Impaired Myocardial Tissue Perfusion Early After Successful Thrombolysis
Impact on Myocardial Flow, Metabolism, and Function at Late Follow-up
Background Impaired tissue reperfusion after successful recanalization of an epicardial coronary artery has been documented both in animals and in patients with acute myocardial infarction. Whether this phenomenon can be demonstrated with positron emission tomography (PET) and whether it has an effect on late recovery of flow, metabolism, and function are unknown.
Methods and Results Thirty patients with an acute myocardial infarction and TIMI flow grade 3 of the infarcted vessel at 90 minutes after thrombolytic therapy were studied. Within 24 hours after thrombolysis, at 5 days and at 3 months, myocardial blood flow was measured with 13NH3. 18FDG uptake was measured at 5 days. Radionuclide left ventricular angiograms were acquired at 5 days and at 3 months. In 11 patients (37%), regional myocardial flow was severely impaired (<50% of normally perfused myocardium) despite successful thrombolysis. No recovery of left ventricular function occurred in any of these patients at 3 months. In 12 patients (40%), intermediate flows (50% to 75% of normal) were found, with functional improvement after angioplasty only in regions with a PET mismatch. Seven patients (23%) had high flow values early after successful thrombolysis (>75% of normal) and showed preserved regional contractile function at 3 months.
Conclusions This study is the first demonstration with PET of impaired myocardial tissue perfusion in patients with an acute myocardial infarction after successful thrombolysis. Functional recovery of the reperfused myocardium is observed only when adequate tissue flow is restored. PET may be helpful in selecting patients in whom additional revascularization can improve recovery of left ventricular function.
Temporary occlusion of a coronary artery causes reversible ischemic injury of the myocardium. As the duration of the occlusion prolongs, necrosis develops in an increasing number of myocytes. In canine studies it was demonstrated that viable myocardial tissue persists for at least 3 hours after the onset of ischemia.1 2 During this phase, restoration of flow can save ischemic but viable myocardial tissue.1 3 Interventions such as balloon angioplasty or thrombolysis can restore coronary flow in patients with an evolving myocardial infarction. Coronary angiography is mostly used to evaluate the success of reperfusion therapy. However, myocardial tissue perfusion may remain impaired despite restoration of flow in the previously occluded epicardial coronary artery.4 5 This failure to achieve adequate tissue reperfusion is referred to as “low reflow” or “no reflow” phenomenon.5 6 It is thought that impaired tissue reperfusion is already largely established at the time of reperfusion because of capillary damage induced by ischemia.4 7 8 However, reperfusion itself also appears to induce additional injury.9 For example, in some studies, a delayed, gradual fall in tissue flow has been observed in areas that initially showed adequate reperfusion.10 11 The presence of impaired myocardial tissue perfusion was recently demonstrated with contrast echocardiography in patients with anterior myocardial infarction after thrombolysis.12 Myocardial tissue flow also can be measured with positron emission tomography (PET).13 14 The aim of our study was to further investigate the presence of impaired tissue perfusion in patients after successful thrombolysis with the use of PET and to evaluate its effect on the recovery of flow, metabolism, and function at follow-up.
Patient Selection and Coronary Angiography
Patients with an acute myocardial infarction of less than 6-hour duration were prospectively studied. Patients with typical chest pain of more than 30 minutes and with ST segment elevations of ≥0.1 mV in two or more limb leads or ≥0.2 mV in two or more contiguous precordial leads were enrolled. Patients received either recombinant staphylokinase or front-loaded alteplase with intravenous heparin or streptokinase with either intravenous or subcutaneous heparin, according to the GUSTO-I protocol.15 16 All patients were given oral aspirin.
All patients underwent coronary angiography at 90 minutes after the start of thrombolytic therapy. A control angiography was performed at 24 hours (15 patients) or at 5 days (15 patients). The angiograms were read by two independent experienced angiographers. The patency of the infarct-related vessel was scored according to the Thrombolysis in Myocardial Infarction (TIMI) criteria of reperfusion.17 Only patients with a TIMI flow grade 3 both at 90 minutes and at follow-up were selected for the study. The study was approved by the ethical committee for human research of the University of Leuven.
