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

Enhanced detection of reversible myocardial hypoperfusion by technetium 99m-tetrofosmin imaging and first-pass radionuclide angiography after nitroglycerin administration A m a l i a Peix, MD, Adlin L6pez, BSc, Felizardo Ponce, BSc, Jorge Morales, MD, Adolfo R o d r i g u e z d e ia Vega, MD, Catalina Sin Chesa, MD, A n a Ma. Maltas, CNMT, a n d David Garcia-Barreto, MD, DrSc

Background. Reversal of ischemia after myocardial infarction by revascularization is worthwhile only if viability exists in a sufficiently large portion of the left ventricle. Methods and Results. To determine myocardial hypoperfusion reversibility and its influence on segmental and global function, 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. 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. Fiftynine (79 %) of these segments with improved uptake were also found to have reversible defects on 2°lTl 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 201T1 imaging. Conclusion. Nitroglycerin administration during 99mTc-tetrofosmin scintigraphy improves the detection of myocardium with reversible hypoperfusion in patients with a previous myocardial infarction. (J N u d Cardiol 1998;5;469-76) Key words: tetrofosmin • nitroglycerin ° myocardial scintigraphy • first-pass radionuclide angiography

See related editorial, p 527 Tetrofosmin is a lipophilic, cationic diphosphinel,2 with good and rapid heart uptake (1.2% of the injected activity 5 minutes after injection) and relatively slow myocardial clearance in contrast to a rapid background washout from blood, lung, and liver, 2 which when labeled with technetium-99m can be used to perform myocardial scintigraphies. 99mTc-tetrofosmin perfusion imaging is a valuable method to detect coronary artery disease (CAD) compared with thallium (T1)-201 scintigraphy and coro-

From the Instituteof Cardiology,Havana,Cuba. Receivedfor publicationMay 28, 1997;acceptedFeb. 3, 1998. Reprintrequests:AmaliaPeix,MD, Instituteof Cardiology,17 No. 702, Vedado,Habana4. CP 10400, Cuba. Copyright© 1998by the AmericanSocietyof NuclearCardiology. 1071-3581/98/$5.00 + 0 43/1/89265

nary angiography) -5 As with other Tc-labeled compounds such as sestamibi and teboroxime, its lack of redistribution (RD) may decrease its usefulness in the diagnosis of myocardial viability.6 Nitrates increase regional myocardial blood flow in patients with CADT,8 and have been used in combination with 2°1T1 or sestamibi to improve the detection of myocardial viability.9-1e Tc-labeled compounds permit simultaneous evaluation of myocardial perfusion and function, optimizing the study of patients thought to have CAD.13,TMFor assessing ventricular function, the first-pass technique can be used15,16 with similar results to those obtained with 99mTc radionuclide angiography (RNA). 17 This study was performed to explore whether sublingual nitroglycerin (NTG) can improve 99mTc-tetrofosmin uptake in territories with hypoperfusion. We also performed first-pass multigated RNA during the 99mTctetrofosmin study at rest and with nitrates to compare perfusi0n and functional nitrate imaging in detecting myocardium with reversible hypoperfusion. 469

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Peix et al 99mTc imaging after nitroglycerin administration

MATERIAL AND METHODS Study Population Fifty consecutive patients who had previous myocardial infarction documented with clinical, electrocardiographic, and enzymatic evaluation, did not have previous thrombolysis or aortocoronary bypass surgery, and who were referred to our clinic during the first 6 months of 1996 were included in the study. Most of the patients (n = 43) had symptoms with episodes of stable angina, class II. The other 7 patients had no symptoms. Twenty-six patients had left ventricular (LV) dysfunction with LV ejection fraction (LVEF) <50%. Characteristics of the patients are summarized in Table 1. Every patient underwent 99mTc-tetrofosmin scintigraphy including first-pass RNA. Within 2 weeks thallium myocardial scintigraphy with reinjection was performed. Medication was discontinued in all cases 1 week before the first test was performed.

