Clinical Techniques of Positron Emission Tomography and PET/CT

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CHAPTER 24 Clinical Techniques of Positron Emission Tomography and PET/CT

Positron emission tomography (PET) is a powerful tool that provides high-quality assessment of myocardial diseases. Although PET has been used for more than 25 years as a powerful investigative tool to understand physiologic processes such as myocardial perfusion and metabolism, neuronal and receptor function, and, more recently, molecularly targeted imaging, it is increasingly being accepted in routine clinical practice as a noninvasive tool to evaluate patients with known or suspected coronary artery disease (CAD). The reasons for this increased acceptance are likely multifactorial and related to the exponential growth in the number of PET/CT systems, attributable primarily to the widely accepted role of the technology in clinical oncology, which has led to increased availability; approval by the U.S. Food and Drug Administration of PET radiopharmaceuticals for cardiac imaging; changes in reimbursement; and the increasing documentation of clinical efficacy of PET/CT. All of these factors have contributed to help advance the clinical role of PET/CT in clinical cardiovascular medicine. This chapter reviews the current clinical uses of cardiac PET/CT imaging with a focus on the diagnosis of CAD and assessment of myocardial viability.

RADIOPHARMACEUTICALS

Although several tracers have been used for evaluating myocardial perfusion with PET, the most widely used in clinical practice are rubidium 82 and ammonia N 13. In addition, ¹⁸FDG is the radiotracer of choice for the evaluation of myocardial viability.¹

Rubidium 82

Rubidium 82 is the most widely used radiotracer for clinical PET myocardial perfusion imaging (MPI). It is a potassium analogue that is a generator-product and does not require a cyclotron on site. It has a physical half-life of 76 seconds. This physical characteristic allows the generator to be eluted with greater than 90% yield every 10 minutes. In addition, the rapid reconstitution of the generator allows for fast sequential perfusion imaging and laboratory throughput, maximizing clinical efficiency. The generator is replaced every 28 days (reflecting the physical half-life of its parent radionuclide, strontium 82).

After infusion, rubidium 82 rapidly crosses the capillary membrane and is actively transported to the cell via the sodium/potassium ATP transporter, which depends on coronary blood flow.² Compared with fluorine 18 or nitrogen 13, the positron range and the spatial uncertainty in the location of the decaying nucleus of rubidium 82 (2.6 mm FWHM [full width at half maximum]) is greater than for fluorine 18 (0.2 mm FWHM) or nitrogen 13 (0.7 mm FWHM), mitigating the improved spatial resolution of PET.

Ammonia N 13

Being a cyclotron product, ammonia N 13 use in routine clinical practice is limited to institutions that have a cyclotron on site. It has a physical half-life of 9.96 minutes and has a shorter positron range compared with rubidium 82, resulting in higher signal-to-noise ratio. After injection, ammonia N 13 rapidly disappears from the circulation, permitting the acquisition of images of excellent quality. Although the sequestration of ammonia N 13 in the lungs is usually minimal, it may be increased in patients with depressed left ventricular systolic function or chronic pulmonary disease and, occasionally, in smokers; this may adversely affect the quality of the images. In these cases, it may be necessary to increase the time between injection and image acquisition to optimize the contrast between myocardial and background activity. When inside the myocyte, ammonia N 13 is incorporated into the glutamine pool and becomes metabolically trapped. Only a small fraction diffuses back into the intravascular space.³

Myocardial retention of ammonia N 13 is heterogeneous, with retention in the lateral left ventricular wall being about 10% lower than that of other segments, even in normal subjects. This heterogeneous retention could result in an apparent perfusion defect in the inferolateral wall, limiting its evaluation. Ammonia N 13 allows the acquisition of ungated and gated images of excellent quality. These studies take full advantage of the superior resolution of PET relative to single photon emission computed tomography (SPECT) because the half-life of ammonia N 13 is sufficiently long, and its average positron range is very short. Gated ammonia N 13 imaging can provide accurate assessments of regional and global cardiac function.⁴ This imaging agent is not well suited for peak stress gated imaging, however, because of the 3- to 4-minute time interval between radiotracer injection and start of imaging, and the relatively long (20 minutes) acquisition time.

¹⁸FDG

¹⁸FDG is an imaging agent that is used to assess myocardial metabolic activity. Fluorine 18 has a physical half-life of 109 minutes, allowing regional distribution to clinical sites from local cyclotrons. Although normal myocardium preferentially uses free fatty acids, ischemic myocardium switches to preferential glucose metabolism. Because ¹⁸FDG is a glucose analogue, it provides a unique opportunity to image ischemic but viable myocardium. ¹⁸FDG traces the initial transport of glucose across the myocyte membrane and its subsequent hexokinase-mediated phosphorylation to FDG-6-phosphate. Because the latter is a poor substrate for further metabolism and is impermeable to the cell membrane, it becomes virtually trapped in the myocardium, allowing the imaging of viable cells.

