CHAPTER 54 Nuclear Medicine Imaging of Myocardial Perfusion
Radionuclide myocardial perfusion imaging (MPI) is a well-established, highly accurate, and reproducible noninvasive method to diagnose and assess functionally significant coronary artery disease (CAD). Extensive development and validation have brought this modality to the forefront of quantitative, noninvasive assessment of CAD. High accuracy and reproducibility have also contributed to its widespread adoption as a gold standard to quantify myocardial ischemia. MPI also provides important information regarding myocardial viability and prognosis.
The basic principles of MPI have been validated in animal models and clinical trials over the past several decades.1–4 Accepted clinical guidelines for use, technical aspects of quality control, and protocols for MPI stress testing and imaging for positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been summarized in joint statements from the American Heart Association, American Society of Nuclear Cardiology, and American College of Cardiology,5 and the European Association of Nuclear Medicine and the European Society of Cardiology.6 This chapter highlights and summarizes the current clinical aspects of MPI. Emphasis is placed on describing the rationale and principles of MPI. The authors acknowledge variations in clinical practice based on local expertise and preference; however, space limitations do not permit a detailed discussion of all issues.
The first section reviews current clinical MPI using SPECT. Topics include radiotracers, instrumentation, procedures, and data analysis, including quantification and interpretation. Test performance and prognosis are reviewed under the general topic of interpretation. Assessment of myocardial viability with MPI also is briefly summarized (this is discussed more extensively in Chapter 55). Gated MPI to assess ventricular function is discussed in Chapter 56. Planar imaging produces lower image contrast and is reserved for special circumstances such as claustrophobic patients or patients unable to undergo SPECT imaging. An extensive review has been published.7 The second section reviews MPI with PET. The same general outline is followed in an abbreviated format with salient differences discussed between PET and SPECT.
MYOCARDIAL PERFUSION IMAGING WITH SPECT
Technical Aspects
Radiotracers
SPECT radionuclides in widespread clinical use include thallium 201 and Tc 99m radiotracers. Thallium 201 is a cyclotron-generated, monovalent cation with biologic properties analogous to those of potassium (K+). After intravenous administration, thallium 201 rapidly diffuses from the blood pool into the extravascular space where it is highly extracted by myocytes via the Na+,K+-ATPase pump. The initial myocardial uptake of thallium 201 is proportional to myocardial blood flow (MBF) and extraction fraction. Thallium 201 has the advantage of a high extraction fraction (approximately 85% to 88%), which is maintained up to MBF of approximately 2.5 mL/min/g. Myocardial territories distal to physiologically significant stenoses (i.e., ischemic myocardial regions) are unable to compensate sufficiently at stress with increased blood flow, and a perfusion defect can be detected as a relative reduction in radiotracer activity in this territory.
After administration, thallium 201 begins to redistribute significantly as it equilibrates with the extracellular concentration. In ischemic territories of lower MBF at rest, lower washout of radiotracer also contributes to equilibration. This more uniform myocardial radiotracer distribution at delayed (typically 4 hours) time points (“redistribution”) is deemed “reversible” compared with stress perfusion, and a functionally significant coronary stenosis can be noninvasively diagnosed. Previous studies have verified that administration of a small reinjection of thallium 201 of 37 MBq (1 mCi) at rest improves the detection of viable myocardium.8 This is a widely accepted clinical procedure to enhance the detection of viable myocardium.
Tc 99m-sestamibi and Tc 99m-tetrofosmin are the most commonly used clinical MPI radiotracers. Common properties include high lipophilicity, relatively high first-pass extraction, and insignificant radiotracer redistribution. Conceptually, they can be viewed as radiotracer “microspheres” that define MBF at the time of administration with no significant washout or redistribution at delayed imaging. Their first-pass extraction fractions are lower than that of thallium 201. Their linear relationships with blood flow are maintained up to MBF rates of approximately 2 mL/min/g. Theoretically, this can result in reduced sensitivity for detection of CAD; however, large clinical studies have shown similar overall accuracies compared with examinations performed with thallium 201. These radiotracers enter myocytes by passive diffusion, the diffusion rate of which is proportional to the regional myocardial flow. They are then sequestered in the mitochondria because of the electrochemical gradient, which is maintained in viable myocytes.
