I.INTRODUCTION. Nuclear cardiology has an integral role in the noninvasive detection of coronary artery disease (CAD), assessment of myocardial viability, and stratification of risk. In addition, novel imaging protocols have been instituted to detect and risk stratify patients with certain cardiomyopathies. With respect to CAD, nuclear stress testing imparts improved sensitivity and specificity over standard exercise stress testing. For example, the average sensitivity and specificity of single-photon emission computed tomography (SPECT) with technetium 99m have been reported to be 90% and 74%, respectively—although the exact performance characteristics depend on the prevalence of the disease in the population being studied. Nuclear imaging can provide functional and prognostic information that is quantifiable, reproducible, and readily obtainable in diverse patient populations.
II.INDICATIONS (Table 46.1)
TABLE 46.1 Appropriate Indications for Myocardial Perfusion Imaging—Based on the ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 Appropriate Use Criteria for Cardiac Radionuclide Imaging |
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Patient Group |
Condition |
Imaging Technique |
ER patient with chest pain |
For risk stratification in patient with possible ACS. Initial serum markers and enzymes. ECG is nondiagnostic |
Rest perfusion imaging (with ECG gating, if possible) |
For CAD diagnosis in patient with possible ACS and nondiagnostic ECG. Negative serum markers and enzymes or normal rest perfusion scan |
Same-day rest/stress (ECG-gated) myocardial perfusion imaging |
|
Acute MI/unstable angina |
Assessment of LV function |
Rest myocardial perfusion imaging with ECG gating (rest gated radionuclide angiography is an alternative option) |
ST-elevation MI |
Measurement of infarct size and residual viable myocardium, in an unrevascularized asymptomatic stable patient after completion of the infarct |
Rest myocardial perfusion imaging with ECG gating or with stress perfusion imaging with ECG gating |
Thrombolysis without coronary angiogram, to identify inducible ischemia and myocardium at risk |
Rest and stress myocardial perfusion imaging, with ECG gating whenever possible |
|
Non–ST-elevation MI/unstable angina |
In an unrevascularized stable asymptomatic patient after completion of the infarct, to determine the extent and severity of inducible ischemia, either in the distribution of the “culprit” vessel or in remote myocardium |
Rest and stress myocardial perfusion imaging, with ECG gating whenever possible |
In individuals whose angina is stabilized on medical therapy or in whom the diagnosis is uncertain, to identify the extent and severity of inducible ischemia |
Rest and stress myocardial perfusion imaging, with ECG gating whenever possible |
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To assess the functional significance of a coronary stenosis on angiography |
Rest and stress myocardial perfusion imaging |
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CAD diagnosis in an individual with an intermediate probability of disease and/or risk stratification in someone with an intermediate or high likelihood of disease and able to exercise to 85% MPHR or more |
Those with preexcitation, LVH, on digoxin, or >1 mm ST-segment depression on resting ECG |
Rest and exercise stress myocardial perfusion imaging, with ECG gating whenever possible |
Individuals with left bundle branch block or ventricular-paced rhythm |
Rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
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Patients with an intermediate- or high-risk Duke treadmill score |
Rest and exercise stress myocardial perfusion imaging, with ECG gating whenever possible |
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In an individual with prior abnormal myocardial perfusion scan and new or worsening symptoms |
Repeat rest and exercise stress myocardial perfusion imaging, with ECG gating whenever possible |
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CAD diagnosis in an individual with an intermediate probability of disease and/or risk stratification in someone with an intermediate or high likelihood of disease and not able to exercise |
To identify the extent, severity, and location of inducible ischemia |
Rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
Detection of CAD in patients with ventricular tachycardia |
Patients without known CAD or ischemic equivalent |
Rest and stress myocardial perfusion imaging, preferably exercise stress, with ECG gating whenever possible |
Detection of CAD in patients with syncope |
Patients with intermediate and high risk for CHD and no ischemic equivalent |
Rest and stress myocardial perfusion imaging, preferably exercise stress, with ECG gating whenever possible |
Prior to intermediate- and high-risk noncardiac surgery |
Initial diagnosis of CAD in those with at least one clinical risk factor for adverse perioperative CV events, and poor (<4 METS) or unknown functional capacity |
In those able to exercise, rest and exercise stress myocardial perfusion imaging, with ECG gating whenever possible |
or |
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In those unable to exercise, rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
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In individuals with established or suspected CAD and poor (<4 METS) or unknown functional capacity |
In those able to exercise, rest and exercise stress myocardial perfusion imaging, with ECG gating whenever possible |
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or |
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In those unable to exercise, rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
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Diagnosis of CAD in patients with left bundle branch block or ventricular-paced rhythm and at least one risk factor for adverse perioperative CV events |
Rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
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In suspected or established CAD, prognostic assessment of those with left bundle branch block or ventricular-paced rhythm on rest ECG |
Rest and vasodilator stress myocardial perfusion imaging, with ECG gating whenever possible |
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Equivocal SPECT myocardial perfusion scan |
Clinically indicated SPECT perfusion study is equivocal for CAD diagnosis or risk stratification purposes |
Rest and adenosine or dipyridamole stress PET-myocardial perfusion study |
CAD patient with systolic dysfunction and CHF, with little or no angina |
Prediction of improvement in regional/global LV function following revascularization |
Stress/redistribution/reinjection thallium 201 SPECT perfusion imaging |
or |
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Rest/redistribution SPECT perfusion imaging |
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or |
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Myocardial perfusion plus FDG-PET metabolic imaging |
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or |
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Resting sestamibi SPECT perfusion imaging |
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Prediction of improvement in natural history following revascularization |
Stress/redistribution/reinjection thallium 201 SPECT perfusion imaging |
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or |
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Rest/redistribution thallium 201 SPECT perfusion imaging |
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or |
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Myocardial perfusion plus FDG-PET metabolic imaging |
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ACCF, American College of Cardiology Foundation; ACR, American College of Radiology; ACS, acute coronary syndrome; AHA, American Heart Association; ASE, American Society of Echocardiography; ASNC, American Society of Nuclear Cardiology; CAD, coronary artery disease; CHD, congenital heart disease; CHF, congestive heart failure; CV, cardiovascular; ECG, electrocardiogram; ER, emergency room; FDG, [18F]fluoro-2-deoxyglucose; LV, left ventricular; LVH, left ventricular hypertrophy; METS, metabolic equivalents; MI, myocardial infarction; MPHR, maximal age-predicted heart rate; PET, positron emission tomography; SCCT, Society of Cardiovascular Computed Tomography; SCMR, Society for Cardiovascular Magnetic Resonance; SNM, Society of Nuclear Medicine; SPECT, single-photon emission computed tomography.