ASSESSMENT OF MYOCARDIAL PERFUSION

Figure 24-1 illustrates common protocols used for imaging myocardial perfusion with PET/CT, where the low-dose CT scan is used for attenuation correction.¹ This scan is also called a CT-based attenuation correction scan (CTAC).

FIGURE 24-1 A-D, Protocols for clinical cardiac PET/CT imaging. CAC, coronary artery calcium; CTA, CT angiography; CTAC, CT-based attenuation scan.

(From Di Carli MF, Dorbala S, Meserve J, et al. Clinical myocardial perfusion PET/CT. J Nucl Med 2007; 48:783-793.)

Computed Tomography Scans

After obtaining the topogram, a low-dose CT scan covering the heart region is obtained. The parameters of this low-dose, non–ECG gated CT scan include a slow gantry rotation combined with a high pitch (e.g., 0.5 : 1 to 0.6 : 1), a high tube potential (e.g., 140 kVp), and a low tube current (10 to 20 mA). The scan is obtained during tidal expiration breath-hold or shallow breathing. The rest and stress emission images should each be corrected with its own dedicated transmission scan because of known changes in cardiac and pulmonary volumes during pharmacologic stress. Whether one attenuation scan (e.g., one CTAC) is sufficient to correct the stress and rest transmission scans is yet to be determined.

Emission Scans

For rubidium 82, approximately the same dose (40 to 60 mCi) is injected for the rest and stress myocardial perfusion studies because of the short physical half-life of rubidium 82 (76 seconds). For ammonia N 13, the general trend is to use a lower dose for the rest images (10 mCi) and a higher dose for the stress images (30 mCi), analogous to 1-day SPECT imaging protocols. The low-dose/high-dose protocol is faster than same-dose protocols for rest and stress because it does not require waiting for decay of ammonia N 13 to background levels before a second dose can be administered. Large patients may require large doses for the rest and stress studies. Some laboratories perform stress imaging first because a normal scan may avoid the need for rest imaging. This approach limits the ability to assess rest myocardial blood flow and coronary vasodilator reserve, however, limiting the ability to identify patients with extensive CAD and “balanced” ischemia, as discussed subsequently.

Different protocols can be used to acquire emission scans (see Fig. 24-1), as follows:

1 ECG gated imaging. This is the most common clinical approach. Imaging begins 90 to 120 seconds after rubidium 82 injection, or 3 to 5 minutes after ammonia N 13 injection, to allow for clearance of radioactivity from the lungs and blood pool; the scan duration is approximately 5 minutes for rubidium 82 or 20 minutes for ammonia 13 N (see Fig. 24-1B).

2 Multiframe or dynamic imaging. Imaging begins with the bolus (short infusion) of rubidium 82 or ammonia 13 N and continues for 7 to 8 minutes or 20 minutes (see Fig. 24-1C). The advantage of this approach is that it allows quantification of myocardial blood flow (in mL/min/g) by fitting regional tissue and blood time-activity curves to a suitable kinetic model. Its main disadvantage is that one needs to perform a separate radionuclide injection to obtain ECG gated images from which to assess cardiac function, especially when using rubidium 82. Using ammonia 13 N, one can acquire a short multiframe or dynamic scan (4 minutes) that can be followed with a separate, approximately 15-minute ECG gated scan to assess myocardial perfusion and left ventricular ejection fraction (LVEF), without the need of an additional radionuclide injection owing to its longer physical half-life (approximately 10 minutes) (see Fig. 24-1D). To measure the left ventricular blood time-activity curves noninvasively, one must acquire many dynamic PET image frames while the tracer bolus passes through the right ventricle, the lungs, and the left ventricle. During this interval, it is common for a large amount of activity (approximately 20 to 30 mCi) to be located entirely within the PET scanner’s axial field of view. Because of possible count-rate limitations under such conditions, particularly in three-dimensional scan mode, great care must be taken to ensure the accuracy of the PET system’s corrections for random and scatter coincidences and dead time.

3 List mode imaging. This is the ideal approach because a single injection and data acquisition allows multiple image reconstructions (i.e., summed, ECG gated, and multiframe or dynamic) for a comprehensive physiologic examination of the heart. With this approach, image acquisition begins with the bolus injection of the radionuclide and continues for 7 to 8 minutes for rubidium 82 or 20 minutes for ammonia N 13 (see Fig. 24-1A). List mode imaging requires significant computer power to perform the multiple reconstructions, especially for the three-dimensional image acquisition mode.