An advantage of Tc 99m radiotracers is the short half-life (6.02 hours). This short half-life permits a higher administered activity (approximately 8 to 10 times higher; 14 mSv [1.4 rem] for 1.11 GBq [30 mCi] activity), higher photon flux, and, consequently, higher count images compared with thallium 201. In addition, the higher photopeak of 140 keV results in less soft tissue attenuation, less scatter, and improved spatial resolution. These factors contribute to improved image quality compared with thallium 201, and reduce the time required for image acquisition. This is particularly important because ECG gating with Tc 99m radiotracers is commonly performed. Reduced imaging time also reduces patient discomfort and the likelihood of motion artifacts, which may compromise image quality. Tc 99m is also commercially available from generators, which are widely available at a low cost.
Tc 99m-sestamibi is a lipophilic cationic compound. Tc 99m-tetrofosmin is a diphosphine lipophilic cationic complex of Tc 99m. Tetrofosmin is reported to have faster clearance from the liver and lungs; however, the clinical significance with respect to improved diagnostic accuracy has yet to be established. A large retrospective study has shown that Tc 99m-tetrofosmin scans are essentially equivalent to Tc 99m-sestamibi in determining prognosis in high-risk patients.9 Examples of normal Tc 99m-sestamibi studies are shown in Figures 54-1 and 54-2. A gated study showing the utility of aiding in identifying a breast attenuation artifact is shown in Figure 54-3.
FIGURE 54-1 Normal Tc 99m-sestamibi exercise MPI shows inferior diaphragm attenuation in a male patient. Decreased activity inferiorly is typically mild, gradually increasing in severity from apex to base (arrows). BP, blood pressure; HLA, horizontal long axis; MPHR, maximum predicted heart rate; SA, short axis; VLA, vertical long axis.
FIGURE 54-2 Normal Tc 99m-sestamibi exercise MPI shows anterior breast attenuation in a female patient. Decreased activity anteriorly is typically mild, may gradually increase in severity from apex to base (arrows), and may not follow the typical coronary distribution of a perfusion defect in the left anterior descending artery territory. BP, blood pressure; HLA, horizontal long axis; MPHR, maximum predicted heart rate; SA, short axis; VLA, vertical long axis.
FIGURE 54-3 Normal Tc 99m-sestamibi exercise MPI shows anterior breast attenuation in a female patient. The rest gated study shows normal wall motion and normal wall thickening anteriorly. The rest perfusion study (ungated, second panel, left column) shows mild decreased activity anteriorly that does not involve the apex (noncoronary distribution for a left anterior descending artery stenosis). The stress perfusion study (ungated, second panel, right column) shows no perfusion defect on stress imaging. ED, end-diastole; ES, end-systole; HLA, horizontal long axis; SA, short axis; VLA, vertical long axis.
Instrumentation
Clinical gamma cameras used in SPECT have until more recently been similar in design and performance. The overall system resolution is limited by the lowest resolution component of the entire system. The limiting factor in clinical SPECT spatial resolution is collimator design. Typical Tc 99m full-width half-maximum SPECT spatial resolution is approximately 8 to 9 mm. This resolution can be improved by using “ultra-high” resolution collimation, but at the expense of reduced photon collection efficiency (i.e., lower camera sensitivity). For the same imaging time, higher resolution parallel hole collimation results in lower acquired counts. This can be compensated for by increasing imaging time.
A modest improvement in image resolution may not be deemed necessary if the diagnostic accuracy is not significantly improved, particularly if increasing imaging time results in a higher frequency of patient motion artifacts. Advanced instrumentation and software are currently being tested, with the goal of reducing imaging time while preserving image quality. The specific details of typical clinical instrumentation, including gamma cameras, collimators, and quality assurance (QA), have been well described in a detailed review article.10
Techniques in SPECT
Indications
The American College of Cardiology Foundation and the American Society of Nuclear Cardiology jointly published guidelines for appropriateness criteria.11 The indications deemed most appropriate were those in which patients presented with intermediate or high pretest probabilities in the categories described subsequently. MPI as a screening tool in very low pretest probability patients is generally considered inappropriate.
Appropriate patient populations include the following categories: (1) detection of CAD in symptomatic or asymptomatic patients (chest pain, newly diagnosed heart failure or diastolic dysfunction, newly diagnosed arrhythmias including atrial fibrillation and ventricular fibrillation); (2) risk assessment in patients with intermediate or high pretest probability of CAD; (3) risk assessment in patients with known coronary disease; and (4) evaluation of myocardial viability. Although other indications may be warranted, the above-listed indications were judged to be most appropriate in most referred cases. Typical MPI patterns are shown in Figures 54-4 through 54-6.
