INTRODUCTION

In the United States alone, more than 7.7 million patients are referred yearly for diagnostic cardiac stress testing with radionuclide imaging. Although patients may require pharmacologic stress testing because they are unable to perform adequate physical exercise, dynamic exercise on treadmill or bicycle remains the preferred stress modality. In our nuclear stress laboratory, the percentage of myocardial perfusion studies performed with exercise has remained approximately 50% since 2004. Exercise variables, including maximal workload, duration, hemodynamic response, exercise-induced symptoms, and electrocardiographic (ECG) changes provide invaluable additional information for assessing a patient’s prognosis that are not available with pharmacologic stress. The Duke exercise treadmill score incorporates some of these important exercise variables and allows for risk stratification.¹ However, because of the inherent diagnostic limitations of the exercise ECG and subjective symptoms, patients stratified by the Duke Treadmill Score can be further stratified on the basis of (semi)quantitative stress radionuclide myocardial perfusion imaging (MPI).²

PHYSIOLOGY OF EXERCISE STRESS TESTING

Dynamic exercise increases the metabolic demand of the exercising skeletal muscle which can be met only by increasing the blood flow to the exercising muscle. Under conditions of maximal exertion, the cardiac output may increase more than fourfold to meet this need.³ As shown in Figure 14-1, at low levels of exercise, the increase in cardiac output is due to an increase in both stroke volume and heart rate. However, as the intensity of exercise increases, the contribution of the stroke volume to cardiac output reaches a plateau, and the augmentation of cardiac output becomes primarily dependent on the ability to increase the heart rate further. Of note, the inability to appropriately increase the heart rate in response to exercise predicts severity of coronary artery disease (CAD) and mortality.^4,5 The increase in cardiac output results in a greater myocardial metabolic demand, inducing coronary vasodilation. A recent positron emission tomography (PET) study in human subjects quantifying the change in myocardial perfusion with exercise demonstrated that myocardial blood flow can increase more than fourfold to meet the metabolic demands of the heart during exercise.⁶

Figure 14-1 Hemodynamic and metabolic responses to exercise. A, During low levels of exercise, the increase in cardiac output is due to increases in both heart rate and stroke volume. However, as the exercise increases, stroke volume cannot increase further, and the augmentation of cardiac output is due to continued increases in heart rate. These changes are related to increased sympathetic drive as well as withdrawal of parasympathetic stimulation to the heart. B, Under resting, fasted conditions, fatty acid oxidation is the predominant fuel source for the body. However, with increasing levels of exercise, glucose oxidation plays an increasingly important role in meeting the energy demands of the exercising skeletal muscle. At the point of exhaustion, anaerobic glycolysis and glucose oxidation are required to meet the energy demands.

The above-mentioned hemodynamic changes occur through both neurohormonal and metabolic mechanisms. With the onset of exercise, heart rate and stroke volume both increase through sympathetic activation and parasympathetic withdrawal. During exercise there are several peripheral effects that augment the effects provided by the central sympathetic activation. These include α-adrenergic stimulation of the venous capacitance vessels, resulting in venoconstriction and enhanced venous return, which will increase preload and cardiac inotropy. In addition, skeletal muscle production of lactic acid and adenosine during exercise causes dilation of the arteriolar resistance vessels, reducing the systemic vascular resistance and thereby increasing cardiac output and blood flow to the exercising skeletal muscle.

Metabolic changes occur in association with these hemodynamic adaptations. Specifically, in exercising skeletal muscles, there is a decreasing dependence on fatty acid oxidation and an increasing dependence on glucose oxidation to meet the energy needs until maximum oxygen consumption is achieved. At that point, glucose is the exclusive oxidative substrate. Further increases in the level of exercise above the anaerobic threshold cause the release of lactate from exercising skeletal muscle. Interestingly and in contrast, with increasing exercise, the myocardium continues to oxidize both fatty acids and glucose and also increases the utilization of lactate produced by the exercising skeletal muscle for energy (see Fig. 14-1).

The intensity of exercise can continue to increase until the point at which the heart cannot meet the metabolic demands of the exercising muscles (i.e., blood flow to muscles can no longer provide adequate amounts of substrate or remove metabolic byproducts). In the case of a healthy individual, this is generally at the level of the exercising skeletal muscle. However, in the case of an individual with critical coronary artery stenoses, the inability to exercise can be due to the limited ability to provide adequate blood flow to the heart muscle. It is in this latter scenario that myocardial ischemia is manifested and provides the rationale for exercise stress testing.

