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Stress Testing and Nuclear Imaging
Stress ECG and stress imaging studies are widely used noninvasive procedures that provide important information on cardiac function and the presence of hemodynamically significant coronary artery disease (CAD). The correct use of stress testing is critically important for the cost-effective management of patients with known or suspected CAD. When the most appropriate procedure is performed, it provides important diagnostic and prognostic information that determines the optimal management strategy to be undertaken for that individual. Stress testing is also used in patients with known CAD to determine exercise “prescriptions” before cardiac rehabilitation ( Fig. 10.1 ).
Evaluation for Hemodynamically Significant Coronary Artery Disease (CAD) in Clinically Stable Patients.
LBBB , Left bundle branch block; LVH , left ventricular hypertrophy.
Exercise Stress Testing
Exercise stress testing (EST) involves subjecting a patient to increasing levels of exercise with continuous ECG monitoring for myocardial ischemia and arrhythmias. Although the sensitivity and specificity of stress ECG for the detection of CAD are low (range: 55%–75%) compared with more advanced testing (including the use of imaging), stress ECG is widely available, relatively inexpensive, and can provide important prognostic information about the patient. Generally, diagnostic treadmill stress testing is done on patients with a low or intermediate pretest likelihood of having CAD. However, EST can also be used in patients with known CAD to evaluate the effectiveness of current therapies, to ascertain overall functional capacity, to determine general prognosis, and/or to provide an exercise prescription. In children with congenital heart disease, EST can be used to quantify functional capacity.
The sensitivity of EST for detecting CAD is proportional to the heart rate (HR) achieved during exercise. Thus, in preparation for the study, patients are usually asked to transiently discontinue medications that affect HR response (e.g., β-blockers or calcium channel blockers). Patients should fast for at least 4 hours before the test. Exercise is done on a treadmill, or alternatively, using a bicycle ergometer. In special circumstances, arm ergometry and isometric hand exercises can be used. There are several different protocols for EST. All of them start exercise at a given rate and incline angle, and then gradually increase one or both parameters until an adequate HR and exercise endurance are achieved. Generally, exercise is continued until the patient reaches a target HR of at least 85% of the maximum predicted HR (MPHR) for the age of the patient (220 beats/min − age in years ± 10 to 12 beats/min). Studies that have correlated ECG changes with CAD generally involve reaching this target HR.
Once a patient reaches the target HR, they should continue to exercise until fatigued or until signs or symptoms develop. If a patient exceeds a double product (HR × systolic blood pressure) of 25,000 or attains an exercise level of at least 5 metabolic equivalents as a secondary target, the test may be considered adequate. Hemodynamic instability, gross ECG changes, or severe patient symptoms are also indications to terminate the procedure. At the end of exercise testing, the patient slowly reduces the intensity of exercise. Vigorous exercise results in increased blood flow and pooling in the extremities, and a “step-down” phase (low-level exercise) allows the patient to re-equilibrate before ceasing exercise. After exercise termination, patients are monitored in a supine position until they are no longer tachycardiac (i.e., HR <100 beats/min) if not back to baseline HR. Importantly, if there were any ECG changes or symptoms experienced by the patient during the study, posttest monitoring should be continued with any necessary treatments until these have been resolved, even if hemodynamics (HR and blood pressure) have returned to acceptable levels. The posttest monitoring serves to reveal any arrhythmias or ST-segment changes that may develop and that may be late signs of ischemic disease ( Fig. 10.2 ).
The ECG must be interpreted with certain caveats. Although the standard 12-lead configuration can be used, in many instances, a modified 12-lead configuration is substituted. This involves placing limb leads more proximally than is done for a standard ECG (e.g., electrodes are placed on the shoulders rather than the arms). This modification results in ST-segment changes being accentuated and more easily detected during stress, but it is also a baseline stress ECG that differs from a supine ECG done with standard lead placement.
