Blood tests are available for several substances that suggest the presence of myonecrosis (i.e., recent death of myocardial cells), inflammation, or hemodynamic stress (eFig. 13-4).3–5
Cardiac biomarkers classified according to the different pathologic processes they indicate.
When myocardial infarction (myonecrosis) occurs, proteins from the recently necrotic myocytes are released into the peripheral blood, where they can be detected using specific biochemical assays. These biomarkers of myonecrosis (a) aid in the diagnosis (or exclusion) of myocardial infarction as the cause of chest pain; (b) facilitate triage and risk stratification of patients with chest discomfort; and (c) identify patients who are appropriate candidates for specific therapeutic strategies or interventions. Cardiac troponin (cTn) is the preferred biomarker for the diagnosis of myonecrosis.5 Other available biomarkers of necrosis include creatine kinase-MB (CK-MB) and myoglobin.
Troponin (Tn) I and T are contractile proteins found only in cardiac myocytes. In the patient with myocardial infarction, cTn is detectable in the blood 2 to 4 hours after the onset of symptoms and remains detectable for 5 to 10 days (eFig. 13-5). cTn is the preferred marker for evaluating the patient suspected of having a myocardial infarction, since it is the most sensitive and tissue-specific biomarker available. In the patient with ischemic chest pain and electrocardiographic (e.g., ST segment) abnormalities, the presence of an elevated serum cTn concentration establishes the diagnosis of myocardial infarction, and the absence of such an elevation excludes it. The use of high-sensitive cTn assays improves the early diagnosis of patients with suspected myocardial infarction, particularly the early exclusion of it.6
Time course of the appearance of various markers in the blood after acute myocardial infarction. (Reprinted from Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease—The present and the future. J Am Coll Cardiol 2006;48:4. Copyright © 2006, with permission from Elsevier.)
In the patient with an acute coronary syndrome, detection and quantitation of cTn in the blood provide prognostic information and guide management. Acute coronary syndrome patients with an elevated serum cTn concentration have a roughly fourfold higher risk of death and recurrent MI in the coming months when compared with those with normal cTn concentrations. They benefit (i.e., have a reduced incidence of death, recurrent myocardial infarction, and recurrent ischemia) from more intensive antiplatelet and antithrombotic therapy as well as prompt coronary angiography and revascularization, whereas those with a normal serum cTn obtain no benefit from such intensive therapy.7,8 Thus, serum cTn concentrations are used for diagnostic, prognostic, and therapeutic purposes in the patient with suspected or proven CAD.
On occasion, the serum cTn concentration may be elevated in a patient without CAD in whom myonecrosis occurs because myocardial oxygen demands markedly exceed oxygen supply (caused, e.g., by tachycardia or severe systemic arterial hypertension) or nonischemic cardiac injury occurs (i.e., myocardial contusion caused by blunt trauma to the chest) (eTable 13-3). In the patient with an elevated serum cTn concentration, the clinician must decide if the observed abnormal serum cTn concentration is the result of CAD or another condition.
eTable 13-3 Conditions Associated with an Increased Serum Troponin Concentration |Favorite Table|Download (.pdf)
eTable 13-3 Conditions Associated with an Increased Serum Troponin Concentration
|Myocardial infarction||Pulmonary embolism|
|Acute coronary syndrome||Strenuous exercise|
|Congestive heart failure||Respiratory distress|
|Cardiac defibrillation||Infiltrative disorders|
|Cardiac ablation||Acute limb ischemia|
|Cardiac contusion||Inflammatory disease|
|Hypertension or hypotension||Rhabdomyolysis|
When serum cTn measurements are not available, the best alternative is the MB isoenzyme of creatine-kinase (CK-MB), which is a cytosolic carrier protein for high-energy phosphates that is released into the blood when myonecrosis occurs. Although it was initially thought to be cardiac specific, CK-MB is now known to be present in small amounts in skeletal muscle; as a result, it may be detectable in the blood of patients with massive muscle injury, as occurs with rhabdomyolysis or myositis.
In the patient with a myocardial infarction, CK-MB can be detected in the blood 2 to 4 hours after symptom onset; its serum concentration peaks within 24 hours, and it remains detectable in the blood for 48 to 72 hours. To document the characteristic rise and fall of CK-MB concentrations, blood samples should be obtained every 4 to 8 hours. Although CK-MB is not as sensitive or cardiac-specific a biomarker as cTn, its blood concentration declines more rapidly than cTn, which makes it the preferred biomarker for evaluating suspected recurrent infarction in the patient who experiences recurrent chest pain within several days of myocardial infarction. With recurrent infarction, the typical rise and fall of the serum CK-MB concentration is interrupted by a second elevation. Conversely, serum cTn concentrations decline slowly following myocardial infarction; hence, they are not as sensitive as CK-MB for diagnosing recurrent infarction.
The serum myoglobin concentration is elevated in the patient with myonecrosis, but it has a low specificity for myocardial infarction because of its high concentration in skeletal muscle. Because of its small molecular size and consequent rapid release (within 1 hour) following the onset of myonecrosis, it is utilized as a very early marker of myocardial infarction. When it is combined with a more specific marker of myonecrosis, such as cTn or CK-MB, myoglobin is useful for the early exclusion of myocardial infarction.
Inflammatory processes participate in the development of atherosclerosis and contribute to the destabilization of atherosclerotic plaques, which may ultimately lead to an acute coronary syndrome. Several mediators of the inflammatory response, including acute-phase proteins, cytokines, and cellular adhesion molecules, have been evaluated as potential indicators of underlying atherosclerosis and as predictors of acute cardiovascular events.
C-reactive protein (CRP) is an acute-phase reactant protein produced by the liver.9 Although a receptor for CRP is present on endothelial cells, controversy exists regarding whether CRP is simply a marker for systemic inflammation or participates actively in atheroma formation.10,11 In the absence of acute illness or myocardial infarction, serum concentrations of CRP are relatively stable, although they are influenced by gender and ethnicity.
Epidemiologic studies have shown that the relative risk of future vascular events increases as the serum high-sensitive CRP (hs-CRP) concentration increases.9 Values greater than 3 mg/L are associated with an increased risk for developing CVD; conversely, values less than 1 mg/L are associated with a low risk. Those between 1 and 3 mg/L are considered to be at intermediate risk. To measure serum CRP concentrations accurately, a hs-CRP assay is required. In an individual with an elevated serum hs-CRP concentration, the measurement should be repeated several weeks later to exclude the possibility that an acute illness was responsible for the elevation. Measurements should not be taken when subjects are acutely ill (e.g., with any acute febrile illness) or have a known autoimmune or rheumatologic disorder. Serum CRP concentrations above 10 mg/L are likely caused by an acute or chronic systemic illness.
Although the relative risk of future vascular events increases as the serum concentration of hs-CRP increases, controversy continues as to whether hs-CRP concentrations provide sufficient incremental information above traditional risk factors to warrant routine testing in subjects without known CVD in an attempt to prevent an adverse event (so-called primary prevention).9,12,13 Recent guidelines have suggested that CRP is useful in patients who are considered (on the basis of traditional risk factors) to be at intermediate risk for CAD in an attempt to guide the intensity with which their risk factors are modified.9,12 Only limited data have suggested that interventions that lower CRP concentrations (i.e., aspirin and statins) are beneficial.14–16
Multiple studies17,18 of patients with acute coronary syndromes have demonstrated the capacity of hs-CRP concentrations—measured at the time of hospitalization or hospital discharge—to help to predict cardiovascular outcomes during the hospitalization or during long-term followup. This prognostic information appears to be independent of and complementary to data obtained from the history and electrocardiogram (ECG). hs-CRP concentrations may be useful for monitoring the response to statin therapy, in that those with low hs-CRP concentrations after statin therapy have better clinical outcomes than those in whom these concentrations are high.14,16 Based on these data, the measurement of serum hs-CRP concentrations in patients with acute coronary syndromes is recommended as reasonable (class IIa) for risk stratification when additional prognostic information is desired.5 In contrast, its routine use is not recommended in the absence of compelling data identifying its role in guiding specific therapy.
Other novel markers of inflammation and/or plaque stabilization that have been shown to provide prognostic information in patients with an acute coronary syndrome are myeloperoxidase, CD40 ligand, P-selectin, pregnancy-associated plasma protein A, interleukin 6, matrix metalloproteinase-9, soluble intercellular adhesion molecule 1, and fibrinogen.3,5,19
Sidebar: Clinical Controversy...
Assessing an individual’s risk for CVD is important in guiding treatment. Many risk factors for CVD have been identified (i.e., hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking, and family history of CVD). Whether hs-CRP concentrations provide sufficient incremental information above traditional risk factors to warrant routine testing in subjects without known CVD in an attempt to prevent an adverse event (so-called primary prevention) is unknown.
Markers of Hemodynamic Stress
B-type natriuretic peptide (BNP) and its precursor, N-terminal pro-brain natriuretic protein (NT-proBNP), are released from ventricular myocytes in response to increases in wall stress. As a result, their serum concentrations typically are increased in patients with congestive heart failure. They may also be elevated in patients with an acute coronary syndrome as a result of left ventricular systolic dysfunction, impairment of ventricular relaxation, and myocardial stunning.5,20
Since serum BNP and NT-proBNP concentrations manifest substantial biologic variability, their serum concentrations in an individual subject must increase or decrease at least twofold to provide assurance that a “real” change has occurred. In addition, when considering the normal range for an individual, one must be aware that considerable variation in serum concentrations exists according to age, gender, weight, and renal function. Women and older patients have a higher normal range, whereas obese patients have lower values than the nonobese. Patients with renal failure often have substantially higher values.
Elevated BNP and NT-proBNP concentrations support a suspected diagnosis of heart failure or lead to a suspicion of heart failure when a diagnosis is unclear. Conversely, a normal value (BNP less than 100 pg/mL [100 ng/L; 28.9 pmol/L] or NT-proBNP less than 300 pg/mL [300 ng/L; 35.4 pmol/L]) in an untreated patient strongly suggests that heart failure is not present.20,21 In a study of 1,568 patients seeking medical attention after the abrupt onset of dyspnea, plasma BNP was significantly higher in those with clinically diagnosed heart failure than in those without (mean value, 675 pg/mL [675 ng/L; 10 pmol/L] compared with 110 pg/mL [110 ng/L; 31.8 pmol/L], respectively); those with known heart failure but with a noncardiac cause of dyspnea had intermediate values (mean, 346 pg/mL [346 ng/L; 100 pmol/L]).22
Plasma BNP concentrations provide prognostic information in patients with acute decompensated heart failure: in-hospital mortality is threefold higher in those in the highest BNP quartile when compared with the lowest quartile.23 Similarly, in patients with compensated CHF, plasma BNP concentrations provide valuable prognostic information, in that each 100 pg/mL (100 ng/L; 28.9 pmol/L) increase in plasma BNP in these subjects is associated with a 35% increase in the relative risk of death.24 Although the measurement of BNP can be used for prognostic purposes in patients with CHF, its role in assessing treatment efficacy and modifying drug therapy is not clearly established.
