Ischemic Heart Disease

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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. Chapter 241 deals with the development and treatment of atherosclerosis. This chapter focuses on the chronic manifestations and treatment of ischemic heart disease. The following chapters address the acute phases of this disease.
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. Genetic factors, a high-fat and energy-rich diet, smoking, and a sedentary lifestyle are associated with the emergence of IHD (Chap. 241). In the United States and Western Europe, it is growing among low-income groups, but primary prevention has delayed the disease to later in life in all socioeconomic groups. Despite these sobering statistics, it is worth noting that epidemiologic data show a decline in the rate of deaths due to IHD, about half of which is attributable to treatments and half to prevention by risk factor modification.
Obesity, insulin resistance, and type 2 diabetes mellitus are increasing and are powerful risk factors for IHD. With urbanization in countries with emerging economies and a growing middle class, elements of the energy-rich Western diet are being adopted. As a result, the prevalence of risk factors for and of IHD itself are both increasing rapidly in those regions such that a majority of the global burden of IHD occurs there. Population subgroups that appear to be particularly affected are men in South Asian countries, especially India and the Middle East. In light of 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. In normal conditions, for any given level of a demand for oxygen, the myocardium will control the supply of 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 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 also can be limited by spasm (see Prinzmetal’s angina in Chap. 244), arterial thrombi, and, rarely, coronary emboli as well as by ostial narrowing due to aortitis. Congenital abnormalities such as the 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 also can occur if myocardial oxygen demands are markedly increased and particularly when coronary blood flow may be limited, as occurs in severe left ventricular 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. 237). 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 in a patient, such as an increase in oxygen demand due to left ventricular 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 also can cause ischemia. When it causes angina, this condition is referred to as microvascular angina.
Coronary Atherosclerosis
Epicardial coronary arteries are the major site of atherosclerotic disease. The major risk factors for atherosclerosis [high levels of plasma low-density lipoprotein (LDL), low plasma high-density lipoprotein (HDL), cigarette smoking, hypertension, and diabetes mellitus (Chap. 241)] disturb the normal functions of the vascular endothelium. These functions include local control of vascular tone, maintenance of an antithrombotic surface, and control of inflammatory cell adhesion and diapedesis. The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions between blood cells, especially monocytes and platelets, and the activated vascular endothelium. Functional changes in the vascular milieu ultimately result in the subintimal collections of fat, smooth muscle cells, fibroblasts, and intercellular matrix that define the atherosclerotic plaque. This process develops at irregular rates in different segments of the epicardial coronary tree and leads eventually to segmental reductions in cross-sectional area, i.e., plaque formation.
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 of 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 to cause myocardial ischemia at rest or with minimal stress.
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 and the proximal left anterior descending coronary artery, are particularly hazardous. Chronic severe coronary narrowing and myocardial ischemia frequently are 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 stenosis in a proximal epicardial artery, 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 atherosclerosis), pathologic spasm (Prinzmetal’s angina), or small platelet-rich plugs also can 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. During ischemia, regional disturbances of ventricular contractility cause segmental hypokinesia, akinesia, or, in severe cases, bulging (dyskinesia), which can 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 relaxation and then contraction. 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 left ventricular 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 myocardial infarction (Chap. 245).
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 converted 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).
Ischemia also causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion of T waves and, when more severe, displacement of ST segments (Chap. 228). Transient T-wave inversion probably reflects nontransmural, intramyocardial ischemia; transient ST-segment depression often reflects patchy 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. 233). Most patients who die suddenly from IHD do so as a result of ischemia-induced ventricular tachyarrhythmias (Chap. 273).
Asymptomatic versus Symptomatic Ihd
Postmortem studies of accident victims and military casualties in Western countries have shown that coronary atherosclerosis often begins to develop before 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. 230). Postmortem examination of patients with such obstructions without a history of clinical manifestations of myocardial ischemia often shows macroscopic scars secondary to myocardial infarction in regions supplied by diseased coronary arteries, with or without collateral circulation. According to population studies, ~25% of patients who survive acute myocardial infarction may not come to medical attention, and these patients have the same adverse prognosis as do those who present with the classic clinical picture of acute myocardial infarction (Chap. 245). Sudden death may be unheralded and is a common presenting manifestation of IHD (Chap. 273).
Patients with IHD also can present with cardiomegaly and heart failure secondary to ischemic damage of the left ventricular myocardium that may have caused no symptoms before 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 myocardial infarction (Chap. 245). 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. Various diseases that cause myocardial ischemia as well as the numerous forms of discomfort with which it may be confused are discussed in Chap. 12. Males constitute ~70% of all patients with angina pectoris and an even greater proportion of those less than 50 years of age. It is, however, important to note that angina pectoris in women is often atypical in presentation (see below).