The presence of myocardial ischemia during the test is suggested if previously normal ST segments show flattened or downsloping depression >1 mm below the baseline in three consecutive beats. An important issue concerns ST-segment changes that can occur in some individuals simply because of the increased respiratory rate that accompanies exercise. A prestress or poststress ECG performed with hyperventilation should be done to allow comparison of ECG changes that are associated with an increased respiratory rate.
The prognostic information obtained from a treadmill stress test is often useful for deciding on the next diagnostic or therapeutic step for a given patient. Of the several methods used for prognosis after EST, the most widely used is the Duke Treadmill Score. The time of exercise, the presence (or absence) of ST-segment changes during the study, and patient symptoms are used to determine a score that correlates with event-free survival.
Bicycle-based studies use a comparable approach to provide similar information. The patient maintains a steady, pedaling rate over a period of time with regular increases in the intensity required for pedaling. At comparable HRs, a higher level of physiological stress (reflected by metabolic equivalents) is present in individuals walking on a treadmill than individuals pedaling a bicycle. However, the data available for comparing these two forms of exercise are limited. Caution should be used in translating clinical information between forms of exercise.
Contraindications to exercise include unstable coronary syndrome, decompensated heart failure (HF), severe obstructive valvular or hypertrophic cardiomyopathic disease, untreated life-threatening arrhythmias, and advanced atrioventricular block. Under certain circumstances, exercise testing under rigorously controlled conditions is performed on patients with aortic stenosis to determine their suitability for aortic valve replacement. Severe baseline hypertension (>220/120 mm Hg) or the presence of large arterial aneurysms are also contraindications, as are systemic illnesses such as acute pulmonary embolus and aortic dissection. Exercise studies should be used cautiously in individuals with an implantable cardiac defibrillator (ICD), particularly if their underlying ECG shows a prolonged QRS interval (due to an underlying bundle branch block or paced rhythm), because in this circumstance, the defibrillator may “recognize” the rapid HR induced by exercise as ventricular tachycardia. Arrhythmias such as uncontrolled atrial fibrillation may also make interpretation of exercise stress ECGs difficult or impossible, and patients with these arrhythmias should be considered for a stress imaging study.
Cardiac Stress Imaging
Stress imaging studies combine either EST or an infusion of either dobutamine or a coronary vasodilator with imaging of the heart. Imaging can be accomplished by a variety of modalities; those most commonly used are echocardiography or nuclear imaging. MRI has also been used, and CT is being studied as a modality for stress imaging. Stress imaging is preferred over EST without imaging in several settings: (1) when the ECG is uninterpretable for myocardial ischemia; (2) when a patient is unable to adequately exercise (but can undergo a pharmacological stress imaging study); or (3) when a treadmill stress test is positive for ischemia in a low-risk patient, and correlation by imaging is preferred to cardiac catheterization. Individuals with an abnormal baseline ECG, particularly with ST-segment abnormalities, should be referred for a stress imaging study, because ECG changes in the setting of an abnormal baseline are far less specific for CAD. Patients with significant left ventricular hypertrophy on their baseline ECG or those taking digoxin have similar limitations for interpretation of ischemia with exercise. Stress imaging could be used as a primary modality, rather than ECG-only stress testing, in patients with an intermediate to high pretest likelihood of disease because of its higher sensitivity and specificity. Even with rapid advances in other modalities, stress imaging remains a highly effective and available modality to evaluate ischemia and function at present, and it is likely that this will be the case in coming years.
Myocardial Perfusion Imaging
Myocardial perfusion imaging (MPI) involves injection of a radiopharmaceutical that distributes throughout the myocardium in a manner dependent upon coronary blood flow. Images are obtained of the radiopharmaceutical distribution attained near peak stress and at rest. Changes in the distribution of the radiopharmaceutical can reflect comparable blood flow at rest and during stress, diminished blood flow with stress compared with rest (reflecting stress-induced ischemia), or diminished blood flow both with stress and at rest, which can be correlated with previous myocardial infarction (MI). Left ventricular function and ejection fraction (EF) and left ventricular size at rest and with stress can also be measured with this technique. The sensitivity of stress nuclear imaging for detection of hemodynamically significant CAD is 85% to 90%. The prognostic value of a negative stress nuclear imaging study is also excellent in otherwise low-risk to intermediate-risk patients.
