CHAPTER 18: NUCLEAR CARDIOLOGY

Nuclear cardiology is an integral part of routine cardiovascular practice. This chapter provides a synopsis of nuclear cardiology procedures and the published evidence of their role in the diagnosis, risk assessment, and management of patients with suspected or known coronary artery disease (CAD). In the technical section, the focus is on single-photon emission computed tomography (SPECT) since positron emission tomography (PET) is the subject of Chapter 19. Guidelines and appropriate use criteria combine SPECT and PET, and considerations of the applications are similar; therefore, the clinical portions of this chapter discuss both approaches. While nuclear cardiology has a broad potential role in molecular imaging, myocardial perfusion imaging (MPI) with SPECT and PET makes up the vast majority of current clinical nuclear cardiology procedures; hence, MPI is the primary subject of this chapter. In the chapter, CAD generally refers to the presence of an obstructive stenosis, in contradistinction to coronary atherosclerosis, which is used to denote the presence of any atherosclerotic plaque in the coronary arteries. The term nuclear MPI will be used when the discussion refers to both SPECT and PET-MPI approaches.

Historical Perspectives in Nuclear Cardiology

The roots of nuclear cardiology began with the assessment of radioactivity transit times in the central circulation in the 1920s,¹ followed by clinical assessment of cardiac output in the late 1940s.² The Anger scintillation camera, the imaging device still used today for the majority of all nuclear cardiology procedures, ushered in the practical clinical use of nuclear cardiology in the late 1960s by providing images of the cardiac distribution of radioactivity. The commercial availability of thallium-201 (²⁰¹Tl) in 1976 initiated the broad application of clinical MPI. In the early 1980s, SPECT, using a rotating Anger camera detector, became widely available, increasing the ability to localize and quantify regional myocardial perfusion defects. In 1990, technetium-99m (^99mTc)-sestamibi was approved for use in the United States, followed shortly thereafter by ^99mTc-tetrofosmin. The higher myocardial count rates of the ^99mTc agents made it possible to perform electrocardiogram (ECG)-gated SPECT-MPI by obtaining images from the different parts of the cardiac cycle (gated SPECT). By 2003, more than 90% of SPECT-MPI used gated SPECT, providing routine objective clinical assessments of rest and stress myocardial perfusion and function.³ PET scanning became available in the early 1980s and its application for myocardial viability using ¹⁸F-Fludeoxyglucose (FDG) and MPI with ¹³N-ammonia and ¹⁵O-H₂O was described soon thereafter. In the early 1990s, rubidium-82 (⁸²Rb), a generator-produced PET radiopharmaceutical, became available, broadening clinical adoption of PET-MPI as well as opening the possibility of dynamic SPECT-MPI to quantify bloodflow.

There has been an evolution over time of the applications of clinical nuclear cardiology, roughly corresponding to the decades since its introduction. In the 1970s, nuclear cardiology procedures were validated for the detection of CAD, and their application was developed in conjunction with the concepts of Bayesian analysis. In the 1980s, first reports of the prognostic application of MPI appeared, followed by reports of its incremental value for risk stratification in a variety of patient subsets in the 1990s. Coupled with this growing body of supporting evidence, the establishment of the American Society of Nuclear Cardiology (ASNC) led to a period of marked growth of the field. In the decade of the 2000s, the concept of predicting benefit from revascularization for improving referral to coronary angiography emerged. In the current decade, with the imperative to reduce the growing costs of medical care, the focus of interest has turned to assessing the value of nuclear cardiology as it impacts medical care and improves patient outcomes.

Basic Concepts of Gated SPECT-MPI

SPECT-MPI is performed using a scintillation camera and an intravenously injected radiopharmaceutical that distributes to the heart in proportion to regional myocardial perfusion. Various standardized SPECT-MPI protocols are used for imaging at rest and after exercise or pharmacologic stress. For SPECT, conventional scintillation camera detectors rotate to cover a 180-degree arc around the patient in a semicircular or elliptical fashion, collecting a series of planar projection images at regular angular intervals. The three-dimensional (3D) distribution of radioactivity in the myocardium is then mathematically reconstructed from the two-dimensional projections, and the resulting data are displayed in series of slices in the short-axis, vertical long-axis, and horizontal long-axis orientations. For gated SPECT (Fig. 18–1), the feature that distinguishes it from nongated SPECT is that the projection images are acquired in 8 to 16 phases of the cardiac cycle based on ECG triggering (gating). Reconstruction of a summation of the frames is used to assess myocardial perfusion, and reconstruction of each of the separate phases is used to evaluate ventricular function. Recently, solid-state detector cameras with new acquisition geometries have been introduced that do not require detector rotation around the patient and offer the potential for reducing the time and the patient radiation dose associated with SPECT-MPI.^4,5

Radiopharmaceuticals

The radiopharmaceuticals used for SPECT-MPI and their properties (Table 18–1) share the characteristic that they are accumulated in viable myocardium in proportion to regional myocardial blood flow (Fig. 18–2). The concept that CAD can be detected with this approach is based on the ability to detect a reduction in myocardial perfusion in a region supplied by a significantly stenosed vessel when compared with a normal region during hyperemia. The relationship between the quantitative degree of coronary artery narrowing and the maximal hyperemic response was first elucidated by Gould in 1974.⁶ Resting myocardial perfusion is normal until the luminal diameter narrowing of a coronary artery exceeds 90% to 95%. With maximal coronary hyperemia produced by dipyridamole, Gould demonstrated a progressive decrease in the hyperemic response associated with increasing degrees of stenosis above a threshold of 50% diameter narrowing.

Since the work of Gould, it has become widely recognized that multiple factors beyond focal percent stenosis can also affect the degree of hyperemia achievable in diseased vessels. These include stenosis length, myocardial mass distal to the stenosis, plaque composition, diffuse atherosclerosis, nonatherosclerotic microvascular disease, and endothelial dysfunction.^7,8 In general, a significant reduction in maximal hyperemia is usually present when stenosis severity exceeds 70%.⁹ However, when compared to assessment of fractional flow reserve (FFR), considered the gold standard, only 35% of vessels visually assessed as having 50% to 70% stenosis manifest a decrease in maximal hyperemia.¹⁰ With quantitative coronary angiography, only one-third of vessels with more than 50% stenosis manifest normal hyperemic response.¹¹

The ability of nuclear MPI to assess the hyperemic response is related to the degree of extraction of the myocardial perfusion tracer employed during its first pass through the myocardium. The amount of the injected tracer in the myocardium at the time of imaging (net extraction) is a function of the proportion extracted by the myocardium (extraction fraction) and the amount retained at the time of imaging. With the exception of oxygen-15 water, which is generally used only for research purposes, all available nuclear radiopharmaceuticals manifest a roll-off in extraction as coronary flow reaches high levels. Because moderate stenoses may produce a decrease in flow only at very high flow rates, the net extraction is one of the most important characteristics of perfusion tracers. Figure 18–2 illustrates the net extraction of the various SPECT and PET myocardial perfusion tracers. Figure 18–3 illustrates a highly extracted and retained PET tracer (Flurpiridaz-F18) and compares it to ^99mTc-sestamibi.¹²

Thallium-201

The monovalent cation thallium is a potassium analog that is avidly extracted from the blood by myocardial cells. A cyclotron-generated radionuclide with a half-life of 73 hours, ²⁰¹Tl emits photons at 69 to 80 keV (90% abundance) and at 167 keV (10% abundance). Because of its relatively long half-life of 73 hours, the absorbed radiation dose per unit injected is much higher with ²⁰¹Tl than with ^99mTc agents. For the same radiation dose to the patient, approximately one-tenth as much radioactivity with ²⁰¹Tl can be injected compared with ^99mTc, making imaging times longer and generally providing lower information density (“counts”) in the clinical images. ²⁰¹Tl has superior physiologic properties for MPI compared with the ^99mTc agents. Unlike the ^99mTc agents, with ²⁰¹Tl, the linear relationship between myocardial blood flow and ²⁰¹Tl uptake is more maintained during hyperemic stress up to high levels of flow (approximately > 3 mL/min/g) before the previously noted roll-off in uptake occurs¹³ (see Fig. 18–2). Unbound within the myocardial cells, ²⁰¹Tl redistributes over time^14,15; its initial distribution is proportional to regional myocardial perfusion, and at equilibrium, the distribution of ²⁰¹Tl is proportional to the regional potassium pool, which represents viable myocardium.¹⁶ By virtue of these properties, myocardial perfusion defect reversibility can be imaged at multiple times with a single injection of ²⁰¹Tl. The mechanisms of ²⁰¹Tl redistribution include differential washout rates between hypoperfused but viable myocardium and normal zones, and washin from the blood to initially hypoperfused zones. For practical purposes, the time it takes for ²⁰¹Tl to reach its ultimate distribution in viable myocardium varies, such that delayed redistribution imaging (at 24 hours rather than 3-4 hours) is commonly used to gain the greatest amount of information from thallium studies regarding defect reversibility and myocardial viability.^17,18

The washout rate of ²⁰¹Tl is a function of the concentration gradient between the myocardial cell and the blood. Hyperinsulinemic states drive thallium into cells, leading to reduced blood ²⁰¹Tl concentrations and slowing redistribution; thus carbohydrates are avoided prior to and for 4 hours following ²⁰¹Tl injection.¹³ An inverse relationship between the degree of coronary stenosis and subsequent redistribution of ²⁰¹Tl (ie, late redistribution) has been reported.¹⁸ Late redistribution of ²⁰¹Tl—that is, defect reversibility seen on 24-hour imaging and not seen on standard 4-hour redistribution imaging—was reported to be common with standard ²⁰¹Tl SPECT stress/4-hour/late redistribution protocols.¹⁹ 24-hour imaging was also shown to detect a substantially greater number of viable segments than stress/reinjection protocols (P < .0001).¹⁷

^99mTc-Sestamibi and ^99mTc-Tetrofosmin

^99mTc is produced from a molybdenum-99 generator, has a half-life of 6 hours, and emits monoenergetic gamma rays at 140 keV. The greater count rates achieved clinically with ^99mTc agents, compared to ²⁰¹Tl, result in improved image quality. Following extraction from the blood, ^99mTc-sestamibi and ^99mTc-tetrofosmin are quickly bound by mitochondria, and only a limited amount of myocardial washout (or washin) occurs over time.^13,20 Thus, with these tracers, separate rest and stress injections are required to evaluate perfusion defect reversibility. A drawback of both perfusion tracers is that they exhibit a greater roll-off of extraction with increasing coronary flow and lower net extraction by the myocardium than thallium.²¹ Another drawback of the ^99mTc tracers is their gastrointestinal excretion, resulting in greater hepatic and gastrointestinal uptake than thallium, not infrequently interfering with inferior myocardial wall visualization, particularly after rest injection.¹³

From a practical standpoint, a main advantage of the ^99mTc agents is greater flexibility than provided by ²⁰¹Tl. Because of their mitochondrial binding, they do not require imaging to commence immediately after the stress injection for maximal sensitivity in detecting perfusion defects. In contrast, with ²⁰¹Tl, imaging must be performed soon after stress testing (recommended to begin within 10-15 minutes) because rapid redistribution can cause mild perfusion defects to become undetectable by the time imaging begins. ^99mTc sestamibi or tetrofosmin, imaging can commence as late as 2 hours after injection. Additionally, when patient motion, soft tissue attenuation, or other artifact is considered to be responsible for the production of a perfusion defect, image acquisition can simply be repeated (eg, in the prone position²²), without concern that defects may no longer be detectable due to redistribution of the tracer.

SPECT-MPI Stress Protocols

Patient Preparation for Stress Imaging: Anti-Ischemic Medications and Caffeine-Containing Compounds

In general, for purposes of diagnosis or initial risk stratification, stress nuclear MPI is performed with the patient off anti-ischemic medications,²³ because these medications may limit the development of ischemia during the stress test. When feasible, use of beta-blockers or long-acting calcium channel blockers should be discontinued for 48 hours before, and long-acting nitrates should be discontinued for 12 hours before, stress imaging.²³ With respect to exercise, lower peak heart rates would be achieved in patients on beta-blockers, reducing sensitivity for detection of hemodynamically significant CAD. It has also been shown that patients with normal exercise SPECT-MPI who achieve less than 80% to 85% maximum predicted heart rate (MPHR) are at greater prognostic risk than those who achieve maximal workload.^24,25 With respect to pharmacologic stress, it has been²⁶ reported that compared with SPECT-MPI performed off cardiac medications, dipyridamole SPECT-MPI performed on medications was associated with smaller reversible perfusion defects and a marked lowering of overall sensitivity for detecting disease in individual vessels (62% vs 92%).²⁷ Another study has demonstrated that acute beta blockade reduces the size of adenosine stress myocardial perfusion defects and doubles the likelihood of false-negative studies (14.3% vs 28.6%).²⁸ Although initial risk stratification studies are generally performed off cardiac active medications, potentially useful clinical information regarding ischemia in daily life can be derived from exercise or pharmacologic SPECT-MPI performed on cardiac medications.²³

With respect to caffeine, patients should be off of compounds containing caffeine or theophylline, as well as cardiac-active medications, prior to vasodilator stress testing.²⁹ In general, discontinuation of caffeine-containing medicines, foods, or beverages for 24 hours prior to use of adenosine or dipyridamole, and 12 hours prior to use of regadenoson, is recommended.^23,30 Methylxanthines, such as theophylline or caffeine, block adenosine binding and can reduce the coronary vasodilation effects of adenosine, regadenoson, or dipyridamole, leading to false-negative stress perfusion studies. In a recent multicenter randomized study, patients underwent two regadenoson stress MPI procedures, once with and once without caffeine prior to regadenoson administration. In the scan in which the patients had received caffeine prior to regadenoson stress, there was a shift of the MPI results to a lower ischemia category in a majority of patients, and the number of reversible segments decreased by 60%.³¹ The results of this study were added to the regadenoson package insert in 2011.³² Given variations in the amount of caffeine in coffee, tea, and various foods, as well as interindividual variations in the half-life of caffeine in the blood, abstinence from caffeine for the longer period for all agents (24 hours) would be preferred. A recent study found residual serum caffeine in 8% of participants despite careful instruction prior to the study.⁴²

The recommendations are that patients avoid caffeine for 24 hours prior to their study, in case there is a need for administration of pharmacologic stress. If a patient fails to achieve 85% of MPHR during exercise, regadenoson can be injected prior to tracer injection while the patient is still exercising or immediately after, as discussed below, provided the patient is off of caffeine.^33,36 Regarding supplementing an inadequate exercise test with regadenoson, injecting regadenoson during a slow walk recovery and verifying the absence of ischemic ST-segment changes prior to injecting regadenoson may provide a greater margin of safety than injecting regadenoson at peak exercise stress.³⁶ Of note, even in patients referred for pharmacologic stress, 50% to 60% of patients are able to undergo adequate exercise stress, allowing the measurement of exercise capacity and avoiding stress pharmacologic drug costs and side effects.^34,35 Dipyridamole-containing medications should be held for 48 hours prior to adenosine or regadenoson stress, because they can potentiate the effects of the vasodilator stress agents.

Exercise Stress Protocols

Exercise stress is preferred over pharmacologic stress for use with SPECT-MPI in patients who can exercise adequately because it allows assessment of exercise capacity, heart rate (HR), and blood pressure (BP) responses (including HR reserve and HR recovery); symptoms; and ST-segment response (although such ST-segment changes may occur with pharmacologic stress). This provides additional clinical information that can be useful in clinical decision making.^23,37 For exercise SPECT-MPI, the tracer is injected at maximal stress. Exercise is continued for an additional 1 minute at peak workload to ensure that the myocardial tracer uptake reflects distribution of blood flow at the time of maximum flow achieved. Unless contraindicated, exercise stress testing should be maximal, terminated by symptoms, and not based on the HR achieved. If less than 85% of age-adjusted MPHR (220 – age) is achieved, and unless there is clear clinical or ECG evidence of ischemia, the stress is considered inadequate, and switching to pharmacologic stress should be considered. When the exercise duration is less than 3 minutes on the Bruce protocol (or five or more metabolic equivalents [METs]), a normal SPECT is associated with a much greater event rate than in those with greater exercise capacity, similar to that seen in patients deemed unable to exercise.³⁸ Postexercise stress imaging routinely commences 15 minutes after stress but , as noted above, with the ^99mTc perfusion tracers, imaging can begin up to 2 hours after stress injection. The advantage of starting imaging earlier is that it increases the opportunity to observe stress-induced wall motion abnormalities (“stunning”) during gated SPECT acquisition.³⁹ Initiating image acquisition too early, before the patient has not fully recovered from stress, potentially introduces artifactual defects related to increased depth of respiration very early after stress, causing the heart to gradually move cephalad during the early portion of SPECT acquisition. (“upward creep of the heart”)⁴⁰

Pharmacologic Stress Protocols

Vasodilator Stress (SPECT or PET)

For patients who cannot achieve an adequate level of exercise (at least 85% of MPHR²³) pharmacologic stress testing is the preferred approach to stress.⁴¹ The preferred pharmacologic stress agents for SPECT -and PET-MPI are coronary vasodilators: adenosine, regadenoson, or dipyridamole (Table 18–2). These agents provide a three- to five-fold increase in coronary flow. Dipyridamole blocks the cellular reuptake of adenosine, increasing the extracellular adenosine concentration. Increased extracellular adenosine results in coronary vasodilation. Regadenoson is a selective A_2A adenosine receptor agonist, approved for clinical use in the United States in 2008.⁴² The diagnostic accuracies of SPECT-MPI using exercise or vasodilator stress have been found to be equivalent, despite the higher coronary flow rates associated with the vasodilators.⁴³ In patients who have taken dipyridamole-containing medications in the 48 hours prior to testing, adenosine or regadenoson administration should be avoided, because it could result in overstimulation of adenosine receptors.³⁰

Vasodilator stress is frequently associated with chest discomfort and shortness of breath, even in normal subjects, and thus, unlike exercise, with vasodilator stress, these symptoms are not considered to indicate the presence of ischemia. Vasodilator stress frequently causes an increase in HR and a decrease in BP. With adenosine and dipyridamole, these changes are mild, but with regadenoson, the HR increase has been reported to be more marked.²⁹ The clinical assessment and hemodynamic responses to vasodilators are not useful in identifying patients in whom the pharmacologic effects of adenosine or dipyridamole may have been blocked by caffeine. HR may increase with vasodilator stress even though myocardial blood flow increase may be blunted, and conversely, failure of HR or BP to change with adenosine stress does not imply lack of myocardial perfusion response.⁴⁴ However, it has been shown that resting tachycardia and failure to mount a reflex tachycardia in response to vasodilator stress are associated with an increase in mortality risk.^45,46

Dipyridamole Infusion

Dipyridamole is usually infused at 140 μg/kg/min for 4 minutes (total dose 0.56 mg/kg), but some investigators have recommended increasing the dose by 50%.⁴³ The maximal effect occurs approximately 3 to 4 minutes after end of the infusion, and hyperemia persists for approximately 20 to 30 minutes. Mild transient adverse effects are common, including chest pain, shortness of breath, dizziness, and flushing. Severe adverse effects are rare, being noted in only 1 of 10,000 patients.⁴⁷ Persistent side effects or significant adverse events after dipyridamole, adenosine, or regadenoson stress can usually be reversed by intravenous aminophylline, usually 50 to 100 mg intravenously over 30 to 60 seconds. Because of the potential adverse effect of severe bronchospasm, dipyridamole is contraindicated for asthmatics.

Adenosine Infusion

Adenosine is infused intravenously (140 μg/kg/min), usually over 4 to 6 minutes, with radiopharmaceutical administration at 2 to 3 minutes of infusion.^43,48 Transient side effects occur more frequently than with dipyridamole,⁴³ but because of the brief duration of action (approximately 13 seconds), reversal with aminophylline is rarely used. With adenosine, there is an increased incidence of transient advanced atrioventricular (AV) block. Adenosine is considered contraindicated for patients with second- or third-degree AV block, sick sinus syndrome, or bronchospasm.

Regadenoson

Selective A_2A receptor agonists have the potential for reducing the high frequency of uncomfortable systemic adverse effects and the risk of bronchoconstriction in asthmatics that are associated with adenosine and dipyridamole (Fig. 18–4). At the time of this writing, regadenoson is the only selective A_2A adenosine receptor agonist to receive US Food and Drug Administration (FDA) approval, based on the results of two phase III studies that demonstrated equivalency to adenosine for the detection of reversible perfusion defects.²⁹ Regadenoson has become the vasodilator stress agent most commonly used in the United States. Unlike adenosine and dipyridamole, which require infusions and weight-based dosing, regadenoson is injected over a 10-second period with a fixed dose (0.4 mg) in a prefilled syringe, without requiring an infusion pump.³⁰ Side effects have been reported to be better tolerated than adenosine.²⁹ The radiopharmaceutical is injected over 10 to 20 seconds after intravenous injection of regadenoson.³⁰ The peak effect is seen approximately 1 minute after injection, and peak blood flow lasts for approximately 2 minutes. There is a three-phase washout period with this agent, such that side effects can be more prolonged than with adenosine. Because of the longer physiologic effect of regadenoson, reversal of side effects with aminophylline is more commonly necessary with regadenoson than with adenosine.

Regadenoson is considered contraindicated for patients with second- or third-degree AV block or sinus node dysfunction unless a functioning pacemaker is present.³⁰ A large phase IV study (999 patients) has reported the safety of regadenoson in patients with stable chronic obstructive pulmonary disease or asthma, but appropriate resuscitative measures should be available in case bronchospasm should occur.^30,49 Regadenoson is well tolerated in patients with renal impairment, but there is increased frequency of diarrhea in patients with end-stage renal disease.^50,51,52 High-grade AV block/asystole may be the result of a vasovagal response, so atropine should be administered if no response to aminophylline is observed.⁵³ The regadenoson and adenosine package inserts were updated in 2014 to reflect that regadenoson and adenosine may lower the seizure threshold, and that if seizures occur, aminophylline is not recommended because it may prolong regadenoson- and adenosine-related seizures.³²

Vasodilator Stress with Low-Level Exercise with SPECT-MPI

It has become increasingly common to combine vasodilator stress with low-level exercise.⁵⁴ With dipyridamole, low-level exercise is begun after the end of dipyridamole infusion, and with adenosine, low-level exercise is performed during the infusion. With regadenoson, low-level exercise is started before injection, allowing the vasodilator and tracer to be injected during exercise, or the regadenoson can be added to inadequate exercise as described above.^55,56,57 Exercise, even at low levels, reduces splanchnic blood flow and, thereby, hepatic uptake of ^99mTc-sestamibi or ^99mTc-tetrofosmin, facilitating early postinfusion imaging with these tracers (as early as 10-15 minutes following injection) compared to the 1-hour delay required when adjunctive exercise is not performed. Another key benefit of adjunctive exercise is a marked reduction in the frequency and severity of adverse effects from the vasodilator stress agents, possibly due to the increased attention to the task of walking inpatients who usually have reduced exercise capacity. Being able to perform low-level exercise also provides additional prognostic information.^58,59 Given all of these advantages, it is widely recommended that low-level exercise be combined with vasodilator stress for MPI when possible, with the exception of patients with left bundle branch block (LBBB) or paced rhythm in whom it is preferable not to have the increased HR associated with exercise.

Use in LBBB and Right Ventricular Pacing

With exercise stress, patients with LBBB frequently demonstrate reversible defects in the septal wall in the absence of CAD. Because of the relationship between the increase in HR and the presence of perfusion defects without CAD in LBBB and paced ventricular rhythms, vasodilator stress is preferred over exercise in these patients; the vasodilator stress protocols are performed without adjunctive low-level exercise.²³ Stress modalities that do not increase HR as markedly as exercise, such as vasodilator stress without walking, are generally considered preferable in LBBB patients.⁶⁰ HR increases more with regadenoson stress than with adenosine; however, it has been reported that this does not result in an increase in perfusion defects in the left anterior descending coronary artery (LAD) or septal territories.⁶¹ With exercise SPECT-MPI, the perfusion defect associated with LBBB in the absence of LAD disease most commonly involves the interventricular septum with sparing of the apex of the left ventricle, a pattern that would be uncommon for LAD disease.²⁷ Myocardial perfusion defects in the inferior and apical walls have also been reported in the absence of CAD in patients with prolonged right ventricular (RV) pacing.⁴³ Despite the high HR associated with regadenoson, no increase in the false-positive rate has been shown with this agent.

