Nuclear Medicine Stress Test

Procedures

Patient Preparation

The following instructions should be given before the procedure:

• The patient should follow appropriate fasting protocols, typically fasting for 4 to 6 hours before the test.
• The patient's medical history should be reviewed, with particular attention to medication allergies and any previous reactions to radiotracers.
• The patient should refrain from consuming caffeinated beverages for at least 12 hours before the test.
• The patient should abstain from smoking or using tobacco products for at least 8 hours before the test.
• The patient should wear comfortable shoes, particularly if the stress component of the test involves exercise.
• The patient should avoid close contact with infants and small children for the remainder of the day due to residual radiation from the radiotracer.
• The patient should avoid medications such as nitroglycerin, theophylline, isosorbide, and phosphodiesterase type-5 (PDE-5) inhibitors if undergoing a regadenoson stress test.
• The patient should avoid beta-blockers and vasodilators if undergoing a dobutamine stress test.
• Informed consent should be obtained from the patient after a thorough discussion of the procedure, including its indications, benefits, and potential risks.

Tracer Administration

• Intravenous access should be established, typically through an antecubital vein.
• A radiopharmaceutical, such as technetium-99m (Tc-99m) or thallium-201 (Tl-201), should then be administered.
• The selection of tracers depends on the specific clinical scenario and the facility protocol. Tc-99m is preferred in many centers due to its favorable imaging characteristics and relatively lower radiation exposure.

Stress Induction

• Patients undergoing exercise stress testing are instructed to perform physical activity on a treadmill or stationary bicycle, while their heart rate and ECG are monitored to ensure safety.
• For patients who are unable to exercise—due to physical limitations or baseline ECG abnormalities—pharmacological agents such as adenosine, dipyridamole, or regadenoson are used to simulate the effects of exercise by inducing coronary vasodilation.

Image Acquisition

• Rest imaging: Images are obtained 15 to 20 minutes after tracer administration at rest to capture baseline myocardial perfusion.
• Stress imaging: Following stress induction, a second dose of the tracer is administered, and imaging is performed. The timing of the imaging is crucial and varies based on the tracer used. For example, SPECT images are typically obtained shortly (within 10-20 minutes) after stress to ensure optimal visualization of perfusion differences.
• Dual-isotope imaging using a combination of Tl-201 and Tc-99m is occasionally used, while PET-MPI typically utilizes rubidium-82 or nitrogen-13 ammonia (N-13 ammonia). Due to the short half-lives of PET tracers, pharmacological stress testing with vasodilators is generally preferred over exercise-based stress testing.[4] 
  • When the radioactive tracer is administered intravenously, it allows visual assessment of coronary blood flow and perfusion to the cardiac muscles. Please refer to StatPearls' companion resource, "Myocardial Perfusion Scan," for additional information on commonly used tracers for SPECT MPI.
• Imaging is typically performed using a specialized gamma camera capable of SPECT or PET scanning. The choice between SPECT and PET depends on the availability of equipment and the specific diagnostic requirements.

Data Analysis and Interpretation

• The acquired images are processed using specialized software to generate perfusion maps that illustrate relative myocardial blood flow during rest and stress.
• Radiologists or cardiologists evaluate the images for regions of ischemia (reduced blood flow), which typically appear as cold spots on the perfusion maps. They compare rest and stress images to distinguish between reversible ischemia (indicating potential improvement with revascularization) and irreversible ischemia.
• Additional analyses, such as left ventricular volume and ejection fraction, may also be performed to evaluate global ventricular function.[5]

Indications

In recent years, the range of modalities available for evaluating CAD has expanded significantly. Non-invasive options now include perfusion echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI).

The clinician must determine the pre-test probability of CAD before selecting an appropriate diagnostic test. Patients with an intermediate probability for CAD are most likely to benefit from additional cardiovascular testing.[6] Nuclear stress testing is especially valuable in guiding management decisions for these patients, particularly when revascularization is being considered.

Pharmacological stress testing with MPI is indicated when exercise stress testing is not feasible due to an abnormal ECG or the patient’s inability to exercise. 

Scenarios in which a nuclear stress test may be used for evaluation are listed below. 

• Patients with suspected CAD: This includes individuals presenting with chest pain suggestive of angina and an intermediate to high probability of acute coronary syndrome (ACS). However, nuclear stress testing should not be performed in patients with ongoing or unstable symptoms until those symptoms have been stabilized.
• Patients with a prior history of CAD who present with new or worsening symptoms.
• Patients with new-onset left bundle branch block or ventricular pacing evident on ECG.
• Patients with a recent ACS who were treated conservatively or partially revascularized within the past 3 months for risk assessment.
• Asymptomatic patients with a prior history of coronary artery bypass grafting performed more than 5 years ago or percutaneous coronary intervention performed more than 2 years ago may be appropriate candidates for one-time cardiac stress testing.
• Patients presenting with dyspnea suspected to be of cardiac origin.
• Patients with newly diagnosed congestive heart failure should be evaluated for reversible causes, such as CAD.[7]

Normal and Critical Findings

Stress Induction Modalities and Pharmacological Agents

There are 2 primary modalities used to induce cardiac stress—exercise and pharmacological stress.[8]

In patients who are able to exercise, physical activity is the preferred method of stress induction to achieve the desired cardiac workload. Exercise-based testing provides additional diagnostic information, including assessment of symptoms, hemodynamic response, functional capacity, and cardiac prognosis. The radioactive tracer is typically injected near peak exertion, and exercise should continue for at least 1 additional minute to allow adequate tracer distribution. Depending on the SPECT radioactive tracer used, image acquisition may begin immediately or be delayed by several hours. For PET imaging, pharmacological stress is generally preferred due to the short half-life of PET tracers.

