Definition and pathophysiology
Cardiovascular disease (CVD) is the leading cause of death among women worldwide and in the United States. In the United States, approximately one in four female deaths is attributed to CVD. The cardiovascular burden in women includes coronary heart disease, heart failure and stroke; the lifetime risk for a 40-year-old woman has been estimated at approximately one in two for CVD, one in three for coronary heart disease, one in five for heart failure and one in five for stroke.
Sex and gender are distinct but interacting determinants of cardiovascular health. Sex refers principally to biological characteristics, including chromosomal complement, anatomy, physiology and hormonal influences. Gender encompasses sociocultural roles, behaviours, relationships, power structures and social expectations. Both influence the prevalence, manifestations, diagnosis, management, treatment response and outcomes of cardiovascular disease.
The biological differences between females and males arise partly from the chromosomal distinction between XX and XY individuals and are reflected in cardiovascular structure and function. Sociocultural factors contribute independently to differences in exposure to risk, access to care, clinical assessment and treatment. These influences are particularly important because women have historically been perceived as being at lower cardiovascular risk, including after menopause, contributing to delayed assessment and undertreatment.
Traditional cardiovascular risk factors
Several conventional risk factors have sex-dependent effects:
Blood pressure rises more steeply in women from young adulthood, resulting in a greater lifetime burden of hypertension.
Hypertension becomes more prevalent in women than men after approximately 65 years of age.
Hypertension-related left ventricular hypertrophy, concentric remodelling, reduced longitudinal strain and heart failure with preserved ejection fraction are more frequent in women.
Diabetes confers greater cardiovascular risk in women than in men.
Smoking, obesity and psychosocial factors are associated with a greater cardiovascular impact in women.
Obesity, physical inactivity and depression are more common in women.
Dyslipidaemia, hypertension, diabetes and obesity become increasingly prevalent after the menopausal transition.
Women with type 2 diabetes also have a higher prevalence of cardiovascular complications and death than men. Despite the effectiveness of preventive interventions in both sexes, women are less likely to receive statins, aspirin or referral to cardiac rehabilitation and are less likely to attain blood-pressure treatment goals.
Female-specific and female-predominant risk factors
Risk assessment should include reproductive and pregnancy-related history. Female-specific or female-predominant factors associated with later cardiovascular risk include:
Premature menopause
Premature ovarian insufficiency
Hypertensive disorders of pregnancy
Preeclampsia
Preterm delivery
Gestational diabetes
Small-for-gestational-age delivery
Placental abruption
Pregnancy loss
Polycystic ovary syndrome
Functional hypothalamic amenorrhoea
Fertility therapy and assisted reproductive technology
The extent to which these conditions confer risk independently of conventional factors, and whether they improve risk classification, remains incompletely established. Data concerning premature menopause and subsequent hypertension or diabetes are insufficient to support firm conclusions.
Systemic inflammatory and autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, are important risk-enhancing conditions and are more prevalent in women. Chronic kidney disease and several other comorbidities also contribute to the disproportionate cardiovascular burden in women.
Depression and anxiety are approximately twice as prevalent in women and are important risk factors for acute coronary syndromes and cardiovascular mortality. Women experience a greater impact from chronic self-perceived stress and marital stress, whereas job-related stress has a greater impact in men. Women may also have a higher inflammatory response to stress, which has been associated with subsequent adverse cardiovascular outcomes in individuals with ischaemic heart disease.
Menopause and hormonal considerations
The menopausal transition is accompanied by increasing prevalence of traditional cardiovascular risk factors. Earlier onset of menopause and longer duration since menopause have been associated with cardiovascular outcomes, although the source material does not provide quantitative estimates for these associations.
Hormone replacement therapy in post-menopausal women does not reduce the risk of ischaemic myocardial disease and may introduce other health risks. During perimenopause, temporary hormone therapy may alleviate mood disturbances and severe vasomotor symptoms; this observation does not establish a cardiovascular preventive indication.
Genetic considerations
No genetic marker or polygenic risk score is currently established for improving cardiovascular risk assessment in women beyond traditional methods. A literature-derived score based on 46 single-nucleotide polymorphisms predicted coronary heart disease in men but not in women in one multiethnic study.
