Chronic Ischemic Heart Disease

Michael H. Crawford, MD

General Considerations

For clinical purposes, patients with chronic ischemic heart disease fall into two general categories: those with symptoms related to the disease, and those who are asymptomatic. Although the latter are probably more common than the former, physicians typically see symptomatic patients more frequently. The issue of asymptomatic patients becomes important clinically when physicians are faced with estimating the risk to a particular patient who is undergoing some stressful intervention, such as major noncardiac surgery. Another issue is the patient with known coronary artery disease who is currently asymptomatic. Such individuals, especially if they have objective evidence of myocardial ischemia, are known to have a higher incidence of future cardiovascular morbidity and mortality. There is, understandably, a strong temptation to treat such patients, despite the fact that it is difficult to make an asymptomatic patient feel better, and some of the treatment modalities have their own risks. In such cases, strong evidence that longevity will be positively influenced by the treatment must be present in order for its benefits to outweigh its risks.

Pathophysiology & Etiology

In the industrialized nations, most patients with chronic ischemic heart disease have coronary atherosclerosis. Consequently, it is easy to become complacent and ignore the fact that other diseases can cause lesions in the coronary arteries (Table 6–1). In young people, coronary artery anomalies should be kept in mind; in older individuals, systemic vasculitides are not uncommon. Today, collagen vascular diseases are the most common vasculitides leading to coronary artery disease, but in the past, infections such as syphilis were a common cause of coronary vasculitis. Diseases of the ascending aorta, such as aortic dissection, can lead to coronary ostial occlusion. Coronary artery emboli may occur as a result of infectious endocarditis or of atrial fibrillation with left atrial thrombus formation. Infiltrative diseases of the heart, such as tumor metastases, may also compromise coronary flow. It is therefore essential to keep in mind diagnostic possibilities other than atherosclerosis when managing chronic ischemic heart disease.

Myocardial ischemia is the result of an imbalance between myocardial oxygen supply and demand. Coronary atherosclerosis and other diseases reduce the supply of oxygenated blood by obstructing the coronary arteries. Although the obstructions may not be enough to produce myocardial ischemia at rest, increases in myocardial oxygen demand during activities can precipitate myocardial ischemia. This is the basis for using stress testing to detect ischemic heart disease. Transient increases in the degree of coronary artery obstruction may develop as a result of platelet and thrombus formation or through increased coronary vasomotor tone. Although it is rare in the United States, pure coronary vasospasm in the absence of atherosclerosis can occur and cause myocardial ischemia and even infarction. In addition, in the presence of other cardiac diseases, especially those that cause a pressure load on the left ventricle, myocardial oxygen demand may outstrip the ability of normal coronary arteries to provide oxygenated blood, resulting in myocardial ischemia or infarction. A good example would be the patient with severe aortic stenosis, considerable left ventricular hypertrophy, and severely elevated left ventricular pressures who tries to exercise. The manifestations of chronic ischemic heart disease have their basis in a complex pathophysiology of multiple factors that affect myocardial oxygen supply and demand.

Clinical Findings

A. Risk Factors

Coronary atherosclerosis is more likely to occur in patients with certain risk factors for this disease (Table 6–2). These include advanced age, male gender or the postmenopausal state in females, a family history of coronary atherosclerosis, diabetes mellitus, systemic hypertension, high serum cholesterol and other associated lipoprotein abnormalities, and tobacco smoking. Additional minor risk factors include a sedentary lifestyle, obesity, high psychological stress levels, and such phenotypic characteristics as earlobe creases, auricular hirsutism, and a mesomorphic body type. The presence of other systemic diseases—hypothyroidism, pseudoxanthoma elasticum, and acromegaly, for example—can accelerate a propensity to coronary atherosclerosis. In the case of nonatherosclerotic coronary artery disease, evidence of such systemic vasculitides as lupus erythematosus, rheumatoid arthritis, and polyarthritis nodosa should be sought. Although none of these risk factors is in itself diagnostic of coronary artery disease, the more of them that are present, the greater the likelihood of the diagnosis.

