ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 13, No. 3, 147-153, 1999 
A new method to evaluate ischemic heart disease: Combined use of rest thallium-201 myocardial SPECT and Tc-99m exercise tetrofosmin first pass and myocardial SPECT 
Yong-ih KIM,* Hideki GOTO,* Katsuhiro KOBAYASHI,* Yoshihiro SAWADA,* Yoshitaka MIYAKE,** Go FUJIWARA ** Tomoya OKADA*** and Tsunehiko NISHIMURA*** 
*Department of Internal Medicine, Nishiyodo Hospital **Department of Radiology, Nishiyodo Hospital ***Division of Tracer Kinetics, Biomedical Research Center, Osaka University, Medical School 
We developed a new diagnostic method for simultaneously evaluating myocardial ischemia, myocardial viability and ventricular function in less than 90 minutes by combined use of rest thallium-201 (Tl) SPECT and exercise Tc-99m tetrofosmin (TF) first pass and SPECT. The subjects were 9 healthy controls, 19 angina pectoris patients, and 19 old myocardial infarction patients, in all of whom coronary angiography had been performed. Rest Tl myocardial SPECT was performed first, and was followed by exercise TF myocardial SPECT. We also performed first pass radionuclide angiography by TF during maximum exercise on a bicycle ergometer to assess the left ventricular ejection fraction (LVEF). The total examination time was less than 90 minutes. SPECT diagnosis was performed by semi-quantitative analysis. LVEF below 55% was regarded as abnormal. In the patients with angina pectoris, analysis according to the coronary artery showed that the diagnostic accuracy of SPECT was 85.0% for ischemia in the region of the left anterior descending branch (LAD), 87.5% for the left circumflex branch (LCX) and 77.8% for the right coronary artery (RCA). The accuracy of diagnosis for angina pectoris was 82.1%, as determined by SPECT alone, and rose to 89.3% when the LVEF levels were also taken into consideration. In the patients with old myocardial infarction, the diagnostic accuracy of SPECT was 84.2% for the LAD, 92.3% for the LCX and 85.0% for the RCA. Analysis by patients showed that the accuracy of diagnosis for myocardial infarction was 85.7%, as determined by SPECT alone. The diagnostic accuracy, however, rose to 89.3% when the LVEF levels also were taken into consideration. In conclusion, it was demonstrated that this combined diagnostic method was highly reliable for evaluating ischemic heart disease within a short time. 
Key words: 201TI, 99mTc-tetrofosmin, myocardial SPECT, exercise radionuclide angiography 
Received December 9, 1998, revision accepted February 24, 1999. For reprint contact: Tsunehiko Nishimura, M.D., Ph.D., Division of Tracer Kinetics, Biomedical Research Center (D9), Osaka University, Medical School, Yamadaoka, 2-2, Suita, Osaka 565-0871, JAPAN. 
INTRODUCTION 
201TI is quite useful for detecting myocardial ischemia and for evaluating myocardial viability,1,2 but is affected by absorption and scattering because of low gamma-ray energy spectrum. In addition, the maximal dose is limited because of the relatively long half decay time. 99mTc-labeled myocardial agents that provide better SPECT images have recently been developed.3-6 99mTc-tetrofosmin (Tetrofosmin) has shown promise in a variety of clinical applications because of lower accumulation in the liver than other 99mTc-labeled compounds, easy preparation at room temperature, a high labeling rate of more than 95% over 6 hours after preparation and the absence of adverse effects such as metallic taste.7-10 The phase 1 through phase 3 clinical studies in Japan have also demonstrated that Tetrofosmin provides excellent SPECT images, similar sensitivity in detection of ischemic heart disease11-14 and higher specificity than 201Tl.7-16 Tetrofosmin, however, needs to be administered both at rest and after exercise, because there is no redistribution.17,18 Berman et al. have developed new approaches to rapid evaluation of ischemic heart disease in a short time by using both 201Tl and 99mTc-labeled tracers, 19-22 Noting the special properties of Tetrofosmin, which also can be used to evaluate ventricular function 23 we developed a new diagnostic method for simultaneously evaluating myocardial perfusion and ventricular function within 90 minutes by using both 201Tl and Tetrofosmin. 
