Exercise Stress Test

Exercise testing has been used for more than 60 years for diagnostic purposes in symptomatic patients [including patients with acute chest pain without ischemia by electrocardiogram (ECG) and serum markers] and for prognosis and risk stratification in patients with known coronary artery disease (CAD), such as history of myocardial infarction or documented CAD by coronary angiography or computed tomography angiography and in those with high risk for the presence of CAD, such as patients with diabetes mellitus, peripheral, or cerebral vascular disease.

Exercise Modalities

  1. (1)

    Exercise using a treadmill is done according to the standardized protocols (most often the Bruce or modified Bruce protocol) with incremental treadmill speed and incline (Tables 1, 2).

    Table 1 Bruce protocol
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    Table 2 Modified Bruce Protocol
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  2. (2)

    Exercise using an upright or recumbent bicycle uses standard speed with incremental resistance.

Exercise Testing

Detailed recommendations for exercise testing performance including (1) testing environment, (2) equipment [treadmill, bicycle, ECG monitoring, blood pressure (BP) monitoring], (3) emergency preparation and protocols, (4) patient preparation (including informed consent), (5) test performance, and (6) personnel qualifications are described in detail in the 2009 Recommendations for clinical exercise laboratories: a scientific statement from the American Heart Association (AHA).1

Performance of exercise testing describing normal and abnormal response to exercise, evaluation of the test results are described in detail in 2013 Exercise Standards for Testing and Training: a scientific statement from the American Heart Association.2

Recommendations for performance of exercise testing by nonphysicians (clinical exercise physiologists, registered nurses, nurse practitioners, physician assistants, and physical therapists) as well as the role of supervising physician have been published recently.3

Recommendations for testing specific populations [women, older adults, asymptomatic patients, prior to noncardiac surgery and exercise testing combined with cardiopulmonary exercise testing (CPET)] can be found in the following documents:

  1. (1)

    Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the AHA;4

  2. (2)

    2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines;5

  3. (3)

    Clinician’s Guide to cardiopulmonary exercise testing in adults: a scientific statement from the AHA.6

Absolute Contraindications

Absolute contraindications for exercise stress testing include the following:

  1. (1)

    High-risk unstable angina. However, patients with chest pain syndromes at presentation who are stable and without ECG evidence of ischemia and without serum biomarker evidence of myocardial injury can undergo exercise stress testing.

  2. (2)

    Decompensated or inadequately controlled congestive heart failure (HF).

  3. (3)

    Systolic BP at rest >200 mmHg or diastolic BP at rest >110 mmHg.

  4. (4)

    Uncontrolled cardiac arrhythmias (causing symptoms or hemodynamic compromise).

  5. (5)

    Severe symptomatic aortic stenosis.7

  6. (6)

    Acute pulmonary embolism.

  7. (7)

    Acute myocarditis or pericarditis.

  8. (8)

    Acute aortic dissection.

  9. (9)

    Severe pulmonary hypertension.

  10. (10)

    Acute myocardial infarction (less than 2 to 4 days), if clinically stable.

  11. (11)

    Acute symptomatic medical illness.

Relative Contraindications

Relative contraindications for exercise stress testing include the following:

  1. 1.

    Known significant left main coronary artery stenosis.

  2. 2.

    Asymptomatic severe aortic stenosis.7

  3. 3.

    Hypertrophic obstructive cardiomyopathy or other forms of severe left ventricular outflow tract obstruction.

  4. 4.

    Significant tachyarrhythmias or bradyarrhythmias.

  5. 5.

    High-degree atrioventricular (AV) block.

  6. 6.

    Electrolyte abnormalities.

  7. 7.

    Mental or physical impairment leading to inability to exercise adequately.

  8. 8.

    If combined with imaging, patients with complete left bundle branch block (LBBB), permanent pacemakers, and ventricular pre-excitation [Wolff-Parkinson-White (WPW) syndrome] should preferentially undergo pharmacologic vasodilator stress test (not a dobutamine stress test).

Limitations

Exercise stress testing has a lower diagnostic value in patients who cannot achieve an adequate heart rate and BP response due to a noncardiac physical limitation, such as pulmonary, peripheral vascular or musculoskeletal abnormalities, or due to lack of motivation. These patients should be considered for pharmacologic stress testing with myocardial perfusion imaging. Also, for a meaningful test evaluation, exercise should last at least 4 to 6 minutes.

Procedure

  1. (1)

    Patient preparation: nothing should be eaten at least 3 hours before the test. Patients scheduled for later in the morning or afternoon may have a light breakfast (e.g., cereal, fruit). Caffeine should be avoided for at least 12 hours similar to vasodilatory stress testing because exercise stress tests, at times, need to be converted to a pharmacologic stress test. If possible, insulin-dependent diabetics should be scheduled for the morning hours.

  2. (2)

    BP medication(s) with antianginal properties (β-blocker, calcium channel blocker, and nitrates) will lower a stress test’s diagnostic utility.8 Generally, discontinuation of these medicines is left to the discretion of the referring physician. Regularly taken medication should be recorded prior to testing.

  3. (3)

    An intravenous (IV) cannula (larger size than 24-gauge is preferred) should be inserted for radiopharmaceutical injection.

  4. (4)

    The electrocardiogram should be monitored continuously during the exercise test and for at least 4 minutes into the recovery phase. In addition, the resting heart rate should return to close to baseline and exercise-induced ST-segment changes and symptoms should resolve. A 12-lead electrocardiogram should be (automatically) obtained at every stage of exercise, at peak exercise, and at the termination of recovery phase. In addition, in case of abnormalities (e.g., arrhythmias, etc.) a 12-lead electrocardiogram should be obtained.

  5. (5)

    The heart rate and BP should be recorded at least every 3 minutes during exercise, at peak exercise, and for at least 4 minutes into the recovery phase.

  6. (6)

    The end point of all exercise tests should be symptoms (moderate to severe chest pain, excessive shortness of breath, fatigue). Achievement of 85% of maximum, age-adjusted, predicted heart rate is not an indication for termination of the test. Note: In patients with known CAD (and particularly if tested taking regular medication), the prognostic value of the test is preserved without reaching 85% of maximum predicted heart rate.

  7. (7)

    The radiopharmaceutical should be injected as close to peak exercise as possible. Patients should be encouraged to exercise for at least 1 minute after the radiotracer injection. If needed, treadmill speed and/or inclination can be decreased after tracer injection.

  8. (8)

    Patients referred for a diagnostic stress test may be converted to a pharmacologic stress test or a combination of both if they cannot exercise adequately for a meaningful period of time.

Indications for Early Termination of Exercise

Indications for early termination of exercise include the following:

  1. (1)

    Moderate to severe angina pectoris.

  2. (2)

    Marked dyspnea.

  3. (3)

    Fatigue.

  4. (4)

    Ataxia, dizziness, or near-syncope.

  5. (5)

    Signs of poor perfusion (cyanosis and pallor).

  6. (6)

    Patient’s request to terminate the test.

  7. (7)

    Excessive ST-segment depression (>2 mm from baseline).

  8. (8)

    ST elevation (>1 mm) in leads without diagnostic Q-waves (except for leads V1 or aVR).

  9. (9)

    Sustained supraventricular or ventricular tachycardia.

  10. (10)

    Development of LBBB or intraventricular conduction delay that cannot be distinguished from ventricular tachycardia.

  11. (11)

    Drop in systolic BP of greater than 10 mmHg from baseline, despite an increase in workload, when accompanied by other evidence of ischemia.

  12. (12)

    Hypertensive response (systolic BP >230 mmHg and/or diastolic pressure >115 mmHg).

  13. (13)

    Inability to monitor the electrocardiogram or systolic BP.

  14. (14)

    In patients with implantable cardioverter defibrillators, when the heart rate attained is within 20 beats per minute of the lowest heart rate at which therapy (antitachycardia pacing or shock) is programmed to be delivered.

Achievement of 85% of maximum, age-adjusted, predicted heart rate is not an indication for early termination of the stress test.

For review of serious complications of myocardial stress testing and their management, refer to the article by Dilsizian and colleagues. 9

Pharmacologic Vasodilator Stress

There are currently three coronary vasodilator agents available: dipyridamole, adenosine, and regadenoson. Adenosine and its analog regadenoson work by producing stimulation of A2A receptors. Dipyridamole inhibits the phosphodiesterase enzymes that break down cAMP and inhibits the cellular reuptake of endogenous adenosine, thereby indirectly acting as an adenosine agonist. Methylxanthines (e.g., caffeine, theophylline, and theobromine) are competitive inhibitors of adenosine receptors that require withholding methylxanthines prior to testing and permit the reversal of the effect with aminophylline or caffeine when clinically indicated (Figure 1). Aminophylline should be on hand during testing for reversal of serious side effects of vasodilator stressors.

Figure 1
figure 1

Mechanism of action of coronary vasodilators. ADP, Adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; AV, atrioventricular; and cAMP, cyclic adenosine monophosphate

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NOTE: Some of the pharmacologic stress protocols described in this section fall outside of manufacturer package insert guidelines but have been documented in the literature and are now commonly used in the clinical practice of nuclear cardiology. The practitioner should be familiar with the package insert for each medication.

