Basic properties of myocardial perfusion agents

INTRODUCTION — Radionuclide myocardial perfusion imaging (MPI) involves the visualization of a radiopharmaceutical that is distributed throughout the myocardium in proportion to coronary blood flow, thereby permitting the determination of relative blood flow in various regions of the heart. Regional coronary blood flow (delivery) determines the amount of tracer activity within a specific area; close correlation between flow and activity has been demonstrated with the currently available radiopharmaceuticals over a physiologic range of coronary blood flow.

Perfusion imaging is dependent upon the physical properties of the radiolabeled tracer, its delivery, and its extraction and retention by the myocyte. Both cell membrane integrity and energy utilization are necessary for intracellular extraction and retention of tracer. Thus, retained tracer activity is synonymous with myocyte viability. Revascularization of such segments can lead to improvement in left ventricular function. (See "Evaluation of hibernating myocardium" and "Treatment of ischemic cardiomyopathy".)

The ideal perfusion agent would have the following characteristics:

●High first pass myocardial extraction

●Linear relationship between uptake and flow

●Uptake independent of metabolic state

●Stable distribution during imaging

Several radiolabeled myocardial perfusion agents are available. Understanding the basic properties of these agents is necessary in order to choose the proper agent for a particular clinical setting and to fully understand the results of radionuclide myocardial perfusion imaging (table 1). (See "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)

SPECT TRACERS — Single photon emission computed tomography (SPECT) is the most commonly used myocardial perfusion imaging technique. Thallium-201 and technetium-99 tracers can be used in SPECT MPI.

Thallium-201 — Thallium-201 (Tl-201) is a radioactive element that is similar to potassium analogs first used in perfusion imaging, but with superior imaging characteristics.

General characteristics — Tl-201 has the following general characteristics:

●It is cyclotron produced and therefore requires off-site manufacturing.

●The principal photopeaks are gamma rays at 135 keV (2.7 percent) and 167 keV (10 percent), and mercury X-rays of 69 to 83 keV (85 to 90 percent) [1].

●The physical half-life of thallium-201 is prolonged (73 hours), limiting the overall amount that can be administered to 2 to 4 mCi.

●Thallium uptake is partly an active process involving the Na-K-ATPase pump. Due to the relatively small contribution of active transport, extraction and uptake of thallium is relatively unaffected by ischemia, hypoxia, or digoxin, and is directly proportional to coronary blood flow [2-5].

●The relationship between flow, as measured by microspheres, and myocardial thallium activity is linear and proportional up to at least twice the resting flow rates [5,6].

●Thallium uptake may overestimate flow within a region with low flow rates, and underestimate flow at high flow rates [6,7].

Thallium-201 has the following advantages:

●Myocardial uptake is proportional to flow

●Redistribution allows a single injection for both stress and rest images

●It is considered the "gold standard" for viability assessment among single photon agents (see "Assessment of myocardial viability by nuclear imaging in coronary heart disease")

However, it also has two disadvantages:

●Low photon energy results in more scatter and soft tissue attenuation

●Longer physical half-life limits the allowable dose, which reduces image quality

Redistribution — Following thallium's initial extraction, there is a continuous exchange between the myocyte and the extracellular compartment, resulting in a phenomenon called redistribution. Intake of thallium into the cell continues via additional extraction of thallium that still remains in the blood (arterial input), and recirculation of tracer that has already been washed out of the intracellular compartment. Thallium may leak out of various regions within the myocardium at different rates, based upon coronary blood flow. Thus, an area that has higher coronary flow may permit the egress of thallium at a faster rate than a region of low flow, demonstrating a "differential washout" of thallium.

Redistribution often begins as early as 20 minutes following thallium administration (figure 1) and may result in the partial or total resolution of perfusion defects noted shortly after stress imaging [8]. Thus, post-stress imaging should begin within 15 minutes after the initial injection. The redistribution process allows thallium to assess the relative regional coronary blood flow following stress, and under "resting" conditions, after a single injection of tracer [7].