Clinical presentation and symptoms
Women with myocardial ischaemia may present differently from men. Differences in symptoms can contribute to differential triage, investigation and early treatment. Women with signs or symptoms suggestive of cardiac ischaemia therefore require careful assessment rather than assumptions based on sex or perceived risk.
Women more often have less obstructive coronary artery disease than men. Consequently, symptoms of myocardial ischaemia may occur despite the absence of substantial obstructive disease on coronary evaluation. The source material identifies ischaemia with no obstructive coronary artery disease, myocardial infarction with non-obstructive coronary arteries and Takotsubo cardiomyopathy as important entities in women, but does not provide detailed symptom profiles or diagnostic criteria for these conditions.
Depression, anxiety and psychosocial stress may coexist with cardiovascular symptoms and adversely affect cardiovascular risk. These factors should be considered within the overall clinical assessment without attributing potentially cardiac symptoms to psychological causes alone.
Evaluation and physical examination
Assessment should begin with recognition that CVD is common and clinically important in women at all stages of life. Particular attention is required in younger women, among whom cardiovascular mortality has shown little improvement over recent decades and may be especially high when CVD is present.
Risk assessment
A comprehensive cardiovascular history should include:
Hypertension, dyslipidaemia, diabetes, smoking, obesity and physical inactivity
Chronic kidney disease
Autoimmune and systemic inflammatory disorders
Depression, anxiety and chronic psychosocial stress
Menstrual and menopausal history
Age at menopause and possible premature menopause
Pregnancy complications, including hypertensive disorders, preeclampsia, gestational diabetes, preterm delivery, small-for-gestational-age delivery, placental abruption and pregnancy loss
Polycystic ovary syndrome
Functional hypothalamic amenorrhoea
Fertility treatment or assisted reproductive technology
Socioeconomic circumstances and access to care
Risk scores such as the PCE and SCORE2 use sex-specific equations, but generally do not incorporate female-specific risk factors. Lifetime risk estimation may be more appropriate than relying solely on a 10-year estimate, given the later average onset of CVD in women and their longer life expectancy.
Physical examination should be directed toward the suspected cardiovascular condition and conventional risk factors. The source material does not specify a sex-specific physical-examination protocol.
Pregnancy and exercise-related assessment
Pregnant women with known structural heart disease require cardiovascular evaluation before undertaking intensive exercise. Pregnancy increases plasma volume and cardiac output by approximately 50%, and the added haemodynamic stress of exercise may cause compromise in women with structural disease.
Moderate aerobic exercise is generally considered safe in women and is associated with lower prevalence of excessive weight gain, postpartum obesity, gestational diabetes and pre-eclampsia. Female athletes may continue intensive training during pregnancy, although the source material recommends avoiding a heart rate above 90% of the age-predicted maximum to reduce the risk of fetal bradycardia.
Diagnostics
Ischaemic heart disease
Women are less likely than men to be referred for diagnostic testing, despite ischaemic heart disease being the leading cause of mortality in women. Diagnostic evaluation may be less accurate for obstructive coronary artery disease in women, and women more frequently have non-obstructive disease. These differences should be incorporated into diagnostic reasoning and should not be interpreted as evidence that symptoms are non-cardiac.
The source material does not specify an ECG algorithm, imaging modality, biomarker threshold or invasive testing pathway for women with suspected ischaemia.
Cardiovascular imaging and structural disease
Sex-specific interpretation is relevant to cardiovascular imaging. Body-surface-area-normalized thresholds for aortic and cardiac chamber dimensions may provide more appropriate assessment in women with smaller body size.
In congenital heart disease and hereditary or congenital aortopathy, counselling before pregnancy is particularly important. Intervention thresholds may be lower in absolute terms for aortic surgery in women with hereditary or congenital heart disease-associated aortopathy. Similar individualized considerations may apply to pulmonary valve replacement in patients with repaired tetralogy of Fallot.
Valvular heart disease
Men and women have similar overall likelihood of valvular heart disease, but the distribution by valve and pathology differs:
| More frequent in women | More frequent in men |
|---|---|
| Mitral valve disease, including prolapse | Aortic stenosis |
| Rheumatic mitral disease | Aortic regurgitation |
| Tricuspid regurgitation | Aortic disease associated with bicuspid aortic valve |
Endocarditis involving any valve is more frequent in men. Female sex is associated with higher mortality in several valvular conditions, including early mortality after treatment. Risk-prediction tools such as STS and EuroSCORE include sex as a risk factor, but many prediction models are derived predominantly from male populations and may be affected by referral bias. This may contribute to undertreatment or delayed intervention in women.
