

IMPORTANCE OF TRADITIONAL RISK FACTORS — The general approach to atherosclerotic cardiovascular disease (ASCVD) risk assessment and management in females is similar to that in males, as traditional risk factors are relevant for all adults [4]. This is discussed separately. (See "Overview of established risk factors for cardiovascular disease".)

Additional ASCVD risk markers which are either specific to or more common in females are discussed below. Some of these conditions (certain autoimmune disorders; history of premature menopause; and history of pregnancy-associated conditions associated with ASCVD risk, such as preeclampsia) are included in the American College of Cardiology/American Heart Association (ACC/AHA) list of risk-enhancing factors for clinician-patient risk discussion (table 1) [7]. These risk factors are not included in standard risk calculators as their value in enhancing ASCVD risk assessment and modifying management has not been established. Some of these risk factors may predict increased risk of developing traditional risk factors such as hypertension and diabetes mellitus, as discussed below. (See 'Pregnancy-associated risk markers' below and 'Other conditions associated with cardiovascular disease risk' below.)

PREGNANCY-ASSOCIATED RISK MARKERS — A number of adverse pregnancy outcomes (APOs) are associated with increased subsequent cardiovascular risk [8,9]. Thus, screening for and managing cardiovascular risk factors is an important component of care for patients who have experienced APOs. (See "Gestational hypertension", section on 'Maternal prognosis' and "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Follow-up' and "Overview of preventive care in adults", section on 'Cardiovascular disease prevention'.)

The value of including APOs in atherosclerotic cardiovascular disease (ASCVD) risk classification has not been established. Studies examining the predictive role of APOs suggest that they may not materially enhance ASCVD risk assessment after accounting for established cardiovascular risk factors [8,10].

Lactation is associated with reduced ASCVD risk. (See 'Protective effect of lactation' below.)

Hypertensive disorder of pregnancy — Hypertensive disorder of pregnancy (HDP) includes preeclampsia, gestational hypertension, as well as chronic hypertension occurring during pregnancy. HDP is associated with increased risk of developing chronic hypertension as well as increased risk of ASCVD. It has not been established whether HDP is an independent predictor or ASCVD risk beyond its association with chronic hypertension and other traditional risk factors.

The risk of developing chronic hypertension and ASCVD in individuals with preeclampsia or gestational hypertension is discussed further separately. (See "Gestational hypertension", section on 'Maternal prognosis' and "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Long-term maternal risks of pregnancy-associated hypertension'.)

Gestational diabetes — Gestational diabetes is associated with an increased risk of developing type 2 diabetes and ASCVD, as discussed separately. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Long-term risk'.)

Preterm delivery and delivery of infants with fetal growth restriction — Patients who have a spontaneous delivery prior to 37 weeks of gestation have an increased risk of developing ASCVD when compared with those who deliver at term, as discussed separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis", section on 'Long-term maternal consequences'.)

Adverse cardiovascular prognosis for individuals delivering an infant with fetal growth restriction is discussed separately. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Maternal'.)

Placental abruption — Placental abruption is associated with increased subsequent risk of maternal ASCVD, as discussed separately. (See "Acute placental abruption: Management and long-term prognosis", section on 'Long-term maternal prognosis'.)

Spontaneous pregnancy loss — Patients who have experienced spontaneous pregnancy loss (miscarriage, not induced abortion) or stillbirth have elevated subsequent risk of ASCVD, particularly coronary heart disease (CHD) [11-17]. While the cause of this association has not been fully elucidated, it may relate to procoagulant and proinflammatory states that are associated with recurrent miscarriages. Pregnancy loss is also associated with increased risk of developing hypertension and type 2 diabetes [15]. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Stillbirth: Incidence, risk factors, etiology, and prevention".)