First-pass Multigated RadionucUde Angiography First-pass multigated RNA was acquired in the 35-degree left anterior oblique projection with the patient supine with the use of a digital gamma camera (GCA 501 S, Toshiba) equipped with a low-energy all-purpose collimator. The maximal count rate of the gamma camera was 0.38 Mcounts/sec. A 20% window was centered at the 140 keV photopeak of 99mTc. Twelve millicuries of 99mTc-tetrofosmin at rest and 33 mCi after 0.6 nag sublingual NTG administration were injected with an indwelling cannula previously inserted into an antecubital vein of the fight arm for the first-pass study. The tracer bolus was then injected and flushed with 20 mL 0.9% (wt/vol) saline solution. The study was acquired in frame mode (16 frarnes/RR cycle), synchronized with the patient's electrocardiogram signal. The acquisition time was 25 to 35 seconds depending on the patient's heart rate and added heart beats (3 to 6). A set of images was obtained proportionally to t/(m.60/k), where t is acquisition time, m is the number of heart beats acquired, and k is the heart rate of the patient. The number of counts in the rest end-diastolic frame was 12.2 Kcounts and in the post-NTG frame was 35.6 Kcounts. After that procedure, a set of images where the LV was better seen was chosen, and a region of interest was traced on the LV with semiautomatic software. The LV volume curve was then obtained, and LVEF was calculated twice by the conventional method with the mean value for analysis. The difference between the 2 calculations was never higher than 2 units. A significant change after NTG administration was defined by modification of the global LVEF of >-4 units compared with the baseline value and an improvement of segmental contractility. The choice of the threshold of 4 ejection fraction units was based on the first-pass RNA reproducibility in our laboratory (data not yet published). For regional wall motion analysis, the LV wall was divided into three segments (septal, inferoapical, and posterolateral), and the motion of each segment was evaluated with the following score: 0 -- normokinesis, 1 = mild hypokinesis, 2 = severe hypokinesis, 3 = akinesis, and 4 = dyskinesis. The wall motion was analyzed blindly and independently by 2 experienced observers who did not know which study was after NTG. In case of disagreement (5% of assigned scores) the final score was given by consensus with the collaboration of a third observer. According to the comparison between the basal

Journal of Nuclear Cardiology September/October 1998

and post-NTG scores, each asynergic segment was classified as either improved (wall motion score decrease >1 grade) or unchanged.

Myocardial Perfusion Scintigraphy With 99mTc-Tetrofosmin. Three 99mTc-tetrofosmin scintigraphies were performed by planar technique: 1 at rest, 1 after administration of 0.6 mg NTG, and 1 after a symptomlimited stress test done in the upright position on an ergometric bicycle (MEDIFIT 400L) with 25 W load increment every 2 minutes and continuous monitoring of symptoms, electrocardiogram, heart rate, and blood pressure. A 2-day interval separated the rest/post-NTG and the exercise studies. At peak exercise, 15 mCi 99mTc-tetrofosmin was administered intravenously, and the patient continued to exercise for an additional period of 60 seconds. The mean times between the injection and the beginning of image acquisition (depending on the laboratory availability) were as follows: 103 _+48 minutes at rest, 62 + 23 minutes after NTG, and 72 + 29 minutes after stress. With 201Tl. Following the same stress protocol, 3 mCi 201T1 was administered intravenously at peak exercise, and the patient continued to exercise for an additional 60 seconds. Stress images were acquired 5 to 10 minutes later. Redistribution images were obtained 4 hours after exercise testing while the patients were resting. Immediately thereafter, all patients received a second injection of 1 mCi 201T1, and reinjection (RI) images were acquired 20 minutes later. In both scintigraphies, anterior, 45-degree left anterior oblique, and 70-degree lateral views were obtained with a 128 x 128 word matrix until 500,000 counts per image were accumulated. The images were smoothed with a 9-point filter, and each view was divided as follows: anterior: anterolateral, inferior, and apical segments; 45-degree left anterior oblique: septal, inferoapical, and posterolateral segments; 70-degree lateral: anterior, posterior, and apical segments. Regional 99mTc-tetrofosmin and T1 uptake underwent quantitative analysis. In each view the myocardial segment with the maximum counts was considered the normal reference region. 99mTc-tetrofosmin and 2roT1uptake in all other segments was then expressed as the percentage of the activity measured in the reference region. To assess the normal range for quantitative data analysis, the 99mTc-tetrofosmin and 2roT1 myocardial scintigraphies of a group of 15 age-matched normal subjects (13 men, 2 women) with no evidence of cardiovascular or pulmonary disease were also considered. These subjects had normal clinical examination, echocardiogram, and stress electrocardiogram. A myocardial segment was considered abnormal if stress 99mTc-tetrofosmin or 2°iT1 uptake was >2 SD below the mean observed in the same region for normal subjects. Segments with abnormal uptake were subgrouped (on the basis of severity of reduction in tracer activity) as moderate (>50% of peak activity) and severe (<50% of Peak activity) defects. A segment with reduced activity on stress 99mTc-tetrofosmin or 201T1 imaging was considered reversible if the activity increased >_10% on rest or after NTG 99mTc-tetrofosmin or on RD or RI 201T1images. A segment with reduced activity on stress 99mTc-tetrofosmin or

