Cardiovascular disease (CVD) is the most common cause of death in women in developed countries and is responsible for more than the combined number of deaths due to the next seven causes and more than all types of cancers combined. In the United States, CVD mortality in women exceeds that of men. Coronary heart disease is mainly responsible with 24%,1–4 and although death from ischemic heart disease (IHD) has declined in men, its incidence is stable in women.5,6

Despite the burden of coronary disease in women, CVD is still considered a disease of men and there is a false perception that women are in some way protected. IHD in women appears to have its own characteristics, although women are relatively under-represented in studies and registries.1,7

This lack of representation in randomized clinical trials has delayed recognition of specific cardiovascular risk factors by extrapolating results from studies of the male population. There are significant gaps in knowledge of CVD in women. In an analysis of gender-specific differences in the characteristics, development, management, and prognosis of acute coronary syndrome (ACS) between 1994 and 2002 in the RISCI, PRIAMHO I and II, Descartes and TRIANA trials conducted by the Working Group on Ischemic Heart Disease and Coronary Care Units of the Spanish Society of Cardiology, only 24.3% of 48369 patients were women.8

On average, women suffer myocardial infarction (MI) 7–10 years later than men, and show a poorer prognosis and 20% higher short-term mortality than men, independently of age.9

The precise reasons for this gender difference in the prognosis of acute IHD are unknown. However, epidemiological studies suggest that differences in mortality cannot be explained by possible protective effects of hormones. They give more weight to elements of the metabolic syndrome, such as hyperlipidemia or diabetes, which appear to be more prevalent in women, and to differences in clinical presentation or disparities in the use of diagnostic and therapeutic resources. Furthermore, gender-linked genetic factors, which may be critical to the development of the disease, are even less well understood.10

It is important to promote education and discussion on the differences in presentation, development, and treatment of ACS in both sexes and to obtain new indications for IHD in women. Editors of medical journals have highlighted the need for studies specifically on women that will indicate whether gender influences prognosis, including complications and adverse effects, in female patients who have suffered a high-risk ACS.11

We set out to determine the differences in epidemiology, presentation and evolution of high-risk ACS in men and women, analyzing the possible effect of gender on mortality in-hospital and during a 6-month follow-up period after the acute coronary event. We also studied the association between gender and adverse cardiovascular events including post-infarction angina, reinfarction, and heart failure in the same follow-up period.

This was a prospective analytical cohort study of patients admitted consecutively to our hospital between January 2006 and December 2007 with a diagnosis of high-risk ACS with and without ST-segment elevation according to the criteria of the ACC/AHA (American College of Cardiology/American Heart Association).12,13 Patients were treated according to the ACC/AHA guidelines.

Exclusion criteria were the presence of solid organ or hematological malignancy, fever or sepsis at the time of the study, autoimmune and inflammatory diseases, stage 5 chronic renal failure according to the 2002 National Kidney Foundation guidelines,14 and the absence of reliable records. Of the 590 patients initially selected, 31 were excluded, and the final sample analyzed was thus 559 patients.

The study collected data prospectively on a consecutive series of patients who suffered high-risk ACS treated with an up-to-date therapeutic protocol for unstable IHD. The women in the study population were older and had a more unfavorable clinical profile, with poorer initial prognosis according to the GRACE risk score, and suffered a greater number of adverse cardiovascular events including post-infarction angina, reinfarction and heart failure, as well as increased in-hospital and all-cause mortality, in comparison to men. However, on multivariate analysis, these gender differences disappeared, which suggests that more or less favorable evolution depends to a large extent on the baseline characteristics of the groups.

Women had older mean age than men (63.1 vs. 72.7 years) and began to suffer coronary acute events a decade later, which is attributable, in part, to the protective effect of estrogens, according to some studies.15 Elevated total cholesterol, LDL cholesterol, and triglyceride levels, and lower HDL-C levels during menopause may contribute to the increased risk, especially from the sixth decade of life.16 In addition, estrogens, through the nitric oxide pathway, induce smooth muscle cell dilation and inhibit vascular proliferation.17,18 For years, these data were considered to suggest that exogenously administered estrogen could have a cardioprotective effect. However, the results of clinical trials on both primary (WHI and WISDOM) and secondary prevention (HERS and ESPRIT), and in angiographic endpoints (WAS, WELL-HART and WAVE), advised against the use of hormone replacement therapy, showing negative results and even greater progression of atherosclerosis and increased adverse effects such as CVD, deep vein thrombosis, pulmonary embolism and stroke, not to mention the potential carcinogenic effect on the breast, ovaries, and endometrium.19,20 Furthermore, studies focused on elderly patients with MI and a difference in age of less than one year between women and men have shown that hospital mortality in women is higher than in men (40% and 25%, respectively), which leads us to conclude that the age factor alone does not explain a worse prognosis. Also, if age is associated with a higher prevalence of risk factors for cardiovascular and other disease, then this confers a greater early mortality in women with MI.21

