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Alexandru Ceamburu1, Razvan Constantin Serban1, Ioana Sus1,2, Eva Katalin Lakatos1,2, Zoltan Demjen1, Paul Ciprian Fisca1,2, Laszlo Hadadi1,2, Cristina Somkereki1,2, Alina Scridon2

1 Emergency Institute for Cardiovascular Diseases and Transplantation, Targu Mures, Romania
2 University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania

Abstract: Objectives – Previous studies reported outcome differences following ST-segment elevation myocardial in-farction (STEMI) between genders. We aimed to evaluate gender-related differences in in-hospital post-STEMI outcomes and to identify the substrate of such differences, if present. Methods – Cardiovascular risk factors, hemodynamic, electro-graphic, echocardiographic, angiographic status, and blood parameters at hospital admission were retrospectively assessed for 672 patients presented with STEMI treated by primary percutaneous coronary intervention. In-hospital post-STEMI outcomes were evaluated. All parameters were compared between female and male patients. Results – Among all STEMI patients, 30.3% were females. Compared to male patients, women were older and more often had a history of heart failure (p≤0.0001). They were also more frequently hypertensive (p = 0.02) and diabetic (p< 0.001). Post-STEMI, female patients presented more often cardiogen shock (p = 0.01) and required more frequently diuretic therapy (p< 0.001). In-hospital mortality was also higher in female than in male patients (p< 0.01). However, after adjusting for the potential confounders, female gender did not remain an independent predictor of in-hospital mortality (p=0.16). Conclusions – Female patients had higher rates of post-STEMI complications and higher in-hospital mortality. However, these gender-related differences appear to be fully explained by the higher cardiovascular risk factors burden in females. Keywords: female, gender, outcomes, risk factors, ST-segment elevation myocardial infarction.

BACKGROUND
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. According to the World Health Organization, an estimated 17.9 million people died from CVDs in 20161. Among CVDs, acute myocardial infarction (AMI) represents one of the most important causes of morbidity and mortality. In Romania, AMI was responsible for 84.2 deaths per 100.000 inhabitants in 20162. Several studies have reported higher in-hospital mortality in women compared with men pre-senting with ST-segment elevation myocardial infarc-tion (STEMI)3-6. The reason for this between-gender difference in post-STEMI outcomes remains unclear. Several hypotheses have been proposed to explain the higher risk of mortality in women, including more seri-ous co-morbidity, longer time to revascularization, or less likelihood to receive guideline-recommended in-vasive procedures4,6. However, most of these studies were performed in the pre-percutaneous coronary intervention (PCI), or even in the prethrombolytic era. Therefore, we aimed to identify the most rele-vant gender-related differences regarding in-hospital post-STEMI outcomes in patients treated by primary PCI and, if present, to identify the substrate of such differences.

MATERIAL AND METHODS
Study population
The study included consecutive patients treated by primary PCI for STEMI in our center between January 2011 and December 2016. The study complied with the Declaration of Helsinki; the research protocol was approved by the local institutional Ethics Committee. Patients enrolled were older than 18 years, with STEMI (type I) hospital admission, treated by primary PCI within the fi rst 12h after symptoms onset or 12h to 24h after symptoms onset if they presented signs of persistent ischemia. Patients who required throm-bolytic treatment prior to PCI were excluded. Pati-ents were also excluded if they presented left bundle branch block or paced rhythm, or if they had a history of coronary artery by-pass graft surgery.

Baseline clinical characteristics
Variables including demographic and cardiovascular risk factors (age, smoking status, arterial hypertensi-on, diabetes mellitus, obesity, heart failure, chronic kidney disease, chronic respiratory diseases, previo-us MI) and treatment history (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhi-bitors and/or angiotensin II receptor blockers, statins) were retrospectively collected and analyzed. Chronic kidney disease was defined as an estimated glomeru-lar filtration rate < 60 ml/min/1.73 m2 on admission according to the Cockroft-Gault equation, as descri-bed previously7. Data regarding clinical presentation (Killip class), hemodynamic status (blood pressure, heart rate, left ventricular ejection fraction), time from symptoms onset to presentation, and electrocar-diographic parameters (sum of ST-segment elevation and ECG localization of STEMI) at hospital admission were also assessed. Angiographic parameters, inclu-ding the SYNergy between PCI with TAXUS™ and Cardiac Surgery (SYNTAX I) score, pre- and post-PCI Thrombolysis in Myocardial Infarction (TIMI) flow, thrombus aspiration and glycoprotein IIb/IIIa inhibitors usage, and PCI-related complications such as iatroge-nic coronary artery dissection, coronary perforation, angiographic no-reflow, angiographically visible distal embolization, and acute intra-PCI occlusion were also evaluated. All data were compared between female and male patients.

