Nuclear Cardiology and Molecular Imaging
Sean R. McMahon
Josiah Bote
William Lane Duvall
INTRODUCTION
Nuclear cardiology plays a fundamental role in the noninvasive diagnosis and management of cardiovascular disease, which is the leading cause of death in the Western world. It employs radiolabeled tracers, predominantly technetium-99m (99mTc), in the performance of cardiovascular imaging studies, which include myocardial perfusion imaging (MPI), metabolic imaging, ventricular function assessment, cardiac amyloid studies, and myocardial innervation imaging. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) used for MPI in the evaluation of coronary artery disease (CAD) are the mainstays of nuclear cardiology imaging. However, nuclear cardiology has also expanded beyond the assessment of obstructive CAD to targeted metabolic imaging with F-18-flourodeoxyglucose (18F-FDG) used in the evaluation of myocardial viability and in the diagnosis of sarcoidosis, to technetium-99m-pyrophosphate (99mTc-PYP) used for diagnosis of cardiac amyloidosis, and to iodine-123-metaiodobenzylguanidine (123I-mIBG) for the identification of cardiac neuronal dysfunction. With millions of nuclear cardiology imaging procedures performed annually, the diagnostic information gained from these studies allows physicians to cost-effectively manage their patients with known or suspected cardiovascular disease. The role of nuclear cardiology and molecular imaging in patient management continues to evolve, and its clinical use continues to expand.
FUNDAMENTALS OF CARDIAC NUCLEAR SCINTIGRAPHY
Physical Principles and Instrumentation
Nuclear cardiology is based on imaging the radioactive decay of isotopes. To become more stable, unstable isotopes undergo radioactive decay, which emits energy that can be collected and used for image construction. Gamma decay emits photons, also known as gamma rays, which are used in SPECT, and positron decay creates an annihilation event that produces two high-energy photons used in PET.
Isotopes for medical imaging are produced from their parent nuclei via four methods, which are fission, neutron activation, cyclotron bombardment, and generator elution.1 Fission and neutron activation occur in a nuclear reactor. A cyclotron is a linear accelerator that bombards stable nuclei with high-energy charged particles to create new elements. Generators are used to store a mother isotope produced in a nuclear reactor, and, when needed, the daughter isotope is eluted and combined into a radiopharmaceutical.
Thallium-201 (201Tl) was the first radioactive isotope used in widespread SPECT MPI. It is a potassium analog with a half-life of 73 hours, and emits several gamma rays with different energy spectra (69-80 keV, 135 keV, and 167 keV). 201Tl is produced in a cyclotron. Owing to the limitations of thallium, the long half-life resulting in greater radiation exposure and low-energy photons resulting in suboptimal gated images, 99mTc was introduced as an alternative agent. 99mTc emits a higher energy photon of 140 keV and has a shorter half-life of 6 hours, resulting in superior image quality and lower effective dose to the patient. 99mTc is commercially acquired from a molybdenum-99 (99Mo) generator.
Radionuclides used in PET imaging decay by emitting positrons. When a positron interacts with an electron, an annihilation event ensues, and two 511 keV photons are emitted at a 180-degree angle to each other and detected by the PET camera system. The two isotopes used for PET MPI are Rb-82, which has a half-life of 75 seconds and is produced from a strontium-82 (82Sr) generator, and N-13 ammonia (13N) with a half-life of 10 minutes, which is produced in a cyclotron. 18F-FDG, which is produced in a cyclotron, has a half-life of 110 minutes, and is the principal radiopharmaceutical for PET metabolic imaging. Oxygen-15-labeled water (15O water) can also be used as a radiotracer for quantifying myocardial blood flow, but is not routinely used clinically.
Current SPECT cameras employ either traditional sodium-iodide (Na-I) crystals or newer high-efficiency cadmium-zinc-telluride (CZT) crystals.2 Conventional, dual-head SPECT cameras have two camera heads attached to a gantry that rotates around the patient in a step-and-shoot or continuous manner while acquiring images over a 180-degree arc. The camera heads are composed of a collimator, Na-I crystal, and photomultiplier tubes. The crystals produce visible light photons when struck by gamma rays that are converted into electronic signals, allowing for localization of the origin of the activity. High-efficiency cameras have improved sensitivity, superior energy resolution, and finer spatial resolution through the utilization of cardiocentric collimation and camera geometry along with CZT crystals.
