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Enhanced detection of reversible myocardial hypoperfusion by technetium 99m-tetrofosmin imaging and first-pass radionuclide angiography after nitroglycerin administration

Peix Amalia; López Adlin; Ponce Felizardo; García-Barreto David

Institute of Cardiology, Habana, Cuba

Material and Methods

Introduction: Reversal of ischemia after myocardial infarction by revascularization is worthwhile only if viability exists in a sufficiently large portion of the left ventricle.
Objectives: To determine myocardial hypoperfusion reversibility and its influence on segmental and global function in a Tc-99m tetrofosmin scintigraphy with first-pass radionuclide angiography after nitroglycerin administration.
Material and Methods: We studied 50 patients after myocardial infarction. Three technetium 99m-tetrofosmin scintigraphies were performed: 1 at rest, 1 after 0.6 mg sublingual nitroglycerin (NTG), and 1 after injection at peak stress. First-pass multigated radionuclide angiography was obtained at rest and after NTG. Each patient also underwent a stress-redistribution-reinjection thallium-201 scintigraphy.
Results: During stress 99mTc-tetrofosmin, 104 segments had normal uptake, 51 showed moderately reduced uptake, and 186 had severely reduced uptake. Of these 186 segments, 33 (18%) improved at rest, and 41 (22%) improved only after NTG. Fifty-nine (79%) of these segments with improved uptake were also found to have reversible defects on 201Tl imaging. In the 26 patients with ventricular dysfunction, a 73% agreement was found between the functional and 99mTc-tetrofosmin uptake post-NTG improvement, whereas a 69% agreement was found with thallium reinjection. No significant differences were seen between 99mTc-tetrofosmin and 201Tl imaging.
Discussion: Our results seem to confirm the hypothesis that NTG administration should enhance the detection of viable mycardium in a Tc-99m tetrofosmin scintigraphy by increasing flow. Peripheral vasodilator actions of nitrates could result in an increase in ejection fraction; so, we considered possible improvement only in those cases with amelioration of the segmental contractility, explained by an increase in collateral blood flow to ischemic but viable zones. This would explain thje concordance in results between functional and perfusion imaging.
Conclusion: Nitroglycerin administration during 99mTc-tetrofosmin scintigraphy improves the detection of myocardium with reversible hypoperfusion in patients with a previous myocardial infarction.



99mTc-tetrofosmin perfusion is a valuable method to detect coronary artery disease (CAD), compared with thallium (Tl)-201 scintigraphy and coronary angiography. As other Tc-labeled compounds, such as sestamibi and teboroxime, its lack of redistribution (RD) decreases its usefulness in the diagnosis of myocardial viability.
Nitrates increase regional myocardial blood flow in patients with CAD, and have been used in combination with 201Tl or sestamibi to improve the detection of myocardial viability.
Tc-labeled compounds permit simultaneous evaluation of myocardial perfusion and function, optimizing the study of patients suspected of having CAD. For assessing ventricular function, the first-pass technique can be used, with similar results as those obtained with Tc-pyrophosphate radionuclide angiography (RNA).



To explore if nitroglycerin (NTG) can improve 99mTc-tetrofosmin uptake in hypoperfused territories and to compare perfusion and function nitrate imaging in detecting reversible hypoperfused myocardium.


Material and Methods: 

Fifty consecutive patients with prior confirmed myocardial infarction (MI) were included. Twenty-six patients had a left ventricular (LV) dysfunction. Characteristics of patients are summarized in Table 1.