A.Coronary artery disease
1.Diagnosis. Nuclear perfusion studies are performed to establish noninvasively the diagnosis of CAD in the following situations: history of stable angina; chest pain of unclear causation; unstable angina after stabilization; abnormal exercise test result without symptoms; risk stratification in the setting of multiple factors thought to confer a high likelihood of subclinical CAD; scheduled standard exercise testing in the setting of an abnormal electrocardiogram (ECG; because of left ventricular [LV] hypertrophy with associated repolarization changes, ST-depression >1 mm, manifest preexcitation pattern on ECG, digoxin use, left bundle branch block, or ventricular-paced rhythm); and previously nondiagnostic graded exercise test.
2.Assessment of the physiologic importance of known coronary lesions. Perfusion imaging can assist in the determination of the functional significance of a coronary stenosis that is in the “moderate-to-severe” (50% to 70%) range on angiographic evaluation. It can therefore be useful to evaluate a specific coronary lesion before proceeding to percutaneous intervention. This remains an accepted indication for nuclear perfusion imaging, although its use for this purpose is being supplanted by other modalities that can assess the functional significance of coronary lesions at the time of angiography (e.g., fractional flow reserve).
3.Assessment after therapeutic intervention. In the past, perfusion imaging was often performed as a routine follow-up procedure after percutaneous intervention and coronary artery bypass grafting (CABG). More recent recommendations on appropriate use of this modality suggest that routine screening in asymptomatic patients who have been successfully revascularized by either method is not necessarily warranted, except in the evaluation of patients more than 5 years after CABG. On the other hand, radionuclide perfusion imaging is certainly appropriate in patients who have undergone prior revascularization and are presenting with recurrent symptoms consistent with coronary ischemia.
4.Risk stratification. With nuclear imaging, it is possible to stratify risk among patients with stable angina or unstable angina, those who have had myocardial infarction (MI), and those about to undergo noncardiac operations.
5.Identification of prior MI, particularly among patients with angiographically normal coronary arteries when thrombolysis or coronary vasospasm is suspected, is afforded by nuclear imaging.
B.Assessment of left ventricular function. Although nuclear imaging is used less often for this purpose than in the past because of the desire to reduce patients’ radiation exposure when possible, gated blood pool imaging remains an accurate method of determining the ejection fraction.
C.Diagnosis of cardiomyopathy. Nuclear imaging studies with novel protocols have been utilized to detect infiltrative cardiomyopathies such as amyloidosis and sarcoidosis. Additionally, if a nonischemic cardiomyopathy is suspected, nuclear imaging is sometimes used to rule out CAD and ischemic cardiomyopathy particularly if coronary angiography is not feasible or desired.
III.CONTRAINDICATIONS. In addition to standard contraindications to exercise stress testing, specific considerations apply uniquely to nuclear imaging in general and the subgroup of dipyridamole stress perfusion studies.
A.General contraindications to nuclear studies. Nuclear imaging is contraindicated for patients who have had iodine 131 therapy within 12 weeks; technetium 99m studies within 48 hours, including bone, lung, multigated acquisition (MUGA), liver, tagged red blood cell (to evaluate gastrointestinal bleeding), and renal scans; indium 111 scans within 30 days; gallium 67 scans within 30 days; and oral intake within 4 hours (except for water).
B.Contraindications to dipyridamole, adenosine, or regadenoson administration include allergy to any of these agents, allergy to aminophylline, ongoing theophylline therapy (must be discontinued for 36 hours), history of uncontrolled asthma or reactive airway disease, significant atrioventricular nodal block, and caffeine consumption within 12 to 24 hours. A relative contraindication is recent use of vasodilator medications (within 12 to 24 hours depending upon the medication) which will render the vasodilator stress agent ineffective in further dilating the coronary vasculature.
IV.EQUIPMENT. The most basic tool in nuclear imaging is the gamma (γ) camera, which is used to detect γ-rays (i.e., x-ray photons) produced by the chosen radionuclide. There are two types of γ-cameras commonly utilized in nuclear cardiology.
A.A single-crystal camera consists of one large sodium iodide crystal. Other essential elements of this camera include the collimator, a lead device that screens out background or scattered photons, and the photomultiplier, an electronic processor that translates photon interactions with the crystal into electric energy.
1.Electric signals from the photomultiplier are processed by the pulse height analyzer before reaching a final form. Only signals in a specified energy range are incorporated into the interpreted images. The range recognized by the pulse height analyzer is adjustable and is established on the basis of the radiopharmaceutical used.
2.Digitalization of the single-crystal camera has greatly enhanced its performance.
B.A multicrystal camera works with an array of crystals with increased count detection capability. Because of the availability of an individual crystal to detect scintillation at any given time, this type of camera can be used to detect many more counts than can a single-crystal camera.
Specially dedicated γ-cameras are the foundation of nuclear imaging in cardiology.
C.SPECT cameras utilize a single crystal to acquire multiple two-dimensional (2D) images which are reconstructed to generate a 3D image.
1.Innovations in cardiac imaging have produced ultrafast SPECT cameras. These cameras are able to decrease scan time and radiation dose by constraining all available cameras to image only the cardiac field of view. There is a resulting increase in count sensitivity at no loss of, or even a gain in, resolution.
D.In the case of positron emission tomography (PET) scanning, a positron camera is used to detect the photon products of positron annihilation. Interaction between a positron and an electron causes annihilation, with the generation of two high-energy photons (511 keV) that travel in opposite directions.
1.A multicrystal camera is used and oriented in multiple concentric rings. Each crystal is linked optically to multiple photomultipliers. The crystals are oriented in diametric pairs positioned exactly 180° apart such that each pair of crystals must be struck simultaneously by annihilation photons to record activity. Background interference and stray photon energy are automatically accounted for, and artifact is limited.
2.Most positron cameras contain bismuth germanate for annihilation photon detection.
