Overview of stress radionuclide myocardial perfusion imaging

INTRODUCTION — Radionuclide myocardial perfusion imaging (rMPI) enables evaluation of cardiac perfusion and function at rest and during dynamic exercise or pharmacologic stress for the diagnosis and management of patients with known or suspected epicardial and microvascular coronary artery disease. Radionuclide MPI requires the administration of a radioactive perfusion tracer (also called a radiopharmaceutical or radioisotope), usually intravenously, and a special camera system, single-photon emission computed tomography (SPECT), or positron emission tomography (PET), to detect the gamma photons. It is important to note that there is no contrast agent used in rMPI. Myocardial perfusion images are usually acquired at rest and following stress, with increasing adoption of stress-only imaging, and many available combinations of one- versus two-day rest-first versus stress-first protocols, as discussed below. A specialized computer program reconstructs the acquired images into standard displays (image 1).

Radionuclide MPI provides important information on rest and stress myocardial perfusion, myocardial ischemia and infarction, microvascular dysfunction, viability, and global and regional left ventricular systolic function, which can signify the presence and extent of underlying coronary artery disease. In addition, rMPI is a powerful tool for risk stratification of patients with known or suspected coronary artery disease.

To detect the presence and extent of stress-induced myocardial ischemia, a radioisotope must also be administered at rest and under conditions of stress, and rest and stress images can then be compared. Stress testing in conjunction with rMPI is accomplished using either exercise (treadmill or bicycle), pharmacologic agents (preferably vasodilators, but if contraindicated, dobutamine), or a combination of both vasodilator stress and low-level exercise.

An overview of the indications, contraindications, techniques, and safety of stress rMPI will be provided here (table 1). Exercise treadmill testing and stress echocardiography, as well as the advantages and disadvantages of stress rMPI as compared with other stress modalities, are discussed separately. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Overview of stress echocardiography" and "Stress testing for the diagnosis of obstructive coronary heart disease" and "Selecting the optimal cardiac stress test".)

INDICATIONS — There are several established indications for stress radionuclide myocardial perfusion imaging (rMPI) [1-3]:

●Evaluation of chest pain in patients with known or suspected coronary artery disease (see "Stress testing for the diagnosis of obstructive coronary heart disease")

●Assessment of myocardial viability (see "Evaluation of hibernating myocardium" and "Assessment of myocardial viability by nuclear imaging in coronary heart disease")

●Evaluation of dyspnea of possible cardiac origin (see "Approach to the patient with dyspnea")

The multi-society 2021 chest pain guidelines review the diagnostic evaluation of patients presenting with acute and stable chest pain [4]. The algorithm of which modality is utilized for coronary artery disease evaluation relies on the pretest probability or patient risk based on contemporary cardiovascular risk scores and/or calcium scoring, if known. Patients in low-risk categories, defined by age <40 years or with a calcium score of zero, may not need additional testing or can undergo exercise electrocardiography (ECG). In patients presenting with chest pain with intermediate risk, stress imaging is favored (class I) given the relatively lower sensitivity of exercise ECG. The choice of rMPI over other imaging stress modality may depend on institutional expertise.

A full discussion of the indications for stress testing is presented elsewhere. (See "Selecting the optimal cardiac stress test", section on 'Indications for stress testing'.)

CONTRAINDICATIONS — The only contraindication to radionuclide myocardial perfusion imaging (rMPI) itself is pregnancy, due to the unknown effects of radiation exposure on the fetus (see "Diagnostic imaging in pregnant and lactating patients"). Patients with severe claustrophobia may not tolerate certain types of scanners with smaller and enclosed gantries.

Most of the contraindications relate to stress testing. The contraindications to exercise stress rMPI are the same as those for standard exercise ECG testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Contraindications'.)

In addition, specific contraindications to pharmacologic rMPI are primarily related to the medications used as the stress agent:

●Vasodilators (ie, adenosine, dipyridamole, and regadenoson) are contraindicated in patients with hypotension, generally <90 mmHg (since these drugs tend to lower the blood pressure), sinus node dysfunction, high-degree atrioventricular (AV) block (in the absence of backup pacemaker capability), and reactive airways disease. Vasodilators should not be used in patients with active wheezing due to bronchospastic airway disease, even though this side effect may be promptly reversed by aminophylline. Data suggest that regadenoson administration may be tolerated in patients with mild or moderate reactive airway disease, as small, randomized, double-blind studies of patients with mild or moderate asthma [5] and patients with moderate or severe chronic obstructive pulmonary disease [6] found that regadenoson was well tolerated with no significant differences in FEV1 compared with placebo. For use of regadenoson in patients with asthma or other reactive airway disease in our laboratory, we use the additional screening criteria of clinical stability with no recent exacerbation or medication changes for lung disease in the past 30 days, baseline FEV1 of greater than 60 percent (at clinician discretion), not wheezing on examination, and not O₂ dependent. (See 'Selective A2A receptor agonists' below.)

●Methylxanthines such as aminophylline, theophylline, caffeine, or theobromine block the effect of adenosine and should be held for at least 12 hours (and ideally 24 to 48 hours) prior to the test.