Dobutamine Stress (SPECT and PET)

An alternative to vasodilator stress is inotropic stress with dobutamine. At present, dobutamine stress is usually reserved for patients with asthma, patients with chronic obstructive pulmonary disease with bronchospasm, or patients who have ingested caffeine close to the time of testing. With the increased use of regadenoson, which has fewer contraindications, dobutamine stress nuclear MPI has markedly decreased in many nuclear laboratories. Dobutamine stress results in a lower-rate pressure product than exercise and a lower peak coronary blood flow with vasodilator stress. Adverse effects, including ventricular ectopy, are more common than with vasodilator stress. The protocol used is the same as that used for dobutamine stress echocardiography. As with echocardiography, atropine is commonly used in addition to dobutamine if the MPHR (> 85%) is not achieved.

SPECT-MPI Imaging Protocols

Stress ^99mTc-Sestamibi or ^99mTc-Tetrofosmin Protocols

A variety of protocols can be used with these agents, including 2-day stress/rest, same-day rest/stress, same-day stress/rest, and dual-isotope. Because uptake and radiation dosimetry of these compounds are similar, the recommended acquisition protocols for these tracers are the same. After intravenous injection, the myocardial distribution of these agents does not change significantly over time. Therefore, in contrast to ²⁰¹Tl, which redistributes into viable myocardium, separate rest and stress injections are needed with ^99mTc-sestamibi or ^99mtetrofosmin SPECT (Fig. 18–5)⁴³ to assess reversibility of perfusion defects. With these agents, if imaging artifact is suspected on supine images, additional prone imaging can be performed to increase the specificity of SPECT-MPI (Fig. 18–6).^22,43,62

The most common ^99mTc agent protocol is same-day low-dose rest/high-dose stress (see Fig. 18–5A).⁴³ The protocol takes approximately 2 to 4 hours. Compared to a stress-first protocol, there is a reduction in stress-defect contrast, because approximately 15% of the radioactivity observed at the time of stress imaging comes from the preexisting resting injection. Additionally, the protocol always involves two injections, not allowing for elimination of the rest if the stress is normal. An advantage of the rest/stress sequence is that the resting images can be inspected prior to stress testing, enabling the identification of patients with unexpected rest perfusion defects. For application in patients with acute chest pain, the protocol has the advantage of allowing for image assessment for perfusion defect on the resting scan prior to exercise and for cancellation of stress if unexpected perfusion defect is present.

The same-day low-dose stress/high-dose rest sequence (see Fig. 18–5B) has the advantage of optimal perfusion defect contrast, with no contribution from a prior rest injection. An important advantage is that the sequence allows for cancellation of the rest portion of the test if the stress images are normal. (see Fig. 18–5C).⁴³ The resultant “stress-only” protocol reduces the overall radiation dose of the SPECT-MPI procedure by 75% and reduces the overall time of the study for the patient by a similar amount. The principal drawback of this approach is that the count rates associated with the low dose stress images are low. In obese patients, in whom a low-dose injection may result in inadequate image quality, a 2-day stress/rest protocol may be preferred. Both stress and rest studies are obtained after injection of standard doses of ^99mTc-sestamibi or ^99mTc-tetrofosmin. Viability assessment with ^99mTc-sestamibi or ^99mTc-tetrofosmin may be improved by the administration of nitroglycerin prior to the rest-injection study.^43,64

Stress ²⁰¹Tl Protocols

As noted, unlike ^99mTc-sestamibi and ^99mTc-tetrofosmin, which are fixed within the myocardial cells, ²⁰¹Tl redistributes over time. This property has important implications for acquisition protocols. Initial poststress image acquisition should be started promptly (within 15 minutes) because early ²⁰¹Tl redistribution can decrease sensitivity for CAD if poststress imaging is delayed. The initially described stress/redistribution protocol is still commonly used (Fig. 18–7). It was later reported that reinjection with a small dose of ²⁰¹Tl could improve detection of perfusion defect reversibility.^65,66 Sublingual nitroglycerin prior to ²⁰¹Tl reinjection may further improve assessment for defect reversibility. If unexpected, nonreversible defects are found at 4-hour imaging (see Fig. 18–7A), additional 24-hour imaging has been reported to improve detection of defect reversibility.^17,18 If late redistribution imaging is performed, a separate rest injection prior to this late imaging should not be given, because resting hypoperfusion could result in incorrect information regarding myocardial viability.

Dual-Isotope Protocols

Because of the increased radiation burden associated with the dual-isotope approach, its use is not recommended unless both ischemia and viability testing are needed. A rest ²⁰¹Tl/stress ^99mTc-sestamibi or ^99mTc-tetrofosmin dual-isotope SPECT protocol (see Fig. 18–5B)⁴⁸ takes advantage of the Anger camera’s ability to collect data in different energy windows. It is usually performed with separate rest/stress acquisitions and can include redistribution thallium images either before the stress study (see Fig. 18–7B) or at 24 hours (after stress) (see Fig. 18–7B) if a rest defect is present. An alternative rapid “reverse dual” protocol (stress thallium/rest ^99mTc-sestamibi or ^99mTc-tetrofosmin) using lower radionuclide doses and camera systems capable of faster acquisitions have been reported, allowing the use of ²⁰¹Tl as the stress agent (preferable because of superior net extraction compared with ^99mTc-sestamibi or ^99mTc-tetrofosmin) while maintaining a relatively low radiation burden for the patient.⁶⁷

Stress-Only Imaging

Standard myocardial perfusion SPECT imaging protocols traditionally have consisted of a rest acquisition first followed by a second acquisition after exercise or pharmacologic stress. As noted above, stress-first protocols offer the opportunity to maximize the number of studies with stress-only imaging, resulting in several potential benefits.^87,88,89,90 The rest study is not performed when stress imaging is not clearly normal; thus, there is reduced imaging time, lower radiation exposure, and lower cost.⁸⁸ In addition, a 40% lower radiation exposure to nuclear cardiology staff has been reported.⁹¹

Limitations of the stress-only protocol are that transient ischemic dilation (TID) and stunning (decrease in ejection fraction [EF] or wall motion on poststress compared with rest imaging or development of poststress worsening of wall motion) cannot be assessed.⁸⁸ The approach can also result in a higher false-positive rate than rest/stress imaging because failure of a minor defect to change between rest and stress can be used to identify artifact. The use of attenuation correction or two-position imaging is of greater importance for the stress-only protocol; they increase the percentage of normal stress images and thus reduce the percentage of patients who have to return for rest imaging.⁸⁸ A challenge for implementation is the need for real-time review of the stress images to decide if rest imaging is required. Automated quantitative analysis can be a useful aid in making this determination. Because patients undergoing pharmacologic stress are, as a group, at higher risk, it has been suggested that the stress-only approach may be more appropriate for patients who can exercise. It is not used in patients with known or expected resting perfusion defects.⁸⁸ Multiple studies have documented that normal stress-only MPI studies are associated with the same excellent prognosis as normal rest/stress MPI studies.^89,92,93,94

SPECT Myocardial Viability Protocols

Although PET and MRI are considered superior for viability assessment, rest/redistribution ²⁰¹Tl SPECT-MPI is the optimal SPECT approach for assessment of myocardial viability¹⁴ (see Fig. 18–7C; Fig. 18–8). Theoretically, the effectiveness of ²⁰¹Tl SPECT-MPI for viability assessment could be improved by administration of nitroglycerin prior to the rest injection. Importantly, 24-hour imaging may show additional redistribution compared to 4-hour imaging,^17,43 because, as noted above, in the setting of a critical coronary stenosis with reduced resting blood flow, the time to complete redistribution may be delayed. Stress-redistribution and late imaging for assessment, as well as dual-isotope protocols, can also be used to assess myocardial viability as discussed above.

Rest ^99mTc-sestamibi and ^99mTc-tetrofosmin can also be used for assessment of myocardial viability. However, they are not considered optimal because, unlike ²⁰¹Tl, they reflect only myocardial perfusion and do not redistribute into the potassium pool. These agents underestimate viability in the presence of myocardial hibernation with resting hypoperfusion. To assess hypoperfused but viable myocardium with these agents, administration of nitroglycerin prior to rest injection is recommended.^64,68

Technical and Radiation Dose Considerations

New Generation of SPECT-MPI Instrumentation

Dramatic advances in cardiac SPECT instrumentation have been introduced to clinical practice in recent years, allowing both a decrease in imaging time and a reduction in patient radiation dose. These developments include innovative designs of the gantry dedicated to cardiac imaging, new photon detectors, and new collimators.^69,70 In parallel, software reconstruction methods incorporating resolution recovery and computed tomography (CT)–based attenuation correction have been developed, which allow further reduction in imaging time or radiation dose.⁷¹ Two hardware vendors have introduced compact cardiac scanners with cadmium-zinc-telluride (CZT) detectors, coupled with high-sensitivity collimation (multipinhole or high-sensitivity, parallel-hole—focusing on the myocardium). It is estimated that more than 300 of such high-efficiency cardiac scanners were in use worldwide as of 2015, and the number is increasing by about 100 per year. The new scanners can achieve simultaneous improvement in sensitivity (five to eight times higher than with conventional MPI SPECT) and in image resolution (up to two times higher). To date, these new techniques have been utilized primarily to dramatically reduce the routine scan time. With faster imaging, patient comfort is markedly improved, and motion artifacts are reduced. However, these systems also allow low-dose (~ 4-6 mSv)⁷² stress/rest or rest/stress imaging at fast imaging times or ultra-low radiation dose (~ 1 mSv) stress-only scans at standard imaging times (10-12 minutes).^73,74,75

Two-Position Imaging

One of the most difficult problems in interpretation of SPECT-MPI is the differentiation of artifactual from true perfusion defects. Soft-tissue attenuation and patient motion are the two major sources of artifact. Imaging the patient in two different positions decreases both types of artifacts. Regarding soft-tissue attenuation, shifting of attenuating organs occurs between supine and prone positions, particularly involving the breast and the diaphragm, the latter determining the position of subdiaphragmatic structures. Imaging the patient in the prone position with the nuclear detector rotating underneath the patient, as well as the standard supine imaging, decreases the frequency of attenuation artifacts in the inferior wall and breast and also decreases motion artifact (see Fig. 18–6).⁷⁶ However, prone imaging alone may create artifactual anteroseptal defects caused by the more pronounced sternal attenuation in this position.⁴³ As a consequence, combined prone and supine imaging (two-position imaging) with the sestamibi or tetrofosmin has been described. With two-position SPECT, perfusion defects are considered present only when they are seen on the images in both positions.

Patients with inferior wall defects on supine SPECT-MPI but normal on prone SPECT-MPI were shown to have as low a risk of subsequent cardiac events as patients with normal supine-only studies.⁷⁶ Visual analysis of prone and supine images has demonstrated improved interobserver agreement as compared to supine-only analysis.⁷⁷ A quantitative method for computer-based interpretation of combined supine and prone sestamibi SPECT images has recently been reported.²² With this approach, supine and prone images are compared to their respective normal databases, and only regions found concordantly abnormal by both positions are considered abnormal. The combined quantitation has demonstrated an increase in the normalcy rate without a loss of sensitivity. Regarding motion artifact, two-position imaging decreases false-positive findings, because motion artifact, occurring at the same time and to the same degree in two separate acquisitions, is unlikely.

With the more recently available CZT detector instrumentation, additional novel protocols have been developed with two rapid sequential scans in two patient positions (supine-upright⁷⁸ or supine-prone,⁷⁹ depending on the scanner). As with the conventional camera systems, two-view imaging provides improved differentiation of true perfusion defects from artifacts with these systems. With one of the systems using a multipinhole technology, the addition of prone imaging may allow for detection of position-related artifacts, which may occur with limited field-of-view gantry of the new scanners.⁸⁰ In the other system using a standard semiupright position, the use of an additional supine acquisition reduces artifact in the same manner as it does with the conventional systems.⁷⁷

Attenuation Correction

Several manufacturers offer hardware and software implementation of attenuation correction protocols for SPECT and PET-MPI. Attenuation correction is considered mandatory for PET-MPI because of more pronounced attenuation effects in positron emission. Several reports have compared the diagnostic accuracy of attenuation-corrected and non–attenuation-corrected SPECT-MPI using a variety of commercially available approaches. In general, these studies have demonstrated improved specificity with no change in overall sensitivity by visual analysis^81,82 and overall improvement in accuracy for detection of obstructive CAD by automated computer analysis in a large cohort.⁸³ Despite these considerations, attenuation correction is not yet widely used for SPECT-MPI, because of the increased cost and complexity of the attenuation correction hardware, the potential for imaging artifacts resulting from misregistration of attenuation maps, additional radiation dose and imaging time, and the lack of a common approach to its commercial implementation by vendors.⁸⁴ These difficulties—with the exception of the misregistration artifact—are lessened with the use of hybrid SPECT/CT or PET/CT systems. With these systems, attenuation correction is routinely applied. By observing both attenuation-corrected and non–attenuation-corrected images, misregistration artifacts are reduced. The SPECT/CT or PET/CT approaches offer the important benefit of providing the capability to assess coronary artery calcium (CAC) and myocardial perfusions in a single examination. Recently, methods for automated alignment for attenuation correction CT scans or even calcium CT scans with MPI images have been developed by vendors,^85,86 which may allow further improvement of clinical protocols.

Minimizing Radiation Dosimetry/Best Practices

The As Low As Reasonably Achievable (ALARA) Principle highlights the goal to minimize radiation dosimetry in all patients while maintaining high-quality imaging. In 2010, the ASNC set an initial goal to decrease the radiation dose in at least 50% of SPECT and PET-MPI studies to 9 mSv or less.⁹⁵ Table 18–3 lists best practices that can help achieve this goal and/or minimize each patient’s effective radiation dose.^95,96,97 The standard rest/stress ^99mTc-based study is associated with an 11-mSv radiation dose. The annual background radiation dose is 3 to 4 mSv.⁹⁸

Stress/rest protocols are preferred because they allow the potential for performance of stress-only SPECT if stress studies are normal. Stress-only ^99mTc studies decrease the radiation dose by approximately 75%. Furthermore, as noted above, ultra-low radiation dose (~1 mSv) stress-only scans at standard imaging times (10-12 minutes) can now be achieved with CZT detector systems.^{73,74,75 99m}Tc-based protocols are preferred over ²⁰¹Tl protocols due to more favorable radiation dosimetry. For example, a stress-only ^99mTc-based study with a standard camera is associated with approximately a 2.5-mSv dose compared with an 11- to 15-mSv dose of a stress ²⁰¹Tl study. Dual-isotope (rest ²⁰¹Tl/stress ^99mTc) protocols are the highest radiation dose protocols; therefore, they should be avoided unless combined perfusion and viability imaging is needed. Because of the very short half-life of each of the PET-MPI tracers, rest/stress PET-MPI is associated with a very low radiation dose of approximately 2 to 3 mSv. Figure 18–9 includes the comparison of radiation stress scan doses from various MPI techniques, including those achievable with latest generation equipment for SPECT-MPI.

The interpretation of SPECT and PET-MPI is performed by visual or computer-based quantitative methods.

Perfusion Defects

Perfusion defects are characterized by their type as well as their extent and severity. The various defect types are illustrated in Fig. 18–10 for stress and rest SPECT-MPI and in Fig. 18–11 for rest SPECT-MPI viability patterns. These perfusion defect patterns also apply to PET-MPI. Figure 18–11A illustrates the pattern seen in hibernating myocardium. The distribution of SPECT abnormalities provides information regarding the location of coronary artery stenoses. Representative examples of SPECT defect locations associated with individual coronary artery stenoses are illustrated in Figs. 18–12 and 18–13.

Visual Semiquantitative Segmental Scoring

Semiquantitative perfusion scoring systems standardize the visual interpretation of scans and provide global indices for overall assessment of extent and severity of perfusion abnormality. Furthermore, they are more systematic and reproducible than simple qualitative evaluation.

Seventeen-Segment Model

The 17-segment scoring system for SPECT- and PET-MPI is used as recommended for all noninvasive cardiac imaging modalities by the American Heart Association (AHA) in 2002, (Fig. 18–14).⁹⁹ Segmental assignment is based on three short-axis slices (four distal [apical], six middle, and six basal) representing the entire left ventricle, with the apical segments visualized in a midventricular long-axis image. Each of the 17 segments has a distinct descriptor and is scored for defect severity using a five-point system (0 = normal; 1 = mild [equivocal]; 2 = moderate; 3 = severe reduction of a radioisotope; and 4 = absence of detectable tracer uptake).^23,27 Severe reversible perfusion defects with scores of 3 or 4 (see Fig. 18–12 second row and bottom row; see Fig. 18–13 second row and bottom row) can be reported as consistent with a critical (≥ 90%) coronary stenosis.²⁷ The differences between the 17- and the previously described 20-segment models are that, with 17-segment scoring, the smaller size of the distal (apical) short-axis slice is accounted for by four versus six segments and the apex is one rather than two segments, more accurately reflecting the size of these segments.

Summed Scores

Segmental scoring systems lend themselves to the derivation of summed segmental scores as global indices of perfusion.^23,100 The overall extent and severity of perfusion defects is reflected by the summed stress score (SSS), the summed rest score (SRS), and the summed differences score (SDS), with the latter defined by SSS – SRS and measuring the degree of reversibility. Risk groups may be defined using SSS categories (Table 18–4).^23,27

Percent Myocardium Abnormal

We subsequently describe expression of overall perfusion defects as percent myocardium involved (percent stress, percent reversible, and percent fixed) and now routinely use this approach for clinical reporting and prognostic publications.²⁵ The conversion of summed scores to percent myocardium is accomplished by dividing the summed scores by the worst segmental score possible in the specific model used (68 for 17 segments, 80 for 20 segments) and multiplying by 100. The benefits of this approach are that it provides a measure with intuitive implications (percent myocardium hypoperfused) not possible with the unitless summed scores, it can easily be applied with scoring systems using varying numbers of segments (eg, 17, 20, 14, 12), and it is applicable to quantitative methods that directly measure these abnormalities as percent myocardium (see Table 18–4). In general, risk groups by the percent stress abnormal, which correlate with SSS risk groups, are as follows: % to 1%, normal; 2% to 4%, borderline/equivocal; 5% to 9%, mildly abnormal; 10% to 14%, moderately abnormal; and 15% or more, severely abnormal.^{25,27,101,102} When converted to percent myocardium abnormal, the prognostic implications of the 17- and 20-segment scoring systems have been shown to be equivalent.¹⁰³

Quantitative Analysis

A variety of commercial software packages are available to assist in image interpretation, and the various quantitative measurements they can provide are summarized in Table 18–5. With respect to myocardial perfusion assessment, these computer approaches generally operate by automatic determination of the amount of radioactivity observed at rest and stress within each voxel or small zone of the myocardium, scaling this amount by the maximal amount of radioactivity in the myocardium (normalization) and then comparing this scaled amount to the lower limit of normal. The perfusion defect size (extent) represents the proportion of voxels below the normal limit, which would correlate best with the number of visually abnormal segments. The total perfusion deficit (TPD) in another application assesses both the proportion of voxels below normal limits and the degree by which they are abnormal and would correlate best with the summed segmental scores. The change between rest and stress is also assessed, providing information about perfusion defect reversibility. It is possible to automatically register and subtract the rest images from the stress images or serial stress or rest studies from previous studies, resulting in a “change” image without requiring comparison to protocol specific normal limits. The change image reflects the amount of regional perfusion change.¹⁰⁴ The results are most commonly displayed using polar maps. Figure 18–15 displays polar maps associated with the various scan abnormalities shown in Figs. 18–12 and 18–13. The major clinical value of the quantitative analysis packages is in providing an objective assessment of the presence and magnitude of perfusion defects. It further gives the reader a “second expert” opinion, which is of importance even for experts; given the subjective nature of visual assessment. Quantitative assessment of serial studies is also more reproducible than expert visual assessment.^105,106 Moreover, it is also highly useful in facilitating decision making in individual patients regarding the need to perform a rest scan following a stress study or to simply perform a stress-only procedure. Recent developments in computer-based quantitative analysis of SPECT-MPI have been shown to provide equal or greater accuracy in detecting CAD than expert visual assessment.³⁷ The results of quantitative analysis have been shown to be prognostically useful and may complement information derived from visual analysis alone.^107,108 These computer-based quantitative programs do not currently take into account artifacts (eg, patient motion); therefore, the final interpretation currently always includes visual verification and, if necessary, modification.^3,27

The quantitative MPI discussed thus far assesses with SPECT- or PET-MPI the presence and magnitude of regional myocardial perfusion abnormalities by comparison with more normal zones. This is called relative quantitation. With PET, the high count rates allow quantitation of the first-pass arrival of the radiotracer, permitting assessment of absolute myocardial perfusion in milliliters/gram/minute as well as myocardial flow reserve, comparing rest and stress perfusion. With this approach, each segment or region can be assessed on its own, avoiding the reliance on comparison to perfusion of a normal area.

Overall Scan Assessment Based on Perfusion Findings

The final scan interpretation should express whether perfusion scan is abnormal and the degree to which it is abnormal. Summed stress scores 0-1 are considered normal, 2-3 borderline/equivocal, 3 probably abnormal and 4 or more definitely abnormal. For percent myocardium abnormal or TPD, 2-3% is considered equivocal, 4% probably abnormal, and 5% or greater definitely abnormal. There is general agreement that the category of “borderline” or “equivocal” is needed for circumstances in which the interpreting physician is uncertain whether mild perfusion defects are attributable to true perfusion abnormality or to imaging artifact. The use of the terms “probably or “definitely” abnormal are optional.