V.MECHANICS AND TECHNIQUES
A.Image acquisition. Basic perfusion imaging can be performed by means of planar and tomographic techniques. The tomographic, or SPECT, method is most commonly used today.
1.Planar images are acquired in three views: anterior, left anterior oblique (LAO), and steep LAO or left lateral (LLAT) orientation (Fig. 46.1). The patient is supine for anterior and LAO views but is placed in the lateral decubitus position for LLAT image acquisition. Planar imaging may superimpose vascular distributions and therefore can compromise the ability to implicate a specific vascular supply when a defect is present. For example, normally perfused myocardial segments may overlap perfusion defects in a separate distribution.
FIGURE 46.1 Standard planar views and vascular territories. Circ, circumflex artery; LAD, left anterior descending artery; LAO, left anterior oblique; RCA, right coronary artery.
TABLE 46.2 Characteristics of Common Perfusion Agents |
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Attribute |
Thallium 201 |
Technetium 99m Sestamibi/Tetrofosmin |
Rubidium 82 |
Nitrogen 13 Ammonia |
18F-fluorodeoxyglucose (FDG) |
Energy (keV) |
69–83 |
140 |
511 |
511 |
511 |
Dose (mCi) |
2.5–3.5 |
20–30 |
30–60 |
10–20 |
10–20 |
Half-life |
74 h |
6 h |
76 s |
10 min |
110 min |
Cyclotron required |
Yes |
No |
No |
Yes |
Yes |
Perfusion imaging |
Yes |
Yes |
Yes |
Yes |
No |
Viability evaluation |
Yes |
Yes |
No |
No |
Yes |
Redistribution |
Yes |
Yes (minimal) |
No |
No |
No |
Gating (electrocardiogram) |
No |
Yes |
Yes |
Yes |
No |
2.Using SPECT, a series of planar images are usually obtained over a 180° arc to reconstruct a 3D representation of the heart. The arc typically extends from the 45° right anterior oblique plane to the 45° left posterior oblique plane, with the patient in the supine position.
a.Three orientations are analyzed in the final representation: short axis, vertical long axis, and horizontal long axis. A computer-generated display, the polar map, is also analyzed as a quantifiable representation of count density.
b.Unlike planar imaging, SPECT can be used to separate vascular territories and improve image interpretation. SPECT, however, also increases the time needed for image acquisition and requires close attention to quality control issues.
B.Radiopharmaceuticals available for nuclear imaging include thallium 201, technetium 99m, and several positron imaging agents. Each possesses specific energy characteristics, kinetic profiles, and biodistribution (see below as well as Table 46.2 and Section X for further details).
1.Thallium 201
a.General characteristics. Thallium 201 (i.e., thallous chloride) is a metallic element in group IIIA of the periodic table; it is produced in a cyclotron. Thallium emits γ-rays at an energy range of 69 to 83 keV and has a half-life of 73 hours. The biologic activity of this element is very similar to that of potassium; the ionic radii of the two elements are virtually identical. Thallium is actively transported into cells by the sodium–potassium adenosine triphosphatase (Na–K ATPase) pump.
b.Kinetics. Approximately 5% of the administered dose of thallium 201 is distributed to the myocardium, proportionate to the blood flow delivered to the coronary circulation.
(1)The initial uptake of thallium 201 by myocardium is directly related to regional blood flow. The myocardial extraction of thallium 201, however, increases at low flow rates (<10% of basal) and decreases at high flow rates (more than twice the basal rate).
(2)Washout. Almost 85% of the thallium 201 is extracted by myocytes in the first pass. After initial uptake into myocytes, a state of continuous exchange across the cell membrane occurs. The distribution of this radiotracer changes after administration, and thallium 201 washes out from the myocytes, a process called redistribution. Thallium 201 washout generally approaches 30% at 2 to 2.5 hours after injection.
(3)Ischemic myocardium. Uptake of thallium 201 in ischemic myocardium is lower than uptake in nonischemic segments, and washout time is slower than that from nonischemic zones.
(4)Over time, counts become equal in the ischemic and nonischemic regions (or thallium 201 concentration may increase in ischemic regions) so that thallium 201 concentrations in these disparate areas approach one another. This disparity is taken advantage of during thallium 201 viability imaging.
2.Technetium 99m–labeled agents
a.General characteristics. Technetium 99m is a radiopharmaceutical that can be produced on-site in molybdenum 99–technetium 99m generators. It possesses several ideal imaging characteristics.
(1)Technetium 99m has a half-life of 6 hours and emits γ-rays with a single photopeak of 140 keV. Thus, radiation exposure is decreased as compared to Thallium because of the shorter half-life.
(2)Technetium 99m–labeled perfusion agents include 99mTc-sestamibi, 99mTc-tetrofosmin, and 99mTc-teboroxime. Some studies suggest that 99mTc-tetrofosmin has more rapid hepatobiliary clearance than sestamibi, which reduces the impact of liver uptake and allows for imaging sooner after injection.
b.Kinetics. After administration of 99mTc-sestamibi, approximately 40% to 60% of the agent is extracted by the myocardium. Initial uptake of the agent is proportional to regional myocardial blood flow, and it is bound to the inner mitochondrial membrane. 99mTc-tetrofosmin has similar pharmacokinetics to 99mTc-sestamibi. Myocardial washout of 99mTc-sestamibi and 99mTc-tetrofosmin is very slow, and little redistribution occurs. The absence of redistribution requires two separate injections of the agent, at rest and at peak stress (either exercise or pharmacologic). This can be performed with a same-day or 2-day protocol.
VI.IMAGING PROTOCOLS
A.Thallium 201
1.General features. Stress imaging with thallium 201 involves initial injection at peak stress (either exercise or pharmacologic) and immediate imaging, followed by redistribution images 3 to 4 hours after injection.
a.Because of the long half-life of thallium 201 (73 hours), limited amounts are administered to reduce the total radiation exposure to the patient. Although a single injection is typically used because of the redistribution phenomenon, a second injection may be given to enhance the filling of reversible defects.
b.The low energy range of thallium 201 is marginal for imaging with the γ-camera because of scatter and diminished spatial resolution.
