Introduction

Coronary artery disease (CAD) remained the leading cause of death in the United States and was responsible for 840,768 deaths in 2016. Cardiovascular disease is the number one cause of mortality worldwide, with 17.6 million deaths annually.[1] Cardiac stress testing is an important diagnostic tool for known or suspected coronary artery disease.[2] Eight million nuclear stress tests are performed annually in the United States.

While stress testing can be performed in a variety of ways, more commonly performed and widely available are exercise electrocardiography (EKG) and exercise or pharmacological stress testing along with imaging such as echocardiography or radionuclide myocardial perfusion imaging (rMPI).  It can help establish the diagnosis, risk stratify, and guide therapy in patients with coronary artery disease.

An intravenous radioactive tracer is administered, and gamma photons are captured using single-photon emission computer tomography (SPECT) or positron emission tomography (PET).

Myocardial perfusion images are obtained during rest and after stress with either exercise or pharmacological agents, preferably vasodilators. Both the images are then compared to detect myocardial perfusion, viability, and global left ventricular systolic function, which generally signifies the presence and extent of coronary artery disease.

Procedures

Radionuclide MPI provides essential information on myocardial perfusion at rest and exercise or pharmacological testing with the help of a radioactive tracer.

Commonly used tracers for SPECT MPI are technetium-99m based (Tc99m and Tc99m tetrofosmin) or thallium-201.[3] Dual isotope in combination with thallium-201 and technetium-99m are sometimes used, while PET MPI uses rubidium-82 or N13-ammonia. Half-lives of PET tracers are short; hence pharmacological stress testing with vasodilators is preferred than exercise stress testing.[4] When the radioactive tracer is administered intravenously, it allows visual assessment of coronary blood flow and perfusion to the cardiac muscles.

Indications

In recent years, the number of modalities for the evaluation of CAD has rapidly expanded. Non-invasive testing now includes perfusion echocardiography, computed tomography, and magnetic resonance imaging. 

The clinician must determine the pre-test probability for CAD prior to selecting the diagnostic test. Patients with intermediate probability for CAD are most likely to benefit from additional cardiovascular testing.[5] Nuclear stress testing plays an important role in determining the management of these patients, especially when revascularization is being considered.

Pharmacologic stress testing with myocardial perfusion imaging is indicated when exercise stress testing cannot be performed due to an abnormal EKG or the patient's inability to exercise. 

Scenarios in which a nuclear stress test may be used for evaluation include: 

• Patients with suspected coronary artery disease
• Typically, patients who have chest pain suggestive of angina and intermediate to a high probability of acute coronary syndrome (ACS). However, it should not be performed in patients with ongoing or unstable conditions prior to the relief of symptoms.
• Patients with prior history of CAD with new or worsening symptoms
• Patients who have new-onset left bundle branch block (LBBB) or ventricular pacing in the EKG
• Patients with a recent ACS who were treated conservatively or partially revascularized within the past 3 months for evaluation of risk assessment
• Patients with a prior history of coronary artery bypass graft (CABG) of more than 5 years or percutaneous coronary intervention (PCI) of more than 2 years and are asymptomatic, one-time testing cardiac stress testing is appropriate.
• Patients with dyspnea and suspected cardiac origin
• Patients with newly diagnosed congestive heart failure to evaluate reversible causes such as CAD

Normal and Critical Findings

There are primarily two modalities of stress – exercise or pharmacological.

In patients who can exercise, it is the preferred form of stress to achieve cardiac workload. It can also measure several factors such as symptoms, hemodynamic response, physical activity, and prognosis of cardiac activity. The radioactive tracer is injected near the peak of physical activity, and it should be continued for at least a minute of exercise to allow the radioactive tracer to distribute. Depending on the SPECT radioactive tracer, image acquisition may begin immediately or can be delayed up to a few hours. Due to the short half-life of PET tracer, pharmacological stress is preferred in these patients.

In patients who are unable to exercise or achieve an adequate heart rate response, there are several pharmacological agents to achieve cardiac stress. Broadly speaking, there are two types, vasodilator or inotropic/chronotropic drugs. 

