Sex and Cardiovascular Disease
For many years, cardiovascular disease was considered a male disease. Consequently, common data of registries, clinical trials and the like, were all reported for the entire patient population and only until recently has it become mandatory to report data on males and females separately. Indeed, the evidence for sex differences between females and males in disease mechanisms, clinical presentation and natural history of cardiovascular diseases, as well as the response to medical  and interventional treatment strategies is overwhelming . For instance, women bleed more when using oral anticoagulants than men do . In addition, male and female hearts do differ, not only in size and structure, but also in the disease phenotypes of different forms of cardiac conditions . Furthermore, the prevalence of risk factors and risk modulators differ between sexes, with co-morbidities like rheumatoid arthritis and other autoimmune diseases being more frequent in females .
Of note, female patients tend to develop heart failure with preserved ejection fraction, while males are more likely to suffer from ischaemic cardiomyopathies or heart failure with reduced ejection fraction (fig. 1, online appendix) [6–8]. Comorbidities, such as arterial hypertension and diabetes mellitus are very common in elderly females, while in males, smoking and hyperlipidaemia are more common. Besides, while myocardial infarction has been considered primarily a male disease, it is now clear that about a third of patients with acute coronary syndromes (ACS) are female . Importantly, in ACS, females tend to present with atypical chest pain, present later to the emergency units than males do and more often have myocardial infarction with non-obstructive coronary artery disease. Finally, there are distinct acute cardiac conditions, primarily occurring in females, such as Takotsubo Syndrome , as well as spontaneous coronary artery dissection (SCAD) . Interestingly, while Takotsubo is primarily a disease of post-menopausal woman, SCAD occurs almost exclusively in woman in the fertile age, particularly during and after pregnancy, suggesting the abundance and lack of female sex hormones are importantly involved in some cardiac conditions affecting women.
Sex differences have also been reported for arrhythmias. For instance, women have a lower prevalence of atrial fibrillation, are of older age at presentation and differ in triggers and substrate , as well as clinical presentation (e.g., women are more likely to be symptomatic) and natural history [13, 14]. Women more often receive medical treatment instead of catheter-based ablation  and if they undergo such procedures they experience higher rates of complications .
It became clear, that in cardiovascular medicine, sex truly matters and has to be considered by physicians when seeing patients of both sexes, in the acute setting and in the clinic . To emphasise this fact, initiatives to incorporate sex as a biological variable into research, design and publication began in 2001 when the landmark publication by the Institute of Medicine, now the National Academy of Medicine, “Does Sex Matter?” was published . In this seminal paper, the institution stated that “biological sex influences health and disease from womb to tomb”. Of further note, the institute clarified that in the English language sex should refer to the biological and gender to the cultural aspects of humans.
In the current and the following special issue of Cardiovascular Medicine on sex and cardiovascular diseases, experts from different parts of Switzerland addressed sex- and gender-relating issues for several conditions, from hypertension and diabetes to chronic and acute coronary syndromes and from cardio-oncology to heart failure. The editors of Cardiovascular Medicine hope that these two special issues on sex and cardiovascular disease will provide a comprehensive overview on what is known today about the influence of sex on different cardiovascular conditions. The articles will give a deeper insight into sex differences and what it means for the diagnosis and management of female patients presenting in the acute and chronic setting.
1 Vinereanu D, Stevens SR, Alexander JH, Al-Khatib SM, Avezum A, Bahit MC, et al. Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial. Eur Heart J 2015 Dec;36(46):32683275. doi: 10.1093/eurheartj/ehv447.
2 Timmis A, Vardas P, Townsend N, Torbica A, Katus H, De Smedt D, et al. Atlas Writing Group, European Society of Cardiology. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J 2022 Feb;43(8):716–799. doi: 10.1093/eurheartj/ehab892.
3 Alotaibi GS, Almodaimegh H, McMurtry MS, Wu C. Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis. Thromb Res 2013 Aug;132(2):185–189. doi: 10.1016/j.thromres.2013.07.017.
