Ischemic Heart Disease: Introduction
Ischemic heart disease (IHD) is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium; it typically occurs when there is an imbalance between myocardial oxygen supply and demand. The most common cause of myocardial ischemia is atherosclerotic disease of an epicardial coronary artery (or arteries) sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery.
IHD causes more deaths and disability and incurs greater economic costs than any other illness in the developed world. IHD is the most common, serious, chronic, life-threatening illness in the United States, where 13 million persons have IHD, >6 million have angina pectoris, and >7 million have sustained a myocardial infarction (MI). A high-fat and energy-rich diet, smoking, and a sedentary lifestyle are associated with the emergence of IHD (Chap. 235). In the United States and western Europe, it is growing among low-income groups rather than high-income groups (who are adopting more healthful lifestyles), while primary prevention has delayed the disease to later in life in all socioeconomic groups.
Obesity, insulin resistance, and type 2 diabetes mellitus are increasing and are powerful risk factors for IHD. With urbanization in the developing world, the prevalence of risk factors for IHD is increasing rapidly in these regions such that a majority of the global burden of IHD is now occurring in low-income and middle-income countries. Population subgroups that appear to be particularly affected are men in South Asian countries, especially India. Given the projection of large increases in IHD throughout the world, IHD is likely to become the most common cause of death worldwide by 2020.
Central to an understanding of the pathophysiology of myocardial ischemia is the concept of myocardial supply and demand. Under normal conditions, for any given level of a demand for oxygen, the myocardium will be supplied with oxygen-rich blood to prevent underperfusion of myocytes and the subsequent development of ischemia and infarction. The major determinants of myocardial oxygen demand (MVO2) are heart rate, myocardial contractility, and myocardial wall tension (stress). An adequate supply of oxygen to the myocardium requires a satisfactory level of oxygen-carrying capacity of the blood (determined by the inspired level of oxygen, pulmonary function, and hemoglobin concentration and function) and an adequate level of coronary blood flow. Blood flows through the coronary arteries in a phasic fashion, with the majority occurring during diastole. About 75% of the total coronary resistance to flow occurs across three sets of arteries: (1) large epicardial arteries (Resistance 1 = R1), (2) prearteriolar vessels (R2), and (3) arteriolar and intramyocardial capillary vessels (R3). In the absence of significant flow-limiting atherosclerotic obstructions, R1 is trivial; the major determinant of coronary resistance is found in R2 and R3.
The normal coronary circulation is dominated and controlled by the heart's requirements for oxygen. This need is met by the ability of the coronary vascular bed to vary its resistance (and, therefore, blood flow) considerably while the myocardium extracts a high and relatively fixed percentage of oxygen. Normally, intramyocardial resistance vessels demonstrate an immense capacity for dilation (R2 and R3 decrease). For example, the changing oxygen needs of the heart with exercise and emotional stress affect coronary vascular resistance and in this manner regulate the supply of oxygen and substrate to the myocardium (metabolic regulation). The coronary resistance vessels also adapt to physiologic alterations in blood pressure in order to maintain coronary blood flow at levels appropriate to myocardial needs (autoregulation).
By reducing the lumen of the coronary arteries, atherosclerosis limits appropriate increases in perfusion when the demand for flow is augmented, as occurs during exertion or excitement. When the luminal reduction is severe, myocardial perfusion in the basal state is reduced. Coronary blood flow can also be limited by spasm (see "Prinzmetal's Variant Angina" in Chap. 238), arterial thrombi, and, rarely, coronary emboli as well as by ostial narrowing due to aortitis. Congenital abnormalities, such as origin of the left anterior descending coronary artery from the pulmonary artery, may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults.
Myocardial ischemia can also occur if myocardial oxygen demands are markedly increased and when coronary blood flow may be limited, as occurs in severe left ventricular (LV) hypertrophy due to aortic stenosis. The latter can present with angina that is indistinguishable from that caused by coronary atherosclerosis largely owing to subendocardial ischemia (Chap. 230). A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxyhemoglobin, rarely causes myocardial ischemia by itself but may lower the threshold for ischemia in patients with moderate coronary obstruction.
Not infrequently, two or more causes of ischemia coexist, such as an increase in oxygen demand due to LV hypertrophy secondary to hypertension and a reduction in oxygen supply secondary to coronary atherosclerosis and anemia. Abnormal constriction or failure of normal dilation of the coronary resistance vessels can also cause ischemia. When it causes angina, this condition is referred to as microvascular angina.
Epicardial coronary arteries are the major site of atherosclerotic disease. The major risk factors for atherosclerosis [high plasma low-density lipoprotein (LDL), low plasma high-density lipoprotein (HDL), cigarette smoking, hypertension, and diabetes mellitus] (Chap. 235) disturb the normal functions of the vascular endothelium. These functions include local control of vascular tone, maintenance of an antithrombotic surface, and impairment of inflammatory cell adhesion and diapedesis. The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions with blood leukocytes, especially monocytes, and platelets. Monocyte interaction ultimately results in the subintimal collections of fat, smooth-muscle cells, fibroblasts, and intercellular matrix (i.e., atherosclerotic plaques), which develop at irregular rates in different segments of the epicardial coronary tree and lead eventually to segmental reductions in cross-sectional area.
There is also a predilection for atherosclerotic plaques to develop at sites of increased turbulence in coronary flow, such as at branch points in the epicardial arteries. When a stenosis reduces the diameter of an epicardial artery by 50%, there is a limitation on the ability to increase flow to meet increased myocardial demand. When the diameter is reduced by ~80%, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice area can reduce coronary flow dramatically and cause myocardial ischemia.
Segmental atherosclerotic narrowing of epicardial coronary arteries is caused most commonly by the formation of a plaque, which is subject to rupture or erosion of the cap separating the plaque from the bloodstream. Upon exposure of the plaque contents to blood, two important and interrelated processes are set in motion: (1) platelets are activated and aggregate; and (2) the coagulation cascade is activated, leading to deposition of fibrin strands. A thrombus composed of platelet aggregates and fibrin strands traps red blood cells and can reduce coronary blood flow, leading to the clinical manifestations of myocardial ischemia.
The location of the obstruction influences the quantity of myocardium rendered ischemic and determines the severity of the clinical manifestations. Thus, critical obstructions in vessels, such as the left main coronary artery or the proximal left anterior descending coronary artery, are particularly hazardous. Severe coronary narrowing and myocardial ischemia are frequently accompanied by the development of collateral vessels, especially when the narrowing develops gradually. When well developed, such vessels can, by themselves, provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased demand.
With progressive worsening of a proximal epicardial artery stenosis, the distal resistance vessels (when they function normally) dilate to reduce vascular resistance and maintain coronary blood flow. A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls. When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction. In these circumstances, ischemia, manifest clinically by angina or electrocardiographically by ST-segment deviation, can be precipitated by increases in myocardial oxygen demand caused by physical activity, emotional stress, and/or tachycardia. Changes in the caliber of the stenosed coronary artery due to physiologic vasomotion, loss of endothelial control of dilation (as occurs in diabetes mellitus), pathologic spasm (Prinzmetal's angina), or small platelet-rich plugs can also upset the critical balance between oxygen supply and demand and thereby precipitate myocardial ischemia.
Effects of Ischemia
During episodes of inadequate perfusion caused by coronary atherosclerosis, myocardial tissue oxygen tension falls and may cause transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium. Coronary atherosclerosis is a focal process that usually causes nonuniform ischemia. Regional disturbances of ventricular contractility cause segmental akinesia or, in severe cases, bulging (dyskinesia), which can greatly reduce myocardial pump function.
The abrupt development of severe ischemia, as occurs with total or subtotal coronary occlusion, is associated with almost instantaneous failure of normal muscle contraction and relaxation. The relatively poor perfusion of the subendocardium causes more intense ischemia of this portion of the wall (compared with the subepicardial region). Ischemia of large portions of the ventricle causes transient LV failure, and if the papillary muscle apparatus is involved, mitral regurgitation can occur. When ischemia is transient, it may be associated with angina pectoris; when it is prolonged, it can lead to myocardial necrosis and scarring with or without the clinical picture of acute MI (Chap. 239).
A wide range of abnormalities in cell metabolism, function, and structure underlie these mechanical disturbances during ischemia. The normal myocardium metabolizes fatty acids and glucose to carbon dioxide and water. With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is degraded to lactate; intracellular pH is reduced, as are the myocardial stores of high-energy phosphates, i.e., ATP and creatine phosphate. Impaired cell membrane function leads to the leakage of potassium and the uptake of sodium by myocytes, as well as an increase in cytosolic calcium. The severity and duration of the imbalance between myocardial oxygen supply and demand determine whether the damage is reversible (20 min for total occlusion in the absence of collaterals) or whether it is permanent, with subsequent myocardial necrosis (>20 min).
Ischemia also causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion of T waves and, when more severe, by displacement of ST segments (Chap. 221). Transient T-wave inversion likely reflects nontransmural, intramyocardial ischemia; transient ST-segment depression often reflects subendocardial ischemia; and ST-segment elevation is thought to be caused by more severe transmural ischemia. Another important consequence of myocardial ischemia is electrical instability, which may lead to isolated ventricular premature beats or even ventricular tachycardia or ventricular fibrillation (Chap. 226). Most patients who die suddenly from IHD do so as a result of ischemia-induced ventricular tachyarrhythmias (Chap. 267).
