Atypical Angina and Acute Coronary Syndrome in Women
A 77-year-old woman lost consciousness while stepping out of an automobile. She had previously been feeling well and had been playing cards earlier in the day with friends. She quickly became alert, but while awaiting the ambulance and during the ambulance ride to the hospital, she developed recurrent syncope. Heart rates in the 20s to 30s were recorded and were unresponsive to atropine and epinephrine. Brady-arrhythmia persisted in the emergency room, associated with nausea and vomiting. The patient was intubated. She had no signs of congestive heart failure on examination or chest x-ray. An electrocardiogram showed normal sinus rhythm with complete heart block and left bundle branch block. External pacing was applied, and the patient was transferred to a tertiary care center. A temporary pacemaker was subsequently inserted. She was noted to have periods of normal sinus rhythm with a right bundle branch block and left anterior fascicular block. She used her pacemaker intermittently overnight.
The patient had a long history of non–insulin-dependent diabetes mellitus, hypertension, and hyperlipidemia. Over the previous 6 months she had noted an uncomfortable pulsing sensation in her throat, often accompanied by transient disequilibrium and lightheadedness. She attributed the symptoms to possible gastroesophageal reflux and did not seek medical attention. She had a similar sensation the day of admission preceding her syncopal event. She denied any history of chest pain but had noted unusual fatigue over the previous month.
On the morning following admission she was able to be extubated. An echocardiogram demonstrated moderately reduced left ventricular function and septal wall hypokinesis. Troponin peaked at 6, and a cardiac catheterization was performed. She was noted to have a relatively small, diffusely diseased vessel with a high-grade stenosis of the mid left anterior descending artery. A stent was successfully deployed (Figure). She was placed on intravenous glycoprotein IIb/IIIa inhibitor overnight. Postprocedural course was uncomplicated. The pacemaker was removed and no further heart block was noted as beta-blocker therapy was instituted. Due to the history of alternating right and left bundle branch block in the setting of syncope, infranodal conduction disease was suspected, and a permanent pacemaker was inserted.
Coronary vascular disease is the leading cause of death among women in the United States, although its significance is clearly underrecognized by the female population. Nearly two in three women will die of coronary artery disease (CAD). Accurate diagnosis of CAD in women has been challenging due to the high prevalence of atypical presentations and lack of suspicion by both women and their doctors. This case illustrates many of the features of acute coronary syndrome in women. Ignoring symptoms or failing to seek medical attention often occurs in the elderly female population. Symptoms can go unrecognized because women often do not experience classic anginal chest pain (Table). Chest pain, the hallmark of coronary ischemia, was reported as a prodromal symptom during 1 month prior to acute myocardial infarction (MI) in only 30% of women retrospectively studied in a recent large cohort of patients.1 Only slightly more than half the patients experienced chest pain at the time of the acute MI. The most frequent prodromal symptoms were fatigue, sleep disturbance, shortness of breath, and indigestion, whereas the most frequent acute symptoms included shortness of breath, weakness, and unusual fatigue. When chest pain does occur, it is not always the classic pressure-like sensation, but descriptors such as burning, fullness, tightness, and tingling are often used by women. Women are also more significantly likely to present with upper abdominal pain, dyspnea, and nausea as primary complaints during an acute coronary event. Failure to suspect coronary vascular disease in women with atypical symptoms has led to underdiagnosis in the past, as well as reduced referral for diagnostic testing. Despite multiple risk factors, our 77-year-old patient had never been referred for stress testing, and also did not alert her physicians of the throat discomfort and dizziness that she was experiencing.
Chest pain in women is less likely to be associated with flow-limiting coronary stenoses than chest pain in men. Women have a higher frequency of angiographically normal coronary arteries or minimal CAD when presenting with similar symptoms as men. Thus, early symptoms and signs as well as the pathophysiology of CAD in women differs from men, often making the condition more difficult to recognize at an early stage. The pathophysiology of chest pain in women with normal coronary arteries may be related to a specific etiology such as vasospasm, microvascular angina, mitral valve prolapse, or endothelial dysfunction, which is currently a topic of intensive research. The significance of risk factors also has gender differences. Diabetes mellitus is a more important risk factor for CAD in women, increasing their risk 3- to 7-fold, as compared with 2- to 3-fold in men. Women are typically 10 years older than men at the time of initial presentation of CAD. Due to older age at presentation, women have a higher prevalence of comorbidities and risk factors such as hypertension, diabetes mellitus, and hyperlipidemia.