The typical patient with angina is a man >50 years or a woman >60 years of age who complains of episodes 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 typically places a 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 to 5 min, and can radiate to either shoulder and to both arms (especially the ulnar surfaces of the forearm and hand). It also can 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 a patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; that radiation pattern is more typical of pericarditis.
Although episodes of angina typically are 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 also may occur at rest [see “Unstable Angina Pectoris,” (Chap. 244)] 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), wall tension, and myocardial oxygen demand that can lead to ischemia and transient left ventricular 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 particular day and from day to day. In such patients, variations in myocardial oxygen supply, most likely due to changes in coronary vasomotor 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 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 of these factors.
Exertional angina typically is relieved in 1 to 5 min by slowing or ceasing activities 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 243-1). Its impact on the patient’s functional capacity can be described by using the New York Heart Association functional classification (Table 243-1).
Table 243–1. 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 Goldman L 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 diabetic patients, 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, occurring more frequently in the winter in temperate climates. Anginal “equivalents” are symptoms of myocardial ischemia other than angina. They include dyspnea, nausea, fatigue, and faintness and are more common in the elderly and in diabetic patients.
Systematic questioning of a 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, occurring at rest, or awakening the patient from sleep. Since coronary atherosclerosis often is accompanied by similar lesions in other arteries, a patient with angina should be questioned and examined for peripheral arterial disease [intermittent claudication (Chap. 249)], stroke, or transient ischemic attacks (Chap. 370). It is also important to uncover a family history of premature IHD (0.2 mV (2 mm), a fall in systolic blood pressure >10 mmHg, or the development of a ventricular tachyarrhythmia. This test is used to discover any limitation in exercise performance, detect typical ECG signs of myocardial ischemia, and establish their relationship to chest discomfort. The ischemic ST-segment response generally is 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. 243-1). 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 nondiagnostic.
Table 243–2. Relation of Metabolic Equivalent Tasks (METs) to Stages in Various Testing Protocolsfunctional Class

Functional Class Clinical Status O2 Cost mL/kg/min
METS Treadmill Protocols

Source: Modified from Fletcher GF et al: Circulation 104:1694, 2001.
Figure 243-1.

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 whether 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. CMR, cardiac magnetic resonance; EBCT, electron beam computed tomography; ECG, electrocardiogram; ECHO, echocardiography; IHD, ischemic heart disease; MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography.
A. Lead V4 at rest (top) and after 41/2 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 artery, which was confirmed at coronary angiography. [Modified from SD Solomon, in E. Braunwald et al (eds): Primary Cardiology, 2nd ed, Philadelphia, Saunders, 2003.] C. Stress and rest myocardial perfusion SPECT images obtained with 99m-technetium 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 nearly 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 cardiac magnetic resonance (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 extended 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. DTPA, diethylenetriamine penta-acetic 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.)

In 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 who are >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 < age 40 or premenopausal women with no risk factors for premature atherosclerosis. It is also increased in patients taking cardioactive drugs, such as digitalis and antiarrhythmic agents, and 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 that 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. 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 myocardial infarction (Table 243-2). 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 left ventricular 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 >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.
Cardiac Imaging
(See also Chap. 229) 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 99m-technetium sestamibi during exercise (or with pharmacologic) stress. Contemporary 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 persistently 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. 243-1). The development of a transient perfusion defect with a tracer such as thallium-201 or 99m-technetium sestamibi is used to detect myocardial ischemia.
Echocardiography is used to assess left ventricular function in patients with chronic stable angina and patients with a history of a prior myocardial infarction, pathologic Q waves, or clinical evidence of heart failure. Two-dimensional echocardiography can assess both global and regional wall motion abnormalities of the left ventricle that are transient when due to ischemia. Stress (exercise or dobutamine) echocardiography may cause the emergence of regions of akinesis or dyskinesis that are 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, as well as myocardial perfusion. CMR can be used to provide more complete ventricular evaluation using multislice MR imaging (MRI) studies.
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 [electron beam (EBCT), and multidetector (MDCT) detection]. Coronary calcium detected by these imaging techniques most commonly is quantified by using the Agatston score, 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 has not been defined. Thus, its role in CT, EBCT, and MDCT scans for the detection and management of patients with IHD has not been clarified.
