Cardiovascular diseases (CVDs) are the leading cause of death globally, yet the intersection of gender and heart health remains an under-explored territory. Historically, the bulk of cardiovascular research has focused on men, leading to a critical gap in understanding how these diseases manifest and progress in women. This oversight has had profound implications: women often experience different symptoms, respond differently to treatments, and face unique risk factors compared to their male counterparts.

In an enlightening exchange with Dr. Maddalena Ardissino, a medical doctor and genetic epidemiologist, we delve into the nuances of women’s cardiovascular health. Dr. Ardissino, who is currently an NIHR Academic Clinical Fellow and Internal Medicine Resident in Cambridge, England, has published crucial research on women’s cardiovascular risk factors this February 2023 in the Journal of the American Heart Association. Her insights challenge the conventional wisdom in cardiology, advocating for a paradigm shift that recognises and addresses the distinct cardiovascular health needs of women.

In this interview, we explore Dr. Adrissino’s findings and discuss broader implications for clinical practice and women’s health advocacy. From the mischaracterisation of women as low-risk patients to the potential risks posed by hormonal factors, Dr. Ardissino’s research is a clarion call for a more bespoke and informed approach to cardiovascular health.

ZH: In your recent study, you mention several correlations in relation to the development of CVDs in women. Can you tell us a bit more about them?

MA: In our study, we found that earlier first birth, a higher number of live births, and earlier menarche were associated with a higher risk of atrial fibrillation, coronary artery disease, heart failure, and stroke in women. However, we did not find an association between the age of menopause and cardiovascular disease.

ZH: Did that surprise you?

MA: Yes, we were quite surprised to not see an association of age at menopause with cardiovascular disease, because many studies have previously reported it. However, it is possible that in previous studies the association was driven by other factors that are associated with an earlier menopause, such as oncological treatments or autoimmune diseases, rather than earlier menopause itself.

ZH: Did any of the risk factors you mentioned show a stronger association?

MA: Unfortunately, from the data we can’t infer which one is the biggest driver of cardiovascular disease proportionally, as the different exposures were all on different scales. However, from the results we can clearly conclude that all of these factors contribute to cardiovascular disease risk.

ZH: So, in other words, if a woman has started her period or had children at a younger age, or if she has had more children, it seems that she has a higher chance of developing CVDs. What physiological mechanisms might be at play, underlying the associated risk factors that you observed?

MA: This was actually one of our key questions, as understanding the mechanistic pathways is the first step in using this information to improve clinical outcomes for women. For example, when we performed a mediation analysis specifically to look in to what was driving this increased risk in relation to earlier menarche, we found that much of it resulted from this factor being associated with a higher body mass index.

ZH: Ah, you mean that women with a higher body mass index appear more likely to have an early onset of menstruation.  Could we say, then, that the link to CVD risk comes from higher body mass aspect rather than from early menarche itself?

MA: It’s certainly possible, as the evidence suggests that maintaining a weight in the recommended range is likely to offset this increased risk partially or even fully for women who had an early menarche.

ZH: What about the other risk factors?

MA: For the increased risk relating to earlier first birth, we found that it could be partially offset by bringing body mass index into a healthy range, decreasing cholesterol levels and decreasing blood pressure .This suggests that clinicians should be aware to monitor these potential modifiable factors in women who had an earlier first birth, and intervene in a timely manner in order to avert the risk of cardiovascular events.

ZH: In your publication, I also read that women more often get mischaracterised as having low risk for cardiovascular risk. You mention that this is because the majority of women with a CVD have an absence of ‘traditional risk factors’, which hints that our expectations of what CVDs look like is based on male patients! Could you expand on this?

MA: Unfortunately, we know from many different studies that a number of different factors contribute to a worse outcome in women after developing heart disease. From the beginning, women are less likely to be diagnosed in a timely manner. This is partly due to the fact that seminal papers in research that initially discovered the key risk factors for cardiovascular disease, such as the British Doctors Study [a long-term 1951-2001 study of heart and lung disease risk from smoking], exclusively recruited and studied men. Even in the ones that did recruit women, like the second Whitehall studies [two studies on the social determinants of cardiovascular health in British civil servants, with the first only recruiting men], women only represented around a third of participants (Marmot et al., 1978; Marmot et al, 1991).

ZH: Which means that risk factors and symptoms that do not show up in men because they are female-specific aren’t recognised by physicians?

Yes, this under-recognition of female-specific risk factors, which is the key issue we aimed to address in our study, leads to mischaracterisation at low risk, delays in diagnosis, and ultimately delays in the initiation of timely treatment. This can be something that influences the outcomes, and unfortunately we know from previous research that women tend to have worse outcomes after major cardiovascular events [for example due to the lesser use of stents to open up blocked arteries].

ZH: The longer you wait to treat the issue, the more difficult it is to get a good result… What differences in prognosis and survival rates do you typically observe between men and women with CVDs? Are some behavioural factors implicated in these outcomes, such as women’s higher propensity to get regular check-ups or to follow treatment?