In a meta-analysis of 10 studies assessing the risk of ASCVD following a miscarriage (nine reported data on CHD, four reported data on cerebrovascular disease, and three reported data on both), individuals with a prior miscarriage were significantly more likely to develop CHD (odds ratio [OR] 1.45, 95% CI 1.18-1.78) but not cerebrovascular disease (OR 1.11, 95% CI 0.72-1.69) [15]. Among 11,518 adults in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (mean follow-up 10.8 years) who had ever been pregnant, there was a significantly greater risk of myocardial infarction, even after adjusting for traditional risk factors, among those with any history of miscarriage (adjusted hazard ratio [HR] 1.42 compared with no pregnancy loss, 95% CI 1.14-1.78) or stillbirth (adjusted HR 2.65, 95% CI 1.37-5.12) [11]. Individuals with recurrent miscarriages (more than three) were at the highest risk of myocardial infarction (adjusted HR 8.90, 95% CI 3.18-24.90).

A meta-analysis found that stillbirth was associated with an increased risk of ASCVD-related mortality (HR 2.23, 95% CI 1.90-2.62) [18].

Protective effect of lactation — As discussed separately, observational data have found that individuals who have lactated have more favorable subsequent cardiovascular and metabolic profiles and reduced cardiovascular risk compared with those who have not lactated. (See "Maternal and economic benefits of breastfeeding", section on 'Cardiovascular disease'.)

OTHER CONDITIONS ASSOCIATED WITH CARDIOVASCULAR DISEASE RISK — A number of other conditions are more common in females and are associated with atherosclerotic cardiovascular disease (ASCVD) risk [6,19].

Timing of menarche — Either early or late menarche appears to be associated with future ASCVD risk [20-24]. For example, in a cohort of 1.2 million females, premature menarche was associated with an increased risk of developing coronary heart disease (CHD; relative risk [RR] 1.27, 95% CI 1.22-1.31) [20]. Similar findings were reported in a 2014 meta-analysis of six smaller cohorts encompassing fewer than 150,000 women, in which each one-year increase in age at menarche was associated with a 3 percent reduction in total mortality [21]. The WISE trial noted a U-shaped curve of major adverse cardiovascular events among 648 females without surgical menopause with early (≤10 years) or late (≥15 years) menarche, with hazard ratios (HRs) of 4.53 and 2.58 respectively [24]. A similar finding of increased risk but of lesser magnitude was noted in the Million Women Study from the United Kingdom [20].

Early menopause — Early menopause (occurring at less than age 40), either naturally, surgically, or chemically is associated with an increased risk of ASCVD [25-28]. In a population-based cohort study of 144,260 post-menopausal females, the risk of incident ASCVD (a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism) at median seven-year follow-up was higher for women with surgical premature menopause (7.6 percent; HR 1.87) and for those with natural premature menopause (6.0 percent; HR 1.36) than for those without premature menopause (3.9 percent) after adjustment for ASCVD risk factors and use of menopausal hormone therapy (MHT) [27]. Similarly, in 73,814 females in the Nurses’ Health Study, early menopause was associated with a higher multivariable-adjusted risk of ASCVD [29].

Diagnosis and management of primary ovarian insufficiency is discussed separately. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Management of primary ovarian insufficiency (premature ovarian failure)".)

Polycystic ovary syndrome — Obesity, insulin resistance, impaired glucose tolerance or type 2 diabetes, and dyslipidemia are common in patients with polycystic ovary syndrome (PCOS), and these metabolic disorders may increase the risk of ASCVD; it is unclear if PCOS is an independent risk factor for ASCVD. These issues are discussed separately. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Metabolic issues' and "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Coronary heart disease'.)

Autoimmune diseases — Rheumatoid arthritis, systemic lupus erythematous (SLE), and antiphospholipid antibody syndrome are more common in females and are associated with increased risk of ASCVD [30]

●Rheumatoid arthritis – Females are at higher risk for rheumatoid arthritis than males. ASCVD in patients with rheumatoid arthritis is discussed separately. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Cardiac disease' and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Noncardiac vascular disease' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

In addition, the incidence of heart failure, atrial fibrillation, and peripheral vascular disease in patients with rheumatoid arthritis is higher than in people without rheumatoid arthritis (see "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis"). Patients with rheumatoid arthritis may be at increased risk for stroke, although the supporting data are not as conclusive as those reporting an increased risk of coronary artery disease. This is discussed in more detail separately. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Stroke'.)

