Stress-Redistribution Imaging

Several recent studies of patients with chronic CAD showed that blood flow under basal conditions may be normal or near normal in myocardial regions, despite severe segmental dysfunction, and that this regional dysfunction improves after myocardial revascularization.^{1,25,26,28,29} In these patients with perfusion-contraction mismatch, the segmental dysfunction is believed to arise from repeated episodes of myocardial ischemia that lead to repetitive stunning, rather than true myocardial hibernation, which, by definition, requires reduced blood flow under basal conditions. Although the relative prevalence of stunning versus hibernation as a causative mechanism for reversible contractile dysfunction in patients with chronic CAD is uncertain, it appears that both processes occur, but most patients have a form of repetitive stunning. In these patients, the finding of reversible ischemia may be the key to determining the viability of dysfunctional segments, which is readily accomplished with stress thallium imaging. Thus, thallium redistribution in an asynergic region with a defect shown on stress imaging predicts improvement of regional contraction after revascularization (Fig. 37-3).^37,38 However, many regions of severely ischemic or hibernating myocardium appear to have irreversible thallium defects on standard exercise-redistribution imaging; hence, the negative predictive value of an irreversible ²⁰¹Tl defect is relatively poor. Up to 50% of regions with “irreversible” thallium defects improve in function after revascularization.^38–43 Thus, standard stress-redistribution thallium imaging has an excellent positive predictive value, but a suboptimal negative predictive value. It is generally accepted that stress 4-hour redistribution imaging does not provide satisfactory precision in differentiating between LV dysfunction arising from infarcted versus hibernating myocardium. This technique often underestimates the presence of viable myocardium and hence the potential for recovery after revascularization.

Figure 37-3 Stress and redistribution (3-hour delay) thallium-201 tomographic images after maximal treadmill exercise, showing a reversible perfusion abnormality in the septal, anterior, and apical regions in a patient with high-grade stenosis of the left anterior descending coronary artery. The finding of reversibly ischemic myocardium is an accurate indicator of viable myocardium.

This concept is supported by studies directly comparing the results of PET imaging and exercise-redistribution thallium scintigraphy. In four studies, between 38% and 47% of apparently irreversible thallium defects (that would have been identified as scar by stress-redistribution thallium imaging) were identified as viable on the basis of regional uptake of fluorine-18 (¹⁸F)-fluorodeoxyglucose (FDG).^44–47 Although these data suggest that metabolic imaging with PET is superior to thallium imaging in the detection of viable myocardium, two limitations of these studies must be emphasized. First, the severity of the reduction in thallium activity within the irreversible thallium defects was not assessed. The importance of quantitative analysis of regional thallium activity is discussed later. Second, the previous comparative studies of thallium scintigraphy and PET all used postexercise thallium imaging followed by a single redistribution study 3 to 4 hours later. As noted earlier, the limitations of 4-hour redistribution imaging are well established.

Modifications in imaging protocols with ²⁰¹Tl considerably enhance the ability of ²⁰¹Tl imaging to detect viable myocardium.^12,20,35 These include late redistribution imaging and ²⁰¹Tl reinjection techniques.

Late Thallium-Redistribution Imaging

In many patients, late imaging at 24 to 72 hours elicits ²⁰¹Tl redistribution in many defects that appear to be irreversible at 3 to 4 hours. This late ²⁰¹Tl redistribution is evidence of viable myocardium.^39,40,48,49 As many as 54% of defects that appear irreversible at 3 to 4 hours show reversibility at 24 hours, although this number is as low as 22% in some studies. ²⁰¹Tl redistribution is a continual process,⁵⁰ and a truly irreversible defect shown on early redistribution images will not reverse later. However, in many viable regions, defect reversal at 3 to 4 hours may be minimal and poorly detected. Hence, the defect may not reverse appreciably on qualitative interpretation, and the increase in relative tracer activity also may not exceed the reproducibility limit on quantitative analysis. In these regions, late redistribution imaging may confirm that defect reversibility has occurred.