B. Symptoms & Signs

The major symptom of chronic ischemic heart disease is angina pectoris, with a clinical diagnosis based on five features:

• The character of the pain is a deep visceral pressure or squeezing sensation, rather than sharp or stabbing or pinprick-like pain.

• The pain almost always has some substernal component, although some patients complain of pain only on the right or left side of the chest, upper back, or epigastrium.

• The pain may radiate from the thorax to the jaw, neck, or arm. Arm pain in angina pectoris typically involves the ulnar surface of the left arm. Occasionally, the radiated pain may be more noticeable to the patient than the origin of the pain, resulting in complaints of only jaw or arm pain. These considerations have led some physicians to suggest that any pain between the umbilicus and the eyebrows should be considered angina pectoris until proven otherwise.

• Angina is usually precipitated by exertion, emotional upset, or other events that obviously increase myocar-dial oxygen demand, such as rapid tachyarrhythmias or extreme elevations in blood pressure.

• Angina pectoris is transient, lasting between 2 and 30 minutes. It is relieved by cessation of the precipitating event, such as exercise, or by the administration of treatment, such as sublingual nitroglycerin. Chest pain that lasts longer than 30 minutes is more consistent with myocardial infarction; pain of less than 2 minutes is unlikely to be due to myocardial ischemia.

For reasons that are unclear, some patients with chronic ischemic heart disease do not manifest typical symptoms of angina pectoris but have other symptoms that are brought on by the same precipitating factors and are relieved in the same way as angina. Because myocardial ischemia can lead to transient left ventricular dysfunction, resulting in increased left ventricular end-diastolic pressure and consequent pulmonary capillary pressure, the sensation of dyspnea can occur during episodes of myocardial supply-and-demand imbalance. Dyspnea may be the patient’s only symptom during myocardial ischemia, or it may overshadow the chest pain in the patient’s mind. Therefore, dyspnea out of proportion to the degree of exercise or activity can be considered an angina equivalent. Severe myocardial ischemia may lead to ventricular tachyarrhythmias manifesting as palpitations or even frank syncope. Severe episodes of myocardial ischemia may also lead to transient pulmonary edema, especially if the papillary muscles are involved in the ischemic myocardium and moderately severe mitral regurgitation is produced. The most dramatic result of myocardial ischemia is sudden cardiac death.

Patients with chronic myocardial ischemia can also have symptoms caused by the effects of repeated episodes of ischemia or infarction. Thus, patients may have manifestations of chronic cardiac rhythm disorders, especially ventricular arrhythmias, or chronic congestive heart failure. Patients may have symptoms related to atherosclerosis of other vascular systems. Patients with vascular disease in other organs are more likely to have coronary atherosclerosis. Those with prior cerebral vascular accidents or symptoms of peripheral vascular disease may be so disabled by these diseases that their ability to either perceive angina or generate enough myocardial oxygen demand to produce angina may be severely limited.

C. Physical Examination

The physical examination is often not helpful in the diagnosis of chronic ischemic heart disease. This is because many patients with chronic ischemic heart disease have no physical findings related to the disease, or if they do, the findings are not specific for coronary artery disease. For example, a fourth heart sound can be detected in patients with chronic ischemic heart disease, especially if they have had a prior myocardial infarction; however, fourth heart sounds are very common in hypertensive heart disease, valvular heart disease, and primary myocardial disease. Palpation of a systolic precordial bulge can occur in patients with prior myocardial infarction, but this sign is not specific and can occur in patients with left ventricular enlargement from any cause. Other signs can also be found in cases of chronic ischemic heart disease, such as those associated with congestive heart failure or mitral regurgitation. Again, these are nonspecific and can be caused by other disease processes. Because coronary atherosclerosis is the most common heart disease in industrialized nations, any physical findings suggestive of heart disease should raise the suspicion of chronic ischemic heart disease.