Adenosine

Mechanism of action

Adenosine induces direct coronary arteriolar vasodilation through specific activation of the A2A receptor (Figure 1). This results in a 3.5- to 4-fold increase in myocardial blood flow. Activation of A1, A2B, and A3 receptors may cause undesirable side effects of adenosine infusion: AV block (A1 receptor), peripheral vasodilation (A2B receptor), and bronchospasm (A2B and A3 receptors). Peak vasodilation after adenosine administration occurs within 1 to 2 minutes after the start of the infusion. The half-life of adenosine is approximately 10 seconds. It is either phosphorylated to adenosine monophosphate by adenosine kinase or degraded to inosine by adenosine deaminase.

Adenosine dose

Adenosine is given as a continuous infusion at a rate of 140 mcg/kg/min over a 6-minute period (Figure 2). The correct weight-based dose for the obese and morbidly obese patients is unclear. It is customary to use weight-based doses up to the weight of 250 lbs (or 125 kg) as the upper limit (Table 3). Tracer injection is performed at 3 minutes, and the infusion is continued for another 3 minutes. A shorter duration adenosine infusion, lasting 4 minutes, has been found to be equally effective for the detection of CAD compared to the standard 6-minute infusion. For shorter duration protocols, the minimum time to tracer injection should be 2 minutes, and the infusion should continue for at least 2 minutes after tracer injection.10

Figure 2
figure 2

Adenosine protocol. IV, Intravenous; kg, kilogram; mcg, microgram; and min, minute

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Table 3 Weight-based dosing of pharmacologic stressors based on metric and standard weights
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Side effects of adenosine

  1. (1)

    Minor side effects are common and occur in approximately 80% of patients. The common side effects are flushing (35-40%), chest pain (25-30%), dyspnea (20%), dizziness (7%), nausea (5%), and symptomatic hypotension (5%). Chest pain is nonspecific and is not necessarily indicative of the presence of CAD.

  2. (2)

    AV block occurs in approximately 8% of cases. However, the incidence of second-degree AV block is only 4%, and that of complete heart block is less than 1%. Most cases (>95%) of AV block are self-limiting and do not require termination of the infusion.

  3. (3)

    ST-segment depression of 1 mm or greater occurs in 5% to 7% of cases. Compared to chest pain, ST changes may be indicative of true ischemia.

  4. (4)

    Fatal or nonfatal myocardial infarction is extremely rare, but has been reported.11

  5. (5)

    Atrial fibrillation has been reported within several minutes of initiation of adenosine infusion.

  6. (6)

    New onset or recurrence of convulsive seizures has occurred infrequently following adenosine administration.

  7. (7)

    Hemorrhagic and ischemic cerebrovascular accidents have occurred.

  8. (8)

    Due to the exceedingly short half-life of adenosine (<10 seconds), most side effects resolve in a few seconds after discontinuation of the adenosine infusion, and IV aminophylline administration is only rarely required.

Hemodynamic effects

Adenosine results in a modest increase in heart rate and a modest decrease in both systolic and diastolic BPs. BP systolic decreased by 10 ± 37 mmHg, and BP diastolic decreased 8 ± 19 mmHg, while heart rate increased by 14 ± 30 bpm.11 Maximum hemodynamic changes after adenosine were as follows: increase in heart rate of more than 40 bpm in 3%, decrease in BP systolic of more than 35 mmHg in 8%, and decrease in BP diastolic of more than 25 mmHg in 5%.

Indications

The indications for adenosine stress perfusion imaging are the same for exercise myocardial perfusion imaging (MPI) and in the presence of the following conditions:

  1. (1)

    Inability to perform adequate exercise due to noncardiac physical limitations (pulmonary, peripheral vascular, musculoskeletal, or mental conditions) or due to lack of motivation. Of note, as with exercise testing, anti-ischemic cardiac medications (including β-blockers, nitrates, and calcium antagonists) have been reported to decrease the diagnostic accuracy of vasodilator stress testing.

  2. (2)

    Baseline electrocardiographic abnormalities: LBBB, ventricular pre-excitation (WPW syndrome), and permanent ventricular pacing.

  3. (3)

    Risk stratification of clinically stable patients into low- and high-risk groups after acute myocardial infarction.

  4. (4)

    Diagnosis or risk stratification following presentation to the emergency department with a presumptive acute coronary syndrome that has been excluded by serial clinical evaluation, ECGs, and serum markers.

Contraindications

Contraindications for adenosine stress testing include the following:

  1. (1)

    Patients with bronchospastic lung disease with ongoing wheezing or a history of significant reactive airway disease should not undergo adenosine stress testing.

  2. (2)

    Second- or third-degree AV block without a functioning pacemaker.

  3. (3)

    Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia, without a functioning pacemaker.

  4. (4)

    Systolic BP less than 90 mmHg. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency.

  5. (5)

    Uncontrolled hypertension (systolic BP >200 mmHg or diastolic BP >110 mmHg).

  6. (6)

    Recent (<48 hours) use of dipyridamole or dipyridamole-containing medications (e.g., Aggrenox).

  7. (7)

    Known hypersensitivity to adenosine.

  8. (8)

    Unstable angina, acute coronary syndromes, or less than 2 to 4 days after an acute myocardial infarction.

Relative contraindications

Relative contraindications for adenosine stress testing include the following:

  1. (1)

    Profound sinus bradycardia (heart rates <40/min).

  2. (2)

    Mobitz Type 1 second-degree AV block (Wenckebach).

  3. (3)

    Ingestion of caffeinated foods or beverages (e.g., coffee, tea, sodas) within the last 12 hours should be avoided (Appendix 1).

  4. (4)

    Severe aortic stenosis (see Special Populations section).

  5. (5)

    Seizure disorder. New onset or recurrence of convulsive seizures has been reported following adenosine administration. Methylxanthine (aminophylline) use is not recommended in patients who experience seizures in association with adenosine administration.

Procedure

  1. (1)

    Patient preparation: nothing should be eaten for at least 3 hours prior to testing. Avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea, or other caffeinated beverages, caffeine-containing drug products (Appendix 1) and theophylline for at least 12 hours prior to the testing. Dipyridamole should be withheld for at least 48 hours (2 days) prior to adenosine administration.

  2. (2)

    An infusion pump is required for adenosine to be administered at a constant infusion rate.

  3. (3)

    An IV line with a dual-port Y-connector is required for the injection of the radiotracer during adenosine infusion.

  4. (4)

    ECG monitoring should be carried out as with exercise stress testing. A 12-lead electrocardiogram will be recorded every minute during the adenosine infusion (4 to 6 minutes).

  5. (5)

    BP should be monitored every minute during infusion and 3 to 5 minutes into recovery or until stable.

  6. (6)

    Adenosine infusion should be given at a rate of 140 mcg/kg/min for 3 minutes followed by the injection of the radiotracer. The infusion should be continued for another 3 minutes. For patients deemed to be at a higher risk for complications (e.g., borderline hypotension, controlled asthma), adenosine infusion may be started at a lower dose (70 to 110 mcg/kg/min). If this dose is tolerated well for 1 minute, the infusion rate should be increased to 140 mcg/kg/min and should be continued for 4 minutes. The radiotracer should be injected 1 minute after starting the 140-mcg/kg/min dose. If the shortened protocol is used (4-minute adenosine infusion), tracer is injected after 2 minutes and is continued for 2 minutes after tracer injection. Adenosine infusion has to continue during tracer injection. Thus, if two IVs are not employed, tracer injection needs to be slow using the dual-port Y-connector. If the adenosine infusion is interrupted, it needs to be restarted immediately.

Combination of low-level exercise with adenosine infusion

Patients who are ambulatory may undergo low-level exercise (e.g., treadmill 1.7 mph, 0% grade) during the adenosine infusion. This results in a significant reduction in the side effects of adenosine (e.g., flushing, dizziness, nausea, and headache) and attenuates the adenosine-induced drop in BP.12 Image quality is improved by decreasing high hepatic and gut radiotracer uptake, which is common with pharmacologic stress perfusion imaging. Low-level exercise is not recommended in patients with LBBB, WPW, and ventricular pacing due to heart rate-related imaging artifacts.

Indications for early termination of adenosine infusion

The adenosine infusion should be stopped early under any of the following circumstances:

  1. (1)

    Severe hypotension (systolic BP <80 mmHg).

  2. (2)

    Development of symptomatic, persistent second-degree or complete AV block.

  3. (3)

    Other significant cardiac arrhythmia.

  4. (4)

    Wheezing.

  5. (5)

    Severe chest pain associated with ST depression of 2 mm or greater.

  6. (6)

    Signs of poor perfusion (pallor, cyanosis, cold skin).

  7. (7)

    Technical problems with the monitoring equipment.

  8. (8)

    Patient’s request to stop.