Elevated plasma concentrations of BNP and NT-proBNP have been observed in subjects with heart failure with depressed left ventricular systolic function, heart failure with preserved left ventricular systolic function, elevated left ventricular filling pressures, left ventricular hypertrophy, atrial fibrillation, and myocardial ischemia. They may be elevated in certain noncardiac conditions, including pulmonary embolism, chronic obstructive pulmonary disease, hypoxemia, sepsis, cirrhosis, and renal failure. As a result, values of BNP or NT-proBNP should not be used in isolation either to confirm or to refute a diagnosis of heart failure.
Elevated serum concentrations of BNP and NT-proBNP may be detected in patients with an acute coronary syndrome. Data from more than 30 studies have indicated that BNP and NT-proBNP are among the most robust predictors of death and heart failure in patients hospitalized with an acute coronary syndrome.5,25–27 Nonetheless, data regarding the potential for these substances to guide specific therapeutic decisions, such as whether to perform coronary angiography and revascularization, have been mixed. At present, therefore, the use of BNP and NT-proBNP in patients with an acute coronary syndrome is limited to risk stratification, for which they can be used to help in the assessment of prognosis.
The chest x-ray provides supplemental information to the physical examination. Although it does not provide detailed information about internal cardiac structures, it can provide information about the position and size of the heart and its chambers as well as adjacent structures. The standard chest x-rays for evaluation of the lungs and heart are standing posteroanterior and lateral views taken with maximal inspiration; portable chest x-rays usually are less helpful. When possible, previous x-rays should be obtained for comparison.
The posteroanterior chest x-ray outlines the superior vena cava, right atrium, aortic knob, main pulmonary artery, left atrial appendage (especially if enlarged), and left ventricle. The lateral chest x-ray allows one to assess the right ventricle, inferior vena cava, and left ventricle. These structures are visualized as shadows of differing density rather than as discrete entities.
Cardiac enlargement is determined by the cardiothoracic ratio (CTR), which is the maximal transverse diameter of the heart divided by the maximal transverse diameter of the thorax on the posteroanterior view. The CTR normally is less than or equal to 0.45, but it may be higher (i.e., less than or equal to 0.55) in subjects with a large stroke volume (e.g., highly conditioned athletes). Certain cardiac conditions, such as heart failure and hypertension, may cause cardiac enlargement, with a resultant high CTR. Individual chamber enlargement can be seen on the chest x-ray. Left atrial enlargement is suspected if the left bronchus is elevated or the atrial appendage is enlarged. Left ventricular enlargement is the most common feature identified on chest x-ray and is seen as a lateral and downward displacement of the cardiac apex. Right ventricular enlargement is best seen on the lateral film, on which the heart appears to occupy the retrosternal space. A large pericardial effusion may appear as a large heart on a chest x-ray, but, in contrast to heart failure, pulmonary vascular congestion is not present (see below).
The pulmonary vessels are examined for size and filling. With diminished pulmonary blood flow, as would be present in the patient with tetralogy of Fallot or pulmonic valvular stenosis, the peripheral pulmonary vessels are small in caliber and underfilled. Increased pulmonary blood flow, as occurs with a high cardiac output or left-to-right intracardiac shunting, may lead to enlargement and tortuosity of the central and peripheral pulmonary vessels. Pulmonary arterial hypertension (increased pulmonary resistance) is identified by enlargement of the central pulmonary arteries and diminished peripheral perfusion. Elevated pulmonary venous pressure—usually the result of an elevated left atrial pressure—is characterized by dilation of vessels in the upper lung zones (e.g., cephalization of flow), owing to recruitment of upper lung vessels when blood is diverted from the constricted vessels in the lower lung zones.
Congestive heart failure causes Kerley B lines (edema of interlobular septae), which appear as thin, horizontal reticular lines in the costophrenic angles. As pulmonary venous pressure increases, alveolar edema becomes evident, and pleural effusions may appear as blunting of the costophrenic angles.
The ECG is a graphic recording of the electrical potentials generated by the heart. The signals are detected by using electrodes attached to the extremities and chest wall (eFigs. 13-6 and 13-7), which are then amplified and recorded (eFig. 13-8). The ECG leads display the instantaneous differences in potential between electrodes. As electrical activity approaches the positive electrode of the lead, it registers a positive (upright) deflection on the ECG, whereas electrical activity in the opposite direction of the positive electrode of the lead registers a negative (downward) deflection.
With electrodes (depicted as dots) attached to each arm and leg, electrical activity on the torso (i.e., frontal plane) is recorded from six different directions. These are known as the limb leads: leads I, II, III, aVF, aVL, and aVR. (Source: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th ed. Figure 245-2, http://accessmedicine.mhmedical.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
A. Electrode positions of the precordial leads. (MCL, midclavicular line; V1, fourth intercostal space at the right sternal border; V2, fourth intercostal space at the left sternal border; V3, halfway between V2 and V4; V4, fifth intercostal space at the midclavicular line; V5, anterior axillary line directly lateral to V4; V6, anterior axillary space directly lateral to V5.) B. The precordial reference figure. Leads V1 and V2 are called right-sided precordial leads; leads V3 and V4, midprecordial leads; and leads V5 and V6, left-sided precordial leads. (Redrawn from Kinney MR, Packa DR, eds. Andreoli’s Comprehensive Cardiac Care, 8th ed. St. Louis, MO: Mosby, 1996, with permission.)
Standard 12-lead electrocardiogram, with six frontal and six precordial leads.
The ECG can be used to detect arrhythmias, conduction disturbances, myocardial ischemia or infarction, metabolic disturbances that may result in lethal arrhythmias (e.g., hyperkalemia), and increased susceptibility to sudden cardiac death (e.g., prolonged QT interval). It is simple to perform, noninvasive, and inexpensive.
Depolarization of the heart initiates cardiac contraction. The electrical current that depolarizes the heart originates in special cardiac pacemaker cells located in the sinoatrial (SA) node, or sinus node, which is located in the upper right atrium near the insertion of the superior vena cava (eFig. 13-9). The depolarization wave is transmitted through the atria, which initiates atrial contraction. Subsequently, the impulse is transmitted through specialized conduction tissues in (a) the atrioventricular (AV) node, which is located in the inferior right atrium near the tricuspid valve; (b) the bundle of His, which is located in the interventricular septum; and (c) the right and left bundles, which rapidly conduct the electrical impulse to the right and left ventricular myocardium via (d) the Purkinje fibers. The depolarization wave front then spreads through the ventricular muscle, from endocardium to epicardium, triggering ventricular contraction.
Schematic representation of the cardiac conduction system. (AV, atrioventricular; SA, sinoatrial.) (From Vijayaraman P, Ellenbogen KA. Bradyarrhythmias and pacemakers. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:1021.)
The ECG waveforms (eFig. 13-10), which are recorded during electrical depolarization of the heart, are labeled alphabetically and are read from left to right, beginning with the P wave, which represents depolarization of the atria. The normal duration of the P wave is up to 0.12 second. The PR segment, created by passage of the impulse through the AV node and the bundle of His and its branches, has a duration of 0.12 to 0.20 second. The QRS complex represents electrical depolarization of the ventricles. Initially, a negative deflection (the Q wave) appears, followed by a positive deflection, the R wave, and finally a negative deflection, the S wave. The normal duration of the QRS complex is less than 0.12 second. Since the left ventricle is much thicker than the right ventricle, most of the electrical wave front is directed toward the former. Accordingly, the precordial leads positioned over the left ventricle (leads V5 and V6) demonstrate a positive (upright) QRS complex, whereas those positioned over the right ventricle (V1 and V2) record a negative (downward) QRS complex.
ECG waveforms are labeled alphabetically and are read from left to right. The P wave represents depolarization of the atria. The PR segment is created by passage of the impulse through the atrioventricular node and the bundle of His and its branches. The QRS complex represents electrical repolarization of the ventricles. The T wave results from ventricular depolarization. A plateau phase called the ST segment extends from the end of the QRS complex to the beginning of the T wave. The ST segment elevates with transmural (full thickness) ischemia and depresses with ischemia. The QT interval—measured from the beginning of the QRS complex to the end of the T wave—includes the time required for ventricular depolarization and repolarization.
Following the QRS complex is a plateau phase called the ST segment, which extends from the end of the QRS complex (called the J point) to the beginning of the T wave. When ischemia occurs, one may observe depression of the ST segment (eFig. 13-11A). When infarction from total obstruction of a coronary artery occurs, ST segment elevation may be observed (eFig. 13-11B). Repolarization of the ventricle leads to the T wave. The T wave usually goes in the same direction as the QRS complex.
A. Anterior wall ischemia with deep T-wave inversions and ST segment depressions in leads I, aVL, and V3 to V6. (Source: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of internal Medicine, 18th ed. Figure e28-1, http://accessmedicine.mhmedical.com/. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.) B. Extensive anterior MI with marked ST elevations in leads I, aVL, V1 to V6, and small pathologic Q waves in V3 to V6. Marked reciprocal ST segment depressions in leads III and aVF. (Source: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th ed. Figure e28-5, http://accessmedicine.mhmedical.com/. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
The QT interval—measured from the beginning of the QRS complex to the end of the T wave—includes the time required for ventricular depolarization and repolarization, and it varies inversely with heart rate. A rate-related (“corrected”) QT interval (QTc) can be calculated as interval; it should be less than 0.44 second. A prolonged QTc interval is caused by abnormalities in depolarization or repolarization that are associated with sudden cardiac death. QTc prolongation may be due to genetic defects in action potential ion channels (e.g., congenital long QT syndrome), drugs (eTable 13-4), or electrolyte disturbances (i.e., hypokalemia, hypocalcemia, hypomagnesemia). Regardless of the cause, QT prolongation increases susceptibility to a potentially lethal arrhythmia, torsades de pointes (a type of ventricular tachycardia).
eTable 13-4 Drugs with Known Risk of QT Interval Prolongation and Potentially Lethal Arrhythmia (Torsades De Pointes) |Favorite Table|Download (.pdf)
eTable 13-4 Drugs with Known Risk of QT Interval Prolongation and Potentially Lethal Arrhythmia (Torsades De Pointes)
The 12 conventional ECG leads record the electrical potential difference between electrodes placed on the surface of the body (eFig. 13-9). The six frontal plane and the six horizontal plane leads provide a three-dimensional (3D) representation of cardiac electrical activity. Each lead provides the opportunity to view atrial and ventricular depolarization from a different angle, much the same way that multiple video cameras positioned in different locations can view an event from different perspectives.
