Ischemic Heart Disease
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[edit] Ischemic Heart Disease
Leonard S. Lilly
Ischemic heart disease (IHD) is the leading cause of mortality in industrialized societies. This condition afflicts 11 million individuals in the United States and is responsible for more than 500,000 deaths annually. Despite these daunting numbers, during the past 3 decades there has been a gradual decline in IHD-related deaths, which likely reflects the recognition and correction of cardiac risk factors and dramatic improvements in medical and surgical therapies. The primary care physician plays a pivotal role in the prevention, diagnosis, and long-term management of individuals with this condition.
The clinical presentation of patients with IHD is highly variable (Table 63-1). It may be manifest by classic exertional angina, but in other cases myocardial ischemia may occur without any symptoms (silent ischemia). Sometimes the first manifestation is an acute myocardial infarction (MI) or sudden death.
Table 63-1 Clinical Definitions
| Syndrome | Description |
|---|---|
| Ischemic heart disease | Condition in which all imbalance between myocardial oxygen supply and demand results in myocardial hypoxia and accumulation of waste metabolites; most often due to atherosclerotic disease of the coronary arteries |
| Angina pectoris | Uncomfortable sensation in the chest or neighboring anatomic structures produced by myocardial ischemia |
| Stable angina | Chronic pattern of transient angina pectoris, precipitated by physical activity or emotional upset, relieved by rest within a few minutes; episodes often associated with temporary depression of the ST segment, but permanent myocardial damage does not result |
| Variant angina | Typical anginal discomfort, usually at rest, which develops because of coronary artery spasm, rather than an increase of myocardial oxygen demand: episodes often associated with transient shifts of the ST segment (usually ST elevation) |
| Unstable angina | Pattern of increased frequency and duration of angina episodes, produced by less exertion, or at rest; high frequency of progression to myocardial infarction if untreated |
| Silent ischemia | Asymptomatic episodes of myocardial ischemia; can be detected by ECG and other laboratory techniques |
| Myocardial infarction | Region of myocardial necrosis due to prolonged cessation of blood supply; most often results from acute thrombus at site of coronary atherosclerotic stenosis; may be first clinical manifestation of ischemic heart disease, or there may be a history of angina pectoris |
[edit] PATHOPHYSIOLOGY OF MYOCARDIAL ISCHEMIA
Myocardial ischemia results when there is an imbalance between myocardial oxygen supply and demand. This most often occurs because of the presence of atherosclerotic plaque within one or more coronary arteries, which limits the normal rise in coronary blood flow in response to increases in myocardial oxygen demand.
The major determinants of myocardial oxygen demand are heart rate, the force of ventricular contraction, and ventricular wall tension. The latter is proportional to ventricular volume and pressure. Conditions that increase myocardial oxygen consumption, such as physical exertion and emotional stress, result in myocardial ischemia unless there is a concomitant rise in oxygen supply.
Myocardial oxygen supply depends on the oxygen-carrying capacity of the blood, coronary blood flow, and the ability of the heart muscle to extract oxygen from circulating blood. The oxygen-carrying capacity relates to the content of hemoglobin and systemic oxygenation, and in the absence of anemia or lung disease it is fairly constant. Unlike other organs, the extraction of oxygen from the blood by heart muscle is nearly maximal in the resting state and cannot be significantly increased during periods of increased demand. Therefore it is primarily the increase in coronary blood flow that adjusts myocardial supply when oxygen demands increase. During periods of increased myocardial work, the local accumulation of vasoactive metabolites stimulates coronary arteriolar dilation and causes the coronary blood flow to rise several-fold. However, when atherosclerotic disease is present, the artery lumen is narrowed and vasodilation is impaired, such that coronary blood flow cannot increase in the face of increased demands, and ischemia may result. When ischemia occurs, it is frequently accompanied by the chest discomfort known as angina pectoris. The predictable pattern of intermittent symptoms of myocardial ischemia during exertion or emotional stress is known as chronic stable angina.
The degree of narrowing in an atherosclerotic vessel is not constant; it can vary from moment to moment because of alterations in coronary vascular tone and vasospasm, which may further reduce blood flow. The mechanism of coronary vasospasm is not known but may relate to endothelial dysfunction in the setting of atherosclerotic disease, with impaired release of natural vasodilators including nitric oxide and prostacyclin. In some patients, alterations of vascular tone play a minor role in narrowing the coronary lumen, but in other individuals the degree of vasospasm may be even more important than the degree of fixed atherosclerotic stenosis itself. In the majority of patients with angina the development of myocardial ischemia results from a combination of fixed and vasospastic stenosis. The variation in vascular tone may explain the variable threshold of angina: one day exertion might not produce any angina at all, but on another day similar effort does result in symptoms of ischemia.
A small number of patients experience episodes of intense focal coronary artery spasm in the absence of underlying atherosclerotic disease. In that situation angina can occur at rest (i.e., not provoked by increased myocardial oxygen demand) because of the marked reduction in coronary blood flow. This form of ischemia, known as variant or Prinzmetal's angina, is rare.
A patient with chronic stable angina may develop a sudden increase in the frequency and duration of ischemic episodes, occurring at lower workloads than previously or even at rest. This acceleration is known as unstable angina, and up to 20% of such patients sustain an MI over the ensuing 3 months. Although the majority of such patients have severe atherosclerotic coronary disease, unstable angina can also arise in patients with only mildly obstructive coronary lesions. Catheterization and angioscopy studies have shown that the pathogenesis of unstable angina is multifactorial, often involving rupture of an atherosclerotic plaque with subsequent platelet aggregation and local thrombus formation. In other cases transient periods of intense coronary vasospasm at sites of atherosclerotic plaque play a role. Similar mechanisms also appear responsible for the development of MI: more than 90% of acute MIs result from an acute thrombus obstructing a coronary artery with resultant prolonged ischemia and tissue necrosis. This summary of the pathophysiology of IHD has therapeutic consequences: the treatment of chronic angina is directed at minimizing myocardial oxygen demand and increasing coronary flow, whereas in the acute syndromes of unstable angina or MI primary therapy is also directed against platelet aggregation and thrombosis.
[edit] EPIDEMIOLOGY OF ISCHEMIC HEART DISEASE
Many large epidemiologic studies have implicated certain habits and predisposing conditions in the development of atherosclerosis and IHD. The Framingham Heart Study, for example, identified four major potentially modifiable risk factors: hyperlipidemia (elevated low-density lipoprotein [LDL] cholesterol or reduced high-density lipoprotein [HDL] cholesterol [see Chapter 71] ), hypertension, cigarette smoking, and diabetes mellitus (Box 63-1). Recently, the American Heart Association has added obesity (a body mass index > 30) to the list of major modifiable risk factors. Several nonmodifiable risk factors include advanced age, male sex, and a family history of premature coronary disease (i.e., coronary disease in related males age 55 or less or females age 65 or less). Other potential risk factors of unproven magnitude include a sedentary lifestyle and stressful emotional states.
| Box 63-1 - Major Risk Factors for Coronary Artery Disease |
LDL, Low-density liprotein; HDL, high-density lipoprotein. |
Correction of the modifiable risk factors is critical to the long-term management of IHD to prevent disease progression and resulting complications. For example, clinical trials discussed in Chapter 71 show that control of abnormal cholesterol levels can substantially slow, and possibly reverse, the development of atherosclerotic plaque, as well as substantially reduce cardiac events and mortality.
In addition to these traditional risk factors, certain blood constituents correlate with the development of atherosclerosis and cardiac events. For example, epidemiologic studies have related the concentration of the amino acid homocysteine to the incidence of coronary, cerebral, and peripheral vascular disease. The risk of MI is three times greater in patients with the highest levels of homocysteine compared with those with the lowest levels. Supplementation of the diet with folate and other B vitamins reduces the level of homocysteine, but it is not yet known whether such therapy improves the coronary risk.
Circulating thrombogenic factors are also related to the development of IHD. For example, an elevated level of plasma fibrinogen is an independent risk factor for coronary artery disease in both men and women. Recent epidemiologic studies have confirmed that individuals with the highest fibrinogen levels are several times more likely to suffer a coronary event than cohorts with the lowest levels. Similarly, elevated levels of coagulation factor VII have been shown to be a risk factor for MI. In one recent report, an elevated factor VII level, in the presence of either smoking or hypertension, increased the relative risk of an MI up to fiftyfold.
[edit] CLINICAL FEATURES OF ANGINA PECTORIS
[edit] History
The most common manifestation of myocardial ischemia is the intermittent discomfort of angina pectoris. Although many laboratory tests can identify the presence of ischemia, the most important aspect of the clinical evaluation remains a careful history to evaluate for anginal symptoms. Several characteristics derived from the history can aid in the differentiation between myocardial ischemia and other causes of chest discomfort (Table 63-2). Features of angina relate to the quality of the discomfort, its location and radiation, precipitating factors, and frequency.
