～（99m）TcN-NOET心肌灌注显像对冠心病诊断的临床应用价值
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摘要
~(99m)TcN-NOET{双[N-乙氧基，N-乙基(二硫代氨基甲酸脂)氮化锝](Ⅴ)}是一种新的中性、亲脂性的锝标记心肌灌注显像剂。多种动物实验及预临床实验均表明，该药物具有较高的心肌摄取率和与~(201)Tl类似的再分布现象。这就意味着该显像剂可能具有~(201)Tl和~(99m)Tc标记化合物的双重优势，从而有可能成为更好的心肌灌注显像剂。本研究通过对50例受检者进行~(99m)TcN-NOET运动-再分布显像，以探究该药物在冠心病诊断上的临床应用价值。方法：10名正常人、1名心肌梗死患者和39名临床拟诊冠心病的患者进行了~(99m)TcN-NOET运动-再分布(注药后2、4小时)心肌灌注显像，并测定不同时间的心／肺比值(HLR)。其中13人进行了冠状动脉造影检查。运动心肌灌注显像和冠状动脉造影之间的时间间隔不超过两个月。结果：根据运动显像(注药后0.5小时)测得的HLR的不同，将50例受检者分为两组，第一组(36人，运动显像HLR＞2)显像结果正常，显影清晰，图像质量好；第二组(14人，HLR＜2)显影较模糊，肺内摄取显像剂较多，图像质量较差。两组受检者的年龄无显著差别(p=0.454)。采用两样本均数比较的t检验方法比较不同时段内两组受检者的HLR，均存在显著性差异(p=0.000)，第一组的HLR高于第二组。再采用无重复数据的两因素方差分析法(two-way ANOVA)分别对两组受检者在不同时间的HLR进行比较：组一不同时间的HLR存在显著性差别(p=0.000)，2小时的HLR要高于0.5小时和4小时，而0.5小时和4小时间则无显著性差异(p=0.087)，说明，对于第一组的受检者，HLR在运动后2小时达到高峰，显影最为清晰；而组二不同时间的HLR则无显著性差异(p=0.063)。第一组受检者中包括10名正常人和5名冠状动脉造影结果正常(狭窄＜50％)者，其余21名患者在4～12个月的随访期间内无特殊相关症状及心脏事件(包括：心源性死亡、非致死性心肌梗死和心绞痛)发生。第二组受检者中，1例心肌梗死患者显像结果表现为不可逆性灌注缺损，4例显像结果为完全可逆或部分可逆性
山西医科大学
2002界布吐创七减开，匕生论文
灌注缺损的患者中有3例经冠状动脉造影证实为冠心病患者，1例为临床
确诊的劳力性心绞痛患者。9例显影结果正常的人中有4例冠状动脉造影
结果异常(狭窄在50%~70%之间)，3人在随访中有心绞痛发作。结论:
1.99mTcN一NoET运动一再分布显像对冠心病的诊断具有肯定的作用。2.
冠心病患者在运动后肺摄取99mTcN一NoET增加，导致HLR下降。所以，
在进行运动99mTcN一OET心肌灌注显像的同时测定HLR，可以进一步提
高99mTcN一oET运动心肌灌注显像对冠心病的诊断灵敏度。3.