Asymptomatic versus Symptomatic IHD
Postmortem studies on accident victims and military casualties in western countries have shown that coronary atherosclerosis often begins to develop prior to age 20 and is widespread even among adults who were asymptomatic during life. Exercise stress tests in asymptomatic persons may show evidence of silent myocardial ischemia, i.e., exercise-induced ECG changes not accompanied by angina pectoris; coronary angiographic studies of such persons may reveal coronary artery plaques and previously unrecognized obstructions (Chap. 223). Postmortem examination of patients with such obstructions without a history of clinical manifestations of myocardial ischemia often shows macroscopic scars secondary to MI in regions supplied by diseased coronary arteries, with or without collateral circulation. According to population studies, ~25% of patients who survive acute MI may not come to medical attention, and these patients carry the same adverse prognosis as those who present with the classic clinical picture of acute MI (Chap. 239). Sudden death may be unheralded and is a common presenting manifestation of IHD (Chap. 267).
Patients with IHD can also present with cardiomegaly and heart failure secondary to ischemic damage of the LV myocardium that may have caused no symptoms prior to the development of heart failure; this condition is referred to as ischemic cardiomyopathy. In contrast to the asymptomatic phase of IHD, the symptomatic phase is characterized by chest discomfort due to either angina pectoris or acute MI (Chap. 239). Having entered the symptomatic phase, the patient may exhibit a stable or progressive course, revert to the asymptomatic stage, or die suddenly.
Stable Angina Pectoris
This episodic clinical syndrome is due to transient myocardial ischemia. Males constitute ~70% of all patients with angina pectoris and an even greater fraction of those less than 50 years of age. Various diseases that cause myocardial ischemia as well as the numerous forms of discomfort with which it may be confused are discussed in Chap. 13.
The typical patient with angina is a man older than 50 years or a woman older than 60 years of age who complains of chest discomfort, usually described as heaviness, pressure, squeezing, smothering, or choking, and only rarely as frank pain. When the patient is asked to localize the sensation, he or she will typically place their hand over the sternum, sometimes with a clenched fist, to indicate a squeezing, central, substernal discomfort (Levine's sign). Angina is usually crescendo-decrescendo in nature, typically lasts 2–5 min, and can radiate to either shoulder and to both arms (especially the ulnar surfaces of the forearm and hand). It can also arise in or radiate to the back, interscapular region, root of the neck, jaw, teeth, and epigastrium. Angina is rarely localized below the umbilicus or above the mandible. A useful finding in assessing the patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; such a radiation pattern is more typical of pericarditis.
Although episodes of angina are typically caused by exertion (e.g., exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, fright, or frustration) and are relieved by rest, they may also occur at rest (Chap. 238) and while the patient is recumbent (angina decubitus). The patient may be awakened at night by typical chest discomfort and dyspnea. Nocturnal angina may be due to episodic tachycardia, diminished oxygenation as the respiratory pattern changes during sleep, or expansion of the intrathoracic blood volume that occurs with recumbency; the latter causes an increase in cardiac size (end-diastolic volume), in wall tension, and in myocardial oxygen demand that lead to ischemia and transient LV failure.
The threshold for the development of angina pectoris may vary by time of day and emotional state. Many patients report a fixed threshold for angina, which occurs predictably at a certain level of activity, such as climbing two flights of stairs at a normal pace. In these patients, coronary stenosis and myocardial oxygen supply are fixed, and ischemia is precipitated by an increase in myocardial oxygen demand; they are said to have stable exertional angina. In other patients, the threshold for angina may vary considerably within any given day and from day to day. In such patients, variations in myocardial oxygen supply, most likely due to changes in coronary vascular tone, may play an important role in defining the pattern of angina. A patient may report symptoms upon minor exertion in the morning (a short walk or shaving), yet, by midday, may be capable of much greater effort without symptoms. Angina may also be precipitated by unfamiliar tasks, a heavy meal, exposure to cold, or a combination.
Exertional angina is typically relieved by slowing or ceasing activities in 1–5 min and even more rapidly by rest and sublingual nitroglycerin (see below). Indeed, the diagnosis of angina should be suspect if it does not respond to the combination of these measures. The severity of angina can be conveniently summarized by the Canadian Cardiac Society functional classification (Table 237-1). Its impact on the patient's functional capacity can be described using the New York Heart Association functional classification (Table 237-1).
Table 237-1 Cardiovascular Disease Classification Chart
Class New York Heart Association Functional Classification Canadian Cardiovascular Society Functional Classification
I Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina present with strenuous or rapid or prolonged exertion at work or recreation.
II Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, in cold, or when under emotional stress or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of stairs at a normal pace and in normal conditions.
III Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Marked limitation of ordinary physical activity. Walking one to two blocks on the level and climbing more than one flight of stairs in normal conditions.
IV Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. Inability to carry on any physical activity without discomfort—anginal syndrome may be present at rest.
Source: Modified from L Goldman et al: Circulation 64:1227, 1981.
Sharp, fleeting chest pain or a prolonged, dull ache localized to the left submammary area is rarely due to myocardial ischemia. However, especially in women and diabetics, angina pectoris may be atypical in location and not strictly related to provoking factors. In addition, this symptom may exacerbate and remit over days, weeks, or months. Its occurrence can be seasonal, being more frequent in the winter in temperate climates. Anginal "equivalents" are symptoms of myocardial ischemia other than angina. These include dyspnea, nausea, fatigue, and faintness, and are more common in the elderly and in diabetic patients.
Systematic questioning of the patient with suspected IHD is important to uncover the features of an unstable syndrome associated with increased risk, such as angina occurring with less exertion than in the past or occurring at rest or awakening the patient from sleep. Since coronary atherosclerosis is often accompanied by similar lesions in other arteries, the patient with angina should be questioned and examined for peripheral arterial disease (intermittent claudication, Chap. 243), stroke, or transient ischemic attacks (Chap. 364). It is also important to uncover a family history of premature IHD (<45 years in first-degree male relatives and <55 in female relatives) and the presence of diabetes mellitus, hyperlipidemia, hypertension, cigarette smoking, and other risk factors for coronary atherosclerosis (Chap. 235). The history of typical angina pectoris establishes the diagnosis of IHD until proven otherwise. In patients with atypical angina (Chap. 13), the coexistence of advanced age, male gender, the postmenopausal state, and risk factors for atherosclerosis increase the likelihood of hemodynamically significant coronary disease.
This is often normal in patients with stable angina when they are asymptomatic, but it may reveal evidence of atherosclerotic disease at other sites, such as an abdominal aortic aneurysm, carotid arterial bruits, and diminished arterial pulse in the lower extremities, or of risk factors for atherosclerosis, such as xanthelasmas and xanthomas (Chap. 235). Examination of the fundi may reveal an increased light reflex and arteriovenous nicking as evidence of hypertension. There may also be signs of anemia, thyroid disease, and nicotine stains on the fingertips from cigarette smoking. Palpation may reveal cardiac enlargement and abnormal contraction of the cardiac impulse (left ventricular akinesia or dyskinesia).
Auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, an apical systolic murmur due to mitral regurgitation. These auscultatory signs are best appreciated with the patient in the left lateral decubitus position. Aortic stenosis, aortic regurgitation (Chap. 230), pulmonary hypertension (Chap. 244), and hypertrophic cardiomyopathy (Chap. 231) must be excluded, since these disorders may cause angina in the absence of coronary atherosclerosis. Examination during an anginal attack is useful, since ischemia can cause transient LV failure with the appearance of a third and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Tenderness of the chest wall, localization of the discomfort with a single fingertip on the chest, or reproduction of the pain with palpation of the chest makes it unlikely that it is caused by myocardial ischemia.
Although the diagnosis of IHD can be made with a high degree of confidence from the clinical examination, a number of simple laboratory tests can be helpful. The urine should be examined for evidence of diabetes mellitus and renal disease (including microalbuminuria) since these conditions accelerate atherosclerosis. Similarly, examination of the blood should include measurements of lipids (cholesterol—total, LDL, HDL—and triglycerides), glucose, creatinine, hematocrit, and, if indicated based on the physical examination, thyroid function. A chest x-ray is important as it may show the consequences of IHD, i.e., cardiac enlargement, ventricular aneurysm, or signs of heart failure. These signs can support the diagnosis of IHD and are important in assessing the degree of cardiac damage.
A 12-lead ECG recorded at rest may be normal in patients with typical angina pectoris, but there may also be signs of an old myocardial infarction (Chap. 221). Although repolarization abnormalities—i.e., ST-segment and T-wave changes—as well as LV hypertrophy and intraventricular conduction disturbances are suggestive of IHD, they are nonspecific since they can also occur in pericardial, myocardial, and valvular heart disease or, in the case of the former, transiently with anxiety, changes in posture, drugs, or esophageal disease. Dynamic ST-segment and T-wave changes that accompany episodes of angina pectoris and disappear thereafter are more specific.