SUBJECTS AND METHODS 
Subjects The subjects were 9 normal controls (5 men and 4 women, the average age; 64.8+-9.4 years old) and 38 patients with ischemic heart disease (29 men and 9 women; average age: 66.0+-9.4 years old), Nineteen of the patients had angina pectoris (AP) and the remaining 19 had old myocardial infarction (OMI). In AP, culprit lesions were 11 in LAD, 7 in LCX and 9 in RCA, respectively. There were 2 triple vessels disease, 4 double vessels disease and 13 single vessel disease. In OMI culprit lesions were 9 in LAD, 4 in LCX and 11 in RCA. There were 2 triple vessels disease, 1 double vessels disease and 16 single vessel disease. 
Protocols As shown in Figure 1 , 201TI myocardial SPECT at rest was performed first, immediately thereafter the subjects performed maximal exercise on a bicycle ergometer and a Tetrofosmin first pass study was performed to evaluate the left ventricular ejection fraction (LVEF). This was followed by Tetrofosmin myocardial SPECT. The time required to complete the examination was less than 90 minutes. 
Data acquisition 201Tl myocardial SPECT Data acquisition was started 20 minutes after 111 MBq of 201Tl was injected at rest. The SPECT images were obtained at 30 seconds per step, rotating 180 degrees between the positions of 45deg.-LPO and 45deg.-RAO. A large field of view gamma camera with a parallel-hole high-resolution collimator (GCA901A/HG, Toshiba, Tokyo, Japan) was used in this study. The data obtained were stored on a 64 x 64 matrix and analyzed by means of a dedicated nuclear medicine computer (GMS5500A, Toshiba, Tokyo, Japan). Scatter correction was performed by using a triple-energy window method. Attenuation correction was not applied. The main window was placed at 71+-24 keV, and a sub-window was set at 4% in front and behind the main window. A low-pass (Butterworth) filter was used for the projection imagings, and a ramp filter for back-projection. Tomographic slices (approximately 5.3 mm thick) were reconstructed relative to the anatomical axis of the left ventricle. Vertical and horizontal long-axis slices and short-axis slices were generated. 
Tetrofosmin first-pass study and myocardial SPECT The subject performed bicycle ergometer exercise with 25-watts increases every two minutes in the modified supine position, the patient's body was raised 45deg., and the legs were lowered 45deg.. When the maximal level of exercise was reached, the patient was positioned close to the gamma camera (GCA 401, Toshiba, Tokyo, Japan) and exercise was stopped. A bolus of 925 MBq of 99mTc-tetrofosmin was administered to perform the first pass study within a few seconds after exercise, so that no apparent motion artifacts occurred. The first pass study was performed at the 30deg.-RAO position by the list mode method. In each case in a nuclear medicine computer (GMS 55U, Toshiba, Tokyo, Japan), the frame rate was calculated in 16 segments, which divided the R-R interval of 2 or 3 heart beats in an electric cardiograph. Tetrofosmin SPECT images were obtained 30 minutes after the exercise, taking 20 seconds per step and rotating 180 degrees between the 45deg.-LPO and 45deg.-RAO positions. The images were collected with the main window set at 140+-24 keV, and a sub-window set at 3% in front and behind the main window. Other conditions were the same as used in 201Tl myocardial SPECT study. 
Data analysis Radionuclide study 
As shown in Figure 2, the representative myocardial SPECT images along the short and vertical long axis were divided into three segments: anterior wall, lateral wall, and inferior wall, as territories of left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA), respectively. The subjects were diagnosed as "normal," "ischemia" or "mfarction (scar)" based on visual comparison of the rest Tl and exercise Tetrofosmin SPECT images by three physicians in conference who had no knowledge of the patients' background. Reversible hypoperfusion was diagnosed as ischemia, and fixed perfusion defect as infarction. LVEF obtained in the first pass study during exercise was determined to be abnormal when the value was below the mean - 2SD of the healthy controls (LVEF < 55%). 