Ventricular Function

It is currently recommended that ECG gating be performed with all SPECT - and PET-MPI protocols, whether ²⁰¹Tl or ^99mTc tracers are used.¹⁰⁹ Gated MPI allows the assessment of a variety of ventricular function parameters, adding diagnostically and prognostically important information to MPI examinations.¹¹⁰ Regional wall motion or thickening is most commonly assessed by semiquantitative visual analysis, using the same segmental system used for perfusion defect assessment. Automatic computer-based methods quantify global function parameters, including left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), end-systolic volume (ESV), and diastolic function. Regional LV myocardial wall motion and thickening can also be quantified from rest gated MPI images. Gating of both the rest and the poststress acquisition provides the ability to detect stress-induced stunning by detecting inducible region wall motion abnormalities poststress.³⁹ Gated images are also useful for distinguishing true perfusion defects from attenuation artifacts. Also, left ventricular (LV) dyssynchrony can be quantified by measuring the onset of contraction of each myocardial sample point relative to the cardiac cycle; this is done by taking the first Fourier harmonic of its temporal displacement curve, the phase angle of which forms the basis for all of the synchrony measurements.¹¹¹ Phase information from all LV sample points can be pooled together into a phase histogram, the parameters of which offer a global measure of intraventricular dyssynchrony. Moreover, regional contraction differences (eg, between the lateral and the septal LV wall) can be measured, similarly to what is done in echocardiography.^111,112,113 Stress-induced wall motion abnormalities on gated SPECT-MPI are a sign of exercise-induced stunning and a marker of severe CAD.¹⁸⁰

Quantitation of ventricular function and volumes with gated SPECT and PET-MPI can be performed by a variety of algorithms.^114,115,116 The approaches are fully 3D and based on the automatic detection of endocardial and epicardial surface points.^117,118,119 In validation studies published to date of LVEF by gated SPECT,³ the agreement between gated SPECT and other standard measurements of LVEF has been shown to be very good to excellent. Although LVEF measured by the various quantitative algorithms correlate highly, the thresholds for abnormality are different, depending on the method used.^120,121 With some methods, the normal threshold for the global LVEF measured by gated SPECT-MPI images is slightly lower than that measured using other imaging modalities (~ 45%), principally because of the use of only eight gating intervals.³ Sixteen-frame gating reduces underestimation of LVEF. Sex-based normal limits for LVEF and LV volumes and volume indices have been reported.¹²² Fully automated scoring of SPECT-MPI LV wall motion and thickening can outperform experienced observers in the detection of CAD.¹²³

Transient Ischemic Dilation of the LV

In addition to perfusion defects, several nonperfusion abnormalities can be observed with nuclear MPI, including size and shape of the TID of the left ventricle,^124,125 RV myocardial uptake,¹²⁶ RV size, and abnormalities of lung uptake or other abnormal extracardiac activity. TID is considered present when the LV cavity appears to be significantly larger in the poststress images than at rest.^124,125 It may represent true changes in LV size or may actually be an apparent cavity dilation secondary to diffuse subendocardial ischemia (obscuring the endocardial border). The latter would explain why TID may be seen for several hours following stress, when true cavity dilation would most likely no longer be present. The correlation between LV TID and lung uptake is weak, suggesting that there may be different pathophysiologic mechanisms for each, and their measurements may be complementary in assessing the extent and severity of CAD for risk stratification.¹²⁷ When accompanied by a perfusion defect, TID is considered to represent severe and extensive ischemia and has been shown to be highly specific for critical stenosis (> 90% narrowing) in vessels supplying a large portion of the myocardium (ie, proximal left anterior descending or multivessel 90% lesions).^124,125 It has also been shown to improve the detection of severe coronary disease when combined with perfusion measures.¹²⁸ Dipyridamole or adenosine-induced TID has similar implications as those associated with exercise.¹²⁹ Figure 18–16 illustrates an example of TID on SPECT-MPI from a patient with severe left main CAD. TID can easily be measured by the quantitative gated nuclear MPI algorithms. TID ratios are typically calculated from the summed (nongated) rest and stress images. The upper limit of normal for the TID ratio with on stress nuclear-MPI depends on the stress type and the imaging protocol used.¹³⁰ With exercise stress, the upper limit of normal for TID has been reported to be 1.14 to 1.19 for same-day rest/stress ^99mTc imaging and 1.22 for dual-isotope imaging.^128,131 With vasodilator stress, for reasons that are not completely understood, the upper limit of normal to consider TID to be present is higher, approximately 1.14 to 1.19 for same-day rest/stress ^99mTc imaging and 1.36 with dual-isotope SPECT.^129,132,133 When unaccompanied by a stress perfusion defect, TID is less specific for severe CAD.¹⁶⁸

Increased Lung Uptake

Increased lung uptake of thallium reflects increased pulmonary capillary wedge pressure. Nonischemic causes of increased pulmonary capillary wedge pressure, such as mitral regurgitation and mitral stenosis, are also associated with increased pulmonary thallium uptake. Increased thallium lung uptake after exercise has been shown to have incremental prognostic information over myocardial perfusion defect assessment.¹³⁴ Prognostic value of increased pulmonary uptake of ^99mTc-sestamibi has recently been reported.¹³⁵

Markers of High Risk on Nuclear MPI

A number of patient characteristics, clinical and ECG stress test findings, and stress MPI findings have been found to be associated with increased patient risk of adverse events (Table 18–6). Clinical high-risk markers tend to be related to patient age, rest ECG abnormalities, diabetes mellitus, presenting symptoms, functional capacity, and prior CAD. Stress test markers of risk include ability to perform exercise, exercise duration, stress-related BP and HR responses, ECG changes, and clinical response in terms of symptoms. MPI high-risk markers include the presence of extensive reversible or fixed defects and direct evidence of the presence of significant LV dysfunction. Hence, for any MPI result, the estimated risk of the patient is increased in proportion to the degree to which other higher risk markers are present. Consideration of markers beyond those provided by assessment of perfusion defects is particularly important in the case in patients found to have normal stress perfusion and function, but with TID, LV enlargement, or severe ST-segment changes.

Chronotropic incompetence, defined as a low percentage of HR reserve achieved [(peak HR – rest HR)/(220 – age – rest HR) × 100], with less than 80% considered abnormal, has been shown to be a powerful predictor of cardiac death and all-cause mortality in patients undergoing exercise SPECT-MPI.^37,136,137 Inability to achieve 80% of HR reserve has been shown to be a more powerful predictor of cardiac death than failure to reach 85% of MPHR.¹³⁷ Also, patients with normal SPECT-MPI but abnormal HR reserve achieved have been shown to be at as high a risk of overall mortality as patients with abnormal SPECT-MPI but normal HR reserve achieved. Impaired chronotropic response to vasodilator stress with ⁸²Rb PET has been reported to be independently predictive of CAD mortality—adding to perfusion defect assessment.⁴⁶ Recently, it has also been shown that exercise capacity, chronotropic incompetence, and abnormal heart rate recovery are independent predictors of cardiac death and add incremental value in risk prediction over risk factors and comprehensive SPECT-MPI assessment.³⁷

Sources of Artifact

As with any diagnostic test, quality control is critical to effective clinical application of nuclear-MPI. Artifactual perfusion defects have a variety of causes, the most common of which are patient motion, breast and diaphragmatic attenuation, reconstruction artifacts caused by adjacent or superimposed extracardiac radioactivity, and poor count statistics.¹⁰⁹ With both SPECT and PET-MPI, several technical artifacts can affect the accuracy of LVEF measurement. LVEFs can be overestimated in analyzing images of small hearts,¹²¹ because of the limitations of spatial resolution. In patients with left ventricular hypertrophy (LVH), LVEF may be underestimated because of failure to accurately determine the endocardial border in the presence of the large muscle mass. Marked arrhythmia results in a falsely low LVEF measurement. Sources of artifact on PET-MPI are further discussed in Chapter 19. As noted below, SPECT two-view imaging—in supine/prone or upright/supine positions—reduces both attenuation and motion artifacts. With hybrid SPECT/CT or PET/CT systems, misregistration of perfusion and attenuation correction images is a major source of artifact.

Assessment of Myocardial Viability

Assessment of myocardial viability with the myocardial perfusion tracers applies to segments with contractile dysfunction.²⁷ Viability is considered present if the degree of uptake at rest, redistribution, or following nitrate-augmented rest injection¹³⁸ is normal or nearly normal. Various patterns of viability associated with regional wall motion abnormality in these studies are shown in Fig. 18–11. The presence of normal or near-normal tracer uptake in an abnormally contracting segment predicts improvement in ventricular function with successful revascularization. A dysfunctional segment or region with severely reduced or absent uptake of radioactivity on a viability study is considered to be nonviable. Areas with moderate reduction of counts in these conditions are usually partially viable, and patients in this group have a variable response in terms of improvement after revascularization. When perfusion defects are seen at rest and not after redistribution (with ²⁰¹Tl) or after separate tracer injection following administration of nitroglycerin, SPECT-MPI is commonly interpreted as showing resting ischemia and considered to represent regions of critically reduced blood flow to viable myocardium,⁶³ generally requiring rapid consideration of revascularization. The use of ¹⁸F-FDG to assess myocardial viability is described in Chapter 19.

The principles underlying the efficient use of stress nuclear techniques and the optimal use of the test results are discussed below. The most common applications are identifying inducible ischemia in patients with suspected disease, assessing the likelihood that a patient with known CAD has ischemia, evaluating patients prior to noncardiac interventions, and assessing the magnitude of ischemia for prognostic purposes. The section that follows explores these applications and discusses the evidence for the use of SPECT and PET-MPI in specific patient populations commonly encountered in clinical cardiology settings. Evidence for SPECT is emphasized below, because PET is covered in Chapter 19.

Selecting the Appropriate Patients for Diagnosis of Obstructive CAD Using Stress Nuclear MPI

Central to appropriate patient selection for nuclear imaging and the interpretation of test results for purposes of establishing the diagnosis of obstructive CAD is the assessment of an individual patient’s pretest likelihood of CAD based on demographic, clinical, and historical information. Bayes’ theorem underlies the selection of SPECT- or PET-MPI for diagnostic testing (see Chap. 19). For a given test result, the post-test likelihood is a function of three variables: patient pretest likelihood of disease and the test sensitivity and specificity. The degree to which the test result alters the post-test likelihood is directly affected by the pretest likelihood of disease. For any test with less than 100% sensitivity and specificity, the greatest shift in post-test likelihood of disease occurs in patients with an intermediate pretest likelihood of CAD. As a benchmark, for a test with sensitivity and specificity of 90%, a patient with a pretest likelihood of 50%¹³⁹ will have a post-test likelihood of 10% (low) with a normal test result and a 90% likelihood (high) with an abnormal test result. For purposes of assessing the post-test likelihood of CAD when using SPECT- or PET-MPI, the patient’s pretest likelihood takes into account all available information, including age, sex, symptoms, risk factors, the degree of coronary atherosclerosis if known (eg, from a CAC score), and the results of the non-nuclear stress testing components of the examination (eg, the duration of exercise and degree of ST-segment depression).

The pretest likelihood or risk assessment is conventionally estimated from published nomograms or by using available computerized programs. Recent data, however, suggest that the commonly used approaches to assessing the pretest likelihood of CAD, based on the work of Diamond and Forrester,¹³⁹ may not be applicable in the types of patients currently being referred for noninvasive testing. From a contemporary series, Cheng and coworkers reported that the Diamond-Forrester criteria markedly overestimated pretest likelihood of CAD in patients referred for coronary computed tomography angiography (CCTA).¹⁴⁰ In 8106 patients from the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry with nonanginal angina, atypical angina, or typical angina, the Diamond-Forrester pretest likelihood of angiographically significant CAD was 51%; however, the observed frequency of 50% or more stenosis on C CTA in these patients was 18%. This overestimation of CAD likelihood was confirmed in the recent PROMISE trial. In the patients in the coronary CT arm of the trial, the pretest likelihood of obstructive CAD was 53% while at least 50% stenosis on C CTA was observed in only 10.7%. As noted below, the overestimation of the pretest likelihood of obstructive CAD is likely a principal factor in the recently observed low frequency of abnormal SPECT-MPI studies.¹⁴¹

Diagnostic Accuracy of SPECT and PET-MPI

The accuracy of diagnostic testing for CAD has been defined on the basis of sensitivity and specificity as compared to an anatomic stenosis standard of either a 50% or 70% diameter-narrowing determined by invasive coronary angiography. A large meta-analysis of 86 studies comprising 10,870 patients and examined the diagnostic accuracy of exercise or pharmacologic stress MPI for detecting significant CAD.¹⁴² Pooling studies published between January 2002 and October 2009, the authors found that SPECT performed without attenuation correction or gating (63 studies) had a sensitivity of 87% and a specificity of 70%. The addition of gating information increased specificity to 78% (19 studies), and the use of attenuation correction further increased specificity to 81% (12 studies).

Several meta-analyses have compared the sensitivity and specificity of SPECT versus PET-MPI techniques. McArdle and colleagues reported on a comparison of the two modalities limiting the SPECT studies to those that used attenuation correction and gating, thus allowing for comparison of contemporary techniques.¹⁴³ Pooling 15 PET and 8 SPECT studies (1344 and 1755 patients), the authors reported a pooled sensitivity of 90% (confidence interval [CI], 0.88-0.92) and specificity of 88% (CI, 0.85-0.91) for PET and sensitivity of 85% (CI, 0.82-0.87) and specificity of 85% (CI, 0.82-0.87) for SPECT. The areas under the summary receiver-operating characteristic curves were 0.95 and 0.90 for PET and SPECT (P < .0001), respectively. This study was limited by interstudy heterogeneity and likely the differential referral patterns for each modality. Parker and coworkers performed a bivariate meta-analysis to compare the sensitivity and specificity of PET versus SPECT stress MPI using a 50% stenosis or more threshold to define obstructive CAD.¹⁴⁴ The authors identified 117 studies, including 108 evaluating SPECT-MPI, 4 evaluating PET-MPI, and 5 evaluating both modalities. A significantly higher pooled mean sensitivity was found with PET (93% [95% confidence interval or CI, 88%-96%]) compared with SPECT (88%) [95% CI, 86%-90%] (P = .035). No significant difference in specificity was present between PET (81% [95% CI, 67%-90%]) and SPECT (76% [95% CI, 72%-79%]) (P = .39). In a multicenter European cohort of 475 symptomatic patients undergoing CCTA and nuclear MPI (Evaluation of Integrated CAD Imaging in Ischemic Heart Disease [EVINCI]) trial, the diagnostic accuracy of detection of obstructive CAD was higher for PET than for SPECT-MPI.¹⁴⁵ For PET-MPI, the diagnostic accuracy, sensitivity, and specificity were 85%, 81%, and 89%, respectively. By comparison, for SPECT-MPI, the diagnostic accuracy, sensitivity, and specificity were 70%, 73%, and 67%, respectively. Given the physiological basis of these tests, a more relevant comparison would be based on FFR by invasive angiography as a gold standard. As part of a comparison of multiple modalities (SPECT, PET, stress echocardiography, CT, or magnetic resonance [MR]) to invasive FFR 37, studies were identified (n = 2048 patients).¹⁴⁶ Using FFR as a gold standard, PET had a lower negative likelihood ratio compared to SPECT (PET 0.14 [95% CI, 0.02-0.87]; SPECT 0.39 [95% CI, 0.27-0.55]) with a greater positive likelihood ratio (PET 7.43 [95% CI, 5.03-10.99]; SPECT 3.76 [95% CI, 2.74-5.16]). PET, MR, and CT perfusion performed similarly in excluding abnormal FFR, whereas MR and PET had similar positive likelihood ratios that were greater than that of CT. SPECT and stress echocardiography were inferior to the three other modalities with respect to both metrics.¹⁴⁶

Referral or Partial-Verification Bias

A major limitation in assessing the diagnostic accuracy of nuclear MPI to detect CAD is that the decision to perform the gold standard test—catheter-based coronary angiography—after nuclear testing is strongly influenced by the MPI result, thereby biasing the population available for the analysis of test accuracy. This is referred to as past test referral bias or verification bias. The referral to invasive angiography is largely driven by the presence of ischemia, particularly the extent and severity of perfusion abnormalities, as well as anginal symptoms, ECG changes, and other clinical factors. This referral pattern results in an overestimation of test sensitivity and a reduction in test specificity, with the most dramatic change occurring in specificity.¹⁴⁷ Importantly, only a small proportion of patients with normal or low-risk MPI findings proceed to invasive coronary angiography, resulting in more variability in specificity measures than in sensitivity. In the extreme case—catheterization in all abnormal MPI but none in normal MPI—test sensitivity and specificity would approach 100% and 0%, respectively. For example, Miller and colleagues reported that in a large series from the Mayo Clinic that the uncorrected SPECT specificity was less than 10% in men, because the referral for invasive angiography in patients having SPECT-MPI is strongly affected by the SPECT results.¹⁴⁸ Adjustments for referral bias have been described.

Normalcy Rate

The normalcy rate has been suggested as surrogate for assessing test specificity without requiring the angiographic standard; thus, it is not being affected by the marked post-test referral bias associated with assessment of specificity based on invasive coronary angiographic stenosis.¹⁴⁷ The normalcy rate is defined as the percentage of patients with normal test results in a population with a low (< 10%) pretest risk of CAD. The 2003 American College of Cardiology (ACC)/AHA/ASNC guidelines reported a normalcy rate for SPECT-MPI of 91%. Even in obese patients, normalcy rates for SPECT-MPI of greater than 90% have been reported when attenuation correction or combined supine/prone imaging is used.^22,149 This measure of “specificity” has limitations that the individuals being tested—generally those who would not be appropriate for testing—are much “healthier” than the patients. Potentially fewer artifacts might occur in these patients (eg, they might be less likely to move during the study), and they are likely to have higher quality images (eg, greater coronary blood flow leading to greater radiopharmaceutical uptake). Thus, normalcy rate is likely to overestimate true test specificity.

Risk Assessment of the Patient with Known or Suspected CAD

Principles of Risk Stratification

The first of the prognostic studies concerning exercise MPI was published by Brown and coworkers in 1983, based on a small cohort of only 100 patients.¹⁵⁰ In 1986, Ladenheim and colleagues reported a landmark study involving the follow-up of 1689 diagnostic patients undergoing exercise ²⁰¹Tl MPI.¹⁵¹ This approach of prognostic accuracy of stress MPI overcame many of the limitations of diagnostic accuracy that have been previously discussed, improving separation of low- to high-risk patient subsets. Both the number of perfusion defects and the severity of perfusion defects were shown to be related to adverse cardiac outcomes in an exponential fashion, with extent and severity of ischemia as independent predictors of outcome (Fig. 18–17). When PET-MPI is used, measurements of myocardial flow have been shown to add information over perfusion defects.

These early results led to a risk-based approach for the application of MPI to patients with known or suspected CAD with stable symptoms. In a risk-based approach, the focus is not on predicting the presence of CAD but on identifying patients at risk for specific, potentially preventable adverse events. Subsequent management then focuses on reducing the risk of these outcomes, whether cardiac death, nonfatal myocardial infarction (MI), or CAD progression. A major goal of management of stable ischemic heart disease (SIHD) patients following stress MPI is adherence and, as needed, intensification of guideline-directed medical therapy.¹⁵² For the high-risk, invasive diagnostic and therapeutic procedures are limited to patients who are most likely to benefit from them. This approach has been extensively evaluated using registry data for both SPECT and PET-MPI.

Risk Thresholds

For the purposes of risk assessment, it has been proposed that low risk be defined as a less than 1% annual cardiac mortality and intermediate risk be defined by the range of 1% to 3% per year.¹⁵³ Because the mortality risk for patients undergoing revascularization is 1% or more (see Chaps. 20 and 44), symptomatic patients with a less than 1% annual mortality risk would not appear to be candidates for revascularization to improve survival. The values of these risk thresholds vary according to the population being tested.

Risk Stratification in Patients with Suspected or Known CAD

Incremental Prognostic Value

The clinical value of SPECT- or PET-MPI for prognostic assessment of CAD results from the incremental or added prognostic information yielded overall data available prior to the test (clinical, historical, and stress data), as first demonstrated by Ladenheim and colleagues.¹⁵⁴ The incremental prognostic value of SPECT- and PET-MPI has since been documented extensively, including a broad spectrum of patient subsets.

Event Risk after a Normal Scan

Extensive literature exists documenting the risk of adverse events following a normal stress SPECT-MPI. A normal scan is generally associated with a less than 1% annual risk of cardiac death or MI, but in higher risk cohorts this risk can be about 2% per year or higher. A meta-analysis of the prognostic value of a normal stress perfusion scan (n = 29,788) revealed that the annual risk of MI or cardiac death after a normal stress MPI is 0.5% (95% CI, 0.3%-0.7%).¹⁵⁵ This low event rate is critical in applying nuclear test information to risk stratification, because in the absence of significant or limiting symptoms, it implies that patients with normal perfusion scans can be managed conservatively. Such an approach requires careful follow-up for signs of clinical worsening and treatment of cardiac risk factors and related symptoms (see Chap. 32). Increasingly, many studies are using all-cause death as an end point, and the degree of comorbidity impacts the annual mortality rates. Thus, the all-cause mortality rates following a normal MPI are expectedly higher than that of cardiac-specific end points.¹⁵⁶

The risk of cardiac events is consistently lower in patients with normal, than in those with abnormal SPECT-MPI, but there are multiple subsets of patients with a normal scan in which the absolute risk is not low. There is a strong temporal component as well in the assessment of risk. A study examining predictors of risk and its temporal characteristics in a series of 7376 patients with normal stress SPECT-MPI identified the following as markers of increased risk and shortened time to a hard event: use of pharmacologic stress, known CAD (Fig. 18–18A), diabetes mellitus (in particular, female diabetics), and advanced age.²⁴ Hence, a dynamic temporal component of risk was present, and the existence of a warranty period for specific patient groups was defined (Fig. 18–18B). The warranty period of a normal scan was further examined by Acampa and colleagues, who documented the importance of diabetes and reduced LVEF (< 45%) in identifying those with a slightly higher CAD event risk and shorter warranty period.¹⁵⁷ Increased risk after normal SPECT has also been reported in patients with dyspnea as the presenting symptom.¹⁵⁸ The importance of exercise duration has also been reported. In 6069 patients with a normal SPECT-MPI study followed for a mean of 10.2 years, the all-cause mortality rate rose progressively as the exercise duration associated with the SPECT study declined. Patients who could not exercise for more than 3 minutes had a mortality that was comparable to that of patients requiring pharmacologic stress.⁵⁹ In a subsequent study, of 12,232 patients with a normal exercise SPECT-MPI study followed for a mean of 11.2 years, hypertension, smoking, diabetes, and exercise capacity were significant predictors, beyond age, of long-term mortality (Fig. 18–19). Combining these predictors, the mortality ranged from 0.2% per year in patients exercising 9 minutes or more and with none of these CAD risk factors to 1.6% per year in patients exercising less than 6 minutes and having two or more of these risk factors.¹⁵⁹ Thus, the lower risk and more functional the patient, the lower the expected annual event rates following a normal MPI. The converse is also true—that the annual event rates are increased in higher risk cohorts, including those of advanced age or with known cardiovascular disease, impaired LVEF, and/or functional impairment. By comparison, patients with normal SPECT-MPI who performed some exercise at the time of stress MPI (combined low-level exercise with pharmacologic stress) have been reported to have event rates that are intermediate, between those who underwent exercise SPECT-MPI and those who had pharmacologic SPECT-MPI without exercise.¹⁶⁰

The contextual nature of risk requires some consideration of expected population mortality and cardiac event risk. As an example, from a study of elderly patients aged 75 to 84 years and 85 years or older, the annual cardiac mortality was 1.0% and 3.3%, respectively. Although these rates are not low, they are lower than the expected cardiac mortality for individuals of these ages in the US population (1.5% and 4.8%, respectively; P < .05 vs normal SPECT-MPI patients).¹⁶¹

The importance of stress-only SPECT protocols has been emphasized in the preceding portions of this chapter. The low risk associated with a normal rest/stress SPECT-MPI has been reported in patients studied with the stress-only protocols. In the largest study to date, Chang and coworkers reported all-cause mortality rates over a 4.5-year median follow-up in 16,854 consecutive patients with a normal gated stress SPECT (stress-only protocol in 8034 patients, both stress and rest imaging in 8820 patients),⁹³ finding lower annualized unadjusted mortality after a stress-only protocol compared to a stress-rest protocol (2.6% vs 2.9%; P = .02). The very low risk associated with a stress-only protocol has been confirmed and extended by other authors.^92,162,163

In some patients, extensive CAD may be missed because of balanced reduction of flow.¹⁶⁴ The latter would lead to a severe underestimation of the extent of ischemia by SPECT-MPI.¹⁶⁵ However, many of the patients with normal SPECT-MPI found subsequently to have high-risk anatomic lesions had abnormal ancillary markers on their SPECT study (eg, TID,¹²⁹ a rest-to-poststress decrease in LVEF, increased lung tracer uptake, or small perfusion defect below threshold to be considered abnormal).¹⁶⁵ A recent study of 580 patients with normal or minimal perfusion abnormalities on stress SPECT-MPI (SSS < 4), who underwent invasive angiography within 2 months after SPECT, reported that the finding of TID, abnormal EF response, or SSS of more than 0 were predictors of the small proportion (7.2%) who were found to have high-risk angiographic findings. Use of a CAC scan can be very helpful in identifying underlying atherosclerotic disease risk, as discussed later in the chapter. When the CAC score is high (400 Agatston units or higher), a normal stress MPI would not exclude significant CAD, as the score would indicate a high likelihood of obstructive CAD. Kaminek and colleagues reported that, in patients with known CAD, a combined approach of SPECT-MPI perfusion-function assessment and CAC improves the identification of multivessel CAD.¹⁶⁶ In general, when nonperfusion abnormalities are present in patients with otherwise normal SPECT-MPI, they are by themselves insufficient to warrant proceeding to invasive coronary angiography. PET-MPI, through the assessments of absolute rest and stress myocardial blood flow and coronary flow reserve (CFR), can improve risk detection and a greater understanding of the burden of obstructive CAD, functionally limiting mild epicardial CAD, or coronary microvascular dysfunction.¹⁶⁷

Event Risk with a Borderline/Equivocal Scan

As noted in the interpretation section, in some patients semiquantitative visual scoring or quantitative analysis results in a study being neither completely normal (percent myocardium abnormal = 0) nor definitely abnormal (percent myocardium abnormal ≥ 5%). In these circumstances, the scan is interpreted as “borderline” or “equivocal.” The equivocal SPECT-MPI study is associated with an increased risk compared to the normal scan. In a study of 18,200 patients followed for a mean of 2.7 years for cardiac death, a significant increase in risk was found in patients with equivocal stress SPECT scans (P < .001) (Fig. 18–20).¹⁰² In a recent study of prognostic assessment using a CZT camera, significantly increased risk of cardiac events was noted in patients with hypoperfusion below the threshold to be considered abnormal.¹⁶⁸ In a recent report of a subset of a large database studying patients with angiographically identified high-risk obstructive CAD following a borderline/equivocal SPECT-MPI study, the presence of a score greater than 0 (but lower than the abnormal threshold of ≥ 5%) was a variable associated with a higher than expected event rate.¹⁶⁹ Thus, for purposes of risk assessment, the scan category of “equivocal” or “borderline” should not be interpreted as being completely normal. Nonetheless, the “equivocal” or “borderline” scan result should not by itself prompt referral to invasive coronary angiography, because a preponderance of patients in this scan category do not have significant CAD.

