Nisha Chandra-Strobos
Glenn A. Hirsch
Chest pain is one of the most common complaints of patients in an ambulatory practice. The major early objective in the diagnosis of patients with chest pain is separating noncardiac from cardiac etiologies. Chapters 42 and 59 describe the various causes of noncardiac chest pain. This chapter describes the pathogenesis of coronary artery disease (CAD) and its most common clinical symptom, angina pectoris. Chapter 63 describes the posthospital medical care and rehabilitation of patients who had a myocardial infarction (MI).
CAD caused by atherosclerosis is one of the most common ailments in the Western world, and it remains the leading nontraumatic cause of disability and death in the United States. Increased public awareness and health education have reduced CAD mortality by >20% in the last 25 years. However, CAD still affects approximately 13,000,000 Americans. Cardiovascular disease accounts for 38% of the total mortality in the United States or approximately the same number of deaths as the next five leading causes combined (cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, and influenza and pneumonia). Of these cardiovascular deaths, coronary heart disease accounts for 53% (1). Chest pain is one of the most common presenting symptoms of patients with CAD who seek medical attention. Health care providers must understand the appropriate diagnostic evaluation and subsequent therapeutic options for patients with chest pain. A detailed history and physical examination are essential when evaluating patients with chest pain. They cannot be replaced by sophisticated procedures; rather, they guide the clinician in selecting the most appropriate diagnostic evaluation.
Pathogenesis
CAD presents in a variety of ways, largely related to the underlying pathophysiology of plaque formation and atherosclerosis. The endothelium plays an integral role in defending against atherosclerosis, modulating vascular tone, and preventing intravascular thrombosis. These endothelial functions are adversely affected by CAD risk factors, even before the development of overt atherosclerosis. In the earliest stages of disease, circulating monocytes adhere to vascular endothelial cells (via adhesion molecules) and migrate into the intima of the blood vessel, where they
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ingest oxidatively modified low-density lipoprotein (LDL) and become trapped as foam cells. Collections of foam cells, known as fatty streaks, may be present even in early childhood. Foam cells die, leading to the development of a lipid core. Smooth muscle cells are signaled to migrate from the media, destroying the internal elastic lamina of the vessel in the process. Calcification of the plaque occurs early and can be visualized noninvasively by electron-beam computed tomography (EBCT; see later discussion). The arterial wall progressively thickens and remodels. Encroachment of plaque into the lumen of a coronary artery occurs late in the atherosclerotic process, reflecting advanced disease. Arterial cross-sectional area is reduced by approximately 40% before a lesion is visible as “significant” CAD on catheterization, a finding demonstrated by use of in vivo intravascular ultrasound (2).
Atherosclerotic progression is accelerated by three processes: endothelial dysfunction, inflammation, and thrombosis. Advanced lesions may be calcified and fibrotic, but more concerning are plaques that have a core of lipid and necrotic tissue surrounded by a thin fibrous cap. This cap contains collagen, and its characteristics are closely related to the risk of plaque rupture, the major cause of acute coronary syndromes. Specifically, a thinner fibrous cap is more likely to rupture. A ruptured plaque exposes the highly thrombogenic underlying collagen matrix and leads to rapid thrombus formation. Complete occlusion of a coronary vessel by thrombus on a ruptured plaque typically causes an acute transmural MI characterized by ST-segment elevation on the electrocardiogram (ECG). Nonocclusive thrombus can cause unstable angina or an MI without ST-segment elevation. Nonocclusive thrombus may not cause symptoms but instead may change plaque geometry and lead to rapid plaque growth.
MIs are classified by their appearance on 12-lead ECG during the acute phase as either ST-segment elevation or non–ST-segment elevation and are treated differently (3, 4, 5, 6). It is important to recognize that an acute MI often arises from rupture of an atherosclerotic plaque that caused <50% luminal reduction by angiography prior to plaque rupture (7,8). On the other hand, a coronary artery that is narrowed by ≥70% is more likely than is a less severe narrowing to cause exertional angina. The discordance between plaque severity and the development of an acute MI indicates that coronary disease is not simply a mechanical problem but instead occurs as the end result of the interplay between mechanical stresses, inflammation, cholesterol deposition, and thrombosis.
Most patients with classic exertional angina by history have fixed atherosclerotic lesions of ≥70% in at least one major coronary artery. Fundamentally, angina is caused by a mismatch between myocardial oxygen supply and demand. Supply is affected by coronary perfusion pressure, coronary vascular resistance, and the oxygen-carrying capacity of blood. Flow is autoregulated over a wide variety of perfusion pressures; therefore, most of the changes in flow result from changes in resistance (i.e., vasodilation). However, the coronary bed beyond a significant flow-limiting stenosis already is maximally vasodilated such that small increases in demand (e.g., increased heart rate and blood pressure during exercise) may result in myocardial ischemia. Oxygen demand is related to heart rate, systolic blood pressure, and wall tension. Wall tension is determined by ventricular pressure, cavity size, and wall thickness. Physical exertion and emotional stress have potent effects on these variables and, not coincidentally, are the common triggers for ischemic chest pain.
Risk Factors
Both genetic and environmental risk factors influence the development of atherosclerotic heart disease. The recognition of risk factors is especially important because many of these conditions can be modified to prevent disease. Landmark epidemiologic surveys, such as the Framingham Heart Study, have helped to define levels of risk for individual risk factors. Treatment guidelines have been revised to include the important interactions between individual risk factors and age. Risk calculators (CAD event risk over 10 years) are available on the Internet at http://www.intmed.mcw.edu/clincalc/heartrisk.html. The 27th Bethesda Conference was designed to bring attention to specific patients at high risk for development of CAD events (9). This work has been incorporated into the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP-III]) (seeChapter 82) (10). The concepts of “risk” and “risk factor” are important in understanding and using the guidelines. The Bethesda Conference outlined four categories of risk based on observational studies and efficacy studies (clinical trials). Table 62.1 summarizes these risk factors.
Category I risk factors are those for which interventions have been proven to reduce the risk of CAD events. They include smoking, elevated LDL cholesterol, diet high in saturated fat, hypertension, left ventricular hypertrophy, and “thrombogenic factors,” which are unnamed but have the potential of being reduced by aspirin.
Category II risk factors are those for which interventions are likely to lower CAD risk. They include diabetes mellitus, physical inactivity, low levels of high-density lipoprotein (HDL) cholesterol, increased levels of triglycerides, obesity, and postmenopausal estrogen deficiency. Since the publication of these findings, diabetes has been reclassified as a CAD “risk equivalent” based on data suggesting that diabetic patients without known CAD have survival rates similar to those of nondiabetic patients who have experienced an MI. The ATP-III guidelines focus attention
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on the “metabolic syndrome,” which incorporates abdominal obesity, atherogenic dyslipidemia (elevated triglycerides, small LDL particles, low HDL cholesterol), elevated blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states. Patients with this syndrome now are appropriately targeted for intensive risk factor modification. Low HDL cholesterol, with the publication of the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (11), now may be considered a category I risk factor, because an intervention to raise HDL cholesterol (i.e., with gemfibrozil) in this trial reduced the incidence of cardiovascular events (12). Although postmenopausal status correctly identifies a cardiac risk factor, evidence from randomized trials demonstrates that hormone replacement therapy may actually increase the risk of cardiovascular events and therefore is not recommended for treatment or prevention of CAD (13,14).
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TABLE 62.1 Risk Factors for Cardiovascular Disease |
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Category III risk factors are those associated with increased CAD risk that may, if modified, lower risk. These include the “emerging” risk factors such as depression, elevated lipoprotein (a) levels, and hyperhomocysteinemia. This list probably should be expanded to include inflammatory markers (elevated white blood cell count, high-sensitivity C-reactive protein, serum fibrinogen, soluble adhesion molecules), thrombotic risk factors (plasminogen activator inhibitor-1), and sleep apnea. Coronary calcification as measured by EBCT (15) can correctly be considered a category III risk factor for now, but it may need to be reclassified (like diabetes mellitus) as a CAD risk equivalent because it is a measure of the subclinical coronary artery plaque burden.
Category IV risk factors are those that are associated with increased risk but cannot be modified. They include age, male gender, low socioeconomic status, and family history of early-onset CAD. Positive family history has been defined as CAD in a male first-degree relative younger than 55 years or in a female first-degree relative younger than 65 years. These factors usually are taken into consideration with the available risk scoring systems.
Diagnosis
History
Character and Location of Ischemic Pain
The discomfort of myocardial ischemia can be described in a variety of ways. Classically, the term angina pectoris describes a “strangulation of the chest,” a helpful point to remember because many individuals describe something other than “pain” and instead mention chest tightness or heaviness. Often it is more effective to ask the patient to describe the discomfort. Some patients may simply hold their clenched fist in the middle of their chest (Levine sign).
Angina typically begins and ends gradually over 2 to 5 minutes and usually is steady in character, although occasionally it waxes and wanes. If ischemic pain continues for >20 minutes, myocardial necrosis (i.e., an MI) is more likely to have occurred. The discomfort of angina pectoris usually is midline and substernal, sometimes with radiation to the shoulder, arm, hand, or fingers, usually to the left. Radiation down the inside of the arm into the fingers supplied by the ulnar nerve is classic. Pain also may radiate into the neck, lower jaw, or interscapular region. Occasionally, a patient has pain only in a referred location and experiences no chest discomfort at all. The pain of myocardial ischemia is diffuse and cannot easily be localized. Rarely is the patient able to point with one finger to the location. When pain can be localized in this way, it likely is noncardiac in origin. The elderly, especially the
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frail elderly, are more likely than are younger patients to experience atypical symptoms such as dyspnea, confusion, or dyspepsia rather than pain.
