Dobutamine Echocardiography and Quantitative Rest-Redistribution 201Tl Tomography in Myocardial Hibernation
Relation of Contractile Reserve to 201Tl Uptake and Comparative Prediction of Recovery of Function
Background The purposes of this study were to evaluate the comparative accuracy of dobutamine echocardiography and quantitative rest-redistribution 201Tl tomography in the prediction of recovery of function after revascularization and to assess the relation of contractile reserve to thallium uptake.
Methods and Results Thirty-four patients with stable coronary disease and regional dysfunction underwent dobutamine echocardiography (2.5 up to 40 μg·kg−1·min−1) and rest-redistribution 201Tl tomography 1 day before revascularization. Resting echocardiography and scintigraphy were repeated at ≥6 weeks. Before revascularization, resting 201Tl uptake was similar in segments demonstrating biphasic or sustained improvement and was higher than in those exhibiting no change or worsening function during dobutamine. After revascularization, 201Tl uptake increased only in segments that showed a biphasic response (from 66±12% to 78±13%; P<.05). Biphasic response had a sensitivity of 74% and specificity of 89% for prediction of recovery. The use of biphasic or sustained improvement responses increased the sensitivity to 86% with a decrease in specificity to 68%. Qualitative thallium assessment provided a high sensitivity (98%) but poor specificity (27%). Quantification of thallium uptake, however, improved its accuracy: a maximal uptake (at rest or redistribution) of ≥60% yielded a 90% sensitivity and a 56% specificity.
Conclusions In patients with myocardial hibernation, biphasic response during dobutamine is less sensitive but more specific for recovery of function, whereas indexes of 201Tl scintigraphy are in general more sensitive and less specific, the least accurate being a qualitative assessment of thallium uptake. The sensitivity and specificity of both methods, however, can be altered depending on the quantitative criteria of thallium uptake or combination of responses of the myocardium to dobutamine.
In patients with severe coronary artery disease, chronic resting ventricular dysfunction may represent necrotic or viable myocardium.1 2 The differentiation of necrotic from hibernating myocardium remains a clinical challenge. Assessment of myocardial viability traditionally has been performed with positron emission tomography.3 More recently, 201Tl imaging has also been used because the cellular uptake of 201Tl depends on preserved myocardial cellular metabolism and perfusion.4 5 6 7 An alternative approach has evolved from clinical and experimental observations demonstrating that hypoperfused, viable myocardium retains residual contractile reserve in response to inotropic stimulation.8 9 10 11 12 A few clinical studies using low-dose dobutamine8 9 11 demonstrated that contractile reserve was a predictor of functional recovery. More recently, we10 showed that the use of high-dose in addition to low-dose dobutamine improved its accuracy in predicting recovery of function after revascularization by identifying an ischemic component at high dose.
To date, a paucity of studies13 14 15 have assessed the comparative accuracy of 201Tl imaging and dobutamine echocardiography (DE) in predicting recovery of function of the hibernating myocardium. These studies evaluated low-dose dobutamine with either planar 201Tl imaging or qualitative thallium tomography (single photon emission computed tomography [SPECT]). The present investigation was designed to study prospectively the comparative accuracy of low- and high-dose DE and quantitative 201Tl SPECT in the prediction of recovery of function after revascularization. Quantitative rest and 4-hour redistribution 201Tl tomography was chosen because of its high concordance with positron emission tomography7 and protocol time efficiency. Furthermore, it provides an opportunity to compare resting perfusion characteristics of dysfunctional myocardial segments that exhibit different wall motion responses to dobutamine.
Patients with chronic stable coronary artery disease and resting regional left ventricular dysfunction already scheduled to undergo revascularization with angioplasty or bypass surgery were included in the study. The decision for revascularization was not influenced by the results of the present study. These individuals represent a different group of patients from those previously reported.10 Inclusion criteria were the presence of significant coronary stenosis (≥70% diameter stenosis) of at least one major epicardial artery and the presence of any resting wall motion abnormality on prior contrast ventriculography or echocardiography. The study protocol was approved by the Institutional Review Boards of Baylor College of Medicine, The Methodist Hospital, and the Veterans Affairs Medical Center in Houston, Tex. Informed consent was obtained from all patients before enrollment. Patients with unstable angina and recent myocardial infarction (<6 weeks) were excluded. Other exclusion criteria included significant valvular heart disease, angioplasty of saphenous vein grafts, a contraindication to the administration of dobutamine, and inadequate echocardiographic imaging.