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Table 1. Patient characteristics No. of patients Sex (M/F) Age (y) Mi localization

MI evolution (mo)

50 48/2 Mean: 53

Minimum 32

Anterior Inferior Anterior/Inferior (mean _+SD)

7.6 70 4 17 _+22

Maximum 70

MI, Myocardial infarction.

Table 2. Stress characteristics Variable

Tf Scintigraphy

Maximal load (W) % Maximal HR achieved Exercise time (min) ST depression (No. patients) Angina (No. patients)

93 + 34 81 -+ 10 8_+3

Thallium scintigraphy 95 _+34 82+_9 8_+3

P value NS NS NS

11

10

NS

4

7

NS

Tf,, 99mTc-tetrofosmin; HR, heart rate. Continuous variables are expressed as mean _+SD.

201T1 images was considered irreversible if the activity did not increase _>10%or increased _>10%but remained <50% on rest or after NTG 99mTc-tetrofosminor on RD or I/I 2roT1images.

Statistical Analysis Values were expressed as the mean -+ SD. The continuous variables were analyzed with a paired Student's 1' test. Qualitative variables were compared with the chi-squared test. For comparison between 99mTc-tetrofosmin and 201T1 scintigraphies, a McNemar's test was used.is A probability value of P < .05 was considered significant.

RESULTS No significant differences were seen in stress characteristics between 99mTc-tetrofosmin and 20~T1 scintigraphies (Table 2). Table 3 shows the hemodynamic response after NTG. There was an increase of LVEF and heart rate and a decrease in systolic and diastolic blood pressure, all statistically significant. A total of 341 segments were analyzed. On stress 99mTc-tetrofosmin images, 104 had normal tracer uptake (84% -+ 6% of peak activity), whereas 51 showed moderate (63% _+8% of peak activity) and 186 severe reduction (42% _+6% of peak activity) of tracer uptake. Of the 186 segments with severe defects at stress, 33 (18%) improved at rest (from 41% +_6% to 59% _+7% of peak activity, P < .001), whereas 41 (22%) improved only after NTG administration (from 39% + 7% to 57%

+_ 6% of peak activity, P < .001). A 79% agreement was seen (59 segments) in the uptake improvement between the 2 radiopharmaceuticals. Of the 112 segments without change on 99mTc-tetrofosmin scintigraphy (from 42% + 6% to 44% + 5% of peak activity, P = NS), 92 (82%) also remained without change on 2roT1 scintigraphy, Twenty-six patients (52% of the total) had ventricular dysfunction. Analyzing the functional response to NTG and 99mTc-tetrofosmin uptake (rest vs NTG), a 73% agreement (19 of 26 patients) was seen between the 2 methods, and a 69% agreement (18 of 26 patients) was seen if the functional response and the 201T1 uptake (RD vs RI) were compared (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 2°lT1 - RD, whereas 43 did not improve (74% agreement between the two scintigraphies). If the response to NTG and RI is also considered, 31 segments improved with both and 26 did not (78% agreement) (Figure 2). No significant differences were seen between the 2 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 2°iT1 - RD, whereas 76 did not improve (74% agreement between the two scintigraphies; P < .05). Considering the response to NTG and to RI, 28 segments improved with both, and 67 did not improve (84% agreement; P = NS) (Figure 3).