2.Variations from standard protocol. Exact imaging techniques vary among institutions. Initial thallium 201 doses range from 2 to 3.5 mCi, acquisition times vary from 20 to 40 seconds per image, and the number of images varies from 32 to 64 depending on whether 180° or 360° image acquisition is used.
a.The use of 360° versus 180° imaging has been the subject of debate. With 180° tomography, contrast is better, there is less artifact, and imaging times are shorter. Slight variations also exist depending on the use of exercise stress testing or pharmacologic stress protocols.
b.When exercise thallium 201 scintigraphy is performed, the radionuclide (2 to 3.5 mCi) is usually injected approximately 1 minute before peak exercise to allow time for distribution. Initial images are obtained within 5 to 10 minutes of injection. Redistribution images are obtained 2.5 to 4 hours after the initial images.
c.This technique is not highly specific for scar at 2.5 to 4 hours because persistent defects may represent viable myocardium in some cases.
(1)For this reason, some advocate delayed (late redistribution) imaging 18 to 24 hours after injection. Some studies indicate that up to 40% of persistent defects exhibit radiotracer uptake after revascularization. Delayed imaging has resulted in further redistribution in as many as 45% of patients.
(2)Alternative approaches in differentiating viable tissue from scar include rest reinjection of thallium 201, in effect to boost fill-in of perfusion defects. As many as 50% of persistent defects have been shown to exhibit improved thallium 201 uptake after rest injection of 1 mCi of thallium 201, suggesting viability.
d.Minor changes in imaging protocol may be observed with pharmacologic stress testing with adenosine, regadenoson, dipyridamole, or dobutamine.
B.Technetium 99m. The relative lack of redistribution requires two injections of technetium 99m to obtain rest and stress images.
1.Basic protocols
a.Same-day protocol. Rest images are obtained first, and stress imaging follows to minimize residual scintigraphic activity caused by the higher dose stress injection. This is the opposite order as compared to thallium imaging.
(1)Rest images are obtained with injection of 7 to 10 mCi of technetium 99m and image acquisition up to 1 to 1.5 hours later. Imaging is delayed because of slower liver clearance with rest injection.
(2)At peak exercise, technetium 99m is injected at typically 3× the dose of the resting images (25 to 30 mCi). Stress images are obtained approximately 45 to 60 minutes after injection. Hepatic uptake of technetium 99m occurs within 15 to 30 minutes of injection, and the tracer is excreted into the gastrointestinal tract through the biliary system. Appearance of the tracer in the gastrointestinal tract can interfere with imaging of the inferior wall of the left ventricle.
b.The separate-day protocol allows time for decay of activity. Larger doses of technetium 99m can be administered for rest and stress images, and there is minimal interference between the images.
(1)Between 22 and 30 mCi of technetium 99m is injected for stress and rest imaging, separated by 1 to 2 days.
(2)The higher doses possible with the 2-day protocol produce increased count density and better image quality at the cost of inconvenience.
2.Factors that affect image quality. Consumption of a fatty meal can enhance biliary excretion of technetium 99m and improve image quality. Because of possible interference from noncardiac uptake, image processing with technetium 99m relies on normalization to the brightest cardiac pixel. Additional artifacts are discussed later.
C.Dual-isotope imaging. Use of both thallium 201 and technetium 99m substantially reduces the time required to obtain stress and rest images.
1.The patient receives thallium 201 at rest (3.5 mCi) and, immediately after rest imaging, undergoes stress. At peak stress, the patient is given an injection of 25 mCi of technetium 99m. Stress images are obtained 15 minutes later.
2.This technique makes use of the dissimilar energy levels of the two radionuclides to shorten the protocol while still allowing acquisition of ECG-gated images (because of the use of technetium 99m).
3.The sensitivity (91%) and specificity (75%) of this combination protocol are comparable to the values for conventional technetium 99m SPECT.
4.The disadvantages of the dual-isotope protocols revolve around comparing images obtained with isotopes with different characteristics. There may be more Compton scatter of thallium 201 than of technetium 99m and thus greater myocardial wall thickness and inability to assess transient ischemic dilatation of the left ventricle.
VII.STRESS PROTOCOLS
A.Exercise stress testing. Standard exercise testing is frequently complemented with nuclear imaging. The radioisotope is injected at peak exercise, and time is allowed for circulation of the agents while exercising (usually at least 1 minute before termination of exercise).
B.For patients who are unable to exercise, pharmacologic stress testing is used in concert with nuclear imaging. Adenosine, regadenoson, and dipyridamole are vasodilators that are useful in noninvasive testing because of differences in coronary flow reserve. In the presence of marked coronary stenosis, the distal vessel is maximally dilated and therefore possesses little flow reserve.
1.Adenosine acts at several different receptors (A1, A2A, A2B, and A3) and thus has several physiologic effects. Its desired effect for the purpose of pharmacologic stress is to substantially enhance coronary flow in normal beds (i.e., those with normal flow reserve), although much less so in distributions supplied by a stenotic artery. The resultant disproportionate flow allows for utilization or heterogeneous radiotracer uptake.
a.Administration. Adenosine is infused at 140 µg/kg/min for 6 minutes. The radiotracer is then injected after 3 minutes of the start of adenosine infusion.
b.Side effects commonly experienced include chest pain, headache, nausea, and flushing which typically resolve in 2 to 5 minutes. Atrioventricular block and bronchoconstriction are the result of effects on the A1 and A3 receptors, respectively. Aminophylline can be given intravenously to reverse intolerable or dangerous side effects if they occur.
2.Dipyridamole is an adenosine reuptake inhibitor, leading to increased extracellular concentrations of adenosine, and thus has very similar effects. It has a longer distribution half-life than adenosine, however, of approximately 25 minutes.
a.Administration. Dipyridamole is infused over a 4-minute period (0.142 mg/kg/min). The maximum vasodilatory effect is achieved 4 minutes after completion of the infusion, and the radiotracer is injected at this point. A slight increase in heart rate (10 beats/min) and decrease in blood pressure (10 mm Hg) are frequently observed.
b.Side effects. Headache, nausea, chest pain, hypotension, dizziness, and flushing have been reported. Severe side effects may necessitate reversal of the dipyridamole effect with aminophylline, given as a 50- to 100-mg intravenous bolus.