However, the estimate of perfusion is different at three to four hours after thallium delivery than under true resting conditions, and it can overestimate the extent of myocardial necrosis. This potential limitation may be overcome by a second injection of a smaller dose of thallium immediately following the redistribution images ("reinjection"). (See "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)

Thallium redistribution can be affected by several factors:

●Changes in coronary blood flow can have a substantial impact upon redistribution, although tracer may be redistributed even without a significant alteration in flow.

●The administration of nitrates appears to facilitate the appearance of thallium redistribution, and consequently the recognition of reversible myocardial ischemia [9].

●Redistribution may be affected by metabolic interventions that alter the transport of thallium (eg, ribose administration), potentially permitting earlier and more obvious determination of redistribution after an ischemic event [10].

Reverse redistribution — Many authors have commented on a finding referred to as "reverse redistribution," in which the perfusion defect appears worse on the delayed redistribution perfusion images (three to four hours after thallium injection) than on the initial images. This phenomenon is thought to be related to hyperemic blood flow that causes enhanced uptake of thallium on initial post-stress images [11], and a more rapid clearance of thallium, producing the appearance of a perfusion abnormality.

Reverse redistribution is consistent with viable myocardium [12]. However, its presence in a patient with a low likelihood of ischemia and without other evidence of ischemia is felt to represent an artifact.

Technetium-99 labeled agents — There are several physical advantages for the use of technetium-99m (Tc-99m) perfusion tracers (table 2):

●The higher photon energy (140 keV) is well suited for gamma camera imaging and may result in less photon attenuation and scatter due to soft tissue when compared with thallium-201. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

●A half-life of six hours and favorable dosimetry permits the administration of substantially more activity, thereby resulting in a high number of emitted photons and improved image resolution. The increased photon flux also permits functional imaging with gated single photon emission computed tomography (SPECT) or first-pass techniques.

●Tc-99m is a generator produced product and as a result, it is readily available (on site) at most institutions.

Two 99m Tc-labeled myocardial perfusion agents are routinely used in clinical practice (sestamibi and tetrofosmin). Each compound has unique properties that make it suitable for certain types of imaging (table 1).

Sestamibi — Tc-99m sestamibi (Cardiolite™) is in a class of compounds known as isonitriles. Sestamibi has the following general characteristics:

●It is a lipophilic monovalent cation with transient hepatic uptake, minimal lung uptake, and a good target-to-background ratio [13].

●The exact mechanism of myocardial uptake of sestamibi is unclear. Uptake appears to be passive across the plasma and mitochondrial membranes with sestamibi being sequestered in the mitochondria by the large negative membrane potential [14]. In experimental models, sestamibi uptake is not blocked by ouabain. Thus, unlike thallium uptake, sestamibi uptake is not dependent upon the Na-K-ATPase pump [3,15].

●The fraction of sestamibi extracted on first pass by the heart is lower than that for thallium [16].

●Distribution within the myocardium is proportional to blood flow until approximately two to three times the resting flow levels, when uptake starts to plateau [17].

●Animal models show that sestamibi myocardial activity overestimates coronary flow at low flow rates, as determined by radiolabeled microspheres [17]. This finding may be attributed to increased extraction of tracers at low flow and, as mentioned above, has also been seen with Tl-201.

Tc-99m sestamibi has the following advantages:

●Myocardial uptake is proportional to flow

●There is stable retention of tracer (minimal redistribution)

●Simultaneous perfusion and function assessment is possible

Sestamibi undergoes minimal redistribution over time [17,18]. This stable distribution has numerous ramifications for the use of this agent:

●Sestamibi is well suited to the prolonged acquisition times associated with tomographic imaging.

●The absence of significant sestamibi redistribution necessitates two separate injections of the radiopharmaceutical, one during peak stress and a second while at rest.

●The lack of sestamibi redistribution permits greater flexibility in scheduling since imaging is not mandated immediately after injection.

●Sestamibi can be used to quantify the area of risk in a patient suffering an acute myocardial infarction. As an example, sestamibi can be injected at the time of presentation, and the patient imaged after stabilization in the coronary care unit. Since sestamibi activity reflects myocardial perfusion at the time of injection, defects on these early images indicate the "area at risk." Subsequent injections and imaging after interventions (eg, thrombolysis) can then be used to demonstrate the amount of salvaged myocardium [19].