The Canadian Cardiovascular Society (CCS) Classification System was designed to provide a simple way of grading anginal symptoms (16).Class I angina occurs with strenuous, rapid, or prolonged exertion but not with ordinary physical activity. Patients with class II anginaexperience slight limitation of ordinary activity. Class II angina occurs on walking or climbing stairs rapidly; walking uphill; walking or climbing stairs after a meal, in cold, or in wind; or under emotional stress. Class III angina produces marked limitations of ordinary physical activity. Angina occurs on walking one or two blocks on level terrain or climbing one flight of stairs under normal conditions and at a normal pace. With class IV angina, the most severe type, the patient is unable to carry on any physical activity without discomfort, and anginal symptoms may be present at rest. A higher CCS class is associated with more extensive CAD and a higher risk of CAD events.
Precipitating Factors
The single most important diagnostic feature of the discomfort of myocardial ischemia is its predictable relationship to exertion, emotional stress, or other situations that may either increase myocardial oxygen demand or reduce supply. The cause of atypical pain, pain in an unusual location or of an unusual character, may be clarified by this relationship. Pain that is experienced at rest, if it is caused by ischemia, suggests unstable angina or MI.
Anxiety and mental stress are important and often overlooked provoking factors in many patients. Angina is more likely to occur during cold or windy weather because of increased peripheral vascular resistance and, consequently, increased myocardial work. Other triggers include sexual intercourse or a heavy meal.
Relief of Ischemic Pain
Because angina is fundamentally caused by a discrepancy between oxygen supply and demand, relief of pain is achieved by increasing coronary blood flow or decreasing oxygen demand. Most people must stop or at least slow the activity responsible for precipitating the pain before it is relieved. Angina often is relieved by sublingual nitroglycerin, but the practitioner and the patient both need to realize that relief of chest pain by nitroglycerin is not specific for myocardial ischemia (17). For example, the pain of esophageal spasm can also be relieved by nitroglycerin.
Physical Examination
The physical findings in patients with CAD are nonspecific. A complete cardiovascular examination should focus on identifying markers of hypertension and dyslipidemia, peripheral vascular disease, or diabetes mellitus. Severe aortic valve disease (stenosis or regurgitation) or pulmonary hypertension without CAD can cause angina pectoris either from left or right ventricular wall strain, respectively, leading to myocardial ischemia.
Electrocardiography
A 12-lead ECG should be obtained as soon as possible in a patient with suspected CAD, although in many cases the ECG is completely normal. The most reliable ECG sign of chronic ischemic heart disease is the presence of a prior MI as manifested by two or more pathologic Q waves in a particular myocardial territory (e.g., anterior, lateral, inferior, etc.) (Fig. 62.1A). The differential diagnosis of Q waves on ECG includes prior MI, healed myocarditis, hypertrophic cardiomyopathy, an infiltrative myocardial disorder such as amyloidosis or sarcoidosis, and Wolff-Parkinson-White syndrome (usually with characteristic findings of preexcitation; see Chapter 64). Nonspecific ST-T wave changes, conduction abnormalities (except for left bundle-branch block [LBBB], discussed later), and arrhythmias do not help establish the diagnosis of myocardial ischemia. However, ST-segment depression with a flat or downsloping ST segment is suggestive of subendocardial ischemia (Fig. 62.1B). It is seldom present on the resting ECG of patients with ischemic heart disease unless they are experiencing angina at the time the tracing is recorded. On the other hand, transient ischemic changes are seen commonly when a patient with CAD is exercised to a point at which chest pain develops. Such ECG changes, appearing with exercise or pain and resolving with rest or with the resolution of pain, usually are an indication of myocardial ischemia. Therefore, the necessity of repeating the ECG at rest or after the chest pain has resolved cannot be overemphasized. ST-segment elevation during chest pain (Fig. 62.1C) suggests acute myocardial injury (e.g., MI) or variant angina (discussed later). T-wave inversion on an ECG taken at rest is a nonspecific finding but can occur after infarction or as a specific transient finding in a patient experiencing angina. Therefore, ECG changes noted during episodes of chest pain not only can confirm the diagnosis of myocardial ischemia but also may indicate the extent and location of the ischemic myocardium. As a general rule, the more widespread the changes on ECG, the greater the extent of myocardium that is involved. ST-segment elevation in the absence of chest pain is common on the resting ECG of healthy young adults and is caused by rapid or “early” repolarization of the ventricle. This pattern (Fig. 62.1D) usually is noted in the mid–left chest leads (V2–V4) but may be more widespread. ST-segment elevation from pericarditis is diffuse and can be associated with PR-segment depression in the limb leads (except aVR, which may show PR-segment elevation).
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FIGURE 62.1. Electrocardiographic strips from patients with suspected ischemic heart disease. A: Q waves suggestive of prior myocardial infarction. B: ST-segment depression developing after exertion. C: ST-segment elevation during coronary artery spasm (variant angina). D: Early repolarization (a normal variant). |
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The presence of ST-T abnormalities in an otherwise healthy person is a nonspecific finding and should not be considered confirmation of CAD. There is a high association of LBBB with organic heart disease (see Chapter 64), especially CAD. Right bundle-branch block (RBBB), on the other hand, is seen commonly in the absence of other cardiac abnormalities.
Cardiac Stress Testing
Exercise Electrocardiography
The exercise stress test is a means of establishing the diagnosis of myocardial ischemia. It also can be used to assess the efficacy of antianginal therapy, to identify patients who are likely to have more severe CAD and a large area of myocardium at risk, and to assess serially the degree of conditioning or exercise capacity in patients of all age groups. The American College of Cardiology (ACC)/American Heart Association (AHA) exercise testing guidelines outline the recommendations for the use of exercise testing in establishing the diagnosis of CAD, in assessing risk and prognosis in patients with symptoms or a prior history of CAD, and the use of exercise testing after MI (18,19). The usefulness of exercise testing in establishing the diagnosis of CAD is based in part on the likelihood that the patient has this condition (i.e., the “pretest probability” of CAD). This can be determined by the patient's age, gender, and symptoms. For example, exercise testing would not be expected to greatly improve the accuracy of diagnosing CAD in an older patient with typical angina (who has a high pretest probability of CAD) nor in a young, asymptomatic individual (who has a low pretest probability of CAD). The usefulness of stress testing in these situations would be limited by false-negative and false-positive findings, respectively. The ACC/AHA guidelines recommend exercise testing to diagnose CAD in adult patients with an intermediate pretest probability of CAD based on gender, age, and symptoms (18,19). For patients with known CAD, the guidelines recommend stress testing for those with a significant change in clinical status. Patients with unstable angina, decompensated heart failure, severe aortic stenosis, or uncontrolled hypertension should not be referred for stress testing because of an unacceptably high risk for provoking a cardiac event during exercise.
Exercise stress testing is based on the rationale that, as the work performed by the patient increases, cardiac work is increased. The increased cardiac work results in increased myocardial oxygen utilization, with a subsequent increased demand in coronary blood flow. If narrowed or obstructed coronary arteries prevent the required increase in coronary blood flow, myocardial ischemia may occur and be manifested as chest pain and/or ECG changes (20).
The simplest and least expensive exercise stress test is the graded, symptom-limited exercise treadmill test. The test requires 12-lead ECG monitoring of the patient while walking on a treadmill at workloads that can be progressively increased by increasing the speed and inclination of the treadmill. A stationary bicycle ergometer (with hand
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pedals) can be substituted for a treadmill, permitting the patient to exercise with his or her arms instead of legs. Although it is not commonly used, this method of stress testing permits exercise by a patient who may otherwise be unable to do so because of lower-extremity claudication, arthritis, or amputation. It also may be useful in the evaluation of patients who have chest pain predominantly or exclusively with work that involves the arms and shoulders.
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FIGURE 62.2. Algorithm for determining the appropriate stress test. See text for a description of the procedures. |
A simple algorithm can be used to decide the type of stress test to recommend (Fig. 62.2). First, the patient's ability to exercise should be assessed. If the patient can walk up a flight of stairs carrying laundry or groceries, for example, a treadmill exercise protocol can generally be chosen to allow the patient to achieve a level of cardiac work that permits meaningful information to be obtained from the test. If the patient cannot perform this task, or one that is comparable, a pharmacologic stress test with cardiac imaging (discussed later) should generally be recommended. The patient's baseline ECG should be reviewed to determine the presence of baseline ST-segment abnormalities that might lower the predictive value of exercise-induced changes. False-positive stress tests are often encountered in women, in patients taking medications such as digoxin or amiodarone, and in patients with left ventricular hypertrophy or mitral valve prolapse (21). For these patients and in those with baseline ST-segment abnormalities, intraventricular conduction defects (i.e., LBBB or RBBB), or other conduction system disorders (e.g., Wolff-Parkinson-White syndrome), the diagnostic accuracy of the exercise stress test can be enhanced by concurrent radioisotopic or echocardiographic imaging (see later discussion). The choice between radioisotopic or echocardiographic imaging depends largely on the expertise of local laboratories.