Arrhythmia and sudden cardiac death
Exercise-related sudden cardiac death is substantially less common in women than men. Among young competitive athletes, reported male-to-female ratios range from 3:1 to 10:1; among older recreational athletes, deaths in men have been reported to be 20-fold more frequent.
Female athletes rarely die suddenly from hypertrophic cardiomyopathy. In one US registry, women represented only 3% of 302 individuals who died from hypertrophic cardiomyopathy. Women with mitral valve prolapse require more detailed risk stratification before intensive exercise: in an Italian pathology registry of 650 sudden cardiac deaths, 7% were attributed to mitral valve prolapse, and most of those affected were women with marked elongation of both leaflets due to extensive myxomatous degeneration.
Many exercise-related sudden deaths in young women occur in the setting of a structurally normal heart at autopsy, suggesting an important contribution from inherited electrical disorders, including long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.
Women have a longer corrected QT interval than men, both in healthy individuals and in those with long QT syndrome. Although the disease genotype is distributed similarly between the sexes, women are more often clinically affected. Female sex is also associated with greater susceptibility to arrhythmias from QT-prolonging drugs and electrolyte disturbances and is an independent risk factor for cardiac events in long QT syndrome.
The source material does not provide a specific ECG protocol, QTc threshold, electrophysiological testing strategy or device-treatment recommendation.
Biomarkers and laboratory findings
The source material does not provide sex-specific biomarker concentrations, laboratory thresholds or recommendations for laboratory testing.
Risk assessment should nevertheless identify diabetes, dyslipidaemia, chronic kidney disease and systemic inflammatory or autoimmune disease, because these conditions contribute substantially to cardiovascular risk in women. The absence of a validated female-specific genetic marker or polygenic risk score means that genetic testing does not currently add an established method of cardiovascular risk classification beyond conventional assessment.
Treatment and management
Primary and secondary prevention
Women should receive the same guideline-recommended preventive therapies as men when indications are present. Evidence-based lifestyle interventions, statins, antihypertensive agents and glucose-modifying therapies benefit women and men to a similar degree.
Management should address:
Blood-pressure control
Lipid lowering
Diabetes treatment
Smoking cessation
Weight management
Physical activity
Psychosocial stress, depression and anxiety
Referral to cardiac rehabilitation when indicated
Women are less likely to receive preventive treatment or achieve treatment targets; active efforts are therefore required to avoid therapeutic disparities. Referral to cardiac rehabilitation should not be withheld because of sex.
Risk-enhancing factors
In primary prevention, premature menopause and preeclampsia are recognized as female-specific risk-enhancing factors that may support initiation or intensification of statin therapy. Other risk-enhancing factors include systemic inflammatory disorders such as lupus and rheumatoid arthritis.
Risk assessment should incorporate reproductive and pregnancy history rather than relying only on traditional scores. Lifetime risk estimation may be particularly useful in women whose short-term risk appears low but whose cumulative exposure to risk factors is substantial.
Ischaemic heart disease and coronary intervention
Women with symptoms or signs suggestive of myocardial ischaemia should undergo careful investigation. The same preventive and medical therapies recommended for men should be provided to women.
Women are less likely to be referred for testing and are undertreated with secondary prevention therapies. After percutaneous coronary intervention, women have demonstrated higher risks of major adverse cardiovascular events and ischaemia-driven target-lesion revascularization at five years in pooled contemporary trial data; this excess risk was principally explained by a greater burden of cardiovascular risk factors and comorbidities. At two years in a contemporary percutaneous intervention population, risks of death or new Q-wave myocardial infarction were similar between sexes, but women had greater risks of bleeding and haemorrhagic stroke.
Following coronary artery bypass grafting and percutaneous coronary intervention, women have been reported to have shorter survival than men in some analyses. These findings reinforce the importance of risk-factor modification, appropriate referral and individualized assessment of bleeding risk.
Hormone therapy
Post-menopausal hormone replacement therapy should not be prescribed to prevent ischaemic myocardial disease. Potential non-cardiovascular and other health risks should be discussed when hormone therapy is considered for other indications.
Exercise and sport
Regular physical activity should be encouraged in women irrespective of age, ethnicity and cardiovascular comorbidity. Moderate aerobic activity is generally safe during pregnancy.