Several studies show that late imaging at 8 to 72 hours shows substantial thallium redistribution in many defects that appear to be irreversible at 3 to 4 hours,^39,40,48,49 and that this late thallium redistribution is consistent with viable myocardium.^40,49 Kiat et al.⁴⁰ reported in 21 patients undergoing myocardial revascularization procedures that 61% of apparently irreversible defects seen at 4 hours reversed at the time of late (18- to 72-hour) redistribution imaging. The revascularization results in this latter study, as assessed by postintervention repeat thallium imaging, provided additional important insights. Of all regions that appeared irreversible at 4 hours, 72% showed improvement after revascularization, confirming earlier studies that found that standard 3- to 4-hour thallium redistribution imaging overestimates the prevalence and severity of irreversible myocardial damage. However, when these 4-hour irreversible defects were further analyzed with the results of late imaging, 95% of regions with late redistribution improved after revascularization, compared with only 37% of regions that remained irreversible on late imaging.⁴⁰ These findings indicate that myocardial segments that show late thallium redistribution represent viable myocardium and that late imaging may considerably improve the identification of viable myocardium in thallium defects that appear irreversible at 3 to 4 hours. The implications of late thallium redistribution for myocardial viability are similar to those of 3- to 4-hour redistribution. Many persistent defects seen at 3 to 4 hours show late redistribution. The positive predictive value of late redistribution is excellent, but the negative predictive value remains poor. The positive predictive value of late redistribution is more than 90%⁴⁰ in predicting improvement after revascularization; thus, defect reversibility with late imaging is an excellent marker of viable myocardium. The negative predictive value of an irreversible defect at 24 hours appears to be only marginally better than that of an irreversible defect at 3 to 4 hours. For example, 37% of irreversible defects seen at 24 hours improve after revascularization,⁴⁰ and 39% of irreversible defects seen at 24 hours show improvement by quantitative analysis when ²⁰¹Tl is reinjected at rest.⁵¹ Moreover, nearly 50% of these defects are metabolically active on PET imaging.⁵² This finding suggests that some ischemic regions may never redistribute, even on late imaging, no matter how long the redistribution period, unless serum thallium levels are augmented.

Thallium-Reinjection Techniques

The reinjection of thallium at rest immediately after the standard 4-hour redistribution image may overcome several of these limitations and may be used to assess myocardial viability in apparently irreversible thallium defects on standard early or late-redistribution images (Fig. 37-4).^53–55 Up to 49% of apparently irreversible defects on 3- to 4-hour redistribution images⁵³ and 39% of these defects on 24-hour redistribution images^51,56,57 show improved or normal uptake after thallium reinjection.⁵³ Additional redistribution imaging obtained hours after the reinjected thallium dose appears to provide no information beyond that obtained by imaging immediately after reinjection.⁵⁸ Fewer than 5% of myocardial regions with persistent defects on 3- to 4-hour redistribution plus reinjection images show evidence of late redistribution. However, late redistribution imaging is important when reinjection is performed at 4 hours without an intervening redistribution study. A simple exercise-reinjection protocol without redistribution imaging may miss unique and important viability information provided by redistribution. Hence, if reinjection protocols are used, it is essential to perform routine 3- to 4-hour redistribution imaging before the reinjection or to perform late-redistribution imaging in patients with persistent defects on stress-reinjection images.⁵⁹

Figure 37-4 Thallium reinjection imaging. Short-axis thallium single-photon emission tomography images obtained after exercise show extensive abnormalities in anterior and septal perfusion that persist on 4-hour redistribution images but improve substantially after reinjection.