Radioisotope Imaging
Radioisotope imaging can enhance the specificity of stress testing by evaluating myocardial function or flow (22). Radioisotope imaging can be used in conjunction with either treadmill exercise testing or pharmacologic stress testing, using either dobutamine to increase cardiac work or adenosine or dipyridamole to alter coronary blood flow (see later discussion). Commonly used imaging modalities include radioisotope imaging with thallium 201 (201Tl)– and/or technetium 99 (99Tc)–based agents (e.g., 99mTc-sestamibi). The usefulness of 201Tl as a perfusion tracer is based on its ability to function as an analogue of ionic potassium. It is very efficiently extracted by healthy myocardial cells, and uptake is proportional to regional perfusion and myocardial viability. 99mTc-sestamibi has a shorter half-life (6 hours) than does 201Tl (73 hours), allowing administration of a larger tracer dose. This and its higher emission energy make it an excellent agent for cardiac imaging. 99mTc-sestamibi is particularly useful in obese patients and in patients with large breasts (because of possible attenuation of the radioisotopic images in the area of the anterior myocardium).
Both 201Tl and 99mTc-sestamibi can be used to assess regional myocardial blood flow, either by planar imaging or by single-photon emission computed tomography (SPECT). Imaging usually occurs at two separate times: the stress scan, obtained very shortly after the patient has exercised or received a pharmacologic agent, and the rest scan, obtained either before or several hours after stress. The radioisotope is injected intravenously at the time of peak exercise (or at the time of peak infusion during a pharmacologic stress test), and scintigraphic images are obtained shortly thereafter, depicting regional myocardial perfusion at the time of peak stress. The rest scan typically is obtained several hours later and shows redistribution of the isotope. Ischemia is indicated by the filling in of a cold spot defined on the stress images (i.e., normalization or “redistribution” of a radioisotopic defect), and infarction is indicated by a persisting cold spot or one with only partial redistribution.
Radioisotope imaging with stress gated blood pool scans (multiple-gated acquisition [MUGA]) also can be used to assess myocardial ischemia. To allow for continuous imaging during exercise, stress MUGA is performed with the patient exercising on a semirecumbent bicycle. The rationale for this test is based on the fact that myocardium that becomes ischemic during graded exercise develops regional wall-motion abnormalities that can be detected by sequential image analyses. This type of imaging labels the blood pool with a radioisotope and gates image acquisition to the ECG. Right and left ventricular volumes, regional left ventricular wall motion, and global and regional ejection fractions can be measured, both at rest and with stress.
The cost of stress testing with radioisotope scanning usually is several times that of a standard exercise test.
Stress Echocardiography
Two-dimensional echocardiography can be used instead of radioisotope scanning to detect areas of regional myocardial dysfunction (as evidenced by a wall-motion
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abnormality) with exercise or pharmacologic stress (23,24). Typically, baseline images are first obtained at rest to determine the adequacy of the echocardiographic images. If these images are technically inadequate (e.g., because of obesity or severe obstructive lung disease), an intravenous ultrasound contrast agent can be used if available; if not, radioisotope images are preferable. If the rest images are technically adequate, the patient undergoes treadmill exercise stress and then images are reacquired immediately, using special software to allow for direct comparison of pre-exercise and postexercise images. If pharmacologic stress testing with dobutamine (see Pharmacologic Stress Testing) is used, the dose of dobutamine is increased in stepwise fashion, and echocardiographic images typically are obtained each time the dose is increased. The safety of dobutamine stress echocardiography is comparable to that of a routine exercise stress test (23,25,26). The sensitivity, specificity, and cost of the test are similar to those of radioisotopic stress testing. Stress echocardiography may be preferred in some cases because additional information is provided that is not obtained with radioisotopic scanning (e.g., presence of pericardial effusion, ventricular hypertrophy, or valvular abnormality). It also avoids exposure to radioactivity.
Pharmacologic Stress Testing
Patients who are unable to exercise because of physical limitations can be evaluated after intravenous administration of dipyridamole, adenosine, or dobutamine in conjunction with an imaging modality. Dipyridamole and adenosine dilate all coronary vessels and generally increase flow to all areas of the heart. Enhanced dilation of normal coronary arteries, compared to that of significantly narrowed vessels, augments differences in flow that usually are not apparent at rest. These agents are suitable for use with radioisotopic imaging modalities that may readily demonstrate this flow heterogeneity. After administration of dipyridamole or adenosine followed by either 201Tl or 99mTc-sestamibi (i.e., the stress image), myocardium supplied by a narrowed coronary artery typically demonstrates a perfusion defect that “fills in” during the rest image. Because of its ultrashort duration of action, adenosine is preferable to dipyridamole for this test.
Dobutamine is a β1-receptor agonist that at high dosages (20–40 µg/kg/min intravenously) increases myocardial contractility and heart rate in a similar manner and extent to exercise. Heart rate may not be affected to the same extent as contractility, and atropine often is administered intravenously to increase the heart rate to the maximal predicted heart rate for age. Dobutamine can be used in conjunction with either echocardiography or radioisotopic imaging for diagnosis of CAD.
Mild side effects (e.g., nausea, flushing, and headache) are common with dipyridamole, adenosine, and dobutamine. Dipyridamole and adenosine (but not dobutamine) can produce severe bronchospasm and therefore must be used with caution or not at all in patients with asthma or chronic obstructive pulmonary disease. Adenosine can cause transient heart block, typically lasting several seconds. Because dobutamine increases atrioventricular conduction, it should not be used in patients with atrial flutter and should be used carefully in patients with atrial fibrillation.
Implications of an Abnormal Stress Test
If treadmill exercise stress testing is performed, factors affecting prognosis include the degree of ST-segment depression, time to development of ST-segment depression during exercise, duration of the ST-segment depression in recovery, and speed of heart rate decline during recovery. In addition, an ischemic ECG response that is accompanied by hypotension generally implies a large amount of myocardium at risk. Prognostic information from pharmacologic stress testing-induced ECG abnormalities is less reliable. The number, size, and location of abnormalities evident on stress imaging studies reflect the location and extent of functionally significant coronary stenoses (27). Both radioisotopic and echocardiographic imaging can detect left ventricular dilation with stress, a finding that suggests global, severe ischemia. Lung uptake of a radioisotopic tracer indicates stress-induced left ventricular dysfunction and suggests multivessel CAD. Many studies have shown that high-risk abnormal stress tests are associated with an increased risk for cardiac events. On the other hand, normal radioisotopic or echocardiographic stress tests are associated with a favorable prognosis. In a review of 16 studies involving almost 4,000 patients over 2 years, a negative perfusion scan was associated with a 0.9% rate of cardiac death per year, similar to that of the general population (28).
Ambulatory Electrocardiography
The ambulatory ECG (Holter monitor) may be useful for detecting myocardial ischemia. However, it is not a good tool for screening patients to make the diagnosis of CAD. In patients with CAD who are symptomatic during ambulatory ECG monitoring, ST-segment elevation or depression can be observed during episodes of pain and at other times as well (silent ischemia; see later discussion). In patients with silent ischemia, the ambulatory ECG is particularly useful for quantifying the degree and frequency of ischemia and assessing the efficacy of therapy.
Electron-Beam Computed Tomography
Studies in the 1970s demonstrated that coronary calcification (detected by cardiac fluoroscopy) was useful in identifying patients with angiographically significant CAD (29).
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EBCT is a highly sensitive technique for detecting coronary artery calcium and may be useful for diagnosing CAD noninvasively (11). ECG gating allows data acquisition within one or two breath-holds, making it a rapid test with limited radiation exposure. The images obtained by this technique allow the determination of a calcium score, which is an index of calcium deposition in multiple arterial segments and is a good approximation for overall plaque burden in the coronary tree. High calcium scores are associated with increased risk for MI (30). The test offers improved discrimination over conventional risk factors in the identification of people with CAD (31). The negative predictive value of EBCT is high. The test is particularly useful for screening asymptomatic individuals with multiple risk factors, in whom an abnormal EBCT should prompt further testing and/or treatment. A very low EBCT score would be reassuring (32).
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FIGURE 62.3. Anatomic representation of the coronary arteries. These vessels are represented as they would be seen on the angiogram. No attempt has been made to convey the third dimension. Careful study of the changes in position of the various branches with rotation of the heart is essential to intelligent interpretation of arteriograms. A: Anteroposterior. B: Lateral. (Modified from Abrams HL, Adams DF. The coronary arteriogram: structural and functional aspects [First of two parts]. N Engl J Med 1969;281:1276, with permission.) |
Cardiac Catheterization and Coronary Angiography
Coronary angiography is defined as the radiographic visualization of the coronary vessels after injection of radiopaque contrast medium (33). This technique provides direct information about the presence of CAD and defines the distribution and severity of obstructive coronary lesions. It is considered the “gold standard” to confirm the diagnosis of CAD. The images obtained are stored as either 35-mm cine film or, more commonly, a digital recording. Percutaneous or cutdown techniques of the femoral or brachial arteries allow insertion of sheaths for the introduction of selective catheters for the right and left coronary ostia, saphenous bypass grafts, or internal mammary arteries. Arteriography is performed as part of cardiac catheterization, which may include left ventriculography and hemodynamic assessment. Figure62.3 shows diagrammatically the coronary arteries and their branches as they appear on coronary arteriography. The three major coronary arteries are the left anterior descending, left circumflex, and right coronary artery. The coronary tree can be divided into 29 segments, but the extent of disease usually is defined as one-vessel, two-vessel, three-vessel, or left main disease, with significant disease taken to mean the presence of ≥50% reduction in diameter (some operators and texts use ≥70% reduction in diameter).