3.Regadenoson is a selective A2A receptor agonist that has been Food and Drug Administration–approved for clinical use in myocardial perfusion imaging since 2008. Two randomized double-blind multicenter trials—ADVANCE-MPI 1 and 2—have demonstrated the safety of this agent in a total of 1,871 patients, as well as an efficacy similar to adenosine for the detection of reversible perfusion defects on SPECT imaging.
a.Administration. Regadenoson is given as a single 0.4 mg (in 5 mL) intravenous bolus and does not require adjustment for body mass index or renal or hepatic function. Its coronary hyperemic effects have an onset within 30 seconds and usually last for 2 to 5 minutes.
b.Side effects of chest pain, headache, nausea, and flushing do occur with regadenoson and typically resolve within 2 to 5 minutes. However, atrioventricular block and bronchoconstriction are far less common than with adenosine or dipyridamole, because of the lack of agonism of the A1 and A3 receptors with this A2A-selective agent. Aminophylline can be given intravenously to reverse intolerable or dangerous side effects if they occur.
4.Dobutamine is an agonist of the β1 and β2 receptors and thus increases both heart rate and contractility (with a mild reduction in systemic vascular resistance).
a.Administration. Infusion is begun at 5 µg/kg/min and increased every 3 minutes to a maximum dose of 40 µg/kg/min. The radiotracer is injected at maximum dose (or at 85% of age-predicted maximum heart rate), and the infusion is continued for 2 to 3 minutes.
b.Side effects associated with dobutamine include ectopy, headache, flushing, dyspnea, paresthesias, and hypotension.
VIII.IMAGE INTERPRETATION
A.Standard view of normal anatomy. The uptake of radiotracer is homogeneous in persons with normal myocardial perfusion. The tracer is predominantly distributed to the left ventricle; the right ventricle usually appears as a faint, thin structure. Understanding and interpreting these images, however, requires an understanding of standard planar and SPECT views of LV anatomic features.
1.Planar images are represented as LAO, anterior–posterior (AP), and LLAT views.
2.Standard SPECT views include the short axis, vertical long axis, and horizontal long axis. The short-axis view is further divided into apical, mid-ventricular, and basal views.
a.As with planar views, SPECT images in various projections correspond with specific myocardial segments (Fig. 46.2).
FIGURE 46.2 Standard tomographic projections and myocardial segments.
b.In addition to the standard SPECT sections, short-axis sections can be compiled into a polar map (so-called bull’s eye display). This computer-generated polar map arranges short-axis tomographic images such that the central portion represents apical slices and the periphery consists of the basal segments.
B.Reviewing sequence. Review of nuclear images follows an organized sequence.
1.Examine unprocessed images for artifact, extracardiac uptake, and evidence of increased lung uptake.
2.Examine rest images. Document defects and their extent and severity.
3.Examine stress images. Document defects and their extent and severity.
4.Evaluate the polar map in comparison with pooled normal images (derived from a database of patients with low probability of having CAD).
5.Compare rest and stress images for enlargement of the LV cavity.
6.Incorporate the gated SPECT images to establish overall ventricular function, volumes, and wall function in areas of questionable perfusion defects. Segmental defects that demonstrate normal motion on gated SPECT images may represent artifact.
7.Examine right ventricular (RV) size and function
C.Characterization of defects. Given that initial perfusion images represent regional myocardial blood flow, defects in these images represent an area of myocardium with relatively less uptake and diminished regional blood flow. Defects can be characterized as fixed, reversible, partially reversible, or as displaying reverse redistribution. (Partially reversible or reverse redistribution are only pertinent with thallium 201 imaging because of redistribution imaging.)
1.Fixed defects. Fixed (i.e., nonreversible) defects are areas of decreased tracer uptake that appear unchanged on both rest and stress images. Fixed defects can represent scar or viable myocardium. With thallium 201 imaging, nonreversibility suggests similar rates of clearance from the two regions.
a.Differentiating scar from viable myocardium in the setting of a nonreversible defect can be accomplished through the use of metabolic radiopharmaceuticals and PET, delayed imaging, or rest reinjection with thallium 201. The level of tracer activity reflects viability. Severe deficits (<50% of normal counts) are less predictive of viability than are milder count deficits.
b.Differentiating viable myocardium from scar is paramount because there is clinical and experimental evidence of improved LV function after revascularization of such hibernating regions (see Chapter 50). As methods of revascularization become increasingly applicable in an arena of increasingly complex patient problems, fully defining the so-called fixed defect through metabolic imaging assumes greater importance (see Sections VIII.D.2 and X.D).
2.Reversible defects are myocardial segments with normal perfusion at rest but decreased perfusion on stress images. This pattern is consistent with the presence of ischemic myocardium in the region of reversibility.
a.In the setting of thallium 201 imaging, normal perfusion at rest (i.e., resolution of the defect) is a function of variable tracer concentrations in ischemic and nonischemic segments, which approach one another as redistribution occurs, along with continuous exchange of myocyte and blood pool thallium 201. Fill-in of reversible defects on thallium 201 images can be enhanced by means of delayed imaging or rest reinjection.
b.Technetium 99m imaging, which does not utilize redistribution, demonstrates reversibility on the basis of differential uptake during stress compared with rest.
3.Partially reversible defects (seen with thallium protocols) are defects seen on stress images that partially resolve on rest images but do not fill in completely. This type of defect is thought to reflect a mixture of scar and ischemic myocardium. Nonetheless, reversibility may be incomplete even in the absence of nonviable tissue and represent purely ischemic myocardium.
4.A pattern of reverse redistribution occurs in thallium protocols when a defect is absent on stress images but is present on rest images or appears larger on rest images than on stress.
a.Such a pattern is seen in the presence of acute MI when the infarct artery has been rendered patent through thrombolysis, percutaneous coronary intervention, autolysis, or another form of revascularization.
b.The pattern is thought to reflect post-MI hyperemia with excess radiotracer uptake in a region of reperfused myocardium followed by accelerated myocardial washout of radiotracer in the defect region.
c.The regions in question may demonstrate viability on PET imaging and do not indicate ischemia.