In-hospital post-ST-segment elevation myocardial infarction outcomes
Patients data were evaluated for in-hospital post-STEMI mortality and in-hospital outcomes and compli-cations, including inotropic and diuretics usage, cardi-ogenic shock, and cardiac arrest. Kidney dysfunction, length of hospital stay, and all-cause mortality were also analyzed. All parameters were compared betwe-en female and male patients.

Statistics
Continuous variables are presented as median and interquartile range. Categorical data are summari-zed using frequencies and percentages. Fisher’s test was used for comparison of categorical data and the Mann-Whitney U test was applied for comparison of continuous variables between the two groups. Multi-ple logistic regression analysis was used to assess the ability of female gender to independently predict in-hospital post-STEMI mortality; the model included all clinical and cardiovascular risk factors that differed sig-nificantly between male and female patients. All tests were two-sided and a p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using the GraphPad Prism 8 software (GraphPad Software, San Diego, CA).

RESULTS
Patients’ characteristics according to gender Out of the total of 672 patients included in the study, 204 (30.3%) patients were of female gender. Compa-red to male patients, female patients with STEMI (Ta-ble 1) were older, were more likely to have a history of arterial hypertension, diabetes mellitus, heart fai-lure, and chronic kidney disease, but they were less likely to be active smokers (all p< 0.05). Female pa-tients also displayed longer time from symptoms on-set to presentation than their male counterparts (p< 0.01). In agreement with their higher disease burden, female patients were also more likely to be on ongoing beta-blocker, calcium channel blocker, renin-angioten-sin-aldosterone system blocker, and statin therapy (all p< 0.05).

Clinical and hemodynamic status at admission according to gender
There was no significant difference between males and females regarding the Killip class on admission. Com-pared to male patients, female patients with STEMI had higher heart rates on admission (p = 0.01), but presented similar blood pressure with their male counterparts (both p >0.05) (Table 2).

Electrocardiographic and angiographic parameters and percutaneous coronary intervention-related complications according to gender
There were no significant between-groups differences regarding the sum of ST-segment elevation (p = 0.19) (Table 3). Anterior STEMI was also similarly common in male and female patients (p = 0.86). Also, there was no signifi cant difference between the two groups re-garding the angiographic parameters or the occurren-ce of PCI-related complications (all p >0.05).

In-hospital evolution according to gender Female patients presented more often cardio-gen shock, kidney dysfunction, and required more frequently diuretic therapy (all p< 0.05) (Table 4). Cardiac arrest was also more common in female than in male patients (p = 0.03). Similarly, length of hospi-tal stay was higher in female compared to male pati-ents (p< 0.01) and female patients presented higher in-hospital mortality compared to their male counter-parts (OR 2.56 [95%CI 1.34-4.92], p< 0.01). However, when corrected for the potential confounders, female gender did not prove to be an independent predictor of in-hospital mortality (p = 0.16) (Table 5).

DISCUSSION
Despite the major advances made in STEMI management over the past decades, particularly with the widespread usage of primary PCI, mortality rates re-main considerable, with an overall rate of in-hospital STEMI-related mortality of 5.8% in the present study. These results are in line with those from previous studies conducted in patients treated by primary PCI for STEMI8,9, including with the data from the national ROmanian ST-Elevation Myocardial Infarction registry (RO-STEMI)10.
Although female patients appear to experience STEMI less frequently than males, females often display worse prognosis, more in-hospital post-STEMI complications, and higher short- and long-term mortality rates following STEMI3-6,11-14. In accordance with these data, female patients represented less than one third of the total population of STEMI patients included in the present study. They also had higher rate of post-STEMI complications and higher in-hospital mortality rates compared to males.
Nevertheless, the contribution of female gender itself to the higher post-STEMI mortality observed in numerous studies, including ours, remains contro-versial. Although female gender has generally been identified as a predictor of post-STEMI mortality in univariate analysis, its ability to independently predict in-hospital post-STEMI mortality remains unclear. In a meta-analysis including 35 studies on patients with STEMI treated by PCI, female gender was identified as an independent predictor of in-hospital and long-term mortality, even after multivariate adjustment.15 Howe-ver, whereas some studies identified female gender as an independent predictor of in-hospital mortality13,16, in others, after adjusting for age, cardiovascular risk factors, or various comorbidities, the association between female gender and increased post-STEMI mortality was either considerably reduced or even en-tirely lost17. These inter-studies differences are most likely due to the different inclusion criteria, different size of the study populations, and different treatment strategies used in the various studies15,17,18. Furthermo-re, many of these data originate from the thrombolytic era, or they were obtained in unselected populations with myocardial infarction both with and without ST-segment elevation or even in patients with the enti-re spectrum of acute coronary syndromes3,4,6,14,16. Meanwhile, few studies have addressed this issue in the specific population of STEMI patients treated by primary PCI13,19.
In line with these data13,19, the present study recor-ded females as having worse post-STEMI outcomes and higher in-hospital mortality rates compared to their male counterparts. Females presented more of-ten cardiogenic shock and required more frequently diuretic therapy; they had more often post-STEMI kid-ney dysfunction, and had longer hospital stay. The ten-dency of women to develop fewer collateral vessels has been proposed to explain the increased risk of post-AMI hemodynamic complications observed in females20. Cardiogenic shock, the most frequent ca-use of death among patients hospitalized with AMI, has also been associated with increased comorbidities burden21, and female gender has been identified as a strong predictor of mortality among patients with AMI and cardiogenic shock12.

