Editorial: Sex differences and cardiovascular therapeutics
Fatma Saaoud
Keman Xu
Yifan Lu
Ying Shao
Xiaohua Jiang1,2 
Hong Wang
Xiaofeng Yang- 1Lemore Center for Integrated Lymphatics and Vascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
- 2Centers of Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
Editorial on the Research Topic
Sex differences and cardiovascular therapeutics
Introduction
Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide (1). Sex and gender as a biological variable, are crucial factors that impact every aspect of clinical and public health practice and research (2–4). In recent times, research investigating sex differences has gained more attention, partly benefit from federal agencies emphasizing the importance of considering sex as a significant biological factor (5). Within cardiovascular medicine, sex and gender affect disease presentation, pathophysiology, diagnostic assessment, responses to treatments, and overall health outcomes (6, 7). Historically, CVD has been perceived as primarily affecting men; however, it is increasingly recognized as a leading cause of morbidity and mortality in women as well (8). While men tend to develop CVD earlier in life, CVD prevalence increases significantly in postmenopausal women, narrowing the gap between the sexes (9). Men have traditionally experienced higher rates of CVD-related events, but women are more likely to die following an acute cardiovascular event (10). The existence of these gender disparities has prompted significant attention, highlighting the crucial significance of considering gender variations in the prevention, diagnosis, treatment, and overall management of CVD (11).
Traditional risk factors such as hypertension, diabetes, dyslipidemia, and smoking affect both sexes, but their impacts can vary between men and women (12–14). Additionally, women may experience unique risk factors including pregnancy-related complications such as gestational diabetes and preeclampsia, as well as endocrine disorders in reproductive age such as polycystic ovary syndrome (PCOS) and early menopause, which are associated with accelerated development of CVD and impaired CVD-free survival (15–17). Biological differences include genetic differences, variation in sex hormonal status, vascular anatomy, endothelial function, and plaque composition, which contribute to differences in the pathophysiology of CVD between men and women (18, 19). Women showed less plaque inflammatory infiltration compared to plaques from age-matched men (20–22). In addition, women often undergo fewer diagnostic tests and experience delays in diagnosis compared to men, leading to disparities in timely intervention and treatment (23). Despite accumulating evidence, the precise roles of biological sex and the sociocultural aspect of gender in the development and consequences of CVDs have not been fully explained. The interplay between sex-specific disparities in genetic and hormonal mechanisms and the intricate nature of gender, including its various components and influencing factors, which give rise to different disease patterns in men and women, requires further investigation.
The extents to which biological factors, such as genes and hormones, contribute to cardiovascular traits and outcomes are still not fully grasped. Heightened recognition of gender's impact has prompted endeavors to assess gender in both retrospective and prospective clinical studies, leading to the creation of gender scores. Yet, the combined or conflicting influences of sex and gender on cardiovascular characteristics, as well as on the mechanisms underlying CVDs, have not been systematically elucidated. The majority of medication are withdrawn after FDA approval due to unexpected adverse effects in women (24). Additionally, there are differences in the effectiveness and side effects of cardiovascular medications between men and women (25). Current guidelines do not provide sex-specific recommendations on the use of antithrombotic drugs in patients with coronary artery disease. Nevertheless, the effectiveness of antithrombotic medications might be impacted by genetic and biological factors associated to sex (26). Women generally exhibit greater platelet reactivity at baseline and in response to low-dose aspirin treatment in comparison to men (27). Despite receiving high-dose statin therapy following acute coronary syndrome, women showed a smaller absolute reduction in low-density lipoprotein cholesterol (LDL) cholesterol levels compared to men (28). Understanding these sex differences is crucial for providing personalized and effective cardiovascular care. It requires including more women in clinical trials, analyzing data by sex, and considering sex-specific factors in treatment decisions. By doing so, healthcare providers can optimize outcomes and reduce disparities in cardiovascular care between men and women.
Sex hormones in CVD
Sex hormones, including estrogen, progesterone, and testosterone, play significant roles in cardiovascular health and disease (29, 30). Estrogen, primarily found in premenopausal women, exerts cardioprotective effects (8, 29, 31). It helps maintain healthy blood vessel function by promoting vasodilation, reducing inflammation, and inhibiting the formation of atherosclerotic plaques. Estrogen also influences lipid metabolism, favoring higher levels of high-density lipoprotein (HDL) cholesterol and lower levels of LDL cholesterol, contributing to a reduced risk of CVDs such as heart attacks and strokes (32, 33).
