Female sex as a biological variable: A review on younger patients with acute coronary syndrome

doi:10.1016/j.tcm.2018.06.002

Trends in Cardiovascular Medicine

Volume 29, Issue 1, January 2019, Pages 50-55

https://doi.org/10.1016/j.tcm.2018.06.002 Get rights and content

Abstract

Although acute coronary syndrome (ACS) mainly occurs in individuals >60 years, younger adults can be affected as well. Women continue to be at higher risk of 30-day mortality after ST-segment elevation myocardial infarction (STEMI) even in the current era of percutaneous coronary intervention (PCI). Importantly, the excess mortality among women is only significant at younger ages. Previous work has suggested that the reason for the differences in outcome is likely multifactorial and may partially be explained by some of the following factors: atypical presentation, delayed presentation, under-recognition of STEMI at initial medical contact, and underuse of medications because of concern regarding increased risk of bleeding. While these hypotheses may be true in some occasions, recent studies pointed out that the proportion of women presenting within 2 h after symptom onset was greater in the younger than in older cohorts. In addition, sex differences in administration of adjunctive medical therapies were greater in the older than in the younger cohort. Thus, there is not any one of the abovementioned factors able to explain the increase in mortality in the young women. Disparities alone could not account for the gap in mortality across sexes. Unless the effects of sex are studied, we will continue to have gaps in the knowledge of potential different mechanisms leading young women and men to die after ACS, which may result in missed opportunities for implementing a better health in our community. Randomizing or balancing the sexes as well as powering studies to detect sex differences is warranted in future research.

Introduction

Although acute coronary syndrome (ACS) mainly occurs in individuals >60 years, younger adults can be affected as well. A recent study [1] has shown that women continue to be at higher risk of 30-day mortality after ST-segment elevation myocardial infarction (STEMI) even in the current era of percutaneous coronary intervention (PCI). Data on 8,834 patients with STEMI in 41 hospitals in Europe were obtained from the International Survey of Acute Coronary Syndromes (ISACS-TC) registry between 2010 and 2016. Participants consisted of 2,657 women (mean age, 66.1 years) and 6,177 men (mean age, 59.9 years). The analysis indicated that women had a significantly higher 30-day mortality risk than men (11.6% versus 6%). After limiting the evaluation to participants undergoing primary PCI, the disparity in sex-specific mortality shrunk to 7.1% for women and 3.3% for men. Early mortality risk was higher among women younger than 60 years than among men in the same age cohort when adjusting for medications and other comorbidities (OR 1.88, 95% CI 1.04–3.26). Sex differences in 30-day mortality risk were not significant among participants aged 60 to 70 years (OR 1.28, 95% CI 0.88–1.88) and those older than 75 years (OR 1.17, 95% CI 0.8–1.73). The extent to which mortality rate differences between young men and women are related to disparities in treatment or dissimilarities in pathophysiology remains a matter of debate. Nevertheless, this study is the first investigation that demonstrates that differences between younger men and younger women in STEMI mortality rates are unrelated even to disparities in treatment. Sex-related pathophysiological differences may contribute to the higher mortality in younger women compared with men of the same age category. This review article strongly supports the view that female sex is a biological variable and contributes to implement the Sex and Gender Equity in Research (SAGER) guidelines that were developed to assist researchers in reporting sex and gender information in publications [2]

Section snippets

Sex matters

“If the present arrangements of society will not admit of woman's free development, then society must be remodeled, and adapted to the great wants of humanity” (Elizabeth Blackwell)

The idea that there are sex-based differences in early mortality after myocardial infarction is not new. One study investigated mortality trend sex differences from 1994 to 1998. Data were collected from the National Registry of Myocardial Infarction (NRMI) on 691,995 patients [3]. The overall mortality rate during

Contradiction in the literature

“Truth comes out of error more readily than out of confusion” (Francis Bacon)

Some scientists argued that the major flaw encountered in the above-mentioned research studies was the failure to calculate outcomes with separate analyses for patients with and without STEMI. Further, some of the early studies on sex difference in outcome predate the era of routine invasive approach and other current standard-of-care medications. One study found a sex-ACS subtype interaction in a large sample of

Can we resolve the contradiction?