Event Risk with Abnormal Scan

The relationship of varying extent and severity of perfusion abnormalities with cardiac outcomes has been reported in numerous, diverse patient subsets.^{103,153,170,171} Consistently, increasing perfusion scan abnormality is associated with an increasing risk of cardiac events, and this risk is further increased in patients with reduced LVEF. The severity of perfusion defects correlates with the degree of stenosis, and extent of perfusion defect correlates with the amount of myocardium subtended by the stenosed vessels.¹⁵¹ As described above, the percent myocardium abnormal, as estimated by 17-segment scoring or quantitative assessments such as TPD, combines the assessments of both extent and severity of perfusion abnormality, and the general categories of abnormality have been described.^25,27,101 Illustration of how these parameters affect risk in various patient subsets is shown in Fig. 18–21. Annual cardiac event rates generally range from 0.7% to 6.7% for patients with normal, mild, moderate, and severely abnormal perfusion scans, with significant variability associated with each level of defect extent and severity; depending on the pretest likelihood of CAD.²⁵ Findings similar to those observed with ^99mTc-sestamibi have been described with ²⁰¹Tl and ^99mTc-tetrofosmin SPECT as well as in a multicenter PET registry.^155,172

Importance of Prescan Data

As noted, prescan information adds incrementally to SPECT data for predicting outcomes. For all groups of patients, risk assessment in an individual patient is improved by taking into account findings other than those of the scan. The presence of high-risk clinical or historical markers identifies a subset of patients at greater risk for any level of scan abnormality (see Fig. 18–21).^{25,101,173,174} Additionally, for any degree of perfusion defect, the risk of adverse events after SPECT-MPI is greater in patients with higher clinical risk, those with including atrial fibrillation,¹⁷⁴ diabetes,^175,176 advanced age,¹⁶¹ reduced LVEF, dyspnea,^158,177 high CAC scores, known CAD, reduced functional capacity, and inability to exercise.

Mildly Abnormal SPECT-MPI

The presence of a mildly abnormal scan (5-9% myocardium) usually implies the presence of CAD but a moderately elevated risk of cardiac event. However, the risk is higher in a variety of subgroups with significant comorbidities and presentations, as mentioned above. The need to take into account all risk predictors is of particular importance in this patient group. A highly important consideration is that with SPECT-MPI or PET-MPI (unless absolute blood flow is being assessed), detection of abnormality is spatially relative; that is, perfusion defects are detected by their comparison to other myocardial regions. Thus, SPECT or PET-MPI without absolute flow measurements may underestimate the extent of hemodynamically significant CAD. Although patients with mildly abnormal SPECT-MPI results have an elevation in cardiac event risk, generally optimal medical therapy approaches are the mainstay in this patient subset, with referral to invasive angiography limited to patients with refractory symptoms.

Moderately to Severely Abnormal SPECT-MPI

As discussed earlier, this category of scan abnormality is associated with high levels of patient risk and even greater in patients with high-risk cardiovascular comorbidities, increased LV size/reduced LV function, extensive scar, or reduced LVEF. As discussed later, patients in this SPECT- or PET-MPI category with extensive ischemia are identified as those in whom knowledge of coronary anatomy may define clinical management. This patient subset benefits from revascularization, as opposed to guideline-directed medical management alone, as is discussed in detail later in this chapter.

Added Value of LV Function and Size Using Gated SPECT or PET

Assessment of LV function on gated SPECT or PET-MPI provides incremental value over perfusion in assessing prognosis. Poststress LVEF and LV ESV provide incremental information over the perfusion defect assessment in the prediction of cardiac death.¹⁷⁸ In a report of 6713 patients, using separate criteria for EF and ESV for men and women, Sharir and coworkers reported that perfusion (percent myocardium ischemic), function (LVEF), and LV volumes (ESV) provide incremental prognostic information regarding cardiac death and hard events¹²² (Fig. 18–22), with particularly high event rates noted among women with reduced LVEF and more than 10% myocardium ischemic. A subsequent study reported that SPECT-MPI determined ischemia and gated LVEF added incrementally to each other for the prediction of adverse events.¹⁷⁹

Other important information that can be derived from gated SPECT-MPI and are related to risk has not been widely included in literature reporting the prognostic assessment (see Table 18–6). These include regional or global stunning. (31, 180) TID of the left ventricle^124,125,129 and pulmonary uptake of radioactivity.¹³⁴ Extensive reversibility of resting ²⁰¹Tl perfusion defects (as determined by 24-hour ²⁰¹Tl imaging after rest ²⁰¹Tl/stress ^99mTc-sestamibi SPECT-MPI) has been shown to be predictive of a higher mortality than would be predicted by rest or stress perfusion defect abnormalities alone.¹⁸¹ As noted below, with the most commonly performed PET-MPI approach—⁸²Rb PET—unlike SPECT, imaging is performed during as opposed to after pharmacologic stress. Any fall in EF is considered abnormal and has been associated with critical coronary stenosis.¹⁸²

As noted above, PET-MPI offers an important characteristic that is not provided by current SPECT-MPI—the quantitation of absolute rest and stress myocardial blood flow and CFR. These absolute flow measurements provide added value in risk assessment as discussed below. Furthermore, they provide an ability to recognize when there has been inadequate vasodilation stimulus caused by caffeine intake by the patient—detected as no increase in flow between rest and stress. Of importance, from a diagnostic perspective, a completely normal PET-MPI study, including normal CFR, has been reported to essentially exclude the presence of high-risk epicardial CAD.¹⁶⁷ In addition, CFR and maximally myocardial blood flow provide assessments of overall myocardial blood flow and thus evaluation for focal epicardial coronary stenosis as well as diffuse epicardial disease and microvascular disease or microvascular dysfunction. This capability of PET flow measurements provides information that is complementary to the invasive assessment of FFR, allowing the identification of diffuse epicardial disease and microvascular dysfunction. These have their own prognostic and therapeutic implications beyond those associated with assessment of an individual epicardial coronary lesions.^183,184

Sex-Based Differences in the Prognostic Value of SPECT-MPI

Recent guidelines for cardiac imaging in women have been published by the AHA.¹⁸⁵ In women, because of breast tissue artifact, false-positive SPECT-MPI examinations are most notable in the anterior and anterolateral segments of the heart and are more common with ²⁰¹Tl than with the ^99mTc agents.¹⁸⁵ Improved accuracy has been reported with use of the ^99mTc agents as well with combined acquisition of gated EF and wall motion imaging and prone imaging and the use of validated attenuation correction algorithms.^185,186

Regarding prognosis, pooled data involving more than 7500 women noted annual rates of cardiac death or nonfatal MI of 0.4% for those with low-risk or normal SPECT-MPI.¹⁸⁷ High-risk MPI findings elevated a woman’s risk by nearly 10-fold, with annual rates of major cardiac events of 6.3% for all women and 10.9% for diabetic subsets of women.¹⁸⁷ With separate criteria for abnormality of ventricular function in women, there was similar prognostic content of combined perfusion and function information from gated SPECT in men and women.¹²²

Coronary vascular dysfunction (often termed coronary microvascular disease [CMD] or dysfunction) has been proposed as a mechanism for mislabeled “false-positive” stress testing results in women, suggesting that some of these studies may represent true perfusion abnormalities without significant epicardial coronary stenosis. Evidence suggests that these SPECT- and PET-MPI perfusion findings may be associated with increased near-term risk of major cardiac events.¹⁸⁸ Multiple reports suggest that prognostically important CAD states not involving epicardial, obstructive CAD occur more frequently in women than in men and that PET-MPI could be useful for detecting this process. A current active field of investigation is to more clearly define the types of CMD and the prevalence of mild epicardial CAD stenosis or high-risk atherosclerotic plaque features (eg, expansive or positive remodeling), in women which may also influence CFR findings.

PET-MPI in Risk Assessment

For PET-MPI, the past decade has witnessed a surge in publications. Along with the assessment of incremental prognostic value, risk stratification, and test performance in various patient subgroups and the role of change in LVEF, the impact of CFR on patient outcomes has also been extensively reported. As recently summarized,¹⁸⁹ a large number of studies have evaluated the prognostic value of stress PET-MPI.^{182,190,191,192,193,194,195} As described for SPECT-MPI, the risk of a normal stress PET is very low, with risk increasing as a function of the extent and severity of perfusion defects.^{182,190,191,193,194}

A recent meta-analysis assessing the prognostic value of stress PET perfusion identified 20 eligible studies (7 prospective) included a median sample size of 551 patients (interquartile range [IQR] 232-1291) with follow-up ranging from 1.0 to 7.3 years for clinical outcomes.¹⁹⁶ These included four studies using NH₃, fifteen using Rb⁸², and one combining patients who underwent either. These studies were published between 1993 and 2013. The authors reported that similar to SPECT, a significant increase in risk of cardiac death was present in patients with at least 10% ischemic myocardium (summary hazard ratio [HR] 1.66, 95% CI 1.51-1.82) or scarred (fixed defect) myocardium (HR 1.83, CI 1.70-1.96). Furthermore, analyses revealed that, an SSS of 4 or more (6% or more) and a CFR less than 2 identified significant associations with major adverse cardiovascular events (HR, 95%, CI 2.30 [1.53-3.44] and 2.11 [1.33–3.36]), respectively].

A recent multicenter registry evaluated the prognostic value of stress PET-MPI in 7061 patients with known or suspected CAD who underwent a rest/stress ⁸²Rb PET drawn from four sites.¹⁹⁴ Risk-adjusted analyses revealed that over a median follow-up of 2.2 years, stress PET results added incremental value over preimaging data for the prediction of cardiac death. Compared to normal studies, mildly, moderately, and severely abnormal studies were associated with HRs of 2.3 (1.4-3.8), 4.2 (2.3-7.5), and 4.9 (2.5 to 9.6; all P < .001), respectively. A study comparing the prognostic value of stress PET by sex was also reported from a subset of 6037 patients in this multicenter effort.¹⁹⁰ In this study, men had greater likelihood of CAD and more frequently had PET abnormalities. Men had a higher mortality during follow-up (5-year mortality: 6.0% vs 3.7%, P < .001; 115 vs 54 deaths). PET results added incremental value in both men and women and had numerically similar adjusted HRs (women 1.81 [1.54-2.14]; men 1.71 [1.52–1.94]). Hence, stress cardiac PET was prognostically valuable for both women and men. This registry has also been used to ascertain and compare the prognostic implications of PET-MPI in normal, overweight, and obese patients.¹⁹⁷ Body mass index (BMI) was grouped in three patient categories: normal (< 25 kg/m²), overweight (25-29.9 kg/m²), or obese (≥ 30 kg/m², with a mean BMI of 30.5 ± 7.4 kg/m²). PET results defined by a percent myocardium abnormal were categorized into normal (0%), mild (1%-9.9%), moderate (10%-19.9%), and severe (≥ 20%). In 6037 patients, a normal PET-MPI was associated with an excellent prognosis with very low annual cardiac death rates in normal (0.4%), overweight (0.4%), and obese (0.2%) patients. Furthermore, in all three BMI-defined categories, greater abnormality of PET-MPI results were associated with increased patient risk. Similarly, PET-MPI results added incremental prognostic value and enhanced risk stratification in all patient subgroups.

As noted above, one of the advantages of cardiac stress PET compared to stress SPECT is the acquisition of peak stress, rather than poststress image data. Hence, PET-MPI provides a rest LVEF, peak stress LVEF, and an LVEF reserve (stress LVEF–rest LVEF). The independent and incremental prognostic implications of rest and peak stress LVEF have been reported.^{182,192,194,198} The prognostic value of the LVEF reserve information was first investigated by Dorbala and colleagues¹⁸² in 985 consecutive patients who underwent gated rest/vasodilator stress ⁸²Rb PET. Over a mean follow-up of 1.7 years, the unadjusted annualized rates of cardiac death or nonfatal MI were greater in patients with an LVEF reserve less than 0% than in those with an LVEF reserve greater than 0% (2.1% vs 5.3%, P < .001). Multivariable survival modeling revealed that after adjustment for clinical, historical, and resting EF data, the LVEF reserve added incremental prognostic value for the prediction of both the end point of cardiac death or nonfatal MI and for all-cause mortality (Fig. 18–23).

In the MPI literature, the terms coronary blood flow and coronary flow reserve, or CFR, have been used interchangeably with the terms myocardial blood flow and myocardial flow reserve. A distinct clinical advantage afforded by the use of PET-MPI over SPECT-MPI is the ability to capture accurate, validated, and reproducible measures of rest and stress absolute flow and flow reserve on a per-vascular territory and global LV basis, as discussed in Chapter 19. In the first large study examining the prognostic implications of impaired vasodilator function relative to indices of PET myocardial perfusion, Murthy and coworkers¹⁹² examined a cohort of 2783 consecutive patients referred for stress PET who were followed up for a median of 1.4 years (IQR 0.7-3.2 years), with cardiac death as the primary end point. After adjustment for multiple factors, including rest LVEF, SSS, and LVEF reserve, compared to the highest tertile of CFR, the lowest tertile had a HR of 5.6 (95% CI, 2.5-12.4) and the middle tertile had a HR of 3.4 (95% CI, 1.5-7.7) (Fig. 18–24).¹⁹² Similarly, Ziadi and colleagues¹⁹⁵ evaluated the added prognostic information provided by CFR using Rb⁸² PET-MPI in 677 patients who were followed for adverse events (median follow-up ~ 1 year). In a Cox model adjusted for pre–PET-MPI data, CFR was an independent predictor of the end point of cardiac death or MI (HR 3.3; 95% CI, 1.1-9.5; P < .029). This relationship persisted after adjustment for stress perfusion data.

Murthy and colleagues extended this work in an investigation of sex-related differences in 405 men and 813 women.¹⁹⁹ This cohort was identified on the basis of having no prior history of CAD and no evidence of CAD-associated perfusion defects on their PET studies. A threshold for abnormality of CFR was less than 2.0. In both men and women, a CFR less than 2.0 was a frequent finding (51% and 54%, equivalence P = .0002). Patients were followed over a median 1.3 years (IQR 0.5-2.3 years) for major adverse cardiac events (cardiac death, nonfatal MI, late revascularization, or hospitalization for heart failure). In both sexes, CFR was incrementally predictive of major adverse cardiac events (HR, 0.80 [95% CI, 0.75-0.86] per 10% increase in CFR; P < .0001). This finding shows an inverse relationship with higher CFR equating to lower risk and vice versa. Interestingly, the authors also reported that in a subgroup of 404 patients without evidence of CAC and with normal stress perfusion imaging in both sexes, a CFR of less than 2.0 was common (44% of men vs 48% of women). Future work is needed to identify its putative role as a therapeutic target.

An additional report focused on examining the prognostic significance of CFR among diabetics as compared to nondiabetics.²⁰⁰ In this report, PET-assessed CFR was performed in a total of 1172 diabetic and 1611 nondiabetic patients who were followed up for a median of 1.4 years (IQR 0.7-3.2 years) for occurrence of cardiac death. An impaired CFR was defined as that falling below the median value and was associated with an adjusted 3.2- and 4.9-fold increase in cardiac death risk in diabetics and nondiabetics (P < .0004). CFR findings had a profound impact on risk assessment among diabetic patients without prior CAD—those with a reduced CFR experienced risk equivalent to nondiabetic patients with CAD while those with preserved CFR had a level of risk similar to that of patients without CAD or without diabetes; both of which were similar to patients with normal PET-MPI and LVEF (Fig. 18–24).²⁰⁰ These data support an integral role for CFR in assessing risk. Even in patients without CAD and with normal LV function, after adjusting for multiple confounders, impaired CFR was associated with both the occurrence of a positive troponin and with major downstream adverse events.²⁰¹

Integrating Clinical Data with Nuclear MPI Results for Risk Assessment

A challenge facing clinicians attempting to apply nuclear MPI results to patient care is to distill all information reported after SPECT-MPI—clinical, historical, stress test, perfusion, and function data—for risk of adverse events for an individual patient or likelihood of obstructive CAD as discussed above. Accurate final estimates of risk must incorporate all relevant prognostic factors. Ideally, validated prognostic assessments can be developed integrating all available sources of information, including nuclear MPI results, and be incorporated into nuclear MPI reporting.

When assessing risk, incorporation of non-nuclear variables obtained at the time of testing is particularly difficult with pharmacologic stress because prognostically important variables used in exercise testing, such as exercise duration and exertional chest pain, are not components of pharmacologic stress testing protocols. To test the potential of a multivariable integration of findings into a single score, a score was developed in 5873 patients studied by adenosine stress who experienced 387 cardiac deaths on follow-up (6.6%).⁵⁸ The authors derived a complex score taking into account all significant variables, including age, percent myocardium ischemic, percent myocardium fixed, diabetes, dyspnea as the presenting symptom, resting HR, peak HR, and ECG findings. Separate scores were calculated for therapeutic choices of medical therapy or revascularization (Fig. 18–25). The results of this study, although not in common clinical use, point the way to how test results may be analyzed in the future. In this regard, improvement in prediction of obstructive coronary disease and post-MPI revascularization has been recently demonstrated by deriving integrated scores by machine learning from imaging and clinical features.^202,203 With the increased applications of machine learning methods and computer-assisted test analysis and reporting, application of these comprehensive assessments—which have the potential of systematically taking into account all available information—may become practical tools to improve the clinical interpretation and reporting of nuclear MPI studies.

Estimating the True Prognostic Value of Nuclear MPI and Post-Test Referral Bias

Although there is compelling evidence that SPECT- and PET-MPI are effective in the prognostic stratification, current data on risk stratification by nuclear MPI may underestimate the strength of this modality because of a prognostic counterpart to the verification bias described earlier. Most prognostic analyses performed to date are comprised of patients undergoing follow-up medical management and without documentation of the adequacy of guideline-directed care. Moreover, many survival analyses also censor revascularized patients at the time of their invasive procedure with varying physician practices of prompt or delayed referral to coronary revascularization. The rationale for censoring of revascularized patients is the traditional viewpoint that surgical intervention improved outcome. This practice is less commonplace today because current randomized trial evidence does not support risk reduction with coronary revascularization as compared to medical therapy.^152,204 Thus, there is a varied relationship between the test results and the referral to revascularization.²⁰⁵ The result is a potential underestimation of the prognostic value of SPECT-MPI; the patients at the highest risk, with the most abnormal test results, are removed from the population being studied.^173,205,206

The reduction in observed event rates resulting in this referral bias in medically treated patients with severe amounts of ischemia on SPECT-MPI²⁰⁶ has been quantified. Thus, reported event rates in observational studies limited to medically treated patients may be high risk but underestimate the true risk in these patients; the patients with the greatest ischemic risk were referred for revascularization and censored from the prognostic studies. Moreover, the quality of medical management is quite disparate, and the relative adherence to SIHD guidelines is unknown.¹⁵² Statistical techniques may be applied in observational cohorts that may yield insight into the potential for stress MPI to define candidates and guide management of SIHD patients.^25,58,205

Nuclear MPI and Clinical Decision Making: Assessment of Cardiac Risk versus Potential Survival Benefit from Revascularization—Randomized Trials and Observational Findings in SIHD

The paradigm of the application of nuclear MPI to patient risk assessment conceptually yields a series of strata, representing the spectrum of risk and where along the continuum of risk the patient undergoing nuclear-MPI falls, after consideration of clinical, historical, stress test, and nuclear MPI results. Beyond risk stratification, optimal selection of patient treatment should be based on reasonable estimates of potential patient benefit with respect to a relevant and important end point with one treatment option versus an alternative. Moreover, the current evidence on the potential benefit of stress MPI should be considered in light of the randomized trial evidence and guideline-directed medical therapy approaches, which largely support equipoise on the use of surgical revascularization even for those with moderate to severe ischemia.¹⁵²

Identifying Optimal Post-MPI Patient Management

Evolving evidence indicates that beyond identifying patient risk, a principal role of nuclear MPI in a testing strategy is the identification of patients who may accrue a clinical benefit in terms of risk reduction with a specific therapeutic approach. Observational evidence is available from registry data and randomized trials regarding the impact of stress MPI for medical management decisions of patients with SIHD.^{207,208,209,210,211} With regard to the observational evidence on a survival benefit with coronary revascularization, in a study of 10,627 patients without prior MI or revascularization, and who underwent stress SPECT-MPI, a survival benefit for patients undergoing medical therapy versus revascularization was shown in the setting of no or mild ischemia, whereas patients undergoing revascularization had an increasing survival benefit over patients undergoing medical therapy when moderate to severe ischemia was present (> 10% of the total myocardium ischemic) (Fig. 18–26).²⁵ Furthermore, the roles of stress perfusion and gated SPECT-MPI EF in identifying this observational benefit have also been compared.¹⁷⁹ Although EF, percent myocardium ischemic, and the percent myocardium fixed are all predictors of cardiac death, the first is by far the best predictor of cardiac mortality. Conversely, only inducible ischemia identified patients who would benefit from revascularization compared with medical therapy (Fig. 18–27). With increasing amounts of ischemia, increasing survival benefit for revascularization over medical therapy was found, across all values of EF. A subsequent study by the same investigators examined this relationship in a large cohort of 13,969 patients, both with and without prior CAD, who were followed-up for an average of 8.7 years after MPI. As previously described, patients without prior CAD (n = 8791) had improved survival with revascularization in the setting of significant ischemia, as did patients with prior revascularization but no prior MI (n = 1542). However, as an overall group, patients with prior MI (n = 3216) did not show benefit with early revascularization as a function of the extent of ischemia (Fig. 18–28). However, patients with more than 10% to 15% of their myocardium ischemic, but with less than 10% of their myocardium with fixed defects, had a survival benefit with revascularization compared to medical therapy alone. These observational findings suggest that it was patients with extensive scar in whom ischemia did not identify a survival benefit.^209,212

The value of MPI-assessed ischemia to identify patients who may benefit from revascularization has been assessed in other observational patient cohorts. In 5200 patients who were aged 75 years or older, increasing ischemia was associated with increasing survival with early revascularization. Of interest, the threshold of ischemia at which this survival benefit appeared to be present was higher (≥ 15%) than observed in the previously described.²¹³ Sorajja and colleagues extended these results in a series of 826 asymptomatic diabetic patients without known CAD who had undergone stress SPECT-MPI. Improved post-MPI survival with revascularization during follow-up was limited to those patents with high-risk SPECT treated with coronary artery bypass grafts (CABGs).²¹⁴ Finally, in a recent study of asymptomatic patients with history of prior revascularization, no benefit with revascularization was found, despite the presence of significant ischemia.²¹⁵ This observational survival benefit was striking in higher risk patients (ie, elderly, requiring adenosine stress, women, and diabetics). Thus, in assessing treatment options in an individual patient, cardiac risk factors, comorbidities, coincidental anatomic findings, and EF all have to be considered along with ischemia to determine the potential advantages of a specific therapeutic strategy.