Coronary angiography and left ventriculography 
Coronary angiography and left venticulography in the 30deg.-RAO position were performed on all the subjects within a week before performance of the radionuclide study. When there was more than 75% coronary artery stenosis, it was considered as positive in accordance with the AHA classification. The left ventriculogram obtained in the 30deg.-RAO position was divided into 5 parts: anterobasal, anterolateral, apical, inferior and inferobasal. The left ventricular regional wall motion was evaluated by the centerline method, and was determined to be abnormal when the value was below the mean - 2SD of the healthy controls. Old myocardial infarction was defined according to wall motion abnormality. 
Statistical analysis 
All the values are expressed as the means+-SD. Differences among the three groups were statistically analyzed by one-way analysis of variance. A value of p < 0.05 was considered significant. 
RESULTS 
Case presentation 
A normal case is shown in Figure 3. Myocardial perfusion is normal, and LVEF during exercise is well maintained at 72%. Figure 4 represents an angina pectoris patient with coronary artery stenosis in both the LAD (segment 7 = 90%, segment 9 = 99%) and the LCX (segment 13 = 99%). Although exercise Tetrofosmin SPECT images showed mild perfusion defects in the anterior and lateral walls, the patient could not be clearly diagnosed as having myocardial ischemia on the basis of the SPECT study alone. It was confirmed, however, that the patient had ischemia, since the LVEF was a low 48%. Figure 5 shows a patient with old inferior myocardial infarction. The study revealed a perfusion defect in the inferior wall and a low LVEF of 43%. 
Radionuclide study 
As shown in Figure 6, significant differences in exercise LVEF were observed among the controls (67.2+-5.7%), AP patients (55.8+-12.3%), and OMI patients (43.1 +-15.3%). Analysis of the diagnostic reliability of SPECT according to each coronary artery showed 80% sensitivity, 88.9% specificity and 84.2% accuracy in the patients with OMI caused by occlusion of the LAD. Similarly, analysis of the reliability of SPECT alone showed 100% sensitivity, 88.9% specificity and 92.3% accuracy for the LCX, and 81.8% sensitivity, 88.9% specificity and 85.0% accuracy for the RCA (Fig. 7a). Similar results were obtained in the AP patients. Analysis of diagnostic reliability of SPECT alone showed 81.8% sensitivity, 88.9% specificity and 85% accuracy in the patients with stenosis of the LAD, 85.7% sensitivity, 88.9% specificity and 87.5% accuracy for the LCX, and 66.7% sensitivity, 88.9% specificity and 77.8% accuracy for the RCA (Fig. 7b). 
The patients were diagnosed as having OMI with 84.2% sensitivity, 88.9% specificity and 85.7% accuracy by SPECT alone in the analysis by patients. When LVEF during exercise was taken into account, the reliability of the diagnosis increased to 89.5% sensitivity, 88.9% specificity and 89.3% accuracy (Fig. 8a). The AP patients were diagnosed as having ischemia with 78.9% sensitivity, 88.9% specificity and 82,1% accuracy, in the SPECT study. When the LVEF findings were taken into account, the reliability of the diagnosis increased to 89.5% sensitivity, 88.9% specificity and 89.3% accuracy (Fig. 8b). 