●Sestamibi can be given to patients with chest pain and nondiagnostic findings on ECG, and images taken later, even after treatment of the chest pain (image 1). This method permits assessment of coronary blood flow at the time of chest pain, allowing for improved triage and management. As an example, a patient with a normal perfusion study after being injected with sestamibi during an episode of chest pain may be triaged to a less intensive care setting or even home, depending upon the clinical circumstances.

●The stable retention and high count rates of Tc-99m sestamibi permits the evaluation of left ventricular function as part of a perfusion imaging protocol. Both gated SPECT and first pass imaging have been performed successfully with this agent [20]. This evaluation may be one of the most valuable clinical attributes of sestamibi scintigraphy.

Although the lack of redistribution would appear to limit the use of Tc-99m sestamibi for the evaluation of myocardial viability and the detection of hibernating myocardium, this does not appear to be the case [21-24]. There are data to suggest that quantitative analysis of sestamibi activity is useful for predicting functional recovery of dysfunctional ventricular segments after revascularization [21]. In addition, nitrate administration prior to tracer injection improves the detection of viable myocardium by reducing the perfusion defect size and intensity in the majority of viable regions [22-24]. (See "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)

Tetrofosmin — Tetrofosmin (Myoview™) is a lipophilic, cationic diphosphine compound. It has good myocardial uptake with rapid clearance from the liver, lungs, and blood [25,26]. The mechanism of uptake into the myocytes is not clear but appears to involve potential driven diffusion across the sarcolemmal and mitochondrial membranes [27].

Important features of Tc-99m tetrofosmin include:

●Myocardial uptake is proportional to flow

●Minimal redistribution occurs

●There may be more rapid washout from the liver than with sestamibi, permitting earlier imaging after injection

Myocardial uptake of tetrofosmin is proportional to microsphere confirmed blood flow until uptake plateaus at flow rates greater than 2.0 mL/min/g [28]. As with sestamibi, there is little myocardial washout over time. Thus, high quality myocardial images can be obtained from five minutes to several hours after injection. The more rapid clearance from the liver with tetrofosmin may lead to less artifact from subdiaphragmatic activity, which is a common problem with Tc-99m sestamibi [29].

Although there is less widespread experience with tetrofosmin compared with the other available agents, the diagnostic accuracy of stress Tc-99m tetrofosmin imaging appears to be similar to that of Tl-201 and Tc-99m sestamibi [29-31]. Given the many similarities between tetrofosmin and sestamibi, these two agents can be used in clinically similar situations:

●Exercise tetrofosmin imaging is of prognostic value in patients with coronary heart disease, adding incremental information to that provided by clinical and exercise data [32,33]. In a multicenter review of 4278 patients, the mortality rate in those with a normal exercise or adenosine tetrofosmin SPECT study was 0.6 percent per year, similar to published rates for normal thallium and sestamibi studies [32].

●Some studies utilizing vasodilator stress have shown that, compared with thallium and sestamibi, tetrofosmin detected fewer ischemic segments, and the extent and severity of reversible defects were smaller. As a result, tetrofosmin may be less sensitive in identifying mild coronary stenoses [34,35].

●Tetrofosmin appears to be useful for the detection of viable myocardium [36-38]. In one report, its ability to predict functional recovery after percutaneous revascularization in patients with a prior myocardial infarction was comparable to that of thallium and sestamibi [38].

●First pass imaging is feasible, and gated SPECT tetrofosmin imaging can also be performed [39].

●Preliminary studies have revealed that tetrofosmin is of clinical utility in patients who present to emergency departments with chest pain and nondiagnostic electrocardiograms [40].

PET TRACERS — Positron emission tomography (PET) imaging differs from single photon emission computed tomography (SPECT) in that PET uses radionuclides that decay by positron emission. PET imaging relies on the detection of two 511 keV gamma photons. Typical PET tracers have short half-lives; they must be synthesized and imaged in a short period of time, which usually requires the presence of an on-site cyclotron. It also limits the ability to use these tracers for exercise-based stress protocols. Like SPECT tracers, PET tracers also must be easily accessible, cost effective, and have a linear extraction over a wide range of myocardial flow.