FIGURE 54-4 Myocardial ischemia. A, Tc 99m-sestamibi exercise-induced myocardial ischemia in the left anterior descending coronary artery (LAD) distribution confirmed at cardiac catheterization. Moderate and severe distal anterior (large yellow arrow), anteroseptal (white arrows), apical (red arrows), inferoseptal, and inferior (small yellow arrows) defects are not present on resting delayed images (mild inferior diaphragm attenuation also present). Bull’s-eye confirms reversibility of defects. LAD and right coronary artery (RCA) stenoses were confirmed at cardiac catheterization. BP, blood pressure; HLA, horizontal long axis; SA, short axis; VLA, vertical long axis. B, Gated Tc 99m-sestamibi MPI shows normal wall motion despite multivessel CAD. End-diastolic (left) and end-systolic (middle) volumes show concentric left ventricular contraction in all regions. Volume curves (right) show normal left ventricular end-diastolic and end-systolic volumes, and normal left ventricular ejection fraction of 58%.
FIGURE 54-5 MI. A, Tc 99m-sestamibi adenosine pharmacologic stress study shows MI without ischemia. The left ventricular cavity is markedly dilated. Severe distal anterior (small white arrows), anteroseptal (small yellow arrow), apical (red arrows), septal (large yellow arrow), and inferoseptal and inferior (large white arrow) defects are present on stress and rest images (i.e., fixed defects). Bull’s-eye confirms irreversibility of defects. HLA, horizontal long axis; ICD, implantable cardioverter-defibrillator; LV, left ventricle; SA, short axis; VLA, vertical long axis. B, Gated Tc 99m-sestamibi MPI shows markedly abnormal wall motion with severe global hypokinesis. End-diastolic (left) and end-systolic (middle) volumes show severe global hypokinesis in all regions. Volume curves (right) show abnormal left ventricular end-diastolic and end-systolic volumes, and abnormal left ventricular ejection fraction of 16%.
FIGURE 54-6 MI and myocardial ischemia. Tc 99m-sestamibi stress study shows MI and myocardial ischemia. Severe distal inferolateral (IL) and inferior defect is fixed (white arrows). Anterior (large yellow arrows) and anterolateral (AL) (red arrows) mild defects are reversible. Inferoseptal region (small yellow arrows), at the periphery of the infarct, shows partial improvement (compare stress with rest images). Bull’s-eye confirms reversibility and irreversibility of defects. HLA, horizontal long axis; LAD, left anterior descending coronary artery; LADD, left anterior descending diagonal coronary artery; LCx, left circumflex coronary artery; RCA, right coronary artery; SA, short axis; VLA, vertical long axis.
A unique clinical scenario for MPI is in the evaluation of acute coronary syndromes in patients presenting to the emergency department.12 In patients without a history of prior myocardial infarction (MI) and an intermediate probability of CAD, the sensitivity for detection is very high. In this population actively having chest pain at the time of radiotracer administration, the negative predictive value of normal MPI is 99% to 100%. If the chest pain has resolved at the time of radiotracer administration, test sensitivity is modestly reduced, and current guidelines recommend repeating radiotracer administration within 2 hours of symptom abatement.12 Because Tc 99m perfusion agents do not have significant redistribution for 6 hours, imaging can be performed after resolution of chest pain and still reflects the myocardial perfusion at the time administration. In patients presenting to the emergency department with chest pain that has resolved, and in whom recent myocardial injury has been excluded by a chest pain protocol including ECG and cardiac enzymes, a subsequent stress MPI study can be safely performed to exclude functional CAD.
As previously mentioned, an important specific indication is for the evaluation of myocardial viability. In most cases, SPECT MPI can accurately assess myocardial viability with a resting thallium 201 study followed by redistribution imaging, or with a stress-redistribution-reinjection thallium 201 protocol.
Contraindications
The contraindications for stress MPI are the same as those for exercise and pharmacologic stress testing without the radionuclide component with the additional concerns related to radiation exposure and radionuclide administration (e.g. pregnant or nursing woman). The radionuclides are administered in tracer quantities, and thus, they have no known pharmacologic side effects. Contraindications for exercise stress testing are well established and include ongoing MI or myocardial ischemia, unstable angina, hypotension, and unstable cardiovascular conditions which could result in exercise induced cardiac fatality. Additional relative contraindications may include those which limit the patient’s ability to exercise such as stroke, severe debilitation, severe peripheral vascular disease or underlying respiratory disease limiting exercise capacity, and altered mental status. Contraindications for pharmacologic stress testing are related to the specific pharmacologic stress agents administered, and are described in the next section under pharmacologic stress testing.