There are also differences in the etiology of sudden death from coronary disease in younger versus older women. Some studies have found a correlation between risk factors and the mechanism of sudden coronary death. Older postmenopausal women are more likely to rupture vulnerable, lipid-laden plaques, in the setting of hyperlipidemia, hypertension, and diabetes, whereas younger women with sudden coronary death have been shown to have more plaque erosion and thrombosis without a high degree of stenoses.2 Other factors such as aggravation of clotting mechanisms by tobacco, and emerging risk factors such as inflammation, lipoprotein (a), and hypercoagulable states have been implicated in younger women. Estrogen may partially protect against the formation of atherosclerosis in premenopausal women; however, endothelium in atheromatous disease is resistant to estrogen’s vasodilatory, antioxidant, and antiproliferative effects. The presence of multiple comorbidities in women adversely influences outcome after MI or myocardial revascularization. Women older than 74 years of age have been shown to have similar mortality rates after an MI as compared to men, but increased mortality rates with progressive decrements below 74 years of age.3
Comorbidities do not account entirely for these sex-related differences. Sex-based differences in mortality prior to hospitalization may also contribute to the variability. An overall increased mortality of women compared to men is primarily due to a nearly 2-fold increase in mortality among women younger than 50 years compared to men of the same age who suffer an MI. Younger women, as compared to younger men, have higher incidences of diabetes, prior congestive heart failure, stroke, and more severe clinical abnormalities at presentation. In the past, the worse outcome in women following MI has also been attributed to differences in utilization of diagnostic procedures including coronary angiography and subsequent revascularization. These differences are less important today, as physicians have become more aggressive in treating women with acute coronary syndromes. Interventional therapy has improved the survival of women with coronary artery syndromes. Historically, women undergoing percutaneous coronary interventions have had decreased procedural success rates and increased mortality compared to men. However, in the era of newer interventional devices, outcomes have significantly improved. Nevertheless, women tend to have more procedural complications, such as coronary artery dissection with balloon angioplasty, hypotension, and need for transfusion and vascular access repair. Some of these complications have been attributed to the presence of small arteries, greater degree of calcification, and more ostial lesions, as well as older age and more comorbidities. Women treated with thrombolytic agents have achieved similar 90-minute patency rates to men, although 30-day mortality rates remain higher.4 Primary angioplasty has improved survival in women and reduced the risk of intracerebral hemorrhage associated with thrombolytic therapy. Despite similar procedural success rates for women and men, in the Stent-PAMI trial, in which a heparin-coated stent with balloon angioplasty was utilized in acute MI, women had slightly increased 6-month mortality (7.9% vs 2.0%) and reinfarction (6.4% vs 2.7%).5
Some studies have shown that an early invasive approach versus a conservative approach guided by symptoms had less benefit in reducing future events such as MI, death, or future revascularizations in women as compared to men.6 However, women presenting with acute syndromes have a higher frequency of angiographically normal arteries and lower rates of 2- and 3-vessel disease, and thus have less to gain from early invasive strategies. Women who require an intervention or urgent coronary bypass often have greater comorbidities, influencing their short-term prognosis, which continues to remain worse than men even in the stent era.
Women who receive intravenous platelet inhibitors (glycoprotein IIb/IIIa receptor antagonists), especially women with diabetes, have a similar composite endpoint reduction to men. The case patient was treated with a glycoprotein IIb/IIIa receptor antagonist for 18 hours following her procedure, particularly because the vessel had a complex lesion and because of her diabetes; both of these factors have been associated with improved outcome with the use of platelet inhibitors. Although the patient in the case presentation did not require surgical intervention, women tend to suffer more complications after coronary artery bypass surgery than men.7 These differences are more marked in younger women compared with older women. Higher incidences of prior stroke, heart failure, diabetes, renal insufficiency, and valve disease among younger women undergoing coronary artery bypass surgery account for some of these sex differences, which tend to be less marked in older patients. Much of the morbidity associated with coronary artery bypass surgery in women is due to higher incidence of congestive heart failure secondary to hypertensive heart disease and diastolic dysfunction without systolic dysfunction.
Hormone replacement therapy is not advocated for the prevention of CAD, particularly in the older patient population because they already have endothelial dysfunction and development of atherosclerotic plaque, and thus may be resistant to the beneficial effects of estrogen. Recent trials have suggested increased incidence of acute myocardial events in the early years following initiation of hormone replacement therapy in the postmenopausal woman, possibly attributed to the prothrombotic effects of estrogen in susceptible patients. Starting hormone replacement therapy at the time of menopause in a population without significant risk factors for atherosclerosis may be protective and beneficial, as ongoing studies will hopefully delineate.8 In the last few years, the American Heart Association has embarked on an aggressive program to encourage the recognition of CAD among women. Evidence-based guidelines for cardiovascular disease prevention in women have been published to guide physicians in the recognition and treatment of women with CAD.9 They have also highlighted the need for ongoing studies in elderly women, in whom cardiovascular disease is common and the leading cause of death.
Outcome of the Case Patient
Due to the history of alternating right and left bundle branch block in the setting of syncope, infranodal conduction disease was suspected, and a permanent pacemaker was inserted. Vascular access was difficult, and the chest x-ray taken the following day demonstrated a small pneumothorax. No enlargement was detected on a film later that day. The patient was asymptomatic and was discharged. The development of this complication demonstrates the increased procedural risks of elderly women with diffuse vascular disease. The patient’s atypical anginal symptoms of throat discomfort and paroxysms of dizziness did not recur. An echocardiogram showed resolution of the septal wall hypokinesis following her revascularization. Given the absence of typical symptoms of angina prior to initial presentation in this patient, future screening for restenosis or progression in CAD will best be performed by an imaging stress test, such as stress echocardiography or nuclear scanning. Risk factor modification by diet and exercise was encouraged. She was also enrolled in a cardiac rehabilitation program, as exercise has been shown to reduce the incidence of future cardiovascular events in elderly women.