The observation that thallium uptake after reinjection represents viable myocardium is substantiated in three subgroups of patients. First, in nine studies^{43,53,60–66} reporting on 295 patients with LV dysfunction who were evaluated again 3 to 6 months after revascularization, improved wall motion occurred in 69% of segments identified as viable by thallium reinjection before revascularization. Such improvement occurred in only 11% of segments considered nonviable by redistribution or reinjection images (Fig. 37-5). Second, in comparative studies with thallium reinjection and PET imaging with FDG, most myocardial segments that were identified as viable by reinjection had metabolic evidence of myocardial viability.^67–69 The concordance between data on thallium reinjection and FDG uptake was excellent, with 51% of regions with severe irreversible thallium defects on 4-hour redistribution studies identified as viable by both thallium reinjection and PET.⁶⁷ Third, in patients who underwent gated MRI to assess regional systolic function, excellent correlation was observed between regional thallium activity and FDG activity in myocardial regions with severely reduced or absent wall thickening.⁶⁸

Figure 37-5 Likelihood of improved regional left ventricular (LV) function after revascularization based on thallium-201 single-photon emission tomography imaging. Data are summarized from nine studies done with stress-redistribution-reinjection imaging^{43,53,60–66} and four studies done with rest-redistribution imaging.^71,73–75 The range of values reported in the individual studies is shown by the horizontal bars connected by vertical lines. The blue bars represent the positive predictive value, and the red bars represent the inverse of the negative predictive value.

These PET data are in keeping with previous studies indicating that up to 50% of regions with apparently irreversible thallium defects have metabolic activity by PET and thus evidence of viability.^44–47 These data also indicate that thallium reinjection is a convenient, clinically accurate, and relatively inexpensive method with which to identify viable myocardium in patients with chronic CAD and LV dysfunction. Thus, thallium reinjection at rest after 3- to 4-hour redistribution imaging provides most of the clinically relevant information on myocardial viability in regions with apparently irreversible thallium defects. Thallium reinjection may be used instead of 24-hour imaging in most patients with a persistent thallium defect on conventional redistribution images.

Rest-Redistribution Thallium Imaging

The finding of exercise-induced ischemia in a patient with LV dysfunction has important prognostic implications that usually identify the patient as a candidate for revascularization therapy. Thus, exercise-redistribution-reinjection thallium protocols are attractive because they provide important information about both jeopardized myocardium and viable myocardium. However, in many patients, the sole clinical issue is the viability of one or more regions of dysfunctional LV myocardium, not whether there is also inducible ischemia. In others, the coronary anatomy is known to be at high risk, and stress testing is contraindicated, although the determination of viability may establish the potential benefit of revascularization. In these patients, rest-redistribution thallium imaging is a practical approach that can yield accurate viability data. It is essential to obtain both initial images (indicating regional perfusion) and subsequent redistribution images. Although early thallium studies yielded mixed results on the predictive accuracy of rest-redistribution imaging,^33,36 subsequent studies show that a quantitative analysis of regional thallium activity in rest-redistribution studies predicts recovery of regional LV function with accuracy that is virtually identical to that achieved with thallium exercise-redistribution-reinjection imaging (see Fig. 37-5).^56,70–75 These results are also comparable to those with PET imaging with FDG. PET achieves a higher positive predictive value, and thallium single-photon emission tomography (SPECT) imaging achieves a higher negative predictive value.

The available data comparing rest-redistribution imaging and stress-redistribution-reinjection imaging indicate comparable positive and negative predictive values for recovery of regional function after revascularization. Both techniques have high sensitivity, yielding a negative predictive value of approximately 90% (see Fig. 37-5). However, specificity is much lower, yielding a positive predictive value of less than 70%. A limitation of this analysis is that thallium data are considered binomially, rather than as a continuum.