D. Laboratory Findings

A complete blood count is useful to detect anemia, which will aggravate angina. Thyroid function tests are also important since hyperthyroidism can aggravate angina and hypothyroidism can lead to atherosclerosis. High-sensitivity C-reactive protein (CRP) has been used to detect the increased inflammation of active atherosclerosis. Values greater than 3 mg/L predict coronary events, but the additive value over standard risk factors is unclear. Mortality can be predicted by brain natriuretic peptide (BNP) or troponin levels in patients with coronary artery disease. Presumably, patients with high CRP, BNP, or troponin levels should be treated more aggressively to reduce risk factors.

E. Diagnostic Studies

1. Stress tests—Because angina pectoris or other manifestations of myocardial ischemia often occur during the patient’s normal activities, it would be ideal to detect evidence of ischemia at that time. This can be done with ambulatory electrocardiography (ECG). Under unusual circumstances, a patient may have spontaneous angina or ischemia in a medical facility, where it is possible to perform an echocardiogram to assess wall motion abnormalities indicative of ischemia or to inject a radionuclide agent and immediately image the myocardium for perfusion defects. Detection of myocardial ischemia during a patient’s normal activities, however, does not have as high a diagnostic yield as exercise stress testing does.

Of the various forms of exercise stress that can be used, the most popular is treadmill exercise, for several reasons: It involves walking, a familiar activity that often provokes symptoms. Because of the gravitational effects of being upright, walking requires higher levels or myocardial oxygen demand than do many other forms of exercise. In addition, walking can be performed on an inexpensive treadmill device, which makes evaluating the patient easy and cost-effective. Bicycling is an alternative form of exercise that is preferred by exercise physiologists because it is easier to quantitate the amount of work the person is performing on a bicycle than on a treadmill. Unfortunately, bicycle exercise does not require as high a level of myocardial oxygen demand as does treadmill walking. Thus, a patient may become fatigued on the bicycle before myocardial ischemia is induced, resulting in lower diagnostic yields. On the other hand, bicycle exercise can be performed in the supine position, which facilitates some myocardial ischemia detection methods such as echocardiography. In patients with peripheral vascular disease or lower limb amputations, arm and upper trunk rowing or cranking exercises can be substituted for leg exercise. Arm exercise has a particularly low diagnostic yield because exercising with the small muscle mass of the arms does not increase myocardial oxygen demand by much. Rowing exercises that involve the arms and the trunk muscles produce higher levels of myocardial oxygen demand that can equal those achieved with bicycle exercise—but not quite the levels seen with treadmill exercise. For these reasons, patients who cannot perform leg exercises are usually evaluated using pharmacologic stress testing.

There are two basic kinds of pharmacologic stress tests. One uses drugs, such as the synthetic catecholamine dobuta-mine, that mimic exercise; the other uses vasodilator drugs, such as dipyridamole and adenosine, that, by producing profound vasodilatation, increase heart rate and stroke volume, thereby raising myocardial oxygen demand. In addition, vasodilators may dilate normal coronary arteries more than diseased coronary arteries, augmenting any differences in regional perfusion of the myocardium, which can be detected by perfusion scanning. In general, vasodilator stress is preferred for myocardial perfusion imaging, and synthetic catecholamine stress is preferred for wall motion imaging.