Pitfalls and Solutions
Quality Assurance
A QA program for gamma camera SPECT operation is essential to avoid artifacts, which could result in misinterpretation of test results. Proof of the establishment and diligent adherence to an equipment QA program is an integral part of laboratory accreditation by the American College of Radiology and the Intersocietal Commission for the Accreditation of Nuclear Medicine Laboratories. Conventional planar and specific SPECT and PET imaging QA procedures should be performed and recorded periodically. Daily QA includes ensuring correct isotope energy peak, and “daily floods” to assess gamma camera imaging field uniformity. Weekly QA includes resolution and linearity checks with “bar phantoms.” Many manufacturers include software that can automatically compute planar measurements including differential and integral flood field uniformity and intrinsic linear resolution from bar phantoms.10
Many SPECT systems include attenuation correction components, using radioactive scanning line sources, low-end CT devices, or diagnostic-quality CT. These attenuation-correcting devices require their own set of daily, weekly, and annual QA procedures. Likewise, PET and PET/CT scanners have specific QA requirements, as specified by the equipment manufacturers and as mandated by laboratory accreditation agencies. Typical PET and PET/CT QA procedures have been reviewed in a more recent publication.10
Description of Techniques and Protocols
Radionuclide Imaging Protocols
Stress Protocols—Pharmacologic versus Exercise Protocols
The most common types of stress protocols in the United States are exercise treadmill and pharmacologic stress test. Exercise stress testing is preferred over pharmacologic testing because it allows a more physiologic assessment of the patient’s functional capacity and symptoms and the hemodynamic response to stress. Additionally, exercise generally results in lower radiotracer uptake in the gastrointestinal tract, improving image quality. The pharmacologic agents routinely used in clinical practice are adenosine, dipyridamole, and dobutamine. Pharmacologic stress tests can be performed on patients who cannot tolerate physical exercise. Patients with left bundle branch block, a known cause of false-positive septal perfusion defects with exercise, may undergo stress testing performed with dipyridamole to decrease the potential for this artifact. Other limiting factors in exercise stress testing are physical deconditioning, peripheral vascular disease, history of stroke, lower extremity amputation, and severe chronic obstructive pulmonary disease.
Exercise Protocols
In normal individuals, peak exercise increases heart rate and myocardial oxygen demand. At peak exercise, MBF typically increases approximately three to four times over that of rest. In patients with significant CAD, this mechanism fails to increase blood flow adequately distal to an obstructive lesion, resulting in an imbalance between oxygen supply and demand.
Before exercise, patients should have nothing per mouth after midnight, and be instructed to wear loose, comfortable clothing. We recommend abstinence from caffeinated substances because of the possibility that a pharmacologic stress test may be needed if an inadequate maximal heart rate is reached during maximal exercise stress testing. Intravenous access is obtained typically in the antecubital vein, ECG leads are securely placed, and the patient’s hemodynamic status is closely monitored and recorded throughout the procedure. The radiotracer is administered at peak or target heart rate while exercising. Hemodynamic and ECG monitoring are continued for at least 5 minutes into the recovery period, or until symptoms or ECG changes resolve. Patients with good functional capacity can typically exercise on the Bruce protocol, which rapidly increases in speed and incline. Patients who are older or debilitated may use a modified Bruce exercise protocol, which more gradually increases in speed and incline to achieve target heart rate. In individuals with significant limitations of physical tolerance or in patients 3 to 5 days post-MI, a Naughton protocol or other low-level exercise protocol may be used at the physician’s discretion.
Pharmacologic Protocols—Adenosine
Adenosine is a coronary vasodilator commonly used in combination with MPI.13 This is a purine base, endogenously produced by myocardial smooth muscle and vascular endothelium. It is derived through extracellular dephosphorylation of adenosine triphosphate (ATP) and adenosine diphosphate (ADP). There are four known receptor subtypes specific for adenosine. A2A is considered a cardiac specific receptor, through which coronary vasodilation is initiated after intravenous adenosine administration.
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