  9. (9)

    Note: For signs or symptoms not significant enough to terminate the test, one can consider shortening the time of infusion from 6 to 4 minutes. The adenosine infusion should be terminated early if there are pronounced hemodynamic changes or wheezing or other symptoms, which are not enough to stop the test.

Reversal of complications and side effects of Adenosine

Most side effects are self-limiting due to the short half-life of adenosine (<10 seconds). Indications for reversal of adenosine using IV aminophylline (50 to 250 mg intravenously at least 1 minute after the tracer injection) include the following:

  1. 1.

    Severe hypotension (systolic BP <80 mmHg).

  2. 2.

    Development of symptomatic, persistent second-degree or complete heart block.

  3. 3.

    Other significant cardiac arrhythmia.

  4. 4.

    Wheezing.

  5. 5.

    Severe chest pain associated with ST depression of 2 mm or greater.

  6. 6.

    Signs of poor perfusion (pallor, cyanosis, cold skin).

Cost/time/pharmacy

Medicare Part B drug average sales price is calculated by the manufacturer every calendar quarter and submitted to CMS (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html). The average price for a single study at 140-mcg/kg/min adenosine over a 6-minute period during the 7 quarters since 2013 was $65 for a 75-kg patient (Table 4).

Table 4 Medicare Part B drug average sales price during the 7 quarters since 1/2013 (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html)
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Regadenoson

Mechanism of action

Regadenoson is an A2A adenosine receptor agonist (Figure 1). Regadenoson is a high-affinity agonist for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor, and weak, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF) by the same mechanism by which adenosine and dipyridamole produce coronary vasodilation. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The last phase consists of a decline in plasma concentration with a half-life of approximately 2 hours.

Regadenoson dose

The recommended intravenous dose of regadenoson is 0.4 mg (5-mL solution) and should be given as an approximately 10-second injection into a peripheral vein using a 22-gauge or larger catheter or needle. A 5-mL saline flush is administered immediately after the injection of regadenoson. The radionuclide tracer is injected 10 to 20 seconds after the saline flush using the same IV line used for regadenoson (Figure 3).

Figure 3
figure 3

Regadenoson protocol. IV, Intravenous; mcg, microgram; and mL, milliliter

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Side effects of regadenoson

  1. (1)

    The most common reactions to administration of regadenoson are shortness of breath, headache, and flushing. The minor adverse events were headache (29%), dyspnea (25%), flushing (17%), chest discomfort (11%), chest pain (8%), angina (8%), dizziness (7%), nausea (6%), and abdominal discomfort (6%).

  2. (2)

    Rhythm or conduction abnormalities were seen in 26%. First-degree AV block was detected in 3% and second-degree AV block in 0.1%. Asystole and QT interval prolongation have been reported.

  3. (3)

    Most adverse reactions begin soon after dosing and generally resolve within approximately 15 minutes, except for headache, which resolves in most patients within 30 minutes.

  4. (4)

    Aminophylline may be administered in doses ranging from 50 to 250 mg by slow intravenous injection (50 mg to 100 mg over 30 to 60 seconds) to attenuate severe and/or persistent adverse reactions at least 1 minute after tracer injection.

  5. (5)

    New-onset or recurrent atrial fibrillation and atrial flutter have been reported following regadenoson administration.

  6. (6)

    New onset or recurrence of convulsive seizures has occurred following regadenoson administration.

  7. (7)

    Refractory ischemia/myocardial infarction, hemorrhagic, and ischemic cerebrovascular accidents have been reported.

  8. (8)

    Refractory ischemia and myocardial infarction have occurred.

Hemodynamic effects

In clinical studies, the majority of patients had an increase in heart rate and a decrease in BP within 15 minutes after administration of regadenoson. Systolic BP decreased by 13 ± 14 mmHg and diastolic BP decreased 10 ± 8 mmHg, while heart rate increased by 25 ± 11 bpm.13 Maximum hemodynamic changes after regadenoson were as follows: increase in heart rate of more than 40 bpm in 5%, decrease in systolic BP of more than 35 mmHg in 7%, and decrease in diastolic BP of more than 25 mmHg in 4%.

Indications

The indications for regadenoson stress perfusion imaging are the same for exercise myocardial perfusion imaging, and in the presence of the following conditions:

  1. (1)

    Inability to perform adequate exercise due to noncardiac physical limitations (pulmonary, peripheral vascular, musculoskeletal, or mental conditions) or due to lack of motivation. Of note, as with exercise testing, anti-ischemic cardiac medications (including β-blockers, nitrates, and calcium antagonists) have been reported to decrease the diagnostic accuracy of vasodilator stress testing.

  2. (2)

    Baseline electrocardiographic (ECG) abnormalities: LBBB, ventricular pre-excitation (WPW syndrome), and permanent ventricular pacing.

  3. (3)

    Risk stratification of clinically stable patients into low- and high-risk groups after acute myocardial infarction.

  4. (4)

    Diagnosis or risk stratification following presentation to the emergency department with a presumptive acute coronary syndrome that has been excluded by serial clinical evaluation, ECGs, and serum markers.

Contraindications

Contraindications for regadenoson stress testing include the following:

  1. (1)

    Patients with bronchospastic lung disease with ongoing wheezing or a history of significant reactive airway disease should not undergo regadenoson stress testing.

  2. (2)

    Second- or third-degree AV block or sinus node dysfunction without a functioning pacemaker.

  3. (3)

    Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia, without a functioning pacemaker.

  4. (4)

    Systolic BP less than 90 mmHg. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency.

  5. (5)

    Uncontrolled hypertension (systolic BP >200 mmHg or diastolic BP >110 mmHg).

  6. (6)

    Recent (<48 hours) use of dipyridamole or dipyridamole-containing medications (e.g., Aggrenox).

  7. (7)

    Known hypersensitivity to adenosine or regadenoson.

  8. (8)

    Unstable angina, acute coronary syndrome, or less than 2 to 4 days after an acute myocardial infarction.

Relative contraindications

Relative contraindications for regadenoson stress testing include the following:

  1. (1)

    Profound sinus bradycardia (heart rate <40/min).

  2. (2)

    Mobitz Type 1 second-degree AV block (Wenckebach).

  3. (3)

    Severe Aortic Stenosis (see “Special Populations” section).

  4. (4)

    Ingestion of caffeinated foods or beverages (e.g., coffee, tea, sodas) within the last 12 hours should be avoided (Appendix 1).

  5. (5)

    Seizure disorder. Regadenoson may lower seizure threshold, and aminophylline should not be used in cases of seizures associated with regadenoson. These seizures may be of new onset, or may be recurrences. In addition, some seizures are prolonged and may require urgent anticonvulsive management.14,15

Procedure

  1. (1)

    Patient preparation: nothing should be eaten for at least 3 hours prior to testing. Avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea, or other caffeinated beverages, caffeine-containing drug products (Appendix A), and theophylline for at least 12 hours prior to the testing. Dipyridamole should be withheld for at least 2 days prior to regadenoson administration.

  2. (2)

    ECG monitoring should be carried out as with exercise stress testing. A 12-lead electrocardiogram will be recorded every minute during the infusion.

  3. (3)

    BP should be monitored every minute during infusion and 3 to 5 minutes into recovery or until stable.

  4. (4)

    Regadenoson (5 mL, containing 0.4 mg of regadenoson) should be given as a rapid (approximately 10 seconds) injection into a peripheral vein using a 22-gauge or larger catheter or needle. Administer a 5-mL saline flush immediately after the injection of regadenoson. Administer the radionuclide MPI agent 10 to 20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as regadenoson.

Combination of exercise with regadenoson administration

Patients who are ambulatory may undergo low-level exercise (e.g., treadmill 1.7 mph, 0% grade) for 1.5 minutes followed by regadenoson administration, tracer injection, and an additional 2 minutes of exercise.16,17 Combining low-level exercise with regadenoson resulted in improved image quality, and was well tolerated without an increase in adverse events. Low-level exercise supplementation is not recommended in patients with LBBB, WPW, and ventricular pacing due to heart rate-related imaging artifacts.

Ambulatory patients with uncertain functional capacity who do not reach their target heart rate may receive regadenoson to supplement submaximal exercise stress with preserved image quality.18-21 Regadenoson administration has been studied at peak exercise holding the maximally attained stage, at reduced exercise, during walk recovery, and at rest. While two of the studies found no differences in the safety and side-effect profile based on the time of regadenoson administration, one study suggested more exaggerated BP responses when administered at peak exercise.

Reversal of complications and side effects of regadenoson

Indications for reversal of regadenoson (50- to 250-mg aminophylline intravenously at least 1 minute after the tracer injection) include the following:

  1. (1)

    Severe hypotension (systolic BP <80 mmHg).

  2. (2)

    Development of symptomatic, persistent second-degree or complete heart block.

  3. (3)

    Other significant cardiac arrhythmia.

  4. (4)

    Wheezing.

  5. (5)

    Severe chest pain associated with ST depression of 2 mm or greater.