5.Artifacts. Apparent perfusion defects may be artifactual and attributed to soft tissue attenuation, a problem that occurs more often with thallium 201 imaging than when a higher-energy agent (technetium 99m) is used.
a.Common causes of the presence of artifacts include breast attenuation in women (affecting the anterolateral, septal, anteroseptal, and posterolateral walls of the ventricle) and diaphragmatic attenuation in men (predominantly altering the inferior and posterior walls).
b.Planar images with perfusion defects seen in only a single view are suspect, and the presence of artifact must be considered.
c.SPECT artifacts may be more elusive because of processing and reconstruction of tomographic images. However, with good technique, most are avoidable. When there is a suspicion for attenuation artifacts as above, attenuation correction processing techniques can be employed to account for these variables.
6.Risk assessment. Identifying the extent and severity of perfusion defects is paramount to quantifying risk. Extent refers to the number of segments affected using the 17 segment model. Severity refers to the degree of decreased radiotracer uptake in each segment. Severity is typically graded on a 0 to 4 scale with 0 being normal radiotracer uptake and 4 being absent radiotracer uptake. A summed score is calculated which is calculated by adding all scores for the given study. A summed score is calculated at rest and at stress, and the difference between these scores is termed the summed difference score.
a.Specific patterns of perfusion imaging that suggest high-risk coronary anatomic features include perfusion defects in more than one vascular distribution, increased lung thallium uptake, and transient ischemic LV dilatation (i.e., transient ischemic dilation). Extent and severity of defects also predicts risk. More will be discussed regarding risk assessment in subsequent sections.
D.Quantitative analysis. The principles of image analysis rely on visual inspection, which is fraught with observer variability.
1.Computer-aided analysis of planar data involves comparison of regional radionuclide activity on stress and rest images; count discordance coincides with reversibility. SPECT data are quantitatively analyzed by means of comparing count densities on short-axis images (displayed as a polar map) with normal age- and sex-adjusted count profiles. Although they improve sensitivity, these methods are used in concert with visual analysis.
2.PET imaging, although evaluated in large part in a visual manner, also possesses great clinical utility with the application of quantitative analysis of myocardial perfusion, myocardial blood flow, and coronary flow reserve. Moreover, significant advances have been made in the ability to quantify absolute—and not just relative—blood flow in different coronary vascular territories using PET imaging. On the basis of analysis of baseline blood flow and flow during vasodilator stress, this technique is useful in revealing functionally important coronary lesions even in the presence of multivessel coronary disease.
a.The administration of adenosine, dipyridamole, or regadenoson should induce at least a twofold to threefold increase in coronary blood flow over baseline in a normal coronary vascular bed. This “flow reserve” is not present in the setting of functionally significant epicardial coronary artery stenosis supplying this myocardial bed (as discussed earlier in the chapter). Thus, relative differences in myocardial perfusion during hyperemia (which may not be appreciated on visual inspection) may be more precisely demonstrated with quantitative analysis of flow reserve.
b.Furthermore, the ability to quantitate absolute myocardial blood flow regionally and globally may help surmount the difficulty in noninvasively diagnosing CAD in the setting of “balanced ischemia” from severe left-main or triple-vessel CAD.
IX.CLINICAL APPLICATIONS
A.Coronary artery disease
1.Detection of CAD. The ability to detect CAD in a noninvasive manner offers numerous additional applications in risk stratification, prognosis, and imaging of acute infarction.
Sensitivity and specificity. Since the introduction of thallium 201 imaging in 1975, the utility of perfusion agents in the diagnosis of CAD has been well established. Quantitative planar imaging and SPECT demonstrate 90% or greater sensitivity.
a.Sensitivity is affected by the number of vessels involved. Single-vessel disease is most likely to produce a false-negative finding. Multivessel CAD rarely produces a normal perfusion scan result. The specificity of planar imaging is 83% and that of SPECT is ~70%.
b.In general, radionuclide imaging is best used to evaluate a population at intermediate risk for CAD. The choice of radionuclide agent seemingly has little effect on the accuracy of these techniques.
c.The introduction of PET, however, has brought with it advanced diagnostic accuracy, with approximately 10% to 15% improvement over SPECT.
(1)Causes of false-positive perfusion study results include attenuation defect, technical inadequacies, coronary vasospasm, anomalous coronary circulation, cardiomyopathy, conduction defects such as left bundle branch block, and recanalization of a thrombosed coronary artery.
(2)Causes of false-negative perfusion study results include a submaximal exercise stress test, anti-ischemic medical therapy, collateral or overlap circulation, inaccurate interpretation of perfusion images or angiograms, acquisition of suboptimal images, presence of balanced coronary stenoses, and delay in stress imaging.
2.Risk stratification. In addition to indicators of higher risk taken from perfusion images, such as increased lung uptake, determinants in the assessment of risk are as follows.
a.Presence of reversible as opposed to fixed defects is associated with greater likelihood of cardiac events related to acute coronary syndrome at follow-up evaluation. This relation has clinical utility in a number of settings, including risk stratification after MI or in the preoperative setting. In one study involving patients who had had MI without complications, patients with single, fixed defects on thallium 201 images had a 6% cardiac event rate, compared with a rate of 51% for those with thallium 201 scans that indicated high risk of such an event.
b.Radionuclide imaging abnormalities have been identified as independent predictors of subsequent infarction or death. In general, the extent and severity of abnormal segments identified on nuclear images can be seen as inversely proportional to survival rate. Normal findings on a nuclear perfusion study, however, suggest an excellent prognosis, with a yearly mortality rate <1% (in patients with a normal ejection fraction). The application of such prognostic information to the care of patients preparing for noncardiac operations reflects significantly on the patient’s surgical risk and has an established role in preoperative evaluation and clearance. For this population, evidence of ischemia on perfusion images portends a higher risk of a perioperative cardiac event.
3.Myocardial perfusion imaging may aid in the diagnosis and risk stratification of patients with acute coronary syndromes.
a.Patients with chest pain of ill-defined origin can be given an injection at rest of thallium 201 or technetium 99m. In the presence of true ischemia, a rest defect may be documented and insight into regional distribution of ischemia and extent of myocardium involved is gained. The absence of any perfusion defect with ongoing chest pain makes a diagnosis of angina less likely.
In the setting of thrombolysis, imaging with technetium 99m can provide important information about reperfusion or lack thereof. Injection of technetium 99m before initiation of thrombolysis captures a picture of hypoperfusion, which can, because of the extensive half-life, be imaged at a later time. Subsequent injections reveal the status of perfusion as the period after thrombolysis proceeds (i.e., persistent, large defect that represents failed reperfusion). Such applications in the setting of thrombolysis and in acute coronary syndromes have limited clinical utility because of the logistics of staffing and availability of radiopharmaceuticals.