●Systemic lupus erythematosus – Systemic lupus erythematosus (SLE) occurs most often in females, particularly young female adults. Epidemiologic studies have identified elevated ASCVD risk (particularly CHD) among patients with SLE compared with the general population. ASCVD in patients with SLE is discussed in detail elsewhere. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Coronary artery disease in systemic lupus erythematosus".)

●Antiphospholipid antibody syndrome – Antiphospholipid antibody syndrome is more prevalent in women and is associated with recurrent venous and arterial thrombosis, valvulopathy, coronary artery disease, and peripheral vascular disease. This condition is discussed separately. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Cardiac involvement' and "Diagnosis of antiphospholipid syndrome" and "Management of antiphospholipid syndrome" and "Antiphospholipid syndrome and the kidney".)

Breast cancer — Observational studies have identified an elevated risk of ASCVD mortality in females with breast cancer. In a systematic review, females with breast cancer had a higher risk of ASCVD death than those in the general population [31]. Mortality was greatest among females who were older at the time of diagnosis (>65 years), Black individuals, and those with a left-sided tumor. One of the included studies found that the elevated ASCVD-mortality risk among breast cancer survivors compared with age-matched controls without breast cancer was evident only seven years after diagnosis [32].

Several mechanisms have been proposed to explain the association between breast cancer and cardiovascular mortality [33,34]. The “multiple hit” hypothesis suggests that the combined effects of underlying ASCVD risk factors, direct adverse effects of cancer therapy on cardiac function, lifestyle perturbations during and after treatment (eg, decreased physical activity) and concomitant metabolic alterations and decline in cardiovascular reserve result in a higher risk of ASCVD [35]. In addition to these “hits,” ASCVD and breast cancer may share some common biological pathways that may explain disease progression [33,36].

Treatment-related risks — Many breast cancer treatments (including radiation therapy, chemotherapy, adjuvant therapies, and endocrine therapies) are associated with early and delayed adverse cardiovascular effects [34]. In addition, patients who experience chemotherapy-induced early menopause have an increased ASCVD risk [33]. (See 'Early menopause' above.)

A comprehensive review of breast cancer therapies, their cardiovascular adverse effects, and recommendations for cardiovascular management is provided elsewhere:

●(See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

●(See "Risk and prevention of anthracycline cardiotoxicity".)

●(See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)

●(See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

●(See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse", section on 'Cardiovascular morbidity'.)

Other risks — Traditional ASCVD risk factors before or at the time of breast cancer diagnosis appear to be the same as those among females without breast cancer [33,37,38]. However, ASCVD and breast cancer share several modifiable risk factors including physical inactivity, obesity or overweight, tobacco use, greater than moderate alcohol intake, and poor diet [34,35,39].

Decreased physical activity has been observed in individuals diagnosed with and treated for breast cancer [40-42]. For example, in a study of 1696 females with newly diagnosed invasive breast cancer, self-reported physical activity significantly decreased six months post-diagnosis, with the greatest decrease noted in recreational activity (eg, running or jogging, aerobic dance or exercise class, and tennis) [42]. Interventions to improve physical activity in persons with breast cancer are presented elsewhere. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Breast cancer'.)

Weight gain is common following breast cancer treatment due to decreased physical activity and changes in diet [33,43-47]. Several trials have demonstrated that weight loss programs can be successfully implemented and achieve weight loss in breast cancer survivors. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Breast cancer'.)

Systemic inflammation and oxidative stress have been implicated in the development of both atherosclerosis and carcinogenesis [36]. Common intracellular signaling pathways lead to chronic inflammation, oxidative stress, and the activation of cellular processes that underlie both diseases [36].

HORMONE THERAPY

Combined estrogen-progestin contraceptives — The use of combined estrogen-progestin hormonal contraception (CHC) is associated with increased cardiovascular risk. Contraceptive decision-making based upon consideration of risks and benefits are discussed separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects' and "Contraception: Counseling and selection" and "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Use in patients with medical disorders'.)