Table 63-2 Differential Diagnosis of Recurrent Chest Pain
| Condition | Helpful distinguishing features |
|---|---|
| Myocardial ischemia | Diffuse tightness/constriction/heaviness; not sharp or pleuritic |
| Brought on by exertion or emotional upset | |
| Pericarditis | Sharp, pleuritic, positional |
| Friction rub | |
| Diffuse ST elevation, PR depression on ECG | |
| Chest wall pain | Sharp, localized pain |
| Reproduced by palpation over painful area | |
| Cervical or thoracic spine pain | Shooting pain or ache worsened by movement of neck or back |
| Pain may be in dermatomal distribution | |
| Esophageal or gastric pains | Nonexertional pains |
| Often associated with dysphagia or gastric reflux | |
| Worsened by certain foods, aspirin, lying supine | |
| May be relieved by antacids | |
| Biliary pain | Right upper quadrant tenderness |
| Fatty food intolerance |
[edit] Quality of Discomfort.
Most often angina is described as a tightness, squeezing, heaviness, pressure, burning, indigestion, or aching sensation. It is only rarely described as a pain, and patients sometimes correct the physician who refers to it as such. It is never sharp, stabbing, prickly, spasmodic, or pleuritic. It is usually a steady discomfort that lasts a few minutes, rarely more than 10, unless unstable angina or an MI is evolving. It always lasts more than a few seconds, which helps differentiate it from some types of musculoskeletal pain. Angina is usually relieved quickly by sublingual nitroglycerin (in less than 5 minutes), which can be a useful distinguishing feature. Sometimes, while describing angina, a patient raises a clenched fist to the sternum (Levine sign) as if to indicate the constrictive sensation by that tight grip.
Symptoms that frequently accompany angina include dyspnea, diaphoresis, and nausea, which resolve quickly with cessation of the chest discomfort.
[edit] Location and Radiation.
Angina is usually a diffuse sensation rather than located at a discrete spot. If the patient can localize the discomfort with a single finger, myocardial ischemia is an unlikely cause. Generally, the discomfort is most intense retrosternally or in the anterior left chest but may occur anywhere between the jaw and the upper abdomen. It frequently radiates to the shoulders, upper back, neck, or inner aspect of the arms, particularly on the left side. Although the location of angina may vary between individuals, it is usually the same sensation in a given patient with each attack, unless an MI is in progress, at which time it is generally more diffuse and severe.
[edit] Precipitants.
Angina, except when due to pure vasospasm, is caused by factors that increase myocardial demand. Typically it is provoked by exertion, such as climbing stairs, walking up an inclined surface, vigorous work using the arms, or sexual activity. Other factors that increase myocardial oxygen demand and can result in angina include emotional excitement, eating a large meal, and physical activities in cold weather. The latter results in vasoconstriction of the extremities, an increase in systemic vascular resistance, and therefore an increase in myocardial wall tension and oxygen requirements. In addition, myocardial ischemia displays a circadian rhythm, such that the threshold for angina is usually lower in the morning hours.
Patients who primarily experience coronary vasospasm most often have symptoms at rest, independent of activities that increase myocardial oxygen demand. Chest discomfort that awakens a patient from sleep may be precipitated by this mechanism, or because of the emotional stress (and therefore increased myocardial oxygen demand) of a bad dream.
[edit] Frequency.
For an individual with IHD the level of exertion needed to precipitate angina and therefore its frequency remains fairly constant (depending on superimposed vascular tone). However, the patient may quickly realize what activities produce angina and avoid them. Therefore it is important to ask about any recent reduction in exertion levels when taking the history.
[edit] Physical Examination
The general examination of patients with suspected IHD should address the manifestations of atherosclerosis as well as transient findings during episodes of angina. External signs of hypercholesterolemia may be present, including arcus senilis and tendinous xanthomas. Funduscopic examination may show evidence of chronic hypertension or diabetes. Also look for signs of hyperthyroidism, which can contribute to increased myocardial oxygen demand.
A general vascular examination should assess for the equality of blood pressure between the two arms (to rule out atherosclerotic narrowings), as well as palpation and auscultation of the carotid and peripheral arteries and examination of the abdomen for evidence of an aortic aneurysm.
On cardiac examination an S4 is common in patients with coronary artery disease (CAD) because of atrial contraction into a ‘stiffened’ left ventricle. This sign is not diagnostic for IHD, however, since it is present in many healthy elderly patients. The cardiac examination may be otherwise normal while the patient is asymptomatic, but during an episode of angina, several transient physical findings may appear. Increased sympathetic tone during chest pain may result in an increase in heart rate and blood pressure. Myocardial ischemia may result in papillary muscle dysfunction with a transient systolic murmur of mitral regurgitation. Ischemia-induced left ventricular wall motion abnormalities may be detected as an abnormal precordial bulge on chest palpation. A transient S3 gallop and pulmonary rales may appear if ischemia-induced left ventricular dysfunction occurs.
[edit] DIAGNOSTIC TESTS
Blood tests to evaluate for underlying risk factors include measurement of the serum lipids (see Chapter 71 ) and fasting serum glucose. The hematocrit and thyroid function tests should be measured if clinically appropriate, since anemia and hyperthyroidism can exacerbate myocardial ischemia.
Noninvasive cardiac testing is useful to confirm the diagnosis of IHD, to help stratify patients into categories of risk, and to guide therapy. Many of these tests are expensive, and it is therefore important to choose the appropriate study for each patient. Beyond the resting electrocardiogram (ECG) they include exercise testing, with or without nuclear scintigraphy, exercise radionuclide ventriculography or echocardiography, pharmacologic stress testing, and ambulatory ECG monitoring.
[edit] Resting ECG
Many patients with CAD have normal baseline ECGs, or may demonstrate pathologic Q waves indicative of previous infarction. In many patients minor ST and T wave abnormalities are present but are not specific for CAD. However, the ECG can be diagnostically useful if recorded during an episode of chest pain, whereupon ischemia often results in transient horizontal or downsloping ST segments or T wave inversions, which normalize following resolution of the pain. Less often, transient ST elevation may be observed, which suggests severe transmural ischemia or coronary artery spasm.
[edit] Exercise Stress Testing
The most useful noninvasive studies in the evaluation of angina involve exercise testing. In patients without resting ST or T wave abnormalities the standard treadmill (or bicycle) exercise test, without additional imaging modalities, should be the initial procedure, since it is the most convenient and cost-effective. For patients whose presentation strongly suggests myocardial ischemia, the exercise test has a sensitivity and specificity greater than 85%. However, when the probability of significant coronary disease is low (e.g., a young woman with prickly chest pains), the test is less specific, and false-positive results are more common.
Exercise testing is most commonly used (1) to confirm the diagnosis of angina, (2) to identify IHD patients at high risk of complications, (3) to assess the response of antianginal therapy, and (4) as a screening procedure for certain asymptomatic populations, such as individuals with strong cardiac risk factors, older patients about to begin exercise programs, and individuals whose well being could affect public safety (e.g., airline pilots).
Different protocols may be used for exercise testing, but in each the intensity of exercise is incrementally augmented (e.g., increased grade and speed on the treadmill) to raise myocardial oxygen consumption. During the test the ECG and heart rate are monitored continuously and the blood pressure measured every few minutes. The product of heart rate and systolic blood pressure (known as the double product) correlates with myocardial oxygen demand and is useful in describing a patient's anginal threshold.
Exercise is continued until a target heart rate (usually 85% of the maximal predicted heart rate based on the patient's age) or symptom-limited end points (e.g., precipitation of anginal pain) are achieved. However, the test should be terminated immediately if hypotension, high-grade ventricular dysrhythmias, or more than 3 mm ST segment depression develop. The complications of exercise testing are few, and death and MI are extremely uncommon. However, the risks are increased and the test should not be performed in individuals with unstable angina or advanced aortic stenosis.
Exercise testing suggests the presence of IHD if the patient's typical chest discomfort is reproduced, or if specific ECG abnormalities develop (Box 63-2). The ECG criteria for a positive test is 1 mm (0.1 mV) horizontal or downsloping ST depression, measured 0.08 second after the termination of the QRS complex. The degree and location of ST segment abnormalities are not always a reliable indication of the extent and anatomic localization of CAD. However, taken together, the magnitude, time of onset, duration, and number of ECG leads that develop abnormal ST segments can predict the severity of CAD. For example, individuals who develop ST depression in multiple leads during the first 3 minutes of exercise are very likely to have left main or severe three-vessel disease. Other criteria for a markedly positive test that are indicative of such severe coronary artery disease and a poor cardiac prognosis are listed in Box 63-2.
| Box 63-2 - Interpretation of Exercise Treadmill Test |
Positive Test
|
Conversely a negative test or one that becomes positive only after 9 minutes of exercise or at a heart rate greater than 160 beats/min correlates with a very optimistic prognosis, even if angina or ST segment depressions develop during the test.
The diagnostic value of an exercise test may be limited by medications, especially β-blockers, which can blunt the achieved heart rate or rise in blood pressure. If the purpose of the stress test is to confirm the presence of angina, such medications should be withheld for 1 to 2 days before the test, and if necessary sublingual nitroglycerin can be used as needed during that time. However, if the purpose is to judge the effects of and gauge medical therapy, then the usual drug regimen should be continued on the day of testing.