Table 1

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First-pass multi-gated radionuclide angiography: was acquired in the 350 left anterior oblique (LAO) projection. Twelve millicuries (mCi) of 99mTc-tetrofosmin at rest (in bolus) and 33 mCi post 0.6mg sublingual (sl) NTG were injected for the first-pass study, that was acquired in frame mode (16 frames / RR cycle), synchronized with the ECG patient’s signal. The acquisition time was 25-35 seconds, according to the patient’s heart rate (HR) and added heart beats (3-6). A set of images was obtained proportionally to t / (m . 60 / k), where: t: acquisition time; m: number of heart beats acquired and k: heart rate of the patient.
A region of interest was traced upon the LV with a semiautomatic software. The LV volume curve was then obtained and LVEF was calculated by conventional method. A significant change post-NTG was defined by modification of the global LVEF ³ 4 units compared with the baseline value and an improvement of segmental contractility. For regional analysis, the left ventricular wall was divided into septal, inferoapical and posterolateral segments and the motion of each segment was evaluated using the following score: 0=normokinesis, 1=mild hypokinesis, 2=severe hypokinesis, 3=akinesis and 4=dyskinesis. According to the comparison between the basal and post-NTG scores, each asynergic segment was classified as either improved (wall motion score decrease ³ 1 grade) or unchanged.
Myocardial perfusion scintigraphy: Three 99mTc-tetrofosmin scintigraphies were performed by a planar technique: one at rest, one post 0.6 mg NTG and other after a symptom-limited stress on ergometric bicycle. A 2-day interval separated the rest / post-NTG and the exercise studies. At peak exercise, 15 mCi of 99mTc-tetrofosmin was administered intravenously. Following the same stress protocol, 3 mCi of 201Tl were administered intravenously at peak exercise. Stress images were acquired 5 to 10 minutes later. Redistribution images were obtained four hours after exercise. Immediately thereafter, all patients received a second injection of 1 mCi of 201Tl, and reinjection (RI) images were acquired 20 minutes later.
In both scintigraphies, anterior, 450 LAO and 700 lateral views were obtained and each view was divided as follows: Anterior: anterolaterolateral, inferior and apical segments; 450 LAO: septal, inferoapical and posterolateral segments and 700 lateral: anterior, posterior and apical segments.
Regional 99mTc-tetrofosmin and 201Tl uptake were quantitatively analyzed. 99mTc-tetrofosmin and 201Tl uptake were expressed as the percentage of the activity measured in the reference region (maximal counts) in each view. A segment was considered abnormal if stress 99mTc-tetrofosmin or 201Tl uptake was > 2 S.D. below the mean observed in the same region for normal subjects. Segments with abnormal uptake were subgrouped as: moderate (³ 50% of peak activity) and severe (< 50% of peak activity) defects. A segment with reduced activity on stress 99mTc-tetrofosmin or 201Tl imaging was considered reversible if the activity increased ³ 10% on rest or post-NTG 99mTc-tetrofosmin or on RD or RI 201Tl images; while a segment with reduced activity on stress images was considered irreversible if the activity did not increase ³ 10% or increased ³ 10%, but remained < 50% on rest or post-NTG 99mTc-tetrofosmin or on RD or RI 201Tl.
Statistical analysis: Values were expressed as the mean ± S.D. The continuous variables were analyzed using a paired Student’s t test. Qualitative variables were compared using chi-square test. For comparison between both scintigraphies a McNemar’s test was used (20). A probability value of p < 0.05 was considered significant.