EXERCISE PROTOCOLS

In the United States, most exercise tests are performed using a motorized treadmill and graded Bruce, modified Bruce, or Naughton protocols. In many other countries, the upright bicycle is the preferred exercise equipment. An important aspect of diagnostic exercise protocols is the gradual, linear increase in workload from a very low level to the maximally tolerated workload. This gradual increase in workload is of importance, since the purpose of physical exercise testing is to reproduce symptoms, and one can generally not predict at which workload symptoms will occur. It is therefore important to also evaluate the patient carefully prior to starting a stress test to determine if the patient is appropriate for exercise stress testing (Table 14-1). Exercise protocols are generally terminated because of the onset of symptoms or fatigue, but they may also be terminated because of the development of significant ECG changes or because the patient becomes hypotensive or develops pulmonary edema. Termination of exercise solely because the predicted target heart rate (85% of age-predicted max) was achieved is a commonly made mistake. Many elderly patients, for example, are capable of achieving a considerably higher heart rate and workload at which symptoms may be unmasked.

Table 14-1 Contraindications to Exercise Stress Testing

PREPARATION FOR EXERCISE

As mentioned, the purpose of exercise testing is to provoke and to reproduce ischemic symptoms during maximal physical effort. The patient should be well informed about the details of the procedure and be motivated to give his/her best effort. Cardioactive medications, such as β-blockers, calcium blockers, or nitrates, may diminish the sensitivity of testing. Therefore, if the exercise test is performed specifically to diagnose CAD in a patient with no prior cardiac history, such medications should be stopped for at least 24 hours and in the case of long-acting medications, 48 hours before the day of testing. On the other hand, in patients with known CAD, a physician may be more interested in the results of testing with the patient on his/her routine medication, which will provide insight into the effectiveness of treatment.

Patients should be instructed to wear comfortable clothing and shoes and be in a fasted state on the morning of the exercise test. Moreover, it is prudent to instruct all patients scheduled for stress testing not to consume any caffeine-containing beverages or food on the morning of testing. The reason for this is that it is not uncommon that a patient is not able to perform adequate exercise. If the patient has not consumed caffeine-containing items, it is easy to switch to pharmacologic stress and ensure a diagnostic test result without having to reschedule the patient. On the other hand, a recent study suggested that a small amount of caffeine does not significantly affect the presence and magnitude of perfusion abnormalities. Although it appears prudent to continue to recommend that patients abstain from caffeine usage prior to the test, consumption of a single cup of coffee may not be a valid reason for cancellation of a vasodilator stress test.⁷

BASIS OF STRESS IMAGING

The conceptual underpinning of radionuclide imaging is the visualization of heterogeneity of regional myocardial blood flow secondary to impaired regional coronary flow reserve downstream of coronary arteries with significant obstructive disease (Fig. 14-2).

Figure 14-2 Schematic representation of the principle of rest/stress myocardial perfusion imaging. Top: Two branches of a coronary artery are schematically shown; the left branch is normal, and the right branch has a significant stenosis. Middle: Rest and stress myocardial perfusion images of the territories supplied by the two branches. Bottom: Schematic representation of coronary blood flow in the coronary branches at rest and during stress. At rest, myocardial blood flow is similar in both coronary artery branches. Coronary blood flow in the abnormal vascular bed was maintained through autoregulatory mechanisms that lower vascular resistance (r) distal of a significant stenosis. When a myocardial perfusion imaging agent is injected at rest, myocardial uptake therefore will be homogenous (normal image on the left). During stress, peripheral vascular resistance (R) decreases in the normal bed (r), resulting in a 2 to 2.5-fold increase of blood flow over baseline. In the abnormal bed, distal from the stenosis, peripheral vascular resistance (r) cannot decrease much further. This creates heterogeneity of regional myocardial blood flow that can be visualized with thallium-201- or technetium-99m-labeled agents as an area with relatively decreased radiotracer uptake (darker left area on stress image).

(Modified from Wackers FJ: Exercise myocardial perfusion imaging, J Nucl Med 35:726–729, 1994.)