2. Electrocardiography—ECG is the most frequently used method for detecting myocardial ischemia because of its ready availability, low cost, and ease of application. The usual criterion for diagnosing ischemia is horizontal or down-sloping ST segment depression, achieving at least 0.1 mV at 80 ms beyond the J point (junction of the QRS and the ST segment). This criterion provides the highest values of sensitivity and specificity. Sensitivity can be increased by using 0.5 mV, but at the expense of lower specificity; similarly, using 0.2 mV increases the specificity of the test at the expense of lower sensitivity. Furthermore, accuracy is highest when ECG changes are in the lateral precordial leads (V₄, V₅, V₆) instead of the inferior leads (II, III, aVF). In the usual middle-aged, predominantly male population of patients with chest pain syndromes, who have normal resting ECGs and can achieve more than 85% of their maximal predicted age-based heart rate during treadmill exercise, the preceding ECG criteria have a sensitivity and specificity of approximately 85%. If the resting ECG is abnormal, if the patient does not achieve 85% of maximum predicted heart rate, or if the patient is a woman, the sensitivity and specificity are lower and range from 70% to 80%. In an asymptomatic population with a low pretest likelihood of disease, sensitivity and specificity fall below 70%.

3. Myocardial perfusion scanning—This method detects differences in regional myocardial perfusion rather than ischemia per se; however, there is a high correlation between abnormal regional perfusion scans and the presence of significant coronary artery occlusive lesions. Thus, when coronary arteriography is used as the gold standard, the sensitivity and specificity of stress myocardial perfusion scanning in the typical middle-aged, predominantly male population with symptoms are approximately 85–95%. Testing an asymptomatic or predominantly female population would result in lower values. Failure to achieve more than 85% of the maximal predicted heart rate during exercise also results in lower diagnostic accuracy. Although treadmill exercise is the preferred stress modality for myocardial perfusion imaging, pharmacologically induced stress with dipyridamole or adenosine produces nearly as good results and is an acceptable alternative in the patient who cannot exercise. Positron emission tomography with vasodilator stress also can be used to detect regional perfusion differences indicative of coronary artery disease.

4. Assessing wall motion abnormalities—Reduced myocardial oxygen supply results in diminishment and, if severe enough, failure of myocardial contraction. Using methods to visualize the left ventricular wall, a reduction in inward endocardial movement and systolic myocardial thickening is observed with ischemia. Echocardiography is an ideal detection system for wall motion abnormalities because it can examine the left ventricle from several imaging planes, maximizing the ability to detect subtle changes in wall motion. When images are suboptimal (< 5% of cases), intravenous contrast agents can be given to fill the left ventricular cavity and improve endocardial definition. The results with either exercise or pharmacologic stress are comparable to those of myocardial perfusion imaging and superior to the ECG stress test detection of ischemia. The preferred pharmacologic detection method with wall motion imaging is dobutamine because it directly stimulates the myocardium to increase contractility, as well as raising heart rate and blood pressure, all of which increase myocardial oxygen demand. In some laboratories, if the heart rate increase is not comparable to that usually achieved with exercise testing, atropine is added to further increase myocardial oxygen demand. Magnetic resonance imaging (MRI) can also be used to assess left ventricular wall motion during pharmacologic stress testing, but there is relatively little experience with this technique.

5. Evaluating global left ventricular performance—Myocardial ischemia, if profound enough, results in a reduction in global left ventricular performance, which can be detected by either a decrease in left ventricular ejection fraction or a failure for it to increase during exercise. Therefore, techniques such as radionuclide angiography and single-photon emission computed tomography (SPECT) left ventricular reconstruction have been used to detect changes in global left ventricular function. Because fairly profound ischemia is required to depress global left ventricular function, this method has not been as sensitive as other techniques. Furthermore, myocardial disease can lead to an abnormal exercise ejection fraction response, which lowers the specificity of the test. In addition, age and female gender blunt the ejection fraction response to exercise, making the test less reliable in the elderly and in women. As a result, there is currently little enthusiasm for the use of global left ventricular function tests alone for detecting ischemic heart disease.

