Richard C. Brunken and Santosh Oommen
Nuclear cardiac imaging has become an integral component of the clinical practice of cardiology over the last several decades. Myocardial perfusion imaging (MPI) facilitates the detection of coronary artery disease (CAD), permits assessment of the physiologic effects of equivocal coronary artery stenoses, and assists in the identification of patients who are likely to benefit from coronary revascularization. In individuals with known or suspected CAD, MPI provides incremental prognostic information beyond that afforded by stress electrocardiography alone and can be used for individual risk stratification for future cardiac events. The fundamentals of nuclear cardiac imaging and image interpretation are discussed in Chapter 10. This chapter focuses primarily on the clinical utility of MPI for patients with suspected or established CAD and how the information derived from these nuclear imaging studies can be used to assist in the care of the patient. The contribution of nuclear imaging to the management of patients with congestive heart failure (CHF) is also briefly discussed.
MYOCARDIAL PERFUSION IMAGING
Principles of Cardiac Nuclear Stress Testing
The usual goal of MPI is to compare the pattern of tissue perfusion in the resting state to that under stress conditions, in order to detect flow-limiting coronary artery stenoses. To understand how MPI is used for this purpose, it is helpful to recall certain aspects of cardiovascular physiology. In the basal resting state, oxygen extraction from myocardial capillary blood approaches 70% and is near maximal. Thus, there is little capacity to augment tissue oxygen delivery by increasing the myocardial extraction of oxygen from the blood when the ventricular workload increases. As a result, increases in the left ventricular workload must be accompanied by nearly proportional increases in myocardial perfusion, in order to meet the oxygen demands of the tissue. Healthy coronary vessels have flow reserves between three and six, meaning that they can increase blood flows about three to six times above rest values during periods of stress.1
In most patients with CAD, autoregulatory changes in arteriolar vascular resistance are capable of maintaining normal tissue perfusion in the resting state. The left ventricular workload is low in the resting state, and the coronary circulation is usually capable of meeting basal myocardial oxygen demands. Thus, images of rest myocardial perfusion are typically normal in patients with CAD who have not had a prior infarction or an acute ischemic event. To detect an obstructive coronary stenosis, it is frequently necessary to use maneuvers that increase tissue perfusion, in order to distinguish between vessels with and without an impaired coronary flow reserve.
Detection of Coronary Stenoses
In an artery with an atherosclerotic lesion, coronary flow reserve decreases nonlinearly as the luminal narrowing increases. The ability of the coronary vessel to increase tissue perfusion during periods of stress becomes increasingly and progressively limited as the luminal stenosis becomes more pronounced.1 During stress, perfusion in myocardium supplied by a coronary vessel with a limited flow reserve will be less than that in regions subtended by healthy arteries. Measurements of stress perfusion in affected areas (in milliliters of blood flow per minute per gram of tissue) typically will exceed resting values but remain less than the values in normal myocardium. Stenoses of 50% to 60% luminal cross- sectional area or greater are usually of sufficient magnitude to impair coronary flow reserve. However, other factors, such as the presence or absence of nonlaminar flow in the vessel, the presence or absence of collateral vessels, the presence of several stenoses in series, stenosis length, eccentricity of the lumen, absolute luminal cross-sectional area, heart rate, and the pressure gradient across the stenosis, may influence the physiologic effects of a coronary stenosis on tissue perfusion.
Images depicting myocardial perfusion during stress conditions show a reduction in the relative tracer concentration, or a stress perfusion defect, in the vascular territories supplied by the arteries with flow-limiting stenoses. The hallmark of stress-induced ischemia is a reversible perfusion defect, one that is present on stress perfusion images but absent on rest perfusion images. In studies in which measurements of coronary flow reserve made with intracoronary Doppler catheters have been compared to single photon emission computed tomography (SPECT) myocardial perfusion images, a strong correlation has been noted between stenosis flow reserves <2.0 and the presence of a reversible perfusion defect. Similarly, noninvasive measurements of myocardial perfusion reserve obtained with positron emission tomography (PET) in patients with CAD suggest that reversible SPECT defects are usually associated with perfusion reserves of 1.8 or less. In general, the more severe the luminal stenosis, the greater is the likelihood that it will be associated with a stress perfusion defect.
The anatomic extent of the stress perfusion defect and the magnitude of the reduction in the relative tracer activity within the defect provide objective information about the effects of a coronary stenosis on tissue perfusion during conditions of high oxygen demand. Commercially available computer programs can be used to compare the count data from a specific patient’s images to those of a normal sexmatched population, to assist in the identification and quantification of myocardial perfusion defects (see Chapter 11). The relative tracer activity concentration within the stress defect provides an indication of the severity of the ischemia. Defect extent, or the amount of the left ventricle that is affected by the perfusion abnormality, can be expressed as the number of myocardial segments with an abnormal tracer concentration, or as the proportion (percent) of all myocardial voxels that have an abnormal tracer concentration. A proximal stenosis in a major epicardial artery will generally produce a stress defect that is larger and more readily detected than one resulting from a stenosis in a distal vessel or a smaller branch artery. The anatomic location of the perfusion defect can be used to infer which of the three major coronary vessels is (are) diseased (see Chapter 11). It may also be possible to deduce whether the stenosis is proximal, mid, or distal, based on the location and anatomic extent of the defect on the stress perfusion images.
Assessment of Relative versus Absolute Myocardial Perfusion
The SPECT or PET myocardial perfusion images used in routine clinical practice for CAD detection depict relative tissue perfusion. It is assumed that at least one area of the visualized myocardium is supplied by a vessel with a normal or near-normal coronary flow reserve. However, in some patients with multivessel CAD, there may be “balanced ischemia," a situation in which the coronary flow reserve of each of the three major coronary arteries is equally or nearly equally impaired. In balanced ischemia, the pattern of perfusion on the stress images appears relatively homogenous. A regional perfusion defect is not identified because me stress defect involves essentially all of the visualized left ventricular myocardium. This has stimulated additional clinical interest in the use of measurements of absolute myocardial blood perfusion (in milliliters of blood flow per minute per gram of tissue) and perfusion reserves from dynamic PET perfusion images. Computer programs used to calculate PET measurements of absolutemyocardial perfusion and perfusion reserve are now “user friendly” and are commercially available for routine clinical use. If a patient’s perfusion reserve measurements are abnormally low, this may result either from balanced ischemia from multivessel stenosis or from global microvascular dysfunction. The prevalence of balanced ischemia in CAD patients due to multivessel stenosis is not well defined and is likely to depend on each nuclear laboratory’s specific referral pattern. In large cardiac referral centers, the prevalence of balanced ischemia is probably <5% of patients referred for nuclear stress testing, and it may be smaller in an office-based practice. Other observations from the stress test itself and either SPECT or PET perfusion imaging can alert the nuclear cardiologist to the possibility of balanced ischemia. These include the onset of anginal symptoms with stress, a significant drop in systolic blood pressure with exercise, electrocardiographic ST-segment changes in response to stress, and acute ventricular dilatation and/or new systolic dysfunction on the gated stress perfusion images. When incorporating the results of a SPECT or PET perfusion imaging study into the management of the patient, the possibility of balanced ischemia should be considered—especially if there are other clinical observations that suggest this possibility—and further diagnostic testing should be pursued accordingly.
Resting Perfusion Defects
Perfusion defects on images acquired in the resting state may arise in several different situations. When a coronary stenosis is very severe (>90% to 95% area stenosis) or there is an unstable lesion with intermittent dynamic obstruction of the lumen, a defect can sometimes be identified on resting perfusion images. In this situation, the diseased vessel may be incapable of maintaining perfusion commensurate with the tissue’s oxygen demands. A second set of perfusion images acquired at a later time may show redistribution, or “fill in” of the resting perfusion defect, as the tissue tracer concentration in this area equilibrates with that in adjacent normal myocardium. Sometimes, a supplemental dose of the perfusion tracer may be given prior to obtaining the late set of images, to assist in the “fill in" of the defect. The clinical implication of the filling in of a resting perfusion defect on redistribution or reinjection perfusion images is that the tissue is viable, and supplied by a vessel with a severe coronary stenosis.