The most widely used test for both the diagnosis of IHD and estimating the prognosis involves recording the 12-lead ECG before, during, and after exercise, usually on a treadmill (Fig. 237-1). The test consists of a standardized incremental increase in external workload (Table 237-2) while the symptoms, ECG, and arm blood pressure are monitored. Performance is usually symptom-limited, and the test is discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, severe fatigue, ST-segment depression >0.2 mV (2 mm), a fall in systolic blood pressure >10 mmHg, or the development of a ventricular tachyarrhythmia. This test seeks to discover any limitation in exercise performance, to detect typical ECG signs of myocardial ischemia, and to establish their relationship to chest discomfort. The ischemic ST-segment response is generally defined as flat or downsloping depression of the ST segment >0.1 mV below baseline (i.e., the PR segment) and lasting longer than 0.08 s (Fig. 237-1). Upsloping or junctional ST-segment changes are not considered characteristic of ischemia and do not constitute a positive test. Although T-wave abnormalities, conduction disturbances, and ventricular arrhythmias that develop during exercise should be noted, they are also not diagnostic. Negative exercise tests in which the target heart rate (85% of maximal predicted heart rate for age and sex) is not achieved are considered to be nondiagnostic.
Evaluation of the patient with known or suspected ischemic heart disease. At the top of the figure is an algorithm for identifying patients who should be referred for stress testing and the decision pathway for determining if a standard treadmill exercise with ECG monitoring alone is adequate. A specialized imaging study is necessary if the patient cannot exercise adequately (pharmacologic challenge is given) or if there are confounding features on the resting ECG (symptom limited treadmill exercise may be used to stress the coronary circulation). At the bottom of the figure are examples of the data obtained with ECG monitoring and specialized imaging procedures. IHD, ischemic heart disease; EBCT, electron beam computed tomography; ECG, electrocardiogram; MR, magnetic resonance; PET, positron emission tomography; ECHO, echocardiography; MIBI, methoxyisobutyl isonitrite; CMR, cardiac magnetic resonance.
A. Lead V4 at rest (top) and after 4½ min of exercise (bottom). There is 3 mm (0.3 mV) of horizontal ST-segment depression, indicating a positive test for ischemia. [Modified from BR Chaitman, in E Braunwald et al (eds): Heart Disease, 6th ed. Philadelphia, Saunders, 2001.]
B. 45-year-old avid jogger who began experiencing classic substernal chest pressure underwent an exercise echo study. With exercise the patient's heart rate increased from 52 to 153 bpm. The left ventricular chamber dilated with exercise, and the septal and apical portions became akinetic to dyskinetic (red arrow). These findings are strongly suggestive of a significant flow limiting stenosis in the proximal left anterior descending coronary artery, which was confirmed at coronary angiography. [Modified from SD Solomon, in E. Braunwald et al (eds): Primary Cardiology, 2d ed. Philadelphia, Saunders, 2003.]
C. Stress and rest myocardial perfusion SPECT images obtained with Tc99m sestamibi in a patient with chest pain and dyspnea on exertion. The images demonstrate a medium size and severe stress perfusion defect involving the inferolateral and basal inferior walls, showing near complete reversibility, consistent with moderate ischemia in the right coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women's Hospital, Boston, MA.)
D. A patient with a prior myocardial infarction presented with recurrent chest discomfort. On CMR cine imaging a large area of anterior akinesia was noted (marked by the arrows in the top left and right images, systolic frame only). This area of akinesia was matched by a larger extent of late gadolinium-DTPA enhancements consistent with a large transmural myocardial infarction (marked by arrows in the middle left and right images). Resting (bottom left) and adenosine vasodilating stress (bottom right) first-pass perfusion images revealed reversible perfusion abnormality that extends to the inferior septum. This patient was found to have an occluded proximal left anterior descending coronary artery with extensive collateral formation. This case illustrates the utility of different modalities in a CMR examination in characterizing ischemic and infarcted myocardium. CMR, cardiac magnetic resonance; DTPA, diethylenetriamine pentaacetic acid (Images provided by Dr. Raymond Kwong, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.)
E. Stress and rest myocardial perfusion PET images obtained with rubidium-82 in a patient with chest pain on exertion. The images demonstrate a large and severe stress perfusion defect involving the mid and apical anterior, anterolateral, and anteroseptal walls, and the LV apex, showing complete reversibility, consistent with extensive and severe ischemia in the mid left anterior descending coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women's Hospital, Boston, MA.)
Table 237-2 Relation of METs to Stages in Various Testing Protocols
Source: Modified from GF Fletcher et al: Circulation 104:1694, 2001.
When interpreting ECG stress tests, the probability that coronary artery disease (CAD) exists in the patient or population under study (i.e., pretest probability) should be considered. Overall, false-positive or false-negative results occur in one-third of cases. However, a positive result on exercise indicates that the likelihood of CAD is 98% in males >50 years with a history of typical angina pectoris and who develop chest discomfort during the test. The likelihood decreases if the patient has atypical or no chest pain by history and/or during the test.
The incidence of false-positive tests is significantly increased in patients with low probabilities of IHD, such as asymptomatic men under the age of 40 or in premenopausal women with no risk factors for premature atherosclerosis. It is also increased in patients taking cardioactive drugs, such as digitalis and antiarrhythmic agents, or in those with intraventricular conduction disturbances, resting ST-segment and T-wave abnormalities, ventricular hypertrophy, or abnormal serum potassium levels. Obstructive disease limited to the circumflex coronary artery may result in a false-negative stress test since the lateral portion of the heart which this vessel supplies is not well represented on the surface 12-lead ECG. Since the overall sensitivity of exercise stress electrocardiography is only ~75%, a negative result does not exclude CAD, although it makes the likelihood of three-vessel or left main CAD extremely unlikely.
The physician should be present throughout the exercise test, and it is important to measure total duration of exercise, the times to the onset of ischemic ST-segment change and chest discomfort, the external work performed (generally expressed as the stage of exercise), and the internal cardiac work performed, i.e., by the heart rate–blood pressure product. The depth of the ST-segment depression and the time needed for recovery of these ECG changes are also important. Because the risks of exercise testing are small but real—estimated at one fatality and two nonfatal complications per 10,000 tests—equipment for resuscitation should be available. Modified (heart rate–limited rather than symptom-limited) exercise tests can be performed safely in patients as early as 6 days after uncomplicated MI (Table 237-2). Contraindications to exercise stress testing include rest angina within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis, uncontrolled heart failure, severe pulmonary hypertension, and active infective endocarditis.
The normal response to graded exercise includes progressive increases in heart rate and blood pressure. Failure of the blood pressure to increase or an actual decrease with signs of ischemia during the test is an important adverse prognostic sign, since it may reflect ischemia-induced global LV dysfunction. The development of angina and/or severe (>0.2 mV) ST-segment depression at a low workload, i.e., before completion of stage II of the Bruce protocol, and/or ST-segment depression that persists for >5 min after the termination of exercise increases the specificity of the test and suggests severe IHD and a high risk of future adverse events.
(See also Chap. 222) When the resting ECG is abnormal (e.g., preexcitation syndrome, >1 mm of resting ST-segment depression, left bundle branch block, paced ventricular rhythm), information gained from an exercise test can be enhanced by stress myocardial radionuclide perfusion imaging after the intravenous administration of thallium 201 or technetium 99m (99mTc) sestamibi during exercise (or a pharmacologic) stress. Recent data also suggest positron emission tomography (PET) imaging (with exercise or pharmacologic stress) using N-13 ammonia or rubidium-82 nuclide as another technique for assessing perfusion. Images obtained immediately after cessation of exercise to detect regional ischemia are compared with those obtained at rest to confirm reversible ischemia and regions of persistent absent uptake that signify infarction.
A sizable fraction of patients who need noninvasive stress testing to identify myocardial ischemia and increased risk of coronary events cannot exercise because of peripheral vascular or musculoskeletal disease, exertional dyspnea, or deconditioning. In these circumstances an intravenous pharmacologic challenge is used in place of exercise. For example, dipyridamole or adenosine can be given to create a coronary "steal" by temporarily increasing flow in nondiseased segments of the coronary vasculature at the expense of diseased segments. Alternatively, a graded incremental infusion of dobutamine may be administered to increase MVO2. A variety of imaging options are available to accompany these pharmacologic stressors (Fig. 237-1). The development of a transient perfusion defect with a tracer such as radioactive thallium or 99mTc sestamibi is used to detect myocardial ischemia.
Two-dimensional echocardiography can assess both global and regional wall motion abnormalities of the left ventricle due to MI or persistent ischemia. Stress (exercise or dobutamine) echocardiography may cause the emergence of regions of akinesis or dyskinesis not present at rest. Stress echocardiography, like stress myocardial perfusion imaging, is more sensitive than exercise electrocardiography in the diagnosis of IHD. Cardiac magnetic resonance (CMR) stress testing is also evolving as an alternative to radionuclide, PET, or echocardiographic stress imaging. CMR stress testing performed with dobutamine infusion can be used to assess wall motion abnormalities accompanying ischemia, and myocardial perfusion CMR can be used to provide rather complete ventricular evaluation using multislice MR imaging studies. Ambulatory monitoring of the ECG can assess myocardial ischemia as episodes of ST-segment depression. Echocardiography or radionuclide angiography should be carried out to assess LV function in patients with chronic stable angina and in patients with a history of a prior MI, pathologic Q waves, or clinical evidence of heart failure.