The time sequence of echocardiographic and 201Tl protocols is shown in Fig 1⇓. Cardiac medications were not withheld before imaging because these often included long-acting preparations. Resting echocardiography and DE were performed 1 day before the planned revascularization. After resting images were obtained, dobutamine infusion was started at 2.5 μg·kg−1·min−1 and increased every 3 minutes to 5, 7.5, 10, 20, 30, and a maximum of 40 μg·kg−1·min−1. Images were obtained from the standard parasternal and apical views. Continuous monitoring of the ECG and blood pressure was performed, and criteria for termination of the test were as previously reported.10
Studies were performed with the use of a Hewlett-Packard Sonos 1000 or 1500 ultrasound system with a 2.5-MHz transducer. Images were recorded on video and digitized on-line in a quad-screen format at rest and at 5 μg·kg−1·min−1, 7.5 μg·kg−1·min−1, and peak dobutamine doses (Tomtec Imaging Systems Inc) and stored on optical disc for later interpretation. This quad-screen display format has been shown to allow an optimal assessment of the biphasic response during dobutamine with this infusion protocol.10 The resting echocardiograms late after revascularization were also digitized using the four views.
201Tl SPECT Protocol
Resting and 4-hour redistribution 201Tl SPECT were performed after the intravenous administration of 3 mCi 201Tl on the same day as DE before the revascularization procedure. Rest-redistribution 201Tl SPECT and echocardiography were also performed on the same day at the time of late follow-up (Fig 1⇑). 201Tl SPECT was performed by use of the methods previously reported from our laboratory.16 17 A large-field-of-view rotating gamma camera with a high-resolution, parallel-hole collimator was used. Data acquisition was performed over a 180° arc (45° left posterior oblique to 45° right anterior oblique view) consisting of 32 frames. The images were reconstructed with the use of a filtered back-projection algorithm using a Butterworth filter with a cutoff frequency of 0.50 Nyquist and order 5. Reconstructed tomograms were then reoriented in the standard short, horizontal long, and vertical long axes for interpretation and quantification of 201Tl uptake.
Analysis of Echocardiographic and 201Tl SPECT Studies
Segmentation of the Left Ventricle
A 13-segment ventricular model was used for the analysis of both echocardiographic and thallium images. This constituted a modification of the 16-segment model previously described,10 in which the inferior and posterior walls have been combined to enhance the accuracy of matching the cardiac segments. Thus, the segments included the basal, mid, and apical segments of the anterior, septal, lateral, and inferoposterior walls. The ventricular apex accounted for the 13th segment. For purposes of matching myocardial segments with coronary distribution at angiography, the anterior wall, septum, and apex were assigned to the left anterior descending artery territory, the lateral wall to the left circumflex, and the inferoposterior wall to the right coronary artery.
The dobutamine echocardiographic studies were interpreted on the quad screen, and a wall motion score was assigned to the ventricular segments at each of the four displayed stages. The images were interpreted by one experienced investigator who was blinded to all other data. Wall motion was semiquantitated by use of a six-grade scoring system as described previously10 : hyperkinesia=0, normal=1, mild hypokinesia=2, severe hypokinesia=3, akinesia=4, and dyskinesia=5. The score reflected the worst wall motion within a particular segment.
The response to dobutamine of ventricular segments with abnormal resting function was classified into one of four types10 on the basis of changes of ≥1 grade in wall motion score: (1) biphasic response—improvement in wall motion at low dose (5 or 7.5 μg·kg−1·min−1) with worsening at higher dose(s); (2) worsening—deterioration of resting wall motion during dobutamine without any improvement; (3) sustained improvement—improvement in wall motion at low dose that persisted or further improved at high dose; and (4) no change—no change in wall motion during dobutamine.
Resting images for each patient before and early and late after revascularization were randomized on the quad screen in comparable views and interpreted by one observer blinded to the timing of the studies and other data. Recovery of function within a segment was defined as a change of ≥2 grades in wall motion score from baseline to late follow-up on the basis of an analysis of intraobserver variability from our laboratory.10 For individual patients, recovery of function was defined as a change of ≥2 grades in ≥2 segments. To assess changes in global ventricular function, a wall motion score index was derived for the entire left ventricle with the use of the sum of individual scores divided by the total number of segments.