6. Evaluating coronary anatomy

A. CORONARY ANGIOGRAPHY—Coronary angiography is the standard for evaluating the anatomy of the coronary artery tree. It is best at evaluating the large epicardial coronary vessels that are most frequently diseased in coronary atherosclerosis. Experimental studies suggest that lesions that reduce the lumen of the coronary artery by 70% or more in area (50% in diameter) significantly limit flow, especially during periods of increased myocardial oxygen demand. If such lesions are detected, they are considered compatible with symptoms or other signs of myocardial ischemia. This assessment is known to be imprecise for several reasons, however. First, the actual cross-sectional area of the coronary artery at the point of an atherosclerotic lesion must be estimated from two-dimensional diameter measurements in several planes. When compared with autopsy findings, stenosis severity is usually found to have been underestimated by the coronary angiography. Second, the technique does not take into consideration that lesions in series in a coronary artery may incrementally reduce the flow to distal beds by more than is accounted for by any single lesion. Thus, a series of apparently insignificant lesions may actually reduce myocardial blood flow significantly. Third, the cross-sectional area is not actually measured routinely. It is instead referenced to a supposed normal segment of artery in terms of a percentage of stenosis or percentage of reduction in the normal luminal diameter or cross-sectional area. The problem with this type of estimate is that it is often difficult to determine what a normal segment of artery is, especially in patients with diffuse coronary atherosclerosis.

Quantitative coronary angiogram measurements are an improvement over this visual inspection technique, but they are not commonly used except in research projects. Epicardial coronary artery anatomy is a static representation at the time of the study. It does not take into consideration potential changes in coronary vasomotor tone that may occur under certain circumstances and further reduce coronary blood flow. In addition, coronary angiography does not adequately evaluate disease in the intramyocar-dial blood vessels; this may be important in some patients, especially insulin-dependent diabetics. In patients with pure vasospastic angina, the coronary arteries are usually normal or minimally diseased. To establish increased vasomotion as the cause of the angina, provocative tests have been used to induce coronary vasospasm in the cardiac catheterization laboratory. The most popular of these is an ergonovine infusion, which is reputed to produce focal vasospasm only in naturally susceptible arteries and not in normal coronary arteries, which usually exhibit only a uniform reduction in vessel diameter. Ergonovine infusion has some risks, however, in that the resultant coronary vasospasm may be difficult to alleviate and can be quite profound. In addition, not all patients with vasospastic angina may respond to this agent. Thus, its use has diminished in favor of ECG monitoring during the patient’s normal daily activities.

B. OTHER TECHNIQUES—ECG or imaging evidence of old myocardial infarction is often presumed to indicate that severe coronary artery stenoses are present in the involved vessel. Myocardial infarction, however, can occur as a result of thrombus on top of a minor plaque that has ruptured and occasionally from intense vasospasm or coronary emboli from the left heart. In these cases, coronary angiography would not detect significant (narrowing of > 50% of the diameter) coronary lesions despite the evidence of an old myocardial infarction. Coronary artery imaging is therefore necessary because estimating the degree of stenosis from the presence of infarction is not accurate. The presence of inducible myocardial ischemia almost always correlates with significant coronary artery lesions. Under the right clinical circumstances, coronary angiography can often be avoided if noninvasive stress testing produces myocardial ischemia. Coronary angiography could then be reserved for patients who have not responded to medical therapy and were being considered for revascularization, where visualizing the coronary anatomy is necessary.

Other imaging techniques have also had some success. Echocardiography, especially transesophageal, can often visualize the first few centimeters of the major epicardial coronary arteries, and MRI has also shown promise. At present, neither of these noninvasive imaging techniques has reached the degree of accuracy needed to replace contrast coronary angiography; however, technical improvements may change this in the future.