PET cameras differ from SPECT cameras because the scintillation detectors surround a patient in a 360-degree
circumferential ring.3 This camera geometry is needed because PET radioisotopes decay by positron emission, which results in two photon pairs that strike opposing detectors at a 180-degree angle from each other. The simultaneous coincidence detection of the two photons is made possible by the detectors completely surrounding the area being imaged. Coincidence events are recorded and reconstruction algorithms used to create the projections of the acquired myocardial or extracardiac activity.3
circumferential ring.3 This camera geometry is needed because PET radioisotopes decay by positron emission, which results in two photon pairs that strike opposing detectors at a 180-degree angle from each other. The simultaneous coincidence detection of the two photons is made possible by the detectors completely surrounding the area being imaged. Coincidence events are recorded and reconstruction algorithms used to create the projections of the acquired myocardial or extracardiac activity.3
TABLE 35.1 Pretest Probability of Coronary Artery Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Myocardial Perfusion Imaging
Indications
MPI is a widely available and frequently employed modality in the assessment of known or suspected CAD, providing both diagnostic and prognostic information. Both SPECT and PET MPI can accurately determine the presence, location, and severity of ischemia or infarction, thus indirectly establishing the diagnosis of obstructive CAD. Furthermore, their results provide useful prognostic information that correlates with future risk of adverse cardiovascular events. Most SPECT or PET MPI studies are performed with the intent to evaluate symptoms, provide risk assessment, or to guide therapy.
Evaluation of Symptoms With Single-Photon Emission Computed Tomography and Positron Emission Tomography Myocardial Perfusion Imaging. Both SPECT and PET MPI are frequently performed to evaluate for underlying obstructive CAD in patients with symptoms suggestive of angina. The sensitivity of SPECT MPI to detect obstructive CAD has been reported as 88% with a specificity of 76%, whereas PET MPI has a reported sensitivity and specificity of 93% and 81%, respectively.4 When evaluating chest pain syndromes, careful patient selection for MPI is needed. Applying concepts of Bayesian probability, a positive result is less likely to be a true positive in low-risk individuals and very likely to be true positive in high-risk individuals (Table 35.1). Hence, in patients with very low pretest probability defined as less than 10% probability for CAD, with interpretable electrocardiograms (ECGs) and who are able to exercise, recommendations are to avoid MPI in favor of treadmill exercise ECG testing (see Chapter 32).5 Similarly, in patients with very high pretest probability (>90%), MPI will not significantly alter posttest probability. Accordingly, stress MPI is best suited for evaluation of symptoms in intermediate-risk patients.
Risk Assessment: Prognostic Implications With Single-Photon Emission Computed Tomography and Positron Emission Tomography Myocardial Perfusion Imaging. Assessment of prognosis and risk is well established with SPECT and PET MPI. Patients with normal perfusion and left ventricular (LV) function have an excellent prognosis with a combined death or nonfatal myocardial infarction (MI) rate of less than 1% per year.6 This, however, is increased in higher risk subsets such as patients with diabetes, reduced ejection fraction, or increased end-diastolic volume.7,8 Furthermore, in patients who are able to exercise, the ability to achieve at least 10 metabolic equivalents (METs) has been shown to correlate with a low prevalence of underlying ischemia and very low rates of cardiac events.9 Strong negative predictive value is also seen in patients who have normal stress-only imaging.10 Conversely, risk has been shown to increase with the extent of myocardial perfusion abnormalities. In patients with LV perfusion defects of less than 10%, 10% to 20%, and greater than 20%, the risk of death, MI, or revascularization was 27%, 31%, and 43% over a 46-month follow-up time, respectively.11 Regardless of perfusion abnormalities, depressed LV function has been associated with a 7.4% rate of nonfatal MI or cardiac death versus 1.8 in normal individuals.12 Transient ischemic dilation (TID) of the LV postexercise is a marker of extensive CAD. One large meta-analysis found TID to have a sensitivity
of 44% and specificity of 88% for the detection of extensive CAD, and important prognostic implications with up to a 6% annual mortality rate if TID is accompanied by ischemia.13
of 44% and specificity of 88% for the detection of extensive CAD, and important prognostic implications with up to a 6% annual mortality rate if TID is accompanied by ischemia.13
The prognostic abilities of SPECT and PET have further been amplified by the use of attenuation correction (AC) and myocardial blood flow quantification techniques, respectively.14,15,16 The incorporation of AC has been shown to decrease the total interpreted burden of ischemia or infarct as measured by the summed stress score (SSS), and has demonstrated superior prognostic availability, likely due to decreased contamination by false-positive results.14 Another modality useful in risk assessment is myocardial flow reserve (MFR), a quantitative measurement of blood flow derived from PET MPI dynamic acquisitions that has validated prognostic utility independently or when added to perfusion images. In a study with 2783 patients with known or suspected CAD, an MFR less than 1.5 was associated independently with a sixfold increased risk of death. Conversely, with an MFR of greater than 2, prognosis was excellent. A low MFR was associated with poor outcomes even in the setting of normal PET MPI.16,17
Therapy Guidance. Stress testing with or without MPI is commonly used for evaluation of acute chest pain in the emergency department (ED), and is useful for decision-making when applied to the appropriate patient population.18 Clinically derived risk scores may aid in the identification of the appropriate patients who can be safely discharged from the ED without stress testing versus those who benefit from further evaluation.19