Positron Emission Tomography
Myocardial blood flow was measured with 13NH3 within 24 hours after the start of thrombolytic treatment, at 5 days, and at 3 months. An 18FDG scan for the evaluation of metabolism was performed at 5 days.
The perfusion studies and the perfusion/metabolism studies were performed with a whole-body positron emission tomograph (model 931-08/12, CTI Siemens) provided with eight detector rings permitting simultaneous acquisition of 15 planes, with an interplane spacing of 6.75 mm. A small cyclotron (cyclone 10/5, Ion Beam Applications) and auxiliary chemical processing equipment were used to produce 18FDG and 13NH3. Before each study, a 2-minute rectilinear scan, used for positioning the heart within the field of view, and a 15-minute transaxial transmission scan with a 68Ge ring source for photon attenuation correction were performed.
Myocardial perfusion was evaluated using 13NH3 ammonia: 20 mCi of 13NH3 in 5 mL saline followed by a 20-mL flush of saline was slowly infused at a constant rate of 10 mL/min. Acquisition was started simultaneously with the injection of 13NH3. In each patient, 19 dynamic frames were recorded (12×10 seconds, 4×30 seconds, 3×2 minutes). Total acquisition time was 10 minutes.
Regional myocardial utilization of exogenous glucose was evaluated with 18FDG. The metabolic studies were performed with use of the euglycemic hyperinsulinemic clamp technique.18 19 The tracer dose of 10 mCi was injected after stabilization of the glucose level between 85 and 95 mg% and not earlier than 50 minutes after 13NH3 injection to allow isotope decay. In each patient, 22 dynamic frames were recorded (8×15 seconds, 4×30 seconds, 2×1 minutes, 2×2 minutes, 6×10 minutes). Total acquisition time was 70 minutes. The time required for image acquisition of the combined 13NH3 and 18FDG study was 2 to 3 hours.
The first 19 frames of the perfusion studies were reconstructed using a Hanning filter with a cutoff frequency of 0.3. The long axis of the left ventricle was indicated manually on the last frame. The myocardial image was resampled into 16 radial slices. The radial slices were delineated using an algorithm developed in our department.20 21 The delineation was used to construct a polar map for every frame. Each polar map was divided into 33 regions: four rings of eight regions and one region for the apex. Absolute flow values were obtained using a three-compartment model.14 Flow values were normalized: A flow index was calculated as the ratio of the flow in the infarcted area divided by the flow in the normally perfused area.
The 22 frames of the metabolic study were reconstructed using a Hanning 0.4 filter. The creation of radial slices, delineation, polar maps, and regional time activity was done in the same way as for the flow studies. Regional glucose utilization was estimated by application of a patlak graphical analysis22 23 using frames 8 to 22. The region in which flow was considered to be normal was used as reference region for 18FDG. 18FDG values were normalized: A metabolic index was defined as the ratio of the glucose utilization in the infarct area over that in the normal zone.
Radionuclide angiography was performed at 5 days and at 3 months. Red blood cells were labeled with 20 mCi of 99mTc. Ten minutes after the injection, an equilibrium gated nuclear angiography was acquired during 10 minutes while the patient was positioned under the gamma camera in a left anterior oblique 45-degree position for visualization of septum, apex, and posterolateral wall. A low-energy, all-purpose collimator was used. The same study was repeated in a left anterior oblique 70-degree position for visualization of anterior wall, apex, and left part of the inferior wall and in an anterior position for visualization of lateral wall, apex, and right part of inferior wall. Global and regional ejection fractions were calculated automatically with the use of standard software (Sopha Medical Benelux). The software was validated with 88 gated bloodpool data sets from the Mayo Clinic (Rochester, Minn.) (y=0.87x+6.2, r=.92, x=Mayo Clinic software, y=Sopha program, SEE=5.5, n=88). A region corresponding to the infarct zone was chosen for evaluation of regional ejection fraction. The same region was used at 3 months for comparison with the 5 day values.
Results are given as mean value±SD. Differences between groups were investigated with the use of ANOVA followed by post hoc testing (Tukey’s honestly significant difference, Tukey HSD).26 Intragroup comparisons were performed using Student’s t tests for paired data with Bonferroni correction. For evaluation of the relationship between flow and both global and regional left ventricular functions, linear regression plots were used. Differences between correlation coefficients were tested using Fisher’s z transformations.