Stress testing is most commonly performed using adenosine, dipyridamole, or dobutamine. Protocols using exercise stress testing with PET/CT have been described.⁵ The use of exercise PET in clinical practice is very limited, however, especially with shorter half-life agents such as rubidium 82 (half-life 76 seconds).

Quality Assurance for Cardiac PET/CT

Hybrid imaging using PET/CT is prone to significant artifacts if not performed correctly. Quality control measures, including routine inspection of the transmission and emission data and the transmission-emission alignment, should always be enforced to obtain high-quality studies. These quality control measures include the following:

1 Count density. The level of statistical noise in the emission and transmission images should be checked to see if enough counts have been acquired; this is crucial with rubidium 82 imaging because of the short half-life of the isotope. Although the image quality of CT transmission images may be suboptimal in heavy patients, this does not seem to compromise the quality of the attenuation correction because the attenuation map is integrated along the PET lines of response to obtain attenuation-correction factors. The most common sources of count-poor emission studies include large patient size, inadequate radionuclide dose or delivery (e.g., problems with intravenous access), and inadequate scan duration.

2 Heart-to-blood pool count ratio. Acquisition of emission images before complete clearance of radiotracer from the blood pool may potentially degrade image quality. The optimal prescan delay for acquisition of ammonia 13 N images is about 3 minutes and for rubidium 82 images is approximately 90 seconds in healthy subjects. The most common factors that prolong circulation time of the radionuclide include severe left ventricular systolic dysfunction (LVEF <30%, either chronic or acute secondary to severe ischemia during stress), right ventricular systolic dysfunction, and primary lung disease. In these clinical settings, increased prescan delay is usually required to improve image quality.¹^,⁶ The use of the list mode imaging protocols is very helpful because assumptions regarding prescan delay are not required.

3 Transmission-emission misalignment. Misregistration of transmission and emission images can result from respiratory or patient motion, and can lead to inaccurate clinical results (Fig. 24-2). Because transmission and emission imaging are sequential, patient or respiratory (e.g., deep inspiration) motion during the emission images is most likely to lead to transmission-emission misalignment and potential attenuation-correction artifacts (see Fig. 24-2). The extent and direction of this misalignment determine whether artifacts are apparent in the attenuation-corrected images. Most commercial PET/CT systems now include software tools to correct for transmission-emission misalignments.

FIGURE 24-2 Transmission-emission misalignment. A, The misaligned CT transmission and rubidium 82 images (right), and the resulting anterolateral perfusion defect on stress-rest rubidium 82 PET (left). The perfusion defect results from applying incorrect attenuation coefficients during tomographic reconstruction to the area of the left ventricular myocardium overlaying on the lung field on the CT transmission scan (arrows). B, The correction of the emission-transmission misalignment (right), and the resulting normal perfusion study.

(From Di Carli MF, Dorbala S, Meserve J, et al. Clinical myocardial perfusion PET/CT. J Nucl Med 2007; 48:783-793.)

Diagnostic Accuracy

Table 24-1 summarizes the published studies documenting the diagnostic accuracy of myocardial perfusion PET imaging for detecting obstructive CAD.⁷ The average weighted sensitivity for detecting at least one coronary artery with greater than 50% stenosis is 90% (range 83% to 100%), and the average specificity is 89% (range 73% to 100%). The corresponding average positive and negative predictive values are 94% (range 80% to 100%) and 73% (range 36% to 100%), and the overall diagnostic accuracy is 90% (range 84% to 98%). Most of the available data have been obtained with dedicated PET cameras, rather than with PET/CT systems. In a more recent study using PET/CT (where the CT was used only for attenuation correction), Sampson and colleagues⁸ reported a sensitivity of 93%, a specificity of 83%, and a normalcy rate of 100%. In this study of patients without known prior CAD, the positive and negative predictive values of PET/CT were 80% and 94%, with an overall accuracy of 87%. All patients with a low likelihood for CAD showed normal scans, for a normalcy rate of 100%. The sensitivity for detecting CAD in patients with single vessel and multivessel (two or more vessels) disease was 92% and 95%. These results were applicable to men and women and to obese and nonobese individuals.

TABLE 24-1 Summary of Published Literature Regarding Diagnostic Accuracy of PET

Comparative Studies of Positron Emission Tomography versus Single Photon Emission Computed Tomography

Two studies have performed a direct comparison of the diagnostic accuracy of rubidium 82 myocardial perfusion PET and thallium 201 imaging in the same patient populations. Go and colleagues ⁹ compared PET and SPECT in 202 patients and showed higher sensitivity with PET than with SPECT (93% vs. 76%), without significant changes in specificity (78% vs. 80%). Stewart and coworkers¹⁰ compared PET and SPECT in 81 patients and observed a higher specificity with PET than with SPECT (83% vs. 53%), without significant differences in sensitivity (86% vs. 84%). The differences between these two studies are likely to be attributable to patient selection resulting in differences in prescan likelihood of CAD.