Observational studies, such as those discussed above, are primarily intended for hypothesis generation and have significant limitations. These include concerns regarding generalizability and dependency on risk adjustment techniques. Use of the latter does not obviate the impact of selection biases, unmeasured covariates, and other factors, on the results of the study.¹⁵⁶ For instance, to what degree the intensity of medical therapy in these studies is equivalent to that used in clinical trials is uncertain. However, these studies are effectiveness studies—treatment received by patients was dictated by clinical practice. Hence, they may better represent patients seen in practice and changes in practice over time than in randomized trials.

These results from single-site observational series have been recently extended by the results of prospective randomized clinical trials of SIHD.^204,216 Shaw and coworkers²¹⁰ reported several important results from the nuclear substudy of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. First, in this subset of COURAGE patients, the addition of percutaneous coronary intervention (PCI) to optimal medical therapy (OMT) resulted in more effective reduction of ischemia and angina symptoms than OMT alone. The reduction in ischemia was documented by comparing pretreatment (baseline) MPI to repeat stress MPI 1 year later. Importantly, regardless of treatment assignment, the magnitude of residual ischemia determined by follow-up SPECT-MPI was proportional to the risk of death or MI, and patients with a greater than 5% reduction in ischemia, measured quantitatively by the TPD at stress minus the TPD at rest, had a reduced rate of death or MI (Fig. 18–29).²¹⁰ Importantly, this substudy within the COURAGE trial was powered to examine an ischemia reduction and not for clinical events. Accordingly, this significant univariable analysis was not statistically significant in adjusted analyses.

An additional study from the COURAGE trial evaluated the results of site-interpreted MPI in 1381 patients randomized to OMT alone versus PCI and OMT who had baseline MPI studies.²¹⁷ Using the results of interpretation of defect extent using a six-segment model, researchers found no difference in rates of death and MI in patients with three segments or more with ischemia versus those patients with less than three segments. Furthermore, patient risk did not increase with worsening extent of ischemia, suggesting a failure to risk stratify. Importantly, this report is unique in reporting the results of MPI interpretation and outcomes from numerous sites in the United States and Canada. The results suggest the possibility that differences between “expert” reads to a variety of readers with varying experience affect outcomes.

The most recent study from COURAGE examined 621 patients with baseline quantitative MPI data and quantitative anatomic data to determine the predictive value of these two measures on patient outcomes (end point of death, MI, and non–ST-segment elevation acute coronary syndromes [ACS]) in medically treated patients as well as to determine whether either of these factors could identify which patients would benefit from one therapeutic approach versus another.²¹⁸ The authors found that, both with and without risk adjustment, coronary anatomic burden and LVEF were significantly associated with patient outcomes. Neither ischemia nor treatment assignment was predictive, although a significant interaction between ischemic burden and coronary artery anatomy was present. Most importantly, however, neither coronary anatomy nor ischemic burden was predictive of which treatment option would be predictive of improved survival.

Finally, the nuclear substudy from Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) included data from SPECT-MPI studies performed 1 year after enrollment in 1505 patients randomized to medical therapy versus medical therapy with revascularization.²¹¹ Thus, the ability to compare reductions in MPI abnormalities following intercurrent randomized treatment was not possible because of a lack of data collection in the prerandomization setting. However, comparing 1-year MPI results in patients who received revascularization plus medical therapy had smaller total defect size and lower percent myocardium ischemia when compared to those receiving medical therapy alone. At 1 year after randomization, 59% of revascularized patients had ischemia compared to 49% with OMT alone (P < .001). Furthermore, 4-year risk of death and MI increased with more severe and extensive MPI defects.²¹¹ As was the case in the COURAGE nuclear substudy, the relationship between treatment, MPI results, and outcomes was not statistically significant. Although there are statistical power issues in the randomized trial comparisons for clinical effectiveness, these data support the main SIHD trial findings, such as from COURAGE and BARI 2D, that revascularization reduces angina and ischemic findings as compared to medical therapy for patients with SIHD. However, no differences in long-term event reduction were reported for either trial when comparing PCI versus medical therapy.

There is little published data evaluating the ability of stress PET-MPI to observationally identify which patients may accrue a survival benefit with revascularization with medical therapy compared to OMT alone. In a study of 2223 patients followed for a median of 3.6 years after PET-MPI, Taqueti and colleagues examined the association of post-MPI treatment, the amount of ischemia present, and post-test patient outcomes.²¹⁹ Cox proportional hazards modeling adjusting for multiple potential confounders, including a propensity score to correct for nonrandomized treatment allocation (P < .0001), revealed significant interactions between ischemia and the use of revascularization (ie, survival increased with the use of revascularization for patients with more extensive and severe ischemia) and between CFR and the number of anti-ischemic medications used (P = .01). As with SPECT, these findings are observational and hypothesis generating, thus further investigations are necessary.

Stress MPI in the SIHD Clinical Practice Guidelines

Applications of nuclear MPI in SIHD are included in the recent ACCF/AHA clinical practice guidelines on SIHD¹⁵² as well as in the European Society of Cardiology (ESC) guidelines for management of stable CAD.²²⁰ They are also covered in the ACCF/AHA multimodality appropriate use criteria (AUC), as discussed below. The ACCF/AHA SIHD guideline assigned a class Ib level of evidence to exercise MPI for patients with an intermediate to high pretest risk who have an ECG for which the exercise response cannot be interpreted and a class Ia for those unable to exercise. An exercise stress MPI in this same subset with an intermediate to high risk in the presence of an interpretable ECG was assigned a class IIa level of evidence. More details on these indications are also provided in the AUC section and in the sections on specific patient cohorts. With regards to ischemia-guided management, the SIHD clinical practice guideline recommend initiation of guideline-directed medical therapy as the initial post-test treatment strategy. However, they also provide variable recommendations for revascularization, including consideration of patient preferences and clinical factors, as well as the high-risk stress test findings.^152,220 In general, the index approach for most patients is OMT with invasive angiography limited to those failing to improve symptoms following treatment intensification. In the ESC guidelines, consideration of revascularization is limited to patients with more than 10% ischemic myocardium.²²⁰ However, as discussed above, there is no randomized trial evidence to demonstrate a therapeutic risk reduction with revascularization as compared to OMT in patients with moderate to severe ischemia (ie, > 10% ischemic myocardium). Current randomized trials fail to support such a threshold benefit and the lack of consistent recommendations across the guidelines reflects the variable evidence base. The ongoing International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial is examining this primary aim with enrollment of about 5000 patients with moderate to severe ischemia on stress imaging. Patients are being randomized to a routine invasive strategy with cardiac catheterization followed by revascularization when appropriate plus OMT or to a conservative strategy of OMT. In the latter group, catheterization and revascularization are reserved for those who fail OMT. Additional SIHD and other MPI trials using MPI are discussed in the special patient population sections below.

Post-MPI Resource Utilization and Cost-Effectiveness Findings

A number of investigators have examined the relationship between SPECT-MPI and subsequent patient management. Overall, there is a clear relationship present in patients with normal scans; only a small proportion undergoes early post–SPECT-MPI cardiac catheterization, usually as a result of clinical symptomatology.^{100,161,208,209,221,222,223,224,225}

As first shown by Hachamovitch and coworkers, the extent and severity of reversible defects shown by the SPECT-MPI result are the dominant factors driving subsequent resource utilization²⁵ (Fig. 18–30). Importantly, even among the patients at greatest post-MPI risk—patients with high postexercise treadmill test likelihood of CAD and moderate to severe MPI abnormalities—only about half the patients were referred to catheterization. These findings, coupling MPI results to catheterization rates and potential underuse of catheterization, have been confirmed by this group and other authors.^{100,161,208,209,221,222,223,224,225} Regarding the cost-effectiveness of this approach, Shaw and colleagues,²²⁵ in a multicenter study of 11,249 patients, extended these results to show that a strategy of SPECT-MPI with selective subsequent catheterization produced a substantial reduction (31%-50%) in costs for all levels of pretest clinical risk compared with a direct catheterization approach (Fig. 18–31), with essentially identical outcomes as assessed by cardiac death and MI rates. Importantly, in the SPECT-MPI strategy, rates of revascularization, rates of cardiac catheterization after normal SPECT-MPI, and the frequency of normal coronary angiographic findings were significantly reduced.²²⁵

A recent prospective, multicenter study, the Study of Myocardial Perfusion and Coronary Anatomy Imaging Roles in Coronary Artery Disease (SPARC), examined referral rates to catheterization and use of medical therapy after clinically ordered SPECT, PET, and CCTA in patients from 40 sites.²²³ In a cohort of 1703 patients with no prior CAD and intermediate to high pretest likelihood of CAD, the authors found that referral rates to catheterization mimicked those in previous studies; after the most abnormal test results, 38% to 61% of patients were not referred to catheterization (Fig. 18–32). Additionally, about half these patients with significant abnormalities did not receive medical therapy. Although there were significant increases in the use of aspirin and beta-blockers post-testing, the change in use of lipid-lowering agents was not significant. Furthermore, only one in five patients were on all three of these medications, most were on one or two of them, and there was no increase in the proportion of patients with increased number of medications after testing (Fig. 18–33). The study did not examine the root cause of these results, but they do suggest that additional studies are needed and, perhaps, postnoninvasive utilization of resources may need to be considered as a quality metric.

The data are robust on the cost consequences that follow the above discussion on post-testing resource consumption testing patterns. Although the older nuclear MPI literature is replete with cost-effectiveness analysis, more contemporary evidence has also recently been reported. In a report including a large number of Medicare beneficiaries (n = 282,830), 180-day costs of stress MPI were compared to those of CCTA.²²⁶ An index testing strategy of CCTA was associated with higher rates of follow-up coronary angiography and revascularization procedures and, as a result, had higher total health care spending (P < .001). The costs for stress MPI were about $4200 lower over 6 months when compared to CCTA.

Similarly, in another report from the SPARC registry, 1703 patients with suspected CAD were enrolled and underwent CCTA (n = 590), stress PET-MPI (n = 548), or stress SPECT-MPI (n = 565).²²⁷ In this registry, stress PET-MPI patients had the highest risk, with 2-year mortality of 5.5%, followed by stress SPECT-MPI (1.7%), and lowest with CCTA (0.7%). The stress PET-MPI patients had the highest costs at $6647 at 2 years, with costs of $4909 for CCTA and $3695 for stress SPECT-MPI. In a decision analytic model, the incremental cost-effectiveness ratio for CCTA versus SPECT was $11,700 per life year saved. These results support that risk is a prominent factor impacting resource consumption patterns and costs following testing; that is, when comparing the cost-effectiveness of tests, risk adjustment is of paramount importance.

The Cost Effectiveness of Noninvasive Cardiac Testing (CeCAT) trial studied 898 patients referred for nonurgent coronary angiography who were randomized in a 1:1:1:1 basis to SPECT, cardiac magnetic resonance (CMR), stress echocardiography, or catheterization. The study was designed to study the noninvasive tests as a gatekeeper to invasive coronary angiography, evaluating mortality and costs.²²⁸ CMR was associated with a higher mortality as compared to the other modalities, and the mortality in the other groups were not significantly different from the mortality in the cath eterization group. Overall, the frequency of cath was eterization reduced by 20% to 25% in the noninvasive testing arms. Stress SPECT-MPI was economically superior to the other noninvasive tests and to cath eterization, with a more than 70% probability of being cost effective (in bootstrap simulations) when compared to stress CMR imaging and echocardiography. The 2-year costs for stress SPECT-MPI were lower than those for invasive coronary angiography. The costs for stress echocardiography were actually higher than for coronary angiography, which the authors attribute to the relatively high risk of the population being studied.

A synthesis of the cost data underscores the importance of pretest risk in assessing cost effectiveness. As expected, as risk increases, there are greater treatment intensity and greater costs of care. Cost-effectiveness of the various noninvasive and invasive approaches depends to a large extent on the risk of the patients being tested.

Comparative Effectiveness

A recent large comparative effectiveness trial compared stress testing, which was predominantly MPI, to CCTA. Sponsored by the National Institutes of Health (NIH)–National Heart, Lung, and Blood Institute (NHLBI), the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) evaluated 10,003 symptomatic patients who were randomized to an initial strategy of CCTA versus functional testing (67% nuclear MPI, 23% stress echocardiography, and 10% exercise ECG).²²⁹ Although all enrollees were symptomatic, the majority (78%) had atypical symptoms with the result being a low risk cohort with a low rate of CAD events. The primary end point was death, ACS, or major procedural complication, which occurred in approximately 3% of randomized patients at 2 years of follow-up. The primary end point was similar by randomization strategy with an HR of 1.04 (95% CI, 0.83-1.29; P = .75). Similarly, the Scottish COmputed Tomography of the HEART Trial (SCOT-HEART) randomized 4146 patients with suspected CAD to CCTA or standard of care arms. In both arms, stress testing was usually performed.²³⁰ The results of this trial do not provide information regarding comparative effectiveness with MPI directly, because only about 10% of the patients in the standard of care arm underwent MPI.

To provide value, MPI must be applied in a population with at least intermediate risk or likelihood of CAD. Notably, the PROMISE trial provided evidence that the pretest likelihood of obstructive CAD and of risk is overestimated by current clinical algorithms. The event rate in the population was substantially lower than expected based on historical data. Whereas the mean pretest likelihood of obstructive CAD by the Diamond-Forrester classification was 53.3 ± 21.4%, the observed prevalence of 50% stenosis or more on CCTA in the CCTA arm was only 10.7% and the prevalence of abnormality on stress testing was only 11.7%. A change in true likelihood of CAD according to age, sex, and symptoms, since the time of the initial descriptions by Diamond and Forrester, may have occurred over time, accounting for these observations. In this regard, recent findings in 39,515 patients undergoing SPECT-MPI over an 18-year period have shown a dramatic fall in the frequency of abnormal SPECT-MPI procedures, despite a rise in the apparent pretest likelihood of CAD (Fig. 18–34). These observations suggest the need to use new algorithms for assessing pretest likelihood of CAD and of risk in patients considered for referral to noninvasive testing. To this end, the recently described CONFIRM risk score developed by Min and colleagues provides an easily applied approach, which has been validated in patients undergoing CCTA and SPECT-MPI studies.²³¹

AUC for Optimal Patient Selection

The ACC, in conjunction with multiple professional organizations, has developed AUC for applications of testing in cardiology. Such AUC play a complementary role along with clinical practice guidelines. The documents were developed to guide health care coverage decisions and are now mandated by many private payers in the United States. Use of the AUC or similar approaches will be required for Medicare coverage beginning in 2018.²³² The initial AUC were published for cardiac radionuclide imaging, which were then updated.^233,234 Recently, a multimodality AUC document was published and replaced prior published documents.²³⁵ Although the recent document includes multimodality criteria including exercise ECG, stress echocardiography, stress magnetic resonance imaging, CCTA, and stress nuclear MPI, we will highlight the criteria directly relevant to stress SPECT and PET-MPI. Of note, the AUC considers the assessments of SPECT and PET-MPI as the same.

In the multimodality AUC for detection and risk assessment in SIHD, three principal scenarios are discussed and rated based on AUC categories: suspected SIHD, known SIHD, and preoperative cardiac assessment.²³⁵ Each modality is rated individually, and the ratings of each procedure were accomplished by evaluating the evidence within the modality and not as a comparison between the modalities. The multimodality AUC categorizes indications for cardiac imaging as appropriate, maybe appropriate, or rarely appropriate. Moreover, the term maybe appropriate also indicates that some of the patients within a given indication will be candidates for MPI. Further, the term appropriate does not mandate testing but supports that a large proportion of patients within a given indication will be candidates for nuclear MPI. Importantly, the term rarely appropriate does not prohibit testing but implies that only a limited number of patients within a given indication will be candidates for nuclear MPI. For nuclear MPI, rarely appropriate indications largely include low-risk or asymptomatic patients. Several published reports have examined the proportion of appropriate indications based on patient referrals to an SPECT-MPI laboratory.^{234,236,237,238} From the largest series, Hendel and coworkers²³⁹ presented data on 5928 patients, with 71%, 15%, and 14% of the studies being categorized as appropriate, maybe appropriate, or rarely appropriate, respectively. The most common rarely appropriate indications were (1) asymptomatic low-risk patients, (2) asymptomatic patients less than 2 years postrevascularization, (3) evaluation of chest pain in low-probability patients with interpretable ECG who were able to exercise, (4) asymptomatic patients (or patients with stable symptoms) with known CAD less than 1 year after angiography or prior abnormal stress nuclear study, and (5) preoperative assessment prior to low-risk surgery. These five indications accounted for 12% of all studies and 92% of the studies that were considered inappropriate. By reducing utilization of inappropriate or rarely appropriate studies, considerable cost savings could be achieved. From a recent meta-analysis in 22 studies in 23,343 patients, the proportion of rarely appropriate testing was 15%.²⁴⁰ This analysis also indicated that rarely appropriate MPI had a 59% reduced odds of being abnormal (P < .0001) when compared to patients with appropriate indications for MPI.

Decision support tools have been developed for use of the AUC and can guide improvements in appropriate referral patterns and reduce unwarranted testing patterns. Lin and colleagues published findings following the introduction of an AUC decision support tool, noting an increase appropriate use (pre: 49% to post: 61%, P = .02) and marked reductions in inappropriate use (pre: 22% to post: 6%).²⁴¹

Reports examining clinical outcomes based on AUC are limited.^242,243 From one series of 1511 patients, the relative hazard for CAD death or MI was elevated nearly four-fold for patients with abnormal MPI when those tested with appropriate or maybe appropriate indication were compared to patients with a rarely appropriate indication (P = .006). A smaller study of 280 patients demonstrated that appropriate studies are more likely to result in abnormal results requiring subsequent revascularization compared to rarely appropriate and maybe appropriate stress studies.²⁴⁴ These studies provide evidence of greater risk stratification by testing when used in patients with an appropriate indication than in patients with rarely appropriate indications.

A principal strength of nuclear cardiology is that large databases have been accumulated resulting in evidence documenting the effectiveness of SPECT and PET-MPI for risk stratification of appropriately selected patients, comprising the full spectrum of patients with suspected or chronic CAD. This evidence has resulted in many class I indications for the use of stress SPECT and PET-MPI.²³ Several specific lines of evidence are described in the following sections. In this section, we highlight the evidence supporting each of the AUC indications. Of note, the AUC considers the assessments of SPECT and PET-MPI as the same.^235,245

Symptomatic Patients with Normal Resting ECG Able to Exercise

Symptomatic patients with normal resting ECGs represent a large subgroup commonly encountered in clinical practice in whom the use of nuclear MPI is applied. The AUC report regarding radionuclides states that it is appropriate to refer symptomatic patients with interpretable ECG who are able to exercise for stress MPI testing if they have an intermediate or high pretest likelihood of CAD, but inappropriate if they have a low pretest likelihood.²⁴⁶ However, in symptomatic patients with a low pretest probability of CAD, interpretable ECG, and ability to exercise, stress nuclear MPI is considered rarely appropriate.

Several studies have examined the added value of exercise SPECT-MPI over clinical and exercise treadmill test (ETT) data in these patients.^154,247,248 The Mayo Clinic group demonstrated that although SPECT-MPI yielded incremental value over clinical and ETT data for the prediction of left main or three-vessel disease, the yield was modest and not cost-effective.²⁴⁸ A study from Cedars-Sinai of 3058 patients with normal resting ECGs then showed that selective use of SPECT-MPI in patients with intermediate to high post-ETT CAD likelihood yielded significant risk stratification, statistical incremental value, and cost-effectiveness in predicting hard events.²⁴⁷ Results from the What is the Optimal Method of Ischemia Elucidation in Women (WOMEN) Trial have shown that the ETT alone without imaging is sufficient in symptomatic women who are able to exercise. A total of 824 symptomatic women capable of exercise and without a prior CAD diagnosis were randomized to an index exercise ECG or exercise SPECT-MPI.²⁴⁹ The trial revealed similar 2-year outcomes (death, ACS, or heart failure hospitalization) for women randomized to the ETT-alone arm and in the exercise SPECT-MPI arm (2-year event rate: 1.7% for exercise ECG arm vs 2.3% for the exercise SPECT-MPI arm; HR 1.3 [95% CI, 0.5-3.5; P = .59]). These results reveal a low risk of 2-year CAD outcomes and support the utility of the exercise ECG as an initial test for evaluation of women capable of exercising and with a normal resting ECG. Of note, in both men and women, patients achieving 10 METs of exercise on ETT have been shown to have excellent prognosis and low likelihood of moderate to extensive ischemia, potentially obviating the need for stress nuclear MPI.²⁵⁰

Symptomatic Patients with Indeterminate or Intermediate-Risk Treadmill Test Result

An important appropriate indication for nuclear MPI are those for the diagnostic or risk evaluation following an ETT with indeterminate stress test findings or intermediate post-ETT risk. MPI has been shown to be most effective in risk stratification and governing management of patients with intermediate Duke treadmill score DTS, derived from exercise-induced chest pain, ST-segment changes, and exercise duration.²²² Similar results were shown in subsequent multicenter studies reporting event rates and catheterization rates.²³ Similar findings have been reported for stress ⁸²Rb myocardial perfusion PET.²⁵¹

Patients with LVH commonly have indeterminate exercise ECG results. Exertional ST-segment depression is frequently seen without significant CAD. SPECT-MPI has been shown to be as effective in patients with LVH as in patients without LVH for identifying obstructive disease and for risk stratification. It has been reported that patients with LVH and a low-risk SPECT-MPI had less than a 1% annual risk of cardiac death or MI, whereas the annual cardiac death or MI rates ranged from 4.9% for patients with mildly abnormal scans to 10.3% for those with moderately to severely abnormal SPECT-MPI.²⁵² Of note, in patients with hypertrophic cardiomyopathy, stress perfusion defects are commonly seen in the absence of significant disease (Fig. 18–35). Indications within the AUC and SIHD clinical practice guidelines support nuclear testing in symptomatic patients with uninterpretable or intermediate exercise ECG response.^23,235,245

Symptomatic Patients Unable to Exercise

The SIHD clinical practice guideline simplified the criteria defining a patient unable to exercise and categorized patients into those with limitations in physical functioning or disabling comorbidity.²⁴⁵ Patients may be categorized as unable to exercise if they are challenged with performing moderate household, yard, or recreational work. In addition, patients with disabling comorbidities are also those unable to exercise and include patients who are frail, of advanced age, marked obesity, with peripheral arterial disease, chronic obstructive pulmonary disease, or orthopedic limitations. These groups form a large proportion of patients who will be referred and have appropriate indications for nuclear MPI.

In patients unable to exercise, guidelines support that pharmacologic stress imaging is useful as the initial test in symptomatic male and female patients with intermediate or high pretest likelihood of CAD.^23,185,246 Consistent with other functionally disabled cohorts, the overall expected risk of major adverse cardiac events in these patients is elevated.²⁵³ As reported by the recent AHA consensus statement on cardiac imaging in women, functionally impaired patients (eg, < 5 METs of exercise) have at least a 2% per year risk of coronary heart disease death or MI, ranking them as having intermediate risk with event rates equivalent to patients with established coronary heart disease.¹⁸⁵ In multivariable models, the need for pharmacologic stress (as opposed to exercise) is itself an incremental predictor of adverse outcomes,²⁴ with event rates that are at least 50% higher than in an exercising population. Event rates are higher when patients undergoing pharmacologic stress are unable to perform adjunctive low-level exercise.⁵⁸ Despite higher event rates observed for patients with a normal resting ECG and an intermediate to high CAD likelihood but inability to exercise, vasodilator stress SPECT-MPI has been shown to be effective for CAD risk stratification.^58,101,174 Recent evidence has reported prognosis in patients with a normal stress MPI over a long period of follow-up.¹⁵⁹ With mean of 11 years of follow-up, the overall annualized all-cause mortality was 0.8%, with values varying based on risk factors, resting HR, and LVEF. The annual all-cause mortality was 1.6% per year for patients with multiple risk factors and exercising less than 6 minutes. Conversely, very low all-cause mortality (0.2%) was reported for patients with high exercise capacity (> 9 minutes) and for those without risk factors. Indications within the AUC and SIHD clinical practice guidelines support the use of nuclear testing in symptomatic patients unable to exercise.^23,235,245

Recently, an arm exercise protocol was applied in a large veteran population with lower extremity disability.²⁵⁴ Results from this report revealed that arm exercise capacity and HR responses provided added risk information to the prognostic value of MPI findings. Although not routinely performed, the use of arm exercise testing provides valuable functional information that may be supplemental to MPI data and is not available when applying pharmacologic stress. Exercise METs during arm testing (P < .001), 1-minute HR recovery (P < .001), and the delta HR measures (P < .001) were independently predictive of cardiovascular mortality.