Atherosclerotic plaques become progressively calcified over time, and coronary calcification in general increases with age. For this reason, methods for detecting coronary calcium have been developed as a measure of the presence of coronary atherosclerosis. These methods involve computed tomography (CT) applications that achieve rapid acquisition of images [ultrafast or electron beam (EBCT) and multidetector (MDCT)]. Coronary calcium detected by these imaging techniques is quantified using the Agatston score most commonly, which is based on the area and density of calcification. Although the diagnostic accuracy of this imaging method is high (sensitivity, 90–94%; specificity, 95–97%; negative predictive value, 93–99%), its prognostic utility and its role in the evaluative algorithm of patients with stable angina pectoris have not yet been defined.
(See also Chap. 223) This diagnostic method outlines the lumina of the coronary arteries and can be used to detect or exclude serious coronary obstruction. However, coronary arteriography provides no information regarding the arterial wall, and severe atherosclerosis that does not encroach on the lumen may go undetected. Of note, atherosclerotic plaques characteristically grow progressively in the intima and media of an epicardial coronary artery, at first without encroaching on the lumen, causing an outward bulging of the artery—a process referred to as negative remodeling (Chap. 235). Later in the course of the disease, further growth causes luminal narrowing.
Coronary arteriography is indicated in (1) patients with chronic stable angina pectoris who are severely symptomatic despite medical therapy and who are being considered for revascularization, i.e., a percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); (2) patients with troublesome symptoms that present diagnostic difficulties in whom there is a need to confirm or rule out the diagnosis of IHD; (3) patients with known or possible angina pectoris who have survived cardiac arrest; (4) patients with angina or evidence of ischemia on noninvasive testing with clinical or laboratory evidence of ventricular dysfunction; and (5) patients judged to be at high risk of sustaining coronary events based on signs of severe ischemia on noninvasive testing, regardless of the presence or severity of symptoms (see below).
Examples of other indications include:
Patients with chest discomfort suggestive of angina pectoris but a negative or nondiagnostic stress test who require a definitive diagnosis for guiding medical management, alleviating psychological stress, career or family planning, or insurance purposes.
Patients who have been admitted repeatedly to the hospital for a suspected acute coronary syndrome (Chaps. 238 and 239) but in whom this diagnosis has not been established and in whom the presence or absence of CAD should be determined.
Patients with careers that involve the safety of others (e.g., pilots, firefighters, police) who have questionable symptoms or suspicious or positive noninvasive tests, and in whom there are reasonable doubts about the state of the coronary arteries.
Patients with aortic stenosis or hypertrophic cardiomyopathy and angina in whom the chest pain could be due to IHD.
Male patients >45 years and females >55 years who are to undergo a cardiac operation, such as valve replacement or repair, and who may or may not have clinical evidence of myocardial ischemia.
Patients following myocardial infarction, especially those who are at high risk after MI because of the recurrence of angina or the presence of heart failure, frequent ventricular premature contractions, or signs of ischemia on the stress test.
Patients with angina pectoris, regardless of severity, in whom noninvasive testing indicates a high risk of coronary events.
Patients in whom coronary spasm or another nonatherosclerotic cause of myocardial ischemia (e.g., coronary artery anomaly, Kawasaki's disease) is suspected.
Noninvasive alternatives to diagnostic coronary arteriography include CT angiography and cardiac MR angiography (Chap. 222). While these new imaging techniques can provide information about obstructive lesions in the epicardial coronary arteries, their exact role in clinical practice has not yet been rigorously defined. Important aspects of their use that should be noted include the substantially higher radiation exposure with CT angiography compared to conventional diagnostic arteriography and the limitations on cardiac MR imposed by cardiac movement during the cardiac cycle, especially at high heart rates.
The principal prognostic indicators in patients known to have IHD are age, the functional state of the left ventricle, the location(s) and severity of coronary artery narrowing, and the severity or activity of myocardial ischemia. Angina pectoris of recent onset, unstable angina (Chap. 238), early postmyocardial infarction angina, and angina that is unresponsive or poorly responsive to medical therapy or is accompanied by symptoms of congestive heart failure all indicate an increased risk for adverse coronary events. The same is true for the physical signs of heart failure, episodes of pulmonary edema, transient third heart sounds, or mitral regurgitation, and for echocardiographic or radioisotopic (or roentgenographic) evidence of cardiac enlargement and reduced (<0.40) ejection fraction.
Most importantly, any of the following signs during noninvasive testing indicate a high risk for coronary events: inability to exercise for 6 min, i.e., stage II (Bruce protocol) of the exercise test; a strongly positive exercise test showing onset of myocardial ischemia at low workloads (0.1 mV ST-segment depression before completion of stage II; 0.2 mV ST depression at any stage; ST depression for >5 min following the cessation of exercise; a decline in systolic pressure >10 mmHg during exercise; the development of ventricular tachyarrhythmias during exercise); the development of large or multiple perfusion defects or increased lung uptake during stress radioisotope perfusion imaging; and a decrease in LV ejection fraction (LVEF) during exercise on radionuclide ventriculography or during stress echocardiography. Conversely, patients who can complete stage III of the Bruce exercise protocol and have a normal stress perfusion scan or negative stress echocardiographic evaluation are at very low risk of future coronary events.
On cardiac catheterization, elevations of LV end-diastolic pressure and ventricular volume and reduced ejection fraction are the most important signs of LV dysfunction and are associated with a poor prognosis. Patients with chest discomfort but normal LV function and normal coronary arteries have an excellent prognosis. Obstructive lesions of the left main (>50% luminal diameter) or left anterior descending coronary artery proximal to the origin of the first septal artery are associated with a greater risk than are lesions of the right or left circumflex coronary artery because of the greater quantity of myocardium at risk. Atherosclerotic plaques in epicardial arteries with fissuring or filling defects indicate increased risk. These lesions go through phases of inflammatory cellular activity, degeneration, endothelial dysfunction, abnormal vasomotion, platelet aggregation, and fissuring or hemorrhage. These factors can temporarily worsen the stenosis and cause abnormal reactivity of the vessel wall, thus exacerbating the manifestations of ischemia. The recent onset of symptoms, the development of severe ischemia during stress testing (see above), and unstable angina pectoris (Chap. 238) all reflect episodes of rapid progression in coronary lesions.
With any degree of obstructive CAD, mortality is greatly increased when LV function is impaired; conversely, at any level of LV function, the prognosis is influenced importantly by the quantity of myocardium perfused by critically obstructed vessels. Therefore, it is useful to collect all the evidence substantiating past myocardial damage (evidence of MI on ECG, echocardiography, radioisotope imaging, or left ventriculography), residual LV function (ejection fraction and wall motion), and risk of future damage from coronary events (extent of coronary disease and severity of ischemia defined by noninvasive stress testing). The larger the quantity of established myocardial necrosis, the less the heart is able to withstand additional damage and the poorer the prognosis. All the above signs of past damage plus the risk of future damage should be considered indicators of risk.
The greater the number and severity of risk factors for coronary atherosclerosis [advanced age (>75 years), diabetes, morbid obesity, accompanying peripheral and/or cerebrovascular disease, previous MI], the worse the prognosis of the angina patient. Evidence exists that elevated levels of C-reactive protein in the plasma, extensive coronary calcification on EBCT (see above), and increased carotid intimal thickening on ultrasound examination also indicate an increased risk of coronary events.
Stable Angina Pectoris: Treatment
Each patient must be evaluated individually with respect to his or her expectations and goals, control of symptoms, and prevention of adverse clinical outcomes, such as MI and premature death. The degree of disability as well as the physical and emotional stress that precipitates angina must be carefully recorded in order to set treatment goals. The management plan should include the following components: (1) explanation of the problem and reassurance about the ability to formulate a treatment plan, (2) identification and treatment of aggravating conditions, (3) recommendations for adaptation of activity as needed, (4) treatment of risk factors that will decrease the occurrence of adverse coronary outcomes, (5) drug therapy for angina, and (6) consideration of revascularization.
Explanation and Reassurance
Patients with IHD need to understand their condition and to realize that a long and productive life is possible even though they suffer from angina pectoris or have experienced and recovered from an acute MI. Offering results of clinical trials showing improved outcomes can be of great value when encouraging patients to resume or maintain activity and return to their occupation. A planned program of rehabilitation can encourage patients to lose weight, improve exercise tolerance, and control risk factors with more confidence.
Identification and Treatment of Aggravating Conditions
A number of conditions may either increase oxygen demand or decrease oxygen supply to the myocardium and may precipitate or exacerbate angina in patients with IHD. Aortic valve disease and hypertrophic cardiomyopathy may cause or contribute to angina and should be excluded or treated. Obesity, hypertension, and hyperthyroidism should be treated aggressively in order to reduce the frequency and severity of anginal episodes. Decreased myocardial oxygen supply may be due to reduced oxygenation of the arterial blood (e.g., in pulmonary disease or, when carboxyhemoglobin is present, due to cigarette or cigar smoking) or decreased oxygen-carrying capacity (e.g., in anemia). Correction of these abnormalities, if present, may reduce or even eliminate angina pectoris.