●Acute myocardial infarction and high-risk unstable angina are absolute contraindications to all types of stress testing. The exception to this is the use of adenosine within one to four days following stabilized myocardial infarction for risk stratification. In the prospective randomized trial of adenosine single-photon emission computed tomography (SPECT) MPI (INSPIRE), gated adenosine SPECT rMPI performed early after acute myocardial infarction accurately identified a sizeable low-risk group with <2 percent death and reinfarction at one year [7].

Full discussions of the contraindications to stress testing, as well as the interactions between medications or diet and vasodilator stress agents, are presented elsewhere. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Contraindications' and "Stress testing: The effect of medications and methylxanthines".)

STRESS TECHNIQUES

Choice of stress method — The choice of stress method is largely governed by patient characteristics. For patients in whom radionuclide myocardial perfusion imaging (rMPI) is indicated, an algorithm for stress method selection is provided (algorithm 1). (See "Selecting the optimal cardiac stress test".)

Exercise rMPI — For single-photon emission computed tomography (SPECT) MPI, a symptom-limited treadmill or bicycle exercise is the preferred form of stress for patients who can achieve an adequate cardiac workload because it provides the most information concerning the patient's exercise capacity, symptoms, hemodynamic response, and prognosis during physiologic activity [8-10]. The inability to perform an exercise test is in itself a marker of increased risk in patients referred for rMPI and those with coronary heart disease (CHD). (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Exercise capacity'.)

The standard exercise protocols used in stress testing are discussed separately. Any of the protocols may be used in conjunction with rMPI. The radioisotope should be injected as close to peak exercise as possible, and then exercise should be continued for at least one more minute to allow the radioisotope to circulate before termination of exercise. The exercise test should be interpreted as detailed elsewhere and incorporated into the final rMPI report and interpretation. For 99m-technetium (Tc99m)-labeled perfusion agents, image acquisition may begin 10 to 15 minutes following termination of exercise, or it may be delayed up to several hours after exercise, as there is no significant redistribution of the tracer. For thallium-201, image acquisition should begin as soon as the patient has recovered from exercise and should not be delayed due to the property of significant redistribution, which can reduce the ability to detect ischemia. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Common exercise protocols'.)

Due to the short physical half-lives of current FDA-approved positron emission tomography (PET) perfusion tracers, pharmacologic stress is preferred over exercise when PET MPI is performed. Depending on the radioisotope and the camera system, tracer administration generally begins during the pharmacologic stress infusion, concomitant with or followed shortly by image acquisition.

Pharmacologic rMPI — For patients who are unable to attain an adequate level of exercise, pharmacologic stress rMPI provides an important alternative to exercise stress testing. The 2009 update of the American Society of Nuclear Cardiology (ASNC) guidelines for nuclear cardiology procedures includes protocols for use of these agents [11,12].

Pharmacologic stress agents are classified as either vasodilator or inotropic/chronotropic drugs (table 1). Vasodilators are preferred over inotropic/chronotropic stress agents for pharmacologic rMPI.

●The major vasodilators for pharmacologic rMPI are adenosine, dipyridamole, and regadenoson. The mechanisms of action and use of the individual agents in rMPI are discussed in detail below. (See 'Vasodilator agents' below.)

●The major inotropic/chronotropic agent used for pharmacologic rMPI is dobutamine (with or without atropine). The mechanism of action of dobutamine and its use in rMPI are discussed in detail below. (See 'Dobutamine rMPI' below.)

Vasodilator rMPI

Mechanism of vasodilator stress — Adenosine, regadenoson, and dipyridamole are effective pharmacologic stress agents because they produce coronary vasodilation, increasing myocardial blood flow during stress on the order of three to five times that of resting myocardial blood flow [13-16]. In a study of 49 patients (24 female, ages 41 to 69) with a normal exercise stress test and low probability for CHD who underwent rest/dipyridamole stress rubidium-82 (Rb-82) PET imaging, absolute myocardial blood flow increased from rest to stress and was higher in women than in men, with some variations depending on the software package used [16]. However, there was substantial interpatient variability in response, which has been previously documented [13,17].

Relative flow differences — The presence of flow-limiting obstructive CHD leads to perfusion defects during vasodilator stress rMPI. These defects reflect the heterogeneity in coronary flow reserve between normal and stenosed coronary artery territories [14,18-20]. Blood flow in normal coronary arteries may increase up to fourfold in response to coronary vasodilation. In the presence of a moderate to severe coronary artery stenosis, the increase in blood flow with vasodilator stress is attenuated, leading to reduced coronary flow reserve in the area subtended by the coronary artery stenosis, and an associated relative reduction in radiotracer uptake. Because of this relative difference in radiotracer uptake, the area supplied by the stenotic coronary artery appears as a perfusion defect when the left ventricular myocardium is normalized to the most normal area with the highest radiotracer uptake. This relative difference in radiotracer uptake may be a limitation in patients with severe multivessel disease where "balanced ischemia" may be present and may be overcome by the use of absolute flow quantification with PET MPI [21,22].

Vasodilator agents

Adenosine — Adenosine is a purine nucleoside molecule that has several important cardiac properties, including regulation of coronary blood flow and heart rate [23].