Symptomatic Patients with a High Pretest Likelihood of CAD

Patients with high pretest likelihood of CAD are excellent candidates for SPECT-MPI. In these patients, the amount of ischemia can be helpful in selecting patients for referral to invasive coronary angiography and for consideration of revascularization. The ACC AUC support nuclear MPI in high-likelihood patients who have an interpretable or uninterpretable ECG as well as in patients able or unable to exercise.²⁴⁶ Supporting this, in a consecutive series of 1270 patients with a high likelihood of CAD (ie, > = 0.85), the annual rate of cardiac death or MI was 1.3% for normal SPECT-MPI, which was found in more than 60% of patients. In this cohort, moderate to severe ischemia (in 10% of the myocardium) is associated with an annual risk of CAD death or MI of 5%, based on a recent meta-analysis.²⁵⁵

Asymptomatic Patients

Asymptomatic patients (without chest pain or ischemic equivalents) with multiple risk factors frequently have an intermediate high-risk global risk score but are largely not considered appropriate candidates for MPI. Appropriate indications for MPI are limited to patients without these symptoms who are being evaluated for arrhythmias or syncope (in the patient with an intermediate to high global risk score).²³⁵ AUC in this category include patients with sustained ventricular tachycardia or fibrillation, exercise-induced ventricular tachycardia, or frequent premature ventricular contractions.

Other asymptomatic groups considered as intermediate to high risk include diabetics (see Asymptomatic Patients with Diabetes Mellitus), patients with peripheral arterial disease, and siblings of patients with premature CAD. These subsets of asymptomatics have a maybe appropriate indication for nuclear MPI.²³⁵ In a study examining asymptomatic siblings of patients with manifest CAD, a cohort acknowledged to be at increased risk for developing CAD, a relative risk of 4.7 for experiencing an adverse cardiac event was reported for individuals with an abnormal scan,²⁵⁶ and the presence of both an abnormal exercise ECG and abnormal perfusion scan yielded a relative risk of 14.5. As predicted by Bayesian principles, however, the routine use of any test for detection of CAD in an asymptomatic population with low risk/low prevalence of CAD will be associated with high cost-effectiveness ratios and low positive predictive values. The overall risk of these patients is not as great as in the symptomatic cohort.^257,258 As discussed later, strategies using initial coronary atherosclerosis assessment using CAC scanning followed by selective SPECT-MPI may prove to be clinically effective and cost effective for identifying asymptomatic patients at risk and guiding their therapy (as noted later in Asymptomatic Patients with Diabetes Mellitus and after CAC Scanning).^259,260,261 Although considered appropriate in asymptomatic high-risk patients, the use of nuclear MPI in asymptomatic patients with intermediate risk is considered maybe appropriate if the rest ECG is uninterpretable, and it is considered rarely appropriate in asymptomatic patients with low risk, interpretable ECG, and ability to exercise.²³⁵

Asymptomatic Patients with Diabetes Mellitus

SPECT-MPI has been reported to be effective in risk stratification of patients with diabetes.^{101,173,176,262} In a study comparing 1271 patients with diabetes to 5862 without, SPECT-MPI risk-stratified patients in both groups, but risk-adjusted event-free survival was worse in patients with diabetes than in those without.²⁶³ These findings were confirmed in a multicenter series.¹⁷⁶ A large single-center study reported that 59% of asymptomatic diabetics have abnormal stress SPECT-MPI studies, including 20% with a high-risk scan defined by a high SSS.²⁶⁴ A further study by this group showed that ECG Q waves and/or evidence of peripheral artery disease identified the most suitable diabetic candidates for screening with SPECT-MPI.²⁶⁵ Subsequent studies have reported that the frequency of abnormal SPECT-MPI in asymptomatic diabetic patients is not high.²⁶⁶ The Diagnostic Imaging in Asymptomatic Diabetics (DIAD) trial suggested that imaging of asymptomatic diabetics is not effective. In DIAD, 1123 patients were randomized to adenosine SPECT-MPI or nonimaging approaches. Although 22% of asymptomatic diabetic patients had ischemia by adenosine SPECT-MPI at baseline,²⁶⁶ at 5-year follow-up there was no significant difference in adverse cardiac outcomes between patients randomized to the imaging and nonimaging approaches. Based on these findings, atherosclerosis testing may be a more effective approach as the initial screening tool of diabetics,^259,260,267 reserving SPECT-MPI for those who have extensive coronary atherosclerosis. As with other patient cohorts, the level of exercise achieved has an important impact on the prognostic implications of SPECT-MPI findings.²⁶⁸

Patients with LBBB and Ventricular Pacing

Current guidelines support nuclear MPI in symptomatic patients with LBBB.²⁶⁹ As previously discussed, pharmacologic stress without adjunctive exercise is recommended in these patients. Vasodilator stress SPECT-MPI has been shown to be an excellent predictor of cardiac events in LBBB patients.²⁷⁰ Regarding patients with ventricular pacemakers, expert consensus is that these patients can be appropriately risk stratified by vasodilator SPECT-MPI, similar to patients with LBBB.²³ The SIHD guidelines give a class I indication for the use of pharmacologic stress nuclear MPI in the patients with LBBB regardless of the ability to exercise to an adequate workload.²⁶⁹ Due to the problem of septal perfusion defect without symptomatic CAD, CCTA may be a preferred in these patients.¹³¹

Patients with Atrial Fibrillation

In asymptomatic patients with new-onset atrial fibrillation, the use of stress SPECT-MPI has been reported to provide risk-stratification information. A large observational report in 16,048 patients on the prognostic value of SPECT-MPI in patients with atrial fibrillation showed that the annual rate of cardiac death in patients with normal SPECT-MPI was 1.6% per year for those with atrial fibrillation and 0.4% for the cohort without atrial fibrillation (P < .001).¹⁷⁴ Of interest, in patients with atrial fibrillation, even patients with only mildly abnormal SPECT-MPI were at much higher risk than those without atrial fibrillation (6.3% vs 1.2% per year, respectively; P < .0001). Nonetheless, recent AUC consider MPI in asymptomatic patients with atrial fibrillation as a maybe appropriate indication.^235,246

Elderly Patients

With the increased longevity of the US population and the age-related increase in CAD prevalence, large numbers of elderly patients are undergoing diagnostic and/or prognostic assessment for CAD. The Duke treadmill score has been reported to be less effective in risk stratification of elderly patients than in younger patients.²⁷¹ The Mayo Clinic group reported that exercise SPECT-MPI provides effective risk stratification in elderly men and elderly women. A cohort of 247 patients, who were 75 years of age or older and were undergoing SPECT-MPI, were followed for a median of 6.4 years for cardiac death. Although the Duke treadmill score was not associated with the risk of cardiac death, MPI-measured SSS was significantly associated with cardiac death and classified 49% of patients as low risk and 35% of patients as high risk, with annual cardiac mortality 0.8% and 5.8%, respectively. More recently, a study of 5200 elderly patients who underwent stress SPECT-MPI and had a 2.8 (± 1.7)-year follow-up reported that both MPI measured ischemia and fixed defect added incrementally over pre-MPI data in both adenosine and exercise stress patients. Furthermore, in a subset of patients who underwent gated SPECT-MPI, EF and perfusion data added incrementally to each other, further enhancing risk stratification. Importantly, modeling of all-cause death in a subset of 684 patients with extended follow-up (6.2 ± 2.9 years) revealed that, after risk adjustment, an interaction between early treatment and ischemia was present such that increasing ischemia was associated with increasing survival with early revascularization, whereas in the setting of little or no ischemia, medical therapy had improved outcomes.²¹³ While the elderly patients with normal SPECT-MPI had a risk of cardiac death that was greater than 1% per year, the risk in these patients was lower than that of the age-matched general population.

Pharmacologic stress testing is increasingly being applied in the elderly, who frequently are unable to exercise adequately, and this group makes up a high proportion of patients undergoing pharmacologic stress imaging. Consistent with data on other functionally impaired patients, elderly patients undergoing pharmacologic stress SPECT-MPI have higher cardiac event rates than patients undergoing exercise stress across the spectrum of test results. Risk stratification by SPECT-MPI has also been reported with dobutamine stress MPI in the elderly, with similar results to those of vasodilator stress.²⁷² Given the frequent finding of high CAC score in the elderly, it is likely that nuclear-MPI studies will remain preferred to CCTA in this group.

Patients with Chronic Kidney Disease

It has long been recognized that chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. This increased cardiovascular risk associated with CKD is in part related to hypertension and dyslipidemia,²⁷³ as well as to activation of both inflammatory mediators and the renin-angiotensin system.^273,274 The cardiovascular mortality in CKD patients is 15 to 30 times the age-adjusted cardiovascular mortality in the general population.^273,275,276

Successful risk stratification of these patients by SPECT-MPI results has been reported in numerous reports.^{277,278,279,280,281} Hakeem and coworkers followed 1652 patients who underwent stress SPECT-MPI for more than 2 years, finding that stress perfusion defects on SPECT-MPI and CKD were independent and incremental predictors of cardiac death after accounting for baseline data, risk factors, LV dysfunction, type of stress used, and symptom status. For any MPI result (normal or abnormal), cardiac mortality is far greater in CKD patients, and the risk increases with increasing degrees of renal failure.²⁷⁹ Nuclear-MPI may be the noninvasive test of choice in symptomatic patients with CKD. Then, because the asymptomatic CKD patient is at high risk, nuclear-MPI use would be classified as maybe appropriate by the AUC. In patients with functional disability, nuclear MPI would be appropriate in patients being evaluated for kidney transplantation.²³⁵ However, it remains uncertain which CKD patients are optimal candidates for nuclear MPI and how clinicians can optimally use the test results to enhance patient outcomes.

Nuclear MPI has a distinct advantage over the use of CMR imaging and CCTA for risk assessment of the CKD patient, because there is no organ toxicity associated with injection of the radionuclide tracers. CMR with gadolinium contrast is contraindicated in these patients due to the risks of nephrogenic systemic fibrosis in renal failure patients. With CCTA, the nephrotoxicity of the iodinated contrast results in this study being contraindicated unless the patient is on dialysis. Even in the dialysis patient, the high CAC scores commonly found in the renal failure patient can reduce the diagnostic and prognostic value of the CCTA study.

African American and Other Racial and Ethnic Patient Subsets

The rate of cardiac death or MI in African Americans with a normal SPECT-MPI is approximately 2% per year,²³ likely a result of higher risk burden.¹⁸⁸ In a multicenter series, 2-year cardiovascular death and MI were compared in 1993 African American and 464 Hispanic patients as compared with 5258 white, non-Hispanics undergoing stress ^99mTc-tetrofosmin SPECT-MPI.¹⁷² Moderate to severely abnormal SPECT-MPI occurred more often in ethnic minority patients (see Chap. 109). The prognostic results noted a 1.4- to 1.6-fold and 2.3- to 5.6-fold higher risk of hard events in African American and Hispanic patients, respectively, compared with white patients with mild and moderate to severely abnormal SPECT-MPI findings (P < .0001 vs whites), likely caused by a higher degree of comorbidity.

Obese Patients

SPECT-MPI remains a highly useful test for diagnosis and prognosis in obese patients, although excess soft tissue attenuation can make scan interpretation more difficult. For obese patients, the ^99mTc agents are considered preferable to ²⁰¹Tl because of the higher photon energy of ^99mTc. Attenuation correction hardware and software, combined with quantitation and ECG gating has been shown to have significantly higher specificity and normalcy rates without loss of sensitivity for detection of CAD in obese patients when compared with studies without attenuation correction.^282,283 Combined supine and prone ^99mTc-sestamibi stress SPECT-MPI acquisitions, without attenuation correction, have been shown to have equally high sensitivity, specificity, and normalcy rates among normal weight, overweight, and obese patients, and have been reported in a large clinical series.¹⁴⁹ Furthermore, these investigators reported that when a quantitative approach to analysis of supine, prone, and combined supine/prone acquisitions was used, the combined supine/prone approach increased the specificity in identifying CAD without significant reduction in sensitivity. This approach was also successfully applied to combined supine/upright imaging of obese patients with new cameras.¹⁶⁸

Regarding prognostic assessment of obese patients, a large study demonstrated that SPECT-MPI is highly effective in risk stratification across weight groups. Normal SPECT-MPI studies were associated with a low risk of events in all weight categories. Interestingly, there was an inverse relationship between weight and risk of cardiac death in the patients with abnormal scans or known CAD.²⁸⁴ Most SPECT imaging tables have weight limits (often 300 lb [136.1 kg]). Recently, two-position imaging using a high-efficiency CZT parallel-hole SPECT-MPI system with a weight limit of 542 lb has been studied in obese patients. With this system, SPECT-MPI was shown to have high accuracy for the identification of patients with 50% or more stenosis on invasive coronary angiography, with excellent image quality even in morbidly obese patients (Fig. 18–36).¹⁶⁸ PET imaging is considered to be superior to conventional SPECT-MPI in obese patients because of the robust attenuation correction and the higher photon energy associated with positron emissions (see Chap. 19). However, in morbidly obese patients who cannot fit in the PET gantry, the new cameras with solid-state detectors may of particular importance.²⁸⁵

Patients with Prior Testing

After CAC Scanning

Evidence supports the use of the CT-derived CAC score as a means to evaluate asymptomatic patients for detection of early, subclinical coronary atherosclerosis.^286,287 This application has been included in the ACCF/AHA guidelines.²⁸⁷ Given the known relationship between CAC and risk, the finding of high CAC burden raises patient risk to intermediate or high levels, resulting in consideration that ischemia testing might be warranted. When the CAC exceeds 400, the rate of an ischemic SPECT-MPI is elevated to at least the intermediate range, and has been reported to be as high as 47%.^287,288,289 Regarding the frequency of indication for this application, CAC scores of 400 or more were found in 9.9% asymptomatic subjects aged 45 to 84 years in the Multi-Ethnic Subclinical Atherosclerosis (MESA) study and, in the Heinz Nixdorf study, 9.6% of patients in the 45- to 75-year age range had these scores.²⁹⁰

Subset analyses have suggested that a lower threshold might be appropriate in higher risk patients, including type 2 diabetics with or without the metabolic syndrome, patients with a family history of premature coronary heart disease, and patients with multiple risk factors.^{260,261,286,291} In these cohorts, a greater frequency of ischemic SPECT-MPI was reported at a CAC score of 100 or greater. In patients with the metabolic syndrome, the frequency of an ischemic SPECT-MPI was 15% for CAC of 100 to 400, equivalent to patients with normal metabolic status with CAC 400 or more.²⁹¹ Anand and colleagues²⁶⁰ prospectively enrolled 510 asymptomatic, type 2 diabetics who underwent CAC and SPECT-MPI. Data from this series revealed that the rate of abnormal SPECT-MPI (including both fixed and reversible defects) was 0% (n = 15) for CAC of 10 or less, 18% (n = 38) for CAC 11 to 100, 23% (n = 70) for CAC 101 to 400, 48% (n = 29) for CAC 401 to 1000, and 71% (n = 28) for CAC greater than 1000. Similar results were reported for patients with a family history of premature coronary heart disease, with a greater frequency of ischemic SPECT-MPI when CAC is 100 or greater.²⁶¹ Consideration of a lower threshold for referral to SPECT-MPI after CAC scoring thus appears reasonable for diabetic and metabolic syndrome patients as well as in patients without metabolic abnormalities when combined risk factors and symptoms indicate a relatively high pretest likelihood of CAD.²⁸⁶ In general, patients with a normal nuclear MPI and extensive CAC have been shown to be at low risk for short-term cardiac events²⁴³; however, increased risk over time in patients with normal SPECT-MPI and increasing CAC has been shown in a large series of patients undergoing both examinations.⁹³

The multimodality AUC have addressed the use of stress nuclear MPI in patients with prior CAC scanning and consider it appropriate or maybe appropriate, depending on the time between CAC scanning and consideration of MPI.

After CCTA

CCTA is increasingly used for detection of CAD and assessment of patients with suspected or known CAD. Although highly accurate for the detection of anatomic coronary stenosis, CCTA is limited in the assessment of the functional significance of stenosis. It has been well established that assessment of percent stenosis even by invasive coronary angiography is limited in this regard. In the FAME trial, 65% of stenosis in the 50% to 69% stenosis category by visually interpreted coronary angiography had FFR greater than 0.8, as did 20% of lesions in the more than 70% stenosis category.¹⁰ With respect to percent stenosis on CCTA and ischemia, similar findings have been reported. In a recent study assessing the use of a functional assessment of CCTA (FFR CT) for predicting invasive FFR, the accuracy of using a greater than 50% stenosis on CCTA for predicting the results of invasive FFR was 65%; stenosis by CCTA had 83% sensitivity and 60% specificity with respect to invasive FFR. The low specificity of CCTA for ischemia can result in an increase in unnecessary invasive coronary angiograms.

Nuclear MPI plays an important role in selected patients following CCTA. The relationship between the degree of stenosis on CCTA and the finding of ischemia on SPECT-MPI has been evaluated in a small series of patients.²⁹² Ischemia was rare in patients with less than 50% stenosis on CCTA (6%). A progressive increase in the frequency of SPECT-MPI ischemia in the corresponding vascular territory was observed in the 5% to 69%, 70% to 89%, and greater than 90% stenosis categories.

Figure 18–37 illustrates the circumstances in which nuclear MPI might be considered after CCTA and for those in whom it should not. Testing for ischemia would not be considered in patients with less than 25% stenosis or for patients whose maximal stenosis is in the 25% to 49% range; further testing is not recommended, unless there are compelling reasons to suspect ischemia. In patients with lesions in the 50% to 69% range—the category considered by CCTA reporting guidelines to be “borderline,”—further testing is generally recommended. CCTA has been shown to frequently overestimate the percent stenosis seen on invasive coronary angiography; therefore, further testing for ischemia in patients with 70% to 89% stenosis is also reasonable, approximately one-half of which will have ischemia.

The multimodality AUC have extensively addressed the use of nuclear MPI in patients with prior CCTA. If CCTA is performed within 90 days, stress MPI is considered appropriate in each of the following categories, concordant with the above discussion: for patients with obstructive CAD (presumably to confirm ischemia and assess its magnitude); in patients with “uncertain” results, specified as equivocal or borderline results where obstructive CAD remains a concern; or when there is a coronary stenosis or anatomic abnormality of unclear significance. Recent data suggests that adding CT perfusion or CT- based FFR may provide this functional information (340, 342).

Patients with a Prior Revascularization

For patients with prior testing, the AUC statement categorizes patients as being evaluated for early MPI (within 90 days) and late MPI (> 90 days) after an index/prior test. For patients being considered for early nuclear MPI following an index procedure, a prior exercise ECG or anatomic evidence of obstructive CAD is considered an appropriate indication for MPI. In general, minimal evidence is available to guide the indications for follow-up testing even late after testing in patients without a change in symptoms and, as such, many indications are categorized as maybe or rarely appropriate.²³⁵ If the patient has new or worsening symptoms, the AUC support the use of nuclear MPI. The evidence for follow-up MPI is detailed below.

After PCI

In the BARI 2D and the COURAGE trials, the rates of ischemia were much lower at 1 year of follow-up in patients in the revascularization arms than in patients in the OMT arms.^210,211 In the BARI 2D trial, this was observed for both PCI and CABG (0.017 and 0.032) compared to the medical therapy arm.²¹¹

However, these findings do not imply that routine testing of patients after revascularization is appropriate. By the multimodality AUC, MPI is appropriate for patients with recurrent symptoms, for those with incomplete revascularization, or when additional intervention is being considered.²³⁵ Nuclear-MPI abnormalities after PCI may detect restenosis, periprocedural myocardial injury, side-branch compromise, de novo disease, or functionally significant angiographic disease in nonrevascularized vessels. As part of a staged procedure, SPECT-MPI can assess the remaining ischemic burden after the initial PCI.

Post-PCI, SPECT-MPI has been extensively used for the detection of silent or minimally symptomatic restenosis. Based on literature reviews and a meta-analysis,^293,294 several statements can be made regarding use of nuclear-MPI for this application. It is superior to ETT and can detect silent restenosis. However, post-PCI patients undergoing SPECT-MPI have a low overall annual event rate, suggesting no need for routine testing, despite the predictive value of abnormal SPECT-MPI for adverse events. Because of the relatively low prevalence of clinically significant silent restenosis in the era of drug-eluting stents, poststent SPECT-MPI is rarely appropriate in the asymptomatic patient for purposes of assessing stent patency.^23,246 Importantly, from a Bayesian perspective, testing these patients with a low prevalence of ischemia would result in a low yield with false positives outnumbering true positives. However, the AUC do state that risk assessment of the asymptomatic patient after PCI is appropriate if there is incomplete revascularization and additional revascularization is possible based on the angiographic findings.²⁴⁶ It is noteworthy that AUC do not cover all conceivable appropriate applications. For example, the AUC did not consider patients with extensive silent ischemia who undergo PCI. The general consensus is that repeat SPECT-MPI testing after PCI would be appropriate in these patients even in the absence of clear symptoms, if the results of PCI were uncertain or when there is clinical suspicion of restenosis.

Recently, the results of the Basel Stent Kosteneffektivitäts Trial LATE IMAGING study were reported regarding the use of SPECT-MPI at 5 years post-PCI.²⁶² The majority of the 339 trial enrollees were asymptomatic at the time of the 4-year SPECT scan. Patients with symptomatic or silent ischemia at the time of MPI had a higher relative hazard for cardiac events. The presence of ischemia remote from the stented territory was independently predictive of events. These trial findings indicate that follow-up use of MPI late after PCI may risk stratify even asymptomatic patients. This application has a maybe appropriate designation in the AUC. Routine testing of the asymptomatic patient less than 2 years after PCI is considered rarely appropriate.

After CABG

Nuclear testing has become central in the assessment of the post-CABG patient. It is known that more than 50% of vein grafts are projected to become occluded by 10 years after surgery; hence, there is an intermediate likelihood of vein graft disease.²⁹³ Thus, a 5-year cutoff point to evaluate the post-CABG patient may be appropriate (depending on the number and type of grafts placed).^{293,295,296,297} In post-CABG patients with new symptoms, nuclear MPI can identify the presence and extent of ischemia and is considered appropriate at anytime after surgery. In asymptomatic patients, nuclear MPI is considered appropriate 5 or more years after CABG. However, only routine nuclear MPI testing of the asymptomatic patient less than 5 years after CABG is considered rarely appropriate.

Preoperative Risk Assessment in Patients Prior to Noncardiac Surgery

A large body of literature exists examining the utility of perioperative cardiac testing with stress MPI in adult patients prior to noncardiac surgery and has been synthesized in a recent ACC clinical practice guideline.²⁹⁸ The guideline acknowledges that assessment of LV function and/or jeopardized myocardium provides an accurate method to complement clinical preoperative risk assessment prior to noncardiac surgery; importantly, however, the guideline does not recommend routine use of preoperative imaging, but rather its selective use in only very limited clinical situations.

This guideline highlighted a stepwise approach for evaluation of patients in the preoperative setting, beginning with an index assessment of functional capacity in patients with an elevated risk, defined as a risk of perioperative death or MI of 1% or more (see Chap. 98). This risk is based on combined surgical and patient characteristics.