More recently, Bateman and associates ¹¹ compared rubidium 82 PET and Tc 99m sestamibi SPECT in two matched patient cohorts undergoing clinically indicated pharmacologic stress perfusion imaging using contemporary technology for SPECT and PET. Overall diagnostic accuracy was higher for PET than for SPECT (87% vs. 71% with a 50% angiographic threshold, and 89% vs. 79% with a 70% angiographic threshold). Differences in diagnostic accuracy reflected primarily the increased specificity (with a marginal advantage in sensitivity) of PET versus SPECT, and applied to men and women and to obese and nonobese individuals.

Evaluation of Multivessel Coronary Artery Disease

The diagnosis of multivessel or left main CAD with diffuse balanced ischemia using MPI remains a challenge. PET (similar to SPECT) often uncovers only the coronary territory supplied by the most severe stenosis. The use of ancillary high-risk markers often helps in ascertaining the presence of multivessel CAD. ECG gating provides a unique opportunity to assess left ventricular function at rest and during peak stress (as opposed to poststress with gated SPECT). More recent data suggest that in normal subjects, LVEF increases during peak vasodilator stress.¹² In the presence of CAD, changes in LVEF (from baseline to peak stress) are inversely related to the magnitude of perfusion abnormalities during stress (reflecting myocardium at risk) (Fig. 24-3) and the extent of angiographic CAD (Fig. 24-4). In patients with three-vessel or left main CAD, LVEF during peak stress decreases even in the absence of apparent perfusion abnormalities (Fig. 24-5). In contrast, patients without significant CAD or with one-vessel disease show a normal increase in LVEF. Consequently, the negative predictive value of an increase in LVEF (from rest to peak stress) of 5% or greater to exclude the presence of three-vessel or left main CAD or both is 97%.¹²

FIGURE 24-3 Bar graph showing the relationship between the magnitude of stress-induced perfusion abnormalities and the delta change in left ventricular ejection fraction (LVEF) (from baseline to peak stress).

(From Dorbala S, Vangala D, Sampson U, et al. Value of vasodilator left ventricular ejection fraction reserve in evaluating the magnitude of myocardium at risk and the extent of angiographic coronary artery disease: a 82Rb PET/CT study. J Nucl Med 2007; 48:349-358.)

FIGURE 24-4 Bar graph showing the relationship between the delta change in left ventricular ejection fraction (LVEF) and the extent of angiographic coronary artery disease (CAD) (>70% stenosis).

FIGURE 24-5 Gated rest-stress rubidium 82 myocardial perfusion PET images illustrating the added value of left ventricular function over the perfusion information. A, Normal increase in left ventricular ejection fraction (LVEF) from rest to peak stress (bottom) in a patient with angiographic single vessel coronary artery disease, showing a single perfusion defect in the inferior wall on the PET images (arrows). B, Abnormal decrease in LVEF from rest to peak stress in a patient with angiographic multivessel vessel coronary artery disease, also showing a single perfusion defect in the inferolateral wall on the PET images (arrows).

(From Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation of coronary artery disease. Circulation 2007; 115:1464-1480.)

PET measurements of myocardial blood flow (in mL/min/g of myocardium) and coronary vasodilator reserve may also help overcome the limitations of relative perfusion assessments with PET to uncover the presence of multivessel CAD. Because myocardial blood flow (in mL/min/g of tissue) and coronary vasodilator reserve (the ratio between peak and rest myocardial blood flow) are inversely and nonlinearly related to stenosis severity, quantitative estimates of coronary hemodynamics by PET allow better definition of the extent of obstructive CAD. PET quantification of myocardial blood flow is well validated using ammonia 13 N.¹³^,¹⁴ Quantitative approaches with rubidium 82 have also been developed.¹⁵^,¹⁶ Validation studies in animals and humans are currently under way.

Risk Stratification

Studies documenting the incremental prognostic value of PET perfusion imaging in predicting patient outcomes are beginning to emerge. Yoshinaga and coworkers ¹⁷ studied the prognostic value of dipyridamole stress rubidium 82 PET in 367 patients who were followed for 3.1 ± 0.9 years. The extent and severity of perfusion defects with stress PET were associated with increasing frequency of adverse events. The negative predictive value of a normal scan to predict hard events (i.e., myocardial infarction or cardiac death) was very high; patients with normal stress PET had an event rate of 0.4%/year. This study, the largest published PET prognosis study to date, was limited, however, by the occurrence of only 17 hard events.