There were no significant differences in stress characteristics between 99mTc-tetrofosmin and 201Tl scintigraphies (Table 2). Table 3 shows the hemodynamic response post-NTG. There was an increase of LVEF and HR; while a decrease in systolic and diastolic BP was recorded, all statistically significant.
A total of 341 segments were analyzed. On stress 99mTc-tetrofosmin images, 104 had normal tracer uptake, while 51 showed moderate and 186 severe reduction of tracer uptake. Of the 186 segments with severe defects at stress, 33 (18%) improved at rest, while 41 (22%) only did it after NTG. There was a 79% agreement (59 segments) in the uptake improvement between the two radiopharmaceuticals. Of the 112 segments without change on 99mTc-tetrofosmin scintigraphy, 92 (82%) were also non viable on 201Tl.
Twenty-six patients (52% of the total) had ventricular dysfunction. Analyzing the functional response to NTG and the 99mTc-tetrofosmin uptake (rest vs NTG), there was a 73% agreement (19 / 26 patients) between the two methods, and a 69% agreement (18 / 26 patients) if one compares the functional response to the 201Tl uptake (RD vs RI) (Figure 1). Of the 73 segments with severe defects on stress 99mTc-tetrofosmin, belonging to patients without ventricular dysfunction, 11 improved at rest (99mTc-tetrofosmin) and during 201Tl - RD; while 43 did not improve (74% of agreement between the two scintigraphies). If one also considers the response to NTG and to RI, 31 segments improved with both and 26 did not do it (78% of agreement) (Figure 2). There were no significant differences between the two scintigraphies.
Of the 113 segments with severe defects on stress 99mTc-tetrofosmin, belonging to patients with ventricular dysfunction, 8 improved at rest (99mTc-tetrofosmin) and during 201Tl - RD; while 76 did not improve (74% of agreement between the two scintigraphies; p < 0.05). Considering also the response to NTG and to RI, 28 segments improved with both and 67 did not do it (84% of agreement; p NS) (Figure 3).
Figure 4 shows the comparison between the two scintigraphies for detection of hypoperfusion reversibility. Among patients with dysfunction, 15 had 201Tl uptake improvement (including RD and RI), and 16 had 99mTc-tetrofosmin uptake improvement (including rest and post-NTG behaviour). Without dysfunction, there was an uptake improvement in 18 and 16 patients, respectively. These results were not statistically different.

Table 2

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Table 3

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Nitrates dilate flow-limiting obstructions in coronary arteries; there is also the vasodilating effect of nitrates on coronary collaterals, which explains the improvement in 201Tl uptake after NTG administration in hypoperfused regions related to totally occluded coronary arteries, but with well-developed collateral circulation.
Galli et al found an average reduction of the perfusion defect after NTG of 29% ± 4% in 20 patients with 99mTc-sestamibi scintigraphy; while Maurea et al found that from 197 segments with severely reduced 99mTc-sestamibi uptake, 54 (27%) improved post-NTG and were also viable with 201Tl.
In this study we focused our analysis on myocardial segments with severe reduction of myocardial uptake, in which the detection of reversible hypoperfusion was of interest.
We found a relatively small percentage of segments (18%) with a reversible hypoperfusion at 99mTc-tetrofosmin rest images, but this improved after NTG administration. Territories with chronic hypoperfusion at rest may have coronary flow reserve that can be elicited by pharmacological stimulation. This could be also appliable to tetrofosmin as a Tc-labeled compound.
Derebek et al found a 91% concordance between 201Tl-reinjection and 99mTc-tetrofosmin following sl isosorbide dinitrate. Flotats et al concurred with these results, but using sl NTG. We found equivalent myocardial hypoperfusion reversibility between 99mTc-tetrofosmin plus NTG and 201Tl-reinjection.
As one serious consequence of myocardial ischemia is contractile dysfunction, we also assess the hemodynamic response to NTG. Nitrates reduce afterload due to their peripheral vasodilator actions. As this could result in an increase in LVEF, we considered possible viability only in those cases with improvement of the segmental contractility. An increase in collateral blood flow to ischemic but viable zones in response to NTG seems to be the cause of segmental contractility improvement. This would explain the concordance in results between functional and perfusion imaging.
As study limitations first-pass RNA done on a single crystal gamma camera can be inadequate for evaluation of wall motion; wall motion analysis by first-pass RNA can be only done in one projection, and that we only compared 99mTc-tetrofosmin results with 201Tl-reinjection scintigraphy, and the real "golden standard" of viability is the functional recovery after a revascularization procedure.


In myocardial infarct patients, NTG administration during a 99mTc-tetrofosmin scintigraphy improves the detection of reversible hypoperfused myocardium.

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