Then, regarding exercise testing, exercise testing with imaging, and pharmacological stress imaging, the guideline recommends that in high-risk patients with excellent functional capacity (> 10 METs), it is reasonable to forgo further exercise testing with cardiac imaging. In patients with elevated risk and unknown functional capacity, it considers it reasonable to perform exercise testing, and then in those with moderate to good functional capacity (≥ 4 METs), to forgo further exercise testing with imaging. Only in patients with elevated risk and poor functional capacity (< 4 METs) does it consider it reasonable to perform exercise or pharmacological testing with cardiac imaging to assess for ischemia, and only then if it will change management. This guideline approach defines additional use of coronary angiography and guideline-directed medical therapy for those with abnormal stress MPI findings. Guidance on appropriate stress MPI candidates was also published in the recent AUC, stating that it is appropriate prior to intermediate-risk or vascular surgery only if the patient has poor functional capacity and at least one clinical risk factor (eg, prior CAD, heart failure, or cerebrovascular disease; diabetes; renal insufficiency).²⁴⁶

Assessment of Therapy: Serial Testing

In patients with no change in symptoms, the need for repeat testing and the appropriate interval for this retesting have not been fully explored. In this regard, the nuclear substudy of the COURAGE trial²¹⁰ provided landmark “proof of principle” data, addressing how serial SPECT testing may predict clinical outcomes. This COURAGE substudy was performed in 314 patients who underwent both prerandomization and 6- to 18-month postrandomization SPECT-MPI. The prerandomization study was performed with patients off of cardiac medications (eg, β-blockers, calcium channel blockers), and the follow-up study was performed with the patients on their medications. The amount of ischemia in the prerandomization SPECT-MPI was similar between patients assigned to PCI and OMT versus OMT alone. Some patients in the OMT-alone group demonstrated dramatic improvement in ischemia (Fig. 18–38). Patients in the PCI plus OMT group more frequently demonstrated significant ischemia reduction (> 5%) when compared with patients receiving OMT alone (33% vs 19%, respectively; P = .0004). Importantly, the frequency of subsequent adverse events over a 4-year period was directly proportional to the amount of residual ischemia measured on the 6- to 18-month postrandomization SPECT-MPI study (see Fig. 18–29). Although this study was not designed to prove that ischemia reduction directly reduces adverse CAD events, it nevertheless provides supportive evidence that serial imaging of ischemia before and after implementation may be useful in defining patient risk.

There is no consensus regarding whether serial testing should be performed with the patients receiving medical therapy, as it was in the COURAGE nuclear substudy, or off antianginal medications. If the purpose of repeat testing is to assess the effects of therapy on ischemia in daily life, then repeat testing would be performed on medications (see Fig. 18–38).

The appropriate interval between serial SPECT-MPI studies in clinical practice is discussed in the recent AUC.²⁴⁶ If the patient has new or worsening symptoms after MPI, repeat stress MPI is appropriate; however, routine repeat testing is not appropriate at any time. Early imaging following abnormal stress imaging within 90 days following the index test is considered a maybe appropriate criterion, as a means of evaluating the response to medical therapy.

Patients with Coronary Stenosis of Unclear Physiological Significance

For patients who are being considered for revascularization and are found to have coronary stenosis that is of uncertain hemodynamic significance, either exercise or pharmacological stress nuclear MPI has a class I indication in the SIHD guidelines.²⁹⁹

Because of the mortality, increasing prevalence of heart failure, and need to tailor therapy to the etiology or the stage of the condition, testing of patients with heart failure will remain common. Various radionuclide methods may be useful in initial staging of congestive heart failure (CHF; measurement of EF and ventricular volumes), ruling out CAD as an etiology, identifying myocardial hibernation, and determining the likelihood of response to interventional therapies. The 2013 ACCF/AHA guideline for the management of heart failure³⁰⁰ summarized the recommendations for the use of imaging in the heart failure patient. Based on this statement, the clinical applications where imaging may play a role include:

1. Repeat measurement of LVEF in patients who have had a significant change in their clinical status, received treatment that may impact cardiac function, or are under consideration for device therapy (class I, level of evidence C)

2. Imaging to detect ischemia and viability in patients with de novo heart failure, known CAD, and no angina, unless the patient is not eligible for revascularization (class IIa, level of evidence C)

3. Viability assessment prior to revascularization in select situations is reasonable in the heart failure patient with CAD (class IIa, level of evidence B)

4. Radionuclide ventriculography for the assessment of LVEF and LV volumes when echocardiography is inadequate (class IIa, level of evidence C)

Multimodality AUC for imaging in heart failure were also published in 2013.³⁰¹ For the evaluation for an ischemic etiology for heart failure, stress nuclear MPI is considered to be appropriate for the evaluation of ischemia in patients with or without angina/anginal equivalent. This was based on the heart failure guidelines giving the use of MPI to define the likelihood of CAD in patients with heart failure and LV dysfunction a class IIb evidence level C irrespective of symptoms. In patients with a known ischemic etiology for their heart failure who are revascularization candidates, stress nuclear MPI to assess the magnitude of ischemia is considered appropriate. Viability assessment is appropriate in patients with LVEF of less than 30%. In patients considered or followed up for implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) devices, radionuclide ventriculography can be used in the evaluation of patients who require a documentation of LVEF.^300,301 In the setting of (re)evaluation of known heart failure, stress nuclear MPI is considered appropriate in the setting of new angina/ischemic equivalent or for the presence of new or worsening heart failure symptoms.³⁰¹ In the heart failure guidelines, repeat measurement of LVEF and LV remodeling are considered useful with a change in clinical status, after a clinical event, or received treatment that may impact cardiac function.³⁰⁰

Detecting CAD as the Etiology of CHF

Because CAD represents the largest etiology of CHF and because the therapy of CAD is so distinct from that of the general management of patients with CHF from other etiologies, ruling out CAD as the cause of CHF is of clinical importance. If a patient with CHF is found to have no abnormalities of myocardial perfusion at stress (percent myocardium ischemic < 5%), the likelihood of CAD as the cause of CHF can be considered low.²³ However, the possibility of balanced reduction of flow masking severe and extensive CAD in a patients with ischemic cardiomyopathy, as mentioned above, must be considered. CCTA and CMR with delayed enhancement likely could be preferable in this regard: the former providing direct coronary assessment and the latter providing assessment of MI (even small) and concomitantly allowing for assessment of multiple other heart failure etiologies.

Identifying Chronically Stunned or Hibernating Myocardium

In patients with CAD and CHF, repetitive stunning or myocardial hibernation are important causes of LV dysfunction that might improve with revascularization. Although ¹⁸F-FDG PET is preferred over SPECT in detecting these conditions, SPECT-MPI protocols using ²⁰¹Tl are effective in distinguishing viable but nonfunctioning myocardium from nonviable myocardium.¹³⁸ As noted above, late redistribution ²⁰¹Tl imaging improves detection of regions of severely hypoperfused but viable myocardium,^18,19 and nitroglycerin-augmented technetium agent protocols might be employed. Myocardium subjected to acute or chronic ischemia may remain viable and demonstrate prolonged alterations in regional and global LV function that can be improved with revascularization.¹³⁸ Consequently, the distinction of ventricular dysfunction caused by fibrosis from that arising from viable myocardium has important implications for patients with low LVEF. Failure to identify patients with these potentially reversible causes of heart failure may lead to progressive cellular damage, worsening CHF, and death.¹³⁸ When available, assessment of myocardial viability directly by ¹⁸F-FDG PET (Chap. 19) or indirectly by late enhancement of scarring by CMR would be preferable to SPECT-MPI viability testing.

Predicting Improved Patient Survival in Ischemic Cardiomyopathy

The demonstration of viable myocardium in patients with CAD and LV dysfunction is commonly used to identify patients with enhanced survival with revascularization but with particularly poor prognosis with medical therapy. A meta-analysis of observational studies based on either radionuclide or echocardiographic assessments that dichotomized patients into groups with or without myocardial viability suggests that only patients with extensive viability have survival improvement with CABG compared with medical therapy³⁰² (Fig. 18–39).

The PET and Recovery Following Revascularization (PARR-2) study was a randomized trial that assessed the use of FDG PET scanning³⁰³ in patients with heart failure, known or suspected CAD, and LVEF of 35% or less. It also served to illustrate that the ability of a test to affect outcomes is dependent on several factors, ranging from the intrinsic measurements possible with the test to the manner in which test results change therapy. In this study, 430 patients in nine centers were randomized to a management plan assisted by FDG PET (n = 218) or standard care (n = 212), with specific recommendations regarding the use of FDG PET information for revascularization decisions. The outcome was a composite of cardiac death, MI, or recurrent hospital stay for cardiac cause within 1 year. In the overall trial, there was a trend for benefit for FDG PET–assisted management in the HR for the composite outcome in the PET versus standard of care arm (P = .15). Importantly, however, when adherence to imaging recommendations was considered, in patients in whom the PET treatment recommendations were followed, the HR was significant (P = .19). These findings illustrate the general concept that test results can have a beneficial effect on outcome only if the test appropriately changes therapy. A post-hoc analysis was performed comparing a subgroup of patients studied in five hospitals with greater experience in, and access to, the use of the PET-assisted strategy in the PARR-2 trial.³⁰⁴ There was a significant reduction in cardiac events in the patient population studied at the five sites with expertise in the performance and application of PET (P = .005) that had not been seen in the overall trial (Fig. 18–40).

In contrast to the prior observational studies, several substudies of the recent NIH-NHLBI–sponsored Surgical Treatment for Ischemic Heart Failure (STICH) trial have reported negative findings with respect to viability and ischemia testing in predicting revascularization benefit in patients with CAD and severe LV dysfunction. The STICH trial assessed the benefits of CABG in 1212 patients with CAD and EF less than 35%. The initial viability substudy reported the results of viability testing accomplished in 618 (51%) of enrolled patients. This testing was performed with SPECT-MPI in approximately two-thirds and with dobutamine echocardiography in the remaining one-third.³⁰⁵ The SPECT studies included (1) stress/redistribution/reinjection or rest/redistribution ²⁰¹Tl or (2) nitrate-augmented ^99mTc rest sestamibi or tetrofosmin protocols. PET or CMR assessments of myocardial viability were not used. Myocardial viability was defined as the presence of 11 or more of 17 segments demonstrating viable myocardium. The presence of substantial amounts of viable myocardium was associated with improved survival in the overall cohort (HR 0.64, 95% CI, 0.48-0.86; P = .003); however, it was not predictive of a benefit in survival with CABG compared to OMT (P = .53). In a subsequent report, 399 patients in STICH who also underwent assessments of stress-induced ischemia were evaluated. Inducible ischemia in these patients with severe LV dysfunction did not identify patients with worse prognosis or those with greater benefit from CABG over OMT.²¹² In a further assessment, in 267 patients randomized to surgical ventricular reconstruction plus CABG compared to CABG alone, the presence of viability was not associated with a mortality benefit from the addition of the ventricular reconstruction.

Numerous methodological criticisms, however, have called question to the validity of the STICH results.³⁰⁶ The study was only a substudy, containing only half of the STICH patients. The assessment mixed the patients having SPECT and dobutamine echocardiography. Viability was not analyzed as a continuous variable, and myocardial hibernation was not reported; that is, the presence of viability in regions with myocardial dysfunction was not addressed. Patients were not randomized on the basis of the viability test results. Compared with PARR-2, the STICH patient population was at lower risk, already being considered appropriate for CABG, having more single-vessel disease, infrequent previous CABG, low incidence of renal dysfunction, and predominantly no clinical heart failure. In contrast, in PARR-2, physicians were uncertain about revascularization decisions and, therefore, needed viability assessment; that is, viability testing was considered clinically indicated. Furthermore, only 19% of patients in the STICH substudy were considered to have nonviable myocardium. More advanced (or alternative) ischemia and viability imaging modalities (ie, using PET and CMR) were not evaluated. Thus, the STICH results need to be interpreted cautiously. Assessments of myocardial viability remain of particular importance in patients with very high surgical risk, in whom assessments of potential benefit of revascularization in heart failure symptoms or survival are crucial factors in clinical decision making. A similar important application of viability assessment is in guiding decision making regarding coronary revascularization versus cardiac transplantation in patients with severe ischemic cardiomyopathy.

Evaluation of Patients with Acute Chest Pain

Almost 8 million individuals are evaluated each year for acute chest pain in the emergency department (ED).³⁰⁷ Despite standardized protocols and high vigilance, between 2% and 6% of patients are erroneously discharged with missed MI,³⁰⁸ with higher mortality than patients who are hospitalized. For patients with normal or nondiagnostic initial ECGs and negative troponin levels on presentation to the ED, an important clinical problem is to distinguish those with ACS requiring hospital admission from those who may be safely discharged. Noninvasive imaging has become part of the standard of care in assessing patients with low to intermediate risk of an ACS in the ED.

Use of SPECT-MPI in the Evaluation of Acute Chest Pain

Rest or rest/stress ^99mTc sestamibi or tetrofosmin SPECT-MPI is commonly used for this purpose. Because of the very strong relationship between an acute MI and acute closure of a coronary artery, a normal rest MPI alone, without stress imaging, provides strong evidence of the absence of MI. A 99% negative predictive value of rest SPECT-MPI alone for MI was reported in several studies beginning in the mid-1990s.³⁰⁷ A prospective, randomized, controlled multicenter trial reported a reduction in hospitalizations when rest SPECT-MPI was incorporated into an ED evaluation strategy of patients presenting with suspected ACS (ERASE Trial).³⁰⁹

When the radiopharmaceutical is injected after pain has subsided and the SPECT-MPI study is normal, stress SPECT-MPI studies are commonly used to further rule out an ACS—as unstable angina might be associated with normal rest perfusion (Fig. 18–41).

Based on extensive literature documenting safety of maximal exercise testing in low-risk ED with a normal ECG and normal serial enzymes (4-6 hours apart), stress SPECT-MPI as the first MPI examination has recently been studied. In a large initial study, Duvall and colleagues³¹² reported the safety and prognosis of stress-only SPECT-MPI studies performed in 2340 patients and compared these to findings in 1805 patients having rest/stress studies (Fig. 18–42). The patients in the stress-only group were younger and had a lower risk profile. All-cause death was 0.5% (11 patients) in the stress-only group. Even higher frequency of stress-only procedures in a similar population has been reported in a study comparing SPECT-MPI to CCTA by the same authors³¹³ in which 939 patients were studied in the ED with SPECT-MPI and 75.4% had stress-only procedures (43.6% pharmacologic). Another recent study comparing an approach of MPI versus CCTA in 310 patients with SPECT reported the use of stress-only MPI in 24%, stress/rest in 24%, and rest-first imaging in 52%.³¹⁴ In both studies, a normal stress SPECT-MPI study was safe and associated with a very low cardiac event rate.

Comparative Use of CCTA and Standard of Care (Most Commonly Including SPECT-MPI) in the Evaluation of Patients with Acute Chest Pain

Three large randomized clinical trials have evaluated the application of CCTA to patients with suspected ACS in the ED in comparison to a standard of care approach. In all of these studies, the patients evaluated were defined as being in a low to intermediate group regarding the likelihood of having an ACS at the time of their ED visit. The first of these was the Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment (CT-STAT) trial, comparing CCTA to rest/stress SPECT-MPI.³¹⁵ In 16 centers, 699 patients were randomly assigned to CCTA (n = 361) or MPI (n = 338) as the index noninvasive test. CCTA resulted in a 54% reduction in time to diagnosis (2.9 vs 6.3 hours) compared with MPI (P < .0001). Costs of care were 38% lower (P < .0001). The diagnostic strategies had no difference in major adverse cardiac events after normal index testing (0.8% in the CCTA arm vs 0.4% in the MPI arm, P = .29). The American College of Radiology Imaging Network–PA (ACRIN-PA) trial³¹⁶ evaluated 1392 low- to intermediate-risk patients (thrombolysis in myocardial infraction, or TIMI, score: 0-2) presenting to the ED to CCTA or the physician-elected-traditional approach to standard care in a 2:1 ratio. Fifty-eight percent of patients in the standard care arm had stress imaging. Patients evaluated with CCTA had a shorter mean hospital stay and were also discharged more rapidly (total length of stay of 18 vs 25 hours; P < .0001) and more frequently (50% vs 23%) than patients undergoing the standard care evaluation.³¹⁶ The Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) II trial³¹⁷ randomly assigned patients, 40 to 74 years of age with symptoms suggestive of ACS but without ischemic ECG changes or an initial positive troponin test, to early CCTA or to standard evaluation in the ED. Only 25% of the 499 patients in the standard care arm had SPECT-MPI. The rate of ACS among 1000 patients with a mean age of 54 ± 8 years (47% women) was 8%. Compared with standard evaluation, in the CCTA group, the mean length of hospital stay was reduced by 7.6 hours (P < .001). A higher proportion of patients were discharged directly from the ED (47% vs 12%, P < .001). There were no undetected ACS and no significant differences in major adverse cardiovascular events at 28 days. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4289 and $4060, respectively; P = .65).

As noted, another recent randomized trial compared CCTA and SPECT-MPI approaches with protocols in which stress-only imaging was used. In 598 patients with chest pain in the ED, the CCTA study was associated with time to diagnosis, shorter hospital stay, and lower costs. However, when stress-only imaging was performed (24%), these outcomes assessments were comparable between SPECT and CCTA.³¹⁴

The results of these studies show that CCTA is of value when compared to an approach using SPECT-MPI in the ED—making CCTA the preferred study for some patients. Importantly, however, there are multiple settings of chest pain in the ED in which SPECT-MPI would be preferred. These include patients with known dense coronary calcification and elderly patients in whom dense coronary calcifications are likely; patients with prior bypass surgery, possibly with prior PCI, and known ischemic cardiomyopathy; and with contraindications to CCTA. Both approaches are effective. Local expertise in the performance and interpretation of these two examinations and the availability of the examinations are additional factors that would favor one approach over the other in an individual patient.

Assessment of imaging in patients with suspected ACS was part of the AUC for cardiac radionuclide imaging.³¹⁸ In patients with acute chest pain presenting with possible ACS, rest/stress nuclear MPI was considered appropriate in the settings found in Table 18–7. In patients with elevated troponin without additional evidence of ACS, rest/stress MPI was also considered appropriate. The AUC also address settings in which nuclear imaging might be appropriate for risk assessment within 3 months of an ACS. Routine testing after primary PCI, including asymptomatic patients prior to discharge or prior to cardiac rehabilitation, was considered inappropriate. The only settings listed as appropriate were to evaluate for inducible ischemia in post-ACS patients without prior coronary angiography. Patients with incomplete revascularization were not specifically addressed. Stress MPI is commonly used in these patients to assess for inducible ischemia. The indication for this could be considered under the category of patients with prior coronary angiography with “coronary stenosis or anatomic abnormality of uncertain significance,” which is given an appropriate category.

Radionuclide angiography (RNA) can be performed by either equilibrium or first-pass methods, with assessments of LVEF, RV EF, LV regional wall motion, and LV volumes and LV diastolic function. Equilibrium RNA uses ECG-gated acquisition, in which each frame corresponds to a specific portion (interval or gate) of the cardiac cycle, identified relative to the R wave on the patient’s ECG. Because of the use of a multiple gated acquisition (MUGA), the term MUGA scan has also been applied to this technique. The cardiac cycle is divided into 16 to 64 intervals, and data from multiple cardiac cycles are averaged to ensure adequate count statistics. With the equilibrium approach, a blood-pool tracer (usually ^99mTc-labeled red blood cells) is used. With the first-pass approach, imaging was performed only during the initial transit of radioactivity through the central circulation. Both techniques can be performed during exercise as well as at rest.

Because of the ability to image the blood-pool radiopharmaceuticals for a substantial time period, SPECT acquisition is also practical with equilibrium RNA. It has been shown that equilibrium blood-pool SPECT acquisition and processing are essentially the same as for SPECT-MPI and thus can be easily adopted in the laboratory where SPECT-MPI is performed. Methods for automatically assessing LVEF from gated blood-pool SPECT have been developed and validated.³¹⁹ Because the SPECT approach avoids the overlap of cardiac chambers inherent in planar imaging, it enhances assessment of regional function and may well become the method of choice for RNA. Techniques for assessing regional asynchrony from the gated blood-pool SPECT have been described and may be of use in predicting the benefit from CRT (Fig. 18–43). Synchrony of contraction can be assessed using gated blood-pool SPECT,^320,321 with potential application as an aide to determining the need for CRT; however, in recent reports, SPECT-MPI has been more commonly used for this application, as discussed later.

Role of RNA in Chronic CAD

Early in the application of nuclear cardiology, the use of RNA was common. Transthoracic echocardiography has now become the standard in the settings in which RNA was previously used. The principal application of RNA remains the measurement of LVEF.²³ This measurement can be used in a variety of settings, such as defining the need for specific therapy, including angiotensin-converting enzyme inhibitors, automatic ICDs, and surgical ventricular restoration; guiding the use of cardiotoxic chemotherapy; and documenting severe reduction of LVEF prior to admission into heart failure trials. RNA can be of value as an arbiter of LVEF when the result of echocardiograph or other methods are uncertain or discordant.

For the detection and management of patients with CAD, exercise RNA played a prominent role in the past, but is now rarely used, predominantly because of advances in stress echocardiography and the ability of gated SPECT-MPI to assess ventricular function as well as myocardial perfusion.

Special Applications of RNA

Assessment of Anthracycline Cardiotoxicity

While echocardiography has become the more common test for this application, RNA can be used in for evaluating the effects of doxorubicin and other anthracyclines on LV function in patients with suspected cardiotoxicity.³²² In an early report, Schwartz and colleagues demonstrated that patients with normal LVEF that had not decreased by more than 15% did not develop cardiotoxicity with continued doxorubicin therapy; however, once EF decreased to less than 45% or by more than 15%, continued doxorubicin therapy was commonly associated with irreversible cardiac failure. In a subsequent report of a large high-risk population from the same group, guidelines were established for the use of continued doxorubicin therapy.³²³ In a group of 70 high-risk patients in whom these guidelines were strictly followed, 2.9% developed subsequent CHF that responded to therapy. Of 212 high-risk patients in whom the recommendations were not closely followed, 21% developed CHF (P < .001 vs the strict-guideline group), which was usually moderate to severe.

The physiologic assessments of nuclear cardiology and the anatomic assessments of CCTA provide complementary information. Their sequential use in settings in which the initial test left clinical uncertainty regarding the clinical question being asked is beneficial. Although recent developments in CCTA have demonstrated that CCTA alone may increasingly be used to assess both the presence and the functional significance of CAD, to date they are not widely applied clinically. Furthermore, stress nuclear imaging remains the dominant initial imaging method. Thus consideration of the clinical value of combined testing of the physiologic and anatomic processes, whether combined or in sequential fashion, remains important. Which type of test might be optimal as the initial test depends on the clinical subset of patients being studied. In asymptomatic patients, there has been dramatic growth in the evidence base supporting the use of CAC scanning with noncontrast CT to assess subclinical atherosclerosis (see Chap. 17). As discussed above, in patients with extensive CAC, usually defined by a threshold of 400 Agatston units or more, assessment with nuclear MPI for the presence and extent of myocardial ischemia can help guide patient management for adding anti-ischemic therapy and consideration of the need for revascularization. Also, as noted above, after CCTA, nuclear MPI may play a role in further risk stratification if the results of the CCTA are not definitive regarding patient management.

The evaluation of symptomatic patients with suspected CAD is the most common application of nuclear MPI. However, in recent years, CCTA has become increasingly utilized as the initial diagnostic test in these patients. CCTA has emerged as the noninvasive method with the highest accuracy for prediction of anatomic stenosis by invasive coronary angiography, with sensitivity in the range of 95%, higher than that associated with all other noninvasive testing.^324,325,326 Furthermore, when compared to nuclear MPI, CCTA is less likely to fail to detect CAD in a patient with high-risk anatomy unless quantitative myocardial perfusion flow reserve assessment is employed (167). A large number of studies have demonstrated high prognostic accuracy of CCTA measures across a broad spectrum of presentations of suspected CAD (327-330). The mortality in patients with entirely normal CCTA studies is extremely low.³²⁷ With each degree of increasing anatomic abnormality, including nonobstructive disease, significant increases in mortality were observed.³²⁷ A long “warranty period” for patients with a normal study has been described: the annual event rate of patients with a normal CCTA study has been reported in multiple studies to be less than 0.25%. Thus, CCTA is likely to increase in application as an initial test in symptomatic patients with suspected CAD. When CCTA is used as the initial test, there is a selective use of nuclear MPI in patients in whom management is unclear after the CCTA study. The role of nuclear MPI in an “initial CCTA” strategy is illustrated in Fig. 18–44. Nuclear MPI also plays a role in other circumstances when the results of CCTA are indeterminate regarding therapeutic options (eg, in the post-PCI or post-CABG patient).