●Activation of adenosine A2A receptors causes coronary vasodilatation through the production of cyclic adenosine monophosphate (AMP), stimulation of potassium channels, and decreased intracellular calcium uptake, resulting in hyperemia.

●Activation of A1 receptors causes atrioventricular (AV) conduction delay, which can result in transient AV block and which explains its use in the management of some supraventricular arrhythmias.

●Activation of A2B, A3, and A4 receptors can mediate bronchospasm by facilitating mast cell degranulation, potentially leading to wheezing and shortness of breath.

Exogenously administered adenosine is rapidly taken up by the cells, especially red blood cells and endothelial cells, explaining the short half-life of five seconds.

When used for stress rMPI, adenosine is administered via an infusion pump at a dose of 140 mcg/kg per minute, typically for six minutes (table 1). The radionuclide is then injected intravenously over 10 seconds after three minutes of adenosine infusion, and the infusion is continued for three additional minutes (figure 1) [11,12]. A shorter-duration adenosine infusion, lasting four minutes, has been found to be equally effective for the detection of obstructive CHD compared with the standard six-minute infusion but is probably less commonly used. For the shorter duration protocol, the minimum time to tracer injection should be two minutes, and the infusion should continue for at least two minutes after tracer injection.

In patients with a remote history of asthma and/or pulmonary function testing with less than 30 percent bronchodilator response, or a mildly positive methacholine challenge, pretreatment with nebulized albuterol (2.5 mg) 15 minutes before adenosine infusion, with or without a graduated infusion of adenosine, may be considered [24]. A graduated adenosine infusion is started at either 50 or 75 mcg/kg/minute with close monitoring for evidence of bronchospasm, followed by dose increases to 140 mcg/kg/minute if no adverse effects are noted during the dose escalation. The radionuclide is injected after one minute of peak adenosine infusion, and the adenosine infusion is continued for another two minutes.

Simultaneous low-level treadmill exercise during adenosine infusion is safe, feasible, well tolerated, results in fewer side effects, and improves image quality [25]. (See 'Combined exercise and vasodilator stress' below.)

Indications for early termination of adenosine infusion include severe hypotension (systolic blood pressure <80 mmHg), symptomatic and/or persistent advanced heart block, wheezing, and/or severe chest pain with associated ST segment changes. Most side effects (table 2) resolve soon after discontinuation of the adenosine infusion, and aminophylline infusion is rarely required to reverse the effects.

Dipyridamole — Dipyridamole produces vasodilation by blocking the cellular reuptake of adenosine, thereby elevating the interstitial concentration of endogenous adenosine and increasing adenosine activity [26,27]. The biologic half-life of dipyridamole is 30 to 45 minutes; it is primarily metabolized in the liver, and only small amounts are excreted in urine (table 1).

When used for stress rMPI with SPECT imaging, dipyridamole is infused at a dose of 140 mcg/kg per minute for four minutes, up to a maximum dose of 0.56 mg/kg; the radionuclide is injected seven to nine minutes after initiation of the infusion or three to five minutes after the completion of the dipyridamole infusion (figure 2) [11,12]. To reverse side effects, aminophylline 125 to 250 mg intravenously is often required and is usually given one to two minutes following radionuclide injection, although doses as low as 25 mg can be effective [28].

Because of the longer half-life of dipyridamole compared with adenosine, patients can receive a dipyridamole infusion and then undergo supplemental low-level exercise, which helps improve image quality by reducing liver and gut activity and attenuates side effects from the vasodilator agent. Symptom-limited exercise testing after dipyridamole infusion can enhance risk stratification for future cardiac events [29]. (See 'Combined exercise and vasodilator stress' below.)

Dipyridamole is used less frequently in SPECT MPI in the United States than the other vasodilator stress agents, mostly due to its longer half-life. However, dipyridamole is used more often in PET MPI and is commonly used in SPECT MPI in Europe.

Selective A2A receptor agonists — The coronary vasodilation induced by adenosine and dipyridamole, which inhibits cellular reuptake of adenosine, is due to stimulation of the adenosine A2A receptors on vascular smooth muscle cells. These drugs also nonselectively activate the adenosine A1, A2B, and A3 receptors, which contributes to many of the common side effects associated with these drugs. Therefore, selective A2A receptor agonists have been developed in an effort to reduce the complications and discomfort from vasodilator stress testing. These newer vasodilator stress agents include regadenoson, binodenoson, and apadenoson. In addition to being the most extensively studied and most widely available of these agents, regadenoson is the only selective A2A receptor agonist approved for use with SPECT MPI in the United States and most other countries.

Regadenoson is a selective A2A receptor agonist that produces hyperemia with rapid onset (30 seconds) for a longer period (approximately two to five minutes) than adenosine, which permits more convenient administration (injection over 10 seconds). The half-life for regadenoson has an initial intravenous peak hyperemia phase of two minutes and a longer intermediate phase of 30 minutes. This is in contrast to adenosine with a half-life of five seconds. Thus, monitoring of patients should be longer after administration of regadenoson than adenosine. Regadenoson has also been combined with low-level and symptom-limited exercise. (See 'Combined exercise and vasodilator stress' below.)