A resting perfusion defect that persists on redistribution or reinjection images sometimes indicates a myocardial scar. In a scar, there is replacement of cardiac myocytes by relatively avascular fibrous tissue. Residual tissue perfusion in the segment with the scar is lower than in normal myocardium, resulting in a reduction in the relative tracer concentration on both the resting and redistribution/reinjection perfusion images. Because of the limited spatial resolution of current gamma cameras and PET tomographs, reductions in perfusion due to a nontransmural scar will be averaged over the minimum resolvable volume of the instrument (the partial volume effect). Thus, it is not possible to attribute an observed reduction in myocardial tracer activity to a scar specifically in the subendocardial, midmyocardial, or epicardial portion of the ventricular wall, as counts will be averaged over the entire thickness of the tissue. In studies of subjects with clinical myocardial infarction (MI), the extent and severity of persistent resting perfusion defects have generally paralleled the loss of viable myocytes, as measured by the size of the leak of cardiac enzymes or by the amount of tissue fibrosis on ventricular specimens.2
If a resting perfusion defect persists on redistribution or reinjection images, an alternative diagnostic possibility is myocardial hibernation, a state in which there is a sustained downregulation of tissue perfusion, metabolism, and function. Although the mechanism by which human myocardium enters into a state of “hibernation” is not well defined, accumulating evidence suggests that multiple repetitive episodes of ischemia (repetitive stunning) may eventually result in myocardial hibernation.3 Histopathologic studies of hibernating myocardium have identified structural and ultrastructural alterations in the tissue. These include a loss of myofibrillar protein, myocyte hypertrophy, accumulation of glycogen within the cytosol of the cardiac myocyte, and alterations in myocyte mitochondrial size and appearance. Modest increases in tissue collagen content have also been reported. As the name suggests, the clinical implication of hibernating myocardium is that the dysfunctional tissue is viable, and that it can be “awakened" by restoration of blood flow and benefit functionally by coronary revascularization.
In both hibernating tissue and myocardial scar, there is a persistent reduction in tissue perfusion. Because there is little or no capacity to increase tissue perfusion with stress in either situation, reductions in relative tracer concentration on resting perfusion images will also be present on stress perfusion images, and therefore appear as a fixed perfusion defect. Myocardial scar and hibernating tissue both exhibit systolic dysfunction, and may be indistinguishable from each other on conventional gated myocardial perfusion scintigraphy. Additional imaging studies are frequently needed in order to distinguish between hibernating (viable) tissue and myocardial scar. Low-dose dobutamine echocardiography, contrast magnetic resonance imaging, and glucose metabolic imaging with PET (below) are some of the methods that have been used to distinguish myocardial hibernation from scar.4
Stress Options for Myocardial Perfusion Imaging
Exercise is generally the preferred stress modality because it permits the simultaneous assessment of other parameters oi clinical interest including patient symptoms, functional capacity, vital signs, and the rate–pressure product as an indirect index of myocardial oxygen consumption. Graded exercise is most commonly performed on a treadmill, using one of several standard stress protocols (see Chapter 23). In order to optimize the examination for the detection of coronary stenoses, it is important to increase the ventricular workload high enough to elicit a significant increase in myocardial perfusion. In clinical practice, the usual goal is for the patient to achieve at least 85% of the maximum predicted heart rate (MPHR) for age. The radioactive perfusion tracer is administered intravenously about 1 to 2 minutes prior to the end of stress, to allow a long enough period of time for myocardial uptake of the imaging agent prior to the termination of exercise. SPECT is the most common imaging modality employed if a patient is undergoing exercise stress MPI, as the technetium and thallium tracers have a half-life long enough to be compatible with exercise testing protocols, as opposed to the 75-second half-life of rubidium-82, the tracer most commonly used in PET cardiac imaging. However, if the testing facility has an on-site cyclotron, nitrogen-13 labeled ammonia (half-life = 10 minutes) can be used as a PET perfusion tracer with exercise stress MPI.
In some patients, an adequate level of exercise cannot be achieved because of orthopedic limitations, peripheral vascular disease, complicating medical illnesses, or the use of medications such as beta-blockers. Stress perfusion imaging is still feasible if a pharmacologic agent can be used to increase myocardial blood flow. About 40% of the MPI tests in the United States are performed using pharmacologic stress.5 Two most commonly used pharmacologic stress agents, adenosine and dipyridamole, are potent coronary vasodilators. Another coronary vasodilator agent more recently approved for clinical use in radionuclide MPI is regadenoson, a selective A2A receptor agonist.6 These agents increase myocardial perfusion by directly dilating the coronary vasculature, thereby “uncoupling” myocardial perfusion from ventricular work. The fourth agent used for MPI is a synthetic catecholamine, dobutamine, which increases tissue perfusion primarily by increasing tissue oxygen demand through its positive inotropic and chronotropic effects. The pharmacologic agents used for stress perfusion imaging are summarized in Table 13.1.
TABLE
13.1 Agents for Pharmacologic Stress Testing
Adenosine is a small molecule that is produced by vascular smooth muscle and endothelial cells. Adenosine can also be generated by the extracellular dephosphorylation of adenosine triphosphate (ATP) and adenosine diphosphate (ADP). Free adenosine within the vascular space can reenter endothelial, vascular smooth muscle, or red blood cells by facilitated transport, or it can bind to specific receptors on the cell membrane. Adenosine induces coronary vasodilatation when it binds to A2A receptors on the surface of the cell. (Adenosine binds to the A1, A2B, and A3 receptors as well, explaining its accompanying effects of AV nodal blockade and bronchoconstriction.) Binding to the A2A receptor causes an increase in intracellular cyclic AMP (cAMP) concentration via a coupled G-protein system that in turn results in coronary artery dilatation. Adenosine has a very short half-life (2 to 10 seconds), because it is rapidly cleared from the vascular space by uptake into endothelial and red blood cells. In normal coronary arteries, adenosine leads to increases in blood flows that are generally three to six times those in the resting state. Adenosine is usually administered as a continuous intravenous infusion at a rate of 140 µg/kg/min over a period of 6 minutes. The radioactive perfusion radiotracer is injected at 3 minutes, midway through the adenosine infusion. Some investigators have indicated that a 4-minute period of infusion of adenosine (with tracer injection at 2 minutes) is as efficacious for the detection of CAD as the 6-minute infusion protocol.
Dipyridamole blocks the cellular reuptake of adenosine. This causes more of the endogenous adenosine within the vascular space to bind to the A2A receptors on the cell surface. Greater receptor binding by adenosine, in turn, promotes coronary vasodilatation. Dipyridamole has a significantly longer half-life than adenosine, inducing coronary vasodilatation that may persist for as long as 30 minutes following its administration. Dipyridamole is given by continuous intravenous infusion over 4 minutes, at a rate of 0.142 mg/kg/min. The radioactive perfusion tracer is injected about 4 minutes after the end of the dipyridamole infusion, to allow achievement of maximal myocardial hyperemia.
Regadenoson is a selective A2A receptor agonist that was approved by the FDA for clinical use in MPI in 2008. Its coronary hyperemic effects have an onset within 30 seconds and usually last for 2 to 5 minutes. Regadenoson is administered intravenously as a single bolus dose of 0.4 mg, followed by a 5 mL saline flush. Two randomized double-blind multicenter trials—ADVANCE-MPI 1 and 2—demonstrated the safety of this agent in 1,871 patients, as well as an efficacy similar to adenosine for the detection of reversible perfusion defects on SPECT imaging.6,7 Regadenoson has not been compared in a clinical trial with adenosine or dipyridamole as a stress agent for cardiac PET imaging.
The side effects of adenosine and dipyridamole are similar and include flushing, chest pain, dyspnea, headache, nausea, hypotension, bronchospasm, and AV block. Of note, regadenoson appears to trigger fewer adverse events and has a favorable side-effect profile as compared to adenosine—a function of its selective agonism of the A2A receptor. Side effects, especially AV block, are more commonly seen with adenosine but tend to be short-lived with this agent—dissipating within seconds of stopping the infusion. With regadenoson and dipyridamole, any side effects experienced tend to persist longer, and treatment with aminophylline (50 to 100 mg IV), a nonselective competitive antagonist, may be required. Clinical studies suggest that the side effects of all three vasodilator agents may be attenuated if the patient is capable of performing exercise in conjunction with the pharmacologic stress. Image quality may also benefit from the performance of adjunctive exercise. Contraindications to the administration of the vasodilator agents include asthma or a history of bronchospastic pulmonary disease, hypotension, unstable angina or acute MI within 2 days, high-degree AV block without a pacemaker, uncontrolled arrhythmias, and critical aortic or mitral valve stenosis. Unlike stress with exercise or IV dobutamine (below), the adequacy of the myocardial hyperemia induced by IV adenosine or dipyridamole cannot be inferred from the changes in heart rate or systemic blood pressure induced by the administration of these agents.
