A 53-year-old woman with a history of hypertension (HTN), diabetes mellitus Type 2 (Type 2 DM), and tobacco abuse presents to urgent care for symptoms of nausea, chest tightness, and bilateral shoulder pain. The discomfort started 4 hours ago and was not relieved with aspirin or antacid. She had recently been going to a chiropractor for pain in her neck and shoulders, which had been persisting over the past week, but felt this pain was more intense. Her blood pressure was elevated to 165/84 mm Hg and pulse to 93 beats per minute (bpm). Physical examination was unremarkable for cardiac findings with a normal S₁ and S₂, no rubs, murmurs or gallops, no pulmonary abnormalities, and no signs of heart failure. Further evaluation demonstrated no arrhythmias or acute ischemic changes on a normal-appearing electrocardiogram (ECG). Biomarkers for ischemia were negative.

CLINICAL FEATURES OF ISCHEMIC HEART DISEASE

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  Angina pectoris is a common presentation of ischemic heart disease (IHD). Based on data from the CASS trial in women who had typical angina, 62% had coronary artery disease (CAD), and even those with atypical features, 40% had CAD.^1,2,3

  
  
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  During an acute ischemic event, many women do not experience typical angina, but have atypical symptoms. This may cause a delay in presentation, evaluation, and therapy. Lack of symptoms with an acute coronary syndrome (ACS) can occur in both men as well as women. But pooled data from large cohort studies have shown this to be more common in women, 37% versus 27%.⁴ Myocardial infarction (MI) without chest pain has been more common in younger women, under the age of 55 years. And this group has a higher associated mortality than men within the same age group.⁵

  
  
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  Other symptoms common in women presenting with ACS include upper abdominal discomfort, dyspnea, and fatigue as well as middle or upper back pain, nausea, indigestion, and loss of appetite.⁴

EPIDEMIOLOGY OF ISCHEMIC HEART DISEASE

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  Heart disease accounts for more deaths in women than cancer. Looking at data from the Centers for Disease Control from 2008, IHD accounts for 24.5% of deaths among women of all races⁶ (see Table 6-1).

  
  
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  Women are 5.5 times more likely to die from heart disease than breast cancer. Lifetime risk of developing IHD after 40 years of age is 32% for women.⁷

  
  
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  Nearly 250,000 women die annually in the United States from IHD. The mortality rate for women is higher than men at initial presentation of MI (52% vs 42%) and within 1 year following an MI (23% vs 18%).^8,9,10

  
  
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  Women, on average, present with IHD 10 years later than men, and occurrence of a clinical event such as MI and sudden death lags behind men by 20 years. However, by the time they reach the eighth decade, both men and women have similar rates of mortality and morbidity. However, mortality and morbidity is higher at the extremes of ages, that is, 35 to 44 years and 75 to 84 years.^1,9,11,12

  
  
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  IHD is an under-recognized and untreated cause of death among women, with only 8% to 20% aware that cardiovascular disease is the major cause of death for women.⁹

PATHOPHYSIOLOGY AND ETIOLOGY OF ISCHEMIC HEART DISEASE

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  Epicardial coronary IHD is an inflammatory vascular process that involves lipid deposition, smooth muscle cell migration, and proliferation with calcification. Without risk factor modification, it evolves over time with progression that may lead to plaque rupture and thrombosis, causing significant disease burden and can even result in an acute myocardial event.

  
  
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  Risk factors in women include advanced age, smoking tobacco, African American ethnicity, family history of IHD, central obesity, metabolic syndrome, DM, HTN or history of preeclampsia, history of autoimmune disease, premature menopause, and poor exercise capacity.¹³ (The strongest risk factors for women are DM, smoking, and HTN.)