  6. (6)

    Signs of poor perfusion (pallor, cyanosis, cold skin).

Cost/time/pharmacy

Medicare Part B drug average sales price is calculated by the manufacturer every calendar quarter and submitted to CMS (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html). The average price for 0.4 mg of regadenoson during the 7 quarters since 2013 was $213.26 (Table 4).

Dipyridamole

Mechanism of action

Dipyridamole is an indirect coronary artery vasodilator that increases the tissue levels of adenosine by preventing the intracellular reuptake and deamination of adenosine (Figure 1). This results in a 3.8- to 7-fold increase in CBF velocity. Dipyridamole-induced hyperemia lasts for more than 50 minutes. Peak vasodilation after dipyridamole administration occurs on average 6.5 minutes after the start of the infusion. The half-life of dipyridamole is approximately 30 to 45 minutes. It is metabolized in the liver to the glucuronic acid conjugate and excreted in the bile.

Dipyridamole dose

Dipyridamole is administered at 0.56 mg/kg intravenously over a 4-minute period (Figure 4). The correct weight-based dose for the obese and morbidly obese patients is unclear. It is customary to use weight-based doses up to the weight of 250 lbs or 125 kg as the upper limit (Table 3).

Figure 4
figure 4

Dipyridamole protocol. IV, Intravenous; kg, kilogram; and mg, milligram

Full size image

Side effects of dipyridamole

  1. (1)

    Minor side effects are common and occur in approximately 50% of patients. These adverse events include the following: chest pain (20%), headache (12%), dizziness (12%), ventricular extrasystoles (5%), nausea (5%), hypotension (5%), and flushing (3%). Chest pain is nonspecific and is not necessarily indicative of the presence of CAD.

  2. (2)

    The incidence of AV block with dipyridamole is less than that observed with adenosine (2%).

  3. (3)

    ST-segment and T-wave changes occurred (8%); however, unlike chest pain, ST changes may be indicative of true ischemia.

  4. (4)

    Fatal or nonfatal myocardial infarction is extremely rare, but has been reported.22

  5. (5)

    Symptoms may last for a longer period of time than other vasodilators (15 to 25 minutes) and may vary significantly in individual patients. Aminophylline (50 to 250 mg intravenously) is often required to reverse these side effects.

Hemodynamic effects

Dipyridamole administration results in a modest increase in heart rate and a modest decrease in both systolic and diastolic BPs. Systolic BP decreased by 14 ± 15 mmHg, while heart rate increased by 17 ± 11 bpm.22 Systolic BP fell to <90 mmHg in 2% of patients.

Indications

The indications for dipyridamole stress perfusion imaging are the same as for exercise MPI and in the presence of the following conditions:

  1. (1)

    Inability to perform adequate exercise due to noncardiac physical limitations (pulmonary, peripheral vascular, musculoskeletal, or mental conditions) or due to lack of motivation. Of note, as with exercise testing, anti-ischemic cardiac medications (including β-blockers, nitrates, and calcium antagonists) have been reported to decrease the diagnostic accuracy of vasodilator stress testing.

  2. (2)

    Baseline electrocardiographic abnormalities: LBBB, ventricular pre-excitation (WPW syndrome), and permanent ventricular pacing.

  3. (3)

    Risk stratification of clinically stable patients into low- and high-risk groups after acute myocardial infarction.

  4. (4)

    Diagnosis or risk stratification following presentation to the emergency department with a presumptive acute coronary syndrome that has been excluded by serial clinical evaluation, ECGs, and serum markers.

Contraindications

The contraindications for dipyridamole stress testing include the following:

  1. (1)

    Patients with bronchospastic lung disease with ongoing wheezing or a history of significant reactive airway disease should not undergo dipyridamole stress testing.

  2. (2)

    Systolic BP less than 90 mmHg. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency.

  3. (3)

    Uncontrolled hypertension (systolic BP >200 mmHg or diastolic BP >110 mmHg).

  4. (4)

    Ingestion of caffeinated foods or beverages (e.g., coffee, tea, sodas) within the last 12 hours should be avoided (Appendix 1).

  5. (5)

    Known hypersensitivity to dipyridamole.

  6. (6)

    Unstable angina, acute coronary syndrome, or less than 2 to 4 days after an acute myocardial infarction.

Note: In patients taking oral dipyridamole, IV dipyridamole may be administered safely and efficaciously.

Relative contraindications

Relative contraindications for dipyridamole stress testing include the following:

  1. (1)

    Profound sinus bradycardia (heart rates <40/min).

  2. (2)

    Second- or third-degree AV block without a functioning pacemaker.

  3. (3)

    Severe aortic stenosis (see Special Populations section).

  4. (4)

    Seizure disorder. Methylxanthine (aminophylline) use is not recommended in patients who experience seizures in association with dipyridamole stress testing.

Procedure

  1. (1)

    Patient preparation: nothing should be eaten for at least 3 hours prior to testing. Avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea, or other caffeinated beverages, caffeine-containing drug products (Appendix 1), and theophylline for at least 12 hours prior to the testing.

  2. (2)

    ECG monitoring should be carried out as with exercise stress testing. A 12-lead electrocardiogram will be recorded every minute during the infusion.

  3. (3)

    BP and ECG should be monitored every minute during infusion and 3 to 5 minutes into recovery or until stable.

  4. (4)

    The drug is infused intravenously over 4 minutes. Although an infusion pump is preferable, dipyridamole can also be administered by hand injection or drip. The radiotracer is injected 3 to 5 minutes after the completion of dipyridamole infusion.

Combination of low-level exercise with dipyridamole infusion

Patients who are ambulatory may undergo low-level exercise (e.g., treadmill 1.7 mph, 0% grade) for 4 to 6 minutes soon after the completion of dipyridamole infusion. Radiotracer is injected during this low-level exercise, and the exercise continues for an additional 2 minutes to allow for tracer uptake in the myocardium. This significantly reduces the side effects and improves image quality.23-26 Low-level exercise supplementation is not recommended for patients with LBBB, WPW, and ventricular pacing due to heart rate-related imaging artifacts.

Indications for early termination of dipyridamole infusion

The dipyridamole infusion should be stopped early under any of the following circumstances:

  1. (1)

    Severe hypotension (systolic BP <80 mmHg).

  2. (2)

    Development of symptomatic, persistent second-degree or complete heart block.

  3. (3)

    Other significant cardiac arrhythmia.

  4. (4)

    Wheezing.

  5. (5)

    Severe chest pain associated with ST depression of 2 mm or greater.

  6. (6)

    Signs of poor perfusion (pallor, cyanosis, cold skin).

  7. (7)

    Technical problems with the monitoring equipment.

  8. (8)

    Patient’s request to stop.

Reversal of complications and side effects of dipyridamole

Indications for reversal of dipyridamole (50- to 250-mg aminophylline intravenously at least 1 minute after the tracer injection) include the following:

  1. (1)

    Severe hypotension (systolic BP <80 mmHg).

  2. (2)

    Development of symptomatic, persistent second-degree or complete heart block.

  3. (3)

    Other significant cardiac arrhythmia.

  4. (4)

    Wheezing.

  5. (5)

    Severe chest pain associated with ST depression of 2 mm or greater.

  6. (6)

    Signs of poor perfusion (pallor, cyanosis, cold skin).

  7. (7)

    Can be considered in the presence of less-severe side effects or ischemic ECG changes if at least 1 minute has elapsed since radiotracer injection.

Cost/time/pharmacy

The average price based on Medicare Part B drug average sales price is calculated by the manufacturer every calendar quarter and submitted to CMS (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html) for a single study at 0.56-mg/kg dipyridamole for a 75-kg patient during the 7 quarters since 2013 was $6.30 (Table 4).

Pharmacologic Synthetic Catecholamine Stress

There is one synthetic catecholamine stress agent available: dobutamine. This agent works by stimulating the β receptor, resulting in an increase in heart rate, BP, and myocardial contractility similar to exercise.

Dobutamine

Mechanism of action

Dobutamine infusion results in direct β1 and β2 stimulation with a dose-related increase in heart rate, BP, and myocardial contractility. Dobutamine increases regional myocardial blood flow based on physiologic principles of coronary flow reserve. A similar dose-related increase in subepicardial and subendocardial blood flow occurs within vascular beds supplied by normal coronary arteries. However, blood flow increases minimally within vascular beds supplied by significantly stenosed arteries, with most of the increase occurring within the subepicardium rather than the subendocardium. At a dose of 20 mcg/kg/min, however, dobutamine-induced coronary flow heterogeneity is similar to exercise but less than that induced by adenosine or dipyridamole. The plasma half-life of dobutamine is 2 minutes with the onset of action within 1 to 2 minutes; however, up to 10 minutes may be required to obtain the peak effect (Figure 5).