For adenosine, regadenoson, and dipyridamole stress, it is important that the patient refrain from the use of drugs such as aminophylline and theophylline prior to the test, as these medications are competitive antagonists of the adenosine membrane receptor.8 These medications effectively blunt the hyperemia induced by these agents and may cause a falsely negative imaging study. Caffeine and caffeine-like substances such as theobromine, whose effects are similar to those of aminophylline, should also be avoided prior to pharmacologic stress testing with vasodilators. Current joint guidelines issued by the American Society of Nuclear Cardiology (ASNC) recommend that patients refrain from the use of caffeine for at least 12 hours prior to vasodilator stress testing.9
Dobutamine is a short-lived (half-life of about 2 minutes) β1-adrenergic receptor agonist that is widely used for stress echocardiography. Unlike stress echocardiography, when dobutamine is used as the stress for nuclear perfusion imaging it is not possible to monitor ventricular function “online." Dobutamine stress should therefore be used with caution for nuclear imaging in patients with reduced left ventricular ejection fraction (LVEF), as new regional contractile abnormalities incited by ischemia could precipitate further deterioration in ventricular function. Dobutamine can be used in patients with bronchospastic pulmonary disease, in whom there is a relative contraindication to the use of the vasodilator stress agents described above. Dobutamine increases cardiac contractility and heart rate and is contraindicated in patients with recent MI, uncontrolled hypertension, or significant cardiac arrhythmias.
Dobutamine is administered as a continuous intravenous infusion, typically starting at 5 to 10 µg/kg/min for 3 minutes and then increasing by 10 µg/kg/min every 3 minutes to a maximum dose of 40 µg/kg/min. If the patient does not achieve 85% of his or her age-related maximal predicted heart rate, he or she can be instructed to perform handgrip exercise and/or be given up to 1 mg of atropine IV to increase the heart rate. The perfusion tracer is administered intravenously 1 to 2 minutes before the end of the dobutamine infusion, to allow enough time for myocardial uptake of the imaging agent. Side effects of dobutamine include palpitations, chest pain, hypertension, hypotension, atrial fibrillation, and ventricular tachycardia. The side effects usually respond to stopping the infusion, or to the intravenous administration of a beta-blocker.
Indications for Myocardial Perfusion Imaging
The appropriate indications for MPI, as listed by the American College of Cardiology (ACC)/American Heart Association (AHA)/ASNC guidelines,10 are summarized in Table 13.2.
TABLE
13.2 Appropriate Indications for MPI
Acute Chest Pain Syndromes
Prompt identification of individuals with acute coronary syndromes (ACSs) provides the best opportunity to salvage viable myocardial tissue and save lives. In some who present to the Emergency Department with chest pain, elevated cardiac enzyme levels and an abnormal electrocardiogram (ECG) provide definitive evidence of an acute MI, and there is no need for imaging to establish the diagnosis. On the other hand, in those with chest pain that is clearly noncardiac in origin, there is little utility in pursuing an aggressive (and expensive) diagnostic imaging strategy to exclude coronary disease. There are, however, about 6 million patients who present to Emergency Departments each year in the United States with chest pain of uncertain etiology, who have normal enzyme levels and a nondiagnostic ECG. It is these patients, in whom an ACS remains a diagnostic possibility, that MPI has the highest clinical benefit.11 Although the relative proportion of individuals with an ACS in this patient group is not large, the probability of an adverse outcome in those with a true coronary event is high if the diagnosis is missed. Reported mortality in Emergency Department patients with an ACS who are mistakenly sent home is as high as 5% to 6%. On the other hand, for those without an ACS who are admitted to the hospital for observation, there are substantial costs associated with the unnecessary utilization of health care services.
Rest SPECT MPI is useful for the evaluation of patients with suspected ACSs. Rest MPI can detect a regional perfusion abnormality in the absence of acute necrosis, especially if the radioactive tracer is injected during or shortly after an episode of chest pain. Reported negative predictive values of a normal rest myocardial perfusion scan in patients with suspected ACSs are as high as 99% to 100%, and up to 97% of patients who have a negative perfusion study in this setting will remain free of cardiac events over a short-term follow-up. Two randomized, prospective studies have shown that access to acute MPI has a beneficial effect on length of stay and hospital costs. It is the position of the ASNC that the evidence supports the use of acute rest MPI for the triage of selected Emergency Department patients with suspected ACSs.11 However, rest perfusion imaging is less helpful in those with a history of prior MI because it is not possible to distinguish a resting perfusion defect due to an acute ischemic event from that of a preexisting scar.
Both thallium-201 and technetium-99m–labeled tracers have been used for rest myocardial imaging in Emergency Department patients. Thallium-201 begins redistributing shortly after its uptake by the myocardium, and images obtained later than 10 to 15 minutes following tracer injection may miss a regional perfusion abnormality. The technetium-99m-labeled tracers are preferred for imaging because they are rapidly trapped in the myocardium and permit imaging of tissue perfusion at the time of tracer injection up to 4 hours later. The sensitivity of acute rest MPI is highest if the radioactive tracer is injected during chest pain, or shortly thereafter. Ideally, the tracer should be administered within 2 hours of the episode of chest pain. In those without prior infarction, identification of a perfusion defect and/or a segmental wall motion abnormality on the rest gated SPECT perfusion images will ordinarily prompt hospital admission and an aggressive work up for an ACS. By contrast, those who have normal scans can be discharged home with a low probability of sustaining an ischemic event in the immediate future.
Current imaging guidelines indicate that rest MPI is not appropriate for patients with definite acute MI.10 However, some who have imaging because of an uncertain clinical picture at presentation will subsequently rule in for acute infarction, and the perfusion images can provide useful information about the anatomic site of injury. If the rest perfusion images are repeated prior to hospital discharge, a measure of the degree of myocardial salvage afforded by treatment can be achieved by subtracting the perfusion defect size on the resting images at discharge (final infarct size) from that on the early images (region at risk).
Risk Assessment after ST-Elevation Myocardial Infarction
Patients with acute STEMI who are suitable for primary percutaneous intervention are usually referred directly for angiography and coronary revascularization. However, current practice guidelines indicate that noninvasive risk stratification is appropriate for stable, low-risk patients (ejection fractions >40%) who have not received reperfusion therapy or who have been treated with fibrinolytic agents.12 Final infarct size, the extent of inducible ischemia, and LVEF are the key elements of risk stratification for stable patients following ST-segment elevation myocardial infarction, and gated MPI is well suited for measurement of these parameters.13
Infarct size can be determined by measuring the amount of the left ventricle with a resting perfusion defect prior to hospital discharge. Clinical studies of patients with acute infarction suggest that resting perfusion defect size is a variable that contributes independently to cardiac risk. Patients with only small fixed perfusion defects generally have a good prognosis, whereas those with resting perfusion defects involving 20% or more of the left ventricle are at higher risk for cardiac events over the ensuing 24 months. The extent of inducible ischemia can be derived from the images by careful subtraction of the size of the rest perfusion defect from that of the stress defect. Inducible ischemia, whether in the clinical infarct zone or in other vascular territories, also contributes to cardiac risk. Patient risk increases as the percent of the left ventricle with stress-induced ischemia increases, with involvement of 10% or more of the ventricle by a reversible perfusion defect placing the patient into a highrisk group. Measurements of LVEF and ventricular volumes can also readily be obtained from the gated perfusion images. In general, as the LVEF declines to <40% there is a progressive and nonlinear increase in the risk of cardiac events. Other scintigraphic observations that have been associated with increased clinical risk in the post-MI patient include transient ischemic dilatation (TID) of the left ventricle on the stress images, and increased pulmonary tracer uptake (especially with thallium scintigraphy) on the stress images.
Stress perfusion imaging with adenosine or dipyridamole can safely be performed as early as 2 days following an acute infarction,14 while present guidelines suggest that submaximal exercise stress testing not be performed before 5 days after an acute event. MPI with vasodilator stress provides incremental prognostic information beyond that afforded by conventional clinical and stress electrocardiographic variables. Vasodilator stress perfusion imaging is more sensitive for the identification of ischemia than submaximal exercise stress testing and is more useful for risk stratification, probably because it is possible to safely achieve a greater degree of hyperemia without inducing frank ischemia using vasodilator stress (Fig. 13.1). Early risk stratification facilitates identification of the high-risk patient and appropriate referral for angiography.
FIGURE 13.1 Annual rates of mortality/recurrent MI in patients with initial uncomplicated MI, according to the results of either dipyridamole (DP) or submaximal exercise (EX) myocardial perfusion scintigraphy. SSS, summed stress perfusion defect score; SDS, summed difference between stress and rest segmental scores; SRS, summed rest perfusion defect score. Low SSS and SRS values were defined by scores of 0-4; intermediate (Intermed) values by scores of 5-8; high values by scores >8. Low SDS values were defined by scores of 0-2, intermediate values by 3-7, and high values by scores >7. Higher perfusion defect scores were associated with higher event rates, and dipyridamole stress imaging provided better risk stratification than submaximal exercise perfusion scintigraphy. (From Brown KA, Heller GV, Landin RS, et al. Early dipyridamole 99mTc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events. Comparison with submaximal exercise imaging. Circulation.1999;100:2060–2066, with permission.)