[edit] Radionuclide Studies
Two types of nuclear studies are used to enhance the diagnostic value of standard exercise tests: myocardial perfusion imaging and radionuclide ventriculography. These tests can provide additional information regarding the location and extent of CAD, and their interpretations are not hampered by resting ECG abnormalities. However, they are more expensive than standard treadmill tests and should be used judiciously (Boxes 63-3 and 63-4).
| Box 63-3 - Commonly Used Forms of Stress Testing |
Standard Tests
|
| Box 63-4 - Criteria for Use of Perfusion Scintigraphy |
ETT, Exercise tolerance test; WPW, Wolff-parkinson-White. |
[edit] Myocardial Perfusion Scintigraphy.
Myocardial perfusion scintigraphy is generally more sensitive and specific than conventional stress testing. During this test a radionuclide (e.g., 201T1 or 99mTc sestamibi) is used, which after peripheral venous injection distributes to the myocardium in proportion to coronary blood flow. The radionuclide is injected at peak exercise, and immediate imaging is performed. Perfusion defects (cold spots) indicate regions of prior infarction or exercise-induced ischemia. Repeat imaging at rest several hours later shows filling in of the zones that were ischemic, differentiating them from regions of previous infarction. The location of perfusion abnormalities correlates with coronary disease in the respective territory (e.g., left anterior descending artery disease results in perfusion abnormalities within the anterior wall). Multiple large perfusion defects correlate with left main or severe three-vessel disease.
In experienced departments of nuclear medicine, thallium scintigraphy has a sensitivity of 75% to 90% but may be positive in up to 20% of normal individuals. In women, attenuation due to breast tissue artifact is a common cause of false-positive studies. In addition to previous MIs, other conditions that may produce persistent myocardial defects include infiltrative disease (e.g., sarcoidosis) and dilated cardiomyopathy.
For patients who are unable to exercise, pharmacologic stress testing in conjunction with myocardial perfusion imaging can be undertaken. IV adenosine (or dipyridamole) produces vasodilation and increases flow to the myocardium perfused by healthy coronaries. This effect steals blood away from stenotic coronaries, creating regional ischemia that can be detected following injection of radionuclides such as 201T1. This type of non-exercise stress test has proven useful in predicting cardiac ischemic events in patients with chronic stable angina and in those about to undergo noncardiac surgery. Another form of pharmacologic stress testing utilizes the adrenergic-stimulating drug dobutamine to artificially increase heart rate and systolic blood pressure.
[edit] Exercise Radionuclide Ventriculography.
Exercise radionuclide ventriculography entails imaging blood flow through the left ventricle during the cardiac cycle at rest and then with exercise. Two commonly used techniques are (1) the first-pass technique, in which a large bolus of radionuclide (e.g., 99mTc) is injected and the tracer is imaged as it flows through the heart as it is quickly cleared from the circulation; and (2) the multigated equilibrium technique (MUGA) in which red blood cells are labeled and several minutes of transventricular flow are analyzed as a composite image.
In normal individuals, contractile function of the left ventricle increases with exercise. Myocardial ischemia is suggested if the ejection fraction falls with exercise or if segmental left ventricular wall motion abnormalities develop. Exercise radionuclide ventriculography has a sensitivity similar to that of 201T1 perfusion imaging, but it is less specific because other etiologies of left ventricular dysfunction can produce similar results.
[edit] Echocardiography
Imaging of the left ventricle by ultrasound can reveal segmental wall motion abnormalities indicative of ischemia or previous infarction. In exercise echocardiography, left ventricular function is assessed before and during vigorous exercise (supine bicycle or treadmill); exercise-induced segmental regional wall motion abnormalities are an indication of ischemia. Exercise echocardiography is therefore analogous to exercise radionuclide ventriculography and has similar sensitivity and specificity for the presence of significant coronary disease.
For patients who are unable to exercise, pharmacologic stress testing with echocardiography can be performed in one of two fashions: (1) using potent vasodilators such as adenosine or dipyridamole (analogous to pharmacologic 201T1 scintigraphy described above), or (2) using an adrenergic stimulating drug (e.g., dobutamine). Either of these techniques signifies the presence of myocardial ischemia by drug-induced left ventricular wall motion abnormalities.
[edit] Ambulatory ECG Monitoring
Frequency-modulated ambulatory ECG monitors detect shifts in the ST segments indicative of ischemia. Approximately 40% of patients with known stable CAD display such transient shifts, and in most cases, asymptomatic silent episodes (described below) are even more common than symptomatic events. The role of this technique in documenting the presence of CAD has not yet been defined; however, some studies have shown its usefulness as a prognostic guide. For example, the absence of ST segment shifts on ambulatory monitoring predicts a low risk of cardiac complications in patients undergoing noncardiac surgery.
[edit] Coronary Arteriography
Coronary arteriography allows selective visualization of the coronary arteries and their major branches and is the most accurate means to detect the presence and extent of CAD. In experienced laboratories it is performed with low mortality (approximately 0.2%) or severe vascular complications (0.7%). However, this technique is costly, is not risk-free, and is seldom needed to simply establish the diagnosis of significant coronary disease. The decision to proceed with arteriography should be dictated by the patient's clinical presentation and only when a change in therapeutic plan is under consideration. Commonly accepted indications for coronary angiography are presented in Box 63-5 and Fig. 63-1.
| Box 63-5 - Common Indications for Coronary Arteriography in Ambulatory Patients |
|
Note that an individual with mild to moderate angina that is reasonably controlled with medical therapy does not generally require cardiac catheterization, since the long-term prognosis and quality of life may not be significantly affected. However, if that individual has other markers of a poor prognosis by exercise testing or impaired left ventricular function, then catheterization should be performed (see Fig. 63-1).
At catheterization, coronary narrowings of greater than 70% are considered significant (i.e., the ones most likely to produce angina). Natural history studies have shown that the mortality of patients with CAD correlates with the number of significantly narrowed vessels, and those with left main disease (defined as a stenosis > 50%) have the highest mortality. Outcomes are correspondingly worse in patients with decreased left ventricular contractile function.
Left ventriculography can be performed at the time of cardiac catheterization to measure global and regional left ventricular function and assess the presence of mitral regurgitation. However, such information can often be derived by noninvasive techniques (echocardiography or radionuclide ventriculography), sparing the patient from additional intravenous contrast material.
[edit] MANAGEMENT OF PATIENTS WITH SUSPECTED ANGINA
[edit] General Principles
Fig. 63-1 summarizes the approach to the evaluation and management of patients with suspected IHD. Once angina is suggested by the clinical history, stress testing is useful to confirm the diagnosis and stratify patients into high-and low-risk groups. The standard form of stress testing is the graded treadmill test, but for those patients with abnormal baseline ECGs or those unable to exercise, the alternative forms of testing are appropriate. Patients with markedly positive stress tests should undergo coronary arteriography because of the high likelihood of left main or three-vessel coronary disease, conditions that could warrant mechanical revascularization. For patients with only mildly positive stress tests or those with nondiagnostic studies, a trial of pharmacologic management is recommended, with further evaluation dictated by the response to therapy. An alternative approach in inactive or elderly patients is to begin a trial of medical therapy based on the clinical history of angina, without stress testing. The early response to therapy would determine whether further evaluation is needed.
The management goals for IHD are to reduce anginal symptoms, prevent complications such as MI, and prolong life. General measures begin with a discussion of the disease and the importance of eliminating risk factors that have led to it. Patients should be encouraged to stop smoking, lose excess weight, and control hypertension and diabetes. Lipid-lowering in appropriate patients is a critical aspect of management. Patients with CAD and an elevated LDL-cholesterol should achieve lower levels (generally <100 mg/dl). HMG-CoA reductase inhibitors are particularly effective in achieving this goal, and such therapy has been shown to reduce the risk of both primary and secondary coronary events (see Chapter 71 ).
There are often psychosocial issues faced by individuals who are diagnosed with angina for the first time. Many patients may be unnecessarily pessimistic about their prognosis, so a frank discussion should stress the common nature of IHD and the advanced therapeutic options available that often allow the quality of life to be unimpaired. Similarly, it is important to inform the patient that transient anginal attacks do not result in permanent heart damage.
Angina is particularly likely to occur during bursts of activity, particularly after periods of rest (e.g., walking up a flight of stairs after watching TV for several hours). Therefore a period of warming up (e.g., walking around the house a few times before mowing the lawn) is often a useful way to prevent angina. In addition, the prophylactic use of nitroglycerin should be encouraged before activities likely to bring on chest discomfort. Angina often exhibits a circadian pattern, with episodes more common in the hours shortly after arising, so the use of prophylactic nitroglycerin before dressing and shaving can be particularly beneficial. If a patient notes that angina is frequently precipitated by emotional upset, attempts should be made to minimize these; counseling or antianxiety medications may be useful.
Patients with stable angina should be encouraged to participate in a regular exercise program, most often walking. Such activity can have a beneficial conditioning effect on skeletal muscles and may contribute to raising the anginal threshold. Patients who exercise are also less likely to smoke and more likely to watch their diet and weight.