99mTcN一NOET具有和2“‘Tl类似的再分布现象，所以可通过9帅几N一oET
运动一再分布显像来区分缺血心肌和瘫痕组织。
Background: 99mTcN-NOET[bis(N-ethoxy, N-ethyl dithiocarbamato)nitrido technetium-99m( V)] is a new neutral lipophilic 99mTc-labeled myocardial perfusion agent with a high first-pass extraction fraction and delayed redistribution kinetics after transient ischemia comparable to what is observed with 201T1. Currently, this compound is in phase III clinical trials in Europe. The purpose of this study was to estimate the utility of this agent in the detection of coronary artery disease (CAD). Methods: 10 normal volunteers, 1 myocardial infarction patients and 39 suspected CAD patients underwent stress-delayed (2 and 4 hr postinjection) 99mTcN-NOET myocardial perfusion imaging, and the heart-lung ratio (HLR) at different time was calculated. 13 patients of them accepted the coronary angiography examination in 2 months post myocardial imaging. Result: According to the exercise heart-lung ratio (EXHLR), 50subjects were divided into 2 groups. G1 (n=36, EXHLR > 2) contained 10 normal volunteers and 5 patients with normal coronary arteries. The other 21 subjects had no relevant symptom and cardiac event (defined as sudden cardiac death, non-fatal myocardial infarction and angina) occurred during the follow-up period of 4 to 12 months. All images of Gl were normal and the quality of the images was good. In G2 (n=14, EXHLR<2), the image of the patient with inferior infarction (double-vessel disease) was fixed defect. Three patients with CAD had complete reversible perfusion defects and two of them were confirmed by coronary angiography (one was single-vessel disease the other was double-vessel disease) and the other one was stable angina patient. The image of the patient with critical stenosis in three vessels was partly reversible perfusion defect. There was significant
difference between the HLR of the two groups at different time, the HLR of G2 was lower than G1 . The quality of all images of G2 was worse than G1 . Nine patients of G2 had normal perfusion images, four of them had significant CAD by qualitative coronary angiography (stenosis 50%-70%), three had angina during the follow-up period. Conclusion: 1 . Stress-delayed myocardial perfusion imaging with 99mTcN-NOET can be used to diagnose CAD and distinguish ischemic myocardium from scar. 2. Exercise-induced increases in pulmonary uptake of 99mTcN-NOET and descent of the HLR are associated with exercise-induced myocardial dysfunction. 3. The HLR may be as an index of the patients with CAD.
山西医科大学
2002界布吐创七减开，匕生论文
灌注缺损的患者中有3例经冠状动脉造影证实为冠心病患者，1例为临床
确诊的劳力性心绞痛患者。9例显影结果正常的人中有4例冠状动脉造影
结果异常(狭窄在50%~70%之间)，3人在随访中有心绞痛发作。结论:
1.99mTcN一NoET运动一再分布显像对冠心病的诊断具有肯定的作用。2.
冠心病患者在运动后肺摄取99mTcN一NoET增加，导致HLR下降。所以，
在进行运动99mTcN一OET心肌灌注显像的同时测定HLR，可以进一步提
高99mTcN一oET运动心肌灌注显像对冠心病的诊断灵敏度。3.
99mTcN一NOET具有和2“‘Tl类似的再分布现象，所以可通过9帅几N一oET
运动一再分布显像来区分缺血心肌和瘫痕组织。
Background: 99mTcN-NOET[bis(N-ethoxy, N-ethyl dithiocarbamato)nitrido technetium-99m( V)] is a new neutral lipophilic 99mTc-labeled myocardial perfusion agent with a high first-pass extraction fraction and delayed redistribution kinetics after transient ischemia comparable to what is observed with 201T1. Currently, this compound is in phase III clinical trials in Europe. The purpose of this study was to estimate the utility of this agent in the detection of coronary artery disease (CAD). Methods: 10 normal volunteers, 1 myocardial infarction patients and 39 suspected CAD patients underwent stress-delayed (2 and 4 hr postinjection) 99mTcN-NOET myocardial perfusion imaging, and the heart-lung ratio (HLR) at different time was calculated. 13 patients of them accepted the coronary angiography examination in 2 months post myocardial imaging. Result: According to the exercise heart-lung ratio (EXHLR), 50subjects were divided into 2 groups. G1 (n=36, EXHLR > 2) contained 10 normal volunteers and 5 patients with normal coronary arteries. The other 21 subjects had no relevant symptom and cardiac event (defined as sudden cardiac death, non-fatal myocardial infarction and angina) occurred during the follow-up period of 4 to 12 months. All images of Gl were normal and the quality of the images was good. In G2 (n=14, EXHLR<2), the image of the patient with inferior infarction (double-vessel disease) was fixed defect. Three patients with CAD had complete reversible perfusion defects and two of them were confirmed by coronary angiography (one was single-vessel disease the other was double-vessel disease) and the other one was stable angina patient. The image of the patient with critical stenosis in three vessels was partly reversible perfusion defect. There was significant
difference between the HLR of the two groups at different time, the HLR of G2 was lower than G1 . The quality of all images of G2 was worse than G1 . Nine patients of G2 had normal perfusion images, four of them had significant CAD by qualitative coronary angiography (stenosis 50%-70%), three had angina during the follow-up period. Conclusion: 1 . Stress-delayed myocardial perfusion imaging with 99mTcN-NOET can be used to diagnose CAD and distinguish ischemic myocardium from scar. 2. Exercise-induced increases in pulmonary uptake of 99mTcN-NOET and descent of the HLR are associated with exercise-induced myocardial dysfunction. 3. The HLR may be as an index of the patients with CAD.