Clinical, Angiographic, and PET Data
Thirty-two patients with a TIMI flow grade 3 patent infarct vessel at 90 minutes were considered for the study. Of these, 2 patients were excluded because of reocclusion at the time of the control angiography. Thus, 30 patients with a TIMI flow grade 3 open infarct vessel at 90 minutes and at follow-up were submitted to the entire study protocol. Clinical characteristics at entry and angiographic results at 90 minutes in all patients are listed in Table 1⇓. Individual flow and metabolism results of all patients at the different time points are given in Table 2⇓. When all patients are considered, normalized flow in the infarcted zone shortly after thrombolysis was 60±7% on average. At 5 days and 3 months, slightly higher flow values were measured (P=NS). Normalized FDG uptake at 5 days was 65±21%. A poor linear relationship (y=0.7x+19, r=.497, P<.05) was present between blood flow and metabolism at this time point. In 22 patients (73%), the decrease of metabolism and flow was concordant (PET match), while in 8 patients (27%) a PET mismatch (decreased flow with preservation of FDG uptake) was found.
Patients were arbitrarily divided post hoc into three groups according to flow values at 24 hours. Patients with a flow index of <50% of the reference zone were defined to have severely impaired reflow (group A). Patients with a flow index between 50% and 75% were considered to have a moderately decreased flow (group B), and patients with a flow index of >75% were considered to have adequate tissue reperfusion (group C). Eleven patients (37%) were included in group A. Twelve patients (40%) had intermediate flow values (group B), and 7 (23%) revealed high flows (group C). Clinical characteristics of the three groups are listed in Table 1⇑. Although the differences were not statistically significant, peak creatine kinase values were higher in group A (1841±442 U/L) than in group B (1485±277 U/L) or in group C (1199±411 U/L), and the time between the onset of symptoms and the start of treatment tended to be longer in group A (194±35 minutes) than in group B (163±41 minutes) or in group C (147±58 minutes). No collaterals to the infarcted area were visible on the angiogram at 90 minutes or at follow-up in any of these patients who all had an open infarct–related vessel on both occasions. None of the patients suffered a reinfarction. Fourteen of the 30 patients (5 in groups A and B and 4 in group C) underwent balloon angioplasty after day 5 because of a severe residual stenosis.
In group A (n=11), similar flow values were found at 24 hours and 5 days (Table 2⇑). Eight patients revealed a PET match, whereas a PET mismatch was found in 3. In group B (n=12), flow values at 5 days were also very similar to those at 24 hours. Four of these patients revealed a mismatch pattern, and in eight a match pattern was observed. In group C (n=7), high flow values were measured both at 24 hours and at 5 days. In one of these patients a mismatch pattern was found, whereas the others showed a match pattern.
Twenty-five patients underwent a control PET study at 3 months (Table 2⇑). Five patients (4 from group A and 1 from group B) refused this control examination. Flow values at 3 months in group A were similar to those obtained at 5 days. High flow values in group C persisted at 3 months. Flow values in group B tended to be higher at 3 months compared with the results at 24 hours and at 5 days. Statistical analysis revealed no significant differences between flow values at 24 hours, 5 days, and 3 months in any of the three groups.
A significant difference in flow was found between group A and both other groups and between group B and group C at 5 days (ANOVA, P<.00001; Tukey HSD, P<.01). At 3 months, a significant difference in flow was found between group A and both other groups but not between group B and group C (ANOVA, P<.001; Tukey HSD, P<.01). Since patients were arbitrarily divided into groups according to normalized flow values at 24 hours, no statistical analysis was performed on the 24-hour flow data (Table 2⇑).
Left Ventricular Function
In 24 patients, left ventricular function was evaluated by means of radionuclide ventriculography at 5 days and 3 months. Six patients (3 of group A, 3 of group B) refused control ventriculography. Mean values for global and regional left ventricular ejection fractions in all patients and in the three groups are summarized in Table 3⇓. In group A, mean global and regional ejection fractions tended to be lower at 3 months than at 5 days, whereas in group B and group C the opposite was observed. These time-related changes, however, were not statistically significant in any of the groups. Global and regional ejection fractions increased from group A to group C both at 5 days and at 3 months. At 5 days, regional ejection fraction of the infarct area was significantly lower in group A as compared with group C (ANOVA, P<.005; Tukey HSD, P<.05). At 3 months, a significant difference was found between group A and both other groups (ANOVA, P<.0001; Tukey HSD, P<.05). Similar results were obtained when global ejection fractions were compared (ANOVA, P<.0005; Tukey HSD, P<.05; both at 5 days and 3 months) (Fig 1⇓). The differences in global and regional ejection fraction between group B and group C were not statistically significant at both time points.