[edit] Pharmacologic Therapy
In the prevention or treatment of angina, pharmacologic therapy is aimed at restoring the balance between myocardial oxygen supply and demand. The agents most useful in this regard are the nitrates, β-blockers, and calcium channel blockers.
[edit] Nitrates.
The major antianginal effect of nitrates is to reduce myocardial oxygen demand. These agents relax vascular smooth muscle, particularly in the venous circulation at usual dosages. Since this action reduces venous return to the heart, there is a corresponding decline in left ventricular volume (a determinant of wall stress), which causes myocardial oxygen consumption to fall. To a lesser extent the nitrates act as arteriolar dilators, an action that beneficially reduces the resistance against which the left ventricle contracts, further reducing wall tension and oxygen demand. A third action of the nitrates is to dilate the coronary arteries with augmentation of coronary blood flow. This action increases myocardial oxygen supply and may be particularly important in the prevention and treatment of coronary artery vasospasm. Experimental animal studies have shown that nitroglycerin redistributes blood flow from normal to ischemic regions of the myocardium, especially in the subendocardial muscle, which may be mediated by increased collateral blood flow.
Rapidly acting nitroglycerin remains the drug of choice to treat acute anginal attacks. Sublingual or aerosol nitroglycerin spray (Table 63-3) typically relieves angina in less than 5 minutes, although sometimes repeated doses are necessary, and can be administered at 5-minute intervals.
Table 63-3 Commonly Used Nitrates
| Usual dosage | Onset of action (min) | Duration of action | Recommended dosing frequency | |
|---|---|---|---|---|
| Short-acting agents | ||||
| Sublingual TNG | 0.15-0.6 mg (usual dose 0.4 mg) | 2-5 | 10-30 min | As needed |
| Aerosol TNG | 0.4 mg (1 inhalation) | 2-5 | 10-30 min | As needed |
| Sublingual ISDN | 2.5-10 mg | 5-20 | 1-2 hr | As needed |
| Long-acting agents | ||||
| Oral ISDN | 5-30 mg | 15-30 | 4-6 hr | tid (mealtimes) |
| Sustained-action | 40 mg | 30-60 | 6-10 hr | bid (once in am, then 7 hours later) |
| Oral PET | 10-40 mg | 30-60 | 3-6 hr | tid (mealtimes) |
| Sustained-action | 30-80 mg | Slow | 6-10 hr | bid (once in am. then 7 hours later) |
| TNG ointment (2%) | 0.5-2 in | 15-60 | 3-8 hr | qid (with one 7-to 10-hr nitrate-free interval) |
| TNG skin patches | 0.1-0.6 mg/hr | 30-60 | Up to 24 hr | Apply in morning, remove in evening |
| Oral ISMO | 20-40 mg | 30-60 | 12-14 hr | bid (once in am, then 7 hours later) |
| Extended-release | 30-240 mg | 30-60 | >12 hr | qd |
| TNG, Nitroglycerin; ISDN, isosorbide dinitrate; PET, pentaerythritol tetranitrate;ISMO, isosorbide mononitrate. | ||||
Some clinical tips on the use of nitroglycerin are indicated in Box 63-6. For many patients the use of nitrates is accompanied by a feeling of generalized warmth and a transient throbbing headache or lightheadedness. This can be quite frightening if not expected, and patients should be warned about these effects. Even better is to stand by as the patient administers the first nitroglycerin in your office, so as to explain these reactions and instill confidence. The patient should also be instructed to sit down before using nitroglycerin the first few times, to avoid the potential of symptomatic hypotension. In addition, advice should be given that, if an anginal episode persists longer than usual or is unresponsive to two nitroglycerin tablets, then the appropriate course is to proceed to the closest emergency department for evaluation of possible unstable angina or MI.
| Box 63-6 - Clinical Tips for Successful Nitroglycerin (TNG) Use |
|
Long-acting nitrates (see Table 63-3) are useful in the chronic prevention of anginal episodes and are available in oral and transdermal preparations. Low initial dosages should be used to avoid headache and lightheadedness and can be augmented over time. Side effects are similar to, but often less pronounced than, those associated with rapidly acting nitroglycerin administration. If a headache occurs, acetaminophen can be prescribed concurrently during the first few days of therapy, after which side effect tends to wane. An important problem associated with chronic nitrate therapy is the development of drug tolerance (i.e., continued administration of the drug leads to decreased effectiveness over time). It can be prevented by allowing an 8-to 10-hour nitrate-free interval each day, and effective dosage schedules to accomplish this are indicated in Table 63-3.
For elderly or inactive patients, long-acting nitrates may alone suffice as chronic antianginal therapy. However, for many physically active individuals additional drugs are usually required.
[edit] β-Blockers.
β-Adrenergic antagonists have become the mainstay of therapy to prevent effort-induced angina and also have been shown to reduce mortality following MI. The main antianginal effect of β-blockers is to reduce myocardial oxygen demand by slowing the heart rate, reducing the force of ventricular contraction, and lowering blood pressure. In the United States only a handful of β-blockers have been approved for the treatment of angina, although most are probably effective and have been used for this purpose (Table 63-4). β-Blockers differ from one another by several properties that influence their choice in certain patient groups, based on their duration of action, selectivity for the β1-receptor, partial β-agonist activity, and α-adrenergic blocking properties. The goal of β1-selectivity is to block myocardial receptors with less effect on bronchial and vascular smooth muscle, of theoretic benefit to those with asthma or intermittent claudication. However, at the high doses used to treat angina, β1-selectivity is often lost.
Table 63-4 β–Blockers Approved for Use in the United States
| Usual oral dosage | β-Agonist activity | |
|---|---|---|
| Nonselective agents | ||
| Carteolol | 2.5-10 mg qd | + |
| Labetalol✢ | 100-600 mg bid | |
| Nadolol† | 40-80 mg qd | |
| Penbutolol | 20 mg qd | + |
| Pindolol | 5-30 mg bid | + |
| Propranolol† | 20-60 mg qid | |
| Sustained-action† | 80-160 mg qd | |
| Timolol† | 20 mg bid | |
| β1-selective agents | ||
| Acebutolol | 200-1200 mg qd | + |
| Atenolol† | 50-100 mg qd | |
| Betaxolol | 10-20 mg qd | |
| Bisoprolol | 2.5-20 mg/d | |
| Metoprolol† | 50-100 mg bid | |
| Sustained-action† | 50-100 mg qd | |
| Esmolol | 50-200 μg/kg/min IV | |
✢Also has α1-blocking properties.
†Approved by FDA for use in coronary artery disease.
β-Blockers with partial β-agonist activity (also termed intrinsic sympathomimetic activity [ISA]) have the unusual property of mild direct stimulation of the β-receptor while blocking the receptor against circulating catecholamines. Thus the resting heart rate tends not to fall as much as with other drugs of this class, but the chronotropic response to exercise is blunted. Agents with ISA may be less desirable in patients with angina, since the comparatively higher heart rates during their use may exacerbate angina, and, unlike β-blockers without this property, they have not reliably reduced mortality following acute MI.
The duration of action of β-blockers largely depends on their lipid solubility and accounts for the different dosage schedules listed in Table 63-4. Esmolol is a very short-acting agent administered intravenously. Its effectiveness and any adverse reactions disappear within minutes of its discontinuation; thus it can be used to test the tolerability of β-blockade. It is used most commonly in the treatment of acute tachydysrhythmias and as a continuous infusion in unstable angina.
Several randomized trials have shown that, following MI, cardiovascular mortality and nonfatal secondary MIs are reduced by β-blocker therapy (see below). Some, but not all, primary prevention trials have shown that β-blockers may reduce the incidence of first MIs among patients with hypertension. These attributes, combined with the β-blockers' ability to raise the anginal threshold at least as well as other antianginal drugs, place them at the forefront of chronic antianginal therapy.
Contraindications to the use of β-blockers include symptomatic congestive heart failure, a history of bronchospasm, marked resting bradycardia or AV block, and peripheral vascular disease with symptoms of claudication. In patients without such contraindications, β-blockers are started at the lower range of doses listed in Table 63-4 and advanced until the resting heart rate falls to 50 to 60 beats/min or side effects occur.
Common side effects of β-blockers include bronchoconstriction in patients with reactive airways disease, the precipitation of congestive heart failure in some patients with left ventricular systolic dysfunction, depression, sexual dysfunction, AV block, exacerbation of claudication, and potential masking of hypoglycemia in insulin-dependent diabetic patients. Rarely, the abrupt cessation of β-blocker therapy can lead to tachycardia, angina, or MI. In addition, β-blockers have the theoretic potential of decreasing coronary blood flow in patients with predominant coronary artery vasospasm (by inhibiting vasodilatory β2-receptors) and should be avoided in such patients. Another long-term adverse effect of β-blocker therapy relates to the serum lipids, since they may result in the reduction of HDL cholesterol and an increase in triglycerides. These values should be monitored in patients with adverse baseline lipid profiles. This effect does not occur with β-blockers that have β-agonist activity (see Table 63-4) or α-blocking properties (i.e., labetalol).
[edit] Calcium Channel Blockers.