引文
1. Gerundini P, Maffiali L. Cationic complex of technetium for myocardial imaging. J Nucl Med 1989;30:1415-1419.
2. Piwnica-Worms D, Kronauge JF,Holman BL, et al. Hexakis (carbomethoxyisopropylisonitrile) technetium(Ⅰ), a new myocardial perfusion imaging agent: binding characteristics in cultured chick heart cells. J Nucl Med 1988, Jan;29(1):55-61.
3. Flynn B, Wernovsky G, Summerville DA, et al. Comparison of technetium-99m MIBI and thallium-201 chloride myocardial scintigraphy in infants. J Nucl Med. 1989 Jul;30(7): 1176-1181.
4. Leppo JA, Meerdink DJ. Comparative myocardial extraction of two technetium-labeled BATO derivatives (SQ 30217,SQ32014) and thallium. J Nucl Med. 1990;31:67-74.
5. Dahlberg ST, Weinstein H, Hendel RC, et al. Planar myocardial perfusion imaging with technetium-99m-teboroxime: comparison by vascular territory with thallium-201 and coronary angiography. J Nucl Med. 1992;33:1783-1788.
6. Pasqualini R, Duatti A, Bellande E, et al. Bis(dithiocarbamato)nitrido technetium-99m radiopharmaceuticals:a class of neutral myocardial imaging agents. J Nucl Med. 1994;35:334-341.
7. Pasqualini R, Duatti A. Synthesis and characterization of the new neutral myocardial imaging agent [~(99m)TcN(noet)_2] (noet=N-Ethyl-N-ethoxy dithiocarbamato). J Chem Soc Chem Commun 1992;18:1354-1355.
8. Ghezzi C, Fegret D, Arvieux CC, et al. Myocardial kinetics of ~(99m)TcN-NOET: a neutral lipophilic complex tracer of regional myocardial blood flow. J Nucl Med. 1995;36:1069-1077.
9. Ghezzi C, Fagret D, Brichon PY, et al. Redistribution of bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m-Tc(Ⅴ) a new myocardial perfusion imaging agent: comparison with 201 thallium redistribution [Abstract]. Circulation.1996;94:Ⅰ-302.
10. Fagret D, Marie PY, Brunotte F, et al. Myocardial perfusion imaging with technetium-99m-Tc NOET: comparison with thallium-201 and coronary angiography. J Nucl Med 1995;36: 936-943.
11. Li SJ, Hu G, Liu JZ, et al. The clinical use of Tc-99m-NOET: comparing with Tc-99m-MIBI. J Nucl Cardiol 2001,8(1):s1.
12. Li S J, Hu G, Tian M, et al. Gated myocardial SPECT imaging with ~(99m)TcN-NOET: comparing with Tc-99m-MIBI. J Nucl Cardiol 2001,8(1):s1.
13. Boucher CA, Zir LM, Belier GA, et al. Increased lung uptake of thallium-201 during exercise myocardial imaging: clinical, hemodynamic and angiographic implications in patients with coronary artery disease. Am J Cardiol 1980 Aug;46(2): 189-196.
14. Gibson RS, Watson DD, Carabello BA, et al. Clinical implications of increased lung uptake of thallium-201 during exercise scintigraphy 2 weeks after myocardial infarction. Am J Cardiol 1982 May;49(7): 1586-1593.
15. Homma S, Kaul S, Boucher CA. Correlates of lung/heart ratio of thallium-201 in coronary artery disease. J Nucl Med 1987 Oct;28(10): 1531-1535.
16．方平，万卫星，吴春英等．心肌显像剂~(99m)TcN(NOET)_2的临床前药理研究．中华核医学杂志1997；17：230-232．
17．方平，周翔，陈正平．心肌显像剂~(99m)TcN(NOET))_2药盒的研制及质量控制．中华核医学杂志1998；18：120-121．
18. Fagret D, Ghezzi C, Arvieux C, et al. The relation between ~(99m)TcN-NOET retention and myocardial blood flow [Abstract]. Eur J Nucl Med 1992;19:670.
19. Ucceli L, Giganti M, Duatti A, et al. Subcellular distribution of technetium-99m-N-NOEt in rat myocardium. J Nucl Med 1995,Nov;36(11):2075-2079.
20. Johnson G, Allton IL, Nguyen KN, et al. Clearance of technetium 99m N-NOET in normal, ischemic-reperfused, and membrane-disrupted myocardium. J Nucl Cardiol 1996;3(1):42-54.