“Contradiction is the lever of transcendence” (Simone Weil)

We did resolve the contradiction at least partially. A key to understanding is first the recognition that STEMI is a unique clinical entity with epidemiology, incidence, and outcomes distinct from that of NSTEMI. STEMI and NSTEMI differ considerably in the management options. Treatment of patients with NSTEMI is more complex and challenging than treatment of patients with STEMI. In STEMI time to reperfusion is a basic factor influencing

Proposed working definition of a younger person

“The first part of life is childhood. The second is your child's childhood. And then the third, old age.” (Barbara Kingsolver)

The results of subgroup analyses by age can result in either consistent or insignificant findings depending on the definition of age used in the study [9]. No subgroup analysis will attain practical usefulness when undertaken without any explanatory background, no matter how significant the results may be [10]. Thus, when does younger age begin in research studies? Our

Cardiovascular disease in the young: a specific role for diabetes in women?

“The important thing is to not stop questioning. Curiosity has its own reason for existing” (Albert Einstein)

According to the United Nations “Population Aging Report” (2009), the proportion of the global population aged less than 60 years was 92% in 1950, 90% in 2000, and is expected to reach 89% in 2050. Patients less than 60 years old represented 43.1% of all patients who presented with STEMI to hospitals enrolled in the ISACS-TC registry over a 6-year period [1]. Thus, there is a substantial

The interplay between diabetes and ischemic artery disease

“The very process of living is a continual interplay between the individual and his environment, often taking the form of a struggle resulting in injury or disease” (Rene Dubos)

The ISACS-TC registry showed that in younger people the presence of diabetes conferred a similar risk of death from any cause, as did a history of prior PCI [1]. The same was not true for women and men older than 60 years, in whom the risk of death was lower for people with diabetes than for those with a history of prior

Angiographic CAD burden and mortality in the young

“The tragedy associated with coronary atherosclerotic heart disease is that it kills or disables people during their prime of life.” (Paul Dudley White)

Atherosclerosis of the coronary arteries is known to have an impact on the development and severity of ACS [27]. Given that young patients with ACS presented an average of two decades earlier than old patients and with fewer risk factors, it is conceivable that researchers observed less multivessel disease, less calcification, and fewer ostial

Sex disparities in treatment

“Whatever women do they must do twice as well as men to be thought half as good” (Charlotte Whitton)

Prior studies have suggested that women with ACS are treated less aggressively than men. In the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) initiative, women were less likely to receive heparin and antiplatelet agents and less likely to undergo

Estimating sex differences in treatment effects using observational data

“If it were not for the great variability between individuals, medicine might as well be a science, not an art” (William Osler)

Many studies have estimated an “average treatment effect” that implicitly assumes a similar treatment effect across sexes. In contrast, therapeutic strategies for ACS may have a different effect in women compared with men. A contemporary example of this is given by the glycoprotein IIb/IIIa inhibitors for which randomized clinical trials have demonstrated efficacy

Sex differences in pathophysiology

“Belief begins where science leaves off and ends where science begins.” (Rudolf Ludwig Karl Virchow)

There could be several reasons for why younger women are more likely to die than young men. Diabetes in women may have a more powerful role than in men [38]. One study found that diabetes was a factor associated with increased risk of 30-day all-cause mortality in the young, but not the old population, and was accompanied by a large sex gap in mortality [1]. Elevated triglycerides have been shown

Trends in sex-related outcomes

“The problem seemed to me not that there are differences but rather how we value these differences” (Sue Monk Kidd)

Bhatt and colleagues examined Nationwide Inpatient Sample (NIS) data from 2004 to 2011 to assess temporal trends and sex differences in revascularization and in-hospital outcomes for younger patients with acute myocardial infarction [51]. The cohort consisted of 1,363,492 adults aged between 18 and 59 years. Of these, 632,930 patients (46.4%) had STEMI. Women were less likely than

What do you do next?

“The laws of science do not distinguish between the past and the future.” (Stephen Hawking)

The United States (US) National Institutes of Health (NIH) now requires that scientists incorporate Sex as a Biological Variable (SABV) in its funded vertebrate animal research by considering whether the system under study operates differently in the two sexes through the comparison of males and females in at least some key experiments. The NIH's view pertains also to clinical trials and observational

Conclusions

“We want to end gender inequality and to do that we need everyone to be involved” (Emma Watson)

Consideration of sex may be critical to the interpretation, validation, and generalizability of research findings. Including sex/ gender analysis in research could save more women from ischemic heart disease

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Cited by (22)

