Introduction

Cardiovascular disease (CVD) has historically been perceived as a male disease; however, it is the leading cause of mortality and morbidity worldwide for both men and women [1]. Despite this, CVD is understudied, underdiagnosed, and undertreated in women [2]. Both sex — biological and anatomical factors — and gender — cultural and societal factors — have been found to be important modifiers of CVD but are often underappreciated in clinical practice. This leads to inequality in the outcomes and treatment of women with CVD. For example, mortality rates are improving at a faster rate in men compared to women [3]. Women also experience a greater delay in emergency response times [4], diagnosis, and revascularization compared to men [5, 6]. These delays are thought to be due to biological differences in the presentation of CVD in women and gender biases in both patients and health care professionals [7, 8]. There is growing recognition for the need to address issues with sex and gender in health research. However, much remains to be done [9,10,11,12].

The aim of this narrative review is to explore the complex sex and gender differences observed in the research, treatments, and outcomes of women with CVD. The review also includes recommendations for research and practice. For context, it is important to distinguish and define both sex and gender. Sex refers to the variation and expression of biological attributes such as genetics (e.g., sex chromosomes), sex hormones, anatomy, and physiology [13, 14]. In comparison, gender is a multidimensional construct that has been developed over time from social, cultural, and behavioral factors. Gender incorporates the dimensions identity, societal roles, interpersonal relationships, and institutionalized gender norms [13].

Examples of Sex-Specific Risk Factors of CVD

There are well established biological sex differences in the risk factors for CVD [15, 16]. Reviews of the literature demonstrate that sex-specific risk factors include age of first menarche, menopause, reproductive endocrine disorders, and pregnancy complications [17,18,19,20]. However, even shared risk factors such as diabetes and smoking have been found to impact CVD risk differently in women. Meta-analyses have demonstrated that the relative risk (RR) of CVD is 44% and 25% higher in women with diabetes and women who smoke when compared to men (RR ratio 1.44 (95% CI 1.27 to 1.63) and 1.25 (95% CI 1.12 to 1.39)) [21, 22], whereas blood pressure, body mass index, and hyperlipidaemia have been found to have a similar impact on CVD risk in men and women [22,23,24]. There are also differences in the presentation of CVD symptoms. While chest pain is the most commonly reported symptom in both men and women, women often have different or asymptomatic presentations compared to men [25]. Women regularly report additional symptoms such as epigastric symptoms, palpitations, and shortness of breath [25]. While understanding sex differences in CVD risk is important, it only provides part of the story. Just as there are differences in biological risk factors, there are differences in sociocultural risk factors between different genders [15, 26, 27].

Examples of Gender-Specific Risk Factors for CVD

Gender-specific risk factors include environmental factors that, for non-biological reasons, contribute to health disparities like exposure to violence, sociocultural behaviors and attitudes, and socioeconomic barriers [11, 28, 29]. A review article by O’Neil et al. [26] describes how gender acts as a social determinant of CVD. O’Neil et al. describe how the adoption of health behaviors is highly gendered. For example, the adoption of certain health behaviors such as being active and playing sports is encouraged in young men more so than in young women [30, 31]. There have been successful school-based intervention that have increased physical activity and reduced risk factors such as obesity in women [32]. These findings demonstrate that some of the gender-specific risk factors can be modified.

Another review conducted by Connelly et al. [13] describes how gender identity (e.g., personality traits and psychosocial stress), gender roles (e.g., carer responsibilities and primary earner status), and gender relations (e.g., marital status) increased CVD risk for women. Further, interpersonal relationships can also impact the risk of CVD. For instance, women who experience intimate partner violence and domestic abuse have an increased risk of CVD (incidence rate ratio 1.44 (95% CI, 1.24–1.6)) [33, 34]. In addition, women who live alone report greater barriers to care, such as greater financial issues in the recovery after acute coronary syndrome [35], which may impact their risk of a secondary event. Sexism has also been proposed as a psychosocial factor that influences the risk of CVD [36]. For example, the experience of sexism has been related to increased alcohol consumption and smoking in women [37], behaviors that increase the risk of CVD.

Gender biases in medical professionals also contribute to the differences in outcomes for CVD between women and men. An example of this gender bias across health outcomes is demonstrated when examining the association between patient-physician gender concordance and patient outcomes. Women have a higher mortality rate and worse outcomes when treated by male doctors [8]. While this may also be due to bias in reporting by women, these outcomes are improved when women have a female doctor or if their male doctor works with women and has treated more women in the past [8]. These biases are also present in the primary health care setting, women are less likely than men to have their CVD risk [38] and smoking status assessed [39]. After treatment for a cardiac event, there are gender biases that impact who bears the burden of care during recovery; in general, women tend to take on caregiving roles within families [40]. This bias may affect to whom information about care and recovery is directed to, for example, in heterosexual couples, the responsibility of care may be placed on the woman. In the care of cancer patients, this burden of care results in women reporting worse mental health outcomes [41, 42]. There is also bias in referral to secondary prevention programs. A meta-analysis conducted in 2015 found that men were 1.5 times more likely to be referred to cardiac rehabilitation (CR) than women (odds ratio 0.68 (95% CI 0.62 to 0.74)) [43]. Once referred to CR, women are also less likely to attend [44, 45•]. This is due to several barriers, including carer responsibilities, work commitments, geographical barriers, and perceptions about program characteristics [46].