DISCUSSION 
99mTc-sestamibi (MIBI),24-26 99mTc-tetrofosmin7-10 and 201Tl have been used as myocardial flow tracers. Tetrofosmin provides excellent images even 30 minutes after intravenous injection, because it has lower liver activity. As with MIBI, however, Tetrofosmin needs to be injected twice, at rest and immediately after exercise, to detect myocardial ischemia and to evaluate myocardial viability,16,18 because it is hardly redistributed at all.17 Although diagnostic protocols for 201Tl in combination with 99mTc-myocardial agents have been tried,19-22 many of them still need to be improved. Noting the properties of Tetrofosmin by which a relatively large dose enables measurement of LVEF by the first pass method,23 we have been able to develop a new diagnostic method for simultaneously evaluating myocardial perfusion and ventricular function in a short time. Many reports on changes in LVEF during exercise have demonstrated that patients with ischemic heart disease exhibit little or no increase in LVEF immediately after exercise,31-33 in contrast with a rapid increase in healthy controls. 27-30 It was also demonstrated that decreasing LVEF valves are correlated with the outcome of ischemic heart disease 34,35 The protocol we developed may therefore be useful in predicting outcome, because LVEF during exercise can be evaluated. In our protocol, however, LVEF cannot be obtained at rest and compared with LVEF during exercise. We therefore judged a patient to have myocardial ischemia if LVEF on exercise was smaller than the mean minus 2SD of the LVEF values of the healthy controls. Our diagnostic protocol is cost-effective, since the examination can be completed in a short time, but whether our protocol functions more effectively than other protocols, in which 201Tl alone is used, is a more important question.11-14 We first identified affected sites in the coronary arteries of OMI and AP patients to assess the reliability of the protocol. In OMI, the reduced wall motion detected by left ventriculography was employed as the gold standard. The accuracy of diagnosis by SPECT was satisfactory: 84.2% for the LAD, 92.3% for the LCX 
and 85.0% for the RCA, as shown in Figure 7a, and 201Tl myocardial SPECT performed 24 hours later may be useful for evaluating myocardial viability as well. We next determined which coronary branch was responsible for AP. Coronary artery branches with more than 75% stenosis were considered as "positive" on coronary angiography, in accordance with the AHA classification. The diagnosis by SPECT was compared with that by the angiographic study to assess the reliability of the protocol. As shown in Figure 7b, the accuracy of the SPECT diagnosis was 85.0% for the LAD, 87.5% for the LCX and 77.8% for the RCA. In two patients with stenosis of the RCA who were in poor condition and could not perform maximal exercise, the sensitivity was a low 66.7%. This effect probably influenced the accuracy of RCA. When these two cases are excluded, the results appear consistent with the findings reported by Mahmood et al.21 We were able to confirm that our protocol is useful in identifying coronary arterial involvements as mentioned above. Another objective of this study was to demonstrate that our protocol is an appropriate screening examination that can be completed in a short time. Figure 8 shows the usefulness of our protocol for analysis by patients as a screening test for evaluating myocardial ischemia. The accuracy of the diagnosis by SPECT alone was 85.7% for OMI and 82.1% for AP, and is therefore satisfactory as a screening examination. Almost 90% accuracy was obtained when LVEF on exercise was taken into consideration. As limitations, the protocol we have presented here includes some complicated steps, such as measurement of LVEF on exercise, but it is evidently a very useful screening test for simultaneously evaluating myocardial perfusion and ventricular function within 90 minutes. In conclusion, we developed a new diagnostic method that allows myocardial perfusion and ventricular function to be simultaneously evaluated within 90 minutes, and, if necessary, myocardial viability can be precisely evaluated by 24-hour 201TI imaging. Thus. The protocol was therefore demonstrated to be very reliable, and we expect it to occupy a secure place in the diagnosis of ischemic heart disease in the near future. 
REFERENCES 
l. Strauss HW, Pitt B. Thallium-201 as a myocardial imaging agent. Semin Nucl Med 7: 49-58, 1977. 
2. Kaul S. A look at 15 years of planar thallium-201 imaging. Am Heart J I 18: 581-601 , 1989. 
3. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulotion 77: 491-498, 1988. 
4. Wackers FT, Berman DS. Maddahi J, Watson DD, Beller GA, Strauss HW, et al. Technetium-99m hexakis 2-methoxyisobutyl isonitrile: Human biodistribution, dosimetry, safety, and preliminary comparison to thallium201 for myocardial perfusion imaging. JNucl Med 30: 301-311, 1989. 