The calcium channel blockers are effective antianginal agents when used alone or in combination with β-blockers or nitrates. They can prevent exertional angina and are also helpful in patients with episodes of coronary vasospasm. Each drug in this class can reduce myocardial oxygen requirements and increase myocardial oxygen supply. However, the available agents (Table 63-5) differ in their structure and specific actions. Nifedipine and the other dihydropyridine calcium blockers are potent arterial vasodilators that reduce systemic vascular resistance, blood pressure, and therefore left ventricular wall stress with a decrease in myocardial oxygen consumption. The resultant fall in blood pressure may trigger an increase in the heart rate, an undesired effect that can be blunted by concomitant use of a β-blocker. Diltiazem and verapamil are also arteriolar dilators but are less potent than the dihydropyridines. However, they demonstrate additional properties that decrease myocardial oxygen demand: they slow the resting heart rate and decrease the left ventricular force of contraction, so concomitant β-blocker therapy is not necessary and in many cases is not desirable.
Table 63-5 Calcium Channel Antagonists
| Usual oral dose | Vasodilatation | ↓ Inotropy | ↓ Heart rate and AV conduction | Adverse effects | |
|---|---|---|---|---|---|
| Verapamil✢ | 40-120 mg tid-qid | Moderate | ↓↓↓ | ↓↓↓ | Hypotension |
| Bradycardia | |||||
| SR formulation | 120-240 mg qd-bid | AV block | |||
| Heart failure | |||||
| Constipation | |||||
| Diltiazem✢ | 30-120 mg tid-qid | Moderate | ↓↓ | ↓↓ | Hypotension |
| Peripheral edema | |||||
| SR formulation | 60-180 mg bid | Bradycardia | |||
| CD formulation✢ | 180-360 mg qd | AV block | |||
| Heart failure | |||||
| Dihydropyridines | |||||
| Marked | 0 to ↓ | 0 | Hypotension | ||
| Nifedipine✢ | 10-30 mg tid-qid | Peripheral edema | |||
| XL formulation✢ | 30-120 mg qd | Headache | |||
| Nicardipine✢ | 20-40 mg tid | † | Flushing | ||
| SR formulation | 30-60 mg bid | † | |||
| Isradipine | 2.5-10 mg bid | † | |||
| Felodipine | 5-20 mg qd | † | |||
| Amlodipine✢ | 2.5-10 mg qd | † | |||
✢Approved by FDA for use in coronary artery disease.
†Least negatively inotropic agents.
Recent reports have questioned the safety of short-acting dihydropyridine calcium channel antagonists as they have been associated with an increased frequency of MI and mortality. Thus calcium channel blockers should be considered secondary agents in the management of stable angina, to be prescribed only after β-blocker and nitrate therapy has been considered. When dihydropyridine calcium channel blockers are used, only the long-acting formulations should be prescribed.
All of the calcium channel blockers have the potential to adversely reduce left ventricular contractility and should be used cautiously in patients with underlying left ventricular dysfunction. Newer dihydropyridines (e.g., amlodipine, felodipine) have the least negative inotropic effects. One study has demonstrated that amlodipine is tolerated in patients with advanced heart failure without causing hemodynamic deterioration or increased mortality when added to a regimen of an ACE inhibitor, diuretic, and digoxin. Other common side effects of the calcium channel blockers are listed in Table 63-5.
[edit] Antiplatelet Therapy.
Coronary thrombosis has been implicated in the majority of patients with MIs and in unstable angina. Aspirin, as an antiplatelet antithrombotic agent, has demonstrated a beneficial role in secondary prevention of coronary events post-MI (see below). Furthermore, a meta-analysis of 300 studies, including 140,000 patients, has shown improved cardiovascular outcomes among patients with angina, with prior MI, and following coronary artery bypass graft (CABG) surgery. In the absence of contraindications (bleeding, gastritis, or drug allergy) aspirin (81 to 325 mg every day) is recommended as part of the routine antianginal regimen. A newer (and costlier) antiplatelet agent, clopidogrel, was recently approved by the FDA for prevention of atherosclerotic events in patients with recent MI, stroke, or peripheral vascular disease. In one large study, this drug was modestly superior to aspirin for prevention of ischemic events. Unlike the closely related drug ticlopidine, it has not been associated with neutropenia or thrombotic thrombocytopenic purpura. At present, we reserve the use of clopidogrel in chronic CAD for patients who are intolerant of aspirin.
[edit] Antioxidant Therapy.
LDL cholesterol undergoes oxidation in proximity to the arterial wall and in that form is particularly prone to contribute to the atherosclerotic process. In the Cambridge Heart Antioxidant Study, the antioxidant vitamin E was compared with placebo in 2002 patients with angiographically documented CAD. After an average of 17 months vitamin E reduced the rate of nonfatal MI, but cardiovascular and total mortality were not reduced. A recent prospective study of 34,486 postmenopausal women without CAD showed that an increased dietary intake of Vitamin E (i.e., from food, not supplements) was associated with lower coronary death rates over a 7-year follow-up period. Although the lack of firm data precludes definite guidelines, some cardiologists recommend that their patients with CAD take 200-400 IU of vitamin E daily. Studies of β-carotene and vitamin C thus far have not shown a reduction in cardiac events.
[edit] Approach to Antianginal Drug Selection
The use of the above antianginal drugs alone, or in combination, depends on the severity of symptoms, concomitant illnesses, and the patient's activity level (Box 63-7). All patients with angina should be taught the proper use of nitroglycerin for acute attacks. For chronic suppression of angina in elderly or inactive patients one can choose a long-acting nitrate (e.g., isosorbide mononitrate extended-release once daily, or nitroglycerin applied each morning and removed at bedtime) plus aspirin, 81 to 325 mg daily.
| Box 63-7 - Medical Management of Chronic Stable Angina |
|
For active individuals with chronic stable exertional angina, consider a β-blocker, and if symptoms persist add a long-acting nitrate or calcium channel blocker (not verapamil, to avoid the additive bradycardic effect), or both. For those with contraindications to β-blockade, a calcium channel blocker is recommended. If the contraindication to β-blockade is the presence of bronchospasm, insulin-dependent diabetes, or claudication, any of the calcium channel blockers approved for angina are appropriate. However, verapamil or diltiazem is preferred because of the effect on slowing the heart rate. For patients with resting bradycardia or AV block, a dihydropyridine calcium blocker is a better choice. In patients with symptomatic congestive heart failure, nitrates are the preferred initial antianginal agents; if additional therapy is needed, amlodipine should be considered.
Patients suspected of having primarily coronary vasospasm should not be treated with β-blockers, which could aggravate coronary constriction; rather nitrates and calcium channel blockers are preferred. In patients with concomitant hypertension, β-blocker or calcium channel blockers are useful in treating both conditions. Similarly, patients with IHD and atrial fibrillation would benefit from a β-blocker, verapamil, or diltiazem, each of which can slow the ventricular rate.
For patients who do not respond to initial antianginal therapy, the drug dosages should be increased unless side effects occur. Combination therapy often allows the successful use of lower dosages of each agent while minimizing individual drug side effects. Typical beneficial combinations include the following:
- A nitrate plus a β-blocker, as the latter blunts the nitrate-associated tachycardia.
- A nitrate plus verapamil or diltiazem for similar reasons.
- A long-acting dihydropyridine calcium channel blocker plus a β-blocker is similarly beneficial, but a dihydropyridine plus nitrate is often not tolerated without concomitant β-blockade because of marked vasodilation, with resultant headache and increased heart rate. As indicated above, a β-blocker should be combined only very cautiously with verapamil or diltiazem because of the potential of excessive bradycardia or precipitation of congestive heart failure in patients with left ventricular dysfunction.
As illustrated in Fig. 63-1, patients with angina who become asymptomatic on medical therapy can be followed clinically without additional interventions. Those individuals with frequent angina refractory to multidrug therapy should be referred for cardiac catheterization and consideration of mechanical revascularization. The approach to patients with diminished but persistent symptoms on medical therapy depends on whether left ventricular contractile function is compromised. Many studies indicate that patients with impaired left ventricular function (e.g., ejection fraction less than 40%) have a worse cardiac prognosis than those with similar coronary disease but preserved left ventricular function. Therefore our policy in patients with even mildly persistent angina is to obtain an assessment of left ventricular function (echocardiography or radionuclide ventriculography); if the ejection fraction is less than 40%, the patient is considered for coronary arteriography to identify those whose prognosis would improve by mechanical revascularization.
[edit] Mechanical Revascularization
As indicated above, many patients with chronic stable angina can be successfully managed by pharmacologic therapy alone. However, for those with refractory symptoms or in certain high-risk subgroups, revascularization procedures, including CABG surgery and percutaneous transluminal coronary angioplasty (PTCA), are recommended.
[edit] Coronary Artery Bypass Graft Surgery.