Cardiovascular disease is characterized by multifactorial etiology. The increased coronary risk is mainly related to risk factors that increase with age. Aging, hypertension, dyslipidemia, diabetes, smoking, physical inactivity, obesity, and family history are important and reinforce each other. In our results, a history of hypertension and diabetes was associated significantly with female gender.

The prevalence of hypertension in the adult population is 28% and more women are affected from the fifth or sixth decades of life (52% vs. 48% in men).22 Its impact in the form of left ventricular hypertrophy is associated with an increased risk of cardiovascular events, conferring a worse prognosis in women than in men.16 Diabetes, especially type 2, is more prevalent in women than in men, particularly after 65 years of age, and is the single most potent cardiovascular risk factor for coronary heart disease. Its impact appears to be even higher than in men.23

We observed higher mortality associated with greater renal dysfunction and this association was significant on admission in women. Renal failure is a poor prognostic factor in patients suffering from an acute coronary event; it is estimated that one third of these patients present renal dysfunction on admission.24 The above factors probably contributed to the increased renal dysfunction in women in our study and the fact that women had more prior heart failure, higher Killip class on admission and more episodes of cardiac decompensation after discharge. We also observed lower EF values in women and an increased frequency of arrhythmias during hospitalization. Although women had fewer previous episodes of IHD than males, their prognosis was less favorable, as also seen in the BADAPIC registry.25

With regard to laboratory tests on admission, anemia, hyperglycemia, and elevated fibrinogen levels were associated with increased mortality in women; in the case of anemia, even after multivariate analysis. The inflammatory mechanism underlying vascular stress in acute coronary events appears to contribute to these laboratory abnormalities. Elevated inflammatory markers predict cardiovascular risk and inflammation may act not only by promoting atherogenesis but also by destabilizing vulnerable plaque. In a study by Arant et al.,26 anemia, defined as a hemoglobin level of less than 12 g/dl, was a predictor of cardiovascular events following an ACS during a follow-up of 3.3 years. In addition, various studies have noted a relationship between the occurrence and severity of hyperglycemia and increased morbidity and mortality in ACS, independently of previously diagnosed diabetes.27

Some studies have found an association, at least in part, between the poorer prognosis in women and gender bias observed in the therapeutic measures applied, especially in reperfusion therapy, whose benefit would be even higher because women are higher-risk patients.28 The CRUSADE study data demonstrate that although IHD in women continues to be associated with older age, as well as with a higher prevalence of diabetes and hypertension, the therapeutic approach continues to be less aggressive, with fewer coronary angiograms and heparin treatments.29 We did not find these differences in the group of patients with ST-segment elevation (62.8% of the sample), and there were no significant differences in fibrinolytic therapy and reperfusion with primary angioplasty, even in women who were more likely to benefit from these treatments.

We believe that all the risk factors known to be associated more closely with female gender may be responsible for their worse outcome. The significance of gender as such is diluted in multivariate analysis. The importance of classical variables as prognostic markers, which are independently associated with higher mortality (EF <50%, Killip class >1, renal dysfunction and anemia on admission) is increasing. Women have a high-risk stratification according to the GRACE score, suffer more adverse cardiovascular events, and have higher mortality, especially in the short term. We are aware that IHD in women is a major problem whose importance is greater than other conditions already known to be leading causes of mortality in women, such as breast cancer. However, we believe that before considering female gender per se an independent predictor of mortality and resigning ourselves to the existence of genetic differences that are not yet well known, we should first increase our efforts to include women in scientific studies and discussion forums rather than merely extrapolate research findings focused mostly on men. We should also promote the implementation of prevention campaigns because, although we deal with the risk factors of men, the prevalence of diabetes, hypertension, dyslipidemia, obesity, and smoking is still increasing in women.

Our work has several limitations: the sample size is small and therefore so is the number of deaths. A longer follow-up period would have provided more information, and it would also have been interesting to investigate the causes of mortality during follow-up.

The authors have no conflicts of interest to declare.