5. Iskandrian AS, Heo J, Nguyen T, Mercuro J. Myocardial imaging with Tc-99m teboroxime: Technique and initial results. Am Heart J 121:889-894, 1991. 
6. Beller GA, Watson DD. Physical basis of myocardial perfusion imaging with the technetium-99m agents. Semin Nucl Med 21: 173-181, 1991. 
7. Sridhara BS, Braat S, Rigo P, Itti R, Cload P, Avijit L, et al. Comparison of myocardial perfusion imaging with technetium-99m tetrofosmin versus thallium-201 in coronary artery disease. Am J Cardiol 72: 1015-l019, 1993. 
8. Kelly JD, Forster AM, Higley B, Archer CM, Booker FS, Canning LR, et al. Technetium-99m tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med 34: 222-227, 1993. 
9. Higley B, Smith FW, Smith T, Gemmel HG. Gupta PD, Gvozdanovic DV, et al. Technetium-99m-1,2-bis[bis(2-Ethoxyethyl)Phosphino]Ethan: Human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. JNucl Med 34: 30-38, 1993. 
10. Smith FW, Smith T, Gemmel H. Gupta PD, Archer C, Davidson J, et al. Phase I study of Tc-99m diphosphine (P53) for myocardial imaging. J Nucl Med 32: 967, 1991. (abstract) 
11. Hguyen T. Heo J, Ogilby D, Iskandrian AS. Single photon emission computed tomography with thallium-201 during Adenosin-Induced coronary hyperemia: Correlation with coronary arteriography, exercise thallium imaging and two-dimensional echocardiography. J Am Coll Cardiol 16: 1375-1383, 1990. 
12. Francisco DA, Collins SM, Go RT, Ehrhardt JC, Van Kirk OC, Marcus ML. Tomographic thallium-201 myocardial perfusion scintigrams after maximal coronary artery vasodilation with intravenous dipyridamole: Comparison of qualitative and quantitative approaches. Circulation 66: 370-379, 1982. 
13. Verani MS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease by controlled coronary vasodilation with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circldation 82: 80-87, 1990.
14. Nishimura S, Mahmarian JJ. Boyce TM, Verani MS. Equivalence between adenosine and exercise thallium-201 myocardial tomography: A multicenter, prospective, crossover trial. JAm Coll Cardiol 20: 265-275, 1992. 
15. Khattar RJ, Hendel RC, Crawley JCW, Wackers FJ, Rigo P, Zaret BL. Improved diagnostic accuracy of planar imaging with technetium 99m-labeled tetrofosmin compared with thallium-201 for the detection of coronary artery disease. J Nucl Cardiol 4: 291-297, 1997. 
16. Jain D. Wacker FJT. Mattera J. McMahon M. Sinus AJ, Zaret BJ. Biokinetics of technetium-99m-tetrofosmin: Myo-cardial perfusion imaging agent: Implication for a one-day imaging protocol. J Nucl Med 34: 1254-1259, 1993. 
17. Nakajima K, Taki J, Shuke N, Bunko H, Takata S, Hisada K. Myocardial perfusion imaging and dynamic analysis with technetium-99m tetrofosmin. J Nucl Med 34: 1478-1484, 1993. 
18. Sridhara B, Sochor H, Rigo P, Braat S, Itti R, Martinez-Duncker D, et al. Myocardial single-photon emission computed tomographic imaging with technetium-99m tetrofosmin: Stress-rest imaging with same-day and sepa-rate-day rest imaging. J Nucl Cardiol 1: 138-143, 1994. 
19. Berman DS, Kiat HS. Train KFVT, Germano G, Maddahi J, Friedman JD. Myocardial perfusion imaging with technetium-99m-sestamibi: Comparative analysis of available imaging protocols. J Nucl Med 35: 681-688, 1994. 
20. Berman DS, Kiat H. Friedman JD, Wang FP, Train KV, Matzer L, et al. Separate acquisition rest thallium-201/stress technetium-99m sestamibi dual-isotope myocardial perfusion single-photon emission computed tomography: A clinical validation study. J Am Coll Cardiol 22: 1455-1464, 1993. 