201Tl SPECT Analysis
Rest and redistribution 201Tl SPECT images, before and after revascularization, were analyzed qualitatively and quantitatively by experienced nuclear cardiologists blinded to all other data. Qualitative analysis of 201Tl uptake was performed visually with a four-point scoring system (1=normal, 2=mildly reduced, 3=moderately reduced, and 4=severely reduced). Computerized two-dimensional polar maps of the three-dimensional myocardial radioactivity were generated for quantitative analysis.16 17 Quantification of 201Tl uptake was performed by another blinded observer. A 10×10-mm region of interest was placed in the area of the worst color-coded uptake, and a percent of maximal count activity was derived in each of the 13 segments. For patient analysis, a mean percent 201Tl uptake was derived by averaging the thallium uptake in the 13 segments in each patient.
All angiograms were analyzed by an investigator blinded to the echocardiographic and 201Tl perfusion data. The severity of coronary stenosis was determined by calipers and expressed as a percent of luminal diameter reduction. Significant coronary disease was defined as ≥70% diameter stenosis of ≥1 major epicardial artery.
All values are expressed as mean±SD. Changes in percent vessel stenosis, wall motion score, and global 201Tl uptake from baseline to after revascularization were compared by use of paired Student's t test. ANOVA was used to compare rest and redistribution 201Tl uptake in cardiac segments grouped on the basis of resting wall motion or dobutamine response. If the F value was significant, a Newman-Keuls multiple comparison test was performed. A χ2 test was used to study differences in the incidence and prediction of recovery of function. Significance was set at a level of P<.05.
A total of 46 patients were enrolled. Two patients developed an acute myocardial infarction early after angioplasty and were subsequently excluded. One patient was excluded because of normal wall motion on the prerevascularization echocardiogram, 2 refused to continue participation in the study before follow-up, and another died before late follow-up. The remaining 40 patients completed the study. Successful revascularization was achieved in 34 patients, 32 of whom had revascularization in the distribution of wall motion abnormalities. Reasons for revascularization were stable angina in 22 patients and congestive heart failure in 12. Six patients were not revascularized and constituted the control group; coronary angioplasty could not be performed in 3 of these patients because of an inability to cross the lesion, and in the remaining 3, the decision to revascularize was changed and was not based on the results of the present study.
The mean age of patients was 61±9 years in the revascularized group and 62±11 years in the control subjects. Mean left ventricular ejection fraction was 39±14% in the revascularized group (<39% in 19 patients and <30% in 13 patients) and averaged 47±20% (range, 23% to 70%) in control patients. Baseline data on the 34 revascularized patients are presented in Table 1⇓. The mode of revascularization was angioplasty in 28 patients and coronary bypass surgery in 6. There were a total of 67 vessels with significant stenosis (≥70% luminal diameter narrowing), of which 46 (69%) were revascularized (33 with angioplasty and 13 with bypass surgery). Mean percent stenosis of the revascularized vessels was 91±8%. In patients who underwent coronary angioplasty, mean percent stenosis decreased from 90±8% to 29±9% (P<.0001). All attempted coronary bypasses were successful without evidence of postoperative infarction. None of the 34 revascularized patients had recurrent angina at follow-up.
Prerevascularization Resting Wall Motion Versus Resting 201Tl Uptake
Of a total of 520 segments in the 40 patients who completed the study, 516 were adequately imaged with echocardiography and were analyzed. The distribution of resting wall motion before revascularization was as follows: 46% of segments had normal resting wall motion, 6% mild hypokinesia, 22% severe hypokinesia, 22% akinesia, and 4% dyskinesia. There were significant differences in resting 201Tl uptake among segments with different degrees of resting wall motion (Fig 2⇓). Mean 201Tl uptake was 80±14% in segments with normal resting wall motion, 66±16% in severely hypokinetic segments, and 49±20% in akinetic or dyskinetic segments (P<.001). The quantitative thallium analysis was compared with the visual assessment of 201Tl uptake. Mean resting 201Tl uptake in segments with visually assessed normal perfusion was 78±14%. Mildly reduced perfusion corresponded to a 201Tl uptake of 54±15%, moderately reduced perfusion to 37±15%, and severely reduced perfusion to 23±10% (P<.0001).