Risk Assessment after Non-ST-Elevation Myocardial Infarction
Updated ACC/AHA guidelines for the management of patients with unstable angina and non–ST-elevation myocardial infarction (NSTEMI) recommend an early invasive approach for those with a high-risk profile who have no significant comorbidities.15 However, the guidelines also suggest that stable patients without high-risk indicators might be managed using either a conservative or an early invasive strategy. Several studies have demonstrated the utility of MPI for the risk stratification of patients following NSTEMI. The presence of perfusion defects (fixed or reversible) on stress testing in stabilized NSTEMI patients is predictive of future events. In one study of 126 men who underwent a Tc-99m sestamibi stress SPECT myocardial perfusion study prior to hospital discharge, the event-free survival in patients with a normal scan was about 90% in the 18-month follow-up period, as compared to 55% in those with abnormal scans. Patients with reversible defects fared less favorably, with an event-free survival of only 30%. The rate of death and recurrent MI in this group was 40%, as compared to 20% for all patients with abnormal scans.
In those with unstable angina or NSTEMI, current AHA/ACC/ASNC imaging guidelines indicate that stress SPECT MPI is appropriate for the identification of inducible ischemia in (a) patients at intermediate or low risk for major adverse cardiac events, (b) patients whose angina is stabilized with medical therapy or in those in whom the diagnosis is uncertain, and (c) patients who have coronary stenoses of uncertain hemodynamic consequence on coronary angiography. Use of rest gated MPI can also be considered for determination of the left ventricular function.
Patients with Suspected or Established Chronic Coronary Artery Disease
Detection of Coronary Stenoses MPI has the highest clinical utility for the detection of flow-limiting coronary arterial stenoses in symptomatic patients with an intermediate pretest probability of disease.10In this scenario, regardless of whether the imaging study is negative or positive, the patient’s posttest probability of disease has been substantially influenced by the results of the test.
In contrast, patients who have either a low or a high pretest probability of disease, MPI is less likely to provide meaningful additional diagnostic information and risk stratification. In those with a low pretest likelihood of disease, correlative angiographic studies indicate that the posttest probability of obstructive disease remains low. On the other hand, the patient with a high pretest probability of disease will continue to have high probability of disease regardless of MPI results.
The reported sensitivity of exercise myocardial perfusion SPECT imaging for detecting coronary stenoses of ≥50% ranges from 71% to 97% (average 87%), whereas specificity ranges from 36% to 100% (average 73%). For vasodilator (adenosine or dipyridamole) stress SPECT, reported sensitivity ranges from 72% to 93% (average 89%), whereas specificity ranges from 28% to 100% (average 75%). For MPI with PET, reported sensitivities range from 83% to 100% (average 97%), whereas specificities range from 73% to 100% (average 87%). In general, reported sensitivities and specificities of PET perfusion studies tend to be slightly higher than for SPECT studies, resulting in greater diagnostic accuracy.16 The higher diagnostic accuracy likely reflects several factors, including the use of transmission images to correct the myocardial images for attenuation and the superior spatial resolution afforded by the PET imaging technique. Although it is not widely used in current clinical practice, recent studies suggest that the use of attenuation correction in conjunction with SPECT myocardial perfusion might enhance its diagnostic accuracy. At the present time, studies directly comparing attenuation corrected SPECT versus PET for the detection of CAD are lacking.
MPI is especially useful for the detection of disease in individuals in whom the electrocardiographic changes with stress are nondiagnostic. These include patients taking digoxin, and those with left ventricular hypertrophy (LVH), ventricular pacemakers, left bundle branch block (LBBB), or Wolff–Parkinson–White syndrome. In those with LBBB, both reversible and fixed perfusion defects have been reported in the absence of obstructive disease on coronary angiography.17 False positive perfusion defects are more common when exercise is used for stress, and for this reason pharmacologic stress imaging is preferred in those with LBBB.18. The perfusion defects are usually localized in the interventricular septum and may reflect actual abnormalities in regional blood flow. The cause of the septal perfusion defects is not clear, but it may reflect compression of perforating septal branch arteries due to the delayed onset of septal contraction resulting in a relative reduction in septal perfusion.
Identifying Disease Severity, Risk and Prognosis
Increasingly, MPI is being used to gauge the risk of cardiac events in symptomatic patients with known or suspected CAD. Some have argued that the use of prognostic endpoints is a better measure of the clinical utility of a test than a direct comparison with disease severity on angiography.
The factors associated with adverse outcomes on MPI studies include a large perfusion defect on the stress images (a summed stress score >8), a large fixed perfusion defect due to prior MI, a large area of reversible ischemia (especially if identified in multiple vascular territories), a LVEF <40%, stress- induced ventricular dyssynergy, TID of the left ventricle, and increased pulmonary uptake of the perfusion tracer.19 An additional report indicates that there is an incremental prognostic value in assessing poststress left ventricular volumes on the gated SPECT perfusion images, with end systolic volumes >70 mL denoting a poorer prognosis.
Markers reflecting left ventricular function, such as the extent of myocardial scar, ventricular ejection fraction, and TID of the ventricle appear to be more predictive of cardiac death.19 In contrast, markers of inducible ischemia, such as exertional symptoms, ECG changes, the extent and severity of a reversible perfusion defect, and associated inducible ventricular dysfunction, appear to be more predictive of an acute ischemic event, that is, the need for urgent coronary revascularization, progression from stable to unstable angina, and acute MI.
The patients most likely to benefit from MPI for risk stratification are those with an intermediate pretest risk of a cardiac event over the ensuing year. Low-risk, intermediate-risk, and high-risk categories have typically been defined as <1%, 1% to 2%, and >2% risk of a cardiac event per year, respectively. In general, patients with an intermediate pretest risk who then proceed to have a normal cardiac SPECT scan have a low annual risk of cardiac events—on the order of 0.6% per year. Several more recent studies have suggested an even lower rate of cardiac death and nonfatal MI in those intermediate-risk patients with a normal cardiac SPECT scan, about 0.2% year. In these latter studies, individuals with an established history of CAD and a normal SPECT perfusion scan had an event rate about 0.9% per annum. In general, the absolute risk associated with a normal SPECT myocardial perfusion scan reflects the specific patient population under consideration. That is, stratification of patient risk depends on the anticipated pretest cardiac event rate in that specific population (Fig. 13.2).
FIGURE 13.2 Meta-analysis of the posttest likelihood of a cardiac event, according to the findings on SPECT myocardial perfusion scintigraphy. The data points associated with a high-risk scan are shown by diamonds; those indicating a low-risk scan are shown by squares. The posttest event rate associated with a high- or low-risk myocardial SPECT perfusion scan reflects the pretest event rate in the population that best reflects the patient’s clinical characteristics. A low-risk SPECT study in a patient from a population in which there is a larger naturally occurring pretest event rate (e.g., a diabetic patient) results in a posttest likelihood of a cardiac event that is somewhat higher than that in a patient from a pretest population with a low event rate. Conversely, a high-risk scan in a patient from a population with a low event rate is associated with a smaller absolute risk than that in a patient from a population with a higher frequency of cardiac events. (With kind permission from Springer Science+Business Media: Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol. 2004;11:171–185.)
For patients with abnormal scans, the risk of a cardiac event increases as the degree of the scan abnormality increases. This was demonstrated in a prospective study of 5,183 consecutive patients who underwent rest and stress MPI. In this investigation, patients with normal scans had a <0.5% annual rate of cardiac death and MI over the ensuing 642 ± 226 days. Those with mildly abnormal scans had a low risk of cardiac death but an intermediate risk of MI (0.8% vs. 2.7% per year), whereas those with moderately abnormal scans had an intermediate risk of cardiac death and MI (2.3% vs. 2.9% per year). The risk of cardiac death and MI was intermediate to high (2.9% vs. 4.2% per year) in the patients with severely abnormal scans.
Although individual authors may vary slightly in their definition of a high-risk myocardial perfusion scan, the annual rate of death or nonfatal MI is about 5.9% in those with high-risk scans. In an individual belonging to a population with a very high pretest cardiac event rate (e.g., about 10% per year), a high-risk scan would stratify the patient to an even higher posttest risk of about 14% to 15% per year (see Fig. 13.2).