Imaging can be done with SPECT or with PET. These systems offer different spatial resolution and use different tracers; however, the basic approach of stress perfusion and the functional images obtained are essentially the same.
Stress With Myocardial Perfusion Imaging
In stress with MPI, the radiopharmaceutical is injected when the patient is at the maximum level of coronary vasodilation, which occurs at peak exercise or pharmacological stress. Exercise stress is preferred for MPI because of the added prognostic information obtained from the hemodynamic response to exercise and functional tolerance. Exercise improves imaging characteristics of the tracers, leading to fewer artifacts and improved accuracy.
The same previously noted contraindications noted for EST apply to patients undergoing exercise MPI. Many of the limitations inherent in ECG-only exercise testing (e.g., left bundle branch block, pacing, atrial fibrillation, left ventricular hypertrophy, and baseline ST- and T-wave changes) can largely be overcome when using MPI. In general, the sensitivity and specificity of MPI for detection of CAD are better when coupled with exercise than when coupled with pharmacological stress. For this reason, if a patient is able to exercise, exercise MPI is preferred.
When patients are unable to exercise (due to poor functional capacity, orthopedic, or other factors) or have a significant left bundle branch block, MPI can be performed using pharmacological stress. Two general approaches are used in pharmacological stress testing: infusion with a coronary vasodilator or with dobutamine.
Dipyridamole, adenosine, and regadenoson are coronary vasodilators used in pharmacological stress MPI. Dipyridamole causes vasodilation by blocking endogenous adenosine breakdown and raising its levels. Adenosine can also be directly infused and is preferred in many centers over dipyridamole because it results in a more consistent serum adenosine level (and more consistent coronary vasodilatation) than does the infusion of dipyridamole. Adenosine infusion is associated with more symptoms than dipyridamole infusion, but these symptoms are short-lived because of its short half-life. Regadenoson acts more specifically on the coronary adenosine (A 2α ) receptors compared with the nonspecific vasodilation action of pure adenosine. Thus, it should have a lower risk of common side effects (e.g., bronchospasm, atrioventricular nodal blockade, and flushing), although these side effects can still be present.
Coronary vasodilators work by increasing blood flow except in areas where hemodynamically significant stenoses are present, precluding vasodilator-induced increased flow. A relative decrease in the intensity of the MPI signal indicates an inability to increase flow to that area of the myocardium, and therefore, the presence of flow-limiting CAD in the coronary artery supplying that area can be deduced.
The use of vasodilators is contraindicated in patients with active bronchospastic disease, and in those with advanced heart block or sick sinus syndrome without a pacemaker. In addition, patients taking aminophylline or theophylline must discontinue the use of these drugs before vasodilator pharmacological stress testing, because these drugs counteract the effects of these vasodilators. Similarly, caffeine intake within the previous 12 hours also blocks the effects of vasodilators. Regadenoson is associated with a lower seizure threshold and is often avoided in patients with a history of seizures. Some also avoid its use in end-stage renal disease. If a patient receiving vasodilators does have either bronchospasm or another side effect with drug infusion, these side effects can be mitigated by infusion of aminophylline or theophylline. It is rare that reversal of the effects of adenosine is required because of its short half-life.
If patients are able to perform submaximal exercise, a combination of a vasodilator with exercise can be performed. This protocol has the advantages of decreasing side effects and improving image quality by decreasing splanchnic tracer accumulation. Vasodilator-exercise protocols allow limited exercising of patients who are not able to attain target HRs. However, patients with contraindications to either exercise or vasodilators (see the preceding text) should not be considered for a combined stress study. In addition, vasodilator EST should not be performed in patients with a history of cerebrovascular and/or carotid disease, especially if walking is the exercise mode. Rapid loss of consciousness and collapse on the treadmill have been reported, due to cerebrovascular perfusion steal, which results from pharmacological vasodilation coupled with exercise ( Fig. 10.3 ).