In order to visualize such heterogeneity of blood flow reliably, a linear relationship must exist between regional myocardial blood flow and regional myocardial uptake of a radiotracer.⁸ Although in general this is true for relatively low flow ranges (up to 1 mL/min/g), as is present under resting conditions and resting myocardial ischemia, at the higher flow ranges (>2 mL/min/g) achieved during stress, especially during vasodilator stress, regional myocardial radiotracer uptake may no longer be linear. At higher rates of blood flow, the uptake of many radiotracers presently used in clinical imaging demonstrates a plateau (Fig. 14-3) known as the roll-off phenomenon.

Figure 14-3 Relationship between coronary blood flow and radiotracer uptake. An ideal flow imaging agent would be plotted on the line of identity. All commonly used radiotracers deviate below the line of identity and show a plateau (“roll-off”) at higher blood flow levels. Typical ranges of coronary blood flow during physical exercise (EX) and pharmacologic vasodilation (Pharm) are shown. As shown on the graph, the roll-off is the least for thallium-201 and more for technetium-99m sestamibi and ^99mTc tetrofosmin.

The suboptimal linearity at higher flow ranges is caused by the limited first-pass extraction fraction of many single-photon radiopharmaceuticals used for MPI. Table 14-2 shows the myocardial extraction fractions of commonly used radiotracers. In addition to myocardial extraction fraction, mechanisms involved in the transmembrane transport and myocardial washout and wash-in affect net myocardial uptake of radiopharmaceuticals. Fortunately this roll-off phenomenon does not significantly affect the ability to identify patients with high-degree (>70%) coronary stenoses. However, in patients with relatively mild CAD, the roll-off phenomenon may potentially result in falsely normal images (Fig. 14-4).

Table 14-2 First-Pass Myocardial Extraction Fraction of Various Radiopharmaceuticals

Figure 14-4 Effect of radiotracer “roll-off” on myocardial perfusion images. In the graph, regional myocardial uptake of a radiotracer uptake is plotted against regional coronary blood flow. The radiotracer shows significant roll-off at flows exceeding 2.5 mL/min/g. In the relative low flow range, because of good linearity of uptake, a myocardial region with 0.75 mL/min/g has significantly less radiotracer uptake than a region with1.5 mL/min/g, resulting in an abnormal image with defect (left image). However, at higher flow ranges, a similar 0.75 mL/min/g flow difference may result in no significant difference in myocardial radiotracer uptake and in a normal image without perfusion defect (right image).

Thallium (²⁰¹Tl), a potassium analog, has a relatively high initial extraction fraction and good linearity to flow. After intravenous administration, continuous washout and wash-in occurs in the myocardium, resulting in Tl-201 myocardial redistribution. Technetium (^99mTc)-labeled agents, such as sestamibi and tetrofosmin, are lipophilic compounds that have lower first-pass extraction fractions than ²⁰¹Tl and bind to mitochondrial membranes in a stable manner based on the mitochondrial membrane potential, and demonstrate minimal washout. Consequently the ultimate net retention of ²⁰¹Tl-labeled and ^99mTc-labeled agents in the myocardium is similar.⁹

INJECTION OF RADIOTRACER

The timing of injection of radiotracer relative to peak exercise and termination of exercise is an important and often not well-appreciated aspect of stress testing. Because the first-pass extraction of the radiotracers is not 100%, myocardial uptake of a radiotracer is not instantaneous at the moment of injection. After injection during stress, the injected bolus reaches the central circulation in about 10 to 15 seconds, and first-pass myocardial extraction takes place. After the initial first transit, recirculation occurs with a rapidly decreasing blood concentration of radiotracer. On average, it takes about 1.5 to 2 minutes for blood radioactivity to decrease to 50% of maximum (Fig. 14-5). This may differ among patients, depending on the level of exercise effort. Furthermore, blood clearance curves are different for various radiotracers (e.g., slightly faster for ^99mTc-labeled agents than for ²⁰¹Tl). The timing of radioisotope injection is based on the fact that it is important to have most of the dose accumulate in the myocardium under conditions in which the heterogeneity of blood flow is maximal, that is, at peak exercise. Termination of exercise at about 1 minute after injection, as is frequently done in clinical practice, may be too early. A substantial amount of radiotracer may still be recirculating at that time. Therefore, it is advisable to encourage patients to continue exercising for at least 2 minutes after injection of radiotracer.

Figure 14-5 Blood clearance of radiotracer. Arterial blood disappearance curve of technetium-99m-sestamibi after injection at peak exercise or pharmacologic vasodilation with dipyridamole. Peak blood pool activity occurs at 0.5 minute for both exercise and pharmacologic testing. At 1.5 minutes after injection, the blood pool activity is 50% of maximum for exercise stress testing. The decrease in blood pool activity is relatively quicker for pharmacologic stress testing.