  
  
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  Of the women suffering from typical or atypical chest pain who undergo coronary angiography, 50% have nonobstructive CAD and 50% of those continue with angina. In ACS/STEMI (ST-segment elevation myocardial infarction), approximately 10% to 25% of women as compared to 6% to 10% of men have nonobstructive CAD, which is 60,000 to 150,000 women a year in the United States.¹⁴ The CASS trial showed 50% of women referred with angina pectoris had minimal or no atherosclerotic epicardial artery obstruction compared to 17% of men.³

  
  
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  Microvascular coronary disease and abnormal coronary vasoreactivity are also causes of ischemia that is mediated by endothelial dysfunction and physiological stimuli such as exercise, mental stress, and acetylcholine.^1,15

  
  
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  Women have smaller coronary arteries as indexed by body surface area. This can lead to increased risk of vascular complications with percutaneous coronary procedures as well as decreased graft patency with surgical revascularization.^16,17,18

  
  
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  In those >40 years old after an initial ACS, women have higher mortality rates than men at 1 year (23% vs 18%, respectively) and within 5 years (43% vs 33%, respectively). Women also have higher rates or recurrent and fatal cardiovascular events as well as heart failure (HF), that is, 40% of initial cardiovascular events are fatal in women.^19,20

PRETEST ASSESSMENT AND RISK STRATIFICATION

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  When a woman presents with chest pain, a process for evaluation begins with a comprehensive history and physical. Assessment is needed to determine her pretest probability for IHD. This will aid in clinical decision-making and test selection.

  
  
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  Evaluation begins with consideration of the pretest probability of IHD for symptomatic patients and with calculation of a 10-year cardiovascular event-absolute risk score for asymptomatic patients. Risk factors such as those previously mentioned can be assessed using risk calculators such as the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), ACC/AHA Practice Guidelines on Exercise testing or the Framingham Heart Study equation to categorize individuals into low, intermediate, and high risk.^8,21,22,23 The lower prevalence and incidence of disease in the female population can cause the risk assessment to have a lower specificity and lower positive predictive value (PPV); therefore, evaluation should also be done on an individual basis with reference to this calculation.

  
  
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  In symptomatic patients, age and assessment of anginal chest pain are used to determine the pretest probability of IHD as very low <5%, low <10%, intermediate 10% to 90%, and high >90%.²¹

  
  
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  Framingham risk categorizes absolute CHD risk over 10 years in asymptomatic women to low as 0 to 10%, moderate >10% to <20%, and high >20%.⁸ In addition, NCEP-ATP III categorizes those with ≥2 risk factors with a 10-year risk <10% as moderate risk and those with a 10-year risk of 10% to 20% to moderately high risk.²³

REST TESTING

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  Resting ECG: On initial evaluation, the resting ECG is a powerful negative predictive value (NPV) if it is normal. Abnormalities such as Q-waves, ST-segment changes, T-wave inversions, LV hypertrophy, arrhythmias, or bundle branch block patterns may indicate potential disease and need for further cardiac evaluation.³

  
  
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  Coronary artery calcium (CAC) scoring is a noncontrast coronary imaging modality reserved for asymptomatic individuals. This is utilized for additional risk stratification beyond traditional Framingham assessment. CAC is standard cinefluoroscopy, which is used in screening for IHD and identifies those at risk using either electron beam tomography (EBT) or a noncontrast multidetector computed tomography (MDCT) scan. It is used in low-risk and a few select intermediate-risk patients. Patients must be able to hold still with arms above their shoulders. It also uses radiation that although small, poses future risks for cancer. This modality helps to identify individuals at increased risk of cardiovascular disease beyond the traditional Framingham risks. The ACC/AHA recommends this test for selected asymptomatic, intermediate-risk women for coronary artery disease detection and risk factor modification.²⁰ The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal epidemiological study that included over 3000 women with a mean follow-up of 3.75 years.²⁴ In the MESA study, 90% of women were classified as low risk based on Framingham assessment. Any calcium score >0 was associated with increased risk of CAD and was predictive of increased cardiovascular events. CAC scores are typically expressed as Agatston score that is a weighted unit of calcium density to represent calcium burden of coronary vessels.^25,26 Figure 6-1 is a noncontrast MDCT scan providing a calcium score. While the overall cardiovascular event rate in the MESA study was low, women with CAC score ≥300 with an absolute rate of a cardiovascular event of 8.6% over a 3.75-year period.^20,24