The six frontal leads can be subdivided into those that view electrical potentials directed inferiorly (leads II, III, aVF), laterally (leads I, aVL), or rightward (aVR). Likewise, the six precordial leads can be subdivided into those that view electrical potentials directed toward the septal (leads V1, V2), apical (leads V3, V4), or lateral (leads V5, V6) regions of the heart. Thus, when ischemia or infarction-related ECG changes occur, the region of the heart affected can be localized by determining which leads manifest abnormalities.
The mean orientation of the QRS vector with reference to the six frontal plane leads is known as the QRS axis. It describes the “major” direction of QRS depolarization, which is typically toward the apex of the heart (i.e., toward the left side of the chest and downward). An abnormality in the direction of QRS depolarization (so-called axis deviation) may occur with hypertrophy or enlargement of one or more cardiac chambers or with remote myocardial infarction, since electrical depolarization does not occur in dead tissue. Hypertrophy or enlargement of the atria or ventricles may also affect the size of the P wave or QRS complex, respectively. Although specific ECG criteria have been developed for diagnosing hypertrophy, the ECG is neither sensitive nor specific for establishing the presence of atrial dilation or ventricular hypertrophy. Other noninvasive modalities (i.e., echocardiography or MRI) are superior to the ECG for evaluating these conditions.
The origin of the electrical impulses (the so-called cardiac rhythm) and integrity of the conduction system can be assessed with a 12-lead ECG. If the SA node is diseased and unable to initiate cardiac depolarization, specialized cardiac pacemaker cells in the AV node or ventricle may initiate cardiac depolarization instead, albeit at a slower rate than the SA node. Alternatively, the SA node may initiate the electrical impulse, but its transmission through the specialized conduction system may be slowed or interrupted in the AV node or bundle of His, resulting in first-degree or advanced (i.e., second- or third-degree) AV block, respectively. Finally, disease in the left or right bundle may slow conduction of the electrical impulse, resulting in a left or right bundle-branch block, respectively.
The ECG provides an assessment of the heart rate, which is normally 60 to 100 beats per minute (beats/min) at rest. Tachycardia is present when the heart rate exceeds 100 beats/min, and bradycardia is present when it is less than 60 beats/min. Tachycardia may originate in the SA node (sinus tachycardia), atrium (atrial flutter or fibrillation, ectopic atrial tachycardia, or multifocal atrial tachycardia), or AV node (junctional tachycardia or AV nodal reentry tachycardia). Collectively, these are termed supraventricular tachycardias. Alternatively, a tachycardia may have its origin in the right or left ventricle (ventricular tachycardia, ventricular fibrillation, and right ventricular outflow tract tachycardia).
Many drugs can affect the specialized cardiac pacemaker cells—causing tachycardia or bradycardia—or the conduction system, which may lead to AV block or sudden cardiac death. A resting ECG should be performed before and after the administration of such drugs, with examination of the rhythm, heart rate, and various intervals (i.e., PR, QRS, and QT) to determine if substantial changes have occurred.
In the patient with chest pain, the resting ECG is examined for ST segment abnormalities that may indicate myocardial ischemia or infarction (i.e., ST segment depression or elevation). In addition, the resting ECG may indicate if the patient has had a remote myocardial infarction.
The ECG is used often in conjunction with other diagnostic tests to provide additional data, monitor the patient, or determine if symptoms correlate with what is observed on the ECG. For example, the patient suspected of having CAD may undergo stress testing with ECG monitoring to assess the presence of provocable ischemia.
Survivors of myocardial infarction may be at risk for life-threatening arrhythmias. In these individuals, myocardial scar tissue creates zones of slow conduction that appear as low-amplitude, high-frequency signals that are continuous with the QRS complex. These small electrical currents (so-called late potentials) are not detectable on a routine, traditional ECG. By using computer programs that amplify and enhance the electrical signal, signal-averaged electrocardiography (SAECG) provides a high-resolution ECG that measures ventricular late potentials, thereby identifying patients at risk of sustained ventricular tachycardia after myocardial infarction.28
Patients with ischemic heart disease and unexplained syncope who are at risk for sustained ventricular tachycardia may be candidates for a SAECG. A SAECG may be useful in the patient with nonischemic cardiomyopathy and sustained ventricular tachycardia, detection of acute rejection following heart transplant, and assessment of the proarrhythmic potential of antiarrhythmic drugs.
Ambulatory Electrocardiographic Monitoring
Ambulatory electrocardiography (AECG), so-called Holter monitoring, can be used to detect, document, and characterize cardiac rhythm or ECG abnormalities during ordinary daily activities. Current continuous AECG equipment is capable of providing an analysis of cardiac electrical activity, including arrhythmias, ST segment abnormalities, and heart rate variability. An AECG can be obtained with continuous recorders (Holter monitors) or intermittent recorders.
During continuous Holter monitoring, the patient wears a portable ECG recorder (weighing 8 to 16 oz), which is attached to two to four leads placed on the chest wall. During monitoring, the patient maintains a diary, in which he/she records the occurrence, duration, and severity of symptoms (e.g., light-headedness, chest pain, palpitations, etc.). The device is typically worn for 24 to 48 hours, after which the continuous ECG recording is scanned by computer to detect arrhythmias or ST segment abnormalities to determine if they are responsible for the patient’s symptoms.
Intermittent recorders (also known as event monitors or loop recorders) are worn for longer periods of time (weeks to months). Although they continuously monitor the ECG, only brief (minutes) segments of it are recorded when the patient activates the device (i.e., when symptoms occur) or a preprogrammed abnormal ECG event occurs. Some intermittent event recorders incorporate a memory loop that permits capture of a rhythm recording during fleeting symptoms, tachycardia onset, and, in some cases, syncope that occurs infrequently. When the patient activates a looping monitor, it records several minutes of the preceding rhythm as well as the subsequent rhythm.
When monitoring is performed to evaluate the cause of intermittent symptoms, the frequency of symptoms dictates the type of recording. Continuous recordings are indicated for the assessment of frequent (at least once a day) symptoms that may be related to disturbances of heart rhythm, for the assessment of syncope or near syncope, and for patients with recurrent unexplained palpitations. In contrast, for patients whose symptoms are infrequent, intermittent event recorders may be more cost-effective in attempting to determine the cause of symptoms. For patients receiving antiarrhythmic drug therapy, continuous monitoring is indicated to assess drug response and to exclude proarrhythmia.
Exercise stress testing, a well-established, relatively low-cost procedure, has been in widespread use for decades. It may be performed (a) to evaluate an individual’s exercise capacity; (b) to assess the presence of myocardial ischemia in the patient with symptoms suggestive of CAD; (c) to obtain prognostic information in the patient with known CAD or recent myocardial infarction; (d) to evaluate the severity of valvular abnormalities; or (e) to assess the presence of arrhythmias or conduction abnormalities in the patient with exercise-induced cardiac symptoms (i.e., palpitations, light-headedness, or syncope).
The patient who is to undergo an exercise stress test should fast for several hours beforehand and dress appropriately for exercise. Before exercise begins, a limited cardiac examination is performed (i.e., auscultation of the lungs and heart), blood pressure and heart rate are recorded, and a standard 12-lead ECG is recorded. Exercise is then initiated, and the ECG, heart rate, and blood pressure are monitored carefully and recorded as the intensity of exercise increases incrementally. The patient is monitored for the development of symptoms (i.e., chest pain, dyspnea, light-headedness, etc.), transient rhythm disturbances, ST segment abnormalities, and other electrocardiographic manifestations of myocardial ischemia. Exercise is terminated with the onset of limiting symptoms, diagnostic electrocardiographic (e.g., ST segment) changes, arrhythmias, or a decrease in blood pressure greater than 10 mm Hg. Otherwise, exercise is continued until the patient achieves 85% of his or her maximal predicted heart rate or is unable to exercise further.
Both treadmill and cycle ergometer devices are available for exercise testing. Although cycle ergometers are less expensive, smaller, and quieter than treadmills, quadricep muscle fatigue is a major limitation in patients who are not experienced cyclists, and subjects usually stop cycling before reaching their maximal oxygen uptake. As a result, treadmills are much more commonly used for exercise stress testing, particularly in the United States.
With treadmill testing, the incline and/or speed of the treadmill is increased incrementally every 2 to 3 minutes. Several treadmill exercise protocols have been developed to accommodate the variations in fitness, age, and mobility of individuals. Accordingly, if the exercise capacity is reported in minutes, the details of the protocol should be specified. Alternatively, the translation of exercise duration or workload into metabolic equivalents (METs) (oxygen uptake expressed in multiples of basal oxygen uptake, 3.5 mL O2/kg/min) has the advantage of providing a common measure of performance regardless of the type of exercise test or protocol used. Most domestic chores and activities require less than 5 METs, whereas participation in strenuous sports, such as swimming, singles tennis, football, basketball, or skiing, requires greater than 10 METs.
Interpretation of the results of exercise testing should include exercise capacity as well as the clinical, hemodynamic, and electrocardiographic responses. The occurrence of chest pain consistent with angina is important, particularly if it results in termination of the test. Abnormalities in exercise capacity, the response of systolic blood pressure to exercise, and the response of heart rate to exercise and recovery may provide valuable information. The most important electrocardiographic findings are ST segment depression and elevation. A positive exercise test is said to have occurred if the ECG shows at least 1 mm of horizontal or downsloping ST segment depression or elevation for at least 60 to 80 milliseconds after the end of the QRS complex.
ST segment changes suggestive of myocardial ischemia that occur at a low level of exercise (less than 6 minutes of exercise or less than 5 METs) are associated with more severe CAD and a worse prognosis than those that occur at a higher workload. An estimate of myocardial oxygen demands can be obtained by calculating the so-called “rate–pressure product” (double product) (i.e., heart rate × systolic arterial pressure).
Most treadmill exercise testing is performed in adults with symptoms of known or suspected ischemic heart disease. In patients for whom the diagnosis of CAD is certain, stress testing is often used for risk stratification or prognostic assessment to determine the need for possible coronary angiography or revascularization. Patients who are candidates for exercise testing may (a) have stable chest pain; (b) be stabilized with medical therapy following an episode of unstable chest pain; or (c) be post–myocardial infarction or post-revascularization.