21. Riou L, Ghezzi C, Mouton O, et al. Cellular uptake mechanism of ~(99m)TcN-NOET in cardiomyocytes from newborn rats: calcium channel interaction. Circulation
1998,Dec 8; 98(23):2591-2597.
22. Zhang Z, Maublant J, Oilier M, et al. Cellular uptake of Tc-99m-NOET, a potent myocardial blood flow imaging agent: comparison with Tl-201, Tc-99m-Sestamibi and Tc-99m-Teboroxime [Abstract]. Circulation 1992;86:Ⅰ-708.
23. Vanzetto G, Fagret D, Pasqualini R, et al. Biodistribution, dosimetry, and safety of myocardial perfusion imaging agent ~(99m)TcN-NOET in healthy volunteers. J Nucl Med 2000; 41:141-148.
24. Giganti M, Cittanti C, Colamussi P, et al. Biodistribution in man of bis(N-ethyl, N-ethoxy) dithiocarbamato] nitrido technetium(Ⅴ), a promising new tracer for myocardial perfusion imaging [Abstract]. J Nucl Med 1994;35:155p.
25. David K, Glover V, Dennis A, et al. Kinetics of bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido 99m-Tc(NOET) in a canine model of transient coronary artery occlusion: comparison with Tl-201 [Abstract]. Circulation 1996;94:Ⅰ-302.
26. Vanzetto G, Calnon DA, Ruiz M, et al. Myocardial uptake and redistribution of 99m-Tc-N-NOET in dogs with either sustained coronary low flow or transient coronary occlusion: comparison with 201Tl and myocardial blood flow.Circulation. 1997,Oct 7;96(7):2325-2331.
27. Brunken RC, Kottov S, Niemaber CA, et al. PET detection of viable tissue inmyocardial segments with persistent defects at ~(201)Tl-SPECT. Radiology 1989;172:65-73.
28. Dilsizian V, Rocco TP, Freedman NMT, et al. Enhanced detection of ischemic but viable myocardium by the rejection of thallium after stress-redistribution imaging. N Engl J Med 1990;323:141-146.
29. Vanzetto G, Glover DK, Ruiz M, et al. 99mTc-N-NOET myocardial uptake reflects myocardial blood flow and not viability in dogs with reperfusion acute myocardial infarction. Circulation 2000; 101:2424-2430.
30. Liu P, Kiess M, Okada RD, et al. Increased thallium lung uptake after exercise in isolated left anterior descending coronary artery disease. Am J Cardiol 1985;55:1469.
2. Piwnica-Worms D, Kronauge JF,Holman BL, et al. Hexakis (carbomethoxyisopropylisonitrile) technetium(Ⅰ), a new myocardial perfusion imaging agent: binding characteristics in cultured chick heart cells. J Nucl Med 1988, Jan;29(1):55-61.
3. Flynn B, Wernovsky G, Summerville DA, et al. Comparison of technetium-99m MIBI and thallium-201 chloride myocardial scintigraphy in infants. J Nucl Med. 1989 Jul;30(7): 1176-1181.
4. Leppo JA, Meerdink DJ. Comparative myocardial extraction of two technetium-labeled BATO derivatives (SQ 30217,SQ32014) and thallium. J Nucl Med. 1990;31:67-74.
5. Dahlberg ST, Weinstein H, Hendel RC, et al. Planar myocardial perfusion imaging with technetium-99m-teboroxime: comparison by vascular territory with thallium-201 and coronary angiography. J Nucl Med. 1992;33:1783-1788.
6. Pasqualini R, Duatti A, Bellande E, et al. Bis(dithiocarbamato)nitrido technetium-99m radiopharmaceuticals:a class of neutral myocardial imaging agents. J Nucl Med. 1994;35:334-341.
7. Pasqualini R, Duatti A. Synthesis and characterization of the new neutral myocardial imaging agent [~(99m)TcN(noet)_2] (noet=N-Ethyl-N-ethoxy dithiocarbamato). J Chem Soc Chem Commun 1992;18:1354-1355.
8. Ghezzi C, Fegret D, Arvieux CC, et al. Myocardial kinetics of ~(99m)TcN-NOET: a neutral lipophilic complex tracer of regional myocardial blood flow. J Nucl Med. 1995;36:1069-1077.
9. Ghezzi C, Fagret D, Brichon PY, et al. Redistribution of bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m-Tc