B.Assessment of ventricular function. In addition to its use in perfusion analysis in CAD, radionuclide imaging can establish cardiac performance. Radionuclide-based assessment of ventricular function includes first-pass radionuclide angiocardiography and gated blood pool imaging.
1.First-pass radionuclide angiocardiography involves injection of a radionuclide and analysis as the agent passes through the central circulation.
a.Technetium 99m–labeled agents are typically administered in bolus form, and scintigraphic data are recorded for 15 to 30 seconds after injection. Multicrystal cameras oriented in a straight anterior projection are used for detection of count rates.
b.This method of ventricular function analysis is more useful in evaluating RV function than is gated blood imaging. In patients with severe LV dysfunction, transit time through the heart may be slowed, thus proximal venous access and rapid administration may be necessary.
2.MUGA scans are an example of gated blood pool imaging or radionuclide angiography. This relies on ECG gating to correlate multiple individual images of the cardiac blood pool to specific phases of the cardiac cycle.
a.For the in vivo method, the patient is administered intravenous stannous chloride. Then, a 2- to 3-mL sample of the patient’s blood is retrieved and bounded with technetium 99m pertechnetate. This sample is then reinjected into the patient intravenously. The stannous ions reduce the technetium, so they will not leak out of the tagged cells. The in vitro method binds the patient’s blood with the stannous ion and technetium prior to reinjection into the patient.
b.A single-crystal γ-camera is used in the LAO, AP, left lateral, and sometimes left posterior oblique projections to obtain serial static images of the cardiac blood pool gated to the R–R interval.
c.Because multiple cardiac cycles are averaged to obtain the final images, this technique is not optimal for evaluating regional wall motion. For many years, though, MUGA was considered a “gold standard” technique for assessment of overall LV ejection fraction. Radionuclide angiography remains a well-validated and highly reproducible method of assessment of overall LV ejection fraction (and importantly, retains this quality especially well at low ejection fractions). The use of this technique is diminishing in the current era of echocardiography and cardiac MRI.
3.ECG-gated perfusion imaging. Perfusion imaging with technetium 99m–labeled tracers during standard nuclear stress testing produces gated images where LV volumes and ejection fraction may be calculated. The standard injection of 20 to 30 mCi of technetium 99m allows evaluation of perfusion and function in a single study.
a.The greatest utility of ECG-gated perfusion imaging may be in elucidating perceived artifacts on perfusion images. For example, if a region has a perceived fixed perfusion defect, yet wall motion is normal in the same region, artifact becomes a more likely consideration as the cause of the filling defect. However, wall motion abnormalities are typically not seen in ischemic segments after exercise nuclear testing because of the delay between peak stress and image acquisition.
b.Comparison of this method with two-dimensional echocardiography in the evaluation of regional wall motion has shown good correlation between the two.
C.Cardiac amyloidosis. Nuclear scintigraphy with 99m technetium pyrophosphate is used in the diagnosis of cardiac amyloidosis. Historically, this agent was used in cardiac disease after MI to assess infarct size, but has been repurposed for use in cardiac amyloidosis. Technetium pyrophosphate is a bone tracer that binds to the calcium in amyloid deposits, particularly in transthyretin amyloidosis; uptake is usually absent in light chain amyloid heart disease. Thus, this test is commonly used to diagnose transthyretin amyloidosis and differentiate it from light chain disease. Uptake is graded based upon visual assessment as well as comparing uptake in the heart versus the contralateral lung on planar images.
D.Myocardial innervation imaging. Radiotracer analogues of sympathetic nervous system factors have been used to assess myocardial innervation and predict risk in certain conditions. Iodine 123 meta-iodobenzylguanidine (MIBG) is a radiotracer which acts as a false neurotransmitter analogue of norepinephrine and is the most frequently used radiotracer for this indication. It is utilized in both adrenal and cardiac imaging, and images are acquired using standard techniques with planar followed by SPECT images.
1.Heart failure: In clinical trials, decreasing MIBG uptake was found to be associated with worsening disease status and mortality. The most striking finding was the greater than 99% negative predictive value; patients with normal uptake had very few cardiac events. This tracer may be able to identify a subset of patients who do not meet ICD criteria who are at high risk for cardiac events. In addition, MIBG uptake was shown to improve after heart failure medical therapy.
X.POSITRON EMISSION TOMOGRAPHY. PET has bolstered the evaluation of CAD by nuclear imaging techniques, both by improving blood flow imaging and by allowing evaluation of metabolic activity. Positron imaging agents can be divided into blood flow tracers and metabolic radiopharmaceuticals.
A.Perfusion (blood flow) tracers. A number of radiopharmaceuticals exist for the assessment of myocardial blood flow. They can be produced by a cyclotron or generator.
1.Rubidium 82, the most readily used blood flow tracer, can be generated on-site without the use of a cyclotron. Much like thallium 201, rubidium 82 is a potassium analogue that is actively transported into myocytes through the Na–K pump. Uptake into myocardium is proportionate to regional blood flow. Approximately 65% of the radiotracer is extracted at first pass. Because of a short half-life (76 seconds), rubidium 82–based imaging protocols can be used to assess myocardial blood flow rapidly (within 1 hour). However, the short half-life also precludes exercise stress PET imaging with this tracer.
2.Other perfusion agents include the cyclotron-produced nitrogen 13 ammonia (half-life 10 minutes) and oxygen 15 water (half-life 123 seconds). Image quality with oxygen 15 water is poor and requires extensive processing to subtract the blood pool, thus is rarely used in current practice. Rb 82 and 13N-ammonia are the perfusion tracers that are used in clinical practice, with Rb 82 carrying the distinct advantage of requiring only a generator instead of a cyclotron. The image quality of 13N-ammonia is excellent, although the impracticality of cyclotron production in most facilities is a limiting factor for this agent. For those facilities capable of 13N-ammonia generation, however, it has the “upside” of a longer half-life than rubidium 82; thus, exercise stress cardiac PET imaging could be performed if desired.
B.Metabolic radiopharmaceuticals. Metabolic imaging with PET depends on the use of radiolabeled substrates of cardiac metabolism, largely in the form of [18F]fluoro-2-deoxyglucose (FDG), carbon 11 palmitate, and carbon 11 acetate.