The ADVANCE-MPI 2 trial, a randomized double-blind trial that compared regadenoson with adenosine in 784 patients, found that regadenoson had similar efficacy to adenosine for detection of reversible perfusion defects [30]. An analysis of the combined data of 1871 patients in the ADVANCE-MPI 1 and 2 randomized trials also demonstrated noninferiority for regadenoson relative to adenosine [31]. In both reports, regadenoson was associated with a decreased overall symptom score (which included flushing, chest pain, and dyspnea) [31,32].

When used for stress SPECT MPI, regadenoson 400 mcg (administered via prefilled single-dose injection) is infused in 10 seconds or less into a peripheral vein using a 22-gauge or larger catheter or needle (figure 3). A 5 mL saline flush should be immediately infused after the regadenoson injection to ensure appropriate drug delivery. The radioisotope is infused 10 to 20 seconds after the saline flush and can be injected directly into the same catheter as regadenoson [11,12]. Exercise may also be performed in conjunction with regadenoson injection if desired. (See 'Combined exercise and vasodilator stress' below.)

In contrast to other pharmacologic stress agents (ie, adenosine, dipyridamole, dobutamine), the pharmacokinetics of regadenoson allow for injection during exercise in patients who begin with an exercise SPECT MPI but who are unable to achieve the desired work-load [33]. The option of transitioning to a pharmacologic protocol allows patients who are ambulatory but with an unclear baseline functional status to start with exercise stress testing given the useful functional information ascertained for ordering providers while preserving diagnostic yield. However, staff monitoring the exercise test in which regadenoson may be administered in recovery for inadequate workload should carefully monitor patients for ischemic symptoms and electrocardiography (ECG) changes as well as for abnormal hemodynamic responses during exercise and in the early recovery phase prior to regadenoson administration. If symptoms and signs of ischemia are present during exercise or in recovery, radiotracer should be administered without regadenoson injection. Regadenoson injection in the setting of ongoing exercise-induced symptoms, ECG changes, and/or hemodynamic abnormalities may lead to adverse events such as myocardial infarction [34]. It is helpful to counsel patients to avoid caffeine the day of stress testing regardless of the initially selected stress modality, as this avoids the need to reschedule if the patient is unexpectedly unable to exercise.

Safety and comparison of vasodilators — Adenosine, dipyridamole, and regadenoson are equally safe in appropriately selected patients and equally effective [13,35-37], although individual subjects have substantial variations in responses to these agents [19]. In our practice, regadenoson is the primary vasodilator agent utilized for pharmacologic stress rMPI due to ease of use (no infusion pump required) and better subjective tolerability [36].

●Clinically important adverse events are uncommon with adenosine [38-40]. In a registry report of 9256 patients who underwent adenosine stress rMPI, the most frequent side effects were second degree AV block (4.1 percent), hypotension (1.8 percent), bradycardia (0.2 percent), third degree AV block (0.8 percent), and bronchospasm (0.1 percent) [39]. All these side effects resolved spontaneously and rapidly with a reduction in the adenosine dose [41]. There were no deaths and only one myocardial infarction. Conversely, minor side effects occurred in 81 percent of patients, with the most common being flushing, nausea, chest pain, dyspnea, and headache (table 2) [39].

●Serious dipyridamole-induced adverse events are rare. In a report of 73,806 patients who underwent dipyridamole stress rMPI, the incidence (per 10,000) of nonfatal myocardial infarction was 1.8, cardiac death rate 1.0, sustained ventricular tachycardia 0.8, and transient ischemic attack 1.2, values which are comparable to those with exercise stress testing [41]. As with adenosine, less serious symptoms, including chest pain (20 percent, most without ST segment changes), headache (12 percent), and dizziness (12 percent), are common with dipyridamole (table 2) [42]. Aminophylline was required in 12 percent of patients and terminated the symptoms in virtually all patients.

●Clinically important adverse events are uncommon with regadenoson. The most common side effects for regadenoson are shortness of breath, headache, and flushing; however, as compared with adenosine, a tolerability comparison between the two agents showed lower overall symptoms with regadenoson when compared with adenosine [36].

In general, both dipyridamole and adenosine, when combined with SPECT MPI, have a comparable sensitivity and specificity of 80 to 90 percent for detection of significant obstructive CHD [43,44]. Regadenoson has been shown to provide diagnostic information comparable to a standard adenosine infusion [30,32].

Combined exercise and vasodilator stress — The combination of low-level treadmill exercise and vasodilator stress test is safe and has the advantages of reducing noncardiac side effects associated with vasodilator stress (table 2), improving image quality by decreasing liver and gut activity with SPECT MPI, and providing prognostic information [45-48].

Several combination exercise and vasodilator stress protocols have been studied and are available, but the most commonly used are those involving low-level exercise. For adenosine, ambulatory patients may walk on the treadmill at 1.7 mph, 0 percent grade during the duration of the six-minute adenosine infusion. For dipyridamole, the same speed may be used for four to six minutes after completion of the drug infusion; the radiotracer is injected during this low-level exercise, and the exercise continues for an additional two minutes to allow for tracer uptake in the myocardium. For regadenoson, the same speed may again be used for 1.5 minutes followed by radiotracer injection and an additional two minutes of exercise [49].