If patients are unable to exercise and also have contraindications to vasodilator stress, dobutamine pharmacological stress can be performed. Dobutamine is more often used for stress echocardiography than for stress MPI, and is similar to exercise in that it increases HR and myocardial contraction. It is administered as an incrementally increasing infusion rate until either the MPHR of the patient or the infusion rate is reached. Atropine can be used for HR augmentation if the target HR is still not reached with maximal dobutamine doses. Stress targets are similar to those for exercise, but it is important to note that because systolic blood pressure can remain constant or fall with dobutamine, whereas it rises with exercise, the double product (and thus, level of stress) associated with a given HR is less during dobutamine testing than with exercise testing. Some clinical variables, such as fatigue, which is useful in EST, are generally not useful with dobutamine administration.
The major contraindications to dobutamine and/or atropine stress MPI are the same as for EST, but also include the presence of narrow-angle glaucoma, and a history of prostatic enlargement and urinary obstruction. In addition, a relative contraindication to dobutamine and/or atropine stress MPI is a propensity for inducible arrhythmias.
Finally, less conventional stress methods such as cold pressor testing and mental stress are described in the literature. Mental stress testing is believed to induce a sympathoadrenal response that has similar effects on the coronary blood flow as the previously described methods, which induces the steal phenomenon and exposes perfusion defects. However, the exact mechanism is unknown. The mental stress test coupled with echocardiography may improve sensitivity of the test but not the specificity. Low sensitivity of the test can be due to inability to identify the stressors that may induce ischemia in a patient. Cold pressor testing is more often used when coronary vasospastic syndromes are suspected, and reduce blood flow to areas where such vasomotor dysfunction exists, thereby inducing ischemia.
An imaging protocol for acute chest pain involves administration of a radiopharmaceutical while the patient is having a chest pain syndrome. In a low-risk to intermediate-risk patient, a normal scan has a high negative predictive value for the absence of an acute coronary syndrome. This protocol has been used in emergency room settings in low-risk to intermediate-risk patients with otherwise undifferentiated chest pain and allows for safe discharge with outpatient follow-up.
Radiotracers
Thallium-201 ( 201 Tl) thallous chloride, a radioactive analogue of potassium, was the most commonly used tracer for myocardial perfusion for several decades. Although its use has declined with the advent of technetium-99m ( 99m Tc)–based agents, it is still sometimes used as part of dual-isotope protocols and in viability imaging. Its relatively low energy results in images that lack resolution, although it has a higher myocardial extraction fraction compared with 99m Tc-based agents. The two most commonly used 99m Tc-based MPI agents are 99m Tc-sestamibi (MIBI) and 99m Tc-tetrofosmin. Images obtained with the two agents are comparable and have a higher resolution than images obtained using 201 Tl for cardiac imaging. MIBI demonstrates a slightly higher extraction fraction than tetrofosmin, although it results in a slightly higher radiation dose to the patient compared with tetrofosmin. A previously used 99m Tc-based agent, teboroxime, demonstrated a substantially higher extraction fraction than the aforementioned agents, but its rapid washout from the myocardium limited its clinical usefulness. Teboroxime is no longer marketed in the United States.
The 99m Tc-agents are the most commonly used SPECT radiopharmaceuticals. Several imaging protocols using these agents have been developed. A commonly used protocol is the 1-day rest-stress, wherein a scan is performed following a low dosage tracer administration to the patient at rest. The second step in this protocol is to stress the patient (exercise or pharmacological stress), administering the resting dosage of the radiotracer at peak stress approximately three times, and then perform imaging again.
