Gender-Related Differences in Patients Presenting with Suspected Acute Coronary Syndromes: Clinical Presentation, Biomarkers and Diagnosis

Acute coronary syndromes (ACS) are a major cause of morbidity and mortality in the Western world, both in men and women [1,2]. Patients with symptoms suggestive of ACS are common in the emergency setting, and assessment of these patients remains challenging due to a wide variety of underlying diseases and an often atypical symptom presentation, particularly in women [3,4]. Given the diagnostic and prognostic importance of a rapid identification of patients with ACS and of those in need for early coronary revascularization, patient triage at the emergency department is paramount, and is mainly based on clinical parameters, electrocardiography (ECG) changes and biomarker profiles [5,6,7,8,9].

In ACS patients, gender-related differences in presentation and outcomes have previously been reported [10,11,12], and besides observed disparities in baseline characteristics, associations between atypical symptoms including back pain, nausea and shortness of breath and female gender were identified [3,4,13]. Data on gender-related differences, however, are mainly based on the ACS patient population, and studies on unselected patients presenting to the emergency department with any signs and symptoms suggestive of ACS are scare, and have mostly been obtained in primary care or were restricted to chest pain syndromes [14,15,16,17]. Furthermore, information on final diagnoses and the proportion of patients undergoing urgent coronary angiography is often lacking. In the heterogeneous patient population presenting with suspected ACS, gender-related disparities in clinical characteristics, biomarker profiles and underlying diagnoses have not yet been fully elucidated. A more thorough characterization of this patient population may expand our understanding of gender-related differences in clinical presentation, and thereby improve patient triage and management in emergency care.

Thus, the aim of this study was to assess gender-related differences in clinical and biomarker profiles, along with the distribution of underlying diagnoses, in patients presenting with symptoms suggestive of ACS.

In the single-centre, prospective, observational MyRiAD (Myeloid Related Protein 8/14 in the Evaluation of Acute Chest Pain in the Emergency Department) study, consecutive patients who presented to the emergency department with any signs and symptoms suggestive of ACS and for whom conventional troponin T (c-cTnT) measurements were requested on clinical grounds, were included from July 2007 to April 2008 [18]. Inclusion criteria were any signs or symptoms suggestive of ACS including chest pain, epigastric pain, dyspnoea, hypotension, lightheadedness, cardiac arrest, palpitations, syncope and nausea as well as a consecutive request by the emergency physician to perform a troponin test to confirm or rule out myocardial ischaemia. Exclusion criteria were symptom onset >24 h, any trauma and any acute or chronic infection. Of 538 patients screened, 377 (70%) were included in the final analyses. The study was conducted according to the principles of the Declaration of Helsinki, and approval to conduct the study was granted by the institutional ethics committee of the University Hospital Zurich. Written informed consent to participate was obtained from all patients.

As previously described [18], patients were assessed at the emergency department, and referral for coronary angiography was left to the discretion of the treating physician, based on the symptoms presented, ischaemic ECG changes and routine biomarker analyses including c-cTnT, myoglobin, creatine kinase (CK), creatine kinase-myocardial band (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimers. Risk assessment was complemented by calculation of the TIMI risk score for unstable angina/non-ST-elevation myocardial infarction or for ST-elevation myocardial infarction, respectively [19,20]. In patients presenting with chest pain, pain intensity as assessed on a pain scale of 1-10 was recorded. Data on time of symptom onset were collected at the emergency department, together with patient characteristics, and the time point of blood harvesting was registered.

Laboratory analyses were performed as previously described [18]. In brief, routine markers including c-cTnT, myoglobin, CK, CK-MB and NT-proBNP were analyzed from heparin plasma with a maximal inter-assay variation of 3.7, 2.5, 1.8, 2.8 and 4.4%, and a detection limit of 10.0 ng/l, 21.0 µg/l, 7.0 U/l, 3.0 U/l and 5.0 ng/l, respectively. The cut-off value for positive c-cTnT measurements was 0.10 µg/l. D-dimers were determined from citrate plasma (Roche Modular Analytics System, Roche Diagnostics, Rotkreuz, Switzerland). Study-specific analyses for the MyRiAD study were described previously; they included the levels of myeloid-related protein 8/14 (MRP 8/14), heart-type fatty acid-binding protein (H-FABP), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), myeloperoxidase (MPO), pregnancy-associated plasma protein A (PAPP-A), insulin-like growth factor 1 (IGF-1), fibrinogen and high-sensitivity cardiac troponin (hs-cTnT) [18]. IL-6 and hs-CRP were determined from heparin plasma, and IGF-1 from serum (Immulite 2000 chemiluminescence analyser) using commercial assays from Siemens Healthcare Diagnostics GmbH (Deerfield, Ill., USA) with a maximal inter-assay variation of 2.7, 3.1 and 4.5%, and a detection limit of 1.5 ng/l, 0.3 mg/l and 3.0 µg/l, respectively. PAPP-A was measured immunochemically by time-resolved amplified cryptate emission (TRACE) from serum (Kryptor analyzer, Brahms AG, Hennigsdorf, Germany), with a maximal inter-assay variation of 4.7% and a limit of detection of 0.004 U/l. Fibrinogen was determined on a CA7000 analyser (Siemens Healthcare Diagnostics GmbH) using commercial assays with a maximal inter-assay variation of 4.8%. MRP 8/14 was measured from serum using dedicated assays (Bühlmann Laboratories, Schönenbuch, Switzerland) with a limit of detection of 0.4 µg/ml and a cut-off value of 4.7 µg/ml. H-FABP levels were analyzed from serum using specific assays (Hycult Biotechnology, Uden, The Netherlands) with a detection limit of 0.1 ng/ml and a cut-off value of 5 ng/ml. Samples were tested in double determination, and if the values differed by >10%, the measurements were repeated, unless absorbance was <0.1 or both concentration values were within the normal range. hs-cTnT was measured from serum utilizing the Elecsys assay (Roche Diagnostics, Mannheim, Germany) with a detection limit of 5 pg/ml and a cut-off value of 13 pg/ml, and MPO was measured from heparin plasma with assays from Immundiagnostik (Bensheim, Germany) with a detection limit of 1.6 ng/ml.

Continuous variables are presented as mean ± SD or median and interquartile range (IQR), and categorical variables given as frequencies and percentages. Normal distribution was tested by the Shapiro-Wilk test. Continuous variables were tested for differences with the Mann-Whitney U test and categorical variables by the Pearson χ² test or the Fisher exact test as appropriate. A stepwise logistic regression analysis by the backward Wald method including all variables with p values <0.20 in univariate analysis was used to determine independent predictors of referral for coronary angiography in multivariate analysis. All tests were 2-tailed, and a p value of <0.05 was considered statistically significant. All statistical analyses were performed using IBM-SPSS version 21 (IBM Corp.) for Windows.

Out of 377 consecutive patients presenting with suspected ACS to the emergency department, 102 (27%) were women. Women were older than men (p = 0.004), and were significantly overrepresented in the elderly patient group, i.e. >75 years (p = 0.01; fig. 1). Women had a lower body mass index (p = 0.007) and were less frequently current smokers (p < 0.001). Other baseline cardiovascular risk factors including diabetes, dyslipidemia, hypertension and a family history of coronary artery disease did not differ between genders. Known coronary artery and peripheral vascular diseases were less frequently observed in female than in male patients (p < 0.05), while the prevalence of cerebrovascular disease was similar (table 1). Estimated glomerular filtration rate was lower in females than in males (p < 0.001; table 1). Medication at presentation including antiplatelet therapy, antihypertensive agents and statins did not differ between genders (table 2).

Compared with men, TIMI risk scores were lower in women (p = 0.004; fig. 2). Of the female patients, 71, 22 and 7% were in the TIMI risk score groups 0-2, 3-5 and 6-8, respectively. Of the male patients, 56, 40 and 4% were in the TIMI risk score groups 0-2, 3-5 and 6-8, respectively.

Mean pre-hospital time delay was 404 ± 375 min for women and 381 ± 317 min for men, respectively (p = 0.59). Most patients presented during hours of daytime (06.00-18.00). Women presented more often during the night hours (18.00-06.00), and men more often during the day (06.00-18.00, p = 0.02; fig. 3). While chest pain was equally reported in both female and male patients (86 vs. 89%; p = 0.59), nausea tended to be more frequent in women (31 vs. 24%, p = 0.08). Vertigo (24 vs. 27%; p = 0.30) and syncope (8 vs. 8%; p = 1.0) were equally reported. In patients with chest pain and documented information on pain intensity (n = 317), pain intensity was equally reported in both women and men (p = 0.97; fig. 4).

c-cTnT at admission was positive in 8% of female and in 14% of male patients (p = 0.16), and hs-cTnT in 32% of female and 50% of male patients, respectively (p = 0.002). Besides CK-MB, all cardiac biomarkers were lower in females than in males (table 3). Out of the 7 inflammatory biomarkers measured, MRP 8/14 and PAPP-A were significantly lower in females than in males, while other markers did not differ between genders (table 3). Comparing hs-cTnT-positive and hs-cTnT-negative patients, besides IGF-1, all of the inflammatory biomarkers including MRP 8/14 and PAPP-A were higher in patients with elevated troponin levels (p < 0.001).

Of the patients presenting to the emergency department with suspected ACS, the initial diagnosis of ACS was made in 31/102 (30%) female and in 141/275 (51%) male patients. Men presented more often with ST elevations (20%; n = 56) than women (13%; n = 13; p = 0.05). Fifty percent (n = 136) of male and 28% (n = 29) of female patients underwent coronary angiography (p < 0.001). Referral for coronary angiography was similar in younger (≤65 years) and elderly (>65 years) patients (43 vs. 45%; p = 0.67). Patients with known coronary artery disease (p < 0.001), ≥3 cardiovascular risk factors (p < 0.001) and ≥2 anginal episodes within the last 24 h (p < 0.001) were more frequently referred for invasive assessment, along with troponin-positive patients (p < 0.001) and patients with ST-segment changes (p < 0.001).

In patients referred for coronary angiography, subsequent coronary revascularization was performed in 18 (19%) women and 109 (40%) men (p < 0.001). Percutaneous coronary revascularization was performed in 18 (18%) female and in 105 (38%) male patients, and coronary artery bypass grafting within 14 days in 4 (1%) male patients, respectively (table 4). Three patients diagnosed with coronary artery disease were treated medically without any coronary revascularization. Two patients (1 female and 1 male) were diagnosed as having Takotsubo cardiomyopathy. One male patient with ST-elevations died before coronary angiography could be performed. Hence, 137 (36%) patients were finally diagnosed with ACS, i.e. 20 (20%) female and 117 (43%) male patients (p < 0.001; table 4).

The initial diagnosis of arrhythmia was more frequently made for females (n = 14, 14%) than for males (n = 18, 7%, p = 0.04). Hypertension tended to be more frequent in women (n = 9, 9%) than in men (n = 11, 4%), albeit without reaching statistical significance (p = 0.07). Musculoskeletal chest pain [15 females (15%) vs. 35 males (13%); p = 0.61] and ‘unspecific symptoms' were diagnosed equally in both genders [14 females (14%) vs. 33 males (12%); p = 0.73]. Final diagnoses varied significantly among gender (p = 0.03; fig. 5). Coronary artery disease was less often diagnosed in women than in men (p < 0.001), while hypertension (p = 0.12), arrhythmias (p = 0.18), ‘unspecific symptoms' (p = 0.16), musculoskeletal chest pain (p = 0.51), syncope (p = 0.26) and gastrointestinal diseases (p = 0.54) were equally reported.

In the low-risk group (TIMI risk score ≤2), 17% of female and 28% of male patients were referred for coronary angiography (p = 0.07), in the intermediate risk group (TIMI risk scores between 3 and 5), percentages reached 48 and 78% (p = 0.02), and in the high-risk group (TIMI risk score ≥6), 86 and 100% (p = 0.39), respectively. In multivariate regression analysis, the association between female gender and referral for coronary angiography remained significant when controlling for age, chest pain, positive c-cTnT, TIMI risk score, hypertension and dyslipidemia (table 5). While in male patients, chest pain (p = 0.005), positive c-cTnT (p = 0.04) and TIMI risk score (p < 0.001) were independent predictors of referral for coronary angiography, in female patients, this applied only to the TIMI risk score (p = 0.02). Including patients with positive hs-cTnT only, female gender remained an independent predictor of lower referral for coronary angiography (HR 0.33, 95% CI 0.12-0.94, p = 0.04) in multivariate analysis.

This study demonstrates that in patients with suspected ACS, women were less likely to have cardiovascular comorbidities, presented with different biomarker profiles and had a different diagnostic spectrum. Women were less often referred for coronary angiography, and were mostly diagnosed with ‘unspecific symptoms'. While symptom duration was similar between genders, a circadian difference with regard to the time of presentation to the emergency department was observed, with women presenting predominantly during the night hours.

Cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, CK and NT-proBNP were lower in women than in men, consistent with the lower rate of ACS in women. The finding that all inflammatory biomarkers besides IGF-1 were increased in patients with positive hs-cTnT levels, but only MRP 8/14 and PAPP-A were lower in women in agreement with a lower ACS rate, points towards gender-related differences in the regulation of inflammatory biomarkers.

Similar proportions of female patients have previously been reported in emergency department studies enrolling chest pain patients [14,21], while in primary care, the proportion of women tended to be higher [15,16], mainly due to the lower-risk patient population encountered in outpatient care. In line with data on chest pain patients [21], most patients presented during the day. The higher percentage of women presenting during night hours differs from another emergency department-based study that reported a similar circadian pattern among chest pain patients irrespective of gender [21 ]; this may, at least in part, have been attributed to variable patient characteristics, inclusion criteria and study designs.

Referral for coronary angiography increased with increasing TIMI risk scores, and hence, clinical decision-making seems to be influenced by a comprehensive analysis of different cardiovascular risk factors, along with cardiac biomarkers and ECG changes. Age per se does not seem to explain differences in referral rate for coronary angiography in different TIMI risk score groups, as referral for invasive assessment did not differ among younger and elderly patients, along with an HR for age of 0.97 in multivariate regression analysis.

Women were less often referred for coronary angiography and less often diagnosed with ACS than men. This observation may indeed be consistent with lower-risk baseline characteristics, also reflected by the lower TIMI risk score and cardiac biomarker levels observed in women. However, female gender remained independently associated with a lower referral for coronary angiography after adjustment for different cardiovascular risk profiles in multivariate analysis. This finding suggests some gender bias, in particular, as presenting complaints and pain intensities were equally reported in female and male patients, and gender differences with regard to false-negative diagnoses can rarely be assessed in observational studies. In addition, while no gender differences with regard to referral for coronary angiography were observed in the high-risk group, less women were referred for coronary angiography in the intermediate risk group, and a similar trend was observed in the low-risk group; this finding suggests that gender-related disparities in clinical decision-making may vary between different risk groups. Consistent with this interpretation, it has previously been suggested that differences in presentation and clinical course alone cannot explain gender differences observed in the frequency of referrals for coronary angiography in patients with suspected ACS [17]. However, the study design precludes the conclusion that more women should be referred for coronary angiography to diagnose coronary artery disease and to improve outcomes in patients presenting with suspected ACS, particularly as concerns were raised in patients with non-ST-elevation myocardial infarction in terms of increased mortality rates and bleeding complications in women when routine invasive strategies were applied [22]. Large-scale clinical studies are needed to assess the role of invasive and non-invasive diagnostic modalities, including exercise ECG, myocardial perfusion single-photon emission computed tomography and coronary computed tomography as well as their impact on outcomes.

In this study, women were discharged most frequently with ‘unspecific symptoms' followed by coronary artery disease and musculoskeletal chest pain. Data on the diagnostic spectrum in these patients are scarce. In primary care, besides coronary artery disease, chest wall syndromes and psychogenic disorders represented the most frequently observed diagnoses [16].

Baseline characteristics differed significantly between genders, with older age, and a lower prevalence of coronary and peripheral artery disease, along with a lower rate of current smokers, in women. While most studies including patients with confirmed or suspected ACS report comparable gender-related differences with regard to known coronary artery disease, age and smoking history [11,14], conflicting results have been observed regarding other baseline cardiovascular risk factors [11,14,15]. Differences between studies may mainly be due to different inclusion criteria, in particular, whether patients with confirmed or suspected ACS were included, and also due to a lower-risk patient population in primary care. Despite an increased prevalence of coronary artery and peripheral vascular disease in men, no significant differences were found with regard to the use of antiplatelet therapy at baseline. Cerebrovascular disease with a prevalence of 12% in women and 7% in men might, at least in part, have contributed to this observation, but further studies are needed to elucidate these findings. The equal percentage of patients on anti-hypertensive agents and statins may be explained by the comparable prevalence of hypertension and dyslipidemia in both women and men.

In this study, symptom duration was calculated as the time period from reported symptom onset to the beginning of treatment in the emergency department, reflected by the point in time of blood harvesting, and was found to be similar in women and men. Consistent findings were reported in primary care, where pre-hospital time delay from call for help until general practitioner consultation did not differ between genders, while doctor-related delay was longer for women [15]. As data on the time point of the call for help were not available, symptom duration could not be further subdivided. In line with other studies on patients with suspected ACS [15], patients with symptoms lasting >24 h were excluded to allow for an assessment of patients presenting with acute complaints. Hence, these findings cannot be generalized to patients with a longer duration of symptoms.

Most research in this field is based on chief complaints, mainly chest pain, but as women are less likely to present with typical symptoms [23], our study included patients with suspected ACS irrespective of the leading complaint, aiming at an inclusion of a wider, less specific patient population. Interestingly, in patients reporting chest pain, pain intensity did not differ between genders, despite the wide variety of underlying diseases. In studies on acute myocardial infarction, however, higher pain intensity scores have been reported by men [24], while in studies enrolling patients with angina, acute myocardial infarction or chest pain, higher pain intensity is reported mostly by women [4,25,26]. Hence, gender disparities in pain perception seem to vary according to the underlying disease.

A limitation of this study is its single center design. As no information was available on the use of non-invasive assessment of coronary artery disease, a comparison between invasive and non-invasive modalities was precluded. Further, we cannot exclude completely that there might be some gender bias with regard to the request of troponin measurements. However, as consecutive patients with suspected ACS were included, the study cohort represents a heterogeneous population of patients that was not limited to chest pain syndromes. The high proportion of patients referred for coronary angiography allowed for confirming or excluding the diagnosis of coronary artery disease by the diagnostic gold standard and not solely based on clinical judgment.

In conclusion, women represented a quarter of patients with suspected ACS, were mostly diagnosed with ‘unspecific symptoms', and were less often diagnosed with ACS and referred for urgent coronary angiography. As the association between female gender and lower referral for coronary angiography remained significant after adjustment for cardiovascular risk factors, some gender bias cannot completely be excluded. In clinical practice, physicians need to take into account gender disparities, aiming at an improved selection of diagnostic and therapeutic strategies for both women and men. In addition, further studies are needed to elucidate gender differences with regard to the pathophysiological mechanisms, risk stratification and treatment responses in patients with suspected ACS.

B.E.S. was partially supported by grants from the Swiss National Research Foundation (Special Programme University Medicine: No. 33CM30-1241112/1 and No. 3100-068118.02/1). K.Y. was supported by the Zürich Heart House - Foundation for Cardiovascular Research. T.F.L. received research grants and consultant fees from Amgen, AstraZeneca, Biosensor International, Biotronik, Eli Lilly, Medtronic and St. Jude Medical. Biomarker analyses were partially been supported by Roche Diagnostics GmbH.

B.E.S. and C.G. contributed equally to this work.