Low-level exercise in combination with vasodilator stress is not recommended in patients with left bundle branch block, Wolff-Parkinson-White syndrome, and ventricular pacing due to the potential for the increase in heart rate during exercise and related imaging artifacts, which may mimic ischemia and reduce the specificity of the rMPI for obstructive coronary artery disease.

Dobutamine rMPI — By increasing both inotropy and chronotropy, dobutamine raises myocardial oxygen demand to a similar level as is seen following exercise. The onset of action is within one to two minutes of intravenous infusion, with a half-life of approximately two minutes (table 1). Atropine may be added to dobutamine when target heart rate (THR) is not achieved at higher doses of dobutamine. The combination of dobutamine and atropine produces hyperemia, with a more than fivefold increase in myocardial blood flow compared with baseline [50]. This change is comparable in magnitude to that induced by adenosine and dipyridamole [13,50].

The standard protocol for dobutamine infusion during rMPI stress testing involves stepwise dose increases every three minutes (figure 4):

●Graded dobutamine infusion in five three-minute stages starting at 5 mcg/kg/minute, followed by 10, 20, 30, and 40 mcg/kg/minute.

●Atropine, in divided doses of 0.5 mg to a total of 2.0 mg, should be administered as needed to achieve THR. Atropine increases the sensitivity of dobutamine echocardiography in patients receiving beta-blockers and in those with single-vessel disease. Some laboratories also use a sustained isometric hand grip or a low-level dynamic foot exercise (with or without atropine) in the late stages of the dobutamine protocol as a supplemental maneuver to achieve peak heart rate. However, for exercise during vasodilator stress, patients should not exercise in the upright position during dobutamine infusion. (See "Overview of stress echocardiography", section on 'Handgrip exercise'.)

The standard endpoint for dobutamine rMPI is the achievement of THR, defined as at least 85 percent of the age-predicted maximum heart rate. The radionuclide is then injected intravenously over 10 seconds and allowed to circulate for at least 60 seconds (figure 4) [11,12]. However, the test may also be terminated following the development of significant symptoms, significant arrhythmias, hypotension (systolic blood pressure less than 90 mmHg), or severe hypertension.

IMAGING TECHNIQUES — The two main radionuclide myocardial perfusion imaging (rMPI) techniques involve the use of either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) camera systems. Both technologies are highly effective in the evaluation and management of patients with known or suspected coronary heart disease (CHD) due to high diagnostic accuracy and prognostic value, although cardiac PET imaging is not as widely available as SPECT imaging [51,52]. Both techniques may be affected by attenuation of gamma rays emitted from the myocardium before leaving the patient and being detected by the camera systems due to the varying tissue densities (eg, breast, diaphragm) and body habitus of the patient. Several techniques for mitigating the effects of attenuation artifacts are discussed below and elsewhere. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

As SPECT camera technologies improve, cameras have become available with enhanced spatial, temporal, and contrast resolution with the potential for quantification of myocardial blood flow. In addition, algorithms have been developed for SPECT MPI that aid in distinguishing attenuation artifacts from true perfusion defects:

●Gated SPECT imaging permits the assessment of systolic wall thickening at end-diastole and end-systole on multiple SPECT tomograms [53]. A fixed defect with normal systolic thickening and wall motion is most consistent with an attenuation artifact rather than a myocardial scar. By contrast, a fixed defect with reduced systolic thickening and hypokinesis represents myocardial scar, a true defect. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

●Multiposition imaging is now possible with many SPECT camera systems and is recommended for at least the stress images if an attenuation correction algorithm is not employed [54]. Two-position imaging is usually performed supine and prone, or supine and upright, to mitigate attenuation artifacts. Prone imaging has been reported to produce less patient motion and less inferior wall attenuation than supine imaging. By comparing supine and prone images (or supine and upright images), artifactual defects will resolve or change their location, whereas true perfusion defects will remain in the same position or with slight rotation from supine to upright due to the slight rotation of the left ventricle. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

●The application of attenuation correction software for photon attenuation and scatter in SPECT rMPI has been shown to significantly improve diagnostic accuracy by reducing the number of false-positive results, and it has been shown to improve the normalcy rate of studies (96 versus 86 percent when using uncorrected images) [55,56]. There was no reduction in overall sensitivity (75 to 78 percent), although the detection of multivessel disease was reduced.

●The creation of an attenuation map from an external radionuclide source or a radiograph noncontrast CT scan (called a transmission scan) is in essence the creation of the opposite image from the image created after the administration of the radioactive perfusion tracer (the emission scan). The attenuation map is then used in the reconstruction process to correct for the effects of attenuation on the final attenuation-corrected images. Care must be taken to align the CT transmission and radionuclide emission images and to avoid truncation of the data. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

An extensive discussion of attenuation artifacts in SPECT imaging is presented separately. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

As compared with SPECT, PET has several advantages that contribute to superior image quality and higher diagnostic accuracy [57]:

●High spatial, temporal, and contrast resolution.