Serial Change in Resting Regional Function
In patients undergoing revascularization, 226 of the 442 segments were in the distribution of revascularized vessels. Individual changes in wall motion from baseline to late follow-up are shown in Fig 3⇓. Of the 161 segments with any abnormal wall motion at baseline, 24 improved by one grade and 42 improved by two grades. A one-grade worsening of wall motion was noted in 7 segments, and none worsened by more than one grade. In nonrevascularized segments (n=216), improvement of one grade was seen in 12 segments and of two grades in 6 segments, and worsening by one grade was seen in 2 segments.
In the control patients, a change in wall motion by one grade was seen in 10 of the 78 segments (12.8%). No segment had worsening or improvement of wall motion by two grades or more. The same wall motion score was therefore observed in 87.2% of segments, with a mean difference (±SD) in wall motion score between studies of −0.14±0.35.
Segments with severe dysfunction at baseline (ie, severely hypokinetic, akinetic, or dyskinetic) were the focus of assessment of recovery of function and its prediction by the use of DE and 201Tl SPECT. There were 244 such abnormal segments (47% of the total). Of 148 segments in the revascularized territory, 42 (28%) exhibited significant (≥2 grades) recovery of function. In contrast, only 5 (5%) of the 96 abnormal segments not revascularized had recovery (P<.001; Fig 4⇓). Improvement in function occurred more frequently in severely hypokinetic segments than in akinetic segments (43% versus 17%; P<.0001). In the control population, none of the severely dysfunctional segments (n=30) had significant recovery of function.
Serial Change in Rest and Redistribution 201Tl SPECT Uptake
In the 148 segments with severe dysfunction in the revascularized territory, baseline 201Tl uptake and changes in uptake after revascularization were different in segments that exhibited ultimate recovery of function than in those that did not (Fig 5⇓). In segments that recovered, an increase in resting 201Tl uptake occurred after revascularization (68±12% to 81±11%; n=42; P<.001), which was achieved in part during redistribution on the baseline study (73±14%; P=.001) (Fig 5⇓). After revascularization, resting and redistribution thallium uptakes were similar.
In revascularized segments without recovery of function, 201Tl uptake was significantly lower than in those with recovery of function, before and after revascularization, and exhibited no significant changes during redistribution or after revascularization (baseline resting uptake of 52±19% versus postrevascularization resting uptake of 55±21%; n=106; P=NS) (Fig 5⇑).
Nonrevascularized Territory and Control Subjects
Resting 201Tl uptake in segments with severe dysfunction in nonrevascularized territories and in control subjects was similar to that of the revascularized territory (59±24%, 57±19%, and 52±18% respectively; P=NS). In nonrevascularized territory, no significant differences in 201Tl uptake from baseline to late after revascularization were observed. Similarly, in the control population, there was no significant change in thallium uptake (baseline rest uptake of 52±18% and redistribution uptake of 53±21%; 6 to 8 weeks' rest uptake of 56±18% and redistribution uptake of 60±19%; P=NS). In segments of control patients (n=78), differences in 201Tl uptake between the early and late resting study averaged 0.14±12% (range, −30% to 28%). Differences in 201Tl uptake of redistribution images between early and late studies were greater than for resting images (P<.05) and averaged 3.8±15% (range, −30% to 43%).
Response of Abnormal Segments to Dobutamine and Relation to 201Tl Uptake
Before revascularization, the distribution of the types of response to dobutamine in the 148 revascularized, severely dysfunctional segments was as follows: biphasic response, 29%; sustained improvement, 18.2%; no change in wall motion, 47.3%; and worsening response, 5.4%. In dysfunctional segments (n=42) of patients receiving β-blockers, biphasic or sustained responses were not blunted (54% and 10%, respectively). Resting 201Tl uptake in the 148 segments grouped by the type of response to DE was different (Fig 6⇓; P<.00001 by ANOVA). Baseline resting 201Tl uptake in segments with biphasic response (66±12%) was similar to those with sustained improvement (60±21%) but higher than in segments showing no change (51±19%) or worsening of wall motion during DE (39±16%). On redistribution, 201Tl uptake increased in segments with biphasic response (66±12% to 72±15%; P<.05) and did not change significantly in segments with the other three types of responses (Fig 6⇓).
After revascularization, resting 201Tl uptake in segments with biphasic response improved to 78±13% without any further increase on redistribution (Fig 6⇑). These segments had the highest 201Tl uptake of all the dobutamine responses. In contrast, segments with sustained improvement or no change in wall motion during DE had no significant changes in thallium uptake after revascularization (Fig 6⇑). In the few segments with worsening response during dobutamine, an increase in resting 201Tl uptake was observed after revascularization that did not reach statistical significance.