Gender-Related Factors Associated With Outcomes of Acute Coronary Syndrome in Young Female Patients
2024, CJC Open
Acute coronary syndrome (ACS) remains a significant global health concern, with a growing recognition of its impact on young adults, particularly young female adults. Although gender-related factors, defined as a social construct that encompasses 4 distinct dimensions (gender roles, gender identity, gender relations, and institutionalized gender) are undoubtedly relevant across age groups, young female patients with ACS face specific challenges and disparities in outcomes, compared to other populations. This narrative review examines the role of gender-related factors—specifically, gender roles, gender identity, gender relations, and institutionalized gender—in influencing objective and subjective ACS outcomes in young female patients. In the 5 articles identified, the objective outcomes included hospital readmission, “door-to-electrocardiography” time, and coronary atherosclerosis progression. Subjective outcomes, such as physical and mental functional status, quality of life, physical limitations, and vital exhaustion, were also examined. Being employed, which is a gender role, emerged as a protective factor against hospital readmission. Gender identity factors such as depression and stress were correlated with negative outcomes, and anxiety influenced “door-to-electrocardiography” times. Institutional factors, including income disparities, affected readmission likelihood. Strong social support decreased physical limitations post-ACS, whereas financial challenges and lower education negatively impacted quality of life and vital exhaustion. These findings underscore the intricate interplay of gender dimensions in shaping ACS outcomes among young female patients. Integrating these insights into clinical practice and research can enhance care, mitigate disparities, and foster improved cardiovascular health in this vulnerable population.
Le syndrome coronarien aigu (SCA) demeure un problème de santé préoccupant à l’échelle mondiale, avec une reconnaissance croissante de ses conséquences chez les jeunes adultes, plus particulièrement les jeunes femmes adultes. Les facteurs liés au genre, définis comme un construit social à quatre dimensions distinctes (les rôles liés au genre, l’identité de genre, les relations de genre et le genre institutionnalisé) sont indéniablement d’une grande importance dans tous les groupes d’âge, mais les jeunes patientes atteintes d’un SCA font face à des disparités et des défis particuliers à l’égard des résultats de santé par rapport à d’autres populations. La présente synthèse narrative propose un examen de l’influence des facteurs liés au genre (plus particulièrement les rôles liés au genre, l’identité de genre, les relations de genre et le genre institutionnalisé) sur les issues objectives et subjectives du SCA chez les jeunes patientes. Dans les 5 articles retenus, les issues objectives incluaient la réadmission à l’hôpital, le temps écoulé entre l’arrivée à l’hôpital et la réalisation de l’électrocardiographie et l’évolution de l’athérosclérose coronarienne. Les issues subjectives, comme le statut fonctionnel physique et mental, la qualité de vie, les limitations physiques et le syndrome d’épuisement, ont également été examinées. Être employé, qui est un rôle de genre, est apparu comme facteur de protection contre la réadmission à l’hôpital. Des facteurs liés à l’identité de genre, comme la dépression et le stress, étaient corrélés à des issues négatives et l’anxiété était liée au temps écoulé entre l’arrivée à l’hôpital et la réalisation de l’électrocardiographie. Les facteurs liés aux institutions, y compris les disparités de revenus, influençaient la probabilité de réadmission à l’hôpital. La présence d’un bon réseau social était associée à de plus faibles limitations physiques après le SCA, alors que les problèmes financiers et un faible niveau d’éducation avaient une influence néfaste sur la qualité de vie et le syndrome d’épuisement. Ces résultats font ressortir les interactions complexes entre les différentes dimensions du genre qui façonnent les issues du SCA chez les jeunes patientes. L’intégration de ces renseignements dans la pratique clinique et dans la recherche scientifique pourrait permettre d’améliorer les soins, de limiter les disparités auxquelles font face ces patientes et de favoriser une meilleure santé cardiovasculaire au sein de cette population vulnérable.
Heterogenicity of diabetes as a risk factor for all-cause mortality after acute myocardial infarction: Age and sex impact
2021, Diabetes Research and Clinical Practice
Citation Excerpt :
We have revealed that the association between T2DM and mortality was substantially more robust in young females. Such interaction was reported in previous studies [4,7,37,38]. However, other studies of young females with ACS with a short-term follow-up have not supported this phenomenon [39,40].
Type 2 diabetes mellitus (T2DM) is a risk factor for mortality after acute myocardial infarction (AMI). We studied the impact of T2DM related to sex and age on post-AMI long-term mortality.
A retrospective study included post-AMI patients. Data were obtained from electronic medical records. We defined the study groups by T2DM, stratified by age-sex. Outcome: up-to-10 years post-discharge all-cause mortality.
16,168 patients were analyzed, 40.3% had T2DM. Ten-year mortality rates were 50.3% with T2DM vs. 33.1% without T2DM, adjHR = 1.622 (p < 0.001). Females (adjHR = 1.085, p = 0.052) and increased age (adjHR = 1.056 for one-year increase, p < 0.001) were associated with a higher risk of mortality (borderline statistical significance for sex). The relationship between T2DM and mortality was stronger in females than in males at < 50 and 60–69 years (p-for-interaction 0.025 and 0.009 respectively), but not for other age groups.
The study implies heterogeneity in the impact of T2DM on mortality of post-AMI patients, being greater among young patients, particularly females, and no significant impact in octogenarians. That implies that young women with T2DM should have advanced measures for early detection of coronary artery disease and tight control of cardiovascular risk factors to lower the propensity to develop AMI.
Meta-Analysis of Gender Disparities in In-hospital Care and Outcomes in Patients with ST-Segment Elevation Myocardial Infarction
2021, American Journal of Cardiology
Citation Excerpt :
However, the fact that age is the primary driver of the gender disparity in post-STEMI mortality should not lead to complacency because this is a multifactorial problem and there are many modifiable risk factors that also contribute to the observed gender differences. Recent studies showed that the gender gap persists after adjustment, particularly in younger females (< 60 years);13-15 but, given the lack of patient-level-data, we were not able to include this subgroup in our study and thus requires further investigation. Moreover, although the multiple regressions for other outcomes were limited by sample size, it appears that female gender is not a significant predictor of repeat MI or stroke after adjustment.
Gender disparities in ST-segment elevation myocardial infarction (STEMI) outcomes continue to be reported worldwide; however, the magnitude of this gap remains unknown. To evaluate gender-based discrepancies in clinical outcomes and identify the primary driving factors a global meta-analysis was performed. Studies were selected if they included all comers with STEMI, reported gender specific patient characteristics, treatments, and outcomes, according to the registered PROSPERO protocol: CRD42020161469. A total of 56 studies (705,098 patients, 31% females) were included. Females were older, had more comorbidities and received less antiplatelet therapy and primary percutaneous coronary intervention (PCI). Females experienced significantly longer delays to first medical contact (mean difference 42.5 min) and door-to-balloon time (mean difference 4.9 min). In-hospital, females had increased rates of mortality (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.84 to 1.99, p <0.00001), repeat myocardial infarction (MI) (OR 1.25, 95% CI 1.00 to 1.56, p=0.05), stroke (OR 1.67, 95% CI 1.27 to 2.20, p <0.001), and major bleeding (OR 1.82, 95% CI 1.56 to 2.12, p <0.00001) compared with males. Older age at presentation was the primary driver of excess mortality in females, although other factors including lower rates of primary PCI and aspirin usage, and longer door-to-balloon times contributed. In contrast, excess rates of repeat MI and stroke in females appeared to be driven, at least in part, by lower use of primary PCI and P2Y12 inhibitors, respectively. In conclusion, despite improvements in STEMI care, women continue to have in-hospital rates of mortality, repeat MI, stroke, and major bleeding up to 2-fold higher than men. Gender disparities in in-hospital outcomes can largely be explained by age differences at presentation but comorbidities, delays to care and suboptimal treatment experienced by women may contribute to the gender gap.
Editorial Commentary: Complex interactions of age and sex on acute coronary syndromes
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2023, Medicine (United States)

