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.

The major disadvantages of thallium 201 are related to its physical properties compared with the properties of Tc 99m radiotracers. The long physical radiotracer half-life (73 hours) limits the administered activity to 148 to 167 MBq (4 to 4.5 mCi) per day because of radiation dose considerations (148 MBq [4 mCi] of activity delivers 24 mSv [2.4 rem] of whole body radiation dose equivalent). Because of radiation dose limitations, low photon flux contributes to lower true count images compared with Tc 99m radiotracer studies. The photopeak of thallium 201 (69 to 83 keV; 95% abundance) is also relatively low; this increases the amount of radiation absorbed and the scatter fraction. Also, spatial resolution and energy resolution of gamma camera imaging is better for the higher 140 keV gamma ray energy of Tc 99m than for the lower energies of thallium 201. The combination of these effects, especially in large patients, adversely affects thallium 201 image quality and can make interpretation difficult.

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

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.

Another unique use of MPI is for risk assessment. A large body of knowledge has shown that the defect size and severity, and the amount of reversibility by MPI are highly predictive of subsequent cardiac events. The negative predictive value of a normal or mildly abnormal study is also very high; these patients have a cardiac mortality of less than 1% per year, which is approximately the same as that of the general population. A highly abnormal study with severe and extensive perfusion abnormalities can have a cardiac event rate of 6% to 8% per year. This significantly higher incidence of adverse cardiac events, including subsequent MI, can have an impact on subsequent clinical management decisions.

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

Radionuclide Imaging Protocols