The most commonly used cardiac PET tracers are Rubidium-82 (Rb-82), Nitrogen-13 (N-13), Oxygen-15 (O-15), and Fluorine-18 (F-18). PET imaging is based on two concepts: myocardial flow and myocardial metabolism. Rb-82, N-13 ammonia, and O-15 water all allow an assessment of myocardial flow, while F-18 fluorodeoxyglucose (FDG) allows an assessment of myocardial metabolism. Tracers such as F-18 flurpiridaz and O-15 have close to linear tracer uptake relative to blood flow, making them especially attractive in the determination of flow reserve.  

Rubidium-82 — Rubidium-82, like thallium, is a potassium analog. It is also dependent on the Na+/K+ ATPase pump for cellular uptake, and its myocardial extraction is similar to that of thallium. The following characteristics make Rb-82 a clinically useful cardiac PET imaging tracer:

●It is generator produced

●It has a short half-life

●It allows high throughput for clinical pharmacologic stress testing

Unlike thallium, rubidium is generator-produced, allowing it to be manufactured on site. It is eluted from the decay of strontium-82 in a generator, which must be replaced approximately every four weeks. Rb-82 decays by positron emission with a half-life of only 78 seconds. Although this short half-life makes the logistics of imaging challenging, it also allows for the rapid completion of a series of rest and stress imaging studies. The cost of the generator is often a fixed monthly expense, making it economically feasible for larger volume centers.

Rb-82 based PET imaging has been compared with SPECT imaging with all of the various SPECT tracers in numerous studies and several systematic reviews [41-45]. Generally, Rb-82 based PET imaging has shown equivalent, if not greater, overall sensitivity, specificity, and accuracy for the detection of coronary disease [43,45]:

●Sensitivity – 84 to 93 percent for PET versus 88 percent for SPECT

●Specificity – 81 percent for PET versus 61 to 76 percent for SPECT

In a small series, Rb-82 has been shown to identify multivessel disease [46]. When used to measure myocardial flow reserve, Rb-82 PET can predict the likelihood of multivessel disease [47]. Additionally, several studies in both patient volunteers and animals have compared Rb-82 with N-13 ammonia and shown that Rb-82 can be useful in the quantification of myocardial blood flow [48,49].

Fluorine-18 — Using F-18, one can create FDG (fluorodeoxyglucose), which is a radiolabeled glucose analog used for metabolic and perfusion imaging, allowing one to distinguish ischemic myocardium from nonviable myocardium [50]. The half-life of F-18 is 110 minutes, and it must be produced in a cyclotron.

The use of FDG was initially reported in 1986 for the assessment of myocardial viability [51]. In patients with poor ventricular function, FDG-PET showed an increased benefit over thallium or sestamibi imaging in improvement of ventricular function [52]. Since that time, there have been increasing data on the prognostic utility of FDG after coronary revascularization [53].

To date, the most extensively studied F-18 perfusion tracer is F-18 flurpiridaz. As of March 2020, F-18 flurpiridaz is not FDA approved in many countries including the United States, and phase 3 clinical trials are ongoing.

F-18 flurpiridaz has drawn attention due to its longer half-life (110 minutes) compared with tracers using rubidium, nitrogen, or oxygen, making it more suitable for cardiac perfusion imaging. With its longer half-life, there is more flexibility with exercise-based stress protocols, and it can be distributed from a centrally-located cyclotron center rather than requiring an on-site cyclotron.

Additionally, due to its physical properties, such as a shorter positron range, it is notable for being able to produce higher spatial resolution images when compared with other PET imaging agents such as Rb-82 and O-15 [54].

F-18 flurpiridaz enters the cell by passive distribution and is concentrated in the mitochondria. Based on animal studies, the heart-to-liver ratio at one hour was high, making it a favorable myocardial imaging agent in its ability to produce high-quality images [55]. Flurpiridaz also exhibits features important for an effective myocardial perfusion agent: flow-independent first-pass extraction and high heart-to-surrounding-tissue uptake. Flow-independent first-pass extraction allows the ability to obtain quantitative myocardial blood flow, a distinct advantage over relative blood flow in the ability to detect balanced ischemia.