Other factors also modulate cardiac risk. For both low-risk and high-risk perfusion scans, the risk of cardiac death or nonfatal MI is higher for pharmacologic stress studies than for exercise studies. With exercise, a low-risk SPECT study nas about a 0.7% annual event rate, wnereas tnat for pharmacologic stress is about 1.2% per year. The annual event rate associated with a high-risk SPECT scan with exercise is about 5.6% per year, and is about 8.3% per year for a pharmacologic stress study.19 Some authors therefore consider the necessity to use pharmacologic stress for MPI (a reflection of a poor functional class), an independent prognostic risk factor.
Gender also influences risk stratification. Although there is little difference between the sexes in the event rates associated with a low-risk SPECT scan, women with a high-risk SPECT scan have an annual cardiac event rate of approximately 6.2%, whereas that for men is about 5.3%. Diabetic patients also have higher event rates, for both low-risk (about 2% per year) and high-risk scans (about 9.5% per year). Therefore, diabetic women constitute the highest-risk patient cohort.
Specific Populations and Situations The use of MPI in selected patient populations and situations merits consideration.
Before and after Coronary Revascularization MPI before percutaneous coronary intervention (PCI). In a patient with atypical symptoms and an equivocal coronary lesion, the stenosis identified on angiography might not be the proximate cause of the individual’s symptoms. Stress MPI is useful to characterize the physiologic effects of equivocal coronary lesions and thereby establish a link between the patient’s symptoms and the angiographic findings.10MPI can also be used to identify the “culprit” vessel(s) in those with mild to moderate lesions in multiple arteries who have clinical evidence for stress-induced ischemia. Of note, evaluation for the functional significance of equivocal or moderate coronary stenoses identified during invasive coronary angiography may also be performed intraprocedurally using fractional flow reserve (FFR).
In order to adequately characterize the flow reserve characteristics of a coronary lesion on SPECT imaging, it is important to insure that adequate hyperemia has been achieved during stress (above). In patients who are unable to achieve at least 85% of their MPHR, pharmacologic stress testing is a practical alternative.
MPI after PCIs. In the first few months after PCI, routine MPI may be of diminished diagnostic value because of an increased incidence of false-positive perfusion defects secondary to endothelial dysfunction and abnormal flow reserve in the coronary bed distal to the site of intervention. Later following successful PCI, the main indication for MPI is recurrence of symptoms. In fact, per the most recent ACC/AHA appropriate-use criteria for cardiac radionuclide imaging, stress MPI in patients who are asymptomatic and <2 years out from their PCI is considered inappropriate.10
MPI after coronary artery bypass graft (CABG). MPI can readily demonstrate the location, extent, and severity of rest and stress-induced perfusion defects in individuals with prior coronary artery bypass surgery. However, interpretation of the perfusion images should be performed considering the alterations in coronary anatomy resulting from the bypass procedure. Inducible ischemia might reflect obstructive disease in a bypass graft, a local problem with a graft anastamosis, or progression of a lesion in a native vessel distal to the insertion of a bypass graft. Ischemia can sometimes be identified in myocardial regions proximal to the insertion of a bypass graft. On gated perfusion images, abnormal septal motion is commonly noted in the post-CABG patient. This may reflect the loss of pericardial constraint as a result of the prior surgical procedure, rather than an intrinsic abnormality in contractile function, as systolic thickening is usually well preserved in those without prior injury.
MPI is most clearly indicated in post-CABG patients who have recurrent anginal or anginal-equivalent symptoms. The value of MPI in asymptomatic patients <5 years is currently listed as “uncertain” by current guidelines. However, in studies that included asymptomatic patients >5 years after CABG, several variables have been linked to an adverse outcome: the extent and severity of inducible ischemia (as measured by the summed reversibility score), perfusion defects in multiple vascular territories, the extent of fixed perfusion defects, and increased pulmonary uptake of thallium.20 As such, stress MPI is also considered appropriate for risk assessment in asymptomatic patients more than 5 years after CABG, according to current guidelines.10
Preoperative Testing prior to Noncardiac Surgery MPI may be used prior to noncardiac surgery to help identify individuals at high risk for perioperative ischemia, infarction, and death.21 Despite advances in medical care, reported mortality rates for perioperative MI are as high as 26%. Moreover, the costs of perioperative morbidity and mortality are of the order of $12 billion per year in the United States. Appropriate medical treatment can reduce perioperative morbidity and mortality, and improve the long-term prognosis of the patient. These facts underscore the need for identification of high-risk surgical patients.
Several clinical scoring systems have been utilized to assess cardiac risk in patients prior to noncardiac surgery. Most of these scoring systems, however, were derived from and applied to general surgical populations with a relatively low prevalence (<10%) of CAD. Use of these scoring systems in populations with a higher prevalence of coronary disease (as, e.g., in those with peripheral vascular disease, in whom the prevalence of CAD may be as much as 60%), underestimates the risk of cardiac events.
Noninvasive preoperative stress testing has its highest utility in patients with intermediate clinical predictors of cardiac risk. These include mild angina, a history of prior MI, compensated CHF, and diabetes mellitus. Current practice guidelines suggest that the patients most likely to benefit from preoperative stress MPI are those with poor functional capacity (able to achieve <4 METs with exercise) who are scheduled to undergo intermediate (e.g., intra-abdominal surgery, carotid endarterectomy) or high-risk (e.g., abdominal aortic aneurysm repair) surgical procedures.10,21
The positive predictive value of MPI for perioperative cardiac ischemia is low (4% to 20%), but the negative predictive value is very high (96% to 100%). Patients with reversible defects have a greater risk of perioperative ischemia than those with fixed defects, and the relative risk increases in proportion to the extent of inducible ischemia on the perfusion imaging study. The evaluation of left ventricular function on gated SPECT perfusion images is important in patients with signs and/or symptoms of heart failure, because reduced ventricular systolic function is correlated with the risk of perioperative heart failure.
Nuclear Stress Testing in Women More women die of cardiovascular disease each year in the United States than from any other cause.22 Although the prevalence of CAD in non-diabetic women <45 years of age is low, it increases significantly following menopause, and is similar to that in men by the seventh decade. Although deaths from CAD are declining in men, the same is not true for women. CAD claims the lives of more than 240,000 women each year in the United States and is a significant cause of morbidity and disability. Women are more likely to die from an acute MI than their male counterparts and are more likely to sustain recurrent infarction. Therefore, early identification of women with coronary heart disease (CHD) affords the best opportunity for intervention and, ultimately, a reduction in cardiovascular mortality.
Current guidelines rely on a Bayesian approach to gauge the relative value of stress testing for the detection of CAD in women. In asymptomatic premenopausal women, there is a low prevalence of coronary disease, cardiovascular risk is low, and the clinical utility of stress testing is generally of limited benefit. However, women with diabetes or peripheral vascular disease are the exception, because there is a higher risk of CAD. Stress testing in these women is appropriate according to current guidelines, even in the absence of symptoms, because of the greater pretest probability of disease. Symptomatic women, those with an intermediate or high pretest likelihood of disease (<50 years of age with typical angina, 50 years or older with typical or atypical chest pain, two or more cardiac risk factors), can be expected to benefit from stress testing.
The diagnostic accuracy of exercise stress electrocardiography for the detection of CAD in women is somewhat limited. ST-segment changes with stress have been reported to be less accurate for the detection of CAD than in men, as a consequence of a higher prevalence of ST–T-wave changes on the resting ECG, lower electrocardiographic voltages, and poorly understood hormonal effects on vascular tone.22Women are generally older when they present for evaluation, and may be limited in their ability to achieve an adequate level of stress because of lower exercise capacity. Reported average sensitivities and specificities of stress electrocardiography for CAD detection in women are about 61% and 70%, respectively as compared to 72% and 77% for men. Current ACC/AHA guidelines suggest that stress electrocardiography be used as a first-line test for CAD detection in women with an intermediate pretest likelihood of disease who have a normal resting ECG and who are capable of achieving an adequate level of stress. In those with baseline ST–T changes on the ECG, or in those in whom an adequate level of stress is unlikely to be achieved, MPI provides an incremental benefit over the stress ECG, for both the diagnosis of CAD and risk stratification. Cardiac imaging is also suggested for women in whom the stress ECG is indeterminate or suggests an intermediate level of risk, as well as in those with an intermediate-risk Duke treadmill score.