Adaptation of Activity
Myocardial ischemia is caused by a discrepancy between the demand of the heart muscle for oxygen and the ability of the coronary circulation to meet this demand. Most patients can be helped to understand this concept and utilize it in the rational programming of activity. Many tasks that ordinarily evoke angina may be accomplished without symptoms simply by reducing the speed at which they are performed. Patients must appreciate the diurnal variation in their tolerance of certain activities and should reduce their energy requirements in the morning, immediately after meals, and in cold or inclement weather.
On occasion, it may be necessary to recommend a change in employment or residence to avoid physical stress. However, with the exception of manual laborers, most patients with IHD can continue to function merely by allowing more time to complete each task. In some patients, anger and frustration may be the most important factors precipitating myocardial ischemia. If these cannot be avoided, training in stress management may be useful. A treadmill exercise test to determine the approximate heart rate at which ischemic ECG changes or symptoms develop may be helpful in the development of a specific exercise program.
Physical conditioning usually improves the exercise tolerance of patients with angina and exerts substantial psychological benefits. A regular program of isotonic exercise that is within the limits of each patient's threshold for the development of angina pectoris and does not exceed 80% of the heart rate associated with ischemia on exercise testing should be strongly encouraged. Based on the results of an exercise test, the number of METS performed at the onset of ischemia can be estimated (Table 237-2) and a practical exercise prescription can be formulated to permit daily activities that will fall below the ischemic threshold (Table 237-3).
Table 237-3 Energy Requirements for Some Common Activities
Less than 3 METs 3–5 METs 5–7 METs 7–9 METs More than 9 METs
Washing/shaving Cleaning windows Easy digging in garden Heavy shoveling Carrying loads upstairs (objects more than 90 lb)
Dressing Raking Level hand lawn mowing Carrying objects (60–90 lb) Climbing stairs (quickly)
Light housekeeping Power lawn mowing Carrying objects (30–60 lb) Shoveling heavy snow
Desk work Bed making/stripping
Driving auto Carrying objects (15–30 lb)
Sitting (clerical/ assembly) Stocking shelves (light objects) Carpentry (exterior) Digging ditches (pick and shovel) Heavy labor
Desk work Light welding/carpentry Shoveling dirt
Standing (store clerk) Sawing wood
Golf (cart) Dancing (social) Tennis (singles) Canoeing Squash
Knitting Golf (walking) Snow skiing (downhill) Mountain climbing Ski touring
Sailing Light backpacking Vigorous basketball
Tennis (doubles) Basketball
Walking (2 mph) Level walking (3–4 mph) Level walking (4.5–5.0 mph) Level jogging (5 mph) Running (>6 mph)
Stationary bike Level biking (6–8 mph) Bicycling (9–10 mph) Swimming (crawl stroke) Bicycling (>13 mph)
Very light calisthenics Light calisthenics Swimming, breast stroke Rowing machine Rope jumping
Heavy calisthenics Walking uphill (5 mph)
Bicycling (12 mph)
Source: Modified from WL Haskell: Rehabilitation of the coronary patient, in NK Wenger, HK Hellerstein (eds): Design and Implementation of Cardiac Conditioning Program. New York, Churchill Livingstone. 1978.
Treatment of Risk Factors
A family history of premature IHD is an important indicator of increased risk and should trigger a search for treatable risk factors such as hyperlipidemia, hypertension, and diabetes mellitus. Obesity impairs the treatment of other risk factors and increases the risk of adverse coronary events. In addition, obesity is often accompanied by three other risk factors—diabetes mellitus, hypertension, and hyperlipidemia. The treatment of obesity and these accompanying risk factors is an important component of any management plan. A diet low in saturated and trans-unsaturated fatty acids and a caloric intake to achieve optimal body weight is a cornerstone in the management of chronic IHD.
Cigarette smoking accelerates coronary atherosclerosis in both sexes and at all ages and increases the risk of thrombosis, plaque instability, MI, and death (Chap. 235). In addition, by increasing myocardial oxygen needs and reducing oxygen supply, it aggravates angina. Smoking cessation studies have demonstrated important benefits with a significant decline in the occurrence of these adverse outcomes. The physician's message must be clear and strong and supported by programs that achieve and monitor abstinence (Chap. 390). Hypertension (Chap. 241) is associated with increased risk of adverse clinical events from coronary atherosclerosis as well as stroke. In addition, the LV hypertrophy that results from sustained hypertension aggravates ischemia. There is evidence that long-term, effective treatment of hypertension can decrease the occurrence of adverse coronary events. Diabetes mellitus (Chap. 338) accelerates coronary and peripheral atherosclerosis and is frequently associated with dyslipidemias and increases in the risk of angina, MI, and sudden coronary death. Aggressive control of the dyslipidemia (target LDL cholesterol <70 mg/dL) and hypertension (target BP 120/80 or less) that are frequently found in diabetic patients is essential, as described below.
The treatment of dyslipidemia is central when aiming for long-term relief from angina, reduced need for revascularization, and reduction in myocardial infarction and death. The control of lipids can be achieved by the combination of a diet low in saturated and trans-unsaturated fatty acids, exercise, and weight loss. Frequently, HMG-CoA reductase inhibitors (statins) are required and can lower LDL cholesterol (25–50%), raise HDL cholesterol (5–9%), and lower triglycerides (5–30%). Niacin or fibrates can be used to raise HDL cholesterol and lower triglycerides (Chaps. 235 and 350). Controlled trials with lipid-regulating regimens have shown equal proportional benefit for men, women, the elderly, diabetics, and even smokers.
Compliance with regard to the health-promoting behaviors listed above is generally very poor, and the conscientious physician must not underestimate the major effort required to meet this challenge. Fewer than one-half of patients in the United States discharged from the hospital with proven coronary disease receive treatment for dyslipidemia. Given the proof that treating dyslipidemia brings major benefits, physicians need to secure treatment pathways, monitor compliance, and follow up.
Risk Reduction in Women with IHD
The incidence of clinical IHD in premenopausal women is very low; however, following the menopause, the atherogenic risk factors increase (e.g., increased LDL, reduced HDL) and the rate of clinical coronary events accelerates to the levels observed in men. Women have not given up cigarette smoking as effectively as have men. Diabetes mellitus, which is more common in women, greatly increases the occurrence of clinical IHD and amplifies the deleterious effects of hypertension, hyperlipidemia, and smoking. Cardiac catheterization and coronary revascularization are often applied more sparingly in women and at a later, and more severe, stage of the disease than in men. When cholesterol lowering, beta blockers after MI, and CABG are applied in the appropriate patient groups, women enjoy the same benefits of improved outcome as do men.
The commonly used drugs for the treatment of angina pectoris are summarized in Tables 237-4, 237-5, and 237-6. Pharmacotherapy for IHD is designed to reduce the frequency of anginal episodes and blunt the surge in the patient's heart rate and blood pressure with exertion so that they can perform daily activities without approaching the heart rate–blood pressure threshold that provokes ischemia. Antiplatelet therapy with aspirin is also used to reduce thrombotic events that may occur with destabilization of atherosclerotic plaques.
Table 237-4 Nitroglycerin and Nitrates for Patients with Ischemic Heart Disease
Compound Route Dose Duration of Effect
Nitroglycerin Sublingual tablets 0.3–0.6 mg up to 1.5 mg Approximately 10 min
Spray 0.4 mg as needed Similar to sublingual tablets
Ointment 2% 6 x 6 in; 15 x 15 cm
Effect up to 7 h
Transdermal 0.2–0.8 mg/h every 12 h 8–12 h during intermittent therapy
Oral sustained release 2.5–13 mg 4–8 h
Intravenous 5–200 g/min Tolerance may be seen in 7–8 h
Isosorbide dinitrate Sublingual 2.5–10 mg Up to 60 min
Oral 5–80 mg, 2–3 times daily Up to 8 h
Spray 1.25 mg daily 2–3 min
Chewable 5 mg 2–2½ h
Oral slow release 40 mg 1–2 daily Up to 8 h
Intravenous 1.25–5.0 mg/h Tolerance in 7–8 h
Ointment 100 mg/24 h Not effective
Isosorbide mononitrate Oral 20 mg twice daily60–240 mg once daily 12–24 h
Pentaerythritol tetranitrate Sublingual 10 mg as needed Not known
Source: Modified from RJ Gibbons et al.
Table 237-5 Properties of Beta Blockers in Clinical Use for Ischemic Heart Disease
Drugs Selectivity Partial Agonist Activity Usual Dose for Angina
Acebutolol 1 Yes 200–600 mg twice daily
Atenolol 1 No 50–200 mg/d
Betaxolol 1 No 10–20 mg/d
Bisoprolol 1 No 10 mg/d
1 No 50–300 g/kg per min
None Yes 200–600 mg twice daily
Metoprolol 1 No 50–200 mg twice daily
Nadolol None No 40–80 mg/d
Pindolol None Yes 2.5–7.5 mg 3 times daily
Propranolol None No 80–120 mg twice daily
Timolol None No 10 mg twice daily
Note: This list of blockers that may be used to treat patients with angina pectoris is arranged alphabetically. The agents for which there is the greatest clinical experience include atenolol, metoprolol, and propranolol. It is preferable to use a sustained release formulation that may be taken once daily to improve the patient's compliance with the regimen.
aEsmolol is an ultrashort acting blocker that is administered as a continuous intravenous infusion. Its rapid offset of action makes esmolol an attractive agent to use in patients with relative contraindications to blockade.
bLabetolol is a combined alpha- and blocker.