1.FDG is a glucose analogue used by ischemic and hibernating myocardium because of a transition to alternative fuel sources in the hypoxic state. There is diminished oxidation of long-chain fatty acids and increased use of glucose as a secondary fuel source during ischemia or hibernation. FDG is phosphorylated to FDG-6-phosphate after transport across the cell membrane. FDG imaging therefore reflects myocardial use of exogenous glucose, and FDG is a widely used metabolic radiopharmaceutical. It has a half-life of 1.83 hours, which means it can be ordered on a daily basis by institutions that do not have an on-site cyclotron—making it the most commonly used metabolic PET imaging agent.
2.[11C]Palmitate is taken up by myocytes, converted to acyl CoA, and relegated to triglyceride stores or β-oxidized to produce [11C]carbon dioxide. The release of this product of β-oxidation is reflective of long-chain fatty acid oxidation in myocardium.
3.[11C]Acetate is metabolized to [11C]carbon dioxide after entering the tricarboxylic acid cycle. Measuring the production of [11C]carbon dioxide in this setting correlates with myocardial oxygen consumption.
C.Protocols. Image acquisition with PET is similar to that with SPECT in that tomographic images are obtained in short-axis, horizontal long-axis (sagittal), and vertical long-axis (coronal) views. A positron camera consists of an array of crystals arranged in a circle. Unlike in SPECT, the camera remains stationary in PET.
1.The heart is localized with the patient’s arms extended above the head. An attenuation scan is performed that allows the density of the surrounding thoracic structures to be subtracted to leave only cardiac count activity. This performance of attenuation correction avoids noncardiac interference which adds a great deal to the accuracy of PET.
2.After the attenuation scan, the positron-emitting radiopharmaceutical is injected, and images are obtained 2 to 5 minutes later. As mentioned earlier in the chapter, two photons are created by the annihilation of the emitted positron colliding with the nearest electron it meets in the tissue surrounding it. These two photons travel exactly 180° apart while the patient is lying in the circular scanner. This is an important concept because it means there is no need for collimation. The detector/analyzer merely has to “accept” the signal it receives only if a simultaneous signal strikes the detector directly across from it in the scanner. This dramatically improves the signal-to-noise ratio that can be achieved during imaging.
3.Metabolic imaging can be undertaken after perfusion imaging with the administration of 5 to 10 mCi of FDG. Tomographic images are typically obtained 30 to 50 minutes after FDG injection.
D.Patterns of perfusion and metabolic imaging. Specific patterns of perfusion and metabolic imaging are identifiable. For example, normal flow–normal FDG (match) indicates normal perfusion and normal metabolic activity. Reduced flow with normal or increased FDG (“flow–metabolism mismatch”) demonstrates viability (i.e., hibernating myocardium). Reduced flow–reduced FDG identifies scar tissue.
1.Diagnosis of CAD. Flow imaging with PET is highly sensitive and highly specific for the detection of coronary stenosis, approaching 93% for both.
a.Higher-energy photons (511 keV), higher count densities, shorter half-life, and “built-in” attenuation correction place PET substantially ahead of SPECT in the accurate detection of CAD.
b.As mentioned before, the ability to quantitate absolute blood flow regionally and globally may help improve the diagnosis of coronary ischemia in the setting of severe multivessel disease and balanced ischemia.
2.Assessment of myocardial viability (see Chapter 50). The use of PET with metabolic radiotracers is the standard for identifying viable myocardium. The presence of a flow–metabolism mismatch, which indicates underperfusion in the presence of metabolically active myocytes, suggests hibernating myocardium. Revascularization of these zones as identified with PET has been shown to result in improvement in wall motion. This utility of nuclear imaging has found increasing application in the selection of patients for revascularization who have ischemic cardiomyopathy and heart failure with low ejection fraction.
3.Cardiac sarcoidosis. FDG-PET imaging is useful in detection and prognosis in patients suspected of having cardiac sarcoidosis. Normal myocardium utilizes glucose and fatty acids for metabolism. Under fasting conditions, myocardial cells shift to utilizing predominantly fatty acids. Inflammatory cells in cardiac sarcoidosis utilize glucose because of high metabolic demands, even during fasting.
a.Sarcoidosis nuclear protocols vary among institutions, but attempt to minimize physiologic glucose uptake in normal myocardial tissue. Patients are advised to prepare for the exam with a prolonged fast (12 to 18 hours) and high-protein, low-carbohydrate diet the day before the exam. Rubidium 82 is injected at rest to evaluate for perfusion defects. FDG is injected and a prolonged delay is utilized (usually 60 minutes) prior to image acquisition.
b.FDG-PET demonstrating areas of decreased perfusion with increased FDG in the setting of non-obstructive CAD is suggestive of active cardiac sarcoidosis.
ACKNOWLEDGMENTS: The author would like to thank Drs. Jeffrey A. Skiles, Gregory Bashian, and Santosh Oommen for their contributions to earlier editions of this chapter.
Landmark Articles
Marshall RC, Tillisch JH, Phelps ME, et al. Identification and differentiation of resting myocardial blood flow in man with positron emission tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia. Circulation. 1983;67:766–778.
Strauss HW, Harrison K, Langan JK, et al. Thallium-201 for myocardial imaging: relation of thallium-201 to regional myocardial perfusion. Circulation. 1975;51:641.
Wackers FJ, Berman DS, Maddahi J, et al. Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety, and preliminary comparison to thallium-201 for myocardial perfusion imaging. J Nucl Med. 1989;30:301–311.
Relevant Book Chapters
Brunken RC, Oomen S. Nuclear cardiac imaging, a primer; Nuclear stress testing. In: Griffin BP, Kapadia SR, Rimmerman CM, eds. The Cleveland Clinic Cardiology Board Review. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:chaps 12 and 13.
Udelson JE, Dilsizian V, Bonow RO. Nuclear cardiology. In: Zipes DP, Libby P, Bonow RO, et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: WB Saunders; 2011:chap 17:293–339.
Relevant Professional Society Guidelines
Hendel RC, Berman DS, DiCarli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging. J Am Coll Cardiol. 2009;53:2201–2229.Brett W. Sperry
Wael A. Jaber