Prediction of Recovery of Function With DE
The prediction of recovery of function with DE is shown in Fig 7⇓. A biphasic response was the best predictor of recovery of contractile function (72%), while the other three responses to DE had lower predictive values, the lowest being for no change in wall motion during DE. Biphasic response alone had sensitivity, specificity, and positive and negative predictive values of 74%, 89%, 72%, and 89%, respectively.
The sensitivity and specificity of combining the biphasic response with other types of responses during DE are shown in Table 2⇓. Combining biphasic with worsening responses increased sensitivity to 76%, with a slight decrease in specificity to 82%. Any improvement in wall motion (ie, combining biphasic and sustained improvement responses) increased the sensitivity to 86% with a fall in specificity to 68%. Similarly, when any change in wall motion during dobutamine was taken as the criterion to predict recovery of function (ie, combining biphasic, improvement, and worsening responses), the sensitivity improved to 88%, with specificity decreasing to 61%. Analysis of akinetic or dyskinetic segments compared with severely hypokinetic segments is shown in Table 3⇓. Overall, similar sensitivities in hypokinetic segments were observed with lower specificities, particularly when any improvement or any change in function was used as the criterion.
Prediction of Recovery of Function With Rest-Redistribution 201Tl SPECT
Rest and redistribution 201Tl uptakes in each of the 148 severely dysfunctional segments before revascularization are shown in Fig 8⇓. All segments with recovery of function had a resting 201Tl uptake >45% or a maximal thallium uptake (rest or redistribution) of >50%. A significant overlap, however, was observed in 201Tl uptake between segments with and without recovery of function (Fig 8⇓). A receiver operator curve was generated for the prediction of recovery of function with the use of resting and maximal (rest or redistribution) 201Tl uptakes. There was a small advantage of maximal 201Tl uptake over resting uptake alone in the accuracy of predicting recovery of function (area under the receiver operator curve of 0.63 versus 0.56, respectively). When a cutoff of ≥50% maximal uptake was used, 201Tl SPECT was 100% sensitive but only 37% specific for predicting recovery of function. Analysis that used a 60% uptake as the cutoff yielded a more optimal combination of sensitivity and specificity of 90% and 56%, respectively (Fig 9⇓). A 65% maximal 201Tl uptake cutoff further improved the specificity to 67%, with a substantial reduction in sensitivity to 71%. In severely hypokinetic segments compared with akinetic or dyskinetic segments, sensitivity was similar with a significant decrease in specificity (Table 3⇑).
When only rest 201Tl uptake was used, cutoffs were ≈5% lower than maximal 201Tl uptake for a comparable degree of accuracy. The sensitivity and specificity of resting 201Tl for a cutoff of 45% were 100% and 38%, respectively. A cutoff of 60% yielded a sensitivity of 77% and specificity of 62%, whereas the most optimum cutoff was a resting thallium uptake of 55% (sensitivity 90%, specificity 51%).
The sensitivity and specificity of semiquantitative, visual 201Tl SPECT analysis was calculated with normal or mildly reduced perfusion (at rest or on redistribution) used as a predictor of recovery of function. The sensitivity of visual analysis was 98%, with a low specificity of 27% (Fig 9⇑).
Echocardiographic characteristics of segments with maximal 201Tl uptake of ≥60% (n=47) that did not improve in function after revascularization were examined to assess whether combination of the two modalities would improve prediction of functional recovery. Wall motion was akinetic in 53% of these segments and severely hypokinetic in 47%. No change in function and sustained improvement during DE were the most prevalent responses (51% and 28%, respectively). In contrast, in the 38 segments that recovered contractile function and had thallium uptake ≥60%, biphasic response was seen in the majority of segments (74%). A sustained improvement response was observed in 13% of the segments, no change in 10.5%, and a worsening response in 2.5%. The combination of 201Tl uptake variables and dobutamine responses did not improve the accuracy of predicting functional recovery by either imaging technique.
Analysis by Patient Group
The wall motion score index in the revascularized group decreased after revascularization (2.38±0.7 to 2.08±0.83; P<.0001) and ejection fraction increased from 39±14% to 43±15% (P=.0002). In contrast, no significant change in the wall motion score index occurred after revascularization in control subjects (2.04±0.82 to 1.90±0.72; P=NS). Similarly, mean percent 201Tl uptake of all segments per patient increased from 68±11.5% to 71±14% (P=.03) in revascularized patients and remained unchanged in the control subjects (67±13% to 67±11%; P=NS).
