Introduction

Adenosine single-photon emission computed tomography (SPECT) thallium-201 (Tl-201) imaging is a noninvasive myocardial perfusion imaging (MPI) test using thallium as a radioisotope.[1] The underlying principle of the test is that when the myocardium is under stress, the diseased ventricle receives less blood flow than the normal heart muscle. The SPECT scan performed after the stress event reveals the distribution of thallium and the relative blood flow to the different parts of the ventricle. Images are also obtained at rest and compared. Thallium is injected and taken up by the myocardial cells so that the initial distribution of the tracer reflects viable myocardium. Images are then taken during stress (induced by adenosine) and at rest to reflect myocardial perfusion and viability.

SPECT Tl-201 is used mainly for myocardial viability assessment when positron emission tomography (PET) or magnetic resonance imaging is not feasible. The American Society of Nuclear Cardiology recommends against using adenosine SPECT Tl-201/technetium 99m (Tc-99m), dual-isotope (rest-stress) imaging for detecting myocardial ischemia, as this protocol exposes patients to greater amounts of radiation (up to 23 mSv) than other isotopes.[2] 

Tl-201 is a potassium analog, a radioactive isotope of thallium with a half-life of 73 hours. Tl-201 is uptaken by myocardial cells and detects an area with hypoperfusion and myocardial infarction as a cold spot.[3] This isotope has many other medical applications, including renal medullary imaging and tumor detection.[4] In clinical practice, Tc-99m agents (Tc-99m Sestamibi and Tc-99m Tetrofosmin) are more commonly employed during SPECT imaging for myocardial ischemia detection due to lower radiation exposure (4.2–6.3 mSv) than Tl-201.[5]

Anatomy and Physiology

Mechanisms of Action of Adenosine and Its Analogs in Nuclear Stress Testing

Adenosine and its analogs play a crucial role in nuclear stress testing by inducing coronary vasodilation, allowing for the assessment of myocardial perfusion in patients who cannot undergo exercise-based tests. The mechanism of action of these agents generally involves activating specific receptors in coronary vessels, effectively increasing blood flow and radioisotope uptake in well-perfused myocardial regions.

Adenosine is a nucleoside composed of adenine and D-ribose. This potent direct coronary vasodilator activates A2A receptors in smooth muscles and endothelium.[6] Adenosine is given as a continuous infusion in pharmacological SPECT stress tests for patients who cannot exercise to increase coronary blood flow and radioisotope uptake by myocardial cells with normal coronary perfusion.

Adenosine increases coronary blood flow 3 to 4 times, with peak onset of vasodilation at 1 to 2 minutes of continuous infusion. The half-life of adenosine is around 10 seconds, after which it undergoes intracellular degradation or phosphorylation. Adenosine is infused at a rate of 140 mcg/kg/min over 6 minutes. Radioisotope is administered during the infusion and at the 3rd minute. The infusion continues after radioisotope injection for at least 2 minutes.

Adenosine has several adverse effects that correlate with the activation of other receptors, such as A1AR, A2B, and A3AR. These adverse effects include hypotension, tachycardia, atrioventricular block, bronchospasm, peripheral vasodilatation, and gastrointestinal symptoms.[7][8] Most patients report minor adverse effects. Symptoms include headache, flushing, chest pain, dizziness, nausea and vomiting. Atrioventricular blocks occur in as many as 8% of patients. However, a 2nd-degree or complete heart block is infrequent. The atrioventricular blocks that arise from the infusion are self-terminating and generally do not require aggressive intervention. A modest heart rate increase and modest systolic and diastolic blood pressure decreases are observed during adenosine infusion.

Other commonly used vasodilator agents for pharmacological SPECT stress tests include regadenoson and dipyridamole. Regadenoson is an adenosine derivative and selective A2A receptor agonist. Compared to adenosine, regadenoson is given as a single injection because of its long half-life and more favorable side effect profile, given its selectivity for the A2A receptor.[9] This agent is the vasodilator most commonly used in pharmacological SPECT stress tests (83%).[10]

Dipyridamole is given if regadenoson is unavailable or impractical to use due to cost constraints. The drug inhibits phosphodiesterase, which breaks down cyclic adenosine monophosphate. This action mechanism prevents the cellular uptake and deamination of adenosine and increases its availability in the intravascular space.