Relationship Between Flow, Metabolism, and Function
In Fig 2⇓, the perfusion data at 24 hours, the PET pattern at 5 days, and the evolution of regional ejection fraction from day 5 to 3 months are represented. Bold symbols in Fig 2⇓ indicate in which patients balloon angioplasty was performed. Patients in the low flow range (<50%) showed no functional improvement. All had severely depressed regional contractile function at 3 months. In the group with intermediate flow values (50% to 75%), only patients with a mismatch pattern revealed functional improvement after angioplasty (Table 2⇑; Nos. 12, 14, and 19). In the high flow range (>75%), all patients revealed preserved contractile function in the infarct region at 3 months. In some patients with high flow values at 24 hours, regional function further improved after 3 months (Table 2⇑; Nos. 24, 26, 28, and 29), without additional therapy.
The correlation coefficient between flow and regional ejection fraction increased significantly from .50 at 5 days to .77 at 3 months (P<.05), whereas the correlation coefficient between flow and global ejection fraction changed from .60 at 5 days to .73 at 3 months (P=NS) (Fig 3⇓).
Impairment of myocardial tissue perfusion after successful thrombolysis, the so-called “low reflow” and “no reflow” phenomenon, has been documented both in the experimental animal and in patients.5 6 12 It is thought that this phenomenon is mainly caused by vascular injury and that it occurs primarily at the time of reperfusion in irreversibly injured myocardium.5 Other observations lead to the conclusion that the presence of impaired perfusion after recanalization is also due in part to a late fall in flow to areas that initially were adequately reperfused.10 In the present study, the occurrence and duration of the low reflow or no reflow phenomenon after successful thrombolysis in patients with acute infarction and its possible impact on recovery of flow, metabolism, and function were examined with the use of PET and repeated scintigraphic evaluation of left ventricular function.
In more than one third of the patients (group A), an important perfusion defect was seen in the reperfused area early after successful thrombolysis (TIMI flow grade 3 of the infarct-related coronary artery). In these patients, no significant improvement of regional myocardial blood flow was found over time, and a significant difference in flow values between these patients and the other groups persisted both at 5 days and at 3 months. This finding indicates that successful recanalization with angiographically documented TIMI flow grade 3 is not necessarily associated with adequate tissue perfusion, hereby confirming recent findings obtained with contrast echocardiography in patients with an anterior infarction.12 Thus, this study in patients, for the first time documents with PET in a quantitative way the presence of severely reduced flow shortly after successful thrombolysis. Functional recovery was not observed in these patients at follow-up, and a severely depressed regional contractile function was present both at 5 days and at 3 months, regardless of the PET pattern at 5 days (match or mismatch). These findings are in concordance with the observation that an intact microvasculature is necessary for functional improvement.27 Our results can be viewed as an indication that a minimal level of capillary perfusion early after recanalization is required to allow for recovery of ventricular contractile function. Alternatively, the level of tissue perfusion after coronary thrombolysis also can be viewed as a reflection of the severity of the global injury resulting from preceding ischemia and reperfusion. In this view, the myocytes and the microvasculature are affected concordantly and the level of tissue perfusion is not a direct pathophysiological determinant of functional recovery. Whichever the relation between tissue perfusion and functional recovery, it is of interest to note that the longest treatment delay was observed in the group without recovery (group A). Although this finding was not statistically significant, it suggests that impaired or no reflow is less likely to occur in early reperfused myocardium and supports the concept that prolonged ischemia plays an important role in this phenomenon.