The ability of the exercise stress test to identify (or to exclude) individuals with CAD is influenced by (a) their exercise capacity (i.e., can the individual perform maximal or nearly maximal exercise?); (b) the presence of baseline electrocardiographic abnormalities (i.e., bundle-branch block or ST segment depression); (c) medications that affect the ECG or the hemodynamic response to exercise (i.e., digoxin and β-adrenergic blocking agents, respectively); and (d) concomitant cardiac conditions that are associated with electrocardiographic abnormalities (i.e., left ventricular hypertrophy, paced rhythm, preexcitation) (eTable 13-5). Thus, patients who are unable to exercise or who have baseline ECG abnormalities require imaging (i.e., radionuclide or echocardiographic) stress testing to detect (or to exclude) CAD, since routine stress testing is unreliable in these individuals.
eTable 13-5 Meta-Analyses of Exercise Testing |Favorite Table|Download (.pdf)
eTable 13-5 Meta-Analyses of Exercise Testing
|Grouping||Number of Studies||Total Number of Patients||Sens (%)||Spec (%)||Predictive Accuracy (%)|
|Meta-analysis of standard exercise test||147||24,047||68||77||73|
|Meta-analysis without MI||58||11,691||67||72||69|
|Meta-analysis without workup bias||3||>1,000||50||90||69|
|Meta-analysis with ST depression||22||9,153||69||70||69|
|Meta-analysis without ST depression||3||840||67||84||75|
|Meta-analysis with digoxin||15||6,338||68||74||71|
|Meta-analysis without digoxin||9||3,548||72||69||70|
|Meta-analysis with LVH||15||8,016||68||69||68|
|Meta-analysis without LVH||10||1,977||72||77||74|
The ability of the exercise stress test to identify the presence of CAD is influenced by the pretest probability of CAD in the population tested. For example, exercise-induced ST segment depression in a 60-year-old man with typical anginal chest pain and multiple risk factors for atherosclerosis (i.e., a high pretest probability) is considered a “true positive” stress test, whereas the presence of same findings in a 30-year-old woman with chest pain believed to be atypical for angina (i.e., a low pretest probability) is most likely to be a “false-positive” test. The relatively poor accuracy of the exercise ECG for diagnosing CAD in asymptomatic subjects has led to the recommendation that exercise testing not be used as a screening tool,29 since false-positive tests are common among asymptomatic adults, especially women, and may lead to unnecessary testing and treatment. Controversy exists as to whether exercise testing should be performed in asymptomatic individuals at increased risk of CAD (i.e., diabetics).
The ACC and AHA have jointly developed guidelines describing the indications for exercise stress testing.29,30
Exercise stress testing is relatively safe, with an estimated risk of myocardial infarction or death of 1 per 2,500 tests. It should be supervised by a physician or a properly trained health professional working directly under the supervision of a physician, who should be in the immediate vicinity and available for emergencies. Exercise stress testing is contraindicated in subjects who are unable to exercise or who should not exercise because of physiologic or psychological limitations (eTable 13-6). Although unstable angina is usually a contraindication to exercise stress testing, it can be performed safely once the patient has responded appropriately to intensive medical therapy. Exercise testing is contraindicated in patients with untreated life-threatening arrhythmias or congestive heart failure. Patients with comorbid diseases, such as chronic obstructive pulmonary disease or peripheral vascular disease, may be limited in their exercise capacity. For patients with disabilities or other medical conditions that limit their exercise capacity, pharmacologic stress testing (with dipyridamole, adenosine, regadenoson, or dobutamine) is an alternative (see Pharmacologic Stress Testing below).
eTable 13-6 Contraindications to Exercise Testing |Favorite Table|Download (.pdf)
eTable 13-6 Contraindications to Exercise Testing
- Acute myocardial infarction (within 2 days)
- High-risk unstable angina
- Uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise
- Symptomatic severe aortic stenosis
- Uncontrolled symptomatic heart failure
- Acute pulmonary embolus or pulmonary infarction
- Acute myocarditis or pericarditis
- Acute aortic dissection
- Left main coronary stenosis
- Moderate stenotic valvular heart disease
- Electrolyte abnormalities
- Severe arterial hypertension
- Tachyarrhythmias or bradyarrhythmias
- Hypertrophic cardiomyopathy and other forms of outflow tract obstruction
- Mental or physical impairment leading to inability to exercise adequately
- High-degree atrioventricular block
Drug therapy is not routinely altered before exercise stress testing, since few data suggest that doing so improves its diagnostic accuracy. Although patients receiving a β-adrenergic or calcium channel blocker may have a blunted increase in heart rate and blood pressure with exercise, exercise stress testing in such patients nonetheless provides information regarding exercise capacity and ischemic ECG alterations. Nitrates do not directly alter exercise capacity, but they may increase the patient’s exercise capacity by preventing or relieving exercise-induced angina. Digoxin produces an abnormal ST segment response to exercise in 25% to 40% of healthy subjects. Because of its long half-life, digoxin should be discontinued for 2 weeks before exercise stress testing to avoid such drug-induced ST segment changes.30
Sidebar: Clinical Controversy...
The relatively poor accuracy of the exercise ECG for diagnosing CAD in asymptomatic subjects has led to the recommendation that exercise testing not be used as a screening tool, since false-positive tests are common among asymptomatic adults, particularly women, and may lead subsequently to unnecessary testing and treatment. However, controversy exists as to whether exercise testing should be routinely performed in asymptomatic individuals at increased risk of CVD (i.e., diabetics) to identify “silent” (asymptomatic) myocardial ischemia.
Using echocardiography, one can evaluate cardiac function and structure with images produced by ultrasound. High-frequency sound waves transmitted from a handheld transducer “bounce” off tissue and are reflected back to the transducer, where the waves are collected and used to construct a real-time image of the heart.
With the exception of the ECG, echocardiography is the most frequently performed cardiovascular test. It is noninvasive, relatively inexpensive, safe, devoid of ionizing radiation, and portable, so that it can be done at the patient’s bedside, in the operating room, or in a physician’s office. Serial echocardiograms can be performed, especially following a cardiac procedure or a change in clinical condition, as well as to follow the progression of the underlying cardiac disease over time. Echocardiography is the procedure of choice for the diagnosis and evaluation of many cardiac conditions, including valvular abnormalities, intracardiac thrombi, pericardial effusions, and congenital abnormalities. It often is used to assess chamber sizes, function, and wall thickness. In the patient suspected of having CAD, echocardiography can be performed before, during, and immediately after exercise or pharmacologic stress (e.g., dobutamine) to evaluate the presence of ischemia-induced ventricular wall motion abnormalities.
Two approaches to echocardiography are used in clinical practice. Transthoracic echocardiography (TTE) is performed with the transducer positioned on the anterior chest wall, whereas transesophageal echocardiography (TEE) is performed with the transducer positioned in the esophagus. Following transducer placement, several modes of operation are possible: M-mode (motion), two-dimensional (2D), 3D, and Doppler imaging.
With M-mode echocardiography, a transducer placed at a site on the anterior chest (usually along the sternal border) records the images of cardiac structures in one plane, producing a static picture of a small region of the heart, a so-called “ice pick view” (eFig. 13-12). Results depend on the exact placement of the transducer with respect to the underlying structures. Conventional M-mode echocardiography provides visualization of the right ventricle, left ventricle, and posterior left ventricular wall and pericardium. If the transducer is swept in an arc from the apex to the base of the heart, virtually the whole heart can be visualized, including the valves and left atrium.
M-mode echocardiogram. The transducer emits an ultrasound beam, which reflects at each anatomic interface. The reflected wave fronts are detected by the probe, which records the images of cardiac structures in one plane, producing a static picture of a small region of the heart, a so-called “ice pick view.” (AML, anterior mitral leaflet; CW, chest wall; IVS, interventricular septum; PML, posterior mitral leaflet; PW, posterior wall; RV, right ventricle.) (Modified from Hagan AD, DeMaria AN. Clinical Applications of Two-Dimensional Echocardiography and Cardiac Doppler. Boston, MA: Little, Brown, 1989, with permission. From Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed., http://accessmedicine.mhmedical.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
2D echocardiography employs multiple windows of the heart, and each view provides a wedge-shaped image (eFigs. 13-13 and 13-14). These views are processed to produce a motion picture of the beating heart. When compared with M-mode echocardiography, 2D echocardiography provides increased accuracy in calculating ventricular volumes, wall thickness, and the severity of valvular stenoses.
2D transthoracic echocardiography. A. Orientation of the sector beam and transducer position for the parasternal long-axis view of the left ventricle. B. 2D image of the heart, parasternal long-axis view. (Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.) (From DeMaria AN, Daniel G, Blanchard DG. Echocardiography. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:369.)
2D transthoracic echocardiography. A. Orientation of the sector beam and transducer position for the apical four-chamber plane. B. 2D image of the apical four-chamber plane. (LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.) (From DeMaria AN, Daniel G, Blanchard DG. Echocardiography. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:372.)
3D echocardiography, which uses an ultrasound probe with an array of transducers and an appropriate processing system, enables a detailed assessment of cardiac anatomy and pathology, particularly valvular abnormalities as well as ventricular size and function (eFig. 13-15). The ability to “slice” the heart in an infinite number of planes in an anatomically appropriate manner and to reconstruct 3D images of anatomic structures makes this technique very powerful in understanding congenital cardiac conditions.31
Real-time 3D echocardiography image, apical four-chamber plane. (From DeMaria AN, Daniel G, Blanchard DG. Echocardiography. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:374.)
Doppler echocardiography is used to detect the velocity and direction of blood flow by measuring the change in frequency produced when ultrasound waves are reflected from red blood cells. Color enhancement allows blood flow direction and velocity to be visualized, with different colors used for antegrade and retrograde flow. Blood flow moving toward the transducer is displayed in red, and flow moving away from the transducer is displayed in blue; increasing velocity is depicted in brighter shades of each color. Thus, with Doppler echocardiography, information regarding the presence, direction, velocity, and turbulence of blood flow can be acquired. Cardiac hemodynamic variables (e.g., intracardiac pressures) and the presence and severity of valvular disease can be assessed noninvasively with Doppler echocardiography.
When TTE is performed, the transducer is placed on the anterior chest wall, and imaging is performed in three orthogonal planes: long axis (from aortic root to apex), short axis (perpendicular to the long axis), and four-chamber (visualizing both ventricles and atria through the mitral and tricuspid valves) (eFigs. 13-13 and 13-14). Sound energy is poorly transmitted through air and bone, and the ability to record adequate images is dependent on a thoracic window that gives the ultrasound beam adequate access to cardiac structures. Accordingly, in approximately 15% of subjects, suboptimal TTE images are obtained, particularly those with large lung volumes (i.e., chronic lung disease or those being ventilated mechanically) or marked obesity. In addition, TTE may not provide adequate or complete images of the posterior cardiac structures (i.e., left atrium, left atrial appendage, mitral valve, interatrial septum, descending aorta, etc.) that are located far away from the transducer.
