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Explanatory power of gender relations in cardiovascular outcomes: the missing piece of the puzzle
  1. Valeria Raparelli1,2,
  2. Marco Proietti3,4,
  3. Stefania Basili5
  1. 1 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  2. 2 Center for Outcomes Research and Evaluation, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada
  3. 3 IRCCS—Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy
  4. 4 Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
  5. 5 Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
  1. Correspondence to Professor Stefania Basili, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome 00144, Italy; stefania.basili{at}

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The awareness that psychosocial factors play a pivotal role in shaping health goes back to 1948 when WHO defined health as ‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’, even though nowadays, the role that psychosocial factors, commonly defined as gender-related factors, play in the exposure to disease and in their development is still neglected by most researchers and barely explored in clinical trials. The inclusion of gender in clinical data analysis is a powerful opportunity to discover differences in the relationship between exposure and outcomes for men and women, which can inform strategies for intervention.

The understanding of the gender-related social factors as reasons for differences in health outcomes is still an unmet need that requires further evaluation in order to address inequities in access to care and prevention of disease. It has been previously reported how gender can explain or even be the main determinant of adverse clinical outcomes among women and men with premature acute coronary disease.1 However, the scientific community is less sensitive to the integration of gender dimension in trial design. The main issue to handle is the lack of a standardised method to measure the complexities of all that gender encompasses including gender identity, social roles, socioeconomic status and interpersonal relationships ( Gender relations dimension refers to how we interact with or are treated by people in the world around us, based on our ascribed gender: civil status is a gender-related factor that may have a relevant impact on health outcomes.

In their Heart paper, Wong and colleagues presented a systematic review and meta-analysis about the role of marital status in predicting the occurrence of coronary heart disease (CHD)-related or cardiovascular disease (CVD)-related death, all-cause death, incident CHD, CVD or stroke.2 After a detailed and extensive search, they selected 34 prospective studies including more than 2 million subjects.

First, the authors found that unmarried subjects are more likely to die from CHD (risk ratio (RR) 1.43, 95% CI 1.28 to 1.60) and from stroke (RR 1.55, 95% CI 1.16 to 2.08).2 While in the case of CHD-related death, the authors did not find any difference between men and women, for the stroke-related one, a significant increase in risk was found for men (RR 1.55, 95% CI 1.15 to 2.11) and the increase in risk was not significant for women (RR 1.52, 95% CI 0.53 to 4.34), even though this difference in risk was not found significant. Unmarried subjects were also found at increased risk of all-cause death (RR 1.31, 95% CI 1.19 to 1.45), with men significantly at higher risk compared with women (p=0.01). Further, an increased risk for CHD incident events was also found in unmarried versus married subjects (RR 1.16, 95% CI 1.04 to 1.28). Interestingly, also an increased risk for incident CHD was found in remarried subjects compared with married ones, even though this evidence is based on one study only.2

Second, also divorced subjects were found at an increased risk for major adverse outcomes. Indeed, an increase in RR was recognised for CHD-related and stroke-related death (33% and 56%, respectively), as well as for all-cause death occurrence (RR 1.43, 95% CI 1.20 to 1.71). Moreover, divorced subjects also had an increase in RR CHD and stroke incident events.2

Lastly, the authors examined some specific groups, respective to the risk of adverse events and death in secondary prevention. Accordingly, a higher risk for death after myocardial infarction occurrence was reported for unmarried (42% RR increase), divorced (36% RR increase) and widowed (68% RR increase) subjects compared with married ones.2

While no other significant differences were found between men and women, in several cases male unmarried and divorced subjects were at higher risk of several major adverse outcomes, but not female ones. Only in the case of incident CHD, remarried women had a significantly higher risk, but not men, even though this evidence is based on one study only.2

Relevantly, the analysis proposed appears to be reliable in methodology and, also, reported an overall low to moderate heterogeneity for most of the significant differences reported across the various outcomes and subgroups. Only in the case of death post-myocardial infarction, a high heterogeneity was found, but notwithstanding this meta-analysis was performed as random effects. In addition to the limitations properly acknowledged by the authors, it is possible to note that despite the large number of subjects involved in most of the analyses, generally there is a low number of pooled studies, with eight studies at the most merged together in only one case. Furthermore, a strong unbalance between the proportion of male and female subjects can be noted in the most of studies, limiting the generalisability of these findings. Conversely, the large geographical representativeness appears to be a strong point of the work presented.

There is worldwide compelling debate regarding the best approach to answer research clinical questions. Currently, international funding agencies such as the National Health Institute,3 Canadian Institute of Health Research ( and the European Commission Gender Horizon 20204 have established policies focused on the integration of sex and gender in grant application to strengthen science and guarantee quality and generalisability of biomedical research, breaking the wall of health inequity. Sex and gender are not interchangeable terms: sex should be used referring to biological factors while gender should be used when reporting behavioural, cultural and socioeconomic aspects. Even though it has been recently reported that there is an increase of women participating in clinical trials testing new drugs in CVD,5 there is still room for improvement.6 Interestingly, gender-related factors, including marital status, may play a role in explaining the lower awareness and access to trial participation of women.

While differences in health status and outcomes have been traditionally attributed to biological sex, it is now increasingly recognised that gender influences our risk of developing diseases. This breakthrough in scientist approach is a priority internationally recognised as the first step to promote human health (figure 1).

Figure 1

Sex and gender as determinants of health and disease across the lifespan.

Specifically, gender is a cross-cutting issue and is mainstreamed in each different aspect of CVD research process.7 A wide range of behavioural factors, psychosocial processes, and personal and cultural factors can create, suppress or amplify underlying biological differences in CVD. Regardless of sex, gender factors emerged as powerful predictors of risk factor acquisition and of 1-year adverse health outcomes in patients with premature and established CVD.1 8 Most significantly, those who exhibited a score most traditionally ascribed to women’s identity and roles in society were more likely to have a recurrent cardiac event within the first year.

It is time to apply a gender-oriented research to step forward our understanding of outcomes beyond biological factors. Gender-related factors are the missing pieces of the puzzle that should be included in the future trial design to ensure a high-quality science. A higher proportion of women must be enrolled to draw final conclusions through a well-powered sex stratify analysis. The mission of future research should be to guarantee the generalisability of clinical findings, going forward the traditional risk factors for CVD development and reappraising the undeniable value of psychosocial and gender-related factors as benchmarks of the well-being and health. Consequently, the next step for clinical research should be to look for gender-based interventions as a feasible pathway to capture and handle the complexity of human health towards better outcomes.



  • Contributors VR, MP and SB conceived, drafted, finalised and approved the final version of this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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