Of 32 patients who underwent revascularization in the distribution of resting wall motion abnormalities, 31 had at least two abnormal segments at baseline; 13 of these patients had recovery of function. The number of segments that recovered averaged 3.2 per patient and constituted 69% of the abnormal segments per patient. The sensitivity and specificity of DE and 201Tl SPECT for predicting functional recovery by patient were similar to those obtained by segmental analysis and are shown in Table 4⇓. Biphasic response as determined by DE had a sensitivity of 85% and a specificity of 83%. When any improvement in function (biphasic or sustained improvement) was used as a criterion, sensitivity was 100% with a specificity of 67%. For maximal 201Tl uptake ≥60%, the sensitivity was 92% with a specificity of 56%.
The present study demonstrates that DE and rest-redistribution 201Tl SPECT imaging are useful modalities in patients with suspected myocardial hibernation. Hibernating myocardial segments, the majority of which exhibited a biphasic response to dobutamine, had overall mild reduction in 201Tl uptake that improved after revascularization. A biphasic response during DE was less sensitive but more specific for recovery of function, whereas indexes of thallium scintigraphy were in general more sensitive and less specific, the least accurate being a qualitative assessment of thallium uptake. The sensitivity and specificity of both modalities, however, could be altered depending on the criteria of 201Tl uptake or the combination of types of responses of the dysfunctional myocardium to dobutamine.
DE and Myocardial Hibernation
There is increasing evidence that the hibernating myocardium exhibits contractile reserve in response to inotropic stimulation.8 9 10 11 12 18 Recent experimental and clinical observations, however, suggest that contractile reserve is present but limited in this condition.10 12 19 An increasing inotropic stimulation leads to depletion of energy stores, resulting in ischemia.18 Recently, the use of high-dose in addition to low-dose dobutamine in patients with suspected myocardial hibernation has unmasked differences in contractile reserve10 19 that had significant implications on the prediction of recovery of function after revascularization. Four types of responses of the dysfunctional myocardium to dobutamine could be differentiated, of which a biphasic response was the most predictive of functional recovery.10 In the present study, which used a similar protocol and a different patient population, the distribution of the DE responses was similar to that reported previously10 except for a lower incidence of worsening response (5% in the present study versus 15%). A biphasic response alone was the best predictor of recovery of function, with a sensitivity and specificity of 74% and 89% for segmental analysis and 85% and 83% for patients, further corroborating earlier observations. A sustained improvement response, although inherently an indicator of residual viable myocardium, was a poor predictor of functional recovery, similar to our earlier observations.10 The consideration of any improvement during dobutamine (biphasic and sustained improvement) increased the sensitivity from 74% to 86% with a decrease in specificity from 89% to 68%.
A possible explanation for the above findings is that in patients with chronic resting dysfunction and coronary artery disease, segments exhibiting augmentation of thickening during low doses of dobutamine may represent chronically underperfused, hibernating myocardium or a combination of remnant viable myocardium and subendocardial infarction, without hibernation. The former condition is associated with reduced resting coronary flow and/or coronary reserve and would exhibit evidence of ischemia with moderate to maximal stress, whereas the latter may not. After revascularization, improvement in ventricular function is likely to be observed in the former subgroup and less likely in the latter. We sought supportive evidence for this concept by assessing 201Tl uptake in these segments. Resting 201Tl uptake was similar in segments with biphasic and sustained improvement responses and was higher than in other responses, compatible with the presence of viable myocardium. However, segments with biphasic response exhibited significant thallium redistribution in contrast to those with sustained improvement, which suggests the presence of ischemia and significant flow limitation at rest in the former response but not in the latter.20 In addition, the increase in resting 201Tl uptake after revascularization in segments with a biphasic response and the lack thereof in those with sustained improvement lends further evidence to the concept that a reduction in resting flow was a significant factor contributing to the reduced thallium uptake and the resting dyssynergy in segments with biphasic response compared with those with sustained improvement.