21. Mahmood S, Gunning M, Bonanji JB, Gupta NK, Costa DC, Jarrint PH, et al. Combined test thallium-201/stress technetium SPECT: Feasibility and diagnostic accuracy of a 90-minute protocol. J Nucl Med 36: 932-935, 1995. 
22. Woldman S, Mcquiston A, Ng A, Martin W, Hutton I. Exercise 201 Tl/rest 99mTc-tetrofosmin myocardial perfusion imaging: A covenient protocol for the assessment of coronary disease. Nucl Med Commun 17: 317-324, 1996. 
23. Takahashi N, Tamaki N, Tadamura E, Kawamoto M, Torizuka T, Yonekura Y, et al. Combined assessment of regional perfusion and wall motion in patients with coronary artery disease with technetium 99m tetrofosmin. J Nucl Cardiol 1: 29-38, 1994. 
24. Cuocolo A, Pace L. Ricciardelli B, Chiariello M, Trimarco B, Salvatore M. Identification of chronic coronary artery disease: Comparison of thallium-201 scintigraphy with reinjection and technetium-99m-methoxyisobutyl isonitrile. J Nucl Med 33: 505-511, 1992. 
25. Cuocolo A, Maurea S, Pace L, Nicolai E, Nappi A, Imbriaco M, et al. Resting technetium-99m methoxyisobutyl-isonitrile cardiac imaging in chronic coronary artery disease: comparison with rest-redistribution thailium-201 scin-igraphy. Eur J Nucl Med 20: 1186-1192, 1993. 
26. DePuey EG. Nichols K, Dobrinsky C. Left Ventricular ejection fraction assessed from gated technetium-99m-sestarrtibi SPECT. J Nucl Med 34: 1871-1876. 1993. 
27. Battler A, Slutsky R, Pfisterer M. Ashbum W, Froelicher V. Left ventricular ejection fraction changes during recovery from treadmill exercise: A preliminary report of a new method for detecting coronary artery disease. Clin Cardiol 3: 14-18, 1980. 
28. Schnider RM, Weintraub WS, Klein LW, Seelaus PA, Agarwal JB, Helfant RH. Rate of left ventricular functional recovery by radionuclide angiography after exercise in coronary artery disease. Am J Cardiol 57: 927-932, 1986. 
29. Dymond DS, Foster C, Grenier RP, Carpenter J, Schmidt DH. Peak exercise and immediate postexercise imaging for the detection of left ventricular functional abnormalities in coronary artery disease. Am J Cardiol 53: 1532-1537, 1984. 
30. Plotnick GD, Becker LC, Fisher ML. Changes in left ventricular function during recovery from upright bicycle exercise in normal persons and patients with coronary artery disease. Am J Cardiol 58: 247-251, 1986. 
31. Slutsky R. Response of the left ventricle to stress: Effects of exercise, atrial pacing, afterload stress and drugs. Am J Cardiol 47: 357-364, 1981.
32. Berger HJ. Reduto LA, Johnsone DE, Borkowski H, Sands JM, Cohen LS, et al. Global and regional left ventricular response to bicycle exercise in coronary artery disease. Assessment by quantitative radionuclide angiocardiography. Am J Cardiol 66: 13-21, 1979. 
33. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Lohnston GS, et al. Real-time radionuclide cineanigiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease. N Engl J Med 296: 839-844, 1977. 
34. Lee KL, Pryor DB, Pieper KS, Harrell FE Jr, Califf RM, Mark DB, et al. Prognostic value of radionuclide angiography in medicaliy treated patients with coronary artery disease. A comparison with clinical and catheterization variables. Circulation 82: 1705-1717, 1990. 
35. Shaw LJ, Heinle SK, Borges-Neto S, Kesler K, Coleman RE, Jones RH. Prognosis by measurements of left ventricular function during exercise. J Nucl Med 39: 140-146, 1998.