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Peix et al 99mTc imaging after nitroglycerin administration

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LVEF plus SEGMENTALCONTRACTILITY improv. (rest vs NTG)

IMPROVED

NOT IMPROVED

(no. of patients)

(no. of patients)

12

6

18

1

7

8

13

13

26

IMPROVED

TOTAL

(no. of patients) NOT IMPROVED (no. of patients) TOTAL Agreement = 73%

pNS

LVEF plus SEGMENTAL CONTRACTILITY improv. (rest vs NTG)

IMPROVED

NOT IMPROVED

(no. of patients)

(no. of patients)

11

7

18

1

7

8

12

14

26

IMPROVED

TOTAL

(no. of patients) e~

NOT IMPROVED (no. of patients) TOTAL Agreement = 69°/,

p NS

Figure 1. Agreement between functional and 99mTc-tetrofosmin uptake changes after NTG (top) or 2°1T1 uptake changes at reinjection (bottom). improv, improvement; TF, Tc-tetrofosrnin.

Table 3. Hemodynamic response Variable Heart rate (beats/min) Systolic BP (ram Hg) Diastolic BP (mm Hg) LVEF(%)

Basal 73 140 92 44

+ 13 _+28 _+ 16 + 12

After NTG 77 125 84 49

_+ 15 _+23 + 14 _+ 14

P value <.001 <.001 <.001 <.001

Values are expressed as mean _+SD. BP, blood pressure.

Table 4 shows the tetrofosmin and thallium uptake according to the presence or absence of dysfunction in the segments with severe reduction of tracer uptake at stress. No significant difference was seen between thallium and tetrofosmin uptake except between the resting (tetrofosmin) and RD (TI) uptake for dysfunctional segments. Segments with normal uptake at stress did not show significant differences in myocardial uptake: 84% _+6% versus 85% _+9% versus 85% -+ 8% of peak activity for stress/rest/NTG 99mTc-tetrofosmin (P =

NS), whereas with stress/RD/RI 201T1 they were 86% _+ 7% versus 87% + 8% versus 87% + 7% of peak activity (P = NS). Of the 51 segments with moderate reduction of tracer uptake at stress, 38 improved at rest (tetrofosmin) and 40 at RD (T1) (from 63% _+8% to 70% _ 10% of peak activity, P < .05 on 99mTc-tetrofosmin scintigraphy and from 65% _+9% to 73% _+ 10% of peak activity, P < .05 on 2°1T1 scintigraphy). No significant difference was seen after NTG or at RI (71% _+ 10% on

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Peix et al 99mTc imaging after nitroglycerin administration

473

TL (STRESS vs RD) IMPROVED

NOT IMPROVED

(no. of segments)

(no. of segments)

11

6

17

13

43

56

24

49

73

IMPROVED

TOTAL

(no. of segments) NOT IMPROVED (no. o! segments) TOTAL

Agre~ement = 74%

p N8

IlL (STRESS vs RI)

IMPROVED

IMPROVED

NOT IMPROVED

(no. of segments)

(no. of segments)

TOTAL

31

8

39

8

26

34

39

34

73

(no. ol segments) NOT IMPROVED (no. ol segments) TOTAL

Agreement -- 78%

p NS

Figure 2. Top, Agreement between 2°lT1 (stress vs redistribution) and 99mTc-tetrofosmin (stress vs rest) segmental uptake in patients without ventricular dysfunction. Bottom, Agreement between 2°1T1 (stress vs reinjection) and 99mTc-tetrofosmin (stress vs NTG) segmental uptake in same patients. Reinjection and NTG analysis include all segments with reversible defects. TF, Tc-tetrofosmin.

Table 4. U p t a k e in s e v e r e d e f e c t s Tf Sclntigraphy Stress REST/RD NTG/RI

D: ND: D: ND: D: ND:

39% -+ 5% 42% +- 60/0 41% -+ 10°/o 460/o _+ 12% 50% ± 13% 53% ± 15%

Thallium $cintigraphy

P value

D: 41% _+ 70/0 ND: 440/0 + 5% D: 500/0 _+90/o ND: 51% *_ 13°/o D: 55% ± 15% ND: 570/0 +_ 14°/o

NS NS <.05 NS NS NS

Values are expressed as mean _+SD % of peak activity.Tf, 99rrq'c-tetrofosmin; D, dysfunctional segments; ND, not dysfunctional segments. 99mTc-tetrofosmin and 73% + 12% of p e a k activity on 2°1T1, P = NS). Figure 4 shows the comparison between the 2 scintigraphies for the detection of reversibility. A m o n g patients with ventricular dysfunction, 15 had 201T1 uptake improvement (including RD and ILl), and 16 had tetrof o s m i n uptake i m p r o v e m e n t (including rest and postN T G behavior). Without ventricular dysfunction there was an uptake i m p r o v e m e n t in 18 and 16 patients, respectively. These results were not statistically different.