Preliminary data from our laboratory in 1602 consecutive patients undergoing rest-stress rubidium 82 myocardial perfusion PET/CT imaging also suggest that this technique provides incremental value to clinical variables in predicting overall survival.¹⁸ In contrast to previous studies, this study was adequately powered by the occurrence of 113 deaths (7% of the study cohort) during a median follow-up period of 511 days. In keeping with previous studies, increases in the extent and severity of stress perfusion defects translated into proportional increases in predicted mortality. In addition, preliminary data from our laboratory in 1274 consecutive patients also confirm the incremental prognostic value of LVEF over stress perfusion imaging.¹⁹ As expected, this analysis showed that mortality hazard was inversely related to LVEF. MPI added incremental value to LVEF (at any LVEF, a higher summed stress score had greater risk), and LVEF added incremental value to MPI (i.e., at any summed stress score, a lower LVEF had greater risk).

The potential to acquire and quantify rest and stress myocardial perfusion and CT information from a single dual-modality study opens the door to expand the prognostic potential of stress nuclear imaging. More recent data from our laboratory suggest that quantification of coronary artery calcium (CAC) scores at the time of stress nuclear imaging using a hybrid approach with PET/CT can enhance risk predictions in patients with suspected CAD.²⁰ In a consecutive series of 621 patients undergoing stress PET imaging and CAC scoring in the same clinical setting, risk-adjusted analysis showed a stepwise increase in adverse events (death and myocardial infarction) with increasing levels of CAC score for any level of perfusion abnormality. This finding was observed in patients with and without evidence of ischemia on PET MPI.

The annualized event rate in patients with normal PET MPI and no CAC was substantially lower than in patients with normal PET MPI and a CAC score of 1000 or greater (Fig. 24-6). Likewise, the annualized event rate in patients with ischemia on PET MPI and no CAC was lower than in patients with ischemia and a CAC score of 1000 or greater. These findings suggest incremental risk stratification by incorporating information regarding the anatomic extent of atherosclerosis in conventional models using nuclear imaging alone, a finding that may serve as a more rational basis for personalizing the intensity and goals of medical therapy in a more cost-effective manner. Although CT angiography as an adjunct to perfusion imaging could expand the opportunities to identify patients with noncalcified plaques at greater risk of adverse cardiovascular events, it is unclear how much added prognostic information there is in the contrast-enhanced coronary CT angiography scan over the simple noncontrast CT scan for CAC determination.²¹

FIGURE 24-6 Cox proportional hazards regression model for freedom from death or myocardial infarction (MI) adjusted for age, sex, symptoms, and conventional coronary artery disease risk factors in patients without ischemia (top panel) and with ischemia (lower panel). CAC, coronary artery calcium.

(From Schenker MP, Dorbala S, Hong ECT, et al. Relationship between coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study. Circulation 2008; 117:1693-1700.)

ASSESSMENT OF MYOCARDIAL VIABILITY

In addition to assessment of myocardial perfusion, PET/CT plays an important role in the evaluation of viability in patients with ischemic cardiomyopathy. This evaluation is of utmost clinical importance because high-risk surgical revascularization seems to afford a long-term survival benefit based on small series.²² Data from large-scale randomized clinical trials are still pending, however, and the selection of patients with severe left ventricular dysfunction for high-risk revascularization is controversial. It is very important to differentiate left ventricular dysfunction caused by scarring from that arising from viable but dysfunctional myocardium. PET/CT plays an important role in the evaluation of these patients and makes this distinction possible.

Hibernation versus Stunning

In patients with CAD and left ventricular dysfunction, the cause of the decrease in the left ventricular contractile function could be secondary to scarring, stunning, or hibernation. The differentiation between these three different pathophysiologic mechanisms is of utmost importance to developing a treatment strategy.

Myocardial scarring results from myocardial infarction or other inflammatory or infiltrative diseases that involve the myocardium. Myocardial stunning is a reversible state of regional contractile dysfunction that can occur after restoration of coronary blood flow following a brief episode of ischemia despite the absence of necrosis.²³ Although commonly regarded as an acute phenomenon, stunned myocardium may also occur in patients with chronic coronary stenosis who experience recurrent episodes of ischemia (symptomatic or asymptomatic) in the same territory. This mechanism is probably the most common form of stunning in patients with chronic left ventricular dysfunction secondary to CAD. Myocardial hibernation refers to a state of persistent left ventricular dysfunction associated with chronically reduced blood flow but preserved viability.²⁴ This chronic downregulation in contractile function at rest is thought to represent a protective mechanism whereby the heart reduces its oxygen requirements to ensure myocyte survival. This protective mechanism can result in a considerable amount of myocardium that is rendered hypocontractile, however, and it may contribute to overall left ventricular dysfunction. Different metabolic patterns are seen in these three states with PET metabolic imaging using ¹⁸FDG, which provides the basis for PET/CT ¹⁸FDG imaging.