Cardiac computed tomography (CT) use is expanding. Noncontrast techniques can rapidly detect calcified coronary artery plaque. The amount of plaque can be quantitated, usually as the Agatston score, which is predictive of future coronary events in an incremental fashion beyond traditional risk factors. The major use of CT coronary calcium score may be to further stratify the risk of an event in intermediate-risk patients where the intensity of risk factor reduction could be altered accordingly. Contrast CT angiography can evaluate the lumen of the coronary arteries and is a useful alternative to stress testing for low to intermediate pretest risk of coronary artery disease patients. More recently, hybrid CT and either SPECT or positron emission tomography scanners are being used to visualize coronary lesions and assess their physiologic significance at one setting. Since most patients with a positive CT scan for either coronary calcium or lesions eventually get a stress test, this combination makes sense.

F. Choosing a Diagnostic Approach

Normally, noninvasive testing is performed first in the evaluation of suspected coronary atherosclerosis in symptomatic patients with an intermediate pretest likelihood of disease. There are several reasons for this: There is less risk with stress testing than with invasive coronary angiography, and cardiac CT has almost no risks. Mortality rates for stress testing average 1 per 10,000 patients, compared with 1 per 1000 for coronary angiography. The physiologic demonstration of myocardial ischemia and its extent forms the basis for the therapeutic approach irrespective of coronary anatomy. Mildly symptomatic patients who show small areas of ischemia at intense exercise levels have an excellent prognosis and are usually treated medically. Knowledge of the coronary anatomy is not necessary to make this therapeutic decision. In general, therefore, a noninvasive technique should be used to detect myocardial ischemia and its extent before considering coronary angiography, which is both riskier and more costly. Asymptomatic patients with a low to intermediate pretest likelihood of coronary artery disease may be better served by a noninvasive coronary artery imaging technique, such as cardiac CT; symptomatic patients may be better served by undergoing the combination of cardiac CT and stress perfusion imaging.

Profound symptoms that occur with minimal exertion are almost certainly due to severe diffuse coronary atherosclerosis or left main obstruction, and it is prudent to proceed directly with coronary angiography. Patients with severe unstable angina should undergo coronary angiography because of the potential increased risk posed by stress testing. If this approach is not appropriate in a particular clinical setting, the clinician might medicate the patient and perform careful stress testing after demonstrating a lack of symptoms on medical therapy. Patients with angina or evidence of ischemia in the early period after myocardial infarction are categorized as having unstable angina and should be taken directly to coronary angiography. The postinfarction patient who is not having recurrent ischemia, however, can usually be evaluated by stress testing and then a decision can be made about the advisability of coronary angiography. If the clinical situation is such that it is likely that stress testing will be inaccurate or uninterpretable, CT or invasive coronary angiography should be performed. Left bundle branch block on the ECG, for example, not only renders the ECG useless for detecting myocardial ischemia but may also affect the results of myocardial perfusion imaging and wall motion studies. Noninvasive techniques have poor diagnostic accuracy in morbidly obese female patients who are unable to exercise. In general, patients whose medical conditions preclude accurate stress testing are candidates for direct coronary angiography.

Which type of noninvasive stress testing to select is based on several factors. The most important of these is the type of information desired; second, certain characteristics of the patient, which may make one test more applicable than another; and third, the pretest likelihood of disease. For example, cardiac CT may be most useful in low-risk patients; stress imaging in intermediate-risk patients; and invasive angiography in high-risk patients. Stress perfusion scanning is more likely than echocardiographic imaging to provide adequate technical quality in obese individuals or those with chronic obstructive pulmonary disease. Cost is also an important consideration, and the ECG stress test is the least expensive. In most patients with a low-to-medium clinical pretest likelihood of disease, using the ECG stress test makes sense, especially because good exercise performance with a negative ECG response for ischemia indicates an excellent prognosis even if coronary artery disease is present. In the patient who is highly likely to have coronary artery disease, however, it is useful to not only confirm the presence of the disease but to document its extent. For this purpose, myocardial imaging techniques are better at determining the extent of coronary artery disease than is the ECG. It is also believed that myocardial perfusion scanning is somewhat better at identifying the coronary arteries involved in the production of ischemia than are techniques for detecting wall motion abnormalities.

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