In those with stable CAD who undergo angiography, MPI may provide further information regarding the hemodynamic impact of indeterminate lesions to aid in the decision about revascularization (Figure 35.1).20 In asymptomatic patients, MPI is reasonable to assess risk and guide therapy after acute coronary syndromes, with incomplete revascularization where further revascularization is feasible or if primary angiography was not performed initially.5,21
Myocardial ischemia is understood to contribute to perioperative morbidity and mortality. Hence, in the preoperative evaluation of patients undergoing noncardiac surgery, MPI plays a role in risk stratification. MPI is deemed inappropriate for assessment before low-risk procedures; however, it is appropriate before intermediate or high-risk procedures in patients with cardiac risk factors and poor functional capacity.22
The additive value of coronary artery calcification (CAC), which is available from combined SPECT/computed tomography (CT) and PET/CT systems, is particularly useful in those patients with normal myocardial perfusion.23 In patients with a paucity of CAC, there is an associated excellent prognosis and little utility for primary prevention outside of traditional guidelines. However, in patients with normal MPI but significant CAC, aggressive risk factor modification may be pursued. Furthermore, the incorporation of CT has been shown to add to diagnostic accuracy and yields independent prognostic information regardless of the MPI results. In patients with a positive MPI, the presence of CAC is associated with a 70% true-positive result compared to only 16% in those with no CAC.24,25
 FIGURE 35.1 Observed cardiac death rates over the follow-up period in patients undergoing revascularization versus medical therapy as a function of the amount of inducible ischemia. As the amount of ischemic myocardium increases beyond 10%, the benefit of revascularization increases as well. (Reprinted with permission from Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation. 2003;107(23):2900-2907.) |
Stress Modality Selection
Once the decision is made to pursue MPI, choosing the appropriate modality is determined by a number of patient factors. Typically, in patients who can exercise, treadmill testing is done with injection of radioisotope at peak exercise, ensuring that the patient has achieved 85% of maximal age-predicted heart rate and adequately increased myocardial work. In patients unable to exercise adequately or those who fail to achieve target heart rate, pharmacologic stress testing is an appropriate alternative. Most patients undergoing pharmacologic stress testing do so with administration of a coronary vasodilator. Coronary vasodilators such as dipyridamole, adenosine, and regadenoson activate the adenosine receptors, resulting in coronary vasodilatation and hyperemia. In diseased arteries, the vasodilation is minimal, resulting in less radiotracer uptake than in healthy myocardium. Both adenosine and dipyridamole are nonselective adenosine agonists activating A1, A2B, and A3 in addition to A2A receptors. However, regadenoson is a selective A2A receptor agonist, resulting in fewer side effects associated with nonspecific adenosine receptor activation.26
Less frequently, dobutamine is used to increase myocardial work by stimulating beta-1 and beta-2 receptors. The result is similar to exercise stress with increased myocardial blood flow in nonobstructed coronary arteries and the ability to detect regional variation of radioisotope uptake. Dobutamine stress protocols utilize incremental increases of dobutamine to target 85% of maximum age-predicted heart rate response. Atropine may be used as an adjunct to increase response to achieve target heart rate.
IMAGING PROTOCOLS
Single-Photon Emission Computed Tomography Imaging Protocol
SPECT imaging protocols may vary depending on clinical factors, equipment, and workflow capabilities. Facilities with newer high-efficiency SPECT cameras benefit from lower radiation exposure and decreased imaging time. The most frequently employed SPECT MPI protocol is a single-day, rest-stress (low-dose/high-dose 99mTc) study. This protocol involves injection of 99mTc at rest followed by rest imaging, then proceeding to stress with repeat isotope injection while undergoing stress (exercise, dobutamine, or vasodilator), followed by stress imaging. However, in obese patients, a 2-day, high-radiotracer-dose stress followed by high-dose rest imaging protocol is often used to allow for diagnostic quality images. In selected patients with low to intermediate risk, a stress-first approach may allow for a reduction in radiation exposure, patient testing time, and an increase in laboratory throughput by proceeding to rest images only if stress perfusion images are abnormal. Patients with a normal stress-only MPI have demonstrated low event rates similar to those who have undergone a full rest-stress SPECT,10 but the use of AC is necessary to increase the yield of the protocol.
Attenuation artifacts have the potential to degrade accuracy of SPECT MPI. Several methods have been implemented to overcome attenuation artifacts including prone imaging, scanning line sources, and CT AC. In a large meta-analysis, the pooled sensitivities for non-AC versus line source or CT AC were 80% and 84%, respectively, with a sensitivity of 68% and 80%, respectively.27 Furthermore, the CT used for application of AC may provide both prognostic and diagnostic information when evaluated for the burden of CAC. The addition of a formal CAC score has been shown to increase the sensitivity of SPECT from 76% to 86% for detection of CAD.28
Acute rest-only MPI is a less commonly used technique that has been found to be accurate and useful in the evaluation of acute chest pain in the ED. This strategy has been useful to expedite diagnosis of MI and safely triage patients with normal results to discharge, resulting in significant hospital cost savings.29 However, coronary CTA has been shown to be highly reliable and with rapid turnaround time paired with cost-effectiveness; thus, CTA has largely supplanted acute rest MPI studies in the ED setting.18
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