View all citing articles on Scopus

^☆: Conflict of interest: None.

^✰✰: Funding: None.

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Female sex as a biological variable: A review on younger patients with acute coronary syndrome☆,✰✰

Abstract

Introduction

Section snippets

Sex matters

Contradiction in the literature

Can we resolve the contradiction?

Proposed working definition of a younger person

Cardiovascular disease in the young: a specific role for diabetes in women?

The interplay between diabetes and ischemic artery disease

Angiographic CAD burden and mortality in the young

Sex disparities in treatment

Estimating sex differences in treatment effects using observational data

Sex differences in pathophysiology

Trends in sex-related outcomes

What do you do next?

Conclusions

Am Heart J

Am J Med

Am J Med

Am Heart J

Int J Cardiol

Am Heart J

Chest

Int J Cardiol

Am Heart J

Int J Cardiol

Am Heart J

Am Heart J

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

Atherosclerosis

J Am Coll Cardiol

J Am Coll Cardiol

Am J Med

Sex differences in outcomes after STEMI: effect modification by treatment strategy and age

JAMA Intern Med

Sex and gender equity in research: rationale for the SAGER guidelines and recommended use

Res Integr Peer Rev

National registry of myocardial infarction 2 participants. Sex‐based differences in early mortality after myocardial infarction

N Engl J Med.

Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality

JAMA

Sex differences in mortality following acute coronary syndromes

JAMA

The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction

Heart

Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials

JAMA