Examples of vasodilators are adenosine, dipyridamole, and regadenoson. They primarily cause coronary vasodilation and increase coronary blood flow during stress, which is 3 to 5 times the resting blood flow. The flow through the normal coronary arteries increases up to fourfold during coronary vasodilation and radiotracer uptake.[6] Flow-limiting stenosis in the coronary artery causes a relative reduction in blood flow during stress leading to reduced radiotracer uptake, reflecting as a perfusion defect.

1. Adenosine acts via the A2A receptor on coronary arteries.[7] Its effect on other receptors such It has a very short half-life, especially red blood cells, and endothelial cells have rapid uptake. It is administered via infusion pump at the dose of 140 mcg/kg/minute, typically over six minutes, then radionuclide is injected over 10 seconds, and adenosine infusion is continued for additional 3 minutes.[8] A shorter duration protocol of 4 minutes has been studied and has shown equally effective results. Simultaneous low-level exercise is safe, well-tolerated, and provides improved image quality.
2. Dipyridamole blocks the cellular uptake of adenosine. Its half-life is 30 to 35 minutes, metabolized primarily by the liver, and excreted in small amounts by urine. It is administered via an infusion pump at the dose of 140 mcg/kg per minute for 4 minutes with a maximum dose of 0.56 mg/kg. The radionuclide is administered 3 to 5 minutes after the infusion. Aminophylline is often used as a reversal agent to reduce side effects. Simultaneous low-level exercise improves image quality, allows us to assess exercise capacity, and risk-stratify future cardiac events.
3. Regadenoson is a selective A2A receptor blocker on vascular smooth muscles. Adenosine and dipyridamole act on the A2A receptor and the A1 receptor on the atrioventricular node and A2B, A3, A4, responsible for common side effects such as AV block and bronchospasm, respectively. Regadenoson has a rapid onset of 30 seconds and lasts about 2 to 5 minutes and an intermediate phase of 30 minutes in contrast to adenosine, which has a half-life of 5 seconds. Reagadesone allows for more convenient administration and monitoring. It is administered at a dose of 400 mcg in a prefilled single-dose syringe over 10 seconds, followed immediately by a 5 ml saline flush.[9] The radionuclide is administered after the saline flush. Regadenoson has an added advantage over adenosine and dipyridamole as it can be given to patients who begin with exercise SPECT MPI but are unable to achieve the cardiac workload.

Examples of inotropic/chronotropic agents are dobutamine with or without atropine.

1. Dobutamine is administered over graded format starting at 5 mcg/kg and gradually increasing it to 10, 20, 30, and 40 mcg/kg/minute at every 3-minute interval.[10] The standard end-point of dobutamine rMPI is to achieve a heart rate of at least 85 percent of the age-predicted maximum heart rate. Atropine at a dose of 0.5 mg at each time to a total dose of 2 mg can be administered as needed to achieve the desired heart rate. The procedure should be terminated if there is any significant arrhythmia, hypotension less than 90 mmHg, or severe hypertension. Regadenoson is becoming increasingly popular and is the primary vasodilator used because of its ease of use and better tolerability.

The most commonly used radioisotope for SPECT imaging is 99m-technetium labeled perfusion agents such as 99m-Tc-sestamibi, 99m-Tc-tetrofosmin. The use of thallium-201 is becoming increasingly less common as Tc99 has higher energy, less attenuation, and less scatter of photons.