Normal myocardium uses different energy-producing substrates to fulfill its energy requirements.²⁵ In the fasting state, free fatty acids (FFA) are mobilized in large quantities from triglycerides stored in adipose tissue. The increased availability of FFA in plasma makes them the preferred energy-producing fuel in the myocardium. In the fed state, however, the increase in plasma glucose and the subsequent increase in insulin levels significantly reduce FFA release from adipose tissue and, consequently, its availability in plasma. In addition, the increased insulin levels mobilize glucose transporters onto the cell membrane, resulting in increased transport and use of exogenous glucose by the myocardium.

Under ischemic conditions, there is a shift to preferential glucose uptake by the myocardium. Noninvasive approaches that can assess the magnitude of exogenous glucose use play an important role in the evaluation of tissue viability in ischemic cardiomyopathy. In addition, prolonged severe reduction of myocardial blood flow rapidly precipitates depletion of high-energy phosphate, cell membrane disruption, and cellular death. Assessment of regional blood flow also provides important information regarding the presence of tissue viability within dysfunctional myocardial regions.

PET/CT Viability Imaging Protocols

Because dysfunctional myocardium that improves functionally after revascularization must retain sufficient blood flow and metabolic activity to sustain myocyte viability, the combined assessment of regional blood flow and glucose metabolism seems most attractive for delineating myocardial viability. With this approach, regional myocardial perfusion is first evaluated after the administration of ammonia 13 N or rubidium 82. Because data regarding the magnitude of stress-induced ischemia and resting viability are important for management decisions, the ideal approach should include rest and stress perfusion imaging (Fig. 24-7). Regional glucose uptake is assessed with ¹⁸FDG, as described subsequently.

FIGURE 24-7 Myocardial viability PET/CT protocols. CTAC, CT-based attenuation scan; ETT, exercise treadmill testing.

(From Di Carli MF. Myocardial viability assessment with PET and PET/CT. In Di Carli MF, Lipton MJ [eds]. Cardiac PET and PET/CT Imaging. New York, 2007, Springer, pp 250-269.)

Patient Preparation for ¹⁸FDG Imaging

A detailed step-by-step description of the available methods for ¹⁸FDG imaging is provided by the “Guidelines for PET Imaging” published by the American Society of Nuclear Cardiology and the Society of Nuclear Medicine.⁶ The most commonly used approaches for ¹⁸FDG imaging include the following (Fig. 24-8):

1 Glucose loading. This is the most commonly used approach to ¹⁸FDG imaging. The goal of glucose loading is to stimulate the release of endogenous insulin to decrease the plasma levels of FFA and to facilitate the transport and use of ¹⁸FDG. Patients are usually fasted for at least 6 hours and then receive an oral or intravenous glucose load. Most patients require the administration of intravenous insulin to maximize myocardial ¹⁸FDG uptake. With this approach, image quality is generally of diagnostic quality, and the reported diagnostic accuracy is very good.

2 Hyperinsulinemic-euglycemic clamp. This approach is technically demanding and time-consuming. It provides the highest and most consistent image quality, however. Based on the reported predictive accuracies, the high image quality does not translate into improved predictions of functional outcome. Because the hyperinsulinemic-euglycemic clamp is technically demanding, most laboratories reserve this approach for challenging conditions (e.g., diabetes and severe congestive heart failure).

3 Acipimox. This is a nicotinic acid derivative that inhibits peripheral lipolysis, reducing plasma FFA levels and, indirectly, forcing a switch to preferential myocardial glucose use. The drug is usually given in combination with a glucose load 60 minutes before ¹⁸FDG administration. The approach is practical and provides consistent image quality. Acipimox is not available for clinical use in the United States, however.

FIGURE 24-8 Timeline of protocols for patient preparation before ¹⁸FDG imaging. FFA, free fatty acids; IV, intravenous.

(From Di Carli MF. Myocardial viability assessment with PET and PET/CT. In Di Carli MF, Lipton MJ [eds]. Cardiac PET and PET/CT Imaging. New York, 2007, Springer, pp 250-269.)

Although several methods have been proposed, only the glucose-loading approach has undergone extensive validation worldwide, and it remains the most commonly used in clinical practice. This approach can be technically challenging, especially in patients with diabetes and congestive heart failure, and aggressive patient preparation is mandatory to optimize diagnostic accuracy. The available evidence suggests that this approach can provide accurate predictions of functional, symptomatic, and prognostic improvement after revascularization, and improve management decisions in patients with poor cardiac function.