DISCUSSION The v a s o d i l a t i n g effects o f nitrates in c o r o n a r y arteries are well known. It has been hypothesized that nitrates dilate f l o w - l i m i t i n g obstructions in c o r o n a r y arteriesl9,2°; there is also the v a s o d i l a t i n g effect of nitrates on coronary collaterals, 21 which explains the improvement in 20IT1 uptake after N T G administration in regions with hypoperfusion related to totally occluded coronary arteries but with well-developed collateral

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Peix et al 99roTe imaging after nitroglycerin administration

Journal of Nuclear Cardiology September/October 1998

TL (STRESSvs RD) IMPROVED (no. of segments) IMPROVED

8

NOT IMPROVED

TOTAL

(no. o! segments) 8

16

21

76

97

29

84

113

(no. of segments) NOT IMPROVED

(no, of patients) TOTAL

Agreement = 74%

p = 0.02

11_(STRESSvs RI) IMPROVED (no. of segments) iMPROVED

NOT IMPROVED

TOTAL

(no. of segments)

28

7

35

11

67

78

39

74

113

(no. of segments) NOT IMPROVED (no. of segments) TOTAL

Agreement = 84%

p NS

Figure 3. Top: Agreement between 201T1(stress vs redistribution) and 99mTC-tetrofosmin(stress vs rest) segmental uptake in patients with ventricular dysfunction. Bottom: Agreement between 201T1(stress vs reinjection) and 99mTc-tetrofosmin(stress vs NTG) segmental uptake in same patients. Reinjection and NTG analysis include all segments with reversible defects. Abbreviations as in Figure 2.

circulation. 22 The increase in coronary blood flow is considered to be responsible for reversibility in 2°1T1 scintigraphy performed after nitrate administration. 9 This vasodilator effect has also been shown with 99mTc-sestamibi scintigraphy. Galli et al. 1° found an average reduction of the perfusion defect after NTG of 29% + 4% in 20 patients, whereas Maurea et al. 11 found that from 197 segments with severely reduced 99mTc-sestamibi uptake, 54 (27%) improved after NTG administration and were also viable with 201T1. Galli et al. 1° showed that 87% of reversible segments after NTG administration had functional recovery after surgery. 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. Although 99mTc-tetrofosmin resembles thallium in the detection of CAD, 3-5 it may underestimate the presence and extent of viable myocardium, 23,24 because like other 99mTc-labeled compounds, tetrofosmin has been considered a flow tracer rather than a viability tracer. 25 But this belief has been recently challenged and, in fact, NTG administration should enhance the detection of

viable myocardium by increasing flow; the results of this study seem to confirm this hypothesis. We found a relatively small percentage of segments (18%) with a reversible hypoperfusion at 99mTc-tetrofosmin rest images, but this percentage improved after NTG administration. Experimental evidence exists that sestamibi uptake and retention require the integrity of cell membrane and cellular viability 26,27 and that necrotic myocardium is unable to extract tracer. 28 But tracer uptake in areas of reduced flow and partially impaired viability seems more directly influenced by blood flow than cell death. 29 Territories with chronic hypoperfusion at rest may also have coronary flow reserve that can be elicited by pharmacologic stimulation. 3° This could be also applicable to tetrofosmin as a Tc-labeled compound. Derebek et al. 31 found a 91% concordance between 20tTl-rejection and 99mTc-tetrofosmin after sublingual isosorbide dinitrate administration. Flotats et al. 32 concurred with these results, but with the use of sublingnal NTG, whereas Cuocolo et al. 33 showed that enhanced 99mTc-tetrofosmin uptake after nitrates in dysfunctional