Segments with a worsening wall motion response during DE had the lowest 201Tl uptake at rest. After revascularization, improvement in resting thallium uptake in these segments was small and remained markedly reduced, suggesting that these segments most likely represent areas of previous myocardial infarction and severe, flow-limiting lesions whereby flow reserve was exhausted, resulting in deterioration of function in response to inotropic stimulation. Although this response is the least observed during DE and is less predictive of recovery of function than a biphasic response, it most likely represents a marker of ischemia, a finding that would justify revascularization in the appropriate setting.
The majority of dysfunctional segments that had no change in wall motion during dobutamine did not exhibit recovery of function after revascularization. Thallium uptake in these segments was reduced compared with those with biphasic and sustained improvement responses and exhibited no redistribution or improvement after revascularization. These observations are compatible with a previous infarction in these areas and no limitations of resting coronary flow. Although 201Tl uptake can be discerned in these segments, similar to previous observations,15 the remnant subepicardial viable myocardial areas are probably too small to contribute to increased thickening in response to inotropic stimulation.21
Rest-Redistribution 201Tl SPECT and Myocardial Hibernation
Myocardial uptake of 201Tl depends on coronary flow characteristics as well as cellular viability.22 23 The rest-redistribution protocol used in the present study was shown to have a high concordance with stress-redistribution-reinjection protocols and positron emission tomography7 24 and offers a cost-effective and time-efficient alternative. Furthermore, it allows the assessment of resting perfusion characteristics of dysfunctional segments with suspected hibernation. In the present study, resting 201Tl uptake was higher and further increased after revascularization in segments that improved function than in those that did not, corroborating previous observations.11 13 25 The findings of overall mild baseline reductions of 201Tl uptake in segments that recovered function are also consistent with recent observations26 by positron emission tomography indicating that myocardial perfusion is mildly reduced at rest while coronary flow reserve is severely limited in hibernating myocardium.
Our results of quantitative 201Tl SPECT reveal a spectrum of sensitivities and specificities for prediction of functional recovery. Previous investigators used between 50% and 60% of maximal 201Tl SPECT activity as the optimal cutoff point.6 25 Ragosta et al6 recently reported on quantitative rest–3-hour redistribution planar 201Tl scintigraphy for prediction of functional recovery. The classification of wall motion with the use of radionuclide ventriculography and the analysis of recovery of function, restricted to segments with severe dysfunction, were similar to the present study. With a cutoff of 50% thallium uptake, their data indicated a sensitivity of 92% with a specificity of 31% and positive and negative predictive values of 57% and 77%, respectively.6 In the present study, similar results were found for a cutoff of 50%. A cutoff of 60% of maximal activity, on either resting or redistribution images, appeared to provide optimal sensitivity and specificity for functional recovery. Quantitative resting 201Tl uptake alone was the second-best index tested. On the other hand, visual interpretation with the use of a semiquantitative scoring index was the worst, providing a high sensitivity but poor specificity. Whether incorporation of stress in the 201Tl protocol is necessary to improve the positive predictive value of thallium scintigraphy remains to be determined. However, a recent study15 comparing low-dose DE with dobutamine-reinjection 201Tl demonstrated a lower specificity of thallium scintigraphy for recovery of function, similar to the present study.
Comparison With Previous Studies
Several studies separately evaluated 201Tl scintigraphy6 25 27 and DE8 9 10 11 for the prediction of recovery of function. Only a few, however, compared the two modalities in the same patients, and none used quantitative rest-redistribution SPECT imaging and high-dose DE. Although earlier investigations13 14 involving a small number of patients showed comparable results, more recently, differences in specificity for recovery of function have been observed. Arnese et al15 reported 38 patients who underwent simultaneous DE and 201Tl SPECT. Only low-dose dobutamine was analyzed for prediction of recovery of function. The sensitivities of low-dose dobutamine and qualitative 201Tl SPECT were 74% and 89%, with specificities of 95% and 48%, respectively. Discrepancies in indexes of myocardial viability have also been observed recently in patients undergoing high-dose DE and exercise 201Tl SPECT.19 Evidence of viability was present in 84% of segments by semiquantitative thallium tomography and in 56% with DE. However, patients were not revascularized to evaluate prediction of recovery of function. The findings in the present study further confirm the differences in the prediction of functional recovery between the two techniques and emphasize the distinction between evidence of residual myocardial viability and prediction of recovery of function. Similar to our earlier observations,10 the present study suggests that the use of high-dose dobutamine, and thus subdivision of inotropic recruitment into biphasic and sustained improvement responses, helps improve the specificity of DE. Findings of a high specificity with the use of low doses of dobutamine in previous studies may be accounted for by different population characteristics, selection criteria for revascularization based on evidence of viability, and/or definition of recovery of function, as suggested by the high incidence of functional recovery (>60%) observed.9 11
Although extreme care was taken to optimize the proper matching of myocardial segments, the possibility of anatomic misalignment is an inherent limitation of studies that attempt to compare different modalities. Restenosis or graft occlusion cannot be completely excluded. We deliberately chose to perform the follow-up studies late enough to allow the hibernating myocardium to recover function yet, it was hoped, early enough to avoid restenosis. All patients were carefully followed up until the final study and had no clinical evidence suggesting recurrent ischemia. Furthermore, the achievement of revascularization was corroborated by the improvement observed in resting thallium uptake at late follow-up only in revascularized segments, with concomitant improvement in regional and global function.