In laboratories using dual-isotope imaging for stress/rest imaging, with a technetium-99m (^99mTc) tracer for stress imaging and ²⁰¹Tl for rest imaging, the rest-redistribution thallium technique for viability assessment can be easily incorporated into the evaluation of patients with LV dysfunction, as discussed subsequently in this chapter. This can be done by performing rest-redistribution thallium imaging before the ^99mTc stress test (Fig. 37-6). Alternatively, if irreversible defects are detected after routine stress/rest imaging, late imaging of thallium redistribution at a time when the technetium has decayed provides additional information regarding viability of myocardium with reduced flow under resting conditions.

Figure 37-6 Rest-redistribution thallium imaging performed as part of a dual-isotope technetium-thallium stress imaging protocol in a 55-year-old patient with severe heart failure and left ventricular dysfunction (ejection fraction 30%). The initial thallium images at rest demonstrate several areas of reduced resting blood flow involving the septum, anteroapical wall, and inferior wall. Thallium redistribution imaging 4 hours later demonstrates substantial redistribution of thallium in the septal, anteroapical, and inferior regions of the left ventricle, indicating myocardial viability, with only the basal portion of the inferolateral wall representing irreversibly damaged myocardium. Following the thallium-redistribution image acquisition, stress imaging with technetium-99m sestamibi demonstrates inducible ischemia in the septum and anterior wall. However, without the redistribution images, routine stress/rest imaging would have given misleading information about viability because of the irreversible defects in the inferior and anteroapical walls.

Quantitative Analysis of Thallium Data

In 12 of the 13 SPECT studies summarized in Figure 37-5, regional thallium activity was analyzed quantitatively rather than with a visual scoring system. It is unclear whether a subjective interpretation of images can replicate these results. However, in most cases, the criteria for viability in these quantitative studies were based on a threshold level of thallium activity such that a thallium level greater than 50% or 60% of the activity in normal myocardial segments was considered viable. This black-and-white approach to the thallium data, classifying myocardial areas simply as viable or nonviable, achieves reasonable results. However, it does not take advantage of one of the greatest strengths of perfusion imaging: the ability to view regional tracer activity as a continuum rather than a simple binary function. Several studies show the nearly linear relationship (Fig. 37-7) between regional thallium activity and the likelihood of recovery of regional function after revascularization.^73–75 This continuous relationship between thallium activity and myocardial viability is confirmed by histologic studies of myocardial biopsy specimens obtained at surgery⁷⁶ that show a significant inverse relationship between thallium uptake and the degree of myocardial interstitial fibrosis (Fig. 37-8). For example, all myocardial segments with thallium activity greater than 50% of normal were considered viable in the study of Perrone-Filardi et al.⁷³ However, 56% of segments with thallium activity of 50% to 60% improved after revascularization, whereas 88% of segments with thallium activity greater than 80% showed functional improvement after revascularization (see Fig. 37-7). This important factor may explain the wide range of positive predictive values of thallium imaging reported in the individual studies summarized in Figure 37-5; there may have been considerable differences in relative thallium activity in regions considered viable in these studies. A corollary to this argument is that relative regional thallium activity provides a high degree of certainty at either end of the thallium-activity spectrum (see Fig. 37-7), but important uncertainty exists for intermediate thallium levels. Recent data suggest that late redistribution imaging (using a rest-redistribution protocol) may provide greater confidence about the potential for recovery of function in a myocardial region with intermediate thallium activity at 3 to 4 hours; 21% of such regions show increased relative thallium activity at 24 hours.⁷⁴

Figure 37-7 The nearly linear relationship between the percentage of peak thallium activity on rest-redistribution imaging and the likelihood of segmental improvement after revascularization. Although various cutoff values have been proposed as “thresholds” for viability, this figure shows the continuous nature of this relationship. LV, left ventricular.

(From Perrone-Filardi P, Pace L, Prastaro M, et al: Assessment of myocardial viability in patients with chronic coronary artery disease: Rest-4 hour-24-hour ²⁰¹thallium tomography versus dobutamine echocardiography, Circulation 94:2712–2719, 1996.)

Figure 37-8

Buy Membership for Internal Medicine Category to continue reading. Learn more here