A variation of this protocol used in some nuclear laboratories for low-risk patients is the stress-rest study. In this case, stress images are obtained first. Resting images can be omitted if the stress images are completely normal, but can be performed on the same or subsequent day if needed. In the former, a lower dosage stress image is obtained followed by a higher dosage rest image. The disadvantage of this approach is that stress images are obtained at lower doses of radiotracer and thus may be of lower quality. A 2-day protocol administration of relatively high dosages of radiopharmaceutical is used for both rest and stress. This protocol allows for better image quality, especially in obese patients in whom high-quality images cannot otherwise be attained. The limitations of this study protocol are the higher radiation doses and the inconvenience of having the patient return on a subsequent day.
A dual-isotope protocol uses 201 Tl for the resting images followed by poststress images obtained with a 99m Tc-based tracer. However, differences in spatial resolution between 201 Tl and 99m Tc can sometimes complicate the interpretation of subtle findings. Imaging can also be performed using 201 Tl only. Because of the limitations of 201 Tl, the only feasible approach is to perform a stress-rest study. The entire study can be performed with a single injection of tracer, and one can obtain additional physiological and prognostic information (e.g., lung uptake) and an assessment of myocardial viability. However, these studies are not done frequently in most laboratories because they are associated with significantly higher radiation doses than those only using 99m Tc-agents, are more time-consuming, and provide lower resolution images.
PET radiopharmaceuticals use positron-emitting radionuclides to create images. Rubidium-82 ( 82 Rb) chloride is a positron-emitting potassium analogue. It has the lowest extraction fraction of the clinically available PET radiopharmaceuticals (~60%). This extraction fraction is still higher than that of either sestamibi or tetrofosmin. The half-life of 82 Rb is short (~75 seconds). There are benefits and limitations for the use of 82 Rb because of its short half-life. The short half-life essentially precludes use of 82 Rb for exercise stress imaging. However, it facilitates obtaining images when the patient is truly at the peak of performance induced by pharmacological stress. For this reason, 82 Rb images can be used to accurately assess cardiac reserve, which are defined as the difference between left ventricular EF at rest and at peak stress. The short half-life of 82 Rb also facilitates obtaining pharmacological stress and resting images in a relatively short period of time. 82 Rb has a lower intrinsic spatial resolution than the other PET agents but is still far better than the SPECT tracers. 82 Rb is produced by a generator system, but this is quite expensive; for this reason, it is only available at some centers.
Nitrogen-13 ( 13 N) ammonia has a high extraction fraction (~83%), higher imaging resolution than 82 Rb, and a 10-minute half-life. It can be used for exercise nuclear imaging. Oxygen-15 ([ 15 O]H 2 O) water is short-lived (half-life of 2 minutes) and possesses a high extraction fraction of approximately 95%. However, its freely diffusible nature means that 15 O is distributed into tissues adjacent to the myocardium, including the lungs and cardiac blood pool. For this reason, imaging is complicated, requiring sophisticated background subtraction techniques. Although both 13 N and 15 O have higher intrinsic spatial resolution than 82 Rb, they require generation in a cyclotron. Their short half-lives mean that these isotopes can only be used in facilities with an on-site cyclotron. For most institutions that perform PET myocardial imaging studies, 82 Rb is preferred for this logistic reason. Newer fluorine-18 ( 18 F)–labeled perfusion tracers that would allow exercise imaging and do not require an on-site cyclotron are being developed and studied. The 18 F tracers have a high extraction fraction and the highest imaging resolution, making them attractive for the assessment of CAD.
PET tracers use protocols based on SPECT imaging. Because of its exceedingly short half-life, 82 Rb protocols can be either rest-stress (more common) or stress-rest. An entire 82 Rb study can be completed within 30 minutes. An advantage of PET tracers is that despite higher γ-emission energies, their radiation doses are comparably lower while delivering better images than the SPECT tracers.
There is increasing interest in stress first protocols in both SPECT and PET modalities. This allows significant radiation and costs reduction, as well as shortens the overall procedure time for the patient. The approach is more feasible with newer technologies, such as iterative image processing, attenuation correction, and cardiac-specific cameras because they can help eliminate many imaging artifacts. These technologies are not specifically reimbursed, but may significantly increase the cost of the procedure to the laboratory, which is a barrier to wider adoption. Nevertheless, the imaging community has dedicated itself to overall radiation dose reduction in an era of rising concerns about radiation exposures from diagnostic testing and healthcare cost containment.