The 1999 ACC/AHA Guidelines for Coronary Angiography outline the indications and contraindications for the procedure (33). The guidelines recommend arteriography for patients with CCS class III or IV angina while receiving medical treatment (marked limitations of ordinary physical activity because of angina or angina at rest, discussed earlier) and those with high-risk criteria on noninvasive testing regardless of angina severity. It may be reasonable to consider coronary arteriography for patients whose angina has improved with medical treatment but remains present, those in whom noninvasive testing has shown evidence of worsening disease, those who cannot tolerate medical therapy, those with angina who cannot be adequately risk stratified because of disability or illness, and those whose occupation involves the safety of others (e.g., pilots, bus drivers) and who have abnormal, but not high-risk, stress test results.
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Inherent in the recommendation for coronary arteriography is the assumption that the patient is a potential candidate for coronary revascularization. If the patient's general medical condition or other medical problems preclude revascularization, or if the patient refuses to consider revascularization regardless of catheterization results, arteriography is ill advised.
Indications for percutaneous coronary intervention ([PCI] including angioplasty and stenting) (34) and coronary artery bypass surgery (35) are reviewed in separate ACC/AHA guidelines and are discussed later in this chapter.
Patient Experience
The patient may undergo cardiac catheterization as part of an evaluation during a hospitalization, but the test itself does not require that the patient be admitted to the hospital. The procedure is not painful, and the patient remains awake throughout the study. Approximately 1 hour before the procedure, the patient is given a sedative, often diazepam (Valium), 5 to 10 mg orally. After the patient is brought to the catheterization laboratory, either the area of the brachial artery or the femoral artery is prepared for sterile procedure. The site of introduction of the catheter usually is selected based on the preference of the operator but also is guided by the presence and extent of peripheral vascular disease. Typically, a catheter is introduced percutaneously through a wire that is threaded through an introducer needle. Under fluoroscopic guidance, the catheter is threaded to the coronary sinuses, and the orifices of the right and left coronary arteries are injected sequentially with contrast medium. The patient is asked to hold his or her breath during the few seconds of the injection. In addition to this part of the test, which visualizes the coronary arteries, studies are typically performed to measure ventricular pressures and to assess left ventricular contraction during injection of dye directly into the left ventricular cavity. During ventriculography, focal wall-motion abnormalities, ventricular aneurysms, and valvular lesions such as mitral regurgitation can be assessed in addition to the measurement of overall left ventricular function and ejection fraction. At the end of the procedure, the catheter is withdrawn, and pressure is applied to the arteriotomy site to achieve hemostasis.
During the procedure, the patient should feel relaxed or even slightly drowsy from the sedation. The patient usually does not feel pain except for the moment when the needle is initially introduced. There is some pressure as the catheter is held in place. The patient may experience a sensation of hot flushing when the dye is injected, particularly when the larger bolus of dye is injected into the left ventricle during ventriculography.
Risks and Relative Contraindications
The major complications of coronary arteriography are MI, stroke, and death. These risks are related to the experience of the laboratory performing the study and to the risk profile of the patient undergoing the test. Risks tend to be lower in young, otherwise healthy patients. Risks tend to be higher in older patients with poor left ventricular function, diabetes mellitus, or peripheral vascular disease, and those who are clinically unstable (e.g., patients with cardiogenic shock, recent acute MI, or decompensated heart failure) at the time of the procedure. In a survey of almost 60,000 patients, mortality from angiography was 0.11%, MI occurred in 0.05%, and stroke occurred in 0.07%. The most common complication was a problem with vascular access, which occurred in 0.43% of patients (36).
There are no absolute contraindications to coronary arteriography. Relative contraindications include renal failure, active gastrointestinal bleeding, acute stroke, severe anemia, coagulopathy, unexplained fever or active untreated infection, severe uncontrolled hypertension, allergic reaction to angiographic contrast agents, and decompensated congestive heart failure (CHF). Renal insufficiency has been the most well-studied complication. It occurs in up to 5% of patients without preexisting renal dysfunction and in 10% to 40% of patients with baseline renal insufficiency. More than 75% of patients who develop renal insufficiency recover normal renal function, although 10% of these patients may require dialysis temporarily. Pretreatment with intravenous hydration (0.9% saline) (37) and limiting the amount of intravenous contrast material used are effective means to avoid contrast-induced renal dysfunction.
For patients with underlying renal dysfunction, pretreatment with N-acetylcysteine (38) or intravenous sodium bicarbonate (39) has been shown to reduce contrast-induced acute renal failure following cardiac catheterization. No direct comparison of these prophylactic measures has been performed to date. Patients taking the oral hypoglycemic metformin should be asked to withhold it for 48 hours prior to the procedure, because the use of iodinated contrast dye in patients taking metformin has been associated with development of lactic acidosis (40). The major predictors of contrast allergy are prior contrast allergy (50% risk of subsequent reaction), iodine allergy, and shellfish allergy. These conditions should be discussed with the patient before referral for angiography. The use of nonionic contrast medium along with pretreatment using corticosteroids and antihistamines may reduce allergic complications.
Computed Tomography Coronary Angiography
High-definition rapid CT scanning has evolved as a potent diagnostic tool for identifying CAD noninvasively. Newer CT devices are able to rapidly scan through a patient's chest using many slices for image acquisition (the current
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state of the art is to use a 64-slice scanner), quickly and accurately identifying unique features of coronary and cardiac anatomy. Multislice cardiac CT scanning is extremely accurate in detecting coronary narrowings in the proximal two thirds of the coronary tree that are demonstrated by conventional coronary angiography, but its resolution of the distal third is less accurate. However, it is superior to conventional coronary angiography in identifying extraluminal vascular abnormalities that result in coronary narrowings but cannot be seen by conventional techniques. Additionally, other noncardiac causes of chest pain, such as aortic dissection, pneumonia, or pulmonary embolus, may be diagnosed by this imaging technique. CT coronary angiography is particularly useful in patients with peripheral vascular disease because it can minimize or avoid catheter-related complications. During CT angiography, the patient receives intravenous radiographic contrast, and the total scanning time usually is ≤15 minutes. Image quality is improved at slower heart rates and patients may receive low doses of β-blockers to facilitate this. Because iodinated contrast is used for this procedure, the risks and precautionary treatment associated with such therapy is the same as for cardiac catheterization.
Treatment of Angina Pectoris
General Therapeutic Considerations
In evaluating and treating patients with angina, it is of paramount importance to identify and treat underlying contributing factors and to modify cardiac risk factors that promote CAD progression if possible.
Hypertension often is present in patients with angina. There is a linear relationship between left ventricular work and myocardial oxygen demand. Left ventricular systolic pressure increases in response to an increase in peripheral vascular resistance. Both systolic and diastolic hypertension can increase myocardial oxygen demand. An attempt should always be made to reduce resting blood pressure to normal in patients with chronic hypertension, including those with isolated systolic hypertension. This can be of crucial importance in reducing the frequency and severity of angina pectoris in the hypertensive patient. β-Blockers and calcium channel blockers (see Chapter 67) are excellent choices in such patients because these agents have other antianginal properties as well. Agents such as hydralazine and minoxidil, which cause a reflex tachycardia, are less desirable.
It is important to achieve a maximal level of pulmonary compensation in patients with angina and coexisting lung disease (see Chapter 60). Chronic hypoxemia, acidosis, and the increased work of breathing in patients with pulmonary disease increase myocardial oxygen demand, decrease myocardial oxygen delivery, or both. Unfortunately, the treatment of angina in patients with severe lung disease often is limited by a real, or perceived, need to avoid the use of β-blockers (see later discussion).
Abstinence from tobacco products is essential because nicotine in tobacco can cause coronary vasoconstriction. Chapter 27 describes techniques used to achieve this goal. Similarly, passive tobacco smoke should be avoided.
The possibility of hyperthyroidism (see Chapter 80) in patients with angina should never be overlooked, particularly in older patients or in those with increasing angina. Often, particularly in the older patient, other obvious signs of hyperthyroidism are not present. For example, hyperthyroidism may be manifested only by an increased frequency or severity of angina, an increase in heart rate in people with atrial fibrillation, or increasing heart failure.
Anemia is important to consider in patients with angina, particularly if the hemoglobin concentration falls to <7 g/dL, when cardiac output must increase to maintain adequate peripheral oxygen delivery at rest. Obviously, this problem is exacerbated in patients with concomitant chronic lung disease and hypoxemia.
Heart failure (see Chapter 66) in patients with angina should always be optimally treated. The real possibility that heart failure is producing angina at rest (see later discussion) or nocturnal angina should be considered. Diuretics, vasodilators, and β-blockers may be useful in patients with rest or nocturnal angina and may reduce the frequency and severity of angina. The calcium channel blocker amlodipine has been shown to be safe in patients with left ventricular dysfunction and may be useful for patients with angina in this setting because it has little negative inotropic effect, reduces preload and afterload, helps decrease left ventricular end-diastolic pressure, and lowers peripheral vascular resistance.