CABG consists of suturing segments of saphenous vein between the ascending aorta and to the coronary arteries distal to their stenotic narrowings (see Chapter 64 ). At present, in most routine cases surgeons attempt to bypass at least one diseased vessel (normally the left anterior descending coronary artery [LAD]) with an internal mammary artery, since the latter results in a higher long-term patency rate (80% to 90% at 10 years) compared with venous bypasses (10% occlusion in the first year, 2% per year for the next 6 years, 5% per year thereafter). Antiplatelet therapy with aspirin has been shown to improve long-term graft patency rates, and aggressive lipid-lowering to achieve an LDL cholesterol < 100 mg/dl has been shown to slow the development of atherosclerosis within bypass grafts.
After CABG anginal symptoms usually are relieved, exercise capacity is improved, and the need for pharmacologic therapy diminishes. The mortality of CABG is low (1% to 3% in otherwise healthy individuals) with an incidence of perioperative MI of 2% to 6%. The risk increases in patients with impaired left ventricular function, those requiring other cardiac procedures (e.g., valve replacement), elderly patients, and those undergoing repeat CABG. In addition the recuperation of elderly or frail patients can be quite slow and accompanied by postoperative reductions of cognitive function. Therefore it is incumbent upon the physician to weigh the potential benefits of surgery against the risks of the procedure and its impact on a patient's total quality of life before recommending bypass surgery. The insight of the patient's long-term primary care physician is of great importance in rendering this decision.
CABG has been shown to prolong survival in patients with (1) greater than 50% obstruction of the left main coronary artery and (2) three-vessel disease and impaired left ventricular contractile function (ejection fraction less than 40%). Patients with one-or two-vessel disease could be expected to have symptomatic improvement with CABG but no increase in longevity compared with medical therapy alone. Many patients with one-or two-vessel disease refractory to medical therapy can be managed by PTCA. In patients with three-vessel disease and preserved left ventricular function the evidence for improved survival with CABG is less clear, and we operate on such patients only if they display persistent symptoms while undergoing medical therapy, they have severe proximal disease (especially of the LAD), or extensive ischemia is demonstrated by noninvasive testing. One recent study demonstrated that in diabetic patients with three-vessel disease, CABG offers a better prognosis than catheter-based interventions (see below).
[edit] Percutaneous Transluminal Coronary Angioplasty and Intracoronary Stents.
With increased experience and improved technology the range of coronary lesions amenable to PTCA has expanded over recent years. It can be successfully performed in multivessel coronary disease as well as in stenoses of coronary bypass grafts. The lesions most likely to benefit are short and are located proximally within a coronary artery away from vessel branch points. Although patients with left main or severe three-vessel disease are usually best-suited for CABG, PTCA is now widely successful in relieving ischemia in patients with one- and two-vessel lesions and selected patients with three-vessel disease. The major complication of the procedure is dissection of the vessel intima with subsequent occlusion of the vessel requiring repeat PTCA or emergent coronary bypass graft surgery. Even after successful PTCA approximately one third of dilated vessels redevelop significant stenosis within the following 6 months. In more than 60% of angioplasty procedures today, metal tubular stents are permanently deployed in the vessel, leaving no, or minimal, residual stenosis and a much improved rate of occlusion or restenosis, using antiplatelet protocols that include aspirin plus ticlopidine. Preliminary results of trials using even more potent antiplatelet agents (glycoprotein IIb/IIIa inhibitors) at the time of stent placement suggest even better long-term cardiac outcomes. As discussed in Chapter 64 , the benefits of stent implantation in each case must be weighed against potential drawbacks, including a higher cost of the procedure and the potential development of in-stent stenosis.
Patients who undergo angioplasty procedures have much shorter hospital stays and easier recuperation compared with those who undergo CABG. This has contributed to the explosive popularity of this technique, but there is concern about its overuse. Although one study has shown that PTCA is superior to medical therapy for symptomatic relief of angina, it did not reduce the risk of infarction or mortality.
Randomized trials have compared the outcome of PTCA versus CABG in patients with coronary lesions in multiple vessels that could be suitably approached by either technique. In 5-year follow-up the risks of MI or death are similar, although patients who underwent PTCA had more frequent recurrence of angina and need for repeat revascularization procedures. In addition, patients with diabetes and two-and three-vessel disease achieved better cardiovascular outcomes with CABG. Thus our general recommendations for patients with refractory angina on medical therapy are as follows: (1) patients with one-and two-vessel disease with normal left ventricular function are referred for catheter-based procedures, and (2) patients with two-and three-vessel disease with widespread ischemia, left ventricular dysfunction, or diabetes, and those with lesions not amenable to catheter-based techniques, are referred for CABG.
[edit] UNSTABLE ANGINA
Patients with CAD may show a stable pattern of symptoms for many years. Unstable angina refers to an acceleration of symptoms in which ischemic episodes occur more frequently, are more intense, last longer, and are precipitated by less activity than previously, or even by rest. A large number of such patients progress to acute MI due to the presence of complicated coronary lesions with ulceration, hemorrhage, or thrombosis at the site of atherosclerotic plaque. In other cases the lesions responsible for unstable angina may heal and the patient's symptoms return to a more stable pattern.
Unstable angina is a medical emergency. The patient should be hospitalized in an ECG-monitored unit and confined to bed (Box 63-8). During episodes of angina transient ST segment shifts or T wave flattening or inversion is likely. In addition, signs of left ventricular dysfunction (pulmonary rales, S3, mitral regurgitation) may accompany ischemic episodes. Contributing factors to the imbalance between myocardial oxygen supply and demand should be considered and corrected, including hypoxemia, anemia, hypertension, thyrotoxicosis, and tachydysrhythmias.
| Box 63-8 - Initial Management of Unstable Angina |
|
Therapy of unstable angina consists of measures to reduce myocardial oxygen demand and increase coronary flow. In addition, since intravascular thrombosis appears to play such an important role in the pathogenesis of unstable angina, antiplatelet and anticoagulant agents are a mainstay of therapy. Both aspirin and intravenous heparin have been shown to decrease the incidence of MI and cardiac death in unstable angina, whether used alone or together. Our policy is to begin aspirin (160 to 325 mg daily) immediately on presentation (the oral antiplatelet drug ticlopidine has also been shown to reduce complications of unstable angina and is a reasonable alternative in aspirin-intolerant individuals). At present, we use full-dose intravenous heparin to achieve an activated partial thromboplastin time (aPTT) of two times control. Low-molecular-weight heparin (i.e. enoxaparin) was recently studied in unstable angina and was found to be even more effective at preventing ischemic events and death (at 30 days and 1-year after administration) than standardized intravenous heparin, although minor bleeding complications were more frequent. Its use is likely to increase in this syndrome. Thrombolytic therapy has not been shown to reduce morbidity or mortality in the setting of unstable angina in the absence of an acute MI.
Drugs that inhibit the platelet glycoprotein IIb/IIIa receptor are an important recent advance in the pharmacologic management of unstable angina, since they further reduce the risk of MI and death. The FDA has approved two intravenous drugs of this class (tirofiban and eptifibatide) for patients with unstable angina, and a third (abciximab) for patients with unstable angina when angioplasty techniques are planned within 24 hours. Consultation with a cardiologist would be appropriate when considering this type of therapy since many patients will subsequently proceed to cardiac catheterization and revascularization procedures.
For patients who are refractory to medical therapy, coronary arteriography should be performed urgently (Fig. 63-2) followed by mechanical revascularization (CABG or percutaneous catheter-based interventions). If facilities for these procedures are not available, an intraaortic balloon pump may be placed transcutaneously to improve diastolic perfusion of coronary arteries and to provide afterload reduction to the left ventricle while the patient is transferred to an institution where revascularization procedures can be undertaken.
For patients who do stabilize on medical therapy, there remains a risk of recurrent unstable angina or MI, and additional evaluation is necessary (see Fig. 63-2). For active patients who were admitted to the hospital with severe symptoms and marked, diffuse ECG evidence of ischemia, elective cardiac catheterization is recommended before discharge to determine whether revascularization procedures are warranted. In selected patients, such as the elderly, those at poor surgical risk, or those with less severe presentations and more limited ECG evidence of ischemia, a less invasive approach is reasonable. That is, after 2 to 3 days, if symptoms of angina have responded to therapy, the intravenous agents can be replaced by oral drugs and gentle ambulation begun. Before discharge, exercise or pharmacologic stress testing should be performed. If spontaneous or exercise-induced ischemia is demonstrated, coronary angiography would be recommended. However, those who do well on exercise testing could be discharged on the oral antianginal regimen with further interventions guided by their symptoms.
Sometimes the recent onset of angina in a previously asymptomatic individual is also termed unstable angina. However, if symptoms occur only on exertion and are quickly relieved by rest or medical therapy, the need for hospitalization and the aggressive therapy indicated in Box 63-8 are often not necessary.
[edit] TYPICAL ANGINA PECTORIS WITH NORMAL CORONARY ARTERIOGRAM
This condition, often referred to as syndrome X, is characterized by classic exertional angina in individuals found to have no significant coronary stenoses at cardiac catheterization. Yet such patients may have convincing evidence of myocardial ischemia at exercise testing and nuclear scintigraphy. Some of these patients have coronary artery spasm, but most do not. Rather, many patients with this syndrome have evidence of inadequate coronary vasodilator reserve: small branches of the coronaries (the resistance vessels not visible by angiography) do not dilate appropriately during periods of increased myocardial oxygen demand, resulting in ischemia. The underlying mechanism is unknown, but the prognosis of such patients is excellent. Symptoms often respond to nitrate or calcium channel blocker therapy.