(From Sand NP, Juelsgaard P, Rasmussen K, et al.: Arterial concentration of ^99mTc-sestamibi at rest, during peak exercise and after dipyridamole infusion. Clin Physiol Funct Imaging 24:394–397, 2004.)

IMAGING PROTOCOLS

Reliable interpretation of stress myocardial perfusion images depends for a large part on optimal quality images. Consistently good quality can be ensured by following image acquisition guidelines published by the American Society of Nuclear Cardiology.¹⁰

Two important variables affect quality of images: the amount of radiotracer injected and imaging time. The injected dose can be adjusted to a patient’s weight, keeping in mind the balance between the image quality and radiation exposure. Imaging time, or time per stop per projection, can also be adjusted to the dose and the patient’s weight. One way to anticipate suboptimal image quality is to record the count rate emanating from a patient’s chest before setting image acquisition parameters. If the count rate is less than that usually recorded for good-quality studies, the time per stop should be lengthened.

At present, four image-acquisition protocols are most commonly used: the 1-day or 2-day rest-exercise ^99mTc-agent imaging protocol, the exercise-redistribution Tl-201 imaging protocol, and the rest/exercise dual-isotope imaging protocol. Numerous studies have shown that each of these protocols yields equivalent clinical results for detection of CAD and for risk stratification. If many patients referred to an imaging facility are overweight (body mass index > 30 kg/m²), ^99mTc-labeled agents and 2-day imaging protocols may be preferred. The most frequently used imaging protocols for ²⁰¹Tl and ^99mTc-labeled agents are schematically shown in Figure 14-6A-D. Technical details of imaging are tabulated in Table 14-3.

Figure 14-6 Commonly used rest/exercise (EX) SPECT imaging protocols. A, Two-day imaging protocol used for ^99mTc-based radiotracer stress/rest imaging, typically used in obese patients. B, One-day imaging used for Tc-99m-based radiotracer stress/rest imaging, typically used in nonobese patients. C, One-day, stress-redistribution imaging protocol used for thallium-201 imaging. D, One-day, dual-isotope imaging protocol. Time intervals and total protocol times are shown.

Table 14-3 Summary of Typical Acquisition Parameters for SPECT Myocardial Perfusion Imaging with ²⁰¹Tl and ^99mTc-Labeled Imaging Agents

Increasing attention is being paid to the radiation exposure associated with imaging procedures, including myocardial perfusion studies. The exposure and the biological effect of radiation, generally assessed in terms of the effective dose, is dependent not only on the absolute amount of radioactivity that is injected but also the quality of the radiation that is emitted, which is the same for the gamma-photon emitting radionuclides used in single-photon emission computed tomography (SPECT) MPI, the half-life of the agent, and the sensitivities of specific organs to the radiation. Based on these factors, the lowest effective dose is achieved with ^99mTc-labeled agents used in a 1-day stress/rest protocol, whereas the highest effective dose is achieved with a dual-isotope protocol (Table 14-4).¹¹ In patients with low to intermediate pretest likelihood of CAD, normal exercise parameters, and normal MPI, it may be possible to perform only stress imaging, thereby reducing the radiation exposure.

Table 14-4 Estimated Effective Doses for Various Myocardial Perfusion Imaging Protocols

DIAGNOSTIC VALUE OF EXERCISE SPECT IMAGING

Since the introduction of stress radionuclide MPI in the mid-1970s, numerous clinical studies have demonstrated the clinical usefulness for detection of CAD. The main objective of exercise SPECT imaging in present-day clinical practice is still predominantly to elucidate whether symptoms suggestive of CAD, such as chest discomfort or dyspnea on exertion, are caused by CAD or whether other etiologies should be pursued. Management decisions may then be guided by extensive published evidence that certain image patterns have important prognostic significance.