  
  
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  Coronary computed tomographic angiography (CTA) is a contrast-enhanced imaging using an MDCT scanner. Imaging technology is constantly evolving. The current published trials typically use 64 multidetector row equipment, with a spatial resolution of 0.6 to 1.0 mm. This provides a sensitivity of 85% to 87% range and specificity of 96%. This modality provides anatomic assessment for IHD typically in combination with CAC. With this study, the most optimal imaging is accomplished using β-blockers or calcium channel blockers to a goal heart rate of 60. In addition, intravenous contrast is used to visualize the coronary arteries. In the obese population, there is concern for decreased signal to noise, resulting in a decreased sensitivity of the imaging examination. Patients with decreased renal function are excluded due to the use of contrast and further renal compromise. Caution is utilized in testing young women due to the heightened lifetime cancer risk with radiation exposure (12.7 milli-Sievert [mSV] for women); however, with advancements in protocols and techniques, the dose of ionizing radiation has continued to decrease. Because this examination is an anatomic assessment, the physiologic data acquired with exercise testing is not obtained and this can limit the clinical usefulness in risk stratification. However, overall with a high NPV in the range of 99%, there is a wide range of clinical applications for this test. Trials have demonstrated comparable diagnostic accuracy between both men and women. With anatomical assessment of the entire vessel lumen and wall, the appearance may show positive remodeling. The phenomenon of positive remodeling is more common in women and may be missed with traditional invasive coronary angiography.^27,28,29 This is identified in Figure 6-2.

STRESS TESTING

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  Diagnostic cardiac stress testing is performed in symptomatic women to identify those patients with CAD that may be flow limiting. This can be assessed with traditional exercise in the form of treadmill stress or supine bike stress. For patients unable to exercise, pharmacologic stress is accomplished with either an ionotropic agent, such as dobutamine, or a vasodilator agent, such as adenosine or regadenoson. Dobutamine increases myocardial contractility and increased chronotropy. Vasodilator agents work to increase a maximal hyperemic response with increasing myocardial blood flow 3.5 to 4 times normal. The area with hemodynamically significant obstruction has an attenuated response that is manifested as perfusion heterogeneity with imaging.

  
  
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  Exercise stress ECG according to the ACC/AHA guidelines is recommended as the initial test for symptomatic woman at intermediate risk for CAD with a normal resting ECG and capable of maximal exercise on a treadmill.²⁰ This has a sensitivity of 60% to 70% and specificity of 70% to 75%. Due to the high NPV, this test is also appropriate in low and low-to-intermediate risk (pretest likelihoods <20%) when the patient has a normal baseline ECG. (ACC class I intermediate, class IIb low risk.)

  
  
  
  
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    Criticisms of this modality exist as it has a lower detection for CAD in women than in men for many reasons. There is a bias toward patient selection for this test and a lower prevalence of obstructive CAD in women. This reduces the sensitivity and specificity for ST-segment depression in women as compared to men.^30,31 Furthermore, women must be able to achieve adequate heart rates, which is challenging for women as this condition is based on algorithms and exercise programs previously designed by male-dominated trials (ideally ≥85% maximal predicted HR on the Bruce protocol).

    
    
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    In addition to ST deviation, functional information is obtained with the exercise test. The Duke Treadmill score (DTS) takes into account not only ST deviation, but also duration of exercise and symptoms, which have shown to more accurately predict IHD in women.³² Additional parameters such as functional capacity and heart rate recovery have improved the diagnostic functionality of this test. Those patients unable to achieve target heart rates, defined as ≥85% age-predicted maximum heart rate or <5-metabolic equivalents (METS), are at higher risk for all-cause mortality as well as MI and IHD.^31,33,34

    
    
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    Exercise stress ECG adds very little to clinical assessment in low-risk pretest patient and high-risk pretest patient management. For intermediate pretest-risk patients, a low-risk stress ECG will assist in prognosis, but does not clarify the presence of disease or etiology of symptoms; therefore, an imaging test is more helpful.