Dipyridamole increases coronary blood flow 3 to 7 times. The hyperemia lasts for 50 minutes, whereas the peak vasodilation is reached at 6.5 minutes after the start of infusion. The half-life is 35 to 40 minutes. This agent is metabolized in the liver and excreted in bile. Dipyridamole is infused at a rate of 0.56 mg/kg over 4 minutes. Radioisotope is injected 3 to 5 minutes after the infusion.

Minor side effects are common and include chest pain, flushing, headache, nausea, vomiting, and dizziness. Dipyridamole is associated with a lower incidence of atrioventricular blocks compared to adenosine. Aminophylline is frequently administered to reverse dipyridamole's minor side effects. Hemodynamically, dipyridamole causes a modest increase in heart rate and a modest decrease in systolic and diastolic blood pressures.

Mechanism of Action of Thallium-201 as a Radiotracer in Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging

Tl-201 is a potassium analog with a half-life of approximately 73 hours. This agent's properties make it a suitable radiotracer for differentiating ischemic from scarred myocardium. Tl-201 decays into mercury-201 (Hg-201), emitting 80-keV x-rays. Tl-201 has a first-pass myocardial extraction of around 85% and is transported into the cell membrane via active transport by Na-K ATPase. The isotope is rapidly cleared from the intravascular compartment. The peak myocardial concentration is achieved in 5 minutes, and the initial uptake is proportional to the regional blood flow. The redistribution phenomenon starts within 10 to 15 minutes of injection.

The normal, ischemic, and scarred parts of the myocardium are differentiated based on the phenomenon of differential washout. Redistribution is unrelated to blood flow and is dependent on the concentration gradient between the myocardial and intravascular compartments. A normal myocardium achieves a high thallium concentration, and clearance occurs more rapidly than in ischemic myocardium. Tl-201 is cleared via the kidneys.[11]

Anatomy and Interpretation of the Scan

The details on the cardiac anatomy of SPECT-MPI and the basics of interpretation may be found in the StatPearls reference "Myocardial Perfusion Scan."[12] The interpretation is based on the 17-segment polar map model, which shows the left anterior descending artery supplying the anterior, anteroseptal, apical, and apical cap segments; the right coronary artery perfusing the inferior and inferoseptal segments; and the left circumflex artery providing circulation to the lateral, anterolateral, and inferolateral segments of the heart.

Perfusion defects are characterized by their presence or absence, number, size, severity, location, and reversibility. These defects may involve single or multiple coronary artery distributions, with areas categorized as small, medium, or large based on quantitative or qualitative assessments. Perfusion defects may be mild, moderate, or severe, reflecting the extent of nuclear activity. Reversibility is evaluated by comparing stress and rest images after proper alignment, with defects classified as fixed, partially reversible, completely reversible, or indicative of peri-infarct ischemia. Additionally, comments are made on global left ventricular function and any segmental wall motion abnormalities.

The electrocardiogram (ECG) changes at baseline and peak should be reported. Any symptoms reported by the patient should be documented. The hemodynamic response should also be noted. 

High-risk features on adenosine-thallium SPECT-MPI include increased lung uptake (reflects increased left ventricular filling pressures), the presence of large or multiple perfusion defects, and transient ischemic dilatation of the left ventricular cavity. The presence of nonviable myocardium predicts a lack of response to revascularization and the need to optimize management with medical therapy.

Indications

Indications for adenosine SPECT-MPI include all the indications for exercise SPECT-MPI and any of the following limitations:

• Inability to exercise due to physical limitation (for example, from peripheral vascular disease, osteoarthritis, mental conditions, and lung disease) or lack of motivation
• Baseline ECG changes, such as paced rhythm, repolarization abnormalities, and preexcitation
• Risk stratification after acute myocardial infarction
• Diagnosis and risk stratification in patients presenting to the emergency department with suspected acute coronary syndrome (ACS) in whom serial ECG, clinical examination, and cardiac markers are unremarkable

Standard indications for SPECT-MPI include the following:

• To diagnose obstructive coronary artery disease (CAD) in patients with intermediate-to-high pretest probability of ischemic heart disease (IHD)
• For risk assessment in patients known to have stable IHD, especially if with a left bundle branch block
• To evaluate coronary stenosis with uncertain physiological significance before revascularization
• To evaluate new or worsening symptoms inconsistent with ACS in patients with stable IHD
• For follow-up assessment after 2 years or longer intervals in patients with stable IHD and previous evidence of silent ischemia or elevated risk for a recurrent cardiac event with a history of incomplete coronary revascularization and an uninterpretable ECG [13]