Examples of Intersecting Sex and Gendered Risk Factors for CVD

It is difficult to disentangle sex and gender influences on the differences in diagnosis, treatment, and outcomes for women with CVD. This is because both gender and sex interact to contribute to this discrepancy (Fig. 1). For example, psychosocial and biological factors increase the risk of mental health issues which in turn have been found to increase the risk of CVD [47]. Overall, these mental health issues disproportionately affect women more than men [48] and have been found to be an independent risk factor for CVD in women [49]. The diagnosis of depression has also been associated with worse outcomes, including morbidity and mortality for people with CVD [50, 51].

Fig. 1
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Examples of the contribution of both sex and gender across the life course on CVD outcomes in women

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Sex and gender also interact to impact how accurately women interpret their CVD risk [5], resulting in men being more likely to interpret their symptoms as cardio specific during myocardial infarction (51.7 vs. 46.0%; p = 0.02) [52]. This misinterpretation of symptoms has been found to result in a 2-h delay in seeking treatment [52]. Qualitative research has also demonstrated how sex and gender interact to impact the delay in treatment for women, the interpretation of risk in combination with symptom presentation, and past responses from health professionals impact the time women take to seek treatment during their first cardiovascular event [53]. On average, women with ST-elevation myocardial infarction (STEMI) have a 30-min longer ischemic time when compared to men after controlling for confounders [5]. After further investigation, there are delays in both symptoms to door time (time taken from the presentation of symptoms to arrival at hospital) and door to balloon time (time from arrival to revascularization) for women [5].

These delays seem to be caused by multiple factors, highlighting complex interactions between sex and gender. As established, women take longer to seek medical treatment (on average 3.2 h for women versus 2.4 for men) [25]. There are also delays in the time it takes for women to arrive at the hospital. In Norway, women with STEMI were given lower priority for ambulance services than men with similar presentations and took longer to arrive at the hospital [4]. Once women arrive at the hospital, there is also a delay in receiving the correct diagnosis and intervention [54]. These delays in receiving life-saving care are associated with a higher mortality rate in women [5]. An Australian study found similar results with women being 18% less likely to receive an urgent care allocation upon admission to the emergency department (OR 0.82 (95% CI 0.79 to 0.85)), 16% less likely to be seen by an emergency physician in the first hour of arrival at emergency (mean difference 0.15 (95% CI 0.13 to 0.1)), 20% less likely to have a diagnostic troponin test (OR 0.80 (95% CI 0.77 to 0.83)), 36% less likely to be admitted to a special care unit (OR 0.64 (95% CI 0.61 to 0.68)), and finally, women were also found to be more likely to die during their hospital admission [55••].

Recommendations for Researchers

Historically, women have been underrepresented in health research, including CVD research [2, 9, 56]. This underrepresentation of women in research partially explains the incomplete understanding of CVD symptomology and presentation in women. For example, the 2016 National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand clinical guidelines for the management of acute coronary syndromes was based on research that had inequality in sex and gender representation [57]. Scovellsce et al. (2020) examined the studies used to inform the guidelines and found that beyond mere participation of women in research, only 70% of studies mention either sex or gender in the body of the publication; 78% of studies included reported on the number of men and women in the study cohort; only 50% and 18% of studies reported on sex or gender disaggregated results respectively in the exposure and primary outcome; and only 23% included sex or gender in the statistical model. These findings highlight the gender bias in evidence underpinning current CVD guidelines and the need for policies to ensure that women are equally represented in all health research, including CVD.

While progress has been made to ensure the inclusion of women in research and the consideration of sex in the analysis of health outcomes, there is still need to consider gender in the analysis and interpretation of health outcomes [19, 58•]. Table 1 describes some of the recommendations for how researchers can do this.

Table 1 Recommendations for researchers
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Recommendations and Clinicians

Based on the persistent sex and gender differences in the risk, diagnosis, and treatment of CVD, several steps must be taken to ensure no group of people are disproportionately affected by CVD. A recent scoping review demonstrated that there are 13 published studies that evaluate interventions aimed at reducing the gender disparity CVD outcomes in health care [77]. This highlights the need for additional evidence-based interventions to address the sex and gender bias in health care. Table 2 describes some of the ways clinician can address these issues.

Table 2 Recommendations for clinicians
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Conclusions

There are sex and gender differences in the risk, presentation, treatment, and research of CVD. These differences have resulted in women being disproportionally affected by CVD. While some differences are due to biological differences between males and females, many can be attributed to biases in both patients, health professionals, and societal norms. Further, sex and gender appear to interact to contribute to the differences in risk and outcomes for women. In order to reduce the inequity in health outcomes for women, these biases must be addressed through improving the communication of biological differences in the presentation of CVD; educating health care professionals on gender bias; offering patient-centered care and programs tailored to women’s needs; and conducting research that includes sex and gender-based analysis. By conducting more inclusive research and addressing the gender biases present in health care, we may start addressing the CVD issues that disproportionately impact half of the world’s population.