Traditionally, cardiovascular disease has been considered a “man’s disease,” but this myth has been debunked in recent years. Recent data show that cardiovascular disease is the leading cause of death in women in developed countries and most emerging economies, with the mortality attributed to cardiovascular disease being higher than the mortality caused by cancer, chronic lower respiratory disease, Alzheimer disease, and accidents combined. Cardiovascular disease in women was commonly neglected by physicians until the two decades ago. Various studies that analyzed the management and outcomes of women with NSTEMI in the late 1990s suggested that treatment strategies for women with cardiovascular disease were less aggressive than for men. In recent years, substantial efforts have been made to increase prevention awareness and promote healthy lifestyles in women. These efforts have been successfully reflected in health surveys: in 1997, only 30% of women in the US surveyed were aware that cardiovascular disease was the primary cause of mortality in women; this percentage increased to 54% in 2009 and has subsequently stabilized when the last survey was conducted in 2012.

The terminology of coronary artery disease, atherosclerotic disease limited to the epicardial coronary arteries, should not be used and should not be confused with ischemic heart disease because there are some differences in this pathology depending on the sex that should be highlighted. Data shows that there are sex-related differences in the clinical presentation, pathophysiology, evaluation, management, and outcomes in patients with cardiovascular disease and, more specifically, in patients with ACS. The clinical presentation of ACS differs between women and men. Women are more likely to present with angina as their first presentation of ischemic heart disease and they are less likely to develop an acute myocardial infarction compared with men. Among patients with ACS, fewer women present with STEMI and more present with unstable angina. An analysis of GUSTO IIb, a trial that included 12 142 patients (30% women), showed that significantly fewer women than men presented with ST-segment elevation,3 and, in the patients with NSTEMI or unstable angina, women were more likely to have unstable angina than were men. The lower rate of STEMI in women was later confirmed in a large registry of 78 254 patients included in the Get With The Guidelines–Coronary Artery Disease registry.4 Women are more likely to experience a wide range of atypical symptoms, such as fatigue, shortness of breath, weakness, nausea, right arm pain, intermammary pain, and epigastric pain, that might make their diagnosis and subsequent management challenging. However, crushing substernal chest pain is the most common presenting symptom, which is also a strong predictor of an acute coronary syndrome in both men and women.

Many hypotheses have been generated regarding the reasons behind the sex-related presentation differences. Biological variances and cardiovascular system differences among women and men are the results of gene expression and the influence of sex hormones. These differences play a fundamental role in the pathophysiology and the disparity in the presentation of ischemic heart disease in women and men. Some cardiovascular conditions are predominant in women, such as those related to autonomic regulation of the arteries, eg, vasospastic disease, Raynaud’s phenomenon, and another vasculitis. Women with ACS also present more frequently with nonobstructive coronary artery disease, whereas, in men, the rupture of atherosclerotic plaque and microembolization is predominate. 

Although the hearts of men and women seem to be structurally similar, some sex-specific differences in the expression of biomarkers in ACS have been described; for example, the baseline concentrations of some biomarkers are different between women and men. The emergence of high-sensitivity assays for cardiac troponin has made the differences between women and men more clear. In a recent prospective cohort study, as assay for high-sensitivity troponin I significantly increased the diagnosis of ACS in women (from 11% to 22%; P<0.001), but it had a minimal effect on the diagnosis in men (from 19% to 21%; P=0.002).6 Additionally, it is more likely to observe an increase in CRP and BNP in women who present with ACS, which reflects a higher prevalence of heart failure and a higher risk profile at the moment of presentation. Other biomarkers, such as proneurotensin, have been shown to be sex-specific and related to incident cardiovascular disease only in women, which might improve the prediction of incident cardiovascular disease.

Regarding the management of cardiovascular disease and ACS, there is strong evidence confirming that medications and invasive procedures are similarly effective in men and women. However, different studies have reported that women are treated more conservatively and they receive fewer evidence-based medications. Accordingly, clinicians should be aware of these differences when diagnosing and managing patients to avoid sex-related bias. 

A substantial body of evidence supports a sex-related difference in short-term mortality after an ACS, especially after STEMI. However, differences regarding long-term outcomes between men and women with ACS are conflicting. Current evidence suggests that age plays an important role in these observed differences in sex-related outcomes. Since the first study reported by Vaccarino et al7 and the subsequent confirmation by many other registries, women who suffer an acute myocardial infarction, either STEMI or NSTEMI, at a young age have a worse prognosis than men in the same age group, with a 22% higher risk of 30-day hospital readmission than young men. In contrast, in patients >65 years old, women appear to have better outcomes than men.7 Although many hypothesis have been proposed, the explanation of sex-related differences in young and middle-aged patients is still unclear. 

In our opinion, the sex-related differences concerning the clinical presentation, management, treatment, and outcomes are obvious in patients presenting with an ACS. Despite the efforts made in recent years to develop new strategies for revascularization and new therapeutic targets that have led to an overall reduction in mortality due to cardiovascular disease, there are still aspects for reflection and improvement. Undoubtedly, one aspect concerns the differences between men and women because women with cardiovascular disease have a persistent suboptimal treatment pattern, higher mortality, and poorer cardiovascular disease outcomes compared with men.

Many aspects remain to be addressed. Are we promoting prevention awareness and healthy lifestyles regardless of sex? Why are women less likely to be treated with invasive strategies and to receive fewer evidence-based medications than are men? Are the disparities regarding clinical presentation only the result of differences in the pathophysiology or rather differences in the recognition or expression of symptoms between women and men? Compared with men, why do young and middle-aged women have a poor prognosis and more adverse outcomes after an ACS? To understand this complex issue better and to answer these crucial questions, we are in dire need of research efforts to reduce sex-related differences between women and men with cardiovascular disease and to improve the clinical management of women with cardiovascular disease.