Patients with a moderate flow reduction (group B) showed functional improvement only when a PET mismatch pattern was present, and an additional revascularization procedure was performed. Further recovery of myocardial function in these patients with a mismatch pattern (indicative of the presence of viable but ischemically endangered myocardium) can explain the finding of significantly higher global and regional ejection fractions as compared with the group with severely impaired flow (group A) at 3 months. A significant flow difference was found between group B and the preserved flow group (group C) at 5 days but not at 3 months. This may be explained by an improvement of flow in patients of group B with a mismatch pattern undergoing additional revascularization because of a residual tight stenosis. It should be noted that, although FDG uptake is known to be a reliable indicator of viability and a good predictor of recovery in chronic situations,28 29 some studies suggest that FDG uptake might be seen both in viable and nonviable tissue in the acute phase, possibly as a result of white blood cell infiltration or membranous damage.30 In another study, however, it was stated that preserved FDG uptake is likely to reflect metabolism of viable myocytes and not leukocyte metabolism, supporting a possible diagnostic role for FDG in acute situations.31 In our study, functional recovery occurred only in patients with a mismatch pattern, suggesting that tissue viability was indeed present in these patients after 5 days. Thus, the combination of a perfusion level between 50% and 75% and a mismatch pattern at 5 days appears to indicate the possibility of further recovery of left ventricular function after additional revascularization. Perfusion levels alone in this group did not predict functional recovery, since a moderate flow deficit can indicate irreversible myocardial damage or insufficient reperfusion in viable myocardium caused by a tight coronary artery stenosis.
Patients with high flow values in the infarcted area at 24 hours (group C) showed preserved contractile function at 3 months. In some patients of this group a low regional ejection fraction was found at 5 days despite high flow values in the infarcted area with further improvement of regional ejection fraction at 3 months, without any additional revascularization therapy. Thus, in these patients myocardial blood flow was restored at 24 hours, thanks to thrombolytic therapy, with a delayed functional recovery of the “stunned” myocardium. This is in agreement with previous findings in patients with reperfused anterior infarction in whom functional improvement in reperfused areas was found only after 14 days to 1 month of reperfusion.32 33 In several other studies it was also stated that functional recovery of stunned myocardium requires several days or even weeks after reperfusion.34 35 The recovery of stunned, dysfunctional myocardium after day 5 also explains the better linear relationship between flow and regional left ventricular function found at 3 months (Fig 3⇑).
All patients underwent a coronary angiography at 90 minutes and had a control angiography at 24 hours or at 5 days. Only patients with TIMI flow grade 3 at both time points were included in this study. During follow-up, none of the patients had clinical or ECG evidence of reinfarction. In none of the patients studied was there observed a dramatic decrease in 13NH3 values suggesting reocclusion at 3 months. Nevertheless, it cannot be excluded that silent reocclusion occurred in some patients at a later time point, which could have affected the recovery of left ventricular function.36
In this study, 13NH3 was used as flow tracer. Flow values obtained with PET depend on the characteristics of the flow tracer used. Previous studies have shown that a good linear relationship exists between myocardial flow measured with microspheres and with 13NH3 over a large flow range, including necrotic myocardial regions, despite the presumed dependence of 13NH3 uptake on cell integrity.37 38
The present study demonstrates that the degree of myocardial tissue reperfusion as measured with PET within 24 hours after successful thrombolysis has an important prognostic significance. Patients with low flow values at 24 hours showed severely impaired regional contractile function at follow-up, whereas high flow values appear to predict good functional recovery at 3 months. Our study, in a limited number of patients, suggests that in patients with a moderate impairment of perfusion at 24 hours, a flow/metabolism scan at 5 days may be useful for the identification of viable but ischemically compromised myocardium (PET mismatch). In these patients, functional improvement can be obtained with additional revascularization procedures. Future studies in a larger group of patients are warranted to confirm the initial results. Our study also suggests that PET may prove to be very useful for the evaluation of additional therapies aimed at the improvement of the microcirculation of the reperfused myocardium.
In this study, for the first time, the presence of impaired reflow after successful thrombolysis was demonstrated and quantified with PET in patients with acute myocardial infarction. The presence of adequate myocardial tissue perfusion early after successful thrombolysis was clearly associated with functional recovery at late follow-up.
This study was supported in part by grant 6-0269-95 from the National Research Council of Belgium (NFW0).
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 1994.
- Received March 20, 1995.
- Revision received May 17, 1995.
- Accepted May 22, 1995.
- Copyright © 1995 by American Heart Association
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