4 Haider A, Bengs S, Luu J, Osto E, Siller-Matula JM, Muka T, et al. Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome. Eur Heart J 2020 Apr;41(13):1328–1336. doi: 10.1093/eurheartj/ehz898.
5 Moran CA, Collins LF, Beydoun N, Mehta PK, Fatade Y, Isiadinso I, et al. Cardiovascular Implications of Immune Disorders in Woman. Circ Res. 2022 Feb;130(4):593–610. doi: 10.1161/CIRCRESAHA.121.319877.
6 Lam CS, Gamble GD, Ling LH, Sim D, Leong KT, Yeo PS, et al. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study. Eur Heart J 2018 May;39(20):1770–1780. doi: 10.1093/eurheartj/ehy005.
7 Lam CS, Arnott C, Beale AL, Chandramouli C, Hilfiker-Kleiner D, Kaye DM, et al. Sex differences in heart failure. Eur Heart J 2019 Dec;40(47):3859–3868c. doi: 10.1093/eurheartj/ehz835.
8 Sotomi Y, Hikoso S, Nakatani D, Mizuno H, Okada K, Dohi T, et al. PURSUIT-HFpEF Investigators. Sex Differences in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc 2021 Feb;10(5):e018574. doi: 10.1161/JAHA.120.018574.
9 Wenzl FA, Kraler S, Ambler G, Weston C, Herzog SA, Räber L, et al. Sex-specific evaluation and redevelopment of the GRACE score in non-ST-segment elevation acute coronary syndromes in populations from the UK and Switzerland: a multinational analysis with external cohort validation. Lancet 2022 Sep;400(10354):744–756. doi: 10.1016/S0140-6736(22)01483-0.
10 Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015 Sep;373(10):929–938. doi: 10.1056/NEJMoa1406761.
11 Adlam D, Alfonso F, Maas A, Vrints C, al-Hussaini A, Bueno H, et al.; Writing Committee. European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J 2018 Sep;39(36):3353–3368. doi: 10.1093/eurheartj/ehy080.
12 Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH. Atrial Fibrillation: Epidemiology, Pathophysiology, and Clinical Outcomes. Circ Res 2017 Apr;120(9):1501–1517. doi: 10.1161/CIRCRESAHA.117.309732.
13 Westerman S, Wenger N. Gender Differences in Atrial Fibrillation: A Review of Epidemiology, Management, and Outcomes. Curr Cardiol Rev 2019;15(2):136–144. doi: 10.2174/1573403X15666181205110624.
14 Ko D, Rahman F, Schnabel RB, Yin X, Benjamin EJ, Christophersen IE. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis. Nat Rev Cardiol 2016 Jun;13(6):321–332. doi: 10.1038/nrcardio.2016.45.
15 Noseworthy PA, Gersh BJ, Kent DM, Piccini JP, Packer DL, Shah ND, et al. Atrial fibrillation ablation in practice: assessing CABANA generalizability. Eur Heart J 2019 Apr;40(16):1257–1264. doi: 10.1093/eurheartj/ehz085.
16 Cheung JW, Cheng EP, Wu X, Yeo I, Christos PJ, Kamel H, et al. Sex-based differences in outcomes, 30-day readmissions, and costs following catheter ablation of atrial fibrillation: the United States Nationwide Readmissions Database 2010-14. Eur Heart J 2019 Sep;40(36):3035–3043. doi: 10.1093/eurheartj/ehz151.
17 Lüscher TF, Miller VM, Bairey Merz CN, Crea F. Diversity is richness: why data reporting according to sex, age, and ethnicity matters. Eur Heart J 2020 Sep;41(33):3117–3121. doi: 10.1093/eurheartj/ehaa277.
18 Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter? Wizemann TM, Pardue ML, editors. Washington (DC): National Academies Press (US); 2001.
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