Source: Modified from RJ Gibbons et al.
Table 237-6 Calcium Channel Blockers in Clinical Use for Ischemic Heart Disease
Drugs Usual Dose Duration of Action Side Effects
Amlodipine 5–10 mg qd Long Headache, edema
Felodipine 5–10 mg qd Long Headache, edema
Isradipine 2.5–10 mg bid Medium Headache, fatigue
Nicardipine 20–40 mg tid Short Headache, dizziness, flushing, edema
Nifedipine Immediate release:a 30–90 mg/d orally
Short Hypotension, dizziness, flushing, nausea, constipation, edema
Slow release: 30–180 mg orally
Nisoldipine 20–40 mg qd Short Similar to nifedipine
Diltiazem Immediate release: 30–80 mg 4 times daily Short Hypotension, dizziness, flushing, bradycardia, edema
Slow release: 120–320 mg qd Long
Verapamil Immediate release: 80–160 mg tid Short Hypotension, myocardial depression, heart failure, edema, bradycardia
Slow release: 120–480 mg qd Long
Note: This list of calcium channel blockers that may be used to treat patients with angina pectoris is divided into two broad classes, dihydropyridines and nondihydropyridines, and arranged alphabetically within each class. Among the dihydropyridines, the greatest clinical experience has been obtained with amlodipine and nifedipine. After the initial period of dose titration with a short-acting formulation, it is preferable to switch to a sustained release formulation that may be taken once daily to improve patient compliance with the regimen.
aMay be associated with increased risk of mortality if administered during acute myocardial infarction.
Source: Modified from RJ Gibbons et al.
The organic nitrates are a valuable class of drugs in the management of angina pectoris that have been in clinical use for over 125 years (Table 237-4). Their major mechanisms of action include systemic venodilation with concomitant reduction in LV end-diastolic volume and pressure, thereby reducing myocardial wall tension and oxygen requirements; dilation of epicardial coronary vessels; and increased blood flow in collateral vessels. The organic nitrates, when metabolized release nitric oxide (NO) which binds to guanylyl cyclase in vascular smooth-muscle cells, leading to an increase in cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle. Nitrates also exert antithrombotic activity by NO-dependent activation of platelet guanylyl cyclase and impairment of intraplatelet calcium flux, and platelet activation.
The absorption of these agents is most rapid and complete through the mucous membranes. For this reason, nitroglycerin is most commonly administered sublingually in tablets of 0.4 or 0.6 mg. Patients with angina should be instructed to take the medication both to relieve angina and also approximately 5 min before stress that is likely to induce an episode. The value of this prophylactic use of the drug cannot be overemphasized.
A pulsating feeling in the head or headache is the most common side effect of nitroglycerin and fortunately is only rarely disturbing at the doses usually required to relieve or prevent angina. Postural dizziness has also been reported. Nitroglycerin deteriorates with exposure to air, moisture, and sunlight, so that if the drug neither relieves discomfort nor produces a slight sensation of tingling at the sublingual site of absorption, the preparation may be inactive and a fresh supply should be obtained. If relief is not achieved by rest and within 2 or 3 min after up to three nitroglycerin tablets, the patient should consult a physician or report promptly to a hospital emergency room for evaluation of possible unstable angina or acute MI (Chap. 239).
Nitrates improve exercise tolerance in patients with chronic angina and relieve ischemia in patients with unstable angina as well as in patients with Prinzmetal's variant angina (Chap. 238). A diary of angina and nitroglycerin use may be valuable for detecting changes in the frequency, severity, or threshold for discomfort that may signify the development of unstable angina pectoris and/or herald an impending MI.
None of the long-acting nitrates is as effective as sublingual nitroglycerin for the acute relief of angina. These organic nitrate preparations can be swallowed, chewed, or administered as a patch or paste by the transdermal route (Table 237-4). They can provide effective plasma levels for up to 24 h, but the therapeutic response is highly variable. Different preparations and/or administration during the daytime should be tried only to prevent discomfort while avoiding side effects such as headache and dizziness. Individual dose titration is important in order to prevent side effects.
Useful preparations include isosorbide dinitrate (10–60 mg orally bid or tid) or mononitrate (30–120 mg orally qd), nitroglycerin ointment (0.5–2.0 in. qid), or sustained-release transdermal patches (5–25 mg/d). Tolerance with loss of efficacy develops within 12–24 h of continuous exposure to all of the long-acting nitrates. The mechanism of development of nitrate tolerance is incompletely understood, but leading hypotheses include inadequate generation of reduced sulfhydryl groups required for biotransformation to NO, inhibition of mitochondrial aldehyde dehydrogenase (responsible for formation of NO), counterregulatory neurohormonal activation with vasoconstriction and fluid retention, and production of oxygen free radical species that inactivate NO and increase the sensitivity of vascular smooth muscle to circulating vasoconstrictors.
In order to minimize the effects of tolerance, the minimum effective dose should be used and a minimum of 8 h each day kept free of the drug so as to restore any useful response(s).
These drugs represent an important component of the pharmacologic treatment of angina pectoris (Table 237-5). They reduce myocardial oxygen demand by inhibiting the increases in heart rate, arterial pressure, and myocardial contractility caused by adrenergic activation. Beta blockade reduces these variables most strikingly during exercise while causing only small reductions at rest. Long-acting beta-blocking drugs or sustained release formulations offer the advantage of once daily dosage (Table 237-5). The therapeutic aims include relief of angina and ischemia. These drugs can also reduce mortality and reinfarction in patients after MI and are moderately effective antihypertensive agents.
Relative contraindications include asthma and reversible airway obstruction in patients with chronic lung disease, atrioventricular conduction disturbances, severe bradycardia, Raynaud's phenomenon, and a history of mental depression. Side effects include fatigue, reduced exercise tolerance, nightmares, impotence, cold extremities, intermittent claudication, bradycardia (sometimes severe), impaired atrioventricular conduction, LV failure, bronchial asthma, worsening claudication, and intensification of the hypoglycemia produced by oral hypoglycemic agents and insulin. Reducing the dose or even discontinuation may be necessary if these side effects develop and persist. Since sudden discontinuation can intensify ischemia, the doses should be tapered over 2 weeks.
Beta blockers with relative 1-receptor specificity, such as metoprolol and atenolol, may be preferable in patients with mild bronchial obstruction and insulin-requiring diabetes mellitus.
Calcium Channel Blockers
Calcium channel blockers (Table 237-6) are coronary vasodilators that produce variable and dose-dependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents as effective as beta blockers in the treatment of angina pectoris. They are indicated when beta blockers are contraindicated, poorly tolerated, or ineffective. Verapamil and diltiazem may produce symptomatic disturbances in cardiac conduction and bradyarrhythmias. They also exert negative inotropic actions and are more likely to aggravate LV failure, particularly when used in patients with LV dysfunction, especially if they are also receiving beta blockers. Although useful effects are usually achieved when calcium channel blockers are combined with beta blockers and nitrates, careful individual titrations of the doses are essential with these combinations. Variant (Prinzmetal's) angina responds particularly well to calcium channel blockers (especially members of the dihydropyridine class), supplemented when necessary by nitrates (Chap. 238).
Verapamil should not ordinarily be combined with beta blockers because of the combined effects on heart rate and contractility. Diltiazem can be combined with beta blockers in patients with normal ventricular function and no conduction disturbances. Amlodipine and beta blockers have complementary actions on coronary blood supply and myocardial oxygen demands. While the former decreases blood pressure and dilates coronary arteries, the latter slows heart rate and decreases contractility. Amlodipine and the other second-generation dihydropyridine calcium antagonists (nicardipine, isradipine, long-acting nifedipine, and felodipine) are potent vasodilators and useful in the simultaneous treatment of angina and hypertension. Short-acting dihydropyridines should be avoided because of the risk of precipitating infarction, particularly in the absence of beta blockers.
Choice between Beta Blockers and Calcium Channel Blockers for Initial Therapy
Since beta blockers have been shown to improve life expectancy following acute MI (Chaps. 238 and 239) while calcium channel blockers have not, the former may also be preferable in patients with chronic IHD. However, calcium channel blockers are indicated in patients with the following: (1) inadequate responsiveness to the combination of beta blockers and nitrates; many such patients do well with a combination of a beta blocker and a dihydropyridine calcium channel blocker; (2) adverse reactions to beta blockers such as depression, sexual disturbances, and fatigue; (3) angina and a history of asthma or chronic obstructive pulmonary disease; (4) sick-sinus syndrome or significant atrioventricular conduction disturbances; (5) Prinzmetal's angina; or (6) symptomatic peripheral arterial disease.