Figure 5
figure 5

Dobutamine protocol. IV, intravenous; kg, kilogram; mcg, microgram; and min, minute

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Dobutamine dose

Dobutamine is infused incrementally starting at a dose of 5 or 10 mcg/kg/min, which is increased at 3-minute intervals to 20, 30, and 40 mcg/kg/min. Radiotracer is injected at peak heart rate with dobutamine infusion continuing for 1 minute following tracer injection. As with exercise stress, achieving greater than 85% of the predicted heart rate is desirable.

Side effects of dobutamine

  1. 1.

    The common side effects are palpitation (29%), chest pain (31%), headache (14%), flushing (14%), dyspnea (14%), and significant supraventricular or ventricular arrhythmias (8% to 10%).

  2. 2.

    Ischemic ST-segment depression occurs in approximately one-third of patients undergoing dobutamine infusion.

  3. 3.

    Severe side effects may require IV administration of a short-acting β-blocker (esmolol, 0.5 mg/kg over 1 minute). IV metoprolol (5 mg) can also be used.

Hemodynamic effects

The hemodynamic response to dobutamine infusion is dose dependent and varies based on the maximal infusion rate obtained. In studies titrating to a maximal dose of 40 mcg/kg/min, heart rate increased 45 ± 18 bpm, while systolic BP increased 30 ± 21 mmHg in one study, and 12 ± 29 mmHg in another.27,28

Indications

Indications for dobutamine stress testing include the following:

  1. (1)

    Dobutamine is a secondary pharmacologic stressor that is recommended only in patients who cannot undergo exercise stress and who also have contraindications to pharmacologic vasodilator stressors (mainly bronchospastic airway disease).

  2. (2)

    Dobutamine perfusion imaging has not been studied as extensively as vasodilator stress perfusion imaging in the evaluation and prognostication of patients with CAD.

Contraindications

Contraindications for dobutamine stress testing include the following:

  1. (1)

    Unstable angina, acute coronary syndrome, or less than 2 to 4 days after an acute myocardial infarction.

  2. (2)

    Hemodynamically significant left ventricular outflow tract obstruction.

  3. (3)

    Atrial tachyarrhythmias with uncontrolled ventricular response.

  4. (4)

    Prior history of ventricular tachycardia.

  5. (5)

    Uncontrolled hypertension (systolic BP >200 mmHg or diastolic BP >110 mmHg).

  6. (6)

    Patients with aortic dissection.

  7. (7)

    Known hypersensitivity to dobutamine.

Relative contraindications

  1. (1)

    Patients who are on β-blockers where the heart rate and inotropic responses to dobutamine will be attenuated.

  2. (2)

    Severe aortic stenosis (see “Special Populations” section).

  3. (3)

    Patients with with symptomatic or large aortic aneurysm.

  4. (4)

    Left bundle branch block.

  5. (5)

    Paced ventricular rhythm.

Procedure

  1. (1)

    Patient preparation: nothing should be eaten for at least 3 hours.

  2. (2)

    An infusion pump is necessary for dobutamine administration.

  3. (3)

    An IV line with a dual-port Y-connector is required for injecting radioisotope during dobutamine infusion.

  4. (4)

    ECG monitoring and BP monitoring should be performed as with other pharmacologic stressors.

  5. (5)

    Dobutamine infusion should start at a dose of 5 to 10 mcg/kg/min. The dobutamine dose should then be increased at 3-minute intervals up to a maximum of 40 mcg/kg/min. The radiotracer should be injected at 1 minute into the highest dobutamine dose (achieving at least 85% of maximal predicted heart disease is desirable), and dobutamine infusion should be continued for 1 minute after the radiotracer injection.

  6. (6)

    Some investigators recommend the addition of atropine (divided doses of 0.25 to 0.5 mg up to 1 to 2 mg) in patients who do not achieve target heart rate with dobutamine alone.

Indications for early termination of dobutamine infusion

The dobutamine infusion should be stopped early under any of the following circumstances:

  1. (1)

    Achieving >85% of the age-predicted peak heart rate (after maintaining for 1 minute following radiotracer injection).

  2. (2)

    Severe hypotension (systolic BP <80 mmHg).

  3. (3)

    Severe hypertension (systolic BP >230 mmHg or diastolic pressure >115 mmHg)

  4. (4)

    Significant cardiac arrhythmia. Termination for ventricular tachycardia or atrial tachyarrhythmia is more likely with dobutamine than with other stressors.

  5. (5)

    Severe chest pain associated with ST depression of 2 mm or greater. Termination for ST-segment depression is more likely with dobutamine than with other stressors.

  6. (6)

    Signs of poor perfusion (pallor, cyanosis, cold skin).

  7. (7)

    Technical problems with the monitoring equipment.

  8. (8)

    Patient’s request to stop.

Reversal of complications and side effects of dobutamine

Severe side effects, arrhythmia, or ST changes may require IV administration of a short-acting β-blocker (esmolol, 0.5 mg/kg over 1 minute). IV metoprolol (5 mg) can also be used.

  1. (1)

    Severe hypertension (systolic BP >220/110 mmHg).

  2. (2)

    Significant cardiac arrhythmia.

  3. (3)

    Severe chest pain associated with ST depression of 2 mm or greater.

Cost/time/pharmacy

The average price based on Medicare Part B drug average sales price is calculated by the manufacturer every calendar quarter and submitted to CMS (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/index.html) for a 250-mg IV bag of dobutamine during the 7 quarters since 2013 was $6.59 (Table 4).

For review of serious complications of myocardial stress testing and their management, refer to the article by Dilsizian and colleagues. 9

Special populations for pharmacologic stress

Obesity

The correct dose for the obese and morbidly obese patient is unclear. It is customary to use a weight-based dose of IV dipyridamole, IV adenosine, and IV dobutamine up to the weight of 250 lbs as the upper limit.

Left Bundle Branch Block, Ventricular Pacing, Ventricular Pre-excitation (WPW Syndrome)

Pharmacologic stress with coronary vasodilators (not IV dobutamine) is the preferred stress modality with above rest ECG patterns, both for safety (inability to monitor for ischemia) and diagnostic reasons (e.g., the presence of septal perfusion defects, not always related to obstructive CAD). If rate-dependent LBBB is diagnosed during exercise, the test should be converted to a pharmacologic stress test.

Reactive Airway Disease

Adenosine, regadenoson, and dipyridamole should be administered with caution in patients with a history of reactive airway disease or severe obstructive pulmonary disease. Aminophylline should be available for the treatment of vasodilator-induced bronchospasm. Dobutamine is the preferred agent for pharmacologic stress in patients with a history of significant reactive airway disease or severe obstructive pulmonary disease.

Several studies have shown that a titrated dose adenosine infusion preceded by an inhaled bronchodilator was well tolerated in patients with mild reactive airway disease from COPD or asthma.29-31 Because of its selectivity for the A2A receptor and not the A2B receptor, regadenoson shows promise to avoid bronchoreactivity seen in adenosine and dipyridamole. Two small pilot studies of moderate to severe COPD and moderate asthma showed no statistically significant difference between regadenoson and placebo in bronchoconstrictive reactions as measured by spirometry.32,33 While several other studies have examined the issue,34 the only randomized study enrolled 999 patients with spirometry defined COPD or asthma and found no difference in the rate of bronchoconstriction between regadenoson and placebo, but did find more dyspnea.35

Renal Disease

Dipyridamole, adenosine, and dobutamine have no contraindications to renal dysfunction. The package label of regadenoson states that no serious events were reported through 24 hours of follow-up in stage III or IV renal impairment. In an initial pharmacologic model, regadenoson elimination half-life appeared to be prolonged with decreasing renal function.36 Subsequent published literature, including 423 patients with end-stage renal disease (ESRD) and 745 patients with impaired renal function but not ESRD, has found that the drug was safe, with minimal side effects, and hemodynamic responses similar to patients with normal renal function.37-41

Aortic Stenosis

The use of vasodilator stress for MPI in patients with significant aortic stenosis is limited as surgical valve replacement is recommended for symptomatic patients necessitating an invasive angiogram as opposed to noninvasive testing. Occasionally, MPI was preferred to angiography due to specific clinical considerations, which has become a more frequent occurrence with the advent of transcatheter aortic valve replacement (TAVR). A number of small studies have evaluated the diagnostic accuracy and to varying degrees the safety and tolerability of dipyridamole (141 patients),42-44 adenosine (180 patients),45-48 and regadenoson (50 patients).49 When assessed, there were no significant differences in the hemodynamic responses between patients with severe aortic stenosis and controls.43,48 In a group of 50 pre-TAVR patients with a mean EF of 39%, transient hypotension occurred in 16% of subjects receiving regadenoson.49

There is insufficient safety data on SPECT dobutamine stress in patients with severe aortic stenosis.