●High energy tracers with short radiopharmaceutical half-lives, resulting in enhanced overall image quality, lower radiation, and efficient protocols.

●Robust built-in attenuation correction (whereas attenuation correction is optional with SPECT imaging, it is mandatory with PET).

●Quantitative assessment of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) [22].

●Acquisition of left ventricular systolic function during peak stress for rubidium-82 (Rb-82) [58].

SPECT imaging

SPECT isotopes — 99m-technetium (Tc99m)-labeled perfusion agents (99m-Tc-sestamibi and 99m-Tc-tetrofosmin) are the most commonly used radioisotopes for SPECT MPI. Utilization of thallium-201 (Tl-201) has substantially declined in the past few decades. The physical half-lives of Tc99m and Tl-201 are 6 and 72 hours, respectively. This property allows larger doses of Tc99m-labeled tracers to be administered compared with thallium-201. In addition to higher-dose administration, Tc99m also has higher energy, less scatter, and less attenuation of photons as compared with thallium-201, and is therefore used with far greater frequency in the United States and other countries. Liver uptake is noted for the Tc99m-based agents, particularly during pharmacologic stress, and may be a limitation to interpretation, although this can usually be overcome with procedural modifications, including low-intensity exercise or delayed imaging.

Additional details of the basic properties of the isotopes used in rMPI are discussed at length elsewhere. (See "Basic properties of myocardial perfusion agents".)

SPECT protocols

Single-isotope rest/stress protocol — Single-isotope rest/stress (or stress/rest) protocols using Tc99m-based radiopharmaceuticals are the most commonly performed SPECT MPI studies. Single-isotope protocols may be two-day or one-day studies. Two-day protocols generally use the same activity of radiopharmaceutical for the rest and stress images, which may be performed in any order, though a stress-first or stress-only protocol may be desirable in patients more likely to have a normal scan, in which case the resting scan may not be required. (See 'Single-isotope, stress-only protocol' below.)

The two-day Tc99m-based protocol is useful in larger patients in whom lower-activity administration may be associated with suboptimal image quality, particularly if acquired with older conventional SPECT systems. The main disadvantages of this protocol are the inconvenience of performing the entire rest/stress study in two days, which may not be practical, and the higher radiation dose to the patient.

In many laboratories, the one-day rest/stress or stress/rest Tc99m-based protocol is employed. In this protocol, the second radiopharmaceutical activity is generally three times higher than the rest radiopharmaceutical activity, thereby offsetting the first dose of myocardial radioactivity. With Tc99m-based radiopharmaceuticals, image acquisition should be performed 15 to 60 minutes after radiopharmaceutical injection, depending on whether the acquisition is post-exercise, post-pharmacologic stress, or at rest, but it may be delayed out to two hours post-injection since no clinically significant redistribution occurs with these Tc99m-based radiopharmaceuticals. The estimated total body radiation dose of a typical one-day rest/stress or stress/rest Tc99m-based protocol using conventional SPECT imaging is approximately 11 milliSieverts. This may be substantially reduced by using weight-based radiopharmaceutical activity, newer solid-state camera systems, and/or newer technologies.

Several Tl-201 protocols are available but are less commonly utilized than Tc99m-based protocols due to the higher patient radiation exposure and lower energy leading to suboptimal image quality in larger body habitus. Unlike Tc99m-based protocols, the stress test and stress Tl-201 injection must be performed first. Because clinically significant redistribution of Tl-201 may occur shortly after radiotracer administration, Tl-201 stress image acquisition should be performed generally within 10 minutes following Tl-201 injection. However, if the patient is still breathing hard from the exercise test, imaging should be delayed slightly due to possibility of myocardial creep (artifact from upward movement of the diaphragm from changes in respiratory rate) post-exercise. In patients who achieve stage III or higher on the Bruce protocol, imaging should not start earlier than 15 minutes post-stress, and respiratory rate should be <25 respirations per minute at the start of imaging to reduce upward creep of the diaphragm. At 2.5 to 4 hours following the initial stress Tl-201 injection, the initial Tl-201 redistribution image may be acquired with or without further Tl-201 reinjection [49]. If the initial redistribution image demonstrates a residual defect (or defects), delayed (18 to 24 hours after initial Tl-201 injection) images may be obtained to assess for further redistribution and myocardial viability following a small dose of Tl-201 administration. A rest-only thallium may also be performed for myocardial viability assessment; the protocol begins with an initial rest image, followed by an initial redistribution image, and if necessary, a delayed image.