This syndrome is to be distinguished from other forms of cardiac pathology that produce ischemia in the absence of coronary disease, due to increased myocardial oxygen demand, such as advanced aortic stenosis. In addition, some patients with classic symptoms of angina and normal coronary arteries do not have organic illness at all. They have no evidence of ischemia by exercise scintigraphy or other testing and may suffer from anxiety disorders. An understanding attitude by the physician, reassurance of an excellent prognosis, and psychologic counseling may be of great benefit.
[edit] SILENT ISCHEMIA
When patients with chronic stable angina undergo ambulatory ECG monitoring, ST segment shifts usually occur during anginal episodes. But many patients demonstrate similar ischemic ST shifts during the day in the absence of symptoms, and this is termed silent or painless ischemia. Why some episodes are symptomatic and others silent is not known, but the presence of ST shifts on ambulatory monitoring, whether accompanied by symptoms or not, portends increased risk of MI and cardiac death.
In addition, among patients with severe coronary artery disease there is a subset who demonstrate ST shifts with activity, but never experience anginal discomfort. Such individuals have abnormal ST shifts during exercise tests but no accompanying chest pain. These patients are believed to have a defective anginal warning system, the mechanism of which is not known, but this syndrome is more common in diabetics. Despite the lack of symptoms, patients with totally silent ischemia are at risk for acute MI or cardiac death. Indeed, it is estimated that approximately 20% of acute MIs are clinically silent.
The proper management of patients with silent ischemia is the subject of ongoing clinical trials. Although the incidence of asymptomatic shifts can be reduced by antianginal medical therapy, angioplasty techniques, or CABG, it has not been conclusively shown that such treatment alters a patient's prognosis. Thus the management of patients with silent ischemia must be individualized and often depends on the degree of positivity of exercise testing. For example, our policy is that patients with severe or diffuse ischemia on exercise or pharmacologic stress testing are prescribed antianginal medications (e.g., β-blocker or calcium channel blocker plus aspirin) and undergo cardiac catheterization. If significant left main or three-vessel disease with left ventricular dysfunction is demonstrated, mechanical revascularization is usually recommended.
[edit] ACUTE MYOCARDIAL INFARCTION
Acute MI is a dreaded outcome in patients with ischemic heart disease. Nearly 1.5 million people sustain an MI in the United States each year, with a mortality rate of 25%. Nearly 60% of MI-related deaths occur before medical facilities are reached, mostly of the basis of lethal dysrhythmias. The location and extent of myocardial damage determine the acute presentation as well as early and long-term complications of MI. As such, early detection and reperfusion to limit the size of an acute infarct is of paramount clinical importance.
[edit] Etiology
MI is the result of prolonged myocardial ischemia that leads to irreversible necrosis of heart muscle. In more than 90% of cases the causal event is the development of an acute thrombus at the site of underlying coronary atherosclerosis. Although the exact mechanism is not known, such thrombosis appears to be the result of interactions between disturbed atherosclerotic plaque, the coronary endothelium, circulating platelets, and dynamic vasomotor tone of the coronary arterial wall. ‘Vulnerable’ plaques, those most likely to rupture and incite coronary thrombosis, tend to be lipid-laden, with a thin fibrous cap separating the atheroma from circulating blood. These lesions often appear quite minor angiographically, in distinction to chronic, stable plaques with thick fibrous caps that cause more vessel narrowing but are less susceptible to rupture.
Rarely, MI may be due to nonatherosclerotic causes, examples of which are indicated in Box 63-9. These should be suspected particularly in young individuals and those without underlying coronary risk factors. Cocaine use is a rare and unfortunate cause of infarction. It is likely due to the ability of cocaine to increase myocardial oxygen demand, induce coronary vasospasm, and promote coronary thrombosis, in association with platelet activation and endothelial cell dysfunction.
| Box 63-9 - Nonatherosclerotic Causes of Myocardial Infarction |
|
[edit] Clinical Presentation
The initial diagnosis of MI relies on the presenting history, physical examination, and ECG. The most common symptom is severe crushing chest pain, the location of which may be similar to previous angina, but it lasts longer, is more intense, and is often accompanied by nausea, diaphoresis, dyspnea, and the feeling of impending doom. There is a circadian variability to the development of MI, occurring most commonly in the morning hours, soon after awakening. Symptoms of MI usually begin while at rest, and only occasionally are brought on by physical exertion that may have resulted in anginal episodes previously. Rather than severe chest pain, some patients with acute MI present with less pronounced symptoms, including generalized weakness, dyspnea, and indigestion. In up to 20% of cases an acute MI is free of any symptoms and is detected only in retrospect by changes on a routine ECG.
Common physical findings in MI (Box 63-10) relate to impaired left ventricular systolic and diastolic function, associated inflammatory responses, and stimulation of the sympathetic and parasympathetic nervous systems.
| Box 63-10 - Major Physical Signs in Acute Myocardial Infarction |
|
Certain other causes of substernal chest pain may resemble that of acute MI (Table 63-6) and must be considered to avoid inappropriate initial therapy. In particular, aortic dissection or pulmonary emboli may be fatal if not quickly recognized. If confused with MI, inappropriate administration of thrombolytic therapy to patients with pericarditis or aortic dissection could result in severe complications or death.
Table 63-6 Conditions That May Mimic Pain of Acute Myocardial Infarction
| Condition | Clues to diagnosis | Confirmatory studies |
|---|---|---|
| Aortic dissection | Sharp, ripping pain that migrates | Transesophageal echo, MRI, CT, angiography |
| Asymmetry of arterial pulses | ||
| Acute pericarditis | Sharp, pleuritic, positional pain | Pericardial effusion on echocardiogram |
| Pericardial friction rub | ||
| Diffuse ST elevation on ECG | ||
| Pulmonary embolism | Dyspnea, pleuritic chest pain | Ventilation/perfusion scan |
| Predisposing factors for venous thrombosis | Pulmonary angiography | |
| Pneumothorax | Sudden dyspnea, very sharp pain | Chest x-ray |
| Absent breath sounds over affected region | ||
| Esophageal spasm | Worse upon swallowing | Barium swallow |
| History of dysphagia, especially to cold liquids | Esophageal manometry | |
| Acute cholecystitis | Right upper quadrant tenderness | Abdominal ultrasound |
| Nausea, vomiting | ||
| History of fatty food intolerance |
[edit] Electrocardiogram
Typically, ECG changes occur during an acute MI in a characteristic, sequential fashion. As shown in Fig. 63-3, in Q wave infarction, initial hyperacute T waves and ST elevation are present in the leads overlying the involved myocardium. Over the next several hours, as cell death occurs, there is loss of the R wave and progressive Q wave development. The T wave begins to invert, followed by return of the ST segment to its baseline over subsequent days. The T wave may remain inverted for weeks to months before returning to its baseline, but the new Q wave persists as a permanent marker of the infarction. The anatomic site of infarction is determined by the ECG leads affected by these sequential changes (Table 63-7). Note that posterior wall infarctions produce a mirror image pattern in the anterior chest leads, with initial ST segment depression, T wave inversion, and development of tall R waves in leads V1 and V2.
Table 63-7 Myocardial Infarction Localization
| Anatomic site | Leads with acute changes | Coronary artery likely involved |
|---|---|---|
| Inferior | II, III, aVF | RCA |
| Anteroseptal | V1-V2 | LAD (proximal) |
| Anteroapical | V3-V4 | LAD or its branches |
| Anterolateral | V5-V6, I, aVL | Mid-LAD or CFX |
| High lateral | I, aVL | CFX |
| Extensive anterior | V1-V6 | LAD (proximal) |
| Posterior | V1-V2✢ | PDA |
| RCA, Right coronary; LAD, left anterior descending; CFX, left circumflex; PDA, posterior descending. | ||
✢Mirror-image changes in these leads, (i.e., ST depression and tall R waves in Q wave posterior MI).
In non–Q wave infarction, the ECG evolution is more subtle: new ST depression and/or T wave inversions persist for 48 hours or longer in the leads overlying the infarcting segments. The ST segments later normalize, but pathologic Q waves do not appear. Such patients may otherwise have typical symptoms and enzyme abnormalities indicative of acute MI, and the natural history and therapeutic implications of this type of infarct are described below.
In patients with markedly abnormal baseline ECGs (e.g., left bundle branch block) diagnostic ECG evolution may not occur, and the diagnosis of MI relies on the presence of serum markers and other laboratory modalities.
[edit] Serum Markers of Infarction
Certain proteins are released into the circulation in a predictable temporal fashion during acute MI, and are therefore diagnostically helpful.
Creatine kinase (CK) rises in the plasma within 4 to 8 hours, peaks at 24 hours, and returns to normal by 48 to 72 hours. The peak rise is greater and occurs earlier (less than 12 hours) following thrombolytic therapy. The total CK is not specific for myocardial damage; it can also rise after skeletal muscle trauma, and intramuscular injections, and in hypothyroidism.