In early clinical studies employing SPECT thallium-201 scintigraphy, reported sensitivities for the detection of single vessel disease in women were lower than in men. This was attributed to smaller left ventricular chamber sizes in women and to the physical characteristics of the isotope itself. In addition, breast attenuation often resulted in anterior wall defects and false positive tests. With the advent of technetium-99m–labeled tracers and gated imaging, the diagnostic accuracy of MPI has improved significantly in female populations. For example, adenosine sestamibi imaging has been reported to be 91% sensitive and 86% specific for the detection of coronary stenoses. Although the diagnostic accuracy of SPECT MPI in women may be slightly less than that in men, there is a substantial incremental benefit of MPI over the routine clinical variables and stress electrocardiography for risk stratification in female patients.
The Patient with Coronary Calcification on CT The presence of coronary calcification on electron beam CT (EBCT) or multidetector CT (MDCT) is related to the amount and extent of atherosclerotic plaque on coronary angiography. In general, the higher the CT coronary calcium score in a given patient, the poorer the prognosis. Coronary artery calcification has been shown to be an independent predictor of death relative to other clinical variables, with the mortality risk increasing linearly as the coronary artery calcium score increases.23
The information provided by CT and MPI is considered by some to be complementary. In general, the higher the coronary calcium score, the greater is the probability that a perfusion defect will be identified on SPECT MPI. For patients with coronary calcium scores <100, the prevalence of perfusion defects on MPI has been reported to be <1.8%.24 For patients with scores between 100 and 400, the reported prevalence of SPECT perfusion defects is 5.2%, whereas that for patients with calcium scores >400 is 15% to 40%. Current ACC/AHA guidelines indicate it is appropriate to perform stress MPI in patients with Agatston scores >400, as well as for patients who have “high” CHD risk and a coronary calcium score between 100 and 400.
Further clinical studies are needed to determine if the extent of coronary artery calcification contributes to the risk stratification of those with normal myocardial perfusion studies.
The Patient with Severe Stenosis on Coronary CT Angiogram As the technical quality of coronary CT angiography continues to improve, this imaging technique is increasingly being utilized in clinical practice for the detection of obstructive coronary lesions. However, CT angiography is not well-suited for defining the functional significance of coronary lesions of indeterminate severity. Complementary information may be required to ascertain whether these lesions result in ischemia during stress. For this reason, stress MPI is considered appropriate by current ACC/AHA guidelines when noninvasive coronary angiography reveals coronary stenoses of uncertain significance.10
The Asymptomatic Patient with Diabetes Patients with diabetes mellitus are considered by Adult Treatment Panel (ATP III) criteria to have a CHD “risk equivalent,” roughly equal in terms of risk of future cardiac events with patients with known stable CAD, peripheral arterial disease, and cerebrovascular disease. According to current ACC/AHA guidelines, it is considered appropriate to further risk- stratify asymptomatic diabetic patients using stress MPI. It is worth noting, though, that the most recent iteration of the appropriate-use guidelines for cardiac radionuclide imaging were published prior to the release of the 5-year follow-up data regarding cardiac outcomes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. In this study, 1,123 patients with adult-onset diabetes between the ages of 50 and 75 who had no known coronary disease or anginal symptoms were randomized to a baseline screening with adenosine stress MPI or no stress MPI. The trial demonstrated that 22% of patients screened at baseline with radionuclide imaging had silent myocardial ischemia.25 At 5 years follow-up, however, there was no difference between the two randomization arms in terms of cardiac events and mortality.26Although there were significantly more coronary angiograms and revascularizations performed within the first 120 days in patients who underwent baseline screening MPI versus those that did not, these differences equilibrated over the course of the follow-up period—usually due to the development of symptoms and subsequent diagnostic testing in both groups. Interestingly, the event rate in the overall cohort was much lower than anticipated: 0.6% per year, instead of the 2% per year that the study design was based upon. As such, the study was underpowered to detect a 20% difference between the MPI-screened and nonscreened groups. However, the authors questioned whether a reduction in cardiac events from 0.6% to 0.5% per year—even if present—justified routine radionuclide cardiac imaging in asymptomatic diabetic subjects.
At present, ACC/AHA guidelines consider the use of stress MPI for risk stratification in asymptomatic patients with high CHD risk (>20% over 10 years by Framingham risk score, or “CHD risk equivalents” such as peripheral vascular disease, abdominal aortic aneurysm, cerebrovascular disease, and diabetes mellitus) as “appropriate,”10 albeit with a Class IIb indication in asymptomatic diabetics.27 However, it is possible that these guidelines may be amended if further data corroborates lower-than-expected event rates in asymptomatic patients with CHD risk equivalents in an era of improved medical therapy for primary prevention of major adverse cardiovascular events.
NUCLEAR CARDIAC IMAGING IN HEART FAILURE
Role of Nuclear Imaging in Congestive Heart Failure
In individuals with CHF, nuclear imaging can assist in clinical management of the patient by (a) helping to define the etiology of the ventricular dysfunction, (b) characterizing right and left ventricular functions and volumes, (c) determining the relative contributions of myocardial stunning and scar to left ventricular dysfunction, and (d) distinguishing myocardial hibernation from scar in those with chronic ischemic heart disease. Although echocardiography has largely supplanted nuclear imaging for assessing diastolic ventricular function, and for characterizing cardiac performance in hypertrophic and valvular heart disease, nuclear imaging techniques remain extremely useful for the evaluation of patients with systolic heart failure. By the use of nuclear imaging, the clinician is afforded insights into the etiology and prognosis of heart failure in the patient, and perhaps more important, whether coronary revascularization in a high-risk individual is likely to improve symptoms and survival.
Etiology of Heart Failure: Ischemic versus Nonischemic Cardiomyopathy
In patients with impaired systolic function, it is crucial to distinguish myocardial dysfunction due to CAD (ischemic cardiomyopathy) from other causes of dilated heart failure (nonischemic dilated cardiomyopathy). In selected individuals with ischemic cardiomyopathy, coronary revascularization can provide both symptomatic and prognostic benefit, and noninvasive identification of these patients is key for optimal clinical management.28 MPI is helpful for distinguishing between those with and without ischemic cardiomyopathy, and for the identification of those with ischemic cardiomyopathy who might benefit from coronary revascularization.
Generally, patients with left ventricular dysfunction due to CAD have either extensive fixed perfusion defects or a modest number of fixed defects with large reversible stress-induced perfusion defects (suggesting dysfunction on the basis of myocardial stunning). Six studies have shown that the sensitivity of MPI for the detection of CAD in heart failure patients is 100%, with a homogeneous pattern of perfusion having a predictive value of 100% for a nonischemic cardiomyopathic process. However, a fixed perfusion defect does not preclude the possibility of a nonischemic cardiomyopatmc process, for patchy myocardial fibrosis can sometimes be manifest as a fixed defect. In addition, coronary flow reserve can be abnormal in nonischemic cardiomyopathy and reversible perfusion defects have also been reported in these individuals. The specificity of MPI for the identification of ischemic cardiomyopathy in dilated heart failure patients is therefore only about 40% to 50%.
Assessment of Ventricular Function
In addition to gated MPI, assessment of right and left ventricular function and volumes can also be achieved using radionuclide ventriculography. Right ventricular function can be evaluated using a first-pass imaging study, in which a series of images is obtained rapidly as a radioactive tracer is administered intravenously. It is useful for visualizing right ventricular function without the confounding influence of activity in other nearby vascular structures. Alternatively, tomographic equilibrium-gated blood pool imaging can also be used to assess right ventricular function.
Left ventricular function can be evaluated using equilibrium-gated blood pool radionuclide ventriculography. In this technique, an intravenously administered radioactive tracer such as technetium-99m pertechnetate is used to label the patient’s red blood cells. Once the label is uniformly distributed throughout the vascular space, a set of images synchronized to the patient’s ECG is obtained over multiple cardiac cycles. These images depict different times in the cardiac cycle (see Chapter 11). Because background corrected left ventricular counts are proportional to ventricular volume, the ejection fraction can be calculated by subtracting end-systolic counts from end-diastolic counts and dividing by the end-diastolic counts. Unlike echocardiography or contrast ventriculography, computation of the LVEF is independent of any assumptions about the shape of the ventricle.
Radionuclide ventriculography can be performed in nearly anyone with a stable cardiac rhythm, including those with obstructive pulmonary disease and marked obesity. Most of the available computer programs for the analysis of the gated images use automated edge-detection algorithms to define the border of the ventricular cavity in a consistent manner, resulting in LVEF measurements that are very reproducible. In patients wim CHF, the severity of global and regional systolic dysfunction can easily be defined with this imaging technique. Because of the high reproducibility of the LVEF measurements made with this imaging technique, it is also used to monitor the effects of cardiotoxic drugs such as doxorubicin. Serial LVEF determinations allow the clinician to maximize the dose of the chemotherapeutic agent given to the patient while minimizing the risk of CHF due to drug toxicity. The indications for radionuclide ventriculography are listed in Table 13.3.