Lipids and Diet
Most of the recent decline in mortality from heart disease is believed to be related to primary and secondary risk factor reductions (41,42). Numerous randomized controlled trials involving cholesterol reduction have been performed and have supported the ability to reduce CAD morbidity and mortality with both primary and secondary prevention strategies. The West of Scotland Coronary Prevention Study demonstrated significant mortality reduction with treatment of hyperlipidemia with pravastatin in asymptomatic people; the greatest benefit occurred in patients with other risk factors for CAD (43). The landmark Heart Protection Study in the United Kingdom randomized subjects with CAD, peripheral vascular disease, or diabetes to 40 mg of simvastatin or placebo and demonstrated reductions in mortality in simvastatin-treated
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patients regardless of baseline LDL cholesterol levels (44). The value of secondary prevention was established by the Scandinavian Simvastatin Survival Study (45) and the Cholesterol and Recurrent Events (CARE) trial (46). Both trials demonstrated a significant reduction in mortality when LDL cholesterol levels were lowered to approximately 100 to 120 mg/dL. Other trials also have clearly demonstrated that coronary artery lesions did not progress when elevated LDL cholesterol levels were reduced to <100 mg/dL (47,48). More recent trials have compared the effects of more aggressive to less aggressive lipid-lowering strategies, usually by examining the effects of high-dose and lower-dose therapy with a β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor or “statin.” One of these trials demonstrated that 80 mg of atorvastatin reduced the frequency of cardiovascular events to a greater degree than did 40 mg of pravastatin by more intensive lowering of LDL cholesterol (mean LDL cholesterol lowered to 62 mg/dL) (49). Another study compared the effects of 80 mg and 10 mg of atorvastatin in patients with stable CAD and demonstrated clinical benefit with the more aggressive lipid-lowering approach, achieving mean LDL cholesterol levels of 77 mg/dL and 101 mg/dL in the 80-mg and 10-mg groups, respectively (50).
The NCEP guidelines indicate that the desirable LDL cholesterol level is <100 mg/dL in patients with established CAD or with coronary heart disease risk equivalents including diabetes mellitus, multiple risk factors that confer a 10-year CAD risk >20%, or other clinical forms of atherosclerotic disease (i.e., peripheral arterial disease, abdominal aortic aneurysm, or symptomatic carotid artery disease) (10). Updates recommend considering an LDL cholesterol target <70 mg/dL in very-high-risk patients, defined as those with an acute coronary syndrome or with established CAD and multiple major CAD risk factors (especially diabetes mellitus), severe and poorly controlled risk factors (especially cigarette smoking), or the metabolic syndrome (51). Treatment of patients having low HDL cholesterol levels with the fibrate gemfibrozil was shown to reduce the risk of major cardiovascular events in patients with CAD (12). In addition to pharmacologic options for lipid-lowering drug therapy, the guidelines recommend a multifaceted lifestyle approach to reduce CAD risk. This approach calls for reducing the intake of saturated fats to <7% of total calories and reducing dietary cholesterol to <200 mg/day. Achieving an ideal body weight and increasing physical activity also are advised. These lifestyle recommendations are an essential part of treatment for all patients with coronary disease. Chapter 82 discusses these changes in more detail. Obesity has emerged as a national epidemic, with several studies confirming the increased mortality and morbidity from this condition (52). Chapter 83 discusses in detail the various treatment options for this condition.
Alcohol
Alcohol is an acute pressor agent and may be responsible for as many as 10% of all cases of hypertension (53). However, moderate drinking (1–3 drinks per day) is accompanied by an increase in HDL cholesterol level (54). The extent to which the increase in blood pressure associated with heavy drinking mitigates the beneficial effect on HDL remains to be determined (55). A review of lifestyle recommendations for patients with CAD estimated a 20% reduction in mortality with moderate alcohol use (compared with 24% reduction from physical activity and 36% reduction with smoking cessation) (56).
Antioxidants
Although antioxidants may be important in inhibiting atherosclerosis, clinical trials of antioxidant therapy have not demonstrated conclusive long-term benefit. In the Heart Outcomes Prevention Evaluation (HOPE) study, for example, approximately 9,500 patients at high risk for cardiovascular events were randomly assigned to therapy with either 400 IU of vitamin E or placebo for an average of 4.5 years. There was no apparent effect of treatment with vitamin E on cardiovascular outcomes in this study (57). More recently, a meta-analysis of 19 trials suggested the possibility of increasing mortality with high-dosage vitamin E supplementation for CAD prevention, with risk increasing as the dosage of vitamin E exceeded 150 IU/day (58).
Fish Oil and ω-3 Fatty Acids
Fish oils (ω-3 fatty acids) have demonstrated cardiovascular benefit in people who have taken them by decreasing the risk of potentially fatal arrhythmias, slowing plaque progression, decreasing levels of triglycerides, and mildly decreasing blood pressure. Currently, the AHA recommends two servings of fish per week. Similarly, other foods that contain α-linolenic acid, which can be metabolized into ω-3 fatty acids by the body, such as flaxseed, walnuts, soy products, and tofu, are recommended, but the benefit of ω-3 fatty acid production via α-linolenic acid intake is not well delineated (59).
Postmenopausal Hormone Replacement Therapy
Earlier studies demonstrated improvements in surrogate measures such as endothelial function from hormone replacement therapy (HRT). Observational studies suggested a decreased risk for cardiovascular events in women taking HRT compared to women who did not (60,61). This finding led to two randomized, placebo-controlled studies to definitively evaluate the role of HRT in postmenopausal women with chronic stable CAD. The Heart and Estrogen/
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Progestin Replacement Study (HERS) showed that HRT did not result in a reduced risk for cardiovascular death or nonfatal MI (13). The Estrogen Replacement and Atherosclerosis Study (ERAS) failed to show an effect of HRT on the angiographic progression of atherosclerotic heart disease (62). There also is evidence that postmenopausal HRT increases the risk of venous thromboembolic disease (13,63) and gallbladder disease (13) in women with CAD. Therefore, HRT is not recommended for reducing cardiovascular morbidity or mortality in postmenopausal women.
Physical Conditioning
Physical conditioning can improve the exercise tolerance and psychological well-being of patients with stable angina. Additionally, improvements in atherosclerotic risk factors, such as hypertension, glucose intolerance, low HDL cholesterol concentrations, elevated triglyceride levels, and obesity, reduce CAD risk from the perspective of both primary and secondary prevention. The combination of weight reduction and exercise lowers LDL cholesterol concentrations (64). Studies confirm that moderate exercise (20 minutes three times per week) is as effective for weight loss as more vigorous exercise (65). Most large communities have developed supervised exercise programs for patients with CAD. Chapter 63 details the benefits of physical conditioning and exercise programs for patients with heart disease. The AHA-published guidelines for exercise in various patient groups are available on their website (http://www.americanheart.org). Patients with angina should be counseled to avoid physical activities that are known to provoke their symptoms. Health care providers should specifically discuss the safety of sexual intercourse, a subject that people often are reluctant to broach (see Chapter 63). The appropriate level of sexual activity or participation in any stressful physical activity ideally should be based on the results of an exercise stress test. The energy requirements for a broad range of activities are summarized in Table 63.5.
Medical Treatment
The basic objective in treating patients with angina pectoris is not only to relieve or prevent symptoms but also to prevent disease progression. The former goal may be achieved by medical therapy that improves the relationship between myocardial oxygen demand and supply. The latter goal may be accomplished by preventing platelet aggregation and by decreasing the growth of atherosclerotic plaque and the risk of plaque rupture. The major advance in the medical management of angina has been the demonstration that long-acting antiplatelet and antithrombotic agents and vigorous lipid-lowering therapy can improve outcomes in selected patients with CAD. Table 62.2lists practical information about the drugs used most often for treatment of angina.
Nitrates
Traditionally, nitroglycerin and related compounds have been an inexpensive mainstay of treatment of patients with angina pectoris. Nitrates increase coronary blood flow in patients with spasm, but the predominant mechanism of action in most patients is not an increase in blood flow but rather a decrease in myocardial oxygen demand and peripheral vascular resistance. These compounds produce dilation of the venous circulation, reduced venous return, decreased ventricular volume, and decreased wall tension. These effects ultimately reduce myocardial oxygen demand. Nitrates also produce arterial dilation to a lesser degree and thereby reduce the resistance to ventricular ejection. Therefore, the beneficial antianginal effect of nitrates is caused primarily by peripheral vasodilation.
Sublingual nitroglycerin is still the drug of choice in most patients for the relief and prevention of discrete episodes of angina pectoris. The initial dose should be small (0.4 mg) to minimize unpleasant side effects (flushing, headache, light-headedness). Patients should be taught the importance of relieving their pain as soon as possible, and they should be instructed to take nitroglycerin whenever such symptoms appear. If pain is not relieved by two to three tablets of nitroglycerin (the patient should wait at least 5 minutes between doses) or if the need for nitroglycerin increases suddenly and dramatically, the patient should be instructed to call his or her health care provider or go to an emergency facility immediately because of the danger of impending MI. Because nitroglycerin may lose potency on storage, patients should be advised not to keep tablets longer than 3 to 4 months after opening the bottle. If the use of nitroglycerin does not result relieve the angina and the usual side effects are not experienced, the problem may be caused by outdated medicine that has lost its potency rather than by a change in cardiac status. Prophylactic use of nitroglycerin is of particular value in patients who have angina in response to specific and reproducible stress despite other therapies. For example, the patient who develops angina after walking from a car to a place of work can be instructed to take nitroglycerin after the car is parked, wait a few minutes, and then walk to work, thereby preventing pain altogether. The most common side effects of nitroglycerin therapy are flushing and headache. A nitroglycerin sublingual spray has been developed that is designed to deliver 0.4 mg of nitroglycerin with each compression of the nebulizer. Some patients find this preparation more acceptable and more reliable than the tablet.