The pharmacological SPECT stress test is appropriate for the following purposes in patients who cannot exercise or have disabling comorbidities:[14][15]

• For evaluation of the following conditions or findings:
  • New-onset or newly diagnosed heart failure with left ventricular systolic dysfunction
  • Ventricular tachycardia, regardless of the risk for CAD
  • Syncope in patients with intermediate or high risk for CAD
  • Elevated troponin in patients without additional evidence of ACS
  • Possible ACS without ECG evidence of ischemia on ECG and with negative or minimally elevated troponin
  • Intermediate or high-risk Duke treadmill score
  • Asymptomatic, but the IHD risk is high based on Adult Treatment Panel III risk criteria
  • Prior equivocal, borderline, or discordant noninvasive evaluation
  • Coronary calcium score greater than 400 or greater than 100 with a high risk for IHD
• Follow-up assessment 5 years after coronary artery bypass graft
• Preoperative risk assessment of patients undergoing intermediate-risk or vascular surgery who have 1 or more clinical risk factors and functional capacity less than 4 METs
• Viability testing for patients with severe left ventricular systolic dysfunction before revascularization
• Evaluation for inducible ischemia within 3 months of an ACS in hemodynamically stable patients without recurrent symptoms or signs of heart failure

Contraindications

Below are contraindications to the use of adenosine as a vasodilator in SPECT-MPI, as per the American Society of Nuclear Cardiology.

Absolute Contraindications

• Obstructive lung disease with ongoing wheezing or a history of reactive airway disease
• 2nd- or 3rd-degree atrioventricular block without a pacemaker
• Sinus node disease without a pacemaker
• Systolic blood pressure less than 90 mm Hg, especially in the following scenarios:
  • Autonomic dysfunction
  • Hypovolemia
  • Left main coronary artery stenosis.
  • Stenotic valvular heart disease
  • Pericarditis or pericardial effusions
  • Stenotic carotid artery disease with cerebrovascular insufficiency
• Uncontrolled hypertension, ie, with systolic pressure greater than 200 mm Hg or diastolic pressure greater than 110 mm Hg
• Recent use of dipyridamole, ie, less than 48 hours
• Known hypersensitivity to pharmacological vasodilators
• ACS episodes, including unstable angina and a recent acute myocardial infarction, ie, within the last 2 to 4 days

Relative Contraindications

• Significant sinus bradycardia with heart rates less than 40 beats per minute
• Mobitz type 1 2nd-degree atrioventricular block
• Ingestion of caffeinated foods or beverages within the last 12 hours
• Severe aortic stenosis
• Seizure disorder

Equipment

The required equipment and materials include the following:

• Infusion pump
• Intravenous line with dual port
• ECG monitoring system
• Blood pressure apparatus
• Emergency crash cart

Personnel

The study should be conducted and interpreted under the supervision of a qualified nuclear cardiologist or nuclear radiologist. All staff involved should have training in Basic Life Support. Advanced Cardiac Life Support training is encouraged.  

The staff involved should be well-trained in dealing with emergency conditions and completing accurate documentation. Preliminary reporting should be available immediately. The referring physician should be notified if a high-risk finding is found. Final reporting should be available within 72 hours of the test at most.

Preparation

The following measures are recommended during preparation:

• Patients should avoid oral intake 3 hours before the test except for medications with sips of water.
• Patients must avoid any food or beverages containing methylxanthines or caffeine, such as caffeinated coffee and tea, at least 12 hours before the test.
• Dipyridamole should also be avoided 48 hours before the test.
• Both theophylline and aminophylline must be discontinued 24 hours before the test.
• Patients should avoid wearing any metals or other potential attenuators that can lead to attenuation artifacts and poor image quality.
• Antianginal medications, including β-blockers, calcium channel blockers, and nitrates, reduce the diagnostic accuracy of SPECT-MPI. The decision to discontinue these drugs before the test is at the discretion of the referring physician.   
• The patient must sign informed consent.