With TEE, a flexible transducer is advanced into the esophagus and rests just behind the heart, adjacent to the left atrium and descending aorta. When compared with TTE, TEE provides clearer and more detailed images of the mitral valve, left atrium, left atrial appendage, pulmonary veins, and descending thoracic aorta. Because of the transducer’s proximity to the heart, TEE allows one to delineate small cardiac structures (i.e., vegetations and thrombi less than 3 mm in diameter) that may not be seen with TTE. As a result, TEE often is used to assess the presence of (a) mitral valve vegetations, (b) endocarditis complications (e.g., myocardial abscess), (c) left atrial appendage thrombus in the patient with a stroke or under consideration for an elective cardioversion, and (d) aortic dissection.32–38 In addition, the transducer can be advanced into the fundus of the stomach to obtain images of the ventricles. TEE is widely utilized intraoperatively to assess the success of mitral valve repair or replacement and to delineate cardiac anatomy in subjects with congenital heart disease at the time of surgical repair.
Although TEE is a low-risk invasive procedure, complications, such as tearing or perforation of the esophagus, esophageal burns, transient ventricular tachycardia, minor throat irritation, and transient vocal cord paralysis, occur rarely. TEE-related complications in ambulatory, nonoperative settings range from 0.2% to 0.5%, and mortality is less than 0.01%.39 TEE is contraindicated in patients with esophageal abnormalities, in whom passage of the transducer may be difficult or hazardous (e.g., esophageal strictures, tear, tumor, or varices).
The ACC/AHA Task Force has published guidelines for application of echocardiography and stress echocardiography.35,40,41
Myocardial perfusion imaging, the most commonly performed nuclear cardiology procedure, is used to assess the presence, location, and severity of ischemic or infarcted myocardium. It consists of a combination of (a) some form of stress (exercise or pharmacologic), (b) administration of a radiopharmaceutical, and (c) detection of the radiopharmaceutical in the myocardium with a nuclear camera positioned adjacent to the subject’s chest wall.
The most widely used radionuclides are technetium (Tc) sestamibi or tetrofosmin-99m (99mTc-sestamibi or 99mTc-tetrofosmin) and thallium-201 (201Tl). 99mTc is ideal for clinical imaging because it has a short half-life (about 6 hours) and can be generated in-house with a benchtop generator, thereby providing immediate availability. Because of its short half-life, repeat injections can be given to evaluate the efficacy of reperfusion therapy. 201Tl has a much longer half-life (73 hours), which prevents the use of multiple doses in close temporal proximity but allows for delayed imaging following its administration. The production of 201Tl requires a cyclotron. With both radiopharmaceuticals, myocardial perfusion images are obtained with a conventional gamma camera (see below).
Although both 99mTc- and 201Tl-labeled compounds are useful for the detection of ischemic or infarcted myocardium, each offers certain advantages. 99mTc provides better image quality and is superior for detailed single-photon emission computed tomography (SPECT) imaging (see below), whereas 201Tl imaging provides superior detection of myocardial cellular viability.
With 201Tl imaging, the radioisotope is injected IV as the patient is completing exercise or pharmacologic stress. Since thallium (Tl) is a potassium analogue, it enters normal myocytes that have an active sodium–potassium ATPase pump (i.e., viable myocytes). The intracellular concentration of Tl depends on the perfusion of the tissue and its viability. In the normal heart, homogeneous distribution of Tl occurs in myocardial tissue. Conversely, regions that are scarred due to previous infarction or have stress-induced ischemia do not accumulate as much Tl as normal muscle; as a result, these areas appear as “cold” spots on the perfusion scan.
When evaluating for myocardial ischemia, an initial set of images is obtained immediately after stress and 201Tl injection, and the images are examined for regions of decreased radioisotope uptake. Delayed images are obtained 3 to 4 hours later, since 201Tl accumulation does not remain fixed in myocytes. Continuous redistribution of the isotope occurs across the cell membrane, with (a) differential washout rates between hypoperfused but viable myocardium and normal zones and (b) wash in to previously hypoperfused zones. Thus, when additional images are obtained after 3 to 4 hours of redistribution, viable myocytes have similar concentrations of 201Tl. Consequently, any uptake abnormalities that were caused by myocardial ischemia will have resolved (i.e., “filled in”) on the delayed scan and are termed “reversible” defects, whereas those representing scarred or infarcted myocardium will persist as cold spots.
Myocardial segments that demonstrate persistent 201Tl hypoperfusion with stress and redistribution imaging may represent so-called “hibernating myocardium.” This markedly hypoperfused myocardium is chronically ischemic and noncontractile but metabolically active; as a result, it has the potential to regain function if perfusion is restored. Hibernating myocardium can often be differentiated from irreversibly scarred myocardium by injecting additional 201Tl to enhance uptake by viable myocytes, and then repeating the images 24 hours later.42,43
99mTc-sestamibi—also known as methoxy-isobutyl isonitrile (Tc-MIBI)—is the most widely used 99mTc-labeled compound. Similar to Tl, its uptake in the myocardium is proportional to blood flow, but its mechanism of myocyte uptake is different, in that it occurs passively, driven by the negative membrane potential. Once intracellular, it accumulates in the mitochondria, where it remains, not redistributing with the passage of time. Therefore, the myocardial distribution of sestamibi reflects perfusion at the moment of its injection. Performing a 99mTc-sestamibi procedure provides more flexibility than a 201Tl procedure, in that images can be obtained for up to 4 to 6 hours after radioisotope injection and acquired again as necessary. A 99mTc-sestamibi study is usually performed as a 1-day protocol, with which an initial injection with a small tracer dose and imaging are performed at rest, after which (a few hours later) the patient undergoes a stress test, and repeat imaging is performed after injection of a larger tracer dose.
Myocardial perfusion imaging can be performed with either planar or SPECT approaches. The planar technique consists of three 2D image acquisitions, usually for 10 to 15 minutes each. With SPECT, the camera detectors rotate around the patient in a circular or elliptical fashion, collecting a series of planar projection images at regular angular intervals (eFig. 13-16). The 3D distribution of radioactivity in the myocardium is then “reconstructed” by computer from the 2D projections. Gated SPECT is a further refinement of the process, whereby the projection images are acquired in specific phases of the cardiac cycle based on ECG triggering (so-called “gating”). With gated SPECT, myocardial perfusion and function can be evaluated.
Schematic representation of ECG-gated SPECT imaging and acquisition. (From Berman DS, Hachamovitch R, Shaw LJ, et al. Nuclear cardiology. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:545.)
Although stress perfusion imaging with 99mTc- or 201Tl-labeled compounds offers greater sensitivity and specificity than standard exercise electrocardiography for the detection of ischemia (eFig. 13-17),43 they are considerably more expensive and expose the patient to ionizing radiation. As a result, they should be used judiciously. Stress perfusion scans are particularly useful in patients with an underlying ECG abnormality that precludes its accurate interpretation during conventional exercise stress testing, such as patients with a bundle-branch block, previous myocardial infarction, baseline ST segment abnormalities, or taking medications that affect the ST segments (e.g., digoxin).44 When compared with standard exercise testing, nuclear perfusion imaging also provides more accurate anatomic localization of ischemia and quantitation of the extent of ischemia.45
Detection of CAD by exercise SPECT: pooled analysis of 33 studies (≥50% stenoses). Sensitivity, specificity, and normalcy rates from a pooled analysis of 33 studies in the literature using exercise single-photon emission computed tomography (SPECT) myocardial perfusion imaging for detection of coronary artery disease (CAD). Note that the normalcy rate, which is derived from the percentage of patients with normal scans who have less than 5% pretest likelihood of CAD, is shown. This normalcy rate of 91% is significantly higher than specificity.43
Tc scanning is used for the evaluation of cardiac function, myocardial perfusion, and the presence of infarcted myocardium.43,46
Radionuclide ventriculography—so-called multigated acquisition (MUGA) scanning—is a noninvasive method for determining right and left ventricular systolic function, detecting intracardiac shunting, estimating ventricular volumes, and assessing regional wall motion. For the most part, it has been replaced by other noninvasive techniques (i.e., echocardiography and MRI) that provide similar information without ionizing radiation. Nonetheless, it may be performed in the subject in whom suitable echocardiographic images cannot be obtained or who is unable to undergo an MRI study.
During radionuclide ventriculography, 99mTc-pertechnate is introduced into the bloodstream and imaged as it circulates through the heart. The resulting images of the blood pool in the cardiac chambers are analyzed by computer to calculate right and left ventricular ejection fractions.
The radioactive marker can be introduced to the patient’s blood in vivo or in vitro. With the in vivo method, stannous (tin) ions are injected IV, after which an IV injection of 99mTc-pertechnate labels the red blood cells in vivo. With the in vitro method, an aliquot of the patient’s blood is withdrawn, to which the stannous ions and 99mTc-pertechnate are added, after which the labeled blood is reinfused into the patient. The stannous chloride is given to prevent the Tc from leaking from the red blood cells.
Once the radiolabeled red blood cells are circulating, the patient is placed under a gamma camera, which detects the radioactive 99mTc. As the images are acquired, the patient’s heartbeat is used to “gate” the acquisition, resulting in a series of images of the heart at various stages of the cardiac cycle.
Depending on the objectives of the test, the operator may decide to perform a resting or a stress MUGA. During the resting MUGA, the patient lies stationary, whereas during a stress MUGA, the patient is asked to exercise on a supine bicycle ergometer as images are acquired. The stress MUGA allows the operator to assess cardiac performance at rest and during exercise. It is usually performed to assess the presence of suspected CAD.
Infarct-avid radionuclides, such as technetium pyrophosphate (99mTc-PYP), are used to assess the presence and extent of infarcted myocardium. Since 99mTc-PYP binds to calcium that is deposited in the infarcted area, it is known as hot-spot scanning. Hot spots appear where necrotic myocardial tissue is present, which may occur with recent myocardial infarction, myocarditis, myocardial abscesses, and myocardial trauma. Additionally, 99mTc-PYP uptake has been observed on occasion in patients with unstable angina, severe diabetes mellitus, and cardiac amyloidosis.
Uptake of 99mTc-PYP by necrotic myocardium is first detectable about 12 hours after the onset of myocardial infarction, with a peak intensity of 99mTc-PYP at 48 hours. Washout occurs over 5 to 7 days, so 99mTc-PYP is a useful late marker of infarction, especially in the patient suspected of having a painless (e.g., “silent”) infarction.