In contrast, for patients who are unable to exercise or fail to achieve an adequate heart rate response, pharmacological agents are used to induce cardiac stress. These agents fall into 2 main categories—vasodilators and inotropic or chronotropic drugs.

Vasodilators

Common vasodilators include adenosine, dipyridamole, and regadenoson. These agents primarily act by causing coronary vasodilation, which increases coronary blood flow during stress to 3 to 5 times the resting level. Normal coronary arteries can experience up to a 4-fold increase in flow during vasodilation, thereby enhancing radiotracer uptake.[9] In contrast, flow-limiting stenosis results in a relative reduction of blood flow during stress, causing decreased radiotracer uptake and appearing as a perfusion defect on imaging.

• Adenosine: This vasodilator primarily exerts its effects through A2A receptors on coronary arteries.[10] Adenosine has a very short half-life due to rapid uptake by red blood cells and endothelial cells. Adenosine is administered using an infusion pump at a dose of 140 mcg/kg/min over 6 minutes. The radionuclide is injected approximately 10 seconds near the end of the infusion, which is then continued for an additional 3 minutes.[11] A shorter protocol, lasting 4 minutes, has also been studied and demonstrated equally effective results. Simultaneous low-level exercise during adenosine infusion is safe, well-tolerated, and improves image quality.

• Dipyridamole: This vasodilator blocks the cellular uptake of adenosine. Dipyridamole has a half-life of 30 to 35 minutes, is primarily metabolized by the liver, and is excreted in small amounts in the urine. This vasodilator is administered via an infusion pump at a dose of 140 mcg/kg/min for 4 minutes, with a maximum total dose of 0.56 mg/kg. The radionuclide is injected 3 to 5 minutes after the infusion is completed. Aminophylline is often used as a reversal agent to mitigate adverse effects. Simultaneous low-level exercise enhances image quality, helps assess exercise capacity, and aids in risk stratification for future cardiac events.

• Regadenoson: This vasodilator is a selective A2A receptor blocker that acts on vascular smooth muscles. Unlike adenosine and dipyridamole, which act on multiple receptors, including A1 (located on the atrioventricular node) and A2B, A3, and A4 receptors, responsible for common adverse effects such as AV block and bronchospasm, regadenoson has greater receptor specificity. Regadenoson has a rapid onset of about 30 seconds and a duration of 2 to 5 minutes, with an intermediate phase lasting up to 30 minutes, compared to adenosine’s very short half-life of 5 seconds. Regadenoson allows for more convenient administration and monitoring. Regadenoson is administered as a single 400 mcg dose via a prefilled syringe over 10 seconds, followed immediately by a 5 mL saline flush.[12] The radionuclide is administered after the saline flush has been completed. Regadenoson offers an advantage over adenosine and dipyridamole as it can be used in patients who begin exercise SPECT MPI but are unable to achieve the target cardiac workload.

Inotropic or chronotropic drugs

Examples of inotropic or chronotropic agents include dobutamine, with or without the use of atropine.

Dobutamine is administered in a graded format, starting at 5 mcg/kg/min and increasing to 10, 20, 30, and 40 mcg/kg/min at 3-minute intervals.[13] The standard endpoint of dobutamine rMPI is achieving at least 85% of the age-predicted maximum heart rate. If the target heart rate is not reached, atropine may be administered in increments of 0.5 mg, up to a total dose of 2 mg. The procedure should be terminated in the event of significant arrhythmia, hypotension (systolic blood pressure <90 mm Hg), or severe hypertension. Although dobutamine is still used, regadenoson is gaining popularity as the primary vasodilator due to its ease of administration and improved tolerability.

One of the most commonly used radioisotopes for SPECT imaging is Tc-99m-labeled perfusion agents, such as 99m-Tc-sestamibi and 99m-Tc-tetrofosmin. The use of Tl-201 is becoming less common because Tc-99m has a higher energy, resulting in less photon attenuation and scatter.

A single-isotope protocol using Tc-99m can be performed as either a 1-day or 2-day protocol.

• One-day rest/stress (or stress/rest) protocol: In this protocol, the radiopharmaceutical dose used for the second injection is typically 3 times higher than the first. Image acquisition is performed 15 to 60 minutes after the injection, or it may be delayed up to 2 hours, depending on the type of stress applied—exercise or pharmacological. Radiation exposure can be significantly reduced by using weight-based dosing of the radiopharmaceutical agent and using newer solid-state camera systems.