Aspirin is an irreversible inhibitor of platelet cyclooxygenase activity and thereby interferes with platelet activation. Chronic administration of 75–325 mg orally per day has been shown to reduce coronary events in asymptomatic adult men, patients with chronic stable angina, and patients with or who have survived unstable angina and MI. There is a dose-dependent increase in bleeding when aspirin is used chronically. It is preferable to use an enteric-coated formulation in the range of 75–162 mg/d. Administration of this drug should be considered in all patients with IHD in the absence of gastrointestinal bleeding, allergy, or dyspepsia. Clopidogrel (300–600 mg loading and 75 mg/d maintenance) is an oral agent that blocks ADP receptor–mediated platelet aggregation. It provides similar benefits as aspirin in patients with stable chronic IHD and may be substituted for aspirin if aspirin causes the side effects listed above. Clopidogrel combined with aspirin reduces death and coronary ischemic events in patients with an acute coronary syndrome (Chap. 238) and also reduces the risk of thrombus formation in patients undergoing implantation of a stent in a coronary artery (Chap. 240). (In order to reduce the risk of gastrointestinal bleeding, it is recommended that a proton pump inhibitor be prescribed to patients taking a combination of clopidogrel and aspirin.) While combined treatment with clopidogrel and aspirin for at least a year is recommended in patients with an acute coronary syndrome and following implantation of a drug-eluting stent, studies have not shown any benefit of the routine addition of clopidogrel to aspirin in patients with chronic stable IHD.
Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of survivors of MI; patients with hypertension or chronic IHD, including angina pectoris; and those at high risk of vascular disease, such as diabetes. The benefits of ACE inhibitors are most evident in IHD patients at increased risk, especially if diabetes mellitus or LV dysfunction is present, and in those who have not achieved adequate control of blood pressure and LDL cholesterol on beta blockers and statins. However, the routine administration of ACE inhibitors to IHD patients with normal LV function and who have achieved blood pressure and LDL goals on other therapies does not reduce events and therefore is not cost-effective.
Despite treatment with nitrates, beta blockers, or calcium channel blockers, some patients with IHD continue to experience angina, and additional medical therapy is now available to alleviate their symptoms. Ranolazine, a piperazine derivative, was approved for use in January 2006 for patients with chronic angina who continue to be symptomatic despite a standard medical regimen. The mechanism of the antianginal effect of ranolazine is not firmly established, but the leading theory is that the drug inhibits the late inward sodium current (INa). The benefits of INa inhibition include limitation of the Na overload of ischemic myocytes and prevention of Ca2+ overload via the Na+-Ca2+ exchanger. Prevention of Ca2+ overload minimizes diastolic tension and blunts the reduction in coronary nutrient flow that results from compression of the intramyocardial arterioles. A dose of 500–1000 mg orally twice daily is usually well tolerated. Ranolazine is contraindicated in patients with hepatic impairment, with conditions or drugs associated with QTc prolongation, and when drugs that inhibit the CYP3A metabolic system (e.g., ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and large quantities of grapefruit juice) are being taken by the patient.
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with IHD may be associated with a small but finite increased risk of MI and mortality. For this reason, they should generally be avoided in IHD patients. If they are required for symptom relief, it is advisable to coadminister aspirin and strive to use the lowest NSAID dose required for the shortest period of time.
Another class of agents that may be considered are potassium channel openers. These agents open ATP-sensitive potassium channels in myocytes, leading to hyperpolarization of the cell membrane and a reduction of free intracellular calcium ions. The major drug in this class is nicorandil, which is typically administered in a dose of 20 mg twice daily orally for prevention of angina. (Nicorandil is not available for use in the United States but is used in several other countries.) Tolerance to nicorandil's anti-anginal effect may develop with chronic dosing, but there is no cross-tolerance to the organic nitrates.
Angina and Heart Failure
Transient LV failure with angina can be controlled by the use of nitrates. For patients with established congestive heart failure, the increased LV wall tension raises myocardial oxygen demand. Treatment of congestive heart failure with an angiotensin-converting enzyme inhibitor, diuretic, and digoxin (Chap. 227) reduces heart size, wall tension, and myocardial oxygen demand, which in turn helps to control angina and ischemia. If the symptoms and signs of heart failure are controlled, an effort should be made to use beta blockers not only for angina but because trials in heart failure have shown significant improvement in survival. A trial of the intravenous ultrashort acting beta blocker esmolol may be useful to establish the safety of beta blockade in individual patients. Nocturnal angina can often be relieved by the treatment of heart failure. Nitrates are useful and can simultaneously improve the disturbed hemodynamics of congestive heart failure by vasodilatation, thereby reducing preload, and relieve angina by preventing or reversing myocardial ischemia. The combination of congestive heart failure and angina in patients with IHD usually indicates a poor prognosis and warrants serious consideration of cardiac catheterization and coronary revascularization.
While the basic management of patients with IHD is medical, as described above, many patients are improved by coronary revascularization procedures. These interventions should be employed in conjunction with but do not replace the continuing need to modify risk factors and medical therapy. An algorithm for integrating medical therapy and revascularization options in patients with IHD is shown in Fig. 237-2.
Algorithm for management of the patient with ischemic heart disease. All patients should receive the core elements of medical therapy as shown at the top of the algorithm. If high-risk features are present, as established by the clinical history, exercise test data, and imaging studies, the patient should be referred for coronary arteriography. Based on the number and location of the diseased vessels and their suitability for revascularization, the patient is treated with either a percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, or should be considered for unconventional treatments. See text for further discussion. IHD, ischemic heart disease; ASA, aspirin; EF, ejection fraction; ACS, acute coronary syndrome; LM, left main.
Percutaneous Coronary Intervention
(See also Chap. 240) PCI, involving balloon dilatation usually accompanied by coronary stenting, is widely used to achieve revascularization of the myocardium in patients with symptomatic IHD and suitable stenoses of epicardial coronary arteries. Whereas patients with stenosis of the left main coronary artery and those with three-vessel IHD (especially with diabetes and/or impaired LV function) who require revascularization are best treated with CABG, PCI is widely employed in patients with symptoms and evidence of ischemia due to stenoses of one or two vessels, and even in selected patients with three-vessel disease, and may offer many advantages over surgery.
Indications and Patient Selection
The most common clinical indication for PCI is angina pectoris, despite medical therapy, accompanied by evidence of ischemia during a stress test. PCI is more effective than medical therapy for the relief of angina. Whereas PCI improves outcomes in patients with unstable angina and MI, the value of this procedure in reducing the occurrence of coronary death and MI in patients with chronic stable angina has not been established. PCI can be used to treat stenoses in native coronary arteries as well as in bypass grafts in patients who have recurrent angina following CABG.
When coronary stenoses are discrete and symmetric, two and even three vessels can be dilated in sequence. However, case selection is essential in order to avoid a prohibitive risk of complications, which are usually due to dissection or thrombosis with vessel occlusion, uncontrolled ischemia, and ventricular failure (Chap. 240). Oral aspirin, clopidogrel, and an antithrombin are given to reduce coronary thrombus formation. Left main coronary artery stenosis is generally regarded as a contraindication to PCI; such patients should be treated with CABG. In rare cases, such as patients with prohibitive surgical risks, PCI of an unprotected left main can be considered, but such a procedure should only be performed by a highly skilled operator; importantly, there are regional differences in the use of this approach internationally.
Primary success—i.e., adequate dilation (an increase in luminal diameter >20% to a residual diameter obstruction <50%) with relief of angina—is achieved in >95% of cases. Recurrent stenosis of the dilated vessels occurs in ~20% of cases within 6 months of PCI with bare metal stents, and angina will recur within 6 months in 10% of cases. Restenosis is more common in patients with diabetes mellitus, arteries with small caliber, incomplete dilation of the stenosis, occluded vessels, obstructed vein grafts, dilation of the left anterior descending coronary artery, and stenoses containing thrombi. In diseased vein grafts, procedural success has been improved by the use of capture devices or filters that prevent embolization, ischemia, and infarction.
It is usual clinical practice to administer aspirin indefinitely and clopidogrel for 1–3 months after the implantation of a bare metal stent. Although aspirin and the antiplatelet drug clopidogrel may help prevent coronary thrombosis during and shortly following PCI with stenting, there is no evidence that these medications reduce the incidence of restenosis. The use of drug-eluting stents that locally deliver antiproliferative drugs such as rapamycin or paclitaxel can reduce restenosis to near zero within the stent and 3–7% at its edges. Advances in PCI, especially the availability of drug-eluting stents, have vastly extended the use of this revascularization option in patients with IHD. Of note, however, the delayed endothelial healing in the region of a drug-eluting stent also extends the period during which the patient is at risk for subacute stent thrombosis. Current recommendations are to administer aspirin indefinitely and clopidogrel daily for at least 1 year after implantation of a drug-eluting stent. When a situation arises where temporary discontinuation of antiplatelet therapy is desirable, the clinical circumstances should be reviewed with the operator who performed the PCI and a coordinated plan should be established for minimizing the risk of late stent thrombus. Central to this plan is the discontinuation of antiplatelet therapy for the shortest acceptable period of time.