Long-acting nitrates are available in a variety of preparations (Table 62.2). Careful studies confirm the clinical efficacy of both nitroglycerin ointment and isosorbide tablets
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(66,67). When selecting from among available oral preparations, the major considerations should be efficacy, convenience, and cost. Using these criteria, long-acting isosorbide probably is the best choice for ambulatory patients. A nitrate patch for once-daily use is available. It provides controlled release of 0.2, 0.4, or 0.6 mg of nitroglycerin per hour through a semipermeable membrane applied to the skin by means of an adhesive tape. The patch delivers a standardized dose, but constant serum levels of nitrate predispose to the development of tolerance; therefore, the patch should be removed for a period of the day (e.g., at night) (68).
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TABLE 62.2 Selected Drugs Used in the Treatment of Anginaa |
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The side effects of all long-acting nitrates are similar to those produced by sublingual nitrates. Some patients are unable to take long-acting nitrates because of persistent headache, but for most patients this is not a problem. Nitrates can produce orthostatic hypotension and occasionally syncope.
Sildenafil (Viagra) is a drug used for treatment of erectile dysfunction. The drug inhibits cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5, allowing accumulation of cGMP in the corpus cavernosum of the penis. Because nitrates increase cGMP levels but sildenafil inhibits cGMP breakdown, the combination of sildenafil and nitrates may result in severe hypotension. Therefore, sildenafil should not be used by men who are taking nitrates of any kind (see Chapter 63).
β-Blocking Agents
A number of β-blockers are currently available in the United States. These agents vary in their cardioselectivity, their metabolism, and, to some degree, their side effects (see later discussion and Chapters 64 and 67).
In many respects, β-blockade is an ideal approach to the treatment of angina. It decreases heart rate, myocardial contractility, and systemic blood pressure. These effects, alone or in combination, significantly reduce myocardial oxygen consumption and thereby attenuate the frequency or severity of angina in most patients.
An added benefit for patients with ischemic heart disease is that β-blockade often effectively prevents arrhythmias (see Chapter 64). It may decrease or eliminate premature ventricular contractions (PVCs), and the ventricular rate in patients with atrial fibrillation also may be decreased. Furthermore, when PVCs are frequent, the number of hemodynamically effective ventricular contractions is diminished, which decreases coronary as well as peripheral perfusion. In patients who are in atrial fibrillation, decreasing the ventricular response improves left ventricular dynamics by decreasing heart rate, increasing diastolic filling period, and decreasing myocardial oxygen consumption.
The dosage of a β-blocker can be rapidly increased over hours or days until the desired effect is obtained. The heart rate is a useful guide to treatment, with sinus rhythm at a resting rate of 50 to 60 bpm a reasonable goal. However, the ideal dosage is one that not only results in mild sinus bradycardia at rest but also blocks an increase in heart rate with exercise. The dosage necessary to produce this effect and that necessary to relieve angina pectoris may vary considerably.
Although β-blockers are an important part of the management of CHF (see Chapter 66), the acute effect of these drugs is to decrease myocardial contractility, and they should not be used in patients with decompensated CHF.
β-Blockers are contraindicated in a patient with second- or third-degree block (see Chapter 64) because life-threatening bradycardia can be precipitated in such patients.
The nonselective β-blockers (propranolol, nadolol, pindolol, timolol, carvedilol) are relatively contraindicated in patients with intrinsic asthma. A history of allergic asthma or bronchospasm during pulmonary infections should be sought in all patients for whom β-blockers are being considered. Patients with chronic obstructive lung disease may develop increased bronchospasm from β-blockers even if they have no history of allergic or intrinsic asthma. In such patients, a selective β-blocker with minimal β2-blocking effects should be used. Metoprolol and atenolol both are cardioselective and often can be used safely in such patients and in patients with peripheral arterial disease, particularly Raynaud disease, in whom nonselective β-blockers may exacerbate symptoms. However, even these agents have β2-blocking effects at moderate and high dosages and should be used cautiously in these situations.
Although impotence occurs in ≤1% of the susceptible population, it is a major reason for discontinuing the drug in young and middle-age men. This side effect can sometimes be overcome by prescribing a β-blocker with poor lipid solubility and therefore less penetration of the nervous system (e.g., atenolol instead of propranolol). Atenolol may be less likely to cause depression and confusion or to alter sleep patterns, occasional reported side effects of other β-blockers.
Calcium Channel Blockers
Calcium channel blockers reduce the influx of calcium into the slow channels of the myocardium and smooth muscle (see Chapter 64) and thereby cause several important hemodynamic effects, including dilation of coronary arteries, prevention of coronary vasospasm, and production of systemic vasodilation, thus effectively reducing preload and afterload. They have been shown to be effective in the treatment of both stable and unstable angina, and they are effective antihypertensive agents. A number of calcium channel blockers are currently available (Table 62.2).
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Although many are effective in the treatment of hypertension (see Chapter 67), only a few are currently approved for use in patients with angina: nifedipine, nicardipine, amlodipine, verapamil, and diltiazem. A meta-analysis suggested that use of short-acting calcium blockers, when used to treat hypertension, is associated with adverse outcomes (69). More recently, another meta-analysis compared patients treated with diuretics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or clonidine to those treated with intermediate-acting or long-acting calcium channel blockers and showed that those treated with calcium antagonists had a higher risk for MI, CHF, and major cardiovascular events (70). Although calcium channel blockers are effective in treating patients with angina, it seems reasonable to consider other therapies first and to use calcium antagonists only if other antianginal medications do not relieve symptoms.
Nifedipine is a potent coronary and systemic vasodilator and may be used for angina and for treatment of hypertension. The common side effects of nifedipine are dizziness, flushing, headache, nausea, diarrhea, and peripheral edema. The major adverse effect is significant hypotension, which, in association with a reflex tachycardia, can actually intensify myocardial ischemia in a few patients. All side effects usually can be controlled by reducing the dosage of the drug. Nifedipine and other calcium channel blockers should be used cautiously in patients taking digoxin because digoxin excretion may be inhibited and digitalis toxicity may be induced. At higher dosages in patients with reduced left ventricular function, negative inotropy may be observed with nifedipine.
Nicardipine is structurally similar to nifedipine but is less likely to cause hypotension or left ventricular dysfunction. It may be useful in patients with angina and borderline blood pressure.
Amlodipine has been shown to be an effective antianginal and antihypertensive agent. Its safety in patients with significant left ventricular dysfunction makes it a particularly attractive anti-ischemic agent in patients with angina and reduced left ventricular ejection fraction (71). Added advantages are its once-daily dosing and the infrequent incidence of side effects. It has few, if any effects, on the atrioventricular (AV) node. Reflex tachycardia after administration is unusual.
Verapamil is often prescribed for the treatment of hypertension or arrhythmia but is also an effective antianginal agent. However, it has a more potent negative inotropic effect than other calcium channel blockers and significantly retards AV conduction. Therefore, it should not be used in patients with compromised left ventricular function or in those with sinus bradycardia, sick sinus syndrome, or AV block (seeChapter 64). In these situations, amlodipine or nicardipine are safer choices. Verapamil may be particularly beneficial in the patient with a supraventricular arrhythmia who also has angina.
Diltiazem also significantly retards AV conduction, but it has less of a negative inotropic effect than does verapamil and, in contrast to nifedipine, is unlikely to cause hypotension or other side effects (e.g., flushing, headache, edema). It is available as a twice-daily or once-daily preparation.
Caution must be exercised when treating older patients with calcium blockers, especially if they are used in conjunction with a β-blocker or other agents that slow AV conduction (e.g., digitalis) or if used in patients with pre-existing conduction system disease. In such patients, significant heart block and bradycardia can be precipitated but usually resolve after stopping administration of the calcium blocker or after the administration of calcium intravenously. This effect, most commonly seen with verapamil and diltiazem, may occur with other calcium blockers but not with amlodipine.
Anticoagulants and Antiplatelet Drugs
Aspirin (81–325 mg) remains the least expensive agent for reducing platelet aggregation. The AHA/ACC guidelines on the management of chronic stable angina recommend daily aspirin, in the absence of contraindications, for all patients with the condition (72). If aspirin is absolutely contraindicated, clopidogrel (75 mg), an inhibitor of adenosine 5′-diphosphate (ADP)-induced platelet aggregation, may be used. It is generally preferable to ticlopidine, a drug with a similar mechanism of action, because ticlopidine has a slower onset of action and is more often associated with the development of neutropenia and, rarely, thrombotic thrombocytopenic purpura. Clopidogrel is commonly used for at least several months in patients following PCI and has been shown to decrease the rate of restenosis (73). Studies in patients with acute coronary syndromes have demonstrated improved clinical outcomes at 1 year in those taking clopidogrel (74). As with all antiplatelet drugs, clopidogrel is associated with an increased risk for bleeding. Other than the increased bleeding risk, the most common side effect is a skin rash. Despite its significant cost compared to aspirin, several studies have demonstrated the cost effectiveness of clopidogrel in acute coronary syndromes and for percutaneous interventions (75).
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors reduce morbidity and mortality in patients with CHF (see Chapter 66) and should be part of the treatment regimen of patients with CHF and angina. The HOPE study demonstrated that the ACE inhibitor ramipril reduced mortality and the risk of MI and stroke in patients with vascular disease or diabetes plus one other cardiovascular risk factor who were not known to have left ventricular dysfunction or CHF (57). However, a later study examined the use of ACE inhibitors for patients
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having stable CAD with preserved left ventricular function and observed no cardiovascular benefit during almost 5 years of followup (76). Although the routine use of ACE inhibitors cannot be recommended for all patients with CAD and preserved left ventricular function, it certainly should be considered, particularly in patients with coexistent hypertension or diabetes mellitus.