The differences in estrogen levels between men and women, as well as the changes that occur during menopause, contribute to the variation in CVD occurrence between the sexes. Before menopause, women generally have higher levels of estrogen, potentially explaining their lower risk of CVD compared to men of the same age. However, after menopause, when estrogen levels decline, women's risk of CVD increases and may approach that of men (34). Progesterone, another female sex hormone, also plays a role in cardiovascular health, though its effects are less well understood compared to estrogen. Some research suggests that progesterone may have protective effects on the cardiovascular system, such as promoting vasodilation and inhibiting smooth muscle cell proliferation in blood vessels (35, 36).
Androgens, including testosterone and other male sex hormones, can influence cardiovascular health in both men and women. Low levels of testosterone in men have been associated with an increased risk of CVD, including coronary artery disease and heart failure (18). Testosterone influences factors such as blood pressure regulation, lipid metabolism, and the development of atherosclerosis. However, the relationship between testosterone levels and cardiovascular risk is complex, and both low and high levels of testosterone have been implicated in various cardiovascular conditions (33). In addition to testosterone, other androgens such as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) may also impact cardiovascular risk factors (18).
Overall, sex hormones play intricate roles in cardiovascular physiology and pathology. Understanding the interplay between sex hormones and cardiovascular health is essential for developing personalized approaches to preventing and managing CVDs.
Genetic factors that are specific to each sex and influence cardiovascular characteristics
Genetic factors play a significant role in cardiovascular characteristics, with some of these factors being specific to each sex (37). The presence of sex chromosomes (XX in females and XY in males) not only determines primary sexual characteristics but also influences cardiovascular health (38, 39). For instance, genes on the Y chromosome may impact cardiac function (40). Moreover, genetic variations in lipoprotein metabolism can influence the metabolism of lipoproteins differently in men and women (41, 42). For example, certain genetic variants may have a more pronounced effect on the levels of HDL cholesterol in women compared to men, or vice versa (43). Additionally, genes involved in blood pressure regulation may exhibit sex-specific effects. For instance, variations in genes related to the renin-angiotensin-aldosterone system (RAAS) may influence blood pressure in varying ways between men and women (44). Understanding these sex-specific genetic factors is crucial for developing personalized approaches to cardiovascular disease prevention, diagnosis, and treatment. It underscores the importance of considering sex as a biological variable in cardiovascular research and clinical practice.
Our Research Topic: “Sex Differences and Cardiovascular Therapeutics,” featured twelve papers comprising original research papers and reviews (Table 1). These highlights offer a comprehensive perspective on gender-related differences in various CVDs, potential factors contributing to these distinctions, and management strategies. Collectively, these papers contribute to our understanding of sex differences in cardiovascular therapeutics and emphasize the importance of tailored approaches to prevention, diagnosis, and treatment based on gender-specific considerations.
Table 1. Twelve highly viewed research papers, published in our special topic entitled “Sex differences and cardiovascular therapeutics”, are summarized.
Conclusion
Sex differences play a significant role in the epidemiology, pathophysiology, clinical presentation, diagnosis, management, and outcomes of cardiovascular diseases. Recognizing these differences and implementing sex-specific approaches in research, clinical practice, and public health initiatives are essential for reducing disparities and improving cardiovascular outcomes for both men and women. While the differences between sexes in the occurrence and complications of CVDs are widely acknowledged, there are relatively limited data in both clinical and pre-clinical studies that adequately explore the underlying mechanisms regarding sex as a biological variable in CVDs.
Author contributions
FS: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Validation, Writing – original draft. KX: Conceptualization, Writing – review & editing. YL: Conceptualization, Writing – review & editing. YS: Conceptualization, Writing – review & editing. XJ: Conceptualization, Writing – review & editing. HW: Conceptualization, Writing – review & editing. XY: Conceptualization, Funding acquisition, Supervision, Formal Analysis, Visualization, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article.
XY is funded by NIH grants (R01 HL163570-01A1 and 1R01HL147565-01).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher's note
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Keywords: cardiovascular diseases, sex difference, sex hormones, genetic factors, therapeutics
Citation: Saaoud F, Xu K, Lu Y, Shao Y, Jiang X, Wang H and Yang X (2024) Editorial: Sex differences and cardiovascular therapeutics. Front. Cardiovasc. Med. 11:1420293. doi: 10.3389/fcvm.2024.1420293
Received: 19 April 2024; Accepted: 3 May 2024;
Published: 20 May 2024.
Edited and Reviewed by: Masanori Aikawa, Harvard Medical School, United States
© 2024 Saaoud, Xu, Lu, Shao, Jiang, Wang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaofeng Yang, xfyang@temple.edu