MA: Unfortunately, we know from several large-scale studies that the majority of women who have an acute cardiovascular event tend to receive less treatment and have worse outcomes compared to men, after accounting for their risk factor profile at presentation. There are a large number of factors that play into this association, which relate predominantly to institutional factors with some biological factors to consider. For example, in our recent study [on sex-based differences in heart attack and stroke risk factors] we found a disproportionately higher hazard of myocardial infarction associated with hypertension in women compared to men.

ZH: Why might this be?

MA: There are a number of possible factors that might play into this. First, hypertension is a major risk factor for hypertensive disorders of pregnancy, which in turn are known to heighten cardiovascular risk – this association is clearly limited to women. In addition to this potential biological explanation, women with hypertension may also be treated differently to men, for example through avoidance of drug classes contraindicated in pregnancy or while trying to conceive, leading to suboptimal management and therefore more adverse events. Finally, from an institutional perspective, the disproportionately higher risk in women might be seen because seminal trials for blood pressure management (e.g., SPRINT) only contained a relatively small proportion of women (in SPRINT, approximately one-third).

ZH: What are the implications of this low representation?

MA: Well, this raises the question that potentially, treatment thresholds that have been benchmarked in male-predominant populations (e.g. drug doses) might not be perfectly transferrable to female populations in terms of risk optimisation.

ZH: You are a strong proponent and advocate for sex-specific approaches to prevention and treatment of CVDs. How can your research findings inform clinical practice and ultimately improve the cardiovascular care provided to women?

MA: First and foremost, as clinicians, we need to be aware of our responsibility to advocate for our patients, and improve our knowledge regarding the role of reproductive factors (such as earlier first birth and age of menarche mentioned). By recognising these unique risk factors, we can better tailor prevention and treatment plans, and achieve earlier diagnosis. This would be a way to try to prevent the mischaracterisation as low-risk that women experience so much more often than men. Additionally, we are dealing with relatively limited data regarding how to use reproductive and obstetric history in clinical practice. There have been no large-scale studies yet that have calculated how much prognostic benefit including these factors in a risk score calculator, such as QRISK, might have.

ZH: Essentially, understanding how much do the risk factors you mentioned weight when you are trying to diagnose someone.

MA: Exactly, this is going to be the first important step. The second key consideration that is highlighted by both our paper and other work in the field is that even the ‘traditional’ drivers of cardiovascular disease have different roles in women compared to men. Considering that many clinical trials in the field of cardiology have historically been performed in cohorts that were predominantly (or sometimes only!) men, this highlights that we should reconsider whether women actually get the same benefits from treatment as men, or whether we should focus more on some risk factors rather than others. We need increased representation of women in cardiovascular research to understand the unique factors that contribute to CVDs in women and develop targeted intervention to improve their cardiovascular health.

ZH: Should new guidelines be developed to follow sex-specific evidence, is effort being made by clinicians to provide sex-specific advice?

MA: At present, there is relatively little distinction made, except for women of child-bearing age where there might be a greater consideration of avoiding reliance on medications that would be contraindicated in pregnancy (e.g., avoiding metallic valve replacements that would mean lifelong necessity of warfarin [an anti-coagulant], as warfarin must be avoided in pregnancy). At the moment, there is no sex-specific distinction for many of the treatments we prescribe, and for their targets. However, there is growing recognition that this needs to change.

ZH: In my article series, I have been interested in digging into how female hormones and the menstrual cycle – including their modification, e.g. by taking oral contraceptives – influence the risk factors, onset and progression of illnesses in women. Could you comment on their significance in influencing women’s development of cardiac diseases?

MA: This is certainly an area that has been highlighted as potentially important in previous population-based studies, but at the moment we weren’t able to explore it in our study because there wasn’t sufficient data to be able to answer the questions. However, hopefully in the future when sufficient data regarding genetic predictors of hormone levels becomes available, this will be an important further question as it is a clearly clinically relevant and actionable point.

references

Ardissino, M., et al. “Sex‐Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.” Journal of the American Heart Association, vol. 12, no. 5, 7 Mar. 2023, https://doi.org/10.1161/jaha.122.027933. Accessed 24 Mar. 2023.

Marmot, M. G.; Rose, G.; Shipley, M.; Hamilton, P. J. (1978). “Employment grade and coronary heart disease in British civil servants”. Journal of Epidemiology and Community Health. 32 (4): 244 249. doi:10.1136/jech.32.4.244. PMC 1060958. PMID 744814.

Marmot, M. G.; Davey Smith, G.; Stansfield, S.; et al. (1991). “Health Inequalities among British civil servants: the Whitehall II study”. Lancet. 337 (8754): 1387–1393. doi:10.1016/0140-6736(91)93068-K. PMID 1674771. S2CID 2791924.

Regitz-Zagrosek, Vera. “Sex and Gender Differences in Health.” EMBO Reports, vol. 13, no. 7, 15 June 2012, pp. 596–603, www.ncbi.nlm.nih.gov/pmc/articles/PMC3388783/, https://doi.org/10.1038/embor.2012.87.

Remfry, et al. “Sex-Based Differences in Risk Factors for Incident Myocardial Infarction and Stroke in the UK Biobank.” European Heart Journal – Quality of Care and Clinical Outcomes, 22 May 2023, https://doi.org/10.1093/ehjqcco/qcad029. Accessed 14 Oct. 2023.