More importantly, the present study shows that the increased post-STEMI in-hospital mortality seen in women is not related to the female gender per se, but rather to the higher cardiovascular risk factors burden displayed by this population. Compared to males, female patients with STEMI were older, were more frequently hypertensive and diabetic, and had more often a history of heart failure and chronic kid-ney disease. Meanwhile, females were less likely than men to be active smokers, and indicators of infarct size and severity, such as maximum ST-segment ele-vation, myocardial enzymes levels, and left ventricular ejection fraction on admission, were similar between the two genders. These data are in line with those from larger previous studies, which also showed wo-men with STEMI to be elder and to have more often arterial hypertension, diabetes mellitus, heart failure, and chronic kidney disease than male patients3,4,14,22. This clinical setting is not surprising, given that arterial hypertension has been shown to be more common in females than in males after the age of 55 years23. Mo-reover, registry data have indicated an increased like-lihood of hypertensive patients with AMI of being ol-der and having higher prevalence of comorbidities3-5,14. At its turn, the higher prevalence of cardiovascular conditions such as arterial hypertension and diabetes mellitus in the post-menopause increases the risk of chronic kidney disease and promotes acceleration of atherosclerosis, contributing to the increased risk of coronary events in females with advancing age24-26. In addition, in accordance with previous studies3,5, time from symptoms onset to presentation was longer in females than in their male peers. Several hypothesis have been proposed to explain the delayed presentati-on to hospital of female patients with STEMI, including the more advanced age and the often atypical symp-toms in females3,5,27. The more advanced age and the more prevalent diabetes mellitus could further affect the way in which female patients with STEMI perceive their symptoms and could delay their presentation to hospital27.
In the present study, similarly to female gender, ne-ither the time from symptoms onset to presentation, nor a history of diabetes or chronic kidney disease, were independent predictors of in-hospital post-STEMI mortality in the multiple regression analysis. In fact, the only independent predictors of mortality that could explain the higher risk of mortality in females were advanced age (>58 years) and history of heart failure, whereas the presence of arterial hypertension was associated with lower risk of in-hospital morta-lity. Increased risk of mortality among women with STEMI has also been linked to females’ more advan-ced age and more complex comorbidities in previo-us studies. In a recent study performed in 19 Serbi-an centers, the authors reported signifi cantly higher post-STEMI in-hospital mortality rates in female compared to male patients11. In the overall study cohort, mortality rates were shown to increase with advan-cing age11. Meanwhile, a diagnosis of arterial hyperten-sion appears to paradoxically decrease mortality in the post-AMI period. The more frequent prescription of angiotensin converting enzyme inhibitors or angioten-sin II receptor blockers in female compared to male patients (36.7% versus 25.6%), related to the higher prevalence of hypertension among females, may expla-in, at least partially, this reduced-mortality paradox in hypertensive patients with STEMI28,29.

Potential limitations
A number of potential limitations to our study are worth considering. First, this was an observational, re-trospective, single-center study. Thus, our results sho-uld be regarded as hypothesis-generating and should ideally be validated in larger, prospective, multicenter studies. Second, in the present study, mortality was only assessed during hospital stay; long-term post-STEMI mortality was not evaluated. Thus, our results should not be extrapolated to long-term outcomes.

CONCLUSIONS
Female patients represented less than one third of the total study population. They presented higher inci-dence of STEMI-related complications, longer hospital stay, and higher in-hospital mortality rates than their male counterparts. However, after adjusting for the potential confounders, female gender did not rema-in an independent predictor of in-hospital mortality. The excess in mortality observed in female patients with STEMI treated by primary PCI appears to be due not to the female gender itself, but rather to fema-les’ more important cardiovascular risk factors burden (i.e., more advanced age and higher prevalence of heart failure).
Acknowledgment: This work was supported by the University of Medicine and Pharmacy of Targu Mures (research grant number 15609/9/29.12.2017). The first two authors contributed equally to this paper and both should be viewed as first authors.

Conflict of interest: none declared.

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