Initiating and Adjusting Long-Acting Drugs for Angina
The choice of an antianginal regimen should be made after evaluation of the patient's age, angina frequency, lifestyle, and possible mechanism of angina. In addition, the patient's financial resources should be considered because many drugs, although effective, are expensive and are not available in generic form. In patients with stable angina, a β-blocker is the best initial therapy. A nitrate preparation may be used if β-blockers are contraindicated or if β-blockers alone fail to prevent angina (Table 62.2). A calcium channel blocker may be prescribed to patients who have variable chest pain, in whom coronary artery spasm (see Variant Angina) may be playing a role, and to those intolerant of β-blockers. If the patient does not improve, the dosage may be increased weekly until a response is achieved. If the type of treatment selected initially fails to help at a maximally tolerated dosage, another agent can be added or substituted. Because nitrates and β-blockers decrease myocardial oxygen demand by different mechanisms, concomitant use of the two types of therapy is reasonable. If it is necessary to stop β-blocker therapy, it should be tapered over several days to avoid the risk of precipitating angina, which may occur when a β-blocker is abruptly discontinued.
Patients who do not improve after maximal medical management for angina pectoris often are considered for coronary arteriography and possible revascularization. Therefore, it is important to ensure that maximally tolerated doses of medications are used before medical therapy is considered unsuccessful. In general, maximal medical therapy for angina consists of a β-blocker, a long-acting nitrate, and a calcium channel blocker in doses that either achieve the desired effect or cannot be increased because of the side effects. In addition, all patients with angina should take daily aspirin (or clopidogrel if aspirin is absolutely contraindicated).
Percutaneous Coronary Intervention
PCI offers an important option for the treatment of CAD that cannot be controlled by medical therapy. PCI has the ability to restore nearly normal coronary flow in diseased native coronary arteries, without the cost and morbidity of bypass surgery. Various strategies are available, but all generally involve mechanical treatment of the coronary lesion with balloon angioplasty alone, stenting with mechanical devices, varying combinations of atherectomy, plus stenting or laser-guided vessel recanalization. Patients are identified as candidates for PCI based on their coronary anatomy determined by coronary angiography. PCI initially was used to treat patients with only single-vessel, proximal, discrete, noncalcific coronary lesions. However, in skilled hands and through improvements in the stents themselves, PCI has evolved as an appropriate treatment for multivessel CAD. Although there are no absolute contraindications to the procedure, patients with arterial dissection or eccentric calcific and long stenotic lesions are poor candidates and have a higher risk for complications and restenosis. These patients are best treated with surgery if medical therapy alone is ineffective.
Patients who are appropriate candidates for PCI undergo the procedure either immediately after cardiac catheterization or at a later time, depending on the clinical situation and the needs of the particular patient. The patient's experience with PCI is similar to that for cardiac catheterization and coronary arteriography (described earlier in this chapter). The major complications of PCI are abrupt vessel closure and restenosis. The usual restenosis rate after conventional balloon angioplasty is 30%, but the rate can be as high as 40% to 50%. Restenosis most commonly occurs within the first 6 months and can be successfully treated by a second angioplasty. A lack of symptoms after 6 to 8 months usually indicates a favorable long-term prognosis. The use of intracoronary stents has significantly reduced the rates of both abrupt vessel closure and restenosis (77,78). Intracoronary stents typically are stainless steel cylindrical structures and often are self-expanding. They are available in a variety of lengths and sizes, and several types allow treatment of the target lesion with pharmacologic agents to retard restenosis. Evidence demonstrates that such drug-eluting stents have a lower rate of occlusion versus bare-metal stents (79). Stents are delivered and deployed on balloon catheters using guiding catheters and guidewires.
Barring complications, the patient's experience during PCI (with or without intracoronary stent placement) and the time required for the procedure are the same as for coronary angiography (see previous discussion). The only exception is that many patients experience chest pain during inflation of the balloon in the coronary artery. The incidence of major side effects (including coronary artery dissection, MI, and sudden death) is related to the skill and experience of the operator and can be as low as 1% to 4%. Overall, the procedure is successful 80% to 90% of the time. Patients usually can be discharged the day after the procedure and often can return to work 1 week later. After successful angioplasty and stent placement, patients are prescribed aspirin indefinitely and clopidogrel or ticlopidine for at least 4 to 6 weeks and often for at least several months, depending on the type of procedure
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and the patient's clinical condition. Patients who cannot take clopidogrel and who require ticlopidine can develop leukopenia, so blood counts should be checked at 2-week intervals.
Surgical Management
Coronary artery bypass graft (CABG) surgery is one of the most common surgical procedures performed in the United States country today. However, advances in PCI technology and expertise have reduced the number of patients referred for CABG. It is generally accepted that patients with incapacitating angina pectoris who have good left ventricular function and who have not responded to maximal medical therapy should be considered candidates for coronary arteriography and subsequent surgery. Early studies demonstrated that CABG surgery prolongs survival compared with medical therapy in patients with stable angina who have ≥50% stenosis of the left main coronary artery (80) or who have triple-vessel CAD and a left ventricular ejection fraction between 35% and 50% (81). Long-term followup indicates that, in patients with normal left ventricular function, surgery does not result in a survival benefit compared to medical therapy, even in patients with left main or triple-vessel CAD (82). In diabetics, CABG yields better long-term outcomes compared to (usually multiple) PCIs (83).
CABG surgery usually involves the use of saphenous vein bypass grafts and implantation of an internal mammary artery into the native coronary artery circulation or the placement of radial artery conduits as bypass grafts. Some surgeons also use radial or gastric arterial conduits in patients undergoing repeat surgical procedures. The technique used is often based on the surgeon's preference and experience.
CABG usually is performed through a median sternotomy using cardiopulmonary bypass and cardioplegic arrest. Minimally invasive techniques use a limited thoracotomy incision and are associated with less postoperative pain, a shorter stay in the intensive care unit, earlier discharge from the hospital, and a more rapid recuperation. Alternatives to standard bypass procedures can be performed on the beating heart using “off pump bypass surgery” in an effort to avoid some of the embolic complications of traditional cardiopulmonary bypass surgeries. Some centers have little, if any, experience with these techniques, and they are not available in every community. These operations may be technically more challenging and, understandably, there is a shortage of long-term outcome data compared with conventional bypass techniques.
CABG surgery results in complete (or nearly complete) relief of angina pectoris initially in approximately 60% of properly selected patients, and another 20% have a significant decrease in their angina (84). There is a demonstrable increase in exercise tolerance after surgery in approximately 60% to 80% of such patients.
Patients with good left ventricular function have a 1% to 2% mortality rate from surgery, and <4% of patients develop evidence of MI during the perioperative period. Perioperative MI is more likely to occur in older patients and in patients with severe disease distal to a proximal obstruction. Another major complication of bypass surgery is stroke, which may be caused by cerebral hypoperfusion, arterial embolization, or both. The risk of perioperative stroke varies from <1% to approximately 6%, depending on the patient's risk factors (85,86). The risk is highest in patients older than 70 years and in those with pre-existing cerebrovascular disease or a previous stroke (87,88, 89). Patients with significant atherosclerosis of the proximal or ascending aorta or of the carotid or intracranial cerebral arteries are at increased risk. Neuropsychiatric complications of CABG include problems with memory and other cognitive functions. The prevalence of these disturbances varies from approximately 10% to 80% soon after surgery, depending on the manner in which neurocognitive function is assessed (90,91). In general, neuropsychiatric disturbances resolve slowly over several months.
Historically, up to 30% of patients developed recurrent angina within 5 years after bypass surgery. The diagnosis of recurrent angina should be confirmed by exercise stress testing. The initial treatment is the same as it is for patients who have not undergone bypass surgery: β-blockers, nitrates, or calcium channel blockers. Patients who prove to be unresponsive to medical treatment should undergo coronary arteriography in an effort to delineate new lesions that could be amenable to PCI or repeat CABG. In an attempt to prevent formation of such lesions, it is critical to administer aspirin to patients after bypass surgery (see Chapter 57). In all patients undergoing CABG, it is imperative to implement strict risk factor modification, specifically smoking cessation and treatment of hyperlipidemia to achieve an optimal LDL cholesterol level.
The postpericardiotomy syndrome may develop after bypass surgery, usually within 2 to 4 weeks (but sometimes as early as a few days or as late as 6 months after the operation). The syndrome is characterized by fever, fatigue, pleuritic chest pain, and often pleural and pericardial effusions. Laboratory examination shows leukocytosis and an elevated erythrocyte sedimentation rate. Large effusions may require drainage, but most patients respond to diuretics and a nonsteroidal anti-inflammatory drug (e.g., indomethacin 25–50 mg three times per day for 1–2 weeks). Patients who are refractory to such treatment usually respond to prednisone, initially 60 mg/day for 2 to 3 days, with tapering of the dosage over 7 to 10 days. Constrictive pericarditis is a late rare complication of the postpericardiotomy syndrome; when it occurs, pericardial stripping is often necessary.
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Atrial fibrillation is common after CABG surgery, occurring in 30% to 40% of patients (and in >50% in those older than 75 years). The arrhythmia often resolves spontaneously without specific therapy, but it may persist and require anticoagulation, cardioversion, or both. The incidence of postoperative atrial fibrillation may be reduced by prophylactic use of β-blockers or amiodarone (92,93).