Single-isotope, stress-only protocol — A Tc99m-based stress-only protocol is increasingly adopted by laboratories to reduce radiation exposure and resource utilization [59]. In this protocol, the stress test and stress image acquisition with electrocardiography (ECG) gating and/or attenuation correction is performed first and interpreted in a timely manner. If the stress image is completely normal, the resting image is not required and the study is completed in a shorter time frame and with lower patient radiation dose than most conventional paired rest and stress Tc99m protocols. However, if the stress image is abnormal, the resting image may be required and generally needs to be delayed until the following day when higher-dose resting studies may be accomplished. Alternatively, if advanced SPECT technologies are available, the initial stress study may be performed with lower administered activity, and if the images are abnormal, the resting images with higher activity may be performed on the same day. The key to successful implementation of stress-only protocols is careful patient selection, and we typically screen patients for the following:

●Prior abnormal rMPI images

●Known severe CHD or myocardial infarction without prior revascularization

●Known cardiomyopathy

●Weight >300 pounds

If any of the above is/are present, the patient should generally undergo a full rest/stress Tc99m study as the stress image is more likely to be abnormal or equivocal. Prediction models to identify patients suitable for stress-first imaging may be useful guides to appropriately select patients for this protocol [60].

The diagnostic value of stress-only imaging was illustrated in a series of 90 patients who underwent rest/stress ECG-gated technetium-99m sestamibi SPECT rMPI with attenuation correction [61]. Only the stress images were made available for interpretation by 10 experienced readers. Images were read for diagnostic accuracy in the following sequence: rMPI alone, rMPI with ECG-gated SPECT images, and attenuation-corrected rMPI with gated images. Forty-one patients underwent catheterization within sixty days of imaging. Attenuation-corrected data significantly reduced the perceived need for rest imaging (43 versus 77 percent with rMPI alone) and allowed the readers to characterize significantly more studies as definitely normal or abnormal (84 versus 37 percent with rMPI alone). (See "Artifacts in SPECT radionuclide myocardial perfusion imaging", section on 'Attenuation correction'.)

Dual isotope — Utilization of a dual-isotope protocol is generally not recommended due to the higher patient radiation dose associated with the dual isotope approach. In this protocol, 3 mCi of 201-Tl is injected at rest, and images are then acquired within 10 minutes. Subsequently, the stress study is performed using a Tc99m-based radiopharmaceutical. The main advantage of this approach is patient throughput since Tl-201 images can be acquired almost immediately following the rest injection; however, the dual-isotope protocol generally only reduces patient time in the laboratory by approximately 30 minutes and is offset by several disadvantages, including the highest patient radiation dose among all rMPI protocols and the difficulties of interpreting rest and stress images of different resolutions, with the associated challenge of assessing for transient ischemic cavity dilation.

PET imaging

PET isotopes — The current FDA-approved PET perfusion tracers are Rb-82 and 13N-ammonia. 13N-Ammonia use is restricted to centers with an available on-site or nearby cyclotron due to the short physical half-life of 13N of 9.9 minutes. Rb-82 is produced from a strontium-82 generator and is widely used in centers without on-site cyclotrons but generally requires a rapid delivery system due to the very short physical half-life of 75 seconds. The same dose of these PET perfusion tracers is usually administered for both the rest and stress, usually in this order. 13N-ammonia requires a 50-minute period between rest and stress radiotracer administration for decay of the rest radiotracer dose. In addition to image acquisition following tracer administration (termed emission image), PET imaging requires an additional image acquisition using an external radiation source (termed transmission image) using either CT in PET/CT systems, or rod or line sources in dedicated PET systems. Each transmission image is then used for attenuation correction of each emission image. With PET MPI, vasodilator stress is highly preferred because exercise, although feasible with 13N-ammonia, poses technical challenges during PET perfusion imaging [62]. Dobutamine is an alternative when vasodilators are contraindicated. A novel radiotracer that was recently evaluated in clinical trials, F-18 flurpiridaz, is expected to receive FDA approval and improve access to PET imaging. The longer half-life of 109 minutes allows for the utilization with exercise stress, in contrast to the current radiotracer, along with improved access to low-volume centers with proposed utilization of regional cyclotrons.

Quantification of MBF at rest and stress allow for assessment of MFR. In both PET and SPECT imaging, the challenge of "balanced ischemia" in patients with multivessel disease is a concern when transient ischemic dilation is noted. Subendocardial ischemia is the suspected mechanism for the perceived chamber enlargement or TID on the stress perfusion images. A systematic review and meta-analysis of accuracy of TID noted high specificity of this finding with an overall low sensitivity [63]. Moreover, sensitivity is lower in pharmacologic stress protocols. MFR in the setting of multivessel disease is globally reduced, which improves the sensitivity of detection of severe coronary artery disease and minimizes the impact of "balanced ischemia" on the perfusion images. In addition, the CT obtained for attenuation correction is independently useful as an assessment for multivessel coronary calcification. MFR is a useful adjunct in abnormal perfusion studies, as it increases the specificity of abnormal stress perfusion findings when a corresponding decrease in MFR is seen in that coronary distribution.

Microvascular disease is an increasingly recognized phenomenon in patients with anginal chest pain with nonobstructive coronary artery disease. MBF quantification in PET studies allows for the noninvasive assessment of microvascular dysfunction, allowing for tailored antianginal therapies when confirmed.