Pre Solid-Organ Transplantation

The role of cardiac disease evaluation prior to solid-organ transplantation (e.g., kidney and liver) candidates was discussed recently in an expert consensus document by the AHA.50

The safety of regadenoson has been studied in patients with renal impairment (see Renal Disease section) and also in end-stage liver disease. In a study of 168 patients, regadenoson was found to be safe in end-stage liver disease patients with no significant adverse events, and a lower heart-rate response but similar BP response was seen.37 There is a case report of three cases of sinus arrest with adenosine in liver transplant patients with graft failure, so caution should be taken in this particular patient population.51

Women

The role of noninvasive testing in the evaluation of women with suspected ischemic heart disease was recently covered in an AHA consensus statement.4

Caffeine and Coronary Vasodilators

Caffeine, a methylxanthine alkaloid derivative, is a competitive inhibitor of the adenosine receptor due to its similar molecular structure to adenosine. Caffeine binds to the adenosine receptor without activating it, thereby requires withholding methylxanthines prior to testing with adenosine, dipyridamole, or regadenoson. The half-life of caffeine varies widely among individuals based on factors such as age, liver function, medication, smoking use, and pregnancy, and is approximately 5 hours in a healthy adult.52 Caffeine is most commonly found in coffee, tea, soda, energy drinks, and chocolate (Appendix 1). While the caffeine content depends on the particular product and method of preparation, the caffeine contents of some common products are shown in the table in Appendix 1. Decaffeinated coffee still contains up to 13.9 mg of caffeine. A number of studies have shown that even when patients report abstinence from caffeine for 12 to 24 hours, a substantial portion of patients have detectable serum caffeine levels.

The effect of caffeine on the coronary hyperemia induced by adenosine, dipyridamole, and regadenoson may be explained by the difference in their mechanism of action. While dipyridamole is an indirect agonist on the A2A receptor by increasing the concentration of endogenous adenosine, adenosine is a direct stimulator, and regadenoson has a higher A2A receptor affinity. A number of studies have shown limited increase in myocardial blood induced by dipyridamole after caffeine use as well as attenuated myocardial perfusion defects.53-58 Two studies assessing the coronary hyperemia induced by adenosine found no significant attenuation of the effect by caffeine.56,59 It is unclear whether the degree of attenuation of the magnitude of coronary hyperemia caused by caffeine would result in a clinically significant change to myocardial perfusion results.60 A number of studies have investigated the effects of caffeine consumption on the MPI results using adenosine stress finding some effect on imaging,61 but often no significant effect.62,63 The data on regadenoson are somewhat mixed with an animal study reporting that caffeine did not affect the maximum increase in coronary blood flow, but that the duration of hyperemia was shorter.64 Regadenoson-induced hyperemic myocardial blood flow measured by PET was not affected by caffeine ingestion,65 but reversible defects on SPECT myocardial perfusion imaging were smaller with caffeine consumption.66

Patients should abstain from caffeinated products for at least 12 hours, which allows for selection of any of the three vasodilator stressors.

Radiotracers and Protocols

There are a variety of different protocols currently used for SPECT myocardial perfusion imaging. Table 5 contains information about these protocols: the radiopharmaceuticals used, their activities [millicuries, (mCi) or megabecquerels (MBq)], and their radiation effective doses. Figures 6 to 10 provide additional information regarding the timing of stress, injections, and imaging for each protocol. Gated imaging is recommended where feasible, at least during post-stress imaging.

Table 5 Current SPECT myocardial perfusion imaging protocols: recommended radiopharmaceutical activities and their corresponding radiation effective doses
Full size table
Figure 6
figure 6

One (A) and two (B) day rest-stress Tc99m imaging protocols

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Figure 7
figure 7

One (A) and two (B) day stress-rest Tc99m imaging protocols

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Figure 8
figure 8

TL-201 stress-rest imaging protocols

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Figure 9
figure 9

Dual-isotope (Tl-201-Tc99m) imaging protocols (discouraged)

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Figure 10
figure 10

Rest thallium

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The protocol selected for a particular study should be tailored to the patient and to the clinical scenario. No single protocol is optimal for every patient, and nuclear cardiology laboratories should strive to implement patient-centered imaging rather than performing the same protocol for each patient. This includes selecting an appropriate protocol and choosing administered activities that are appropriate for the patient’s habitus, i.e., weight-based dosing. The American Society of Nuclear Cardiology (ASNC) has provided detailed guidance regarding protocol selection for different patient populations in the Preferred Practice Statement on Patient-Centered Imaging,67 and recommends use of that document in tandem with these guidelines. As per the ASNC Information Statement on Recommendations for Reducing Radiation Exposure in Myocardial Perfusion Imaging, using a protocol and administered activities that will result in radiation exposure as low as reasonably achievable (ALARA) for each patient, with radiation effective dose of ≤9 mSv in at least 50% of studies, is an extremely important goal for each laboratory to attain.9 Several techniques can be used to keep radiation ALARA.68 Their under utilization in contemporary practice provides nuclear cardiology laboratories with multiple opportunities to improve patient care.69,70 Where feasible, and particularly for procedures with higher radiation exposure, e.g., effective dose >20 mSv, shared decision-making principles should be employed,71 including discussion of options with the patient.

Selection for a particular patient of the administered activity, within the range of activities for a given radiopharmaceutical, is not an exact science; the same administered activity can result in dramatically different count statistics and image quality in different patients due to differences in pharmacokinetics. Nevertheless, an effort to tailor the administered activity to the patient’s habitus and imaging equipment should be made. For example, thin patients without excessive breast tissue should receive activities at the low end of the recommended range, while many patients weighing more than 250 pounds benefit from the increased count statistics of a 2-day protocol with 18 to 30 mCi administered each day. A variety of weight-based strategies can be used, in that strong evidence supporting one particular weight-based dosing scheme does not exist. As one strategy to consider, many laboratories may find it suitable in 1-day studies to perform the first injection with 8 mCi of Tc-99m for patients with BMI ≤25 kg/m2, 9 mCi of Tc-99m for patients with BMI >25-30 kg/m2, 10 mCi of Tc-99m for patients with BMI >30-35 kg/m2, and 12 mCi of Tc-99m for patients with BMI >35 kg/m2 or a large chest, with three times this activity used for the second dose of the day. In obese patients undergoing 2-day protocols, radiation dose can be optimized by performing stress imaging on the first day, and only performing rest imaging if these images are abnormal. For laboratories with advanced software (e.g., incorporating noise reduction and resolution recovery) and/or hardware (e.g., cameras with multiple cadmium-zinc-telluride detectors) enabling more efficient count detection,72-74 reduced-dose protocols should be considered, a set of which are included in Table 5.

SPECT myocardial perfusion imaging protocols utilize three radiopharmaceuticals: thallium 201 and two technetium 99m agents (Tc-99m sestamibi and Tc-99m tetrofosmin). Details regarding these radiopharmaceuticals and the protocols using them follow. Information related to PET protocols and radiopharmaceuticals are described in the PET Imaging Guidelines.75

NOTE: The suggested radiopharmaceutical activities in this section are for current camera and processing protocols as defined in the SPECT Imaging Guidelines.76 Some of the radiopharmaceutical activities described in this section fall outside of the manufacturer package insert guidelines but are now commonly used in the clinical practice of nuclear cardiology.

The radiation dosimetry values provided in Table 5 are point estimates of doses to a typical patient. Doses were determined using average administered activities, most recently published International Commission on Radiological Protection (ICRP) dose coefficients, and ICRP Publication 103 tissue weighing factors. Tc-99m doses represent an average for sestamibi and tetrofosmin.

Gated imaging is recommended where feasible. Results of gating are most reliable with higher doses of technetium-based perfusion tracers but satisfactory results have been reported with lower dose technetium as well as thallium-201.

Radiation effective dose values listed here are dose to a reference individual. Doses were determined using the most recent published International Commission on Radiological Protection (ICRP) organ dose coefficients, and ICRP Publication 103 tissue weighing factors. Tc-99m doses represent an average for sestamibi and tetrofosmin.

Tc-99m-Labeled Tracers

Mechanism of action

Tc-99m sestamibi and Tc-99m tetrofosmin have very similar characteristics: lipid-soluble, cationic, physical half-life of 6 hours, produces 140-keV photons, first-pass extraction less than Tl-201, uptake and mitochondrial retention dependent on blood flow, and transmembrane energy potentials. Their myocardial washout (redistribution) is clinically negligible. These agents are excreted via the hepatobiliary system and excreted into the gastrointestinal tract. Lacking significant redistribution, Tc-99m-labeled tracers require two separate injections at stress and rest. The two agents have sufficiently similar characteristics, in that recommended protocols use similar camera setup and acquisition times and vary only in the optimal time for image acquisition following rest, exercise, and pharmacologic stress. Optimal validation of imaging times has not been extensively studied, and factors such as camera availability and the presence of liver and gastrointestinal activity influence the optimal imaging times. In the figures, a range of imaging times is suggested. The whole-body effective dose for Tc-99m-based perfusion agents varies between sestamibi and tetrofosmin, and between administration at rest and stress, and between data sources and methods of calculation, but as a very rough figure is approximately 0.3 mSv per mCi of Tc-99m injected.

Imaging Protocols (Figures 6, 7)

  1. (1)

    Tracer-specific imaging times

  2. (a)

    For Tc-99m sestamibi, minimum delays of 15 to 20 minutes for exercise, 45 to 60 minutes for rest, and 60 minutes for pharmacologic stress are recommended.