Pharmacologic Stress Testing
In the patient undergoing myocardial perfusion imaging for the evaluation of CAD, exercise stress is preferred over pharmacologic stress, since it allows an assessment of the patient’s exercise capacity, symptoms, ST segment changes, and level of exertion that results in ischemia. In the individual who is unable to exercise adequately (because of orthopedic limitations or inability to ambulate), a pharmacologic stress test can be performed in conjunction with various imaging modalities, such as Tl planar scanning, SPECT, MRI, or echocardiography.43–45
Vasodilator Stress Testing
The vasodilators—dipyridamole, adenosine, and regadenoson—are the preferred pharmacologic stress agents for myocardial perfusion imaging. Following the administration of one of these, blood flow increases threefold to fivefold in undiseased coronary arteries and minimally, or not at all, in arteries with flow-limiting stenoses. Since radioisotope uptake by the myocardium is directly related to coronary arterial blood flow, the region of myocardium perfused by an artery with a flow-limiting stenosis appears as a “cold spot” on the nuclear perfusion scan following vasodilator administration.
Adenosine and regadenoson dilate coronary arteries by binding to specific adenosine receptors on smooth muscle cells in the coronary arterial media. Dipyridamole causes coronary vasodilation by blocking the cellular uptake of adenosine, thereby increasing the extracellular adenosine concentration. Currently, adenosine and regadenoson are used more often than dipyridamole because of their rapid onset and termination of action. Since methylxanthines (i.e., caffeine and theophylline) block adenosine binding and can interfere with the vasodilatory effects of these agents, foods and beverages containing caffeine should not be ingested during the 24 hours before their administration.
During a vasodilator stress test, the patient normally manifests a modest increase in heart rate, a fall in blood pressure, and no or minimal electrocardiographic changes. Chest pain, shortness of breath, flushing, and dizziness occur commonly during vasodilator administration. As a result, the symptomatic, hemodynamic, and electrocardiographic responses to vasodilator administration do not provide insight into the presence or absence of CAD.
Dipyridamole is administered IV at 0.142 mg/kg/min for 4 minutes, with the maximal effect occurring 3 to 4 minutes after the infusion has ended. Adenosine is administered IV at 0.140 mg/kg/min for 6 minutes, with the maximum effect occurring 30 seconds after the infusion is completed. Regadenoson has a 2- to 3-minute biologic half-life—as compared with adenosine’s 30-second half-life—so it is administered as a 0.4 mg IV bolus (given in less than 10 seconds) followed immediately by a saline flush. At the end of the dipyridamole infusion or regadenoson injection or 3 minutes after initiation of adenosine infusion, Tl is administered, after which nuclear imaging follows immediately and can be repeated 24 hours later to distinguish scarred from hibernating myocardium.
Since these agents may induce severe bronchospasm in subjects with a history of asthma, they should not be administered to such individuals. With adenosine and regadenoson, advanced AV block may occur. Fortunately, severe side effects are rare, occurring in only 1 in 10,000 patients receiving these agents, and they usually are reversed with IV aminophylline, 75 to 125 mg.
In the patient referred for stress testing to assess the presence of CAD, pharmacologic stress is indicated for those unable or with a contraindication to exercise. This includes patients with (a) a chronic debilitating illness, such as pulmonary, liver, or kidney disease; (b) older age and decreased functional capacity; (c) limited exercise capacity due to injury, arthritis, orthopedic problems, neurologic disorders, myopathic diseases, or peripheral vascular disease; (d) an acute coronary syndrome; (e) postoperative state; and (f) β-blocker or other negative chronotropic agents that interfere with the subject’s ability to achieve an adequate increase in heart rate in response to exercise.
Pharmacologic stress testing has a similar sensitivity and specificity to exercise stress testing (eFig. 13-18). In an analysis of 17 studies of almost 2,000 patients, pharmacologic stress testing had a sensitivity of 89% and a specificity of 75% for detecting ischemic heart disease.43 As with routine stress testing, the sensitivity and specificity are affected by the prevalence and pretest likelihood of CAD in the population being studied.
Detection of CAD by vasodilator SPECT (stenoses of 50% or greater). Sensitivity and specificity for detection of coronary artery disease (CAD) by vasodilator stress. The definition of a significant lesion was 50% or greater stenosis by coronary angiography. These data represent a pooled analysis from the literature.43 (SPECT, single-photon emission computed tomography.)
Dobutamine Stress Testing
The patient who is not a candidate for vasodilator stress testing (because of a history of bronchospasm, advanced AV block, or recent caffeine ingestion) or does not desire infusion of a radiopharmaceutical may undergo a dobutamine stress test with echocardiographic imaging. Dobutamine, a synthetic catecholamine, is an inotropic agent that increases heart rate and myocardial contractility, thereby increasing myocardial oxygen demands. In regions of the heart where myocardial oxygen supply is insufficient to meet the increased demands (because of a flow-limiting stenosis in the coronary artery supplying that region), ischemia develops and causes regional abnormalities in contraction that may be observed with echocardiography.
When used for stress testing, dobutamine is infused at 5 mcg/kg/min for 3 minutes, followed by infusions of 10, 20, 30, and 40 mcg/kg/min each at 3 minutes until a target heart rate is achieved. To achieve a further increase in myocardial oxygen demands, atropine (0.5 to 1 mg) may be injected to augment the dobutamine-induced increase in heart rate, and handgrip exercise may be performed concomitantly to achieve an increase in blood pressure. The ECG and blood pressure are monitored throughout the test, and echocardiographic images are obtained during the last minute of each dobutamine dose infusion and during recovery. For the patient with suboptimal echocardiographic images, dobutamine stress testing may be combined with radionuclide perfusion imaging, in which case Tl is injected 2 to 3 minutes before completion of the dobutamine infusion.
Since β-blocker and calcium channel blocker therapy may interfere with the heart rate response to dobutamine, it is recommended that they be discontinued before the test. Dobutamine stress testing is relatively well tolerated, with ventricular irritability occurring rarely (0.05%). The dobutamine infusion is discontinued with the appearance of severe chest pain, extensive new wall motion abnormalities, ST segment changes suggestive of severe ischemia, tachyarrhythmias, or a symptomatic fall in systemic arterial pressure. β-Blockers can be used to reverse most adverse effects if they persist. Dobutamine stress testing is contraindicated in patients with aortic stenosis, uncontrolled hypertension, and severe ventricular arrhythmias.
A review of 37 studies of 3,280 patients reported that dobutamine stress testing had a sensitivity of 82% and a specificity of 84% for detecting CAD (eFig. 13-19). The sensitivity was highest in subjects with three-vessel CAD (92%).47
Sensitivity and specificity for exercise and dobutamine echocardiography. Note a slightly higher sensitivity for exercise echo compared with dobutamine echo.47
Computed tomographic (CT) scanning is becoming increasingly popular as a primary screening procedure in the evaluation of individuals with suspected or known CVD, since it provides similar information as other diagnostic modalities, such as echocardiography and catheterization, yet it is less invasive than the latter.48–50 In recent years, technologic advances have enhanced CT’s definition and spatial resolution of cardiac structures, such as coronary arteries, valves, pericardium, and cardiac masses. In addition, CT provides an accurate measurement of chamber volumes and sizes as well as wall thickness.
CT scanners produce images by rotating an x-ray beam around a circular gantry (e.g., opening), through which the patient advances on a moving couch. Two types of CT scanners are used for cardiac imaging: electron beam computed tomography (EBCT) and mechanical CT.50 With EBCT, the electron x-ray tube remains stationary, and the electron beam is swept electronically around the patient. With mechanical or conventional CT, the x-ray tube itself rotates around the patient, and the use of multirow detector system rays (i.e., multislice CT) allows acquisition of up to 320 simultaneous images, each 0.5 mm in thickness. With either type of CT, the image acquisition is gated to the ECG to minimize radiation exposure, and cardiac images are obtained at end inspiration (i.e., during a breath hold) to minimize artifact caused by cardiac motion.
Since EBCT has no moving parts, it requires a shorter image acquisition time and exposes the patient to less radiation when compared with conventional CT (less than 1 rad [10 mGy] vs. 15 rad [150 mGy], respectively). With EBCT, image resolution is sufficient to assess global and regional ventricular function and coronary anatomy, but it is insufficient to provide an accurate assessment of the presence and severity of CAD. However, it can reliably detect the presence and extent of coronary arterial calcification, which is expressed as a coronary artery calcium (CAC) score in Agatston units (eFig. 13-20). Although the presence of coronary arterial calcification correlates with the total atherosclerotic plaque burden in epicardial coronary arteries, it does not predict the presence or location of flow-limiting (greater than 50% luminal diameter narrowing) coronary arterial stenoses, nor does the lack of coronary arterial calcium exclude the presence of atherosclerotic plaque.48–50
CT scans of the left coronary artery in two asymptomatic men. Two asymptomatic men, 51 and 81 years of age, underwent coronary artery calcium (CAC) imaging with multidetector CT. There is calcification of the left main and proximal left anterior descending coronary arteries in both the younger patient (A) and the older patient (B). The CAC score for the younger man, although relatively low at 80, places him in the 85th percentile for severity of CAC for men in his age group. The older man’s CAC score is higher, at 1,054, but the severity of his CAC relative to that for men in his age group is lower—in the 70th percentile. (From Bonow RO. Should coronary calcium screening be used in cardiovascular prevention strategies? N Engl J Med 2009;361:990–997. Copyright © 2009 Massachusetts Medical Society. All rights reserved.)
The distribution of calcification scores in populations of individuals without known heart disease has been studied extensively. These studies have shown that the amount of coronary arterial calcification increases with age, and men typically develop calcification 10 to 15 years earlier than women.50 Coronary arterial calcification is detectable in the majority of asymptomatic men over 55 years of age and women over 65 years of age. The person who undergoes coronary calcium screening with EBCT receives a score in Agatston units as well as a calcium score percentile, with which his/her score is compared with a population of subjects of similar age and gender.
Unlike EBCT, multislice CT has sufficient resolution to visualize the coronary arteries (eFig. 13-21). To accomplish this, radiographic contrast material is administered IV, and a β-blocker is given to slow the heart rate to less than 70 beats/min in order to minimize motion artifact. Compared with conventional coronary angiography, cardiac CT has a sensitivity of 85%, a specificity of 90%, a positive predictive value of 91%, and a negative predictive value of 83% for detecting or excluding a coronary arterial stenosis of 50% or more luminal diameter narrowing.51 It has limited diagnostic utility in patients with extensive coronary arterial calcification or a rapid heart rate, due to artifacts caused by high-density calcified coronary arterial stenoses or cardiac motion, respectively. Vessels with a luminal diameter less than 1.5 mm cannot be assessed reliably with cardiac CT, since the resolution is insufficient. Recent advances in cardiac CT technology have enabled the assessment of the physiologic significance of coronary arterial stenoses using myocardial CT perfusion imaging.52
Sixteen-slice MDCT in a 49-year-old man with chest pain. (1a) Coronary angiography showing a severe stenosis in the left anterior descending (LAD) artery. (1b) MDCT axial slice visualizing high-grade stenosis (arrow) and calcification. (1c) MDCT three-dimensional volume-rendering technique showing the LAD stenosis. (1d) MDCT curved multiplanar reconstruction of the LAD. (2a) Coronary angiography of the right coronary artery (RCA), which is normal. (2b) MDCT volume-rendering technique of RCA. (Ao, aorta; DB, diagonal branch; LV, left ventricle; MDCT, multidetector computed tomography; PT, pulmonary trunk; VB, ventricular branch.) (Reproduced with permission from Berman DS, Hachamovitch R, Shaw LJ, et al. Roles of nuclear cardiology, cardiac computed tomography, and cardiac magnetic resonance: Assessment of patients with suspected coronary artery disease. J Nucl Med 2006;47:74–82.)