Journal of Nuclear Cardiography Volume 5, N u m b e r 5 ;469-76

segments with severe reduction of tracer uptake at rest correlated with metabolic activity by fluorine 18 deoxyglucose positron emission tomography imaging• In agreement with these results, we found equivalent myocardial hypoperfusion reversibility between 9 9 m T c tetrofosmin plus NTG and 2°lT1 reinjection. But in segments with moderate reduction of tracer uptake at stress, the administration of NTG or the reinjection did not modify significantly the uptake attained at rest or at redistribution. It was only in severe defects, which must correspond to a more severe ischemia, where NTG showed its usefulness comparable with the reinjection of 2°iT1. This result could be due to the nitrates' pharmacologic action on collateral circulation• One serious consequence of myocardial ischemia is contractile dysfunction. 34 We also considered it important to assess the hemodynamic response to NTG. Firstpass RNA at rest provides assessment of regional and global ventricular function similar to gated single photon emission computed tomography. 14 Nitrates alter loading because of their peripheral vasodilator actions. 7,35 Because this could result in an increase in LVEF, we considered possible improvement only in those cases with amelioration 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. 36-38 This would explain the concordance in results between functional and perfusion imaging• 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 done in only one projection, so we could merely analyze the inferoapical and posterolateral segments in case of inferior myocardial infarction and the septal segments in the anterior ones. Thus this prevented the assessment of all the myocardial segments with severe functional impairment. • The dose for the resting tetrofosmin scintigraphy of 12 mCi is suboptimal for the first-pass study, but we had to use it because according to the protocol (rest-NTG studies the same day), we had to inject a threefold higher dose for the second study, and the patient's dosimetry prevented a higher first dose. • We compared only 99mTc-tetrofosmin results with 201Tl-reinjection scintigraphy, and the real "golden standard" of viability is the functional recovery after a revascularization procedure. Conclusion

In patients with myocardial infarction, NTG administration during a 99mTc-tetrofosmin scintigraphy

Peix et al 99mTc imaging after nitroglycerin administration

475

1 8 `¸

16 14" 12 ~ 10 8~

6 4 2

O Improved

Not Imp.

Improved

Not Imp.

Figure 4. Comparison of 99mTc-tetrofosmin and thallium for myocardialhypoperfusionreversibility.First haIf offigure represents patients with ventricular dysfunction, and second half represents those without ventricular dysfunction. Black bars correspond with thallium; gray bars correspond with 99rnTc-tetrofosmin results. Uptake analysis includes all segmentswith reversibledefects (at rest or after NTG on Tc-tetrofosminscintigraphy or at redistribution or reinjection on thallium). Note that there is no significant difference. Tf, Tc-tetrofosmin;S, stress; R, rest; impr, improved.

improves the detection of myocardium with reversible hypoperfusion. We thank Jennifer Lewis Uribe, MD, Amersham's Healthcare Sales Manager for Latin America, and Alfredo Luaces, Lic, Amersham's Agent in Cuba, f o r their support and invaluable aid. We also thank Kent Hill, PhD, for his comments and positive criticisms in the review of this article•

References 1, Kelley JD, Forster AM, Higley B, et al. Technetium-99m-tetrofosmin: a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med 1993;34:222-7. 2. Higley B, Smith FW, Smith T, et al. Technetium-99m-l,2 bis (bis (2ethoxyethyl) phosphino) ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. J Nuel Meal 1993;34:30-8. 3. Heo J, Cave V, Wasserleben V, Iskandrian AS. Planar and tomographic imaging with technetium 99m-labeled tetrofosmin. Correlation with thallium-201 and coronary angiography. J Nucl Cardiol 1994; 1:317-24. 4. Tamaki N, Takahashi N, Kawamoto M, et al. Myocardial tomography using technetium-99m-tetrofosminto evaluate coronary artery disease. J Nucl Med 1994;35:594-600. 5. Rigo P, Leclercq B, Itti R, Lahiri A, Braat S. Technetium-99m-tetrofosmiu myocardial imaging: a comparison with thallium-201 and angiography. J Nucl Med 1994;35:587-93. 6. Jain D, Wackers FJTh, Mc Mahon M, Zaret BL. Is there any redistribution with 99rnTc-tetrofosmin imaging? A quantitative study using s~rial planar imaging. Circulation 1992;86:1-46. 7. Abrams J. Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. Am J Cardiol 1992;70:30B-42B. 8. He ZX, Verani MS, Liu XJ. Nitrate-augmented myocardial imaging for assessment of myocardial viability. J Nucl Cardiol 1995;2:352-7. 9. He ZX, Darcourt J, Guigner A, et al. Nitrates improve detection of

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