The majority of revascularization was achieved with coronary angioplasty. Although revascularization may be incomplete, the use of angioplasty offers advantages over surgery, such as the avoidance of problems diagnosing intraoperative myocardial infarction in patients who do not improve perfusion or wall motion after bypass surgery and avoidance of the difficulties encountered in interpretation of wall motion (paradoxical septal motion and increased cardiac translation) after surgery. Quantification of regional function may provide a more objective assessment of regional function; however, it is limited in the presence of excessive cardiac translation. Semiquantitative assessment of regional function with a wall motion score has the added advantage of integrating information from multiple views. On the basis of previous analysis of variability in wall motion in our laboratory using the same scoring system, an improvement of at least two grades was defined as significant. This was further corroborated with the similar variability observed in control patients. In addition to improving the reliability of the analysis, this definition imparts more clinical significance to the degree of functional recovery.
Conclusions and Implications
The present study demonstrates that DE and thallium scintigraphy are useful modalities in patients with suspected myocardial hibernation. Hibernating myocardial segments, the majority of which exhibited a biphasic response to dobutamine, had an overall mild reduction in resting 201Tl uptake, which improved after revascularization. A biphasic response during dobutamine is less sensitive but more specific for recovery of function, whereas indexes of 201Tl scintigraphy are in general more sensitive and less specific, the least accurate being a qualitative assessment of thallium uptake. The sensitivity and specificity of DE and quantitative 201Tl SPECT, however, can be altered depending on the criteria of 201Tl uptake or combination of the types of responses of the dysfunctional myocardium to dobutamine. Low-dose DE identifies viable segments by eliciting augmentation in contraction. Addition of higher doses allows further subcategorization within this heterogenous group for better identification of those likely to recover systolic function with revascularization. These collective findings provide further evidence that myocardial hibernation is accompanied by a mild reduction in resting flow with limited reserve and an attainable ischemic threshold during moderate stress.
Although recovery of myocardial function is an important goal for revascularization in patients with ischemic heart disease and ventricular dysfunction, other significant end points include improvement in symptoms, exercise tolerance, and cardiac event–free survival. The magnitude of the impact of revascularization on all cardiovascular end points on the basis of the detection of myocardial viability with echocardiography and radionuclide techniques remains to be determined.
This study was supported by a grant from the John S. Dunn, Sr Trust Fund. The authors acknowledge Helen A. Kopelen, RDMS, Tracy Ferrando, RDCS, and Hussain Al-Nezir, MD, for their help in patient recruitment and coordination; Nicholas Kutka, MD, for his coordination of the scintigraphic studies at the Veterans Affairs Medical Center; and the sonographers and nuclear technologists at the Methodist Hospital and the Veterans Affairs Medical Center for performance of the echocardiographic and scintigraphic studies. The authors thank Miguel A. Quin˜ones, MD, for his helpful review of the manuscript and Eula Landry for her secretarial assistance in preparing the manuscript.
Reprint requests to William A. Zoghbi, MD, Director of Echocardiography Research, Baylor College of Medicine and The Methodist Hospital, 6550 Fannin SM-677, Houston, TX 77030.
Guest editor for this article was Robert O'Rourke, MD, University of Texas Health Science Center, San Antonio.
Presented in part at the Scientific Sessions of the American College of Cardiology, New Orleans, La, March 20, 1995.
- Received May 21, 1996.
- Revision received September 9, 1996.
- Accepted September 30, 1996.
- Copyright © 1997 by American Heart Association
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