Independent of its use in assessing coronary arteries, cardiac CT often is used in the subject with suspected aortic dissection, in whom its accuracy in detecting dissection is greater than 90%. In the patient with possible constrictive pericarditis, the pericardium can be evaluated for thickening and calcification. In the patient with a possible cardiac mass, CT scanning allows one to assess the size and location of the mass, and tissue density differentiation may aid in its characterization. Cardiac CT can be used to calculate left ventricular volumes, ejection fraction, and mass, and these measurements obtained with CT scanning are superior in accuracy and reproducibility to those obtained with echocardiography or angiography. CT scans allow visualization of congenital heart defects. Although MRI may provide similar information without exposing the patient to ionizing radiation, many patients have contraindications to MRI (i.e., those with an implanted metallic device). In such patients, cardiac CT is an alternative method for visualizing cardiac anatomy.
Positron Emission Tomography
Positron emission tomography (PET) is a relatively new modality for diagnostic imaging in patients with suspected or known CVD. Among imaging techniques, it is unique in its ability (a) to provide quantitative imaging with high temporal resolution; (b) to image a large number of physiologically active radiotracers; and (c) to apply tracer kinetic principles so that in vivo imaging can be performed. With PET, myocardial metabolic activity, perfusion, and viability can be assessed.42,43 Using appropriate positron-emitting biologically active tracers, PET can measure regional myocardial uptake of exogenous glucose and fatty acids, quantitate free fatty acid metabolism, ascertain myocardial energy substrates, and evaluate myocardial chemoreceptor sites.
In the fasting state (i.e., low serum glucose and insulin concentrations), fatty acids are the preferred energy source of the myocardium. Following the ingestion of carbohydrate, serum glucose and insulin concentrations increase, and glucose becomes the preferred myocardial fuel. Glucose also is the major myocardial fuel during ischemia, since ischemia impairs mitochondrial fatty acid oxidation. Using positron-emitting isotopes, such as oxygen-15 (15O-oxygen), carbon-11 (11C-palmitate or 11C acetate), and fluoride-18 (18F-fluorodeoxyglucose), myocardial oxygen consumption and substrate utilization can be measured, from which ischemic and nonischemic regions of the heart can be identified.42 PET usually is used in conjunction with pharmacologic stress testing to provoke ischemia, with images obtained before and after stress.
Tracers such as rubidium-82 (82Rb) and nitrogen-13 (13N) are retained in the myocardium in proportion to blood flow. PET imaging with these agents allows one to measure myocardial blood flow at rest and during pharmacologically induced hyperemia. Thus, PET can be used to assess the physiologic significance of coronary arterial stenoses, which is useful when attempting to determine if a luminal diameter narrowing of intermediate severity (50% to 70%) is causing ischemia.
In the patient with noncontractile myocardium, PET is considered to be the “gold standard” technique for distinguishing infarcted myocardium from chronically ischemic, metabolically active myocardium that has the potential to regain function if perfusion is restored (so-called “hibernating myocardium”).42 Myocardial infarction and ischemia can be distinguished by analysis of PET images of the glucose analogue 8F-fluorodeoxyglucose (FDG), which is injected after glucose administration, and the perfusion tracer 13N-ammonia. Regions that show a concordant reduction in myocardial blood flow and FDG uptake (“flow–metabolism match”) are considered to be irreversibly injured, whereas regions in which FDG uptake is relatively preserved or increased despite a perfusion defect (“flow–metabolism mismatch”) are considered to be ischemic (eFig. 13-22). This approach more accurately predicts recovery of regional function after revascularization than does SPECT imaging. The magnitude of improvement in heart failure symptoms after revascularization in patients with left ventricular dysfunction correlates with the preoperative extent of FDG “mismatch.”53
Patterns of myocardial perfusion (upper panel) and metabolism (with 18F-FDG; lower panel). A. Normal myocardial perfusion and metabolism. B. Severely reduced myocardial perfusion in the anterior wall associated with a concordant reduction in 18F-FDG uptake (arrow), corresponding to a match. C. Mildly reduced perfusion in the lateral and posterior lateral wall associated with a segmental increase in glucose metabolism (mismatch). D. Severely reduced myocardial perfusion in the lateral wall with a segmental increase in 18F-FDG uptake (arrow), reflecting a perfusion metabolism mismatch. (From Schelbert HR. Positron emission tomography for the noninvasive study and quantitation of myocardial blood flow and metabolism in cardiovascular disease. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, eds. Hurst’s the Heart, 12th ed. New York: McGraw-Hill, 2004:675.)
The main strengths of PET compared with SPECT are its superior spatial resolution and ability to assess myocardial viability accurately.42,43 The limited availability of PET scanners and the need for a cyclotron on site are its main limitations.
Cardiac Catheterization and Angiography
Cardiac catheterization plays a pivotal role in the evaluation of patients with suspected or known cardiac disease; in addition, it has become an important therapeutic alternative to cardiac surgery in many patients who require nonmedical therapy.
Diagnostic cardiac catheterization is appropriate under several conditions. First, it is often performed to confirm or to exclude the presence of a cardiac condition that is suspected from the patient’s history, physical examination, or noninvasive evaluation. In such a circumstance, it allows an assessment of the presence and severity of cardiac disease. For example, in a subject with progressive angina pectoris or a positive exercise stress test, coronary angiography allows the physician to visualize the coronary arteries sufficiently to assess the presence and extent of CAD. Second, catheterization is often helpful in the patient with a confusing or difficult clinical presentation in whom the noninvasive evaluation is inconclusive. For instance, a hemodynamic evaluation or coronary angiography may be useful in the patient with unexplained dyspnea. Third, data obtained at catheterization may provide prognostic information that is helpful in guiding therapy. Such is the case, for example, in the patient with cardiomyopathy, in whom the hemodynamic data obtained at catheterization are used to guide medical therapy and to assess the need for and timing of cardiac transplantation.
The only absolute contraindication to catheterization is the refusal of a mentally competent subject to provide informed consent. Relative contraindications (eTable 13-7) mostly involve conditions in which the risks of the procedure are increased or the information obtained from it is potentially unreliable. In these circumstances, the benefits of having the data that are obtained at catheterization must be weighed against the procedure’s increased risks. Catheterization usually is not performed in the patient who refuses therapy for the condition for which diagnostic catheterization is recommended.
eTable 13-7 Relative Contraindications to Cardiac Catheterization |Favorite Table|Download (.pdf)
eTable 13-7 Relative Contraindications to Cardiac Catheterization
- Decompensated heart failure (e.g., pulmonary edema)
- Uncontrolled ventricular irritability
- Uncontrolled systemic arterial hypertension
- Acute or severe renal insufficiency
- Difficulty with vascular access
- Electrolyte imbalance (i.e., hypokalemia or hyperkalemia)
- Digitalis intoxication
- Active infection or febrile illness
- Uncorrected bleeding diathesis
- Severe anemia
- Active bleeding from internal organ
- Severe allergy to radiographic contrast material
- Mental incompetence
Because catheterization is an invasive procedure, its performance is associated with major and minor risks. The incidence of a major complication (death, myocardial infarction, or cerebrovascular accident) during or within 24 hours of diagnostic catheterization is 0.2% to 0.3%. Deaths, which occur in 0.1% to 0.2% of patients, may be caused by perforation of the heart or great vessels, cardiac arrhythmias, acute myocardial infarction (AMI), or anaphylaxis to radiographic contrast material.
Numerous minor complications may cause morbidity but exert no effect on mortality. Local vascular complications occur in 0.5% to 1.5% of patients. The injection of radiographic contrast material occasionally is associated with allergic reactions of varying severity, and a rare individual has anaphylaxis. Of patients with a known allergy to contrast material, only about 15% have an adverse reaction with its repeat administration, and most of these reactions are minor (e.g., urticaria, nausea, vomiting). In most patients with a previous allergic reaction to radiographic contrast material, angiography can be performed safely, but premedication with glucocorticosteroids and antihistamines and the use of a different contrast material usually are recommended. Use of excessive quantities of radiographic contrast material may result in renal insufficiency, particularly in patients with preexisting renal dysfunction and diabetes mellitus.
Cardiac catheterization is generally performed with the patient in the fasting state and mildly sedated. Anticoagulants are discontinued before the procedure (warfarin for several days, heparin for 4 to 6 hours). Cardiac catheterization requires vascular access, which is usually obtained percutaneously via the femoral, brachial, or radial vessels.
With the percutaneous approach, the area overlying the vessel is aseptically prepared and locally anesthetized. The vessel is punctured with a needle, through which a flexible metal wire is advanced into the vessel’s lumen, over which a sheath with a sideport extension is advanced into the vessel. The sideport extension allows continuous monitoring of arterial pressure (through an arterial sheath) or infusion of fluids (through a venous sheath) as catheters are advanced through the sheath to the heart. When the procedure is completed, the catheters and sheaths are removed, after which local pressure is applied or a closure device is used to achieve hemostasis. If the femoral approach is used, the patient remains at bedrest for 2 to 8 hours to minimize the chance of hemorrhage. With the radial and brachial approaches, bedrest following sheath removal is not necessary.
During routine right heart catheterization, measurements of pressures and blood oxygen saturations in the vena cavae, right atrium, right ventricle, pulmonary artery, and pulmonary capillary wedge (PCW) position can be performed, and cardiac output can be quantified (eTable 13-8 lists normal values). The measurement of right-sided pressures helps the physician to evaluate the severity of tricuspid or pulmonic stenosis, to assess the presence and severity of pulmonary hypertension, and to calculate pulmonary vascular resistance. In the absence of pulmonary vein stenosis (a rare condition), the PCW pressure accurately reflects the left atrial pressure. Occasionally angiography is performed to define right-sided anatomic abnormalities or to evaluate the severity of right-sided valvular regurgitation.
eTable 13-8 Normal Hemodynamic Values |Favorite Table|Download (.pdf)
eTable 13-8 Normal Hemodynamic Values
|Cardiac index (L/min/m2)||2.6–4.2|
|Stroke volume index (mL/m2)||35–55|
|Pressures (mm Hg)|
|Left atrium (PCW)|
|Systemic vascular resistance|
|Pulmonary vascular resistance|
|Oxygen consumption (mL/min/m2)||110–150|
|AV O2 difference (mL/dL)||3–4.5|
With left heart catheterization, mitral and aortic valvular function, left ventricular pressures and function, systemic vascular resistance, and coronary arterial anatomy can be assessed. To perform angiography or to measure the pressure in the left ventricle, a catheter is usually advanced retrograde across the aortic valve.