Successful PCI produces effective relief of angina in >95% of cases and has been shown to be more effective than medical therapy for up to 2 years. More than one-half of patients with symptomatic IHD who require revascularization can be treated initially by PCI. Successful PCI is less invasive and expensive than CABG, usually requires only 1–2 days in the hospital, and permits savings in the initial cost of care. Successful PCI also allows earlier return to work and the resumption of an active life. However, this economic benefit is reduced over time because of the greater need for follow-up and for repeat procedures.
Coronary Artery Bypass Grafting
Anastomosis of one or both of the internal mammary arteries or a radial artery to the coronary artery distal to the obstructive lesion is carried out. For additional obstructions that cannot be bypassed by an artery, a section of a vein (usually the saphenous) is used to form a connection between the aorta and the coronary artery distal to the obstructive lesion.
Although some indications for CABG are controversial, certain areas of agreement exist:
The operation is relatively safe, with mortality rates <1% in patients without serious comorbid disease and normal LV function, and when the procedure is performed by an experienced surgical team.
Intraoperative and postoperative mortality increase with the severity of ventricular dysfunction, comorbidities, age >80 years, and lack of surgical experience. The effectiveness and risk of CABG vary widely depending on case selection and the skill and experience of the surgical team.
Occlusion of venous grafts is observed in 10–20% of patients during the first postoperative year, in approximately 2% per year during 5- to 7-year follow-up, and in 4% per year thereafter. Long-term patency rates are considerably higher for internal mammary and radial artery implantations than saphenous vein grafts. In patients with left anterior descending coronary artery obstruction, survival is better when coronary bypass involves the internal mammary artery rather than a saphenous vein. Graft patency and outcomes are improved by meticulous treatment of risk factors, particularly dyslipidemia.
Angina is abolished or greatly reduced in ~90% of patients following complete revascularization. Although this is usually associated with graft patency and restoration of blood flow, the pain may also have been alleviated as a result of infarction of the ischemic segment or a placebo effect. Within 3 years, angina recurs in about one-fourth of patients but is rarely severe.
Survival may be improved by operation in patients with stenosis of the left main coronary artery as well as in patients with three- or two-vessel disease with significant obstruction of the proximal left anterior descending coronary artery. The survival benefit is greater in patients with abnormal LV function (ejection fraction <50%). Survival may also be improved in the following patients: (1) those with obstructive CAD who have survived sudden cardiac death or sustained ventricular tachycardia; (2) those who have undergone previous CABG and who have multiple saphenous vein graft stenoses, especially of a graft supplying the left anterior descending coronary artery; and (3) those with recurrent stenosis following PCI and high-risk criteria on noninvasive testing.
Minimally invasive CABG through a small thoracotomy and/or off-pump surgery can reduce morbidity and shorten convalescence in suitable patients but does not appear to significantly reduce the risk of neurocognitive dysfunction postoperatively.
Indications for CABG are usually based on the severity of symptoms, coronary anatomy, and ventricular function. The ideal candidate is male, is <80 years of age, has no other complicating disease, has troublesome or disabling angina that is not adequately controlled by medical therapy or does not tolerate medical therapy and wishes to lead a more active life, and has severe stenoses of two or three epicardial coronary arteries with objective evidence of myocardial ischemia as a cause of the chest discomfort. Great symptomatic benefit can be anticipated in such patients. Congestive heart failure and/or LV dysfunction, advanced age (>80 years), reoperation, urgent need for surgery, and the presence of diabetes mellitus are all associated with a higher perioperative mortality.
LV dysfunction can be due to noncontractile or hypocontractile segments that are viable but are chronically ischemic (hibernating myocardium). As a consequence of chronic reduction in myocardial blood flow these segments downregulate their contractile function. These can be detected by using radionuclide scans of myocardial perfusion and metabolism, PET, CMR imaging, or delayed scanning with thallium-201; or by improvement of regional functional impairment, provoked by low-dose dobutamine. In such patients, revascularization improves myocardial blood flow, can return function, and can improve survival.
The Choice between PCI and CABG
A number of randomized clinical trials have compared PCI and CABG in patients with multivessel CAD who were suitable technically for both procedures. The redevelopment of angina requiring repeat coronary angiography and repeat revascularization is higher with PCI. This is a result of restenosis in the stented segment (a problem largely solved with drug-eluting stents) and the development of new stenoses in unstented portions of the coronary vasculature. It has been argued that PCI with stenting focuses on culprit lesions while a bypass graft to the target vessel also provides a conduit around future culprit lesions proximal to the anastomosis of the graft to the native vessel (Fig. 237-3).
Difference in the approach to the lesion with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). PCI is targeted at the "culprit" lesion or lesions, whereas CABG is directed at the epicardial vessel, including the "culprit" lesion or lesions and future culprits, proximal to the insertion of the vein graft, a difference that may account for the superiority of CABG, at least in the intermediate term, in patients with multivessel disease. (Reproduced from BJ Gersh et al: N Engl J Med 352:2235, 2005.)
Comparison of mortality rates in patients treated with CABG versus PCI is a complex issue. There is an early increased risk of mortality with CABG, but when considering a longer time horizon, such as 5 years, mortality is lower with CABG compared with PCI.
Based on available evidence, it is now recommended that patients with an unacceptable level of angina despite optimal medical management be considered for coronary revascularization. Patients with single- or two-vessel disease with normal LV function and anatomically suitable lesions are ordinarily advised to undergo PCI (Chap. 240). Patients with three-vessel disease (or two-vessel disease that includes the proximal left descending coronary artery) and impaired global LV function (LVEF <50%) or diabetes mellitus or those with left main coronary artery disease or other lesions unsuitable for catheter-based procedures should be considered for CABG as the initial method of revascularization.
Unconventional Treatments for IHD
On occasion clinicians will encounter a patient with persistent disabling angina despite maximally tolerated medical therapy for whom revascularization is not an option (e.g., small diffusely diseased vessels not amenable to stent implantation or acceptable targets for bypass grafting). In such situations unconventional treatments should be considered.
Enhanced external counterpulsation utilizes pneumatic cuffs on the lower extremities to provide diastolic augmentation and systolic unloading of blood pressure in order to decrease cardiac work and oxygen consumption while enhancing coronary blood flow. Clinical trials have shown that regular application improves angina, exercise capacity, and regional myocardial perfusion.
Additional options include transmyocardial laser revascularization (to increase intramyocardial channels of blood flow), and the currently experimental approaches of gene and stem cell therapies are under study.
Asymptomatic (Silent) Ischemia
Obstructive CAD, acute MI, and transient myocardial ischemia are frequently asymptomatic. During continuous ambulatory ECG monitoring, the majority of ambulatory patients with typical chronic stable angina are found to have objective evidence of myocardial ischemia (ST-segment depression) during episodes of chest discomfort while they are active outside the hospital, but many of these patients have more frequent episodes of asymptomatic ischemia. In addition, there is a large (but as yet unknown) number of totally asymptomatic persons with severe coronary atherosclerosis who exhibit ST-segment changes during activity. Some of these patients exhibit higher thresholds to electrically induced pain, others show higher endorphin levels, and still others may be diabetics with autonomic dysfunction.
Frequent episodes of ischemia (symptomatic and asymptomatic) during daily life appear to be associated with an increased likelihood of adverse coronary events (death and MI). In addition, patients with asymptomatic ischemia after suffering a myocardial infarction are at greater risk for a second coronary event. The widespread use of exercise ECG during routine examinations has also identified some of these heretofore unrecognized patients with asymptomatic CAD. Longitudinal studies have demonstrated an increased incidence of coronary events in asymptomatic patients with positive exercise tests.
Asymptomatic Ischemia: Treatment
The management of patients with asymptomatic ischemia must be individualized. Thus, the physician should consider the following: (1) the degree of positivity of the stress test, particularly the stage of exercise at which ECG signs of ischemia appear, the magnitude and number of the ischemic zones of myocardium on imaging, and the change in LVEF which occurs on radionuclide ventriculography or echocardiography during ischemia and/or during exercise; (2) the ECG leads showing a positive response, with changes in the anterior precordial leads indicating a less favorable prognosis than changes in the inferior leads; and (3) the patient's age, occupation, and general medical condition.
Most would agree that an asymptomatic 45-year-old commercial airline pilot with 0.4-mV ST-segment depression in leads V1 to V4 during mild exercise should undergo coronary arteriography, whereas the asymptomatic, sedentary 75-year-old retiree with 0.1-mV ST-segment depression in leads II and III during maximal activity need not. However, there is no consensus about the appropriate procedure in the large majority of patients for whom the situation is less extreme. Asymptomatic patients with silent ischemia, three-vessel CAD, and impaired LV function may be considered appropriate candidates for CABG.
The treatment of risk factors, particularly lipid lowering as described above, and the use of aspirin, beta blockers, and statins have been shown to reduce events and improve outcomes in asymptomatic as well as symptomatic patients with ischemia and proven CAD. While the incidence of asymptomatic ischemia can be reduced by treatment with beta blockers, calcium channel blockers, and long-acting nitrates, it is not clear whether this is necessary or desirable in patients who have not suffered a myocardial infarction.