Menopausal hormone therapy — Cardiovascular risk associated with menopausal hormone therapy (MHT) and patient selection for MHT are discussed separately. (See "Menopausal hormone therapy: Benefits and risks" and "Treatment of menopausal symptoms with hormone therapy", section on 'Contraindications'.)

RISKS IN TRANSGENDER INDIVIDUALS — Risk factors for ASCVD appear similar in transgender individuals as their cis gender counterparts and include older age, diabetes, and chronic kidney disease [48].

●Transgender women – Epidemiological studies suggest that transgender women have a higher risk of myocardial infarction, ischemic strokes, and venous thromboembolic events compared with cisgender (gender identity is the same as sex assigned at birth) women; however, whether this risk is higher than cisgender men is not clear [49-54]. It is not clear whether the increased risk of ASCVD in transgender women is due to gender-affirming hormone therapy or related to their natal sex (ie, male sex at birth).Observational studies suggests that the use of estrogen by transgender women confers an increased risk for ASCVD [53,55,56], perhaps due to a deleterious effect on ASCVD risk factors (eg, lipids and insulin sensitivity) [49,57]. Management of cardiovascular risk factors may decrease the hazards associated with long-term hormone therapy [55]. (See "Primary care of transgender individuals", section on 'Cardiovascular disease' and "Overview of established risk factors for cardiovascular disease".)

●Transgender men – There is no clear evidence to suggest that transgender men have an increased risk of ASCVD compared with either cisgender men or cisgender women [50-53,55,56]. Masculinizing hormone therapy alters lipid parameters associated with increased cardiovascular risk, but studies have shown mixed effects on other risk factors, such as blood pressure and insulin sensitivity [49,52,55,56,58,59].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Assessment of cardiovascular risk" and "Society guideline links: Primary prevention of cardiovascular disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Coronary artery disease in women (The Basics)")

SUMMARY AND RECOMMENDATIONS

●The general approach to atherosclerotic cardiovascular disease (ASCVD) risk assessment in females is similar to that in males, as traditional risk factors are relevant for all adults. Some additional risk markers are either specific to or more common in females; the value of these factors in enhancing risk assessment has not been established. Some of these risk factors predict increased risk of traditional risk factors such as hypertension and diabetes. (See 'Importance of traditional risk factors' above and "Overview of established risk factors for cardiovascular disease".)

●Some adverse pregnancy outcomes (APOs) are associated with increased subsequent cardiovascular risk in observational studies. These include hypertensive disorder of pregnancy, gestational diabetes, preterm delivery, placental abruption, and spontaneous pregnancy loss. Thus, screening for and managing cardiovascular risk factors is an important component of care for patients who have experienced adverse pregnancy outcomes. (See 'Pregnancy-associated risk markers' above and "Gestational hypertension", section on 'Maternal prognosis' and "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Follow-up' and "Overview of preventive care in adults", section on 'Cardiovascular disease prevention'.)

●Other conditions or factors associated with increased ASCVD risk include early menarche, late menarche, early menopause, polycystic ovary syndrome (PCOS), and some autoimmune disorders. (See 'Other conditions associated with cardiovascular disease risk' above.)

●Breast cancer is associated with increased risk of cardiovascular mortality. This association may be caused by the combined effects of underlying ASCVD risk factors, adverse cardiovascular effects of cancer therapy, and adverse metabolic and cardiovascular effects of lifestyle perturbations during and after treatment. (See 'Breast cancer' above.)

●Individuals who have lactated have reduced cardiovascular risk compared with those who have not lactated. (See 'Protective effect of lactation' above and "Maternal and economic benefits of breastfeeding", section on 'Cardiovascular disease'.)

●Transgender women have a higher risk of ASCVD compared with cisgender women; however, it is unclear whether the ASCVD risk for transgender women is higher than that for cisgender men. There is no clear evidence to suggest that transgender men have an increased risk of ASCVD compared with either cisgender men or cisgender women. (See 'Risks in transgender individuals' above.)