Sex and gender matter in cardiovascular disease and beyond

Sex and gender are fundamental drivers of virtually all major causes of death and disease, while gender equality has been shown to improve the health of both women and men at the population level. The term ‘sex’ is generally used to describe biological characteristics, while ‘gender’ is used to address social constructs. Sex and gender are intertwined and interconnect with other key drivers of health, such as age, socioeconomic position, race and ethnicity. Over the past decade, many clinically meaningful sex differences in several aspects of cardiovascular disease (CVD) have been uncovered. Although the lifetime risks are similar when women’s longer life expectancy is considered, CVD develops about 5–10 years earlier in men. The first manifestation of CVD is also different between sexes; women are more likely to have stroke as their first event, while men are more likely to have coronary heart disease (CHD). Presenting symptoms of CHD and stroke can also be different between women and men, which may undermine timely diagnosis and management. Furthermore, although current guidelines for prevention of CVD do not generally differentiate between women and men, women often receive inferior treatments. Also, while the key modifiable risk factors for CVD are the same for women and men, including high blood pressure, smoking, high cholesterol, obesity and diabetes, there are some notable sex differences in the magnitude of the adverse effects conferred by these risk factors. For example, while diabetes is a strong risk factor for myocardial infarction (MI) in both women and men, the magnitude of the excess risk of MI conferred by diabetes is almost 50% greater in women than in men. Similarly, current smoking, as compared with never, is associated with a 55% greater excess risk of MI in women than in men. There is a strong link between gender empowerment and the female to male smoking prevalence ratio; countries with the highest women empowerment also have the highest relative female smoking prevalence. Despite growing recognition of the impact of gender in CVD, studies investigating the impact of genderrelated characteristics on the onset of CVD are scarce. Bolijn and colleagues address this important evidence gap. Using data from the Healthy Life in an Urban Setting (HELIUS) study, a multiethnic cohort study in Amsterdam, the Netherlands, they assessed the relationship between six genderrelated characteristics and the risk of incident CVD. The analyses included 18 058 participants (57% women) without prior CVD. Study participants were relatively young for a study on risk factors for CVD incidence; the mean age at study baseline was 44 years in both sexes. Despite this, 194 men and 165 women had been hospitalised for, or died of, CVD during 5 years of followup, leading to an agestandardised CVD incidence per 1000 personyears of 5.4 in men and 3.4 in women. These rates are comparable with those from the Global Burden of Disease Study, which estimated that the incidence of CVD in the Netherlands in 2019 for those aged 40–44 years and 45–49 years, respectively, was 4.5 and 7.9 per 1000 personyears for men and 3.1 and 3.7 per 1000 personyears for women. Unlike many other studies, Bolijn and colleagues not only presented the association between genderrelated characteristics and CVD risk in terms of relative risk, but also in terms of absolute risk. The latter is important given that men routinely have a higher risk of CVD than do women. A risk factor with an identical relative risk for women and men will thus have a greater effect on the risk difference in men than in women. This was clearly illustrated by our late friend and colleague Elizabeth Millett, who showed that the risks of MI were substantially lower in women than in men, even in the presence of risk factors that conferred a greater relative risk in women. To provide the research community, health policy makers and the public with a full picture of sex differences in CVD risk factors, we therefore recommended that all future studies on sex differences in risk factors should present the results both in terms of relative risk and risk differences. In the analyses by Bolijn and colleagues, none of the genderrelated characteristics was associated with risk of CVD in men. In women, they found that those spending a moderate amount of time on household activities (7.75–16 hours a week) had a 44% lower risk of CVD compared with those spending little time (<3 hours a week). Compared with being in fulltime employment, women who were home makers were at 134% greater risk of CVD. The authors conclude that, for women, traditionally feminine characteristics might be related with lower risk of CVD. This is in agreement with findings from a previous study in young patients with acute coronary syndrome (ACS), which showed that feminine gender was associated with a higher risk of recurrent ACS, independent of female sex. As both studies were relatively small, further studies will be needed to confirm these findings and to assess the robustness in settings with different gender norms. The genderrelated characteristics included in the study by Bolijn and colleagues capture only some of the aspects that together encompass the gender construct. Indeed, the gender construct can be described in three related dimensions: gender norms, gender identity and gender relations, which together encompass the socially constructed roles, relationships, behaviours, relative power and other traits that societies routinely ascribe to women and men. The factors studied by Bolijn and colleagues capture some of the socially constructed gender norms that exist in relation to work and emotional support in a highincome setting in Europe. To date, there has been no standard way to operationalise gender in epidemiological studies. However, previous studies have shown that there are sex differences in the relationship between other genderrelated factors and CVD. For example, a pooled analysis of seven studies including 7 095 655 participants and 128 961 CVD deaths assessed sex differences in the relationship between marital status and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands The George Institute for Global Health, School of Public Health, Imperial College London, London, UK The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia