US Pharm. 2022;47(9):HS-2-HS-10.
ABSTRACT: Chest pain is a common presenting symptom among emergency department (ED) patients, reported as the second most common reason for visiting the ED in the United States. Though many symptoms of chest pain related to acute coronary syndrome are similar among men and women, differences in underlying pathophysiology, risk factors, and the coexistence of atypical symptoms predispose women to potential treatment delays and poor outcomes. Women experience increased rates of mortality following an acute myocardial infarction; however, through development of strategies to increase recognition of symptoms, minimize prehospital delays, and increase the rate of medical treatment, we may impact these detrimental clinical outcomes.
Chest pain is a common presenting symptom among emergency department (ED) patients, reported as the second most common reason for visiting the ED in the United States.1 Coronary heart disease (CHD) is estimated to be present in 7.2% of the U.S. adult population, with an annual incidence of acute coronary syndrome (ACS) and myocardial infarction greater than 800,000 events per year.2 Death attributed to CHD occurred in over 360,000 persons in the U.S. in 2019, and approximately 35% of people who experience a coronary event in a given year will die.2
Distinguishing noncardiac and cardiac causes of chest pain is essential to initiate appropriate treatment and avoid detrimental outcomes. Obtaining a detailed history and physical upon presentation to the ED is imperative in the initial evaluation of chest pain and the ability to differentiate ACS or an acute myocardial infarction (AMI) from less severe cardiac or noncardiac etiologies. Typical symptoms in a patient presenting with AMI are often described as chest pain or discomfort with pressure, tightness, and squeezing, which may radiate to jaw, neck, shoulders, arm, or back.3 Cardiac causes, typically referred to as anginal symptoms, include retrosternal chest discomfort with pain, heaviness, tightness, constriction, and squeezing. Conversely, sharp chest pain that increases with inspiration or lying supine is likely unrelated to a coronary event. Anginal symptoms may localize to the substernal region or radiate to the left arm, neck, or jaw. However, pain that radiates to below the umbilicus or hips is likely due to noncardiac etiologies.
ACS includes unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Each of these conditions are associated with acute myocardial ischemia or infarction due to reductions in blood flow to coronary distributions. In patients experiencing chest pain consistent with an ACS, guideline recommendations include an evaluation of a 12-lead electrocardiogram (ECG) to identify changes consistent with coronary ischemia.4,5 Additionally, serial cardiac enzymes including troponin I should be obtained as these are considered highly sensitive and specific for myocardial ischemia.4,5 Patients with non-ST-elevation ACS with refractory angina or hemodynamic or electrocardiographic instability are considered candidates for an urgent invasive strategy, including coronary revascularization.4 Patients identified as experiencing STEMI should undergo immediate reperfusion, including either primary percutaneous coronary intervention (PCI) or fibrinolytic therapy.5 Medical therapies including beta-blockers, ACE inhibitors, antiplatelet agents, and HMG-CoA reductase inhibitors are recommended following the acute management of patients experiencing ACS.4
Discordance exists between men and women in the pathophysiology, risk factors, and presentation of cardiac-related chest pain that give rise to significant differences in management and clinical outcomes among women experiencing ACS. Significant variation exists in the initial assessment, pharmacologic intervention, and revascularization therapies among populations presenting with chest pain. Among the U.S. population, approximately 8.3% of men and 6.2% of women have a diagnosis of CHD. Women constitute about 42% of all patients presenting with a new or recurrent AMI, although women hospitalized for AMI are more likely than males to seek medical care before their hospitalization.2,6
Differences in the rates of hospitalization secondary to AMI have been reported between males and females. Notably, AMI admissions among younger patients defined as aged 35 to 54 years have increased significantly, largely driven by increased rates among younger female patients. Female patients admitted with AMI were more often black and had a history of smoking, hypertension, and diabetes mellitus. Among young patients admitted with an AMI, female patients were less likely to receive multiple guideline-directed medical therapies or undergo invasive coronary angiography or revascularization. In fact, over a 20-year period, women had a 21% lower probability of receiving revascularization compared with men; although with these differences in overall management, 1-year all-cause mortality was similar between males and females.7 In-hospital mortality among women presenting with either STEMI (7.4% vs. 4.6%) or NSTEMI (4.8% vs. 3.9%) was found to be higher compared with males. Females were noted to have prolonged door-to-balloon times among patients undergoing coronary angioplasty and are less likely to receive an early invasive strategy, possibly contributing to these poor outcomes relative to males.8,9
This article aims to discuss key gender-specific differences, including risk factors, pathophysiology, and clinical presentation among women presenting with ACS. Identification of these key determinations by members of the healthcare team will hopefully lead to early diagnosis and treatment and improvement of clinical outcomes for this population.
Males and females share the traditional cardiovascular risk factors, such as cigarette smoking, obesity, hypertension, dyslipidemia, and diabetes mellitus; however, studies suggest that certain risk factors have a more pronounced effect on long-term cardiovascular risk in women compared with men.10,11 Most notably, the presence of hypertension and diabetes increases a patient’s risk for AMI to a greater extent in female patients than in male patients. Hypertension has a population-attributable risk of 36% in women compared with 20% in men. The population-attributable risk for diabetes is 19% and 10% in women and men, respectively, indicating significantly greater contributions for these traditional risk factors for ACS in women.11
In addition to the aforementioned traditional risk factors, other female-specific risk factors include early menopause, pregnancy complications, and inflammatory diseases.10,12,13 A decrease of estrogen levels is correlated with an increased cardiovascular risk in postmenopausal women. Estrogen’s cardioprotective effects are thought to be related to effects on lipids, vasodilation and ability to modulate blood pressure, and anti-inflammatory effects.12,13 Pregnancy complications including preeclampsia, gestational hypertension, preterm delivery, and gestational diabetes carry a higher cardiovascular risk necessitating close monitoring.13
The underlying pathophysiologic mechanisms for a patient’s cardiac chest pain can be broadly distinguished into two categories: obstructive and nonobstructive coronary artery diseasev(CAD). Obstructive CAD and associated chest pain are a result of atherosclerotic plaque formation, which is further delineated into stable angina, chest pain that is predictable and often relieved with rest, and ACS or AMI, chest pain that results from plaque rupture, and subsequent occlusion of the coronary arteries.14 ACS is considered a medical emergency, which is why prompt diagnosis is key to management of patients at risk.
Atherosclerotic plaque rupture resulting in thrombus formation and coronary occlusion is the most common underlying cause leading to an AMI.14 Complete or partial occlusion of the coronary arteries leads to oxygen supply and demand mismatch. This results in myocardial ischemia, subsequently contributing to the typical symptoms of angina that are often reported in the setting of an AMI. Another potential cause of AMI is plaque erosion, which is more commonly found in women.14,15 Plaque erosion refers to the disruption in the endothelial surface that covers the plaque where a thrombus can form, obstructing blood flow through the coronary arteries. Along with chest pain evaluation and an assessment of a patient’s ECG and cardiac biomarkers, the pathophysiologic cause and extent of obstruction are confirmed during coronary angiography.
Plaque rupture and plaque erosion describe underlying mechanisms related to obstructive causes of AMI; however, upon evaluation of cardiac chest pain and ischemia, significantly fewer women are found to have significant obstructive CAD, defined as 70% or greater stenosis in major coronary arteries, compared with men.16 Additionally, in an evaluation of women undergoing coronary angiography, 62% of patients were found to have nonobstructive CAD or less than 50% stenosis.17 This difference highlights the potential contribution of other pathophysiologic mechanisms, such as nonobstructive CAD. This may play a role in understanding and evaluating women presenting with angina symptoms and provides further explanation as to why female patients more commonly present with atypical symptoms.
Another cause of angina is related to microvascular coronary dysfunction (MCD) and is suggested to be a contributing cause of recurrent angina, particularly in female patients.18 While the underlying pathophysiology of MCD as a cause of CAD is not fully understood, it is thought to be related to endothelial dysfunction and alterations in microvascular tone due to dysregulation of vasodilation and vasoconstriction.19 Diagnosis of MCD can be made with coronary angiography once obstructive CAD is ruled out. During angiography, coronary vascular function testing is performed to assess endothelial function and coronary flow reserve. Along with structural abnormalities of the coronary microvasculature, impairment of the coronary flow reserve interferes with the vessels’ ability to vasodilate in the setting of increased oxygen demand, leading to symptoms of angina.
Other nonobstructive causes are more rarely associated with infarction and include coronary artery spasm and spontaneous coronary artery dissection, both of which are thought to occur more commonly in females.3,14
While chest pain remains the most prevalent symptom upon presentation associated with AMI, women are more likely to experience symptoms other than chest pain. Atypical symptoms reported more frequently in women include chest pain described as sharp, burning, or aching and other symptoms such as fatigue, shortness of breath, dizziness, and indigestion.3 Due to the differences noted, women are at risk for underdiagnosis upon presentation, and particular attention should be made upon assessment of a patient presenting with atypical chest pain.20
In a prospective multicenter study, Rubini Gimenez et al evaluated patients presenting to the ED with chest pain to identify any sex-specific differences that may aid in diagnosis of AMI.21 Based on 34 predefined characteristics, chest pain was defined based on characteristics associated with location, size of the pain area, presence of radiation, onset and duration, intensity of the pain, and relieving factors. This study included nearly 2,500 patients (1,679 men and 796 women) with similar baseline characteristics, with the exception that women were significantly older and had a lower prevalence of cardiovascular risk factors and previous CAD. Men and women experienced similar rates of the majority of the chest pain characteristics; however, more women experienced pressure-like pain, pain associated with dyspnea, palpitations, pain radiating to the throat or back, and longer durations of pain. Despite the differences noted, the authors concluded sex-specific differences overall were small with limited clinical utility in diagnosis. Other studies evaluating patient-reported symptoms and subsequent diagnosis highlight some differences in symptoms that women experience, but overall, the typical chest pain symptoms when present are predictive of ACS diagnosis.22,23
A study evaluating gender-specific differences and perceptions of symptoms among younger patients with AMI confirm that the majority of patients characterize chest pain; however, women presented with a greater number of additional nonchest pain symptoms than men. While a greater proportion of women had nonchest pain symptoms, no difference was found between these symptoms, including indigestion, nausea and stomach pain, pressure, burning, or discomfort; pain or discomfort in jaw, neck, arms, palpitations; or shortness of breath.6 The most recent publication from the American Heart Association and American College of Cardiology (ACC/AHA) provides recommendations preferring the use of cardiac, possible cardiac, and noncardiac when referring to chest pain, rather than the classic use of the term “atypical” commonly referenced in the published literature. One concern may be that misdiagnosis or underdiagnosis results from the widespread usage of this terminology, particularly among women.20 In fact, in the aforementioned study by Lichtman and colleagues, women were nearly twice as likely to attribute their symptoms to stress or anxiety.6 While men and women were likely to seek medical care due to persistent symptoms, women were less likely to seek care due to a heart problem and had a longer median time from symptom onset to hospital presentation (3.2 vs. 2.4 hours, P <.004). Women were also more likely to seek medical care before being hospitalized for AMI, although over half of women reported their provider attributed the symptoms to noncardiac-related etiology compared with men (53.4% vs. 36.7%, P <.001).
In addition to being at risk of underdiagnosis, delays in receiving medical care have also been noted in women. Weininger et al evaluated 218 patients with STEMI in which patients were contacted post discharge and interviewed about onset of symptoms and actions taken following symptom onset.24 Twenty-four percent of participants were women, and compared with men, they were older and had a higher incidence of hypertension and diabetes at baseline. Significantly more women than men reported atypical symptoms such as shortness of breath, 62% vs 36%, respectively. In addition, women were less likely to realize symptoms were related to myocardial infarction and more likely to report hesitating before going to the hospital. Many factors play a role in delays in care, including symptom recognition by the patient, but inadequate prehospital evaluation and/or lack of early diagnosis of women upon presentation is also a contributing factor.
When considering the varying spectrum of syndromes associated with cardiac chest pain, the range of symptoms from typical to atypical described in the literature is further explained by a variety of underlying pathophysiology outside of ACS.
ACS is a common clinical diagnosis among men and women with CAD. Patients presenting with complaints of chest pain and other associated symptoms may be evaluated for the presence of concerning features related to coronary occlusion and resultant myocardial ischemia. Differences in underlying pathophysiology of a patient’s chest pain, contributing to variation in clinical presentation and symptomatology, may not fully explain disparities in medical care. Delays in presentation among patients with chest pain determined to be due to an AMI are significantly greater in women compared with men. These delays may be due to lack of recognition, although a study by Newman et al demonstrated that women diagnosed with an AMI are more likely to call 911 than men.25 However, D’Onofrio et al determined that women had a longer time to hospital presentation and were more likely to present more than 6 hours after symptom onset.26 Secondly, unrecognized or atypical symptoms may contribute to differences in the medical management of women presenting with chest pain. In the previously mentioned study, women receiving reperfusion therapy for an AMI were more likely to present with atypical chest pain or no symptoms.26
It could be hypothesized that an atypical clinical presentation may delay recognition of the risk for ongoing myocardial ischemia, therefore leading to delays in assessment and ultimately therapeutic intervention. Identification of life-threatening myocardial ischemia and infarction relies on recognition of symptoms and electrocardiographic evidence. However, studies have demonstrated that women have longer delays to an initial ECG compared with men.27-29 Though delays may be attributable to the presence of noncardiac chest pain, recognition of atypical symptoms and prompt ECG assessment would lead to more expeditious treatment with coronary angiography.27
Revascularization for patients presenting with AMI has demonstrated improved outcomes with the use of thrombolytic therapy and primary PCI. Current guidelines published by AHA/ACC provide recommendations on the role of an urgent early invasive strategy with PCI for NSTEMI patients with refractory angina, hemodynamic or electrical instability, or for stable patients with an elevated risk for clinical events.4 Additionally, AHA/ACC guidelines recommend primary PCI for all STEMI patients with ischemic symptoms fewer than 12 hours. Fibrinolytic therapy should be administered for non-PCI capable hospitals if primary PCI cannot be completed within 2 hours of first medical contact.5 Due to the time-sensitive nature of these revascularization strategies, significant delays in presentation or diagnosis may place women at risk of poor outcomes. Fibrinolytic treatment of AMI may lead to an increased risk of bleeding complications in women and is associated with a significantly increased risk of mortality following delays of more than 6 hours from symptom onset. Though primary PCI demonstrated a lower 30-day mortality compared with fibrinolytic therapy for women, regardless of delay to presentation, delays of more than 6 hours were associated with an increased risk of mortality.30
Though many symptoms of chest pain related to ACS are similar among men and women, differences in underlying pathophysiology, risk factors, and the coexistence of atypical symptoms predispose women to potential treatment delays and poor outcomes. Women experience increased rates of mortality following an AMI; however, through development of strategies to increase recognition of symptoms, minimize prehospital delays, and increase the rate of medical treatment, we may impact these detrimental clinical outcomes.
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3. Mehta LS, Beckie TM, DeVon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation. 2016;133(9):916-947.4. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2014;130(25):e433-e434. Dosage error in article text]. Circulation. 2014;130(25):2354-2394.
5. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2013;128(25):e481]. Circulation. 2013;127(4):e362-e425.6. Lichtman JH, Leifheit EC, Safdar B, et al. Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO Study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients). Circulation.2018;137(8):781-790.7. Arora S, Stouffer GA, Kucharska-Newton AM, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation. 2019;139(8):1047-1056.
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18. Safdar B, D’Onofrio G. Women and chest pain: recognizing the different faces of angina in the emergency department. Yale J Biol Med. 2016;89(2):227-238.19. Naderi S. Microvascular coronary dysfunction—an overview. Curr Atheroscler Rep. 2018;20(2):7.
20. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines[published correction appears in Circulation. 2021;144(22):e455]. Circulation. 2021;144(22):e368-e454.
21. Rubini Gimenez M, Reiter M, Twerenbold R, et al. Sex-specific chest pain characteristics in the early diagnosis of acute myocardial infarction. JAMA Intern Med. 2014;174(2):241-249.22. Ferry AV, Anand A, Strachan FE, et al. Presenting symptoms in men and women diagnosed with myocardial infarction using sex-specific criteria. J Am Heart Assoc. 2019;8(17):e012307.
23. Mirzaei S, Steffen A, Vuckovic K, et al. The quality of symptoms in women and men presenting to the emergency department with suspected acute coronary syndrome. J Emerg Nurs. 2019;45(4):357-365.24. Weininger D, Cordova JP, Wilson E, et al. Delays to hospital presentation in women and men with ST-segment elevation myocardial infarction: a multi-center analysis of patients hospitalized in New York City. Ther Clin Risk Manag. 2022;18:1-9.
25. Newman JD, Davidson KW, Ye S, et al. Gender differences in calls to 9-1-1 during an acute coronary syndrome. Am J Cardiol. 2013;111(1):58-62.26. D’Onofrio G, Safdar B, Lichtman JH, et al. Sex differences in reperfusion in young patients with ST-segment−elevation myocardial infarction: results from the VIRGO study. Circulation. 2015;131(15):1324-1332.
27. Takakuwa KM, Shofer FS, Hollander JE. The influence of race and gender on time to initial electrocardiogram for patients with chest pain. Acad Emerg Med. 2006;13(8):867-872.28. Zègre-Hemsey J, Sommargren CE, Drew BJ. Initial ECG acquisition within 10 minutes of arrival at the emergency department in persons with chest pain: time and gender differences. J Emerg Nurs. 2011;37(1):109-112.
29. Makdisse MRP, Correa AG, Pfeferman A, et al. Women with acute myocardial infarction are more likely than men to have a delayed door-to-electrocardiogram time. Crit Care. 2007;11(suppl 3):P44.30. Weaver WD, White HD, Wilcox RG, et al. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I investigators. JAMA. 1996;275(10):777-782.
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