The CK-MB isoenzyme is more specific for the diagnosis of acute MI. It is present in only tiny quantities in noncardiac tissues and is not greatly influenced by skeletal muscle injuries. The serum CK-MB rises and peaks slightly earlier than the total CK and returns to normal within 36 to 72 hours. Serum CK-MB levels may be elevated in other conditions such as myocarditis, following cardiac surgery, after repetitive cardioversions, and in hypothyroidism. However, in these conditions the temporal sequence of release seen in MI does not occur. In acute MI, the CK-MB (mass assay) is usually greater than 2.5% of the total serum CK. The serum CK and CK-MB isoenzyme should be measured on admission, then 12 and 24 hours later in the diagnostic evaluation of an acute MI.
Isoforms of CK-MB exist in the plasma after an MI and are very sensitive for the detection of infarction. For example, a ratio of CK-MB2/CK-MB1 of >1.5 is more than 90% sensitive for detection of an MI when measured 4 to 6 hours after the onset of coronary occlusion.
Cardiac forms of troponin subunits (cardiac troponin I and T) are also sensitive and highly specific markers of acute myocardial infarction. Their levels begin to rise within 3 hours after the onset of infarction and remain elevated for several days, permitting detection of infarction even in those individuals who present later than 48 hours after the onset of chest discomfort. At many hospitals these are now the preferred markers for detection of acute infarction. Furthermore, the presence and magnitude of these serum markers are of prognostic value in patients with acute coronary syndromes. Studies completed over the past 5 years have shown that higher troponin I levels, or early positivity of a bedside troponin T assay, correlate with greater short-term mortality.
Myoglobin is released into the circulation very early after myocardial injury and can be detected within 2 hours of infarction. However, its rapid renal clearance and low specificity limit its diagnostic role.
Lactate dehydrogenase (LDH) rises within 24 to 48 hours of MI, peaks at 3 to 5 days, and returns to baseline by 7 to 10 days. Historically, its usefulness has been greatest in patients who are admitted to the hospital 2 to 3 days after the onset of symptoms, at which time the CK evolution has already passed; the advent of troponin assays has largely supplanted the need for LDH measurements in that setting. LDH is present in many tissues, but of its five isoenzymes, LDH1 is most specific for the heart. A level of LDH1 greater than LDH2 suggests myocardial necrosis in the appropriate clinical setting.
[edit] Other Laboratory Studies
In some cases the history, ECG, and serum markers are not sufficient to confirm the diagnosis of MI, and other laboratory tests can be useful. For example, acute infarct scintigraphy using 99mTc pyrophosphate is highly sensitive for imaging large transmural infarcts. This type of hot spot scan is positive 2 to 7 days after MI, so is most useful for patients who are seen a few days after the onset of symptoms. In addition, echocardiography and radionuclide ventriculography can identify wall motion abnormalities indicative of infarction, but unless a previous study is available, they do not specify when the injury occurred.
[edit] Management
The in-hospital mortality for acute MI has fallen substantially in the past 30 years thanks to marked improvements in therapy. The primary goals of hospitalization are to achieve rapid reperfusion of the obstructed vessel, to limit the infarct size, and to promptly recognize and manage complications.
[edit] Thrombolytic Therapy.
As indicated above, most MIs result from the formation of an acute thrombus that obstructs a coronary artery. Thrombolytic therapy activates the natural fibrinolytic system to dissolve the responsible thrombus. Large studies have demonstrated that contemporary thrombolytic regimes restore patency in 65% to 85% of infarct-related coronary arteries at 90 minutes after infusion. Such therapy has been conclusively demonstrated to reduce mortality and improve recovery of left ventricular function following acute MI. The greatest benefit occurs when there is early reperfusion with substantial and sustained patency of the obstructed coronary artery.
[edit] Thrombolytic Agents.
The FDA-approved agents are streptokinase (SK), anisoylated plasminogen-SK activator complex (APSAC), tissue plasminogen activator (alteplase or t-PA), and modified plasminogen activator (reteplase or r-PA). Whereas t-PA and SK require continuous intravenous infusions, APSAC and r-PA are administered as short bolus injections, simplifying their delivery. Each of these drugs results in the conversion of the proenzyme plasminogen to active plasmin, which dissolves fibrin clots. However, different mechanisms of action and pharmacology of these drugs result in varying specificity for the thrombus responsible for the MI (Table 63-8). For example, t-PA attaches preferentially to a formed thrombus and lyses it without substantially activating fibrinolysis in the general circulation, in contrast to SK. Nonetheless, bleeding is the most important risk of each of these agents and their adjunctive therapies.
Table 63-8 Thrombolytic Agents
| Streptokinase | APSAC | t-PA (alteplase) | r-PA (reteplase) | |
|---|---|---|---|---|
| Fibrin clot specificity | None | Mild | Moderate | Moderate |
| Patency rate (partial or complete at 90 min) | 50-60% | 60-75% | 75-85% | 80-85% |
| Major advantage | Least expensive | Ease of administration | Survival advantage in certain subgroups | Ease of administration |
| Efficacy and other benefits similar to t-PA | ||||
| Limited systemic lytic state | ||||
| Major complications | Bleeding and antigenic reactions | Bleeding and antigenic reactions | Bleeding | Bleeding |
| Dose | 1.5 Million units IV over 1 hour | 30 Units IV over 5 min | (Preferred accelerated regimen): 15 mg bolus, then 0.75 mg/kg over 30 min (not to exceed 50 mg), then 0.5 mg/kg over 60 min (not to exceed 35 mg) | Two 10 U boluses, 30 min apart |
| Approximate cost ($) | 300 | 1700 | 2200 | 2200 |
Successful reperfusion is heralded by the relief of chest pain, and an early peak of serum CK (within 12 hours). Reperfusion dysrhythmias, especially accelerated idioventricular rhythm, are common and do not usually require therapy (see below). To maintain patency of the coronary vessel following thrombolysis, antiplatelet and anticoagulant therapies are used. Aspirin inhibits platelet function and reduces reocclusion following thrombolysis, so it is administered at the time of admission, and each day thereafter (160 to 325 mg/day). With use of t-PA or r-PA, intravenous heparin is needed to maintain vessel patency after initial thrombolysis, and is administered to achieve an activated PTT of 50 to 75 seconds, for 48 hours. Intravenous heparin may also be beneficial for patients receiving SK or APSAC who are at high risk for systemic emboli (e.g., in the presence of atrial fibrillation, large anterior MI, or left ventricular thrombus). However, if there is a low risk for thromboembolism, patients treated with SK or APSAC do not require IV heparin therapy.
Several trials have compared the efficacy of thrombolytic agents. In 1993, the international GUSTO-1 trial found a small survival advantage of t-PA compared with SK following an MI. In that study, the greatest benefit of t-PA occurred in patients with anterior MI and when treatment was administered within 4 hours after the onset of symptoms. Intracranial hemorrhage was higher with t-PA than SK, but did not negate the net clinical advantage of t-PA. In the TIMI-4 trial, t-PA was also found to be superior to APSAC at achieving early coronary artery patency and clinical outcomes. Thus use of the latter drug has waned. The GUSTO-III trial compared r-PA to t-PA and found similar clinical efficacy of these two agents. Perhaps the most important message from the thrombolytic trials is that early and sustained patency of an infarct-related coronary artery improves survival. No matter which thrombolytic agent is used, it is crucial that patients receive such therapy as quickly as possible. A reasonable goal is a target ‘door-to-drug’ time of 30 minutes in the emergency department.
[edit] Patient Selection.
The criteria for selecting patients for thrombolytic therapy include evidence of an evolving Q wave MI and the ability to administer the thrombolytic drug within a period likely to result in an improved outcome (Fig. 63-4). The greatest survival benefit occurs when thrombolytic therapy is administered less than 6 hours after the onset of chest pain. Nonetheless, several studies have shown that treatment as late as 24 hours into the course of an MI can reduce the mortality rate. Therefore in certain situations, such as a stuttering course of chest pain during an evolving MI, it is reasonable to undertake thrombolytic therapy up to 24 hours after the onset of symptoms.
The major contraindications to thrombolytic therapy are situations that increase the likelihood of bleeding (see Fig. 63-4). In addition, patients who have received SK or APSAC previously should not be rechallenged with either agent because of the potential of allergic reactions. Advanced age is not a contraindication to thrombolytic therapy; although most often administered to those under 75 years old, it should also be considered in older patients who are otherwise healthy and do not have specific contraindications.
Direct PTCA (often with stent deployment) is an alternative to thrombolytic therapy in centers in which it can be performed rapidly by highly skilled cardiologists. Those most likely to benefit from primary PTCA in place of thrombolysis include patients with a contraindication to thrombolytic therapy, with cardiogenic shock, and in the setting of a large anterior MI.
Studies have shown that routine coronary angiography and revascularization following successful thrombolytic therapy offer no advantage, but should be pursued in patients with recurrent spontaneous ischemia, or if ischemia is provoked by a predischarge exercise test (see below).
[edit] Routine MI Management.
Whether or not thrombolytic therapy is adminis