TABLE
13.3 Indications for Radionuclide Ventriculography
Perfusion and Metabolic Imaging for Reversible Left Ventricular Dysfunction
In patients with ischemic cardiomyopathy, regional dysfunction associated with normal resting myocardial perfusion generally represents viable myocardium that is likely to benefit from coronary revascularization. These areas frequently demonstrate a perfusion defect with stress, suggesting that the regional dysfunction results from recent or repetitive myocardial stunning. Individuals with the largest amounts of ischemia may be expected to derive the greatest functional benefit from coronary revascularization.
For patients with regional left ventricular dysfunction and fixed perfusion defects, additional imaging is warranted to identify the presence or absence of viability (myocardial hibernation) in that region. Coronary revascularization can improve regional and global left ventricular function in those with viable but dysfunctional myocardial tissue, and thereby benefit heart failure symptoms and quality of life. Usually, an improvement in the global left ventricular ejection can be anticipated if the extent of hibernating myocardium exceeds 20% to 25% of the ventricle. Data based on meta-analyses of observational studies28 have indicated that coronary revascularization in patients with myocardial viability benefits survival. More recent randomized trial data have been conflicting with regard to a mortality benefit of revascularization based on the presence or absence of viability, and this remains an active area of investigation.29,30A survival benefit could conceivably reflect factors besides an improvement in ventricular function, including prevention of ventricular remodeling and a reduction in ventricular arrhythmogenesis.
Several nuclear imaging options can be used to identify myocardial viability. Markers of viability that have been proposed include the fill-in of a perfusion defect on late (24-hour) thallium-201 redistribution or reinjection images, reversibility of a rest perfusion defect on 3- to 4-hour redistribution images, and demonstration of residual tissue glucose metabolic activity in hypoperfusion myocardial regions (a perfusion-metabolism mismatch) on PET images obtained using the glucose analog F-18 2-fluoro-2-deoxyglucose (FDG). Some have proposed that a relative perfusion tracer concentration >55% to 60% of maximal myocardial activity on rest perfusion images can be used to identify myocardial viability. In a meta-analysis, radionuclide techniques and dobutamine echocardiography had similar positive and negative predictive values for identifying segments with improvement in wall motion following revascularization.31 The nuclear imaging techniques appeared to be slightly more sensitive in identifying viability, as defined by an improvement in function following revascularization, whereas dobutamine echocardiography appeared to be slightly more specific.
SUMMARY
Nuclear cardiac imaging techniques have become an integral component of the practice of clinical cardiology. As with any diagnostic tool, the physician must have a working knowledge of the strengths and limitations of the imaging technology in order to utilize this technology for optimum clinical benefit. In appropriately selected patients, MPI is very useful for identifying obstructive CAD, for characterizing the functional significance of equivocal coronary stenoses, and for risk stratification. In those with CAD and systolic ventricular dysfunction, nuclear imaging techniques can be used to quantitate the severity of the ventricular dysfunction and to monitor the myocardial response to treatment noninvasively. Nuclear imaging techniques may also identify those individuals with ischemic cardiomyopathy who are likely to benefit functionally and prognostically from coronary revascularization.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Wael Jaber and Dr. Manuel Cerqueira for their thoughtful review of this chapter, as well as Dr. Omosalewa Lalude for her contributions to the prior version of this chapter.
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QUESTIONS AND ANSWERS
Questions
1. A 65-year-old man with a 45-pack-year smoking history, hyperlipidemia, intermittent claudication, and hypertension has been experiencing shortness of breath with exertion for 3 months. He is referred for an adenosine cardiac single photon emission computed tomography (SPECT) study for symptom evaluation. His medications include metoprolol, lisinopril, aspirin, theophylline, and simvastatin. During the adenosine infusion, the patient does not report any chest pain, nor are there any ST-segment changes on the electrocardiogram (ECG). High-degree atrioventricular (AV) block develops 30 seconds following the start of the adenosine infusion, prompting the cardiology fellow attending the stress test to stop the infusion. The SPECT perfusion images are interpreted as normal, with no regional ischemia. Despite continuation of medical therapy the patient’s symptoms persist, and 6 weeks later he is referred for cardiac catheterization. At catheterization there is a proximal 75% right coronary artery stenosis, a 75% to 80% proximal left anterior descending artery stenosis, and a 70% to 75% stenosis of the proximal circumflex artery. Possible reasons for the absence of a reversible perfusion defect on the cardiac SPECT study include all of the following except:
a. Ingestion of a chocolate bar 3 hours before the test was performed
b. Right bundle branch block (RBBB) on the resting ECG
c. Provocation of “balanced ischemia” by the adenosine stress
d. Failure to withhold the patient’s medications prior to the test
e. Termination of the adenosine infusion at 30 seconds
2. Which of the following individuals is likely to benefit most from nuclear stress imaging?
a. A 25-year-old man with midline chest pain, which is tender to the touch and intermittently responsive to ibuprofen
b. A 30-year-old woman who gets chest discomfort after eating highly seasoned food but who has no trouble when she plays tennis three times a week
c. A 39-year-old male smoker with shortness of breath on exertion and a mildly elevated low-density lipoprotein (LDL) cholesterol level. His father died suddenly at age 45, and his 42-year-old brother recently had two stents placed in one of his coronary arteries. The resting ECG shows nonspecific ST-T-wave changes.
d. A 76-year-old man, former smoker, with hypertension and recent inferior wall myocardial infarction (MI) treated by placing two stents in the right coronary artery. He was awakened by an episode of chest pain that lasted almost 20 minutes and that has not responded to sublingual nitroglycerin.
e. A 55-year-old female with hypercholesterolemia, hypertension, frequent heartburn, and increasing shortness of breath on exertion. On echocardiography, there is moderate left ventricular hypertrophy (LVH), and aortic valvular calcification with an estimated aortic valve area of 0.69 cm2.
3. A 58-year-old male executive is seen for left-sided chest pain. He has a history of bilateral thumb pain for which he took a cox-2 inhibitor for 2 years before switching to naproxen. He works long hours and admits to fatigue and loss of libido. He has an elevated lipoprotein A (Lpa) level but an otherwise normal lipid profile. The hs-CRP level is normal and a cardiac SPECT study 3 years earlier was normal. He undergoes an exercise cardiac SPECT and exercises to 10 METs on the Bruce protocol, achieving 106% of his maximum predicted heart rate (MPHR). With exercise, he experiences fatigue but no angina. No ST-segment changes are noted with stress. The myocardial perfusion images from the exercise study are shown (see figure).
Based on the results of this scan, his cardiac mortality over the next 3 years can be estimated as:
a. ≤1.5%
b. 3%
c. 5%
d. 6%
e. >9%
4. A 71-year-old man with a history of hyperthyroidism, hypertension, and remote pulmonary embolism is referred for treatment of new-onset atrial fibrillation. He underwent a rest rubidium/dipyridamole stress rubidium-82 perfusion study (see figure).
The myocardial perfusion images are most consistent with:
a. Inferior ischemia
b. Apical and inferior ischemia
c. Anterior wall ischemia
d. Diaphragmatic attenuation
e. Normal perfusion scan
5. A 36-year-old woman presents to the Emergency Room with atypical chest pain. She smokes and there is a family history of coronary artery disease (CAD). The ECG shows a normal sinus rhythm with early repolarization. Cardiac enzymes are negative and the patient is referred for stress myocardial perfusion imaging (MPI). The patient undergoes treadmill exercise using the Bruce protocol. She is able to complete stage 2 of the exercise protocol (7 METs), being limited by leg fatigue. She does not experience chest pain with exercise. She achieves 92% of her maximal age-predicted heart rate. During stress, the ECG shows a new left bundle branch block (LBBB). Rest thallium-201 and stress Tc-99m tetrofosmin images were obtained (see figure).
The myocardial perfusion images demonstrate:
a. Normal study with breast attenuation
b. A fixed septal perfusion defect
c. A reversible septal perfusion defect, indicating disease in the left anterior descending coronary artery
d. A reversible septal perfusion defect, reflecting the development of LBBB with exercise
e. A reversible septal perfusion defect of uncertain etiology
6. An 80-year-old man is referred for a second opinion regarding the need for cardiac surgery. He sustained an inferior MI 12 years ago. Over the last 4 years, he has had increasing shortness of breath, but no angina. Nine months ago he had an echocardiogram that showed mild calcific aortic stenosis, with a left ventricular ejection fraction (LVEF) of 60%. Three months prior to presentation he was hospitalized for congestive heart failure (CHF). Echocardiogram again showed mild aortic stenosis, with a LVEF of 25%. Cardiac catheterization confirmed mild aortic stenosis, and on coronary angiography, there was multivessel CAD. Rest and stress rubidium-82 perfusion images, and 18FDG metabolic positron emission tomography (PET) images, were obtained (see figure).