Initial safety and diagnostic performance trials have shown good image quality and diagnostic performance. A small study of 12 patients showed high myocardial-to-background uptake and a favorable safety profile [56]. In a second larger study, seven minor adverse events were reported out of 143 patients, and the diagnostic accuracy in comparison to SPECT tracers was at least the same if not superior [57]. Initial results of a phase 3 study have been reported, showing superior diagnostic performance of F-18 flurpiridaz as compared with traditional SPECT imaging in obese patients [58].

Nitrogen-13 — As nitrogen is an essential component of basic amino acids, N-13 allows the labeling of amino acids without altering their physiologic properties. These amino acids are important components to myocardial protein synthesis and metabolism in both normal and diseased states. The neutral component diffuses across the cell membranes where it re-equilibrates with ammonium and becomes trapped intracellularly. In vitro studies have shown that in ischemic myocardium, more N-13 becomes trapped within myocytes with a diminished washout of the tracer [59].

N-13 allows gating of both rest and stress images in addition to quantification of myocardial blood flow. In small studies, quantitative myocardial blood flow with N-13 was reproducible and accurate when compared with estimates using Rb-82 [60]. Its limitations are that it has a short half-life (10 minutes) and is cyclotron produced, and its use requires coordination of a cyclotron operator, a radiochemist, and a stress testing technologist. This short half-life however results in decreased radiation exposure to the patient.

Additionally, N-13 PET perfusion and flow reserve have long-term prognostic value. Individuals with abnormal coronary flow reserve measured by N-13 PET had significantly higher rates of major cardiac events over a five-year follow-up [61].

Oxygen-15 — O-15 has a short half-life (2.1 minutes), requiring the use of an on-site cyclotron. Due to its ability to freely diffuse across the cell membrane, it is considered the gold standard for myocardial flow quantification [62]. This same characteristic is what limits its clinical utility. Image quality is less than ideal due to low-count statistics arising from its rapid clearance from the myocardium [63]. At this time, it is not approved for clinical use in the United States.

SUMMARY AND RECOMMENDATIONS — Although the ideal myocardial perfusion agent has not been discovered, several single photon agents are available with differing physical properties and applications (table 1). By understanding the characteristics of these radiopharmaceuticals, appropriate selection of the agent may be accomplished and imaging protocols optimized.

●Thallium-201 has the following advantages and disadvantages:

•Myocardial uptake is proportional to flow.

•Redistribution allows a single injection for both stress and rest images.

•It is considered the "gold standard" for viability assessment among single photon agents. (See "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)

•Low photon energy results in more scatter and soft tissue attenuation.

•Longer physical half-life limits the allowable dose which reduces image quality.

●Technetium-99m (Tc-99m) perfusion tracers have several advantages (table 2):

•The higher photon energy (140 keV) is well suited for gamma camera imaging, and may result in less photon attenuation and scatter due to soft tissue when compared with thallium-201. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)

•A half-life of six hours and favorable dosimetry permits the administration of substantially more activity, thereby resulting in a high number of emitted photons and improved image resolution. The increased photon flux also permits functional imaging with gated single photon emission computed tomography (SPECT) or first-pass techniques.

•Tc-99m is a generator produced product, and as a result, it is readily available (on site) at most institutions.

●Positron emission tomography (PET) imaging differs from single photon emission computed tomography (SPECT) in that PET uses radionuclides that decay by positron emission. PET imaging relies on the detection of two 511 keV gamma photons. Typical PET tracers have short half-lives; they must be synthesized and imaged in a short period of time. The most commonly used cardiac PET tracers are Rubidium-82 (Rb-82), Nitrogen-13 (N-13), Oxygen-15 (O-15), and Fluorine-18 (F-18). PET imaging is based on two concepts: myocardial flow and myocardial metabolism. Rb-82, N-13 ammonia, and O-15 water all allow an assessment of myocardial flow, while F-18 fluorodeoxyglucose (FDG) allows an assessment of myocardial metabolism.

For the routine detection and evaluation of coronary artery disease, thallium and technetium-99m agents have proven efficacy and are comparable in terms of diagnostic accuracy [64]. The technetium-99m agents provide improved image quality and more easily permit simultaneous assessment of ventricular function at a lower radiation dose. However, the choice of agent and protocol will depend upon the needs and requirements of the particular nuclear cardiology laboratory (eg, scheduling, availability, etc).