• Single isotope protocol is done with Tc99m and can be done as a one-day or two-day protocol.
• One-day rest/stress (or stress/rest) study: Radiopharmaceutical agent used for the second injection is generally three times higher than the first dose. Images acquisition is performed 15 to 60 minutes after the injection, or it can be delayed up to 2 hours depending on the type of stress – exercise vs. pharmacological. Radiation exposure can be reduced substantially by using a weight-based radiopharmaceutical agent and a newer solid-state camera system.
• Two-day Tc99m- based protocol: radiopharmaceutical agent is used at the same dosage for rest and stress images. This protocol is more useful in larger patients since low-dose tracer may make image acquisition difficult. But it is cumbersome for patients to perform this entire stress/rest in 2 days.
• Stress only: This is a newly developing model based on the theory that the resting images may not be required in patients whose stress images are normal. This allows for lesser radiation exposure and shorter study time. But should be careful in-patient selection, and patients with no prior abnormal rMPI images, no history of CAD or MI without revascularization or cardiomyopathy, and weight more than 300 lbs should be selected. Diagnostic value is higher in patients who undergo ECG-gated technetium-99m sestamibi SPECT rMPI with attenuation correction. However, if the stress images are abnormal, the patient should undergo rest images the following day with a higher radiopharmaceutical dose. Stress-only using T99m usually causes approximately 3 millisieverts radiation exposure.
• Dual isotope: This protocol is based on using two different isotopes at rest and stress. TI-201 is used at rest and images acquired within 10 minutes, followed by a Tc99m-based agent during stress image acquisition. The advantage of this protocol is the almost immediate acquisition of rest images, but the major disadvantage is, it is associated with higher radiation exposure, difficulty interpreting the data because of different resolutions at rest, and stress. Dual isotope usually causes approximately 22 millisieverts radiation exposure.
• TI-201: This is less commonly utilized because of higher radiation exposure. Stress image acquisition should be done within 10 minutes of TI-201 injection. Unlike the Tc99m based protocol, stress injection should be performed first. If the patient has difficulty breathing with exercise, image acquisition is delayed to avoid myocardial creep – an artifact from the upward movement of the diaphragm. If the patient can achieve stage III or higher Bruce protocol, image acquisition should be delayed up to 15 minutes post-stress, and the respiratory rate should be less than 25 cycles per minute.

PET imaging utilizes rubidium-82 and 13-N ammonia tracers. Rubidium-83 is widely used because it does not require on-site cyclotrons, unlike 13-N ammonia, but it requires a rapid delivery system because its half-life is 75 seconds. PET imaging is different from SPECT because it requires additional external radiation sources for image acquisition and image acquisition after tracer administration. Both images are then used for attenuation correction. Rubidium-81 causes approximately 3 millisieverts radiation exposure, while N-13 ammonia causes 2 millisieverts radiation exposure.

Complications

Major complications usually do not occur with stress testing. Some of the side effects associated with pharmacological agents are described here.

Adenosine might cause wheezing, chest pain with possible ST-segment changes, hypotension. Symptoms rapidly resolve because of the short half-life, with rarely requiring aminophylline to reverse the effects. More common minor side effects are nausea, flushing, dyspnea, and headache.

Serious adverse events with dipyridamole, such as nonfatal myocardial infarction, cardiac death rate, sustained ventricular tachycardia, have been reported, albeit rare. And some minor side effects such as chest pain, headache, and dizziness may occur. Symptoms are completely reversible after the administration of aminophylline. Side effects of regadenoson and dobutamine are as mentioned above.

Patient Safety and Education

Patient education prior to the stress test is important. The most common side effects are headache and flushed feeling. Procedures can occur over a day or two.

Following instructions should be given prior to the procedure:

• Patients should avoid caffeinated drinks at least 12 hours before the test.
• They should be no smoking or tobacco products for at least 8 hours before the test.
• Fast for at least 4 hours before the test.
• Wear comfortable shoes, especially if the stress test is based on exercise.
• The patient should not be around babies or small children for the rest of the day because of residual radiation from your exam.
• Avoid medications such as nitroglycerin, theophylline, isosorbide, PDE-t inhibitors if undergoing a regadenoson stress test.
• Avoid beta-blockers and vasodilators if undergoing a dobutamine stress test.

Clinical Significance

Coronary artery disease is becoming an increasing cause of morbidity and mortality worldwide. In 2020, it was estimated that deaths from CAD might increase to 11.1 million globally.[11] Healthy lifestyle choices such as exercise, dietary interventions, reducing weight, and smoking cessation can substantially reduce CAD.[12] Cardiac stress testing is an extraordinary diagnostic and prognostic tool for patients with suspected heart disease. It evaluates cardiac perfusion and function at rest and after stress, such as exercise or pharmacological. It also assesses functional and anatomic CAD. Multiple secondary interventions to prevent MI and the progression of CAD can be undertaken. An appropriate intervention targeted towards individual patients can reduce the global burden, morbidity and improved quality of life in patients with CAD.[13]