Technique or Treatment

Many protocols are available for conducting a pharmacological SPECT study. The 2 most commonly used protocols in clinical practice involving Tl-201 are described below.[16]

Thallium-201 Stress-Rest-Redistribution

This test evaluates perfusion and viability and involves the following steps:

1. A dose of 2.5 to 3.5 mCi Ti-201 is injected at peak vasodilatation.  
2. Stress cardiac images are then taken after 10 to 15 minutes. 
3. Redistribution and stress cardiac images are then taken after 2.5 to 4 hours. However, this step is optional, depending on the findings from the stress cardiac images.
4. Rest cardiac images are taken 24 hours after the initial injection to assess viability if fixed or minimally reversible defects appear on stress images. An optional step is obtaining viability images after an additional injection of 1 to 2 mCi of Tl-201.

Thallium-201 Rest-Redistribution

This protocol is used for viability testing only and includes the following steps:

1. A patient is injected with a Tl-201 radiotracer at rest.
2. Rest-cardiac images are taken after 10 to 15 minutes.
3. Redistribution cardiac images are then taken after 3 to 4 hours (1-day protocol) or 24 hours from the initial injection (2-day protocol). However, this step is optional, depending on the initial interpretation of images.

Complications

Most of the side effects of this test are related to the use of pharmacological vasodilators and are often self-limited. However, these drugs have correlations with severe side effects such as myocardial infarction.[17][18] All patients should be informed that MPI risks exposure to significant radiation more than computed tomography. Radiocontrast has a small risk of an allergic reaction.

The common side effects of vasodilator testing with adenosine include the following:

• Flushing
• Headache
• Chest discomfort
• Dyspnea
• Gastrointestinal discomfort
• Lightheadedness or dizziness
• Arrhythmias, importantly atrioventricular block
• Paresthesia
• Hypotension
• Nervousness

Aminophylline (50 to 250 mg) or caffeine should be used to reverse pharmacological vasodilator effects if a patient develops severe side effects, including hypotension with systolic pressures less than 80 mm Hg, 2nd or 3rd-degree atrioventricular block, arrhythmia, wheezing, severe chest pain with ST-segment depression, or signs of poor perfusion.[19][20]

Clinical Significance

SPECT stress testing has demonstrated excellent diagnostic and prognostic values for CAD. The sensitivity, specificity, and accuracy of SPECT stress testing for the diagnosis of CAD are 82%, 76%, and 83%, respectively.[21] The risk of cardiac events (cardiac death or myocardial infarction) in patients with normal SPECT scans is less than 1% per year. The rate of cardiac events increases significantly with high-risk scan findings.[22][23] A high-risk scan correlates with a greater likelihood of referral for angiography and increased mortality during follow-up.[24] Importantly, SPECT-MPI guides revascularization in symptomatic patients with known or suspected CAD. SPECT-MPI helps refine risk stratification in patients who are symptomatic or require perioperative clearance.

Enhancing Healthcare Team Outcomes

Healthcare workers in clinical practice should be familiar with the SPECT thallium imaging study, which assesses CAD and guides revascularization based on ischemia. This modality also serves as a method for evaluating myocardial viability when other tests are unavailable. A nuclear cardiologist usually performs the test with a team of nurses and radiology technicians. A nurse is tasked to monitor the patient during the test and is responsible for ensuring that resuscitative equipment is present in the suite before the test is started. A pharmacist specializing in nuclear medicine should assist with proper dosing.

Vital signs and oxygenation must be recorded every few minutes at all times during the test. The team should be apprised immediately if abnormalities are detected. A team approach is vital to prevent complications from the SPECT thallium test. The team must run the test in a coordinated manner, with effective communication between team members. All reports should be reviewed preliminarily, and the referring physician should be promptly informed if any high-risk findings are identified.

Nursing, Allied Health, and Interprofessional Team Interventions

Adequate preparation is essential. The nurse must confirm that the patient has not consumed caffeinated beverages or colas at least 12 hours before the procedure and has not taken theophylline 24 hours before the test. All medications the patient is taking should be documented, along with any prior allergies or history of adverse reactions. Intravenous access must be established, and the laboratory should be well-equipped to ensure the test runs smoothly.

Nursing, Allied Health, and Interprofessional Team Monitoring

The patient should be on continuous ECG monitoring during adenosine infusion and the recovery period. Vital signs should be monitored at baseline and at regular intervals during the test. Any ECG changes during the test should be noted and communicated. The nursing team should be prepared with the necessary medications and equipment to manage arrhythmias or cardiac arrest. Aminophylline and antiemetic medications should also be readily available. The recovery monitoring should end once the patient returns to baseline hemodynamically and is comfortable. Necessary home instructions should be provided to avoid radiation exposure to people around the patient, especially children and pregnant women.