• Two-day Tc-99m–based protocol: In this protocol, the radiopharmaceutical agent is administered at the same dosage for both rest and stress imaging. This is particularly beneficial for larger patients, as low-dose tracers may result in suboptimal image quality. However, completing the stress and rest studies over 2 separate days can be inconvenient for patients.

• Stress-only protocol: This emerging approach is based on the concept that resting images may be unnecessary in patients with normal stress images. This strategy reduces radiation exposure and shortens the total study time. However, careful in-patient selection is essential. Candidates should have no prior abnormal rMPI results, no history of CAD or MI without revascularization, no cardiomyopathy, and a body weight of less than 300 lbs. The diagnostic accuracy is higher in patients undergoing ECG-gated Tc-99m sestamibi SPECT rMPI with attenuation correction. If stress images are abnormal, rest images should be acquired the following day using a higher radiopharmaceutical dose. The stress-only protocol with Tc-99m typically results in approximately 3 millisieverts of radiation exposure.

• Dual-isotope protocol: This protocol uses 2 different isotopes for rest and stress imaging. Tl-201 is administered at rest, with images acquired within 10 minutes, followed by a Tc-99m–based agent for stress imaging. The main advantage of this protocol is the almost immediate acquisition of rest images. However, it has notable drawbacks, including higher radiation exposure and challenges in interpreting images due to differing resolution between rest and stress scans. The dual isotope protocol typically results in approximately 22 millisieverts of radiation exposure.

• Thallium-201: Tl-201 is less commonly used due to its higher radiation exposure. Stress image acquisition should begin within 10 minutes of Tl-201 injection. Unlike Tc-99m–based protocols, the stress injection is performed first. In patients who experience difficulty breathing during exercise, image acquisition may be delayed to minimize the risk of myocardial creep—an artifact caused by upward movement of the diaphragm. If the patient reaches stage III or higher of the Bruce protocol, image acquisition can be delayed up to 15 minutes post-stress, provided the respiratory rate is below 25 cycles per minute.

PET imaging

PET imaging utilizes rubidium-82 and N-13 ammonia tracers. Rubidium-82 is widely used because it does not require an on-site cyclotron, unlike N-13 ammonia, ammonia; however, its very short half-life of 75 seconds necessitates a rapid delivery system. PET differs from SPECT in that it requires additional external radiation sources during image acquisition, and images acquired after tracer administration are used for attenuation correction. Rubidium-82 exposure results in approximately 3 millisieverts of radiation, whereas N-13 ammonia exposure is about 2 millisieverts.

Complications

Major complications rarely occur with stress testing. Some adverse effects associated with pharmacological agents are described below.[14]

Adenosine may cause wheezing, chest pain with possible ST-segment changes, and hypotension. These symptoms typically resolve quickly due to adenosine’s short half-life and rarely require aminophylline for reversal. More common minor adverse effects include nausea, flushing, dyspnea, and headache. As with any intravenous administration, complications at the injection site—such as bruising or infection—can also occur.

Severe adverse events associated with dipyridamole, such as nonfatal myocardial infarction, cardiac death, and sustained ventricular tachycardia, have been reported, although they are rare. Minor adverse effects, including chest pain, headache, and dizziness, may also occur. Symptoms are usually reversible after the administration of aminophylline. The adverse effects of regadenoson and dobutamine are similar to those mentioned above.

Nuclear stress tests are generally considered safe; however, complications may occur in approximately 1 in 5000 individuals. Potential adverse events include chest pain, arrhythmia, myocardial infarction, and hypotension.[15]

The procedure involves a small amount of radiation exposure. Although radiation exposure can increase the risk of cancer, scientists believe that it requires large or frequent doses to pose a significant threat.

Contraindications for the procedure include: 

• Unstable angina
• Aortic dissection
• Pulmonary embolism
• Pulmonary hypertension
• Aortic stenosis
• Arrhythmia
• Congestive heart failure

Patient Safety and Education

Patient education prior to the stress test is essential and should be addressed during the patient preparation phase.

Clinical Significance

Coronary artery disease is becoming an increasingly common cause of morbidity and mortality worldwide. In 2020, it was estimated that CAD-related deaths could rise to 11.1 million globally.[16] Healthy lifestyle choices, including exercise, dietary modifications, weight management, and smoking cessation, can significantly reduce the risk of CAD.[17] 

Cardiac stress testing serves as a valuable diagnostic and prognostic tool in patients with suspected heart disease. The test evaluates myocardial perfusion and cardiac function both at rest and under stress—either through exercise or pharmacological agents—and helps assess both functional and anatomic aspects of CAD. The results can guide secondary interventions aimed at preventing myocardial infarction and slowing disease progression. Tailored interventions for individual patients have the potential to reduce the global disease burden, decrease morbidity, and improve quality of life in those affected by CAD.[18]