Myocardial Perfusion and Glucose-Loaded ¹⁸FDG Patterns

Using the sequential-perfusion ¹⁸FDG approach, four distinct perfusion-metabolism patterns can be observed in dysfunctional myocardium, as follows:

1 Normal perfusion associated with normal ¹⁸FDG uptake

2 Reduced perfusion associated with preserved or enhanced ¹⁸FDG uptake (so-called perfusion-metabolism mismatch), reflecting myocardial viability (Fig. 24-9)

3 Proportional reduction in perfusion and ¹⁸FDG uptake (so-called perfusion-metabolism match), reflecting nonviable myocardium (see Fig. 24-9)

4 Normal or near-normal perfusion with reduced ¹⁸FDG uptake (so-called reversed perfusion-metabolism mismatch) (Fig. 24-10)²⁶

FIGURE 24-9 PET patterns of myocardial viability. Left panel, Concordant reductions in myocardial perfusion (rubidium 82) and glucose metabolism (¹⁸FDG), reflecting myocardial infarction. Right panel, Preserved glucose metabolism (¹⁸FDG) in a territory with decreased myocardial perfusion (rubidium 82), reflecting complete tissue viability.

(From Di Carli MF, Hachamovitch R. New technology for noninvasive evaluation of coronary artery disease. Circulation 2007; 115:1464-1480.)

FIGURE 24-10 PET images of a dog heart in short-axis views obtained at corresponding mid-ventricular levels obtained after reperfusion following four 5-minute left anterior descending coronary artery occlusions, each followed by 5 minutes of reperfusion. Images of blood flow (left column) were obtained with ammonia 13 N and images of glucose metabolism (middle column) were obtained with ¹⁸FDG. Images of oxidative metabolism (reflecting regional myocardial oxygen consumption []) (right column) were obtained with acetate 11 C; the early phase denotes delivery of the tracer to the myocardium, whereas the late phase represents regional washout of the tracer through the tricarboxylic acid cycle (myocardial oxidation). Top panel, Corresponding mid-ventricular short-axis sections of regional blood flow, glucose, and 4 hours after reperfusion. The flow images (left) show near-normal perfusion in the stunned regions (i.e., anterior and anterior septum). Stunned regions showed reduced ¹⁸FDG use (arrow), however, and slow clearance of acetate 11 C (impaired oxidation) relative to normal myocardium (lateral wall). Middle panel, One day after reperfusion. Myocardial perfusion in stunned myocardium is near-normal, glucose uptake (arrow) remains depressed, and the is still lower (arrow) than in normal myocardium. Bottom panel, One week after reperfusion. Blood flow, glucose uptake, and are largely homogeneous. Wall motion and metabolism showed a parallel recovery with time. MBF, myocardial blood flow.

(From Di Carli MF, Prcevski P, Singh TP, et al. Myocardial blood flow, function, and metabolism in repetitive stunning. J Nucl Med 2000; 41:1227-1234.)

The patterns of normal perfusion and metabolism or of a PET mismatch identify potentially reversible myocardial dysfunction, whereas the PET match pattern identifies irreversible myocardial dysfunction. The reversed perfusion-metabolism mismatch has been described in the context of repetitive myocardial stunning,²⁶ and in patients with left bundle branch block.²⁷ Quantitation of regional myocardial perfusion and ¹⁸FDG tracer uptake and their difference can be helpful to assess objectively the magnitude of viability. In addition, gated ¹⁸FDG-PET/CT images can be used to assess global left ventricular function.

Accuracy of PET/CT to Predict Functional Recovery

Myocardial Perfusion

Using only regional myocardial perfusion information, contractile dysfunction was predicted to be reversible after revascularization when regional blood flow was only mildly or moderately reduced (>50% of normal), and irreversible when regional blood flow was severely reduced (<50% of normal). Using these criteria, the average positive predictive accuracy of blood flow estimates for predicting functional recovery after revascularization is 63% (range 45% to 78%), whereas the average negative predictive accuracy is 63% (range 45% to 100%). ¹⁸FDG imaging adds significant independent information for distinguishing reversible from irreversible myocardial dysfunction and improving the diagnostic accuracy of PET/CT in predicting functional recovery.²⁸

Combined Myocardial Perfusion and ¹⁸FDG

The experience with the combined blood flow/¹⁸FDG approach using PET or the PET/SPECT hybrid technique (SPECT perfusion with ¹⁸FDG-PET imaging) has been extensively documented in 17 studies including 462 patients (Table 24-2).²⁸ Contractile dysfunction was predicted to be reversible after revascularization in regions with increased ¹⁸FDG uptake or a perfusion-metabolism mismatch, and irreversible in regions with reduced ¹⁸FDG uptake or a perfusion-metabolism match pattern. Using these criteria, the average positive predictive accuracy for predicting improved segmental function after revascularization is 76% (range 52% to 100%), whereas the average negative predictive accuracy is 82% (range 67% to 100%).