The PET scan demonstrates:
a. A small inferior scar
b. Extensive septal, anterior, apical, and lateral ischemia
c. A small inferior scar, with extensive septal, anterior, apical, and lateral ischemia
d. Extensive myocardial hibernation involving the septal, anterior, apical, and lateral regions, with a small inferior scar
e. Normal regional perfusion and metabolism findings suggest nonischemic dilated cardiomyopathy.
7. In a patient with ischemic cardiomyopathy, which of the following scintigraphic findings suggests that abnormal regional function is unlikely to improve if coronary revascularization is performed?
a. A defect on rubidium-82 PET images with preserved uptake on 18F-fluorodeoxyglucose PET images in the same area
b. A reversible stress-induced perfusion defect in the same region on rest thallium-201/stress Tc- 99m sestamibi SPECT images
c. The region exhibits a Tc-99m sestamibi SPECT perfusion defect with a relative tracer concentration of 55% of maximal myocardial activity. Relative tracer activity on PET images with 18F-fluorodeoxyglucose is 95% of peak maximal myocardial activity.
d. A resting thallium-201 perfusion defect in which the relative tracer concentration is 40% of peak myocardial uptake, and which then increases to 90% of peak myocardial uptake on images obtained following thallium-201 reinjection
e. A matching defect on 13N-ammonia and 18F-fluorodeoxyglucose PET images
8. A 57-year-old man with a history of CAD, prior MI, and remote coronary artery bypass surgery was referred for evaluation for coronary revascularization because of recurrent angina and heart failure symptoms. There was a history of hyperlipidemia, hypertension, and deep venous thrombosis. An implantable cardioverter-defibrillator (ICD) had been placed 2 years before because of ventricular arrhythmias. Echocardiography confirmed global left ventricular systolic dysfunction, with an LVEF of 20%. Rest and stress rubidium-82 perfusion and 18F-fluoro- deoxyglucose PET images were obtained (see figure).
Which of the following statements is true regarding the scintigraphic findings?
a. Left ventricular dysfunction is probably due to a nonischemic cardiomyopathy.
b. On contrast magnetic resonance imaging, pronounced late enhancement will probably be observed in the lateral wall.
c. A reversible perfusion defect is identified in the anterior wall.
d. Coronary revascularization would be unlikely to improve the patient’s heart failure symptoms.
e. On histopathologic examination, extensive myocardial fibrosis would be expected if a biopsy of the lateral wall of the left ventricle were obtained.
9. Which of the following is not a contraindication to pharmacologic vasodilator stress testing with an adenosinergic agent?
a. Severe reactive airway disease
b. Severe symptomatic aortic stenosis
c. LBBB
d. High-grade AV block
e. All of the choices are contraindications to adenosinergic agents.
10. Which of the following are acceptable options for postinfarct risk management in a patient with a permanent ventricular pacemaker who has been conservatively managed during an acute non–ST-elevation myocardial infarction (NSTEMI) and has not undergone coronary angiography prior to discharge?
a. Optimal medical therapy including aspirin, thienopyridine, statin, beta-blocker, and ACE-inhibitor; no need for further diagnostic testing.
b. Optimal medical therapy and resting echocardiogram
c. Optimal medical therapy, resting echocardiogram, and symptom-limited exercise ECG testing
d. Optimal medical therapy, resting echocardiogram, and symptom-limited exercise SPECT imaging
e. Optimal medical therapy and vasodilator stress SPECT imaging with gated ejection-fraction estimate
11. A 63-year-old man is referred to you for the evaluation of exertional chest discomfort. His resting ECG is abnormal. In which of the following situations would MPI NOT be a necessary adjunct to the stress ECG to identify inducible ischemia?
a. Wolff–Parkinson–White pattern on baseline ECG
b. LBBB on baseline ECG
c. LVH with secondary repolarization changes on baseline ECG
d. RBBB on baseline ECG
e. Digitalis effect on baseline ECG
Answers
1. Answer B: Appropriate patient preparation is crucial for successful nuclear stress imaging. Recent ingestion of chocolate and/or theophylline could have blunted the hyperemic effects of adenosine, resulting in a falsely negative study. A 30-second infusion of adenosine might not have delivered a sufficient amount of the drug to produce adequate myocardial hyperemia. Alternatively, in a patient with proximal stenoses of nearly equal severity in each of the major coronary vessels, “balanced ischemia” is also a consideration; in this situation, a regional disparity in myocardial perfusion on the stress images is not identified because the impairment in flow reserve is similar in each of the three vascular territories. Right bundle branch block itself would not be expected to cause a false negative perfusion study.
2. Answer C: The 39-year-old smoker has several cardiac risk factors and is in an intermediate-risk category for an adverse cardiac event. This patient is the one most likely to benefit from diagnostic testing, for a positive stress perfusion study will put him into a high-risk category, whereas a negative stress perfusion study will stratify him into a low-risk patient population. The young man and woman in a and b have noncardiac chest pain; they are in a low-risk population and are unlikely to derive a benefit from stress MPI. The patient in d has known CAD and an unstable clinical picture following recent coronary stenting, and would more appropriately be referred directly for repeat coronary angiography. The patient in e has moderately severe aortic stenosis, and would more appropriately be referred for cardiac catheterization and coronary angiography.
3. Answer A: The myocardial perfusion images in this middle-aged man with atypical chest pain and two cardiac risk factors (male sex, elevated lipoprotein a level) are normal. The risk of a cardiac event over the next 3 years in this patient is ≤ 1.5% (≤ 0.5% per year), according to one study.
4. Answer B: Reversible perfusion defects are identified involving the apical and inferior myocardial regions. In PET imaging, transmission images are used to correct the emission images for attenuation, thus attenuation by the diaphragm should not influence the tracer concentration in the inferior wall.
5. Answer E: A reversible septal perfusion defect is identified on the myocardial perfusion images. The reversible defect could reflect either the onset of LBBB with stress or obstructive coronary disease in the left anterior descending artery or both. Therefore, the findings are equivocal for CAD. The patient had CT coronary angiography following the nuclear imaging study, and this did not reveal any coronary lesions.
6. Answer C: Extensive reversible perfusion defects are noted in the septal, anterior, apical, and lateral regions, and there is a small scar in the inferior region that is best identified on the short-axis images. Because of the extensive ischemia, the patient was referred for coronary revascularization.
7. Answer E: A matching defect on 13N-ammonia and 18F-fluorodeoxyglucose PET images is indicative of myocardial scar, and there is little chance that the region will exhibit improved function if revascularization is performed. Regions with perfusion-metabolism mismatches, or hibernating myocardium, as exemplified by the findings in a and c, are likely to improve functionally if revascularization is performed. Dysfunctional regions with reversible perfusion defects, whether in response to stress (b) or on rest/reinjection thallium-201 images (d), are also likely to benefit functionally from coronary revascularization.
8. Answer C: A reversible perfusion defect is identified in the anterior wall. On the rest rubidium-82 perfusion and 18F-fluorodeoxyglucose images, there is an extensive perfusion-metabolism “mismatch” consistent with myocardial hibernation involving the anterolateral and inferolateral walls, as well as a portion of the inferior wall. There is a small inferior scar. The findings indicate that the patient would benefit from coronary revascularization. Prior histopathologic studies indicate that there is minimal fibrosis in areas with hibernating tissue, and therefore extensive late enhancement on contrast magnetic resonance imaging would not be anticipated.
9. Answer C: LBBB is a situation in which pharmacologic stress is preferred over exercise stress, due to an increased incidence of false-positive septal perfusion abnormalities on MPI with exercise stress. All of the other scenarios are relative contraindications to adenosinergic vasodilator stress.
10. Answer E: The current ACC/AHA guidelines regarding predischarge risk stratification in low-risk patients (i.e., those who are stable and without symptoms of ischemia or heart failure for 12 to 24 hours) who are admitted for unstable angina or NSTEMI—and who have not already undergone coronary angiography— recommend some form of noninvasive stress testing and assessment of LVEF prior to discharge.
This patient has a ventricular pacemaker, and so stress ECG testing alone would be nondiagnostic. Also, the ventricular-paced rhythm makes pharmacologic stress preferable to exercise, due to the increased incidence of false-positive septal perfusion abnormalities with exercise SPECT imaging in that situation.
11. Answer D: All of the other choices render ECGs nondiagnostic with respect to the presence of stress-induced ischemia.