With the variety of techniques available, it is important to choose the optimal imaging modality (SPECT vs. SPECT-CT vs. PET), tracer, stress modality, and imaging protocol, tailoring each for the specific patient situation to maximize the information obtained. For example, the overall prognosis of a normal stress MPI study is better in patients who exercised than in those who were evaluated with a vasodilator study. Careful attention should be paid to understanding the meaning of the results in the context of the history of the patient and how the study was performed. The study design also has to be weighed against the technological abilities of the stress laboratory, throughput, procedure costs, and the radiation exposure of the patient.
Image Interpretation
SPECT nuclear images are analyzed in three ways. The “raw” rotating image interpretation is a critical step that allows the reader to assess whether patient motion, attenuation artifacts (breast overlap, diaphragmatic interference, or other factors) must be considered in interpretation of the study. Occasionally, the presence of significant extracardiac findings such as breast or lung masses, thyroid or parathyroid nodules, and lymphadenopathy is seen on these raw images. The second step is to examine reconstructed images that are presented as “slices” of the myocardium. Using this set of images, it is possible to visualize myocardial perfusion in multiple axes to assess flow-limiting CAD ( Fig. 10.4 and Table 10.1 ). The amount of ischemic or infarct burden can be quantified. By dividing the ventricle into segments (usually 17 or 20) and then deriving scores based on the extent and severity of segments affected by pathology, a quantitative assessment can be made that strongly correlates with patient outcomes. The summation of these data, the “sum score,” can be compared in the rest and stress studies. Third, gated images can also be obtained and reviewed in a looped-cine method. These images allow determination of wall motion abnormalities, ventricular volumes, and left ventricular EFs. Analysis of wall motion also provides an independent means to assess apparent perfusion defects and confirm infarction, ischemia, or the presence of an artifactual perfusion abnormality.
TABLE 10.1
Myocardial Perfusion Patterns
| Scan Finding | Interpretation |
|---|---|
| No perfusion defect on either stress or rest study | Normal |
| Perfusion defect at stress that is normal at rest | Ischemia |
| Perfusion defect both at stress and rest | Myocardial scar |
| Perfusion defect at rest but normal at stress | Probable artifact, consider subendocardial infarction (reverse redistribution) |
Comparison of images obtained at stress with images obtained at rest makes it possible to determine if there is a relative decrease in flow with stress. This reversible myocardial perfusion defect correlates with viable tissue in the distribution of a coronary artery with a significant stenosis and represents an ischemic territory. If a portion of the myocardium has limited perfusion at stress and at rest, this indicates that the myocardium with the nonreversible defect may represent an infarcted area.
Due to the higher isotope energies involved with PET imaging, its inherent attenuation correction, and the superior tracer characteristics of PET radiopharmaceuticals compared with the current 99m Tc-based SPECT agents, PET images are of far superior quality and usefulness in the diagnosis of CAD in both obese and general patients. The approach to interpretation of PET imaging is similar to that described previously for SPECT imaging. Reconstructed perfusion and gated images are approached the same way, but no raw images are displayed because of the manner in which PET images are acquired. An important step to consider in PET is the alignment of the emission and transmission (the latter being CT in PET-CT or MR in PET-MR units) scans. By default, PET has an attenuation correction built in for the reconstruction of its final images. A misalignment between the two portions of the scan can result in serious artifacts, which can be misread if not recognized and/or corrected. Although this can be frequently corrected by manual realignment of the images, occasionally, the relevant scan has to be repeated to obtain the correct data.
PET imaging also makes absolute quantification of myocardial blood flow and coronary flow reserve possible, which is useful for detection of endothelial dysfunction, and assessment of multivessel ischemia that might otherwise appear as normal stress imaging if ischemia is global and balanced.
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