TABLE 24-2 Predictive Values for Segmental Functional Recovery after Revascularization Using Combined Estimates of Myocardial Perfusion and ¹⁸FDG Metabolism with PET

Several studies using different PET approaches have shown that the gain in global left ventricular systolic function after revascularization is related to the magnitude of viable myocardium assessed preoperatively (Table 24-3).²⁸ These data show that clinically meaningful changes in global left ventricular function can be expected after revascularization only in patients with large areas of hibernating or stunned myocardium (≥17% of the left ventricular mass). Patients with large areas of PET mismatch (≥18% of the left ventricle), in particular areas located in the territory served by the left anterior descending coronary artery, had the greatest clinical benefit.

TABLE 24-3 Relationship between the Extent of Viability and the Change in Left Ventricular Ejection Fraction after Revascularization Using Combined Estimates of Myocardial Perfusion and ¹⁸FDG Metabolism with PET

Data evaluating the improvement in the global left ventricular function are limited. Most of the published studies included patients with normal or mild left ventricular dysfunction. The direct extrapolation of the excellent results obtained in patients with regional or mild to moderate left ventricular dysfunction to patients with very low LVEF is problematic. In addition to the degree of viability by ¹⁸FDG-PET/CT, many other factors affect functional outcome after revascularization, including the presence and magnitude of stress-induced ischemia, the stage of cellular degeneration within viable myocytes, the degree of left ventricular remodeling, the timing and success of revascularization procedures, the adequacy of the target coronary vessels, and the timing of left ventricular functional assessment after revascularization.

Impact of Viability Assessment on Patient Outcomes

The goal of viability assessment by PET in the setting of severe ischemic cardiomyopathy is to identify patients in whom revascularization can potentially improve left ventricular function, symptoms, and survival. Multiple studies have addressed this question and are summarized in Table 24-4. The studies included a total of 288 patients with CAD and moderate or severe left ventricular dysfunction. Most of these patients had a history of myocardial infarction and multivessel CAD. Patients with viable myocardium had a consistently higher event rate than patients without viability suggesting an increased risk of a cardiac event for patients with viable myocardium treated medically.

TABLE 24-4 Risk of Cardiac Events for Patients with Moderate to Severe Left Ventricular Dysfunction and Hibernating Myocardium Compared with Patients without Hibernating Myocardium

These data suggest that the presence of ischemic but viable myocardium as assessed by ¹⁸FDG-PET seems to identify consistently patients with left ventricular dysfunction who are at high risk for cardiac events when treated with medical therapy alone. In addition, Allman and colleagues ²⁹ reported a meta-analysis of 24 studies that documented long-term patient outcomes after viability imaging by SPECT, PET, or dobutamine echocardiography in 3088 patients (2228 men, 860 women) with a mean LVEF 32% ± 8% and follow-up for 25 ± 10 months. There was no apparent benefit for revascularization over medical therapy in the absence of demonstrated viability. Meta-regression of the pooled study data in patients with viable myocardium showed an inverse relationship between LVEF and the prognostic benefit associated with revascularization.

The multicenter randomized PARR-2 study did not show a significant reduction in cardiac events in patients with left ventricular dysfunction and suspected coronary disease for ¹⁸FDG-PET–assisted management versus standard care.³⁰ The study included 440 patients with severe left ventricular dysfunction and coronary disease being considered for revascularization, heart failure, or transplantation. Patients were randomly assigned to management assisted by ¹⁸FDG-PET or standard care. The primary outcome, a composite of cardiac death, MI, or hospitalization within 1 year, was not different between the two groups (30% for the PET arm vs. 36% for the standard arm; relative risk 0.82, P = .16); however, 25% of the patients with PET-indicated revascularization did not have it done. In patients who adhered to PET recommendations and in patients without recent angiography, significant benefits were observed (hazard ratio 0.4, P = .035).

Another target for revascularization in these patients is the control of symptoms and hospital admissions for congestive heart failure. We showed a significant linear correlation between the global extent of a preoperative perfusion-metabolism PET mismatch (reflecting hibernating myocardium) and the percent improvement in functional capacity after coronary artery bypass graft surgery in 36 patients with ischemic cardiomyopathy (LVEF 28% ± 6%) (Fig. 24-11).³¹ In this study, a perfusion-metabolic PET mismatch involving 18% or greater of the left ventricle on quantitative analysis was associated with a sensitivity of 76% and a specificity of 78% for predicting a significant improvement in heart failure class after bypass surgery.

FIGURE 24-11 Relationship between the anatomic extent of the perfusion–¹⁸FDG-PET mismatch (% of the left ventricle [LV]) and the change in functional capacity (metabolic equivalents of oxygen consumption [METS]) after coronary artery bypass graft (CABG) surgery in patients with severe left ventricular dysfunction.

(Based on data from Di Carli MF, Asgarzadie F, Schelbert HR, et al. Quantitative relation between myocardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation 1995; 92:3436-3444.)