Coronary Arteriography
(See also Chap. 230) 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 about the arterial wall, and severe atherosclerosis that does not encroach on the lumen may go undetected. Of note, atherosclerotic plaques characteristically are scattered throughout the coronary tree, tend to occur more frequently at branch points, and 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 remodeling (Chap. 241). 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 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 for coronary arteriography include the following:
1. 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.
2. Patients who have been admitted repeatedly to the hospital for a suspected acute coronary syndrome (Chaps. 244 and 245) but in whom this diagnosis has not been established and in whom the presence or absence of CAD should be determined.
3. 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.
4. Patients with aortic stenosis or hypertrophic cardiomyopathy and angina in whom the chest pain could be due to IHD.
5. 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.
6. Patients after myocardial infarction, especially those who are at high risk after myocardial infarction because of the recurrence of angina or the presence of heart failure, frequent ventricular premature contractions, or signs of ischemia on the stress test.
7. Patients with angina pectoris, regardless of severity, in whom noninvasive testing indicates a high risk of coronary events (poor exercise performance or severe ischemia).
8. Patients in whom coronary spasm or another nonatherosclerotic cause of myocardial ischemia (e.g., coronary artery anomaly, Kawasaki disease) is suspected.
Noninvasive alternatives to diagnostic coronary arteriography include CT angiography and cardiac MR angiography (Chap. 229). Although these new imaging techniques can provide information about obstructive lesions in the epicardial coronary arteries, their exact role in clinical practice has not 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. 244), early postmyocardial infarction angina, angina that is unresponsive or poorly responsive to medical therapy, and angina 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, and mitral regurgitation and for echocardiographic or radioisotopic (or roentgenographic) evidence of cardiac enlargement and reduced (<0.40) ejection fraction. Most important, any of the following signs during noninvasive testing indicates 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 after 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 left ventricular ejection fraction 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 for future coronary events. The finding of frequent episodes of ST-segment deviation on ambulatory ECG monitoring (even in the absence of symptoms) is also an adverse prognostic finding.
On cardiac catheterization, elevations of left ventricular end-diastolic pressure and ventricular volume and reduced ejection fraction are the most important signs of left ventricular dysfunction and are associated with a poor prognosis. Patients with chest discomfort but normal left ventricular 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 thrombosis and/or 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. 244) all reflect episodes of rapid progression in coronary lesions.
With any degree of obstructive CAD, mortality is greatly increased when left ventricular function is impaired; conversely, at any level of left ventricular function, the prognosis is influenced importantly by the quantity of myocardium perfused by critically obstructed vessels. Therefore, it is essential to collect all the evidence substantiating past myocardial damage (evidence of myocardial infarction on ECG, echocardiography, radioisotope imaging, or left ventriculography), residual left ventricular 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 is, the less the heart is able to withstand additional damage and the poorer the prognosis is. Risk estimation must include age, presenting symptoms, all risk factors, signs of arterial disease, existing cardiac damage, and signs of impending damage (i.e., ischemia).
The greater the number and severity of risk factors for coronary atherosclerosis [advanced age (>75 years), hypertension, dyslipidemia, diabetes, morbid obesity, accompanying peripheral and/or cerebrovascular disease, previous myocardial infarction], the worse the prognosis of an angina patient. Evidence exists that elevated levels of C-reactive protein in the plasma, extensive coronary calcification on electron beam CT (see above), and increased carotid intimal thickening on ultrasound examination also indicate an increased risk of coronary events.
Treatment: Stable Angina Pectoris
Once the diagnosis of ischemic heart disease has been made, each patient must be evaluated individually with respect to his or her level of understanding, expectations and goals, control of symptoms, and prevention of adverse clinical outcomes such as myocardial infarction and premature death. The degree of disability as well as the physical and emotional stress that precipitates angina must be recorded carefully 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 realize that a long and productive life is possible even though they have angina pectoris or have experienced and recovered from an acute myocardial infarction. Offering results of clinical trials showing improved outcomes can be of great value in encouraging patients to resume or maintain activity and return to work. 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 increase oxygen demand or decrease oxygen supply to the myocardium and may precipitate or exacerbate angina in patients with IHD. Left ventricular hypertrophy, 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 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 that 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.
Physical conditioning usually improves the exercise tolerance of patients with angina and has substantial psychological benefits. A regular program of isotonic exercise that is within the limits of the individual patient’s threshold for the development of angina pectoris and that 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 metabolic equivalent tasks (METs) performed at the onset of ischemia can be estimated (Table 243-2) and a practical exercise prescription can be formulated to permit daily activities that will fall below the ischemic threshold (Table 243-3).