In patients with a high likelihood of CAD or in those with known CAD, physiologic testing with nuclear MPI has generally been preferred over the anatomic approach. The limitations of stenosis assessment alone in guiding the management of stable CAD patients has been discussed above, based on results from the COURAGE and BARI 2D trials. Furthermore, in these patients, extensive coronary calcification is common and may obscure the accurate interpretation of stenosis by CCTA.

In patients in whom nuclear MPI is the initial test, cardiac CT often plays a complementary role (Fig. 18–45). In patients with normal MPI results, CAC scanning can be useful in detecting subclinical atherosclerosis and guiding patient management. A drawback of stress imaging without anatomic assessment in patients with an intermediate likelihood of CAD is that the methods detect only patients with hemodynamically significant lesions and fail to identify patients with subclinical atherosclerosis in whom aggressive medical and lifestyle modification might prevent subsequent cardiac events. Although SPECT-MPI assessment of ischemia is an excellent test of short-term prognosis, CAC scanning may be a better test of long-term prognosis.³³¹ More than a decade ago, it was recognized that high CAC scores are common in patients with normal SPECT-MPI.³³² By combining CAC scanning with nuclear MPI, patients with normal MPI and nonobstructive CAD can be identified and afforded effective preventive therapies. The use of CAC scanning in conjunction with nuclear MPI can also be an aid in increasing certainty in interpretation and accuracy in prediction of hemodynamically significant stenosis in the presence of borderline MPI abnormalities or when there is discordance between the nuclear MPI results and clinical or ECG responses to stress (Fig. 18–46). The coupling of CAC scanning with SPECT or PET-MPI by hybrid scanning would likely increase the effectiveness of nuclear MPI as a first choice approach to management of the patient with suspected SIHD. How CCTA would fare regarding “value” when compared to hybrid CAC/SPECT or PET-MPI imaging has not been studied and would be of great interest.

CCTA is often more definitive than CAC scanning in guiding management of patients with borderline or discordant MPI results as well as in patients with mild degrees of ischemia. The decision to proceed to invasive angiography can be aided by CCTA, which might rule in or out the presence of high-risk anatomic findings. The incremental prognostic value of SPECT-MPI and CCTA has recently been reported in a study of 1295 patients undergoing both studies in sequential fashion.³³³ Thus, clinical strategies are likely to emerge in which selected patients may benefit from both nuclear MPI and CCTA studies.

Hybrid SPECT/CT and PET/CT

With the advent of hybrid SPECT/CT and PET/CT systems, assessment of both coronary anatomic and physiologic can be made as a routine in a single study. As noted above, with such systems, nuclear MPI is routinely coupled with CAC scanning, allowing assessment and management of coronary atherosclerosis that might not be detected by ischemia testing alone. Coupling of MPI and CCTA in the same setting with these systems has also been described.³³⁴ Several studies have evaluated hybrid PET-MPI/CCTA with respect to prediction of hemodynamically significant stenosis defined by invasive angiography in combination with FFR^335,336 and have demonstrated higher accuracy of the combination than with either modality alone. Because it is difficult to predict in advance whether a patient will need both studies, the practicality and cost-effectiveness of the routine combination of the two studies remains in question. If a single test provides sufficient information to accurately guide patient management, the routine performance of the both tests would have resulted in unnecessary radiation.

Combined ANATOMY and Function from CCTA

The recently described method for estimating FFR from the resting CT—FFR CT—also allows the potential to assess both the presence and the physiologic significance of coronary stenosis. Three multicenter studies have demonstrated improved prediction of invasive FFR by the combination of FFR CT with CCTA.^339,340,341 Computed tomography perfusion (CTP) has been described as a method for assessing myocardial perfusion at the time of CCTA, accomplished through acquisition of an additional contrast CT study during vasodilator stress. Improved accuracy in detection of functionally significant stenosis using CTP has been reported.³⁴² A recent meta-analysis of FFR CT and CTP has reported that these methods improve the specificity of CCTA for detecting hemodynamically significant stenosis as defined by FFR.³⁴³ Their combination in a single setting may expand the clinical use of CCTA for the combined purpose of assessing anatomic and functionally significant CAD. Applications of these methods could affect both the choice of initial testing and reduce the need for the sequential performance of testing with CCTA and nuclear perfusion techniques.

The past decade has seen new developments in noninvasive imaging technology and improvements in existing modalities. The options for imaging in known or suspected CAD include echocardiography, CMR, multidetector CT, and PET as alternative or complementary modalities to stress SPECT-MPI. Each modality is likely to play an important clinical role for the foreseeable future. In many patients, these tests will be used in combination to most effectively guide patient management decisions. The ability of myocardial perfusion SPECT to provide standardized procedures that are not highly technologist dependent and provide objective quantization assessments of myocardial perfusion and function with equipment of only moderate expense offers a strength likely to sustain this approach for many years. Over a longer time frame, echocardiography, CT, and CMR may increasingly be used for many of the applications for which SPECT is commonly used today. During this time, however, opportunities for growth of molecular imaging methods both in SPECT and in PET are likely to be developed as growth areas for the field of nuclear cardiology. Although the basic SPECT camera has had little fundamental change over several decades, entirely new SPECT approaches have been introduced recently, offering the potential to increase both sensitivity (reducing imaging time or radiation dose) and resolution.^5,344,345

Recent Cardiac SPECT Applications

Assessment of LV Dyssynchrony: Guidance for CRT

Accurate assessment of ventricular dyssynchrony may improve the selection of patients who benefit from CRT. Because of the four-dimensional nature of the image data sets, gated SPECT can be used to assess ventricular dyssynchrony.^347,348 Studies have shown that an assessment of intraventricular dyssynchrony can be effectively performed by means of phase analysis on gated SPECT-MPI^{111,112,349,350,351} or gated blood-pool SPECT, the latter also allowing the assessment of interventricular dyssynchrony.^320,321,352 Studies have reported that responders and nonresponders from CRT therapy can be distinguished by phase analysis.^350,353,354 Patients with broad dispersion of phase angles are more likely to respond to CRT (see Fig. 18–43). In small single-center trials, sensitivity and specificity for predicting response to CRT have been reported as 70% and 74%,³⁵⁰ 83% and 81%,³⁵³ and 77% and 56% respectively.³⁵² In comparison to tissue Doppler imaging by echocardiography, the SPECT-MPI methods have the advantage of providing true 3D onset of contraction data for the entire left ventricle. Additionally, the methods of analysis are automatic, thus providing high reproducibility. Prospective trials are needed to compare the value of MPI versus echocardiography in predicting benefit from CRT as well as to determine whether this assessment is superior to the standard criterion of prolonged QRS duration for selecting patients for CRT. Other potential applications include guiding CRT LV lead placement toward the site of latest mechanical activation,^355,356 and risk stratification and disease process identification in various populations such as patients with known or suspected CAD,³⁵⁷ hypertension, nonischemic cardiomyopathy with narrow QRS and mildly decreased LVEF,³⁵⁸ ICDs,³⁵⁹ or end-stage renal disease.³⁶⁰ Because of intrinsic differences between published SPECT-MPI methods, algorithm-specific thresholds are recommended for clinical applications.³⁶¹

Cardiac Amyloidosis

With the aging of the population, cardiac amyloidosis is becoming increasingly more prevalent and is now recognized as an under-recognized cause of heart failure. The diagnosis is often suspected in patients with heart failure and an apparent increase in LV mass by echocardiography, without clear explanation such as hypertensive heart disease with LVH or known hypertrophic cardiomyopathy.^362,363 Although endomyocardial biopsy may be required for a definitive diagnosis, it is not used indiscriminately, and noninvasive approaches leading to the diagnosis are of great clinical use.

Hot-spot (infarct-avid) imaging methods for detecting acute MI were among the earliest techniques in nuclear cardiology. The most common of these techniques was the use of ^99mTc-pyrophosphate (^99mTc-PYP)—a standard bone scanning agent—for direct imaging of active calcification occurring in the presence of myocardial necrosis.²³ With improvements in enzymatic diagnosis of myocardial necrosis and with the development of CMR as a method for imaging MI, ^99mTc-PYP is no longer used for acute MI.

^99mTc-PYP is a bone scanning agent that tracks active calcification and was previously used to detect myocardial infarct.³⁵⁶ More than 30 years ago, it was noted that ^99mTc-PYP cardiac uptake was seen in cardiac amyloidosis, demonstrating a characteristic pattern of diffuse, intense myocardial uptake.¹⁷⁴ After the initial reports, it became recognized that many patients with biopsy-proven cardiac amyloidosis did not have abnormal ^99mTc-PYP scans, and for 20-plus years, the method was considered highly specific (because of its characteristic pattern) but not sensitive for cardiac amyloidosis and was not widely used clinically.

Further understanding of the relationship between ^99mTc-PYP and cardiac amyloidosis has led to the ^99mTc-PYP scan now playing an important part in the diagnosis of this disease.³⁶⁴ There are two major types of cardiac amyloidosis: light-chain amyloidosis (AL), associated with a plasma-cell dyscrasia, and transthyretin-related amyloidosis (ATTR), also referred to as senile amyloidosis or wild type, often occurring in the elderly or less commonly representing a familial process (see Chap. 61). The two types of cardiac amyloidosis have different treatments. For AL, a rapidly progressive and almost uniformly fatal disease, chemotherapy or liver transplantation is used. More supportive therapies are used for the more indolent ATTR. Further study of ^99mTc-PYP in cardiac amyloidosis revealed that the characteristic diffuse uptake pattern was seen in ATTR amyloidosis but not in AL, explaining its apparent low sensitivity.^363,365,366 In a recent study, Bokhari and colleagues showed that a 1.5 heart:contralateral lung ratio in ^99mTc PYP imaging accurately distinguished AL (< 1.5) from ATTR (> 1.5) amyloidosis.³⁶⁵ Characteristic patterns of delayed enhancement on CMR are observed in both forms of cardiac amyloidosis.

With respect to the method of imaging ^99mTc-PYP for cardiac amyloidosis, planar imaging is standard and is performed 90 minutes after injection. However, because it may be difficult to distinguish cardiac ^99mTc-PYP uptake from residual ^99mTc-PYP in the blood pool, cardiac SPECT may also be performed. The use of a dual-isotope approach, with ²⁰¹Tl and ^99mTc-PYP, is useful for interpretive certainly regarding the presence and location of the myocardial ^99mTc-PYP uptake.

In terms of clinical application, ^99mTc-PYP imaging, therefore, now plays a central role in the evaluation of cardiac amyloidosis. It becomes part of the standard evaluation of patients with heart failure and unexplained increase in LV mass by echocardiography. CMR is the initial test of choice, being sensitive for both ATTR and AL cardiac amyloidosis. In a proposed diagnostic algorithm for cardiac amyloidosis, Falk and coworkers recommend CMR for initial testing along with assessment for the presence of plasma-cell dyscrasia.³⁶⁷ If CMR is positive and a plasma cell dyscrasia is present, AL is likely and would be confirmed by endomyocardial biopsy. If the CMR is suggestive of cardiac amyloidosis but no plasma cell dyscrasia is found, ^99mTc-PYP imaging is performed. If the PYP scan is negative, other etiologies of hypertrophic cardiomyopathy or infiltrative cardiomyopathy are evaluated.³⁶⁷ Conversely, if the PYP scan is positive, it implies the presence of ATTR, and this finding leads to genotyping and endomyocardial biopsy. ^99mTc-PYP imaging is also useful if CMR is contraindicated, or if it is negative or equivocal and a high clinical suspicion remains present for amyloidosis, then PYP imaging would again be of value if a plasma-cell dyscrasia is ruled out.³⁶⁷ The noninvasive testing with CMR and/or ^99mTc-PYP is not considered definitive, and in most settings, the endomyocardial biopsy is used to establish the diagnosis. Serial scanning with ^99mTc-PYP has not been found to be useful. A recent study by Castano and colleagues showed no significant changes of uptake over an 18-month period, despite significant clinical progression.³⁶⁸

Cardiac Sarcoidosis

Other applications of nuclear cardiology beyond MPI imaging are currently common with PET, as discussed in Chapter 19. Among these, the most common is the use of FDG imaging for diagnosis and guiding patients with known or suspected cardiac sarcoidosis.^369,370

Metaiodobenzylguanidine Imaging: Neuronal Dysregulation in Heart Failure

¹²³I-metaiodobenzylguanidine (mIBG), a single-photon emitting analog of norepinephrine (NE), has extensively been used for almost a quarter of century for the assessment of neuronal dysregulation in patients with heart failure.^371,372,373 It is currently approved for use by the FDA for imaging of myocardial innervation; however, reimbursement for this application is not currently in place, resulting in low rates of its clinical use. Semiquantitative measures^374,375,376 reveal reduced myocardial mIBG uptake in heart failure that has a strong association with the likelihood of adverse outcomes such as ventricular arrhythmias and cardiac and all-cause mortality.^{377,378,379,380,381} mIBG imaging can also verify resolution of neuronal dysfunction in response to treatment with neurohumoral agents or device therapy for heart failure.^{382,383,384,385,386,387,388} Discordance between the extent of mIBG tomographic defect and the myocardial perfusion deficit determines the likelihood of unstable arrhythmias associated with sudden cardiac death and the need for ICD.^{389,390,391,392,393}

The Pathophysiologic Basis of mIBG Imaging in Heart Failure

Neuronal dysregulation plays an important role in the pathogenesis of heart failure (Fig. 18–47). NE synthesis in presynaptic sympathetic neurons and its release into the synaptic cleft are substantially increased in the failing heart. Although NE reuptake from the cleft into the neurons is increased through human norepinephrine transporter 1 (hNET1), it gradually fails to keep pace with the increasing NE spill, because of oxidative stress–mediated reduction in the efficiency of the reuptake mechanism. NE excess in the synaptic clefts leads to postsynaptic sarcolemmal adrenoceptor desensitization and contributes to myocardial remodeling. Increased NE content of the synaptic cleft is also reflected in increased circulating NE levels. Increased release and disproportionately lower reuptake results in 50% lower neuronal NE stores in heart failure. Because mIBG is a structural and functional analog of NE, radiolabeled mIBG has been employed to track the NE metabolism in failing hearts.

mIBG is taken up by the hNET1 with even higher affinity than NE (K_m = 0.31 μM and 1.8 μM, respectively). However, it binds poorly to the adrenergic receptors, exerts only minimal sympathomimetic effects,^394,395 and is not catabolized by monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT).^396,397 Injected mIBG is taken up from the synapse into the neuron by the hNET1 pathway and stored in NE vesicles. With each cycle of neuronal stimulation, a small amount of mIBG reenters the synapse with the release of NE and diffuses back into the vascular compartment to be excreted unchanged by the kidneys. Normally, approximately 1% of the intravenously injected dose of mIBG localizes to the myocardium.³⁹⁸ In heart failure, with increased sympathetic outflow,³⁹⁹ and quantitative reduction in NE uptake sites,⁴⁰⁰ there is more rapid clearance of neuronal mIBG. This is represented by higher washout rate in terms of the percentage reduction in mIBG activity between early (15-minute) and late (4-hour) images. Accordingly, late images show lower myocardial retention of mIBG and are assessed as a lower myocardium-to-background (usually mediastinal) uptake ratio. Lower mIBG retention at 4 hours, as evidenced by a heart-to-mediastinum (H/M) ratio of less than 1.6) and high levels of myocardial washout (> 40%-50% over the 4 hours) are associated with increased occurrence of adverse events such as heart failure progression and cardiac death (Fig. 18–48).³⁷⁵

mIBG Imaging for Prognostic Assessment

The following three studies provide the state-of-art description of the value of mIBG imaging.

1. ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study provided prospective validation of the independent prognostic value of mIBG scintigraphy in assessment of patients with heart failure.⁴⁰¹ The ADMIRE-HF study prospectively evaluated mIBG imaging for identifying symptomatic heart failure patients most likely to experience cardiac events. A total of 961 subjects with New York Heart Association (NYHA) functional class II/III heart failure and LVEF less than 35% underwent mIBG myocardial imaging and MPI and were then followed up for up to 2 years. Time to first occurrence of NYHA functional class progression, potentially life-threatening arrhythmic event, or cardiac death was compared with H/M less than1.60, and 25% of patients experienced events. The HR for H/M greater than 1.60 was 0.40; HR for individual event categories were 0.49, 0.37 and 0.14 for heart failure progression, arrhythmic events, and cardiac death, respectively. Significant contributors to the multivariable model were H/M, LVEF, brain natriuretic peptide (BNP), and NYHA functional class, wherein mIBG imaging provided incremental discriminatory value beyond BNP and LVEF. In a subsequent substudy, 777 patients from ADMIRE-HF without ICD at the time of index mIBG were evaluated. There were 75 all-cause deaths. After adjusting for multiple factors, the H/M ratio analyzed as a continuous variable added incremental prognostic value and enhanced reclassification for survival. Although the H/M ratio did not identify individual patients with enhanced survival with ICD implantation, it identified the absolute benefit gained by ICD use, in groups as assessed by the number of lives saved per 100 treated, suggesting it may play a role in optimizing the cost-effectiveness of ICD placement.⁴⁰²

2. The pooled analyses of independent cohort studies from Japan (the largest user of mIBG imaging) confirmed the long-term prognostic value of cardiac mIBG uptake in patients with heart failure independently of other markers, including NYHA class, BNP, and LVEF. In addition, they demonstrated that categorical assessments could be used to define meaningful thresholds for lethal event risk. Six prospective heart failure cohort studies were updated, and the individual data sets were combined for the patient-level analysis. The database consisted of 1322 patients with heart failure followed up for a mean interval of 78 months; lethal events were observed in 326 patients with the mortality of 5.6%, 11.3%, and 19.7% at 1, 2, and 5 years, respectively. Multivariate Cox proportional hazard model analysis for all-cause mortality identified age, NYHA class, H/M, and LVEF as significant independent predictors. The receiver operating characteristic (ROC)-determined threshold of H/M (1.68) reported progressively decreasing 5-year survival rates with decreasing H/M; all-cause annual mortality was greater than 7% for H/M less than 1.25, and less than 2% annually for (heart-to-mediastinum ratio) HMR of 1.95 or more. Addition of H/M to the clinical information resulted in a significant net reclassification improvement of 0.175. The discriminatory value of H/M was observed at every level of LVEF.

3. To verify previous observations using a rigorous clinical trial methodology, a retrospective review and prospective quantitative reanalysis was performed on a series of mIBG scans acquired during a 10-year period in Europe from 290 heart failure patients. Major cardiac events occurred in 26% patients, wherein the mean H/M ratio was 1.51 ± 0.30 for the event group as compared to 1.97 ± 0.54 for the no event group.⁴³ With an optimum H/M ratio threshold of 1.75, the 2-year event-free survival was 95% for greater, and 62% for H/M ratio less than 1.75. Logistic regression showed H/M and LVEF to be the only significant predictors.

From European and USA studies in 636 heart failure patients, all-cause mortality, cardiac mortality, arrhythmic events and cardiac transplantation during follow-of 37±20 months deaths, cardiac deaths, arrhythmic events, and heart transplants occurred in 13, 11, 5 and 9%, respectively. In multivariate analysis, late H/M was an independent predictor for all event categories, except for arrhythmias. In the European study, the highest event proportions for cardiac transplant and cardiac death were in patients with H/M ratios in the lowest quartile (≤ 1.45), whereas the lowest proportions were for those in the highest H/M ratio quartile (≥ 2.18).⁴⁰³ In contrast, the highest proportion of arrhythmic events was among patients in the second quartile (1.46-1.74), representing those with only mild to moderate neuronal dysfunction. This observation was confirmed in the ADMIRE-HF, where the highest arrhythmic event rate (nonfatal and fatal) was in subjects with H/M between 1.30 and 1.59.⁴⁰¹ The potential for use of mIBG imaging as a cost-effective noninvasive means to individualize heart failure treatments to optimize patient outcomes is both unproven and untapped.³⁷¹

New SPECT Radiopharmaceuticals

Radionuclide imaging has an inherent advantage over other cardiac imaging techniques for assessment of myocardial metabolic and biochemical processes. Although they can examine a wide variety of biochemical processes both PET and SPECT radiopharmaceuticals must go through the standard FDA phase I, II, and III steps prior to commercial availability a highly costly process. For SPECT, two new tracers are in clinical trials using iodine-123 (¹²³I). From a radiochemistry standpoint, ¹²³I is an excellent radionuclide, because, unlike the more commonly used ^99mTc, it is easily incorporated into a wide variety of physiologically important compounds by a halogen exchange reaction in which the iodine replaces a methyl group. From a physical standpoint, ¹²³I has favorable half-life (13 hours), photon energy (159 keV), and radiation exposure characteristics, all nearly as favorable as those of ^99mTc for gamma camera imaging. ¹²³I-mIBG is the only I-123 labeled compound currently available for routine cardiac applications in the United States.

Fatty Acid Imaging

Although radionuclide imaging of fatty acids has been studied for decades, it is not yet in common use, with the exception of one SPECT radiopharmaceutical β-methyliodophenyl pentadecanoic acid (BMIPP), which is in clinical use in Japan. BMIPP is a modified branched-chain fatty acid first introduced by Knapp and coworkers.⁴⁰⁴ This tracer appears to have ischemic memory properties offering unique capability for the assessment of previously severely ischemic myocardium. Discordant myocardial fatty acid uptake/perfusion findings, with less BMIPP uptake than rest ²⁰¹Tl, have been described in patients who have had a recent episode of severe ischemia, with BMIPP representing the previously ischemic zone and the ²⁰¹Tl the infarcted zone.⁴⁰⁵ This finding likely represents a persistent metabolic abnormality out of proportion to the perfusion abnormality at the time of injection. Dilsizian and colleagues recently reported a phase II study in which 32 patients with ischemia by exercise ²⁰¹Tl SPECT were studied by BMIPP SPECT injected with BMIPP at a mean of 6.2 hours after exercise in 21 patients and a mean of 24.9 hours after exercise in 11 patients (Fig. 18–49). More than 90% agreement was observed between the studies for presence of abnormality. In a clinical study from Japan of 111 patients with possible ACS, BMIPP SPECT 1 to 5 days after pain was more sensitive for abnormality in the zone of the culprit vessel than ²⁰¹Tl (74% vs 38%, respectively; P < .05). These findings suggest that a possible clinical application of BMIPP would be assessment of patients presenting several hours to days after a possible severe ischemic episode, potentially providing direct evidence of the recent severe ischemia at a time when perfusion had returned to normal.⁴⁰⁶

Molecular Imaging

The current explosion of information in cell biology has led to initial formulations of numerous imaging agents with specific molecular targets. Perhaps the greatest future potential of the discipline of nuclear cardiology lies in molecular imaging because of the ability of the radiotracer technique to assess minute tracer concentrations in vivo. SPECT and PET methods are thousands of times more sensitive than ultrasound, magnetic resonance imaging, or CT methods.⁴⁰⁷ Although most work has occurred with PET in this regard (Chap. 19), molecular SPECT tracers have also been developed. For example, indium-111 antimyosin antibody,⁴⁰⁷ is highly specific for myocardial necrosis and has been shown to be useful in the assessment of myocarditis⁴⁰⁷ and the necrosis associated with cardiac transplant rejection.⁴⁰⁷ The full commercialization of this molecular imaging agent, however, was not pursued. The most promising of the molecular imaging SPECT radiopharmaceuticals has been ^99mTc-annexin, an agent that allows imaging of apoptosis by specific binding to the exteriorized phosphatidylserine molecules, normally only found in the inner leaflet of the cell membrane and that become exteriorized during apoptosis.⁴⁰⁸ Initial clinical trials with this agent demonstrated high sensitivity for MI. Other clinical settings in which this agent could prove useful as a myocardial imaging agent include myocarditis, transplant rejection, and possibly CHF. Multiple PET radiopharmaceuticals for imaging specific molecular targets are described in the Chapter 19.

This work is supported in part by the Adelson Family Foundation and the Diane and Guilford Glazer Foundation. The authors gratefully acknowledge the invaluable assistance of Mahsaw Motlagh and Frances Wang in preparation of this chapter.