Radiation exposure — The American Society of Nuclear Cardiology (ASNC) and the American Heart Association (AHA) have published recommendations for reducing radiation exposure in MPI [59,64]. The range of radiation exposure varies significantly depending on the study performed and the camera system used, with many newer systems generally requiring lower activity, resulting in lower doses [64]:

●Rest-stress PET rMPI using N-13 ammonia – approximately 2 milliSieverts

●Rest-stress PET rMPI using Rb-82 – approximately 3 milliSieverts

●Stress-only SPECT rMPI using 99m-technetium – approximately 3 milliSieverts

●Rest-stress SPECT rMPI using 99m-technetium – approximately 11 milliSieverts

●Dual-isotope SPECT rMPI using thallium-201 – approximately 22 milliSieverts

ASNC recommends using PET MPI, if PET is available, as one of the first-line strategies for reducing patient radiation exposure in rMPI (algorithm 2), due to the short physical half-lives of the PET perfusion tracers, which lead to lower patient radiation exposure [59]. Another important strategy is the use of newer solid-state SPECT systems and/or novel software, which allow lower activities of radiotracers to be utilized. Stress-only or stress-first protocols should also be considered in eligible patients for radiation reduction purposes. We also recommend reserving Tl-201 protocols for radionuclide assessment of myocardial viability, when PET is not available. ASNC also recommends reserving the dual-isotope protocol, which has the highest patient radiation exposure, only for when myocardial viability is an overriding clinical consideration in patients with advanced CHD, when there is substantially impaired left ventricular systolic function, and when PET is not available. The AHA also recommends alternatives to tests involving radiation (eg, exercise ECG, stress echocardiography, cardiac MRI) in premenopausal women when the alternative test would be appropriate [64]. Other strategies for reducing patient radiation exposure include ensuring appropriateness and clinical need for the study, considering alternative modalities with comparable diagnostic accuracy without radiation in younger patients, and avoiding layered or serial testing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multimodality cardiovascular imaging appropriate use criteria" and "Society guideline links: Stress testing and cardiopulmonary exercise testing".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Nuclear heart testing (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – Radionuclide myocardial perfusion imaging (rMPI) enables evaluation of cardiac perfusion and function at rest and during dynamic exercise or pharmacologic stress for the diagnosis and management of patients with known or suspected coronary heart disease (CHD). Stress rMPI is used primarily to detect the presence and extent of CHD by provoking regional ischemia with variable perfusion as well as detecting regions of infarction with decreased resting perfusion. (See 'Introduction' above.)

●Indications – Similar to other modalities of stress testing (eg, exercise treadmill testing without imaging, stress echocardiography, etc), the majority of stress rMPI studies are performed to evaluate for known or suspected CHD. The two main reasons for performing stress imaging (either stress rMPI or stress echocardiography) instead of an exercise electrocardiography (ECG) are ECG abnormalities at rest which render the stress ECG nondiagnostic for ischemia or the inability to exercise or exercise adequately. (See 'Indications' above.)

●Exercise stress – This is preferred over pharmacologic stress for patients who can perform an exercise test. Exercise rMPI is most commonly performed using a treadmill protocol, with rMPI images both at rest and following peak exercise. Pharmacologic stress is employed in patients who are unable to perform exercise testing. (See 'Exercise rMPI' above and 'Pharmacologic rMPI' above.)

●Vasodilator stress rMPI – This is done with adenosine, dipyridamole, or regadenoson and represents the preferred choice of pharmacologic stress and should be combined with exercise whenever possible. Adenosine, dipyridamole, and regadenoson produce coronary vasodilation and, in the presence of significant coronary stenosis, they induce heterogeneous myocardial blood flow due to differences in coronary flow reserve. The heterogeneity of myocardial blood flow during hyperemia is detectable with a perfusion tracer and single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. (See 'Vasodilator rMPI' above.)

Adenosine, dipyridamole, and regadenoson are generally safe in appropriately selected patients. Clinically important adverse events are uncommon with all of the vasodilators and dobutamine, although some side effects (eg, flushing, headache, dyspnea) occur fairly frequently. (See 'Safety and comparison of vasodilators' above.)

●Dobutamine stress rMPI – This is another option for pharmacologic stress testing in patients who are unable to exercise and in whom vasodilators are contraindicated. By increasing both inotropy and chronotropy, dobutamine raises myocardial oxygen demand to a similar level as is seen following exercise. Atropine may be added to dobutamine when target heart rate (THR) is not achieved at the peak dose of dobutamine. (See 'Dobutamine rMPI' above.)

●SPECT protocols – Single-isotope rest/stress protocols using Tc99m-based radiopharmaceuticals are the most commonly performed SPECT MPI studies, although stress-only protocols are becoming more common in appropriately selected patients. (See 'SPECT protocols' above.)

●PET imaging – PET rMPI, if available, has the added benefits of reducing patient radiation exposure due to the short physical half-lives of the PET perfusion tracers and of absolute quantification of myocardial blood flow. PET rMPI appears to have higher diagnostic accuracy than SPECT MPI, but literature is more limited for PET than for SPECT. The availability of PET rMPI is somewhat limited by the short physical half-lives of the available radioisotopes and PET scanner availability for cardiac imaging. (See 'PET imaging' above.)

ACKNOWLEDGMENT — The authors and UpToDate thank Dr. Athanasios Kapetanopoulos and Dr. Justin Lundbye, who contributed to earlier versions of this topic review.