  3. (b)

    For Tc-99m tetrofosmin, minimum delays of 10 to 15 minutes for exercise, 30 to 45 minutes for rest, and 45 minutes for pharmacologic stress are optimal. Because there is minimal redistribution with these agents, longer delays—up to 2 hours—between the radiotracer injection and imaging can be used when needed.

  4. (2)

    Two-day protocol. Ideally, stress and rest imaging with Tc-99m agents should be performed on two separate days, as shown in Figure 7B, to avoid having residual activity (“shine-through” or “crosstalk”) from the first injection interfere with interpretation of images reflecting the second injection. In larger patients (e.g., >250 lbs or BMI >35) or in female patients where significant breast attenuation is anticipated, a low dose of Tc-99m radiotracer may result in suboptimal images and a 2-day imaging protocol with higher activities (18 to 30 mCi) for each injection may be preferable.

  5. (3)

    One-day protocols. For many patients, 2-day imaging is impractical, and thus stress and rest studies are usually performed using a 1-day protocol as shown in Figures 6A and 7A for exercise and pharmacologic stress. This requires administration of a lower dose (approximately one-fourth of the total dose) for the first injection and a higher dose (approximately three-fourths of the total dose) for the second injection. One-day stress/rest and rest/stress Tc-99m protocols are now typically performed with no significant delay between obtaining the first set of images and injection of the second dose of Tc-99m at stress or rest, as appropriate. The initially proposed 1990 protocol specified a 2-hour delay between injections to allow the first dose to decay in order to maximize the count density ratio and minimize shine-through. However, simply increasing the activity of the second injection provides the same count density ratio achieved by letting the first dose decay (20% in 2 hours). Thus, a 3:1 ratio of activities with a 2-hour delay and a 3.5 to 4:1 ratio with no delay provide similar results.

In patients without a high pre-test probability of a stress perfusion defect or left ventricular dysfunction or dilatation, a low-dose stress/high-dose rest Tc-99m protocol is advantageous because a significant percentage of these patients will have normal stress imaging, thereby enabling obviating the need for the rest imaging with its additional radiation exposure, and permitting performance of stress-only imaging.

Tl-201

Mechanism of action

Tl-201 is an analog of potassium (monovalent cation), with a physical half-life of 73.1 hours, decay by electron capture to Hg-201 with principal emission of 68- to 80-keV X-rays, high first-pass myocardial extraction (85%), active membrane transport into the myocyte, rapid clearance from the intravascular space, and monoexponential washout (redistribution), which starts 10 to 15 minutes after injection. Washout depends on initial tracer concentration in the myocyte and on myocardial blood flow. Clearance occurs via the kidneys. The effective radiation dose for Tl-201 is approximately 4.4 mSv per mCi of Tl-201 injected.

Imaging protocols (Figures 8, 9, and 10)

A single dose of 2.5 to 3.5 mCi of Tl-201 is injected prior to peak exercise stress or at peak pharmacologic vasodilatation, and SPECT imaging starts 10 to 15 minutes later. Redistribution (rest) imaging is done 2.5 to 4.0 hours later. In cases where standard stress-redistribution imaging shows a fixed or minimally reversible perfusion abnormality, myocardial viability can be assessed with a rest image at 18 to 24 hours or following reinjection of an additional 1- to 2-mCi dose of Tl-201. An alternative method for viability assessment is injection of 2.5 to 3.5 mCi of Tl-201 at rest followed by 3- to 4-hour or 18- to 24-hour redistribution imaging. Protocol options and timing for assessment of perfusion and viability are shown in Figures 8 and 10.

Use of dual-isotope imaging, with Tl-201 for initial rest imaging and a Tc-99 labeled tracer for stress perfusion imaging, as shown in Figure 9, allows a shorter duration of the entire imaging protocol. However, there is a significantly higher radiation dose to the patient, and rest and stress images are obtained with different tracers that may increase the false positive rate for ischemia. Except in those elderly patients who require a shorter protocol, or for patients in whom there is a clear indication for both perfusion imaging and viability assessment, and PET or MRI viability assessment is not possible, ASNC recommends against performing dual-isotope MPI.

Cardiac Iodine-123 meta-iodobenzylguanidine (123I-mIBG) Imaging

Mechanism of action

Cardiac iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging assesses sympathetic innervation of the myocardium. MIBG is an analog of the sympathetic mediator norepinephrine (NE), although it is designed to more closely mimic the false neurotransmitter guanethidine. When injected intravenously, MIBG diffuses into the synaptic cleft and is taken up into pre-synaptic sympathetic terminals via the NE transporter-1 (NET1) energy-dependent “uptake-1” process.80-82 Physiologically the uptake-1 process is designed to terminate local sympathetic stimulation by storage and catabolic disposal of NE, but as MIBG behaves as a false neurotransmitter, it is not metabolized and instead accumulates in the pre-synaptic terminal. So, when labeled with a radioisotope, such as iodine-123 (123I), 123I-mIBG imaging depicts function of the uptake-1 process, and thus the integrity and health of cardiac sympathetic innervation.83

Human cardiac imaging of 123I-mIBG was first reported by Kline et al in 1981,84 described at the time as providing “clinicians with insights into ‘wiring of the heart’.”85 Cardiac disease, such as HF and myocardial ischemia, lead to low 123I-mIBG concentration in cardiac innervating sympathetic neurons and is customarily quantified as a heart-to-mediastinum ratio (HMR), as well as an accelerated tracer washout rate (WR) between early and delayed anterior planar images. Much literature demonstrates that an abnormally low HMR and an abnormally high WR are associated with a poorer patient prognosis in patients with HF and reduced ejection fraction (HFrEF).86-90

Indications

Cardiac 123I-mIBG imaging is currently indicated for “scintigraphic assessment of sympathetic innervation of the myocardium in patients with New York Heart Association [NYHA] class II or class III HF and left ventricular ejection fraction [LVEF] ≤35% … and to help identify patients with lower one- and two-year mortality risks, as indicated by an [HMR] ratio ≥1.6.”

Nevertheless, much literature suggests a potential broader use,91 including identification of patients at increased risk of lethal cardiac arrhythmias in the setting of HF,92-95 evaluating primary arrhythmic conditions,96-100 assessing the presence and risk of ischemic heart disease,101,102 including in situations of hibernating myocardium103,104 and post-infarction,105-107 evaluating pre- and post-cardiac transplant patients,108-110 identifying diabetic patients at increased risk from cardiac autonomic dysfunction,111,112 and monitoring toxicity from chemotherapy.113 However, based on currently available literature, published guidelines, and the FDA package insert, the following indications can be recommended:114

  • For patients with NYHA class II or III heart failure with LVEF ≤35% to help stratify risk and to promote more informed clinical decision-making when the result of 123I-mIBG study is likely to influence the decision regarding ICD implant.

The following can be considered a potential emerging indication:

  • For patients who received an ICD for primary and or secondary prevention of SCD who subsequently underwent complete device and lead removal due to definite infection and there is uncertainty on the part of treating physician to proceed with ICD replacement, when the result of 123I-mIBG study is likely to influence the decision regarding device replacement.

Procedure: performing cardiac 123I-mIBG imaging

A schematic of the 123I-mIBG administration and imaging procedure is shown in Figure 11, with details below. Imaging parameters are as shown in Table 6.

Figure 11
figure 11

123I-mIBG imaging protocols

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Table 6 Acquisition setup for 123I-mIBG
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Tracer Administration

123I-mIBG is performed at rest and requires only minimal preparation. The standard procedure used in a recent multicenter study was to keep the patient NPO (except for water) after midnight on the day of imaging.115 It is accepted that standard HF medications such as ß-blockers, angiotensin-converting enzyme inhibitors (ACE-I), and/or angiotensin receptor blockers (ARBs) need not be held.116-119 However, it is recommended to temporarily discontinue medications and substances known to interfere directly with the mechanisms of NE uptake and granule storage, such as opioids, cocaine, tramadol, tricyclic antidepressants sypathomimetrics, some antihypertensive and cardiovascular agents, and antipsychotics (see detail in Table 7).118 In addition, foods containing vanillin and catecholamine-like compounds (e.g., chocolate and blue cheese) should be stopped.120,121 A subanalysis of data from the ADMIRE-HF study showed that neuropsychiatric medications with high potency can result in a falsely low HMR and thus an overestimation of cardiac risk.122

Table 7 Important medications that may affect organ uptake of MIBG
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There are differing views regarding the need for pre-test administration of iodine to prevent thyroid uptake of I-123. Historically, such blockade had been undertaken to shield the thyroid from exposure to unbound radionuclide iodine impurities, but with modern production methods the amount of these is minimal, and many feel that pre-treatment is unnecessary. Nevertheless, a recent study showed that even with an 123I-mIBG preparation of 98% radiochemical purity, unblocked patients have a 50% higher 4-hour thyroid accumulation of unbound 123I compared with pre-treated patients, with an estimated 70-mGy exposure from a 10-mCi administered dose.123 Thus, it is recommended that pre-treatment should be individually determined, to be considered in perhaps younger patients, but less worthwhile in elderly patients with multiple comorbidities and potential risk of iodine allergy. If desired, thyroid blockade can be achieved with oral administration of solutions of potassium iodide or Lugol’s (130-mg iodide for adults, body weight adjusted for children), or for patients allergic to iodine, potassium perchlorate (500 mg for adults, weight adjusted for children), orally administered at least 30 minutes prior to MIBG injection.118

Older studies used a dose of 3 to 5 mCi [111 to 185 megabecquerels (MBq)] administered over 1 minute. However, as it is often difficult to obtain satisfactory SPECT images using these doses, especially in patients with severe cardiac dysfunction, investigators have recently been using up to 10 mCi (370 MBq).80,115 A 10-mCi dose results in radiation exposure of approximately 5 mSv, with highest exposure to the bladder, liver, spleen, gall bladder, heart, and adrenals; the absorbed dose may be higher in patients with severe renal impairment.118

It has been recommended that patients lie quietly in a supine position for about 5 to 15 minutes before administration. As initial images are acquired a few minutes later, the patient should be lying under the camera or in close proximity. The tracer is then administered slowly over 1 to 2 minutes, followed by a saline flush.