Because of the proven prognostic value of stress MPI, it is unlikely that angiographic correlation and sensitivity and specificity will continue to be assessed in large numbers of patients using state-of-the-art technology, other than for local quality assurance purposes or to evaluate new technical advances such as attenuation-correction devices. The sensitivity, specificity, and normalcy values for exercise SPECT MPI have been evaluated in multiple studies and confirm the diagnostic power of this modality.^12–24 Based on a meta-analysis of 79 studies that included a total of 8964 patients, the sensitivity, specificity, and normalcy rate of SPECT MPI are 86%, 74%, and 89%, respectively.^25,26 Figure 14-7 shows representative data for the diagnostic yield for identifying disease in individual coronary arteries.²⁷ Sensitivity for recognizing disease in the left anterior descending coronary artery is higher than that for disease in the right coronary artery or left circumflex coronary artery, with no significant difference in accuracy. The relatively low specificity of SPECT imaging suggests that artifacts due to attenuation and motion are not always recognized. Referral bias has been proposed as another potential explanation for the limited specificity of SPECT imaging.

Figure 14-7 Detection of coronary artery disease in individual coronary arteries. The sensitivity (Sens), specificity (Spec), and accuracy (Acc) for detecting ≥ 50% stenosis in the left anterior descending coronary artery (LAD), right coronary artery (RCA), and left circumflex coronary artery (LCx) are shown.

(Reproduced with permission from Elhendy A, Sozzi FB, van Domburg RT, et al: Accuracy of exercise stress technetium-99m sestamibi SPECT imaging in the evaluation of the extent and location of coronary artery disease in patients with an earlier myocardial infarction, J Nucl Cardiol 7:432–438, 2000.)

Through the years, it has also become clear that complete agreement with coronary angiography is an elusive goal, because stress perfusion imaging and coronary angiography evaluate two different aspects of CAD. Whereas contrast coronary angiography visualizes coronary anatomy and the presence or absence of regional coronary luminal narrowings, radionuclide stress MPI provides noninvasive information about the pathophysiologic consequences of coronary atherosclerosis. Specifically, patients with apparently significant angiographic CAD but normal exercise myocardial perfusion images nevertheless have a favorable prognosis.²⁸ In contrast, patients with relatively mild angiographic CAD but markedly abnormal SPECT images have a less favorable outcome. One study²⁹ demonstrated that in patients with apparently “false-positive” ²⁰¹Tl images and “normal” epicardial coronary arteries, coronary blood flow response to acetylcholine infusion was blunted, indicating endothelial dysfunction (Fig. 14-8). This suggests that “false-positive” images probably were true positives. A better measure of the true specificity of stress MPI is the assessment of normalcy rate in subjects with low (<3%) likelihood of CAD. In our own laboratory, the normalcy rate of ^99mTc sestamibi SPECT was 99% using quantitative analysis of exercise myocardial perfusion SPECT images acquired in 40 normal subjects.

Figure 14-8 Impaired endothelium-dependent vasodilation in abnormal exercise SPECT. Coronary blood flow response to increasing doses of acetylcholine (AC) and to papaverine (PAPA) in patients with normal or minimally diseased (<30% luminal narrowing) epicardial coronary arteries and abnormal (n = 13) or normal (n = 14) exercise SPECT thallium-201 (²⁰¹Tl) imaging. Patients with abnormal ²⁰¹Tl SPECT showed blunted response to endothelial-dependent vasodilation with AC compared to those with normal ²⁰¹Tl SPECT.

(Modified from Zeiher AM, Krause T, Schachinger V, et al: Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 91:2345–2352, 1995.)

ECG-GATED SPECT

Evaluating the left ventricular ejection fraction (LVEF) is important in any cardiac patient. Currently, more than 80% of all SPECT studies are acquired with ECG gating. Gated SPECT provides a means of assessing postexercise resting LVEF, as well as regional wall motion and wall thickening. The routine assessment of LVEF by ECG-gated SPECT has added an important dimension to the overall assessment of patients referred for exercise testing and MPI.³⁰ Although the appearance of motion and the change in count density on cine display of ECG-gated SPECT myocardial perfusion studies is in fact artifactual and caused by improved count recovery during the cardiac cycle due to diminishing partial volume effect, a linear relationship exists with myocardial thickening.³¹

Assessment of LVEF, either normal or abnormal, in a patient with exercise-induced ischemia has important clinical and management consequences.^32,33 Furthermore, it is not rare that a patient is diagnosed as having a previously unknown cardiomyopathy on the basis of the information from a gated SPECT. In some patients, postexercise LVEF may be significantly lower than LVEF on rest SPECT imaging.³⁴ This may indicate postexercise ischemic stunning, which is a marker signifying severe CAD, although the specificity of this finding reflecting stunning may be limited in the setting of a large reversible defect.³⁵

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