Women with structural heart disease should undergo evaluation before intensive exercise during pregnancy. Activities involving forceful contact, substantial risk of falling or abdominal trauma, heavy lifting, scuba diving or exercise at high altitude without acclimatization are not recommended in pregnancy according to the source material.
Women with suspected or definite long QT syndrome require particular caution when competitive sports are considered, because female sex is associated with longer QTc intervals and increased vulnerability to QT-prolonging drugs and electrolyte abnormalities. Women with mitral valve prolapse also require detailed risk stratification before intensive exercise.
Drugs and practical considerations
The source material does not provide drug names, doses, titration schedules or laboratory-monitoring protocols.
The following therapeutic principles are specified:
Statins should be considered or intensified in primary prevention when overall risk and risk-enhancing factors, including premature menopause or preeclampsia, support treatment.
Antihypertensive therapy should be used according to guideline indications, with attention to the documented undertreatment of women and lower rates of goal attainment.
Glucose-modifying therapy should be provided for women with diabetes, recognizing that diabetes may confer greater cardiovascular risk in women.
Aspirin has been identified as a therapy that women are less likely to receive when indicated, but no prescribing criteria or dose is provided.
QT-prolonging drugs require particular caution in women, especially in the presence of long QT syndrome or electrolyte disturbances.
Post-menopausal hormone therapy should not be used as a strategy to prevent ischaemic myocardial disease.
Guideline recommendations
The source material supports the following practice recommendations:
CVD prevention should be actively prioritized in women because CVD remains their leading cause of death.
Cardiovascular risk assessment should include sex-specific and gender-related influences rather than relying exclusively on conventional risk factors.
Premature menopause and preeclampsia should be considered risk-enhancing factors when making statin decisions in primary prevention.
Pregnancy-related complications, including hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, small-for-gestational-age delivery, placental abruption and pregnancy loss, should be included in long-term cardiovascular risk assessment.
Women with possible myocardial ischaemia should be investigated carefully, recognizing that they may have less obstructive coronary artery disease and that diagnostic testing may perform differently than in men.
Women and men should receive the same guideline-recommended preventive therapy when clinical indications are equivalent.
Referral, treatment and follow-up should be designed to reduce sex-related disparities in access and treatment intensity.
Sex-specific interpretation and body-surface-area normalization should be considered when evaluating cardiac chambers and aortic dimensions in women.
Women with structural heart disease should undergo assessment before intensive exercise during pregnancy.
Competitive sports counselling should be particularly cautious in women with long QT syndrome, and detailed risk stratification is warranted in women with mitral valve prolapse.
Post-menopausal hormone therapy should not be used to reduce ischaemic myocardial disease risk.
Decisions regarding intervention in women with valvular, congenital or aortic disease should be individualized because risk scores may be influenced by male-predominant derivation cohorts and referral bias.
Prognosis and follow-up
Women experience substantial cardiovascular morbidity and mortality, including a disproportionate burden of stroke after 65 years of age. Cardiovascular mortality has risen globally, with particularly rapid increases among middle-aged women. In the United States, mortality from CVD in women younger than 55 years has not significantly improved over the past two decades, and younger women with CVD have the highest mortality.
Prognosis varies according to the cardiovascular condition. Female sex is associated with higher mortality in several valvular diseases and with increased early post-treatment risk. After percutaneous coronary intervention, women may have higher long-term major adverse cardiovascular event and target-lesion revascularization risks, although differences are substantially related to the greater burden of risk factors and comorbidity. Bleeding and haemorrhagic stroke risks may also be higher in women after contemporary percutaneous intervention.
Follow-up should be longitudinal and should include reassessment of:
Blood pressure, lipid status and glycaemic control
Weight, physical activity and smoking status
New or persistent symptoms suggestive of myocardial ischaemia
Pregnancy-related and menopausal risk factors
Autoimmune, inflammatory and kidney disease
Depression, anxiety and chronic stress
Adherence to preventive therapy
Participation in cardiac rehabilitation when indicated
Because women may have lower short-term but greater lifetime risk, follow-up should not be discontinued solely on the basis of a low 10-year risk estimate. The clinical record should preserve relevant reproductive and pregnancy history so that cardiovascular risk can be reassessed as risk factors evolve, particularly during and after the menopausal transition.