Adverse Reactions

Adverse reactions to 123I-mIBG are uncommon. Among the side effects reported when 123I-mIBG is administered too quickly are palpitations, shortness of breath, heat sensations, transient hypertension, and abdominal cramps. A rare anaphylactic reaction is also possible.118

Imaging Techniques

While acquisition and processing of planar and SPECT 123I-mIBG images are most often performed with techniques typical for perfusion imaging, there are special issues that need to be considered that will likely result in changes in methodology over time. The current key parameters for 123I-mIBG image interpretation—HMR and washout—require accurate and robust quantitative analysis of counts in the heart and adjacent background regions, and thus could vary in relation to issues, such as the acquisition field of view, the type of collimator used, and how the multiple energy emissions of 123I are taken into account during acquisition and processing. In addition, data in the literature are based on images obtained without using correction for attenuation, Compton scatter or depth-dependent loss of spatial resolution, with use of such techniques likely to produce different values. Finally, increased use of solid-state cameras will likely produce different quantitative 123I-mIBG results from what has been reported for standard Anger cameras.

Anterior planar 123I-mIBG images are acquired for 10 minutes with the patient supine approximately 15 minutes (early) and beginning approximately 3 hours, 50 minutes (late) after tracer administration, and stored in a 128 × 128 or 256 × 256 matrix.115,118 The imaging field of view should include as much of the heart and upper chest as possible, with avoidance of positioning the heart too close to the edge of the field or too close to the center. Positioning should be consistent for the early and late planar images.

With a large field of view, anterior planar image is important for obtaining the desired HMR. The technique for obtaining suitably equivalent images from small-field-of-view SPECT cameras is unclear. In a report from a pilot group of 67 subjects, HMRs calculated from SPECT images using mean counts between heart and mediastinum volumes of interest drawn on transaxial images were equivalent to those obtained by planar techniques for differentiating subjects with normal versus abnormal MIBG uptake.124 More investigations are required to validate this further, including for images obtained with solid-state cameras.

Although the utility of SPECT imaging assessment of regional defects is currently uncertain, based on theoretic consideration106,125,126 and some literature data particularly for primary arrhythmias,96-100 tomographic acquisitions are commonly performed immediately following both the early and late planar images. They are obtained with a minimum of 60 projections at 30 seconds/stop over a 180° arc (45° right anterior oblique to 45°left posterior oblique) and stored in a 64 × 64 matrix.

Much literature is based on 123I-mIBG image acquisition using low-energy high-resolution (LEHR) collimators, with a symmetrically centered energy window of 20% around the main 159-keV isotope photopeak. However, HMR values vary depending on the collimator used, different for low-energy versus medium-energy collimators, but also varying among different low-energy collimator brands.127-129 In part these differences relate to 123I also emitting multiple low-abundance high-energy (>400 keV) photons, especially a 529-keV emission. While on an intrinsic 123I spectrum, the higher energy emissions are small in relation to the principle 159-keV peak, a low-energy collimator blocks many of the 159-keV emissions while allowing septal penetration of the higher energy photons that degrade image quality and affect accuracy of quantitative values, such as HMR.130,131 Although most clinical literature is based on use of a LEHR, in fact the reported HMRs are severely underestimated in relation to the true value.132 Several methods have been explored attempting to overcome this problem when an LEHR is used, including mathematical deconvolution of septal penetration (DSP),130 image acquisition using 123I-dual window acquisition (IDW),133 decreasing the 159-kEV energy window to 15%.132 Although it has been suggested that a medium-energy collimator may be preferred,129 use of a calibration phantom to derive a conversion coefficient for each camera-collimation system may be a better approach.134,135

There have been recent reports on the 123I-mIBG imaging with solid-state cameras. While data from these are encouraging, given the aforementioned discussion, one must consider the image that derived quantitative parameters from these camera(s) may differ from those reported in the literature upon which clinical use is recommended.136-138 Solid-state cameras may provide the image resolution and detail necessary for higher quality SPECT images that can allow assessment of regional sympathetic activity that might be superior to HMR in predicting adverse cardiac events, particularly arrhythmias.139

Derivation of the HMR and Washout (Figures 12, 13)

As the HMR is currently the key result of a 123I-mIBG study, it is important it be derived in a standard way. While there have been attempts to automate the process,140 at present the standard is to manually draw the cardiac and mediastinal regions of interest (ROI).

Figure 12
figure 12

Heart-to-mediastinal ratio (HMR) determination. Illustration of creation of ROI for determination of the heart-to-mediastinal ratio (HMR or H/M): The following steps are recommended: (1) Heart counts: Draw an irregular ROI defining the epicardial border of the heart, with visual determination of the valve plane. If the myocardium is not visualized well, draw the ROI based on the presumed location of the heart. Try to avoid adjacent lung and liver, but counts from these organs sometimes need to be included if that is the only way to get sufficient myocardial counts. (2) Mediastinal counts: (a) Draw a horizontal line to mark the estimated location of the lung apices. If the superior aspect of the image does not include the lung apices because of a limited field of view camera, draw this line at the top of the image display. (b) Draw a vertical line approximately equidistant from the medial aspects of the right and left lungs. (c) Examine the counts for the 12 pixels along the vertical line starting 4 pixels at the horizontal/vertical line intersection point. Identify the pixel with the lowest number of counts; if more than one, choose the most superior. Draw a 7 × 7 square ROI around the pixel. (d) Calculate HMR by dividing the counts/pixel in the total myocardium ROI by the counts/pixel in the 7 × 7 mediastinal ROI

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Figure 13
figure 13

Examples of HMR. Case Examples: (A) Easily seen myocardial border well separated from liver and without significant lung activity. HMR = 1.52; (B) Easily seen myocardial border but with contiguous liver. Myocardial ROI drawn as close to epicardial border as possible with avoidance of liver. HMR = 1.68; (C) Low cardiac counts with adjacent lung activity. Myocardial ROI drawn as close to epicardial border as possible with avoidance of lung. HMR = 1.18; and (D) Barely seen cardiac counts with adjacent lung activity. Myocardial ROI drawn estimating epicardial border with minimization of lung inclusion

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While various techniques have been reported for deriving heart counts,141-143 the currently accepted method118 is an irregular ROI defining the epicardial border of the heart, as this technique permits the most consistency and results in the best estimate of cardiac uptake in counts per pixel. If the myocardium is not visualized well, the ROI should be based on the presumed location of the heart. One should try to avoid adjacent lung and liver, but counts from these organs sometimes need to be included if that is the only way to get sufficient myocardial counts. Mediastinal counts are derived from a square ROI (7 × 7 pixels) in the upper mediastinum below the lung apices and midway between the lungs, and within these constraints positioning the ROI in the area of lowest counts. Mediastinal counts per pixel are determined. The HMR is then calculated by dividing the mean counts/pixel in the total myocardium ROI by the mean counts/pixel in the mediastinal ROI. The technique appears to be fairly robust with a recent study showing only minimal, inconsequential changes in HMR when there are changes in the visually defined heart ROI.144

Although there are various methods of washout rate determination reported, recent European guidelines indicate the following.118

$$ {\text{WR}}_{\text{BKGcorrected}} = \frac{{\{ H_{\text{e}} - M_{\text{e}} \} - \{ (H_{\text{l}} - M_{\text{l}} ) \times 1.21*\} }}{{(H_{\text{e}} - M_{\text{e}} )}} \times 100. $$

*123I decay corrected for 3 hour and 45 minutes, e is the early images, l the late images, BKG the background, H the heart counts per pixel, M the mediastinal counts per pixel, and WR is the washout rate.

There is some controversy regarding whether background subtraction should be performed. Obtaining the WR without background subtraction has been shown to result in lower variability, but also lower value.145