The blood flow measurement most often performed during catheterization is the quantitation of cardiac output. This variable allows an assessment of overall cardiovascular function, vascular resistances, valve orifice areas, and valvular regurgitation. In the catheterization laboratory, the three common methods of measuring cardiac output are the Fick principle, the indicator dilution technique, and angiography.
The Fick principle is based on the fact that when a substance is consumed by an organ, its concentration is the product of blood flow to the organ and the substance’s arteriovenous difference across the organ. Using the lungs as the organ of interest and oxygen as the substance, one can calculate pulmonary blood flow (e.g., cardiac output) using the following formula:
Oxygen consumption is measured by analyzing the patient’s exhaled air, and the arteriovenous oxygen difference is calculated by measuring the oxygen content in a blood sample procured from the aorta and the pulmonary artery.
With indicator dilution, a known amount of indicator is injected as a bolus into the circulation and allowed to mix completely in the blood, after which its concentration is measured. A time–concentration curve is generated, and a minicomputer calculates the cardiac output from the area of the inscribed curve. The most widely used indicator for the measurement of cardiac output is cold solution. A balloon-tipped, flow-directed, polyvinyl chloride catheter (a so-called “Swan-Ganz catheter”) with a thermistor at its tip and an opening 25 to 30 cm proximal to the tip is inserted into a vein and advanced to the pulmonary artery, so that the proximal opening is located in the vena cavae or right atrium and the thermistor is in the pulmonary artery. A known amount of cold fluid is injected through the proximal port; it mixes completely in the right ventricle and causes a change in blood temperature, which is detected by the thermistor. The thermodilution method is relatively inexpensive and easy to perform, and does not require arterial sampling or blood withdrawal.
From the left ventriculogram, the volume of blood ejected with each heartbeat (stroke volume) can be determined. It is then multiplied by the heart rate, yielding the angiographic cardiac output. The measurement of cardiac output by the angiographic method is potentially erroneous in patients with extensive segmental wall motion abnormalities or misshapen ventricles, in whom the determination of stroke volume may be inaccurate.
One of the most important functions of cardiac catheterization is to measure intracardiac pressures. Once a catheter is positioned in a cardiac chamber, it is connected through fluid-filled, stiff, plastic tubing to a pressure transducer, which transforms the pressure signal into an electrical signal that is recorded. During catheterization, pressures are usually measured directly from each of the cardiac chambers: right atrium, right ventricle, pulmonary artery, ascending aorta, and left ventricle. Because the left atrial pressure is transmitted to the pulmonary capillaries, it can be recorded “indirectly” as the pulmonary capillary “wedge” pressure. In addition to measuring pressures from each cardiac chamber, pressures from certain chambers are examined simultaneously to identify or to exclude a gradient between them indicative of valvular stenosis.
The resistance of a vascular bed is calculated by dividing the pressure gradient across the bed by the blood flow through it. Thus:
Because a properly obtained PCW pressure is similar to left atrial pressure, it can be substituted for it in the above equation. These formulae express resistances in arbitrary resistance units. Most often, these values are multiplied by 80 to express them in metric units of dyne/s/cm5. Normal values are displayed in eTable 13-8.
An elevated systemic vascular resistance is often present in the patient with systemic arterial hypertension. It may also be observed in patients with a reduced forward cardiac output and compensatory arteriolar vasoconstriction (often seen in patients with heart failure). Conversely, systemic vascular resistance may be reduced in patients with arteriolar vasodilation (due, e.g., to sepsis) or those with an increased cardiac output (due, e.g., to an arteriovenous fistula, severe anemia, fever, or thyrotoxicosis). An elevated pulmonary vascular resistance often is observed in patients with primary lung disease, pulmonary vascular disease, and a greatly elevated pulmonary venous pressure resulting from left-sided myocardial or valvular dysfunction.
During angiography, radiographic contrast material is injected into the cardiovascular structure of interest, and the images are digitally recorded and stored on a computer-accessible medium (i.e., CD-ROM, DVD, external memory drives, etc.). The resultant angiogram permits the study of cardiac structures in real time, in slow motion, or by single frame.
With angiography of the left ventricle, global and segmental left ventricular function, left ventricular volumes and ejection fraction, and the presence and severity of mitral regurgitation can be assessed. A segment of the left ventricular wall with reduced systolic motion is said to be hypokinetic, a segment that does not move is akinetic, and a segment that moves paradoxically during systole is dyskinetic.
Selective coronary angiography is usually performed to determine the presence and severity of fixed, atherosclerotic CAD and to guide subsequent percutaneous (e.g., angioplasty with or without stent placement) or surgical (e.g., bypass grafting) therapy. Under fluoroscopic guidance, the ostia of the native right and left coronary arteries or bypass grafts are engaged selectively with a catheter, and radiographic contrast material is injected manually during digital image recording. Because atherosclerotic coronary arterial stenoses are often eccentric and the coronary vessels often overlap one another, images are obtained in multiple obliquities, thereby ensuring a complete angiographic assessment of each arterial segment.
Coronary angiography provides radiographic images of the coronary lumina but does not visualize the actual arterial walls. A stenosis is present when a discrete reduction in luminal diameter is noted, and its severity is assessed by comparing it with presumably normal adjacent segments of the same artery. Thus, if atherosclerosis is diffuse and involves the entire artery, angiography may lead to an underestimation of the severity of disease.
Aortography is accomplished with the rapid injection of radiographic contrast material into the aorta. With proximal aortography, the severity of aortic valve regurgitation, the location of saphenous vein bypass grafts, and the anatomy of the proximal aorta and its branches can be assessed. Distal aortography usually is performed to assess the presence of vascular abnormalities, such as aneurysm, dissection, intraluminal thrombus, or branch vessel stenosis.
Valvular Stenosis or Regurgitation
In patients with valvular stenosis, the effective valve orifice area can be calculated with data obtained during catheterization using principles of standard fluid dynamics. The pressures on either side of a stenotic valve are recorded simultaneously, and the flow across it is measured, after which the valve area is calculated.
The presence and severity of valvular regurgitation may be evaluated qualitatively by observing the amount of radiographic contrast material that regurgitates in a retrograde direction across the valve. The magnitude of regurgitation is estimated as trivial (1+), mild (2+), moderate (3+), or severe (4+).
Through a long sheath positioned across the tricuspid valve, a bioptome can be advanced to obtain small pieces (1 to 2 mm in diameter) of myocardial tissue from the right ventricular side of the interventricular septum. Endomyocardial biopsy is used most often to detect transplant rejection and to monitor immunosuppressive therapy in survivors of cardiac transplantation. Less commonly, it is undertaken in the patient with suspected infiltrative cardiomyopathy or active inflammation of the heart (e.g., myocarditis). In experienced hands, complications are uncommon: cardiac perforation occurs in only 0.3% to 0.5%, and the procedure-related mortality is only 0.05%.
Although coronary angiography can identify the presence of a coronary arterial stenosis, it does not provide information regarding its functional significance (i.e., whether it potentially may cause myocardial ischemia). The measurement of fractional flow reserve (FFR) is performed to assess the physiologic significance of a stenosis.24 With this technique, the intraluminal pressure is measured proximal and distal to the stenosis during maximal blood flow (i.e., hyperemia). FFR is defined as the mean pressure distal to the stenosis relative to the pressure proximal to the stenosis. For example, an FFR of 0.50 means that a 50% drop in pressure across the stenosis was noted.
During coronary angiography, a catheter is inserted into the ostia of the coronary artery, through which a wire with a small sensor transducer positioned at its tip is advanced past the stenosis. The mean pressure distal to the stenosis is compared with the mean pressure proximal to it (measured through the catheter) both at rest and after hyperemia (which is induced by injecting a vasodilator, such as adenosine or papaverine). FFR is calculated as the ratio of mean arterial pressure distal to the stenosis and mean aortic pressure under conditions of maximal myocardial hyperemia (eFig. 13-23). An FFR of 1 is normal. An FFR below 0.75 to 0.80 is associated with myocardial ischemia. At this time, it is uncertain if coronary revascularization should be recommended or performed based on an abnormal FFR alone (in the absence of symptoms or other well-established indications).
Simultaneous phasic and mean aortic pressure (Pa, shown in red) and distal coronary arterial pressure (Pd, shown in green) recordings at rest and during maximal hyperemia induced by an IV infusion of adenosine. Fractional flow reserve (FFR) is calculated as the ratio of mean Pd and Pa during maximal hyperemia, which in this case is 47/80 or 0.58. (Reproduced with permission from Pijls NHJ, Sels JE. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012;59:1045–1057.)
Sidebar: Clinical Controversy...
In the patient with minimal or no symptoms, it is unknown if the presence of myocardial ischemia is an indication for coronary revascularization.
Intravascular ultrasound (IVUS) employs a small catheter-mounted ultrasound transducer to provide detailed images of the coronary arterial wall and lumen. In contrast to coronary angiography, which does not visualize the actual arterial wall, IVUS provides quantitative information from within the vessel regarding vessel diameter, circumference, luminal diameter, plaque volume, and percent narrowing. Qualitative information regarding the amount of plaque stenosis, plaque composition (e.g., calcific, fibrous, or fatty plaque), and the presence of plaque versus thrombus, thrombus versus tumor, and aneurysm and hematoma can be provided by IVUS. IVUS is used as a therapeutic adjunct to percutaneous coronary intervention (PCI), atherectomy, stent or graft placement, and fibrinolysis, although its routine use with these modalities may not be justified. These combination procedures may be monitored in real time as the procedure (e.g., atherectomy) is being performed. In recent studies, IVUS has been helpful in the evaluation of the progression or regression of atherosclerosis. Current trials are testing medications for atherosclerosis regression and changes in plaque morphology.
Intravascular optical coherence tomography provides high-resolution, cross-sectional images of tissue with an axial resolution of 10 μm and a lateral resolution of 20 μm. Optical coherence tomographic images of human coronary atherosclerotic plaques are much more structurally detailed than those obtained with IVUS. Clinically, the detection of thin fibrous caps (vulnerable atheromas) (less than 65 μm) is below the resolution of the current 40-MHz IVUS (100 to 200 μm). A summary of testing modalities used in cardiovascular medicine is provided in 57522903 and 57522905.