Dysesthesia, swelling, and itching are common in the leg from which the vein was harvested and can persist for several months. The swelling usually responds to the use of support hose or elevation of the legs periodically during the day. If the itching is severe and there is no evidence of local infection, topical corticosteroid ointments often are effective.
CABG surgery has been shown to prolong life in several patient subsets (see earlier discussion). In addition, 60% of patients who either were working just before bypass surgery or had discontinued work because of cardiac symptoms return to work after surgery. Early ambulation is advisable, and the role of cardiac rehabilitation, as early as 6 to 8 weeks postoperatively, cannot be overemphasized (see detailed discussion in Chapter 63).
Patient Experience
Most patients are discharged within 5 to 7 days after CABG if the operation and postoperative recuperation were uncomplicated. Usually, the patient is transferred from an intensive care unit to an intermediate care unit within 24 hours; early and aggressive mobilization is standard. After discharge, a structured, self-directed exercise program is commonly used. It is recommended that patients not operate a motor vehicle for 6 to 8 weeks after surgery.
Other Therapies
Conventional medical therapy and improved revascularization techniques result in improvement of angina in most patients, but some patients do not improve despite these therapies. Others cannot be treated with certain classes of medications or cannot tolerate maximal doses because of the side effects. In addition, some patients, particularly those with diffuse and/or distal coronary disease, are not appropriate candidates for either PCI or CABG. If conventional treatments cannot be used or fail to relieve symptoms, alternative therapies should be considered.
Enhanced external counterpulsation (EECP) may be considered in patients with class III or IV angina who remain symptomatic despite maximally tolerated medical therapy and who are not believed to be candidates for either PTCA or CABG. EECP is available only in practices with specialized equipment. It involves the use of inflatable pneumatic cuffs that are wrapped around the patient's lower legs and thighs and are sequentially inflated and deflated (using compressed air) in relation to the cardiac cycle. The use of high pressure (300 mm Hg) allows blood to be pumped back to the heart during early diastole in an attempt to increase coronary blood flow and possibly to improve endothelial function and to promote the development of collateral coronary circulation. The patient undergoes therapy for 1 hour per day, 5 days per week in the office setting, usually for a total of 7 weeks. EECP appears to decrease the number of anginal episodes and to improve exercise tolerance (94). EECP is reimbursed by many insurance companies and by Medicare.
Chelation therapy is designed to “leach” calcium out of atherosclerotic plaque by repeated intravenous administration of ethylenediamine tetraacetic acid (EDTA). Although many patients with refractory angina undergo, or are interested in, this form of treatment, a review of published clinical studies of chelation therapy indicates that it is of no clinical benefit (95). Because chelation therapy may produce a number of serious adverse effects, it is not recommended for treatment of patients with angina.
Many new techniques are being studied in an attempt to improve coronary blood flow in patients with refractory angina who are not candidates for conventional revascularization procedures. These include therapeutic angiogenesis (gene therapy to stimulate blood vessel growth in the heart), stem cell therapies, and percutaneous in situ coronary venous arterialization (percutaneous catheter-based coronary bypass). The percutaneous coronary bypass procedure is a new, experimental approach that uses a catheter and a self-expanding connector to create a fistula between a critically narrowed coronary artery and an adjacent coronary vein (96). Whether these experimental techniques become part of the treatment regimen for patients with angina will depend on the results of ongoing trials.
Prompted by earlier animal and clinical studies that implied a potentially infectious contribution to CAD formation and progression, various antibiotic therapies have been tested in patients with CAD, but the results have been disappointing. Therefore, use of antibiotic therapy for treatment of CAD is not recommended.
Unstable Angina
Unstable angina is a term used to describe pain caused by cardiac ischemia that is becoming more intense, is occurring more frequently (often provoked by diminishing effort, perhaps even at rest), and is relieved less readily by nitroglycerin. The syndrome has also been called “crescendo angina” and “preinfarction angina.” Most patients with unstable angina have atherosclerotic plaque rupture and consequent platelet aggregation, leading to coronary hypoperfusion. The term acute coronary syndrome (ACS) is now used to encompass the spectrum of conditions ranging from rest angina to non–ST-segment elevation MI. Patients with ACS are at very high risk and should be hospitalized.
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Although some cases of unstable angina can be managed successfully with aspirin, heparin, β-blockers, and other antianginal therapy alone (which may include calcium channel blockers or nitroglycerin, as discussed previously), others may benefit from more aggressive antiplatelet therapy (e.g., an intravenous glycoprotein IIb-IIIa inhibitor) and/or from early coronary arteriography and revascularization. Consultation with a cardiologist is advised when evaluating and treating a patient with ACS to assess risk and to decide on the optimal therapeutic strategy. Urgent PCI should be considered for patients having rest angina on heparin, ST-segment changes on β-blockers, those who do not respond to aspirin, and those with extensive ECG changes, heart failure, or a high serum troponin level.
Variant Angina
Coronary artery spasm often plays a major role in the pathogenesis of variant angina (also referred to as Prinzmetal angina). This type of angina typically occurs at rest and is not precipitated by exertion or emotional stress. Most patients with variant angina have a fixed, often proximal obstruction of a major coronary artery. Angina in this group often is associated with spasm of the artery near the site of obstruction and is marked by ST-segment elevation at the time of the attack that resolves when the symptoms abate. The variant syndrome in this group of patients commonly occurs after months or years of stable typical angina pectoris or after an MI.
Some patients with variant angina (15%) have normal coronary arteries but have spasm of one of the arteries, which reduces blood supply to the myocardium, resulting in ischemic pain. These patients usually are younger and predominantly are women. These patients usually have no history of typical angina or MI and rarely have a history of a systemic arteritis syndrome. The ST-segment elevation observed during the anginal attack is a manifestation of coronary artery spasm. It occasionally can be confirmed by arteriography. It is important to perform arteriography in such patients because those with normal coronary arteries obviously are not candidates for CABG or PCI, and most respond favorably to treatment with calcium channel blockers, the drugs of choice in such patients. If used without calcium channel blockers, β-blockers may potentiate coronary artery spasm because of unopposed α-adrenergic vasoconstriction.
Angina and MI, probably caused by coronary vasospasm, have been reported in otherwise healthy patients who use cocaine. Coronary vasospasm usually occurs acutely after ingestion or inhalation of cocaine, but it can be observed up to 1 hour after use as a result of vasoactive byproducts of cocaine metabolism. Prolonged episodes of angina in such patients usually respond well to treatment with calcium channel blockers and nitrates because concurrent hypertension is common.
Angina with Normal Coronary ARTERIES
Some individuals have chest pain that is characteristic of angina but on arteriography are found to have normal coronary arteries. Many different possible causes have been described, including coronary vasospasm, abnormal coronary vasodilator reserve (i.e., disease of small coronary vessels), and noncardiac chest pain (especially esophageal disease; see Chapter 42). The prognosis of these patients is generally favorable, with survival comparable to that of age- and sex-matched controls (97). However, chest pain often is recurrent and may result in frequent visits to the emergency department or practitioner's office.
Silent Ischemia
Many episodes of myocardial ischemia are painless. Such “silent ischemia” may be detected either during exercise treadmill testing or by continuous ECG monitoring. Asymptomatic ischemic ST-segment changes on ECG monitoring are common in patients with CAD and have been correlated with transient abnormalities in myocardial perfusion and function.
The presence of silent ischemia within the first 3 days after an MI has been shown to be associated with a greater frequency of recurrent ischemic events. Although several studies have identified silent ischemia to be a poor prognostic factor for patients with CAD (98), whether treatment of such patients in an attempt to eliminate these episodes improves prognosis is unknown.
Coronary Artery Disease in Women
Women with CAD have worse outcomes than do men with comparable disease (21,99). CAD is the leading cause of death in women in the United States. The diagnosis of CAD in women often is harder to establish because symptoms often are atypical (i.e., different from those in men), and false-positive stress tests are more common. Clinicians must be alert to these potential differences in clinical presentations in women, and, if noninvasive testing is warranted, stress testing with radioisotopic or echocardiographic imaging should be considered. The treatment of angina in women is the same as that previously described. Many studies confirm that women who sustain an MI are less likely than men to receive treatments known to improve survival after MI (e.g., aspirin and β-blockers) and are less likely to achieve optimal lipid control. These
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discrepancies are more evident in minority populations. Women are less likely to undergo PCI or CABG and, if referred, generally have more advanced coronary disease at the time of referral than do men.
Summary
Angina remains the cardinal manifestation of coronary disease. The mortality rate of patients with angina depends on a number of factors, including age, the extent and severity of CAD, left ventricular function, and medical comorbidity. The prognosis for older patients, those with diabetes mellitus, and women (see Coronary Artery Disease In Women) is worse than for others with angina.
In general, a 2-year mortality rate of approximately 1.3% has been reported (100). In contrast, the crude first-year mortality rate remains between 10% and 30% for patients with unstable angina (see previous discussion), 8% to 10% for patients surviving 30 days after MI, and 5% to 10% for those with stable angina of 2.5 years’ duration (101, 102, 103, 104).
Newer diagnostic strategies permit earlier diagnosis of CAD. An improved understanding of the pathophysiology of CAD has led to a major emphasis on disease prevention and modification, with the cornerstones of therapy being early identification of high-risk patients (particularly those with diabetes mellitus) and aggressive risk factor modification. Therapy must include strategies to reduce platelet aggregation. Specific therapy for patients with angina includes β-blockers, nitrates, and calcium blockers. This early and aggressive CAD management strategy is rewarded by improved clinical outcomes.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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