Table 243–3. 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)
Knitting Dancing (social)
Golf (walking)
Tennis (doubles) Tennis (singles)
Snow skiing (downhill)
Light backpacking
Stream fishing Canoeing
Mountain climbing Squash
Ski touring
Vigorous basketball
Physical conditioning
Walking (2 mph) Level walking (3–4 mph) Level walking (4.5–5.0 mph) Level jogging (5 mph) Running more than 6 mph
Stationary bike Level biking (6–8 mph) Bicycling (9–10 mph) Swimming, breast stroke Bicycling (more than 13 mph)
Very light calisthenics Light calisthenics Swimming (crawl stroke) Rowing machine Heavy calisthenics Bicycling (12 mph) Rope jumping Walking uphill (5 mph)

Abbreviation: METs, metabolic equivalent tasks.
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 often is 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 reduced caloric intake to achieve optimal body weight are a cornerstone in the management of chronic IHD. It is especially important to emphasize weight loss and regular exercise in patients with the metabolic syndrome or overt diabetes mellitus.
Cigarette smoking accelerates coronary atherosclerosis in both sexes and at all ages and increases the risk of thrombosis, plaque instability, myocardial infarction, and death (Chap. 241). 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. 395). Hypertension (Chap. 247) is associated with an increased risk of adverse clinical events from coronary atherosclerosis as well as stroke. In addition, the left ventricular 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. 344) accelerates coronary and peripheral atherosclerosis and is frequently associated with dyslipidemias and increases in the risk of angina, myocardial infarction, and sudden coronary death. Aggressive control of the dyslipidemia (target LDL cholesterol 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, long stents, 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 a thienopyridine for 1–3 months after the implantation of a bare metal stent. Although aspirin in combination with a thienopyridine may help prevent coronary thrombosis during and shortly after 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 can reduce restenosis to less than 10%. 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 a thienopyridine daily for at least one year after implantation of a drug-eluting stent. When a situation arises in which temporary discontinuation of antiplatelet therapy is necessary, 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. The risk of stent thrombosis is dependent on stent size and length, complexity of the lesions, age, diabetes, and technique. However, compliance with dual antiplatelet therapy and individual responsiveness to platelet inhibition are very important factors as well.
Successful PCI produces effective relief of angina in >95% of cases. 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 and permits savings in the initial cost of care. Successful PCI avoids the risk of stroke associated with CABG surgery, allows earlier return to work, and allows the resumption of an active life. However, the early health-related and economic benefit of PCI is reduced over time because of the greater need for follow-up and the increased need for repeat procedures. When directly compared in patients with diabetes or three-vessel or left main coronary artery disease, CABG was superior to PCI in preventing major adverse cardiac or cerebrovascular events over a 12-month follow-up.
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 the preferred procedure. 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:
1. The operation is relatively safe, with mortality rates <1% in patients without serious comorbid disease and normal left ventricular function and when the procedure is performed by an experienced surgical team. 2. Intraoperative and postoperative mortality rates 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.
3. Occlusion of venous grafts is observed in 10 to 20% of patients during the first postoperative year and in approximately 2% per year during 5- to 7-year follow-up and 4% per year thereafter. Long-term patency rates are considerably higher for internal mammary and radial artery implantations than for 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.
4. Angina is abolished or greatly reduced in ~90% of patients after complete revascularization. Although this usually is 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.
5. 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: (a) with obstructive CAD who have survived sudden cardiac death or sustained ventricular tachycardia, (b) who have undergone previous CABG and have multiple saphenous vein graft stenoses, especially of a graft supplying the left anterior descending coronary artery, and (c) with recurrent stenosis after PCI and high-risk criteria on noninvasive testing.
6. 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 reduce significantly the risk of neurocognitive dysfunction postoperatively.
7. Among patients with type 2 diabetes mellitus and multivessel coronary disease, CABG surgery plus optimal medical therapy is superior to optimal medical therapy alone in preventing major cardiovascular events, a benefit mediated largely by a significant reduction in nonfatal MI. The benefits of CABG are especially evident in diabetic patients treated with an insulin-sensitizing strategy as opposed to an insulin-providing strategy.
Indications for CABG usually are based on the severity of symptoms, coronary anatomy, and ventricular function. The ideal candidate is male, is 80 years), reoperation, urgent need for surgery, and the presence of diabetes mellitus are all associated with a higher perioperative mortality rate.
Left ventricular 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. They can be detected by using radionuclide scans of myocardial perfusion and metabolism, PET, cardiac MRI, 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
All the clinical characteristics of each individual patient must be used to decide on the method of revascularization (LV function, diabetes, lesion complexity, etc). 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 whereas 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. 243-3). By contrast, stroke rates are lower with PCI.
Figure 243-3.

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 mortality rates appear similar in the two revascularization strategies over the long term.
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 ordinarily are advised to undergo PCI (Chap. 246). Patients with three-vessel disease (or two-vessel disease that includes the proximal left descending coronary artery) and impaired global LV function (LV ejection fraction < 50%) or diabetes mellitus and 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. In light of the complexity of the decision making, it is desirable to have a multidisciplinary team, including a cardiologist and a cardiac surgeon in conjunction with the patient’s primary care physician, provide input in conjunction with ascertaining the patient’s preferences before committing to a particular revascularization option.
Unconventional Treatments for Ihd
On occasion clinicians will encounter a patient who has persistent disabling angina despite maximally tolerated medical therapy and 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 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. Experimental approaches such as gene and stem cell therapies are also under active study.
Asymptomatic (Silent) Ischemia
Obstructive CAD, acute myocardial infarction, 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. In addition, many of these patients also have more frequent episodes of asymptomatic ischemia. Frequent episodes of ischemia (symptomatic and asymptomatic) during daily life appear to be associated with an increased likelihood of adverse coronary events (death and myocardial infarction). In addition, patients with asymptomatic ischemia after 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 previously unrecognized patients with asymptomatic CAD. Longitudinal studies have demonstrated an increased incidence of coronary events in asymptomatic patients with positive exercise tests.
Asymptomatic Ischemia
The management of patients with asymptomatic ischemia must be individualized. When coronary disease has been confirmed, the aggressive treatment of hypertension and dyslipidemia is essential and will decrease the risk of infarction and death. In addition, 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 LV ejection fraction that 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 significant (0.4-mV) ST-segment depression in leads V1 to V4 during mild exercise should undergo coronary arteriography, whereas an asymptomatic, sedentary 85-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 most appropriate approach 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 and blood pressure control as described above, and the use of aspirin, statins, and beta blockers after infarction have been shown to reduce events and improve outcomes in asymptomatic as well as symptomatic patients with ischemia and proven CAD. Although 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 had a myocardial infarction.
Further Readings
Antman EM et al: Cyclooxygenase inhibition and cardiovascular risk. Circulation 112:759, 2005[PMID: 16061757] Bhatt DL et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706, 2006[PMID: 16531616] Boden WE et al: Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 356:1503, 2007[PMID: 17387127] Chaitman BR: Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 113:2462, 2006[PMID: 16717165] Cleeman JI et al: Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486, 2001
DeFeyter PJ et al: Bypass surgery versus stenting for the treatment of multivessel disease in patients with unstable angina compared with stable angina. Circulation 105:2367, 2002
Frye RL et al: A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 360:2503, 2009[PMID: 19502645] Gibbons RJ et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina. J Am Coll Cardiol 41:159, 2002
Goldschmidt-Clermont PJ et al: Atherosclerosis 2005: Recent discoveries and novel hypotheses. Circulation 112:3348, 2005[PMID: 16301361] Kim MC et al: Refractory angina pectoris: Mechanism and therapeutic options. J Am Coll Cardiol 39:923, 2002[PMID: 11897431] Kushner FG et al: 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120:2271, 2009[PMID: 19923169] Lee TH et al: Noninvasive tests in patients with stable coronary artery disease. N Engl J Med 344:1840, 2001[PMID: 11407346] Marasco SF et al: No improvement in neurocognitive outcomes after off-pump versus on-pump coronary revascularisation: A meta-analysis. Eur J Cardiothorac Surg 33:961, 2008[PMID: 18424064] McQueen MJ et al: Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): A case-control study. Lancet 372:224, 2008[PMID: 18640459] Mega JL et al: Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354, 2009[PMID: 19106084] Morrow D et al: Chronic coronary artery disease, in Braunwald’s Heart Disease, 8th ed, P Libby et al (eds). Philadelphia, Saunders, 2008
Opie LH et al: Controversies in stable coronary artery disease. Lancet 367:69, 2006[PMID: 16399156] Pretre R et al: Choice of revascularization strategy for patients with coronary artery disease. JAMA 285:992, 2001[PMID: 11209153] Serruys PW et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 360:961, 2009[PMID: 19228612] Van Den Brand MJBM et al: The effect of completeness of revascularization on event-free survival at one year in the ARTS trial. J Am Coll Cardiol 39:559, 2002
Weintraub WS et al: Predicting cardiovascular events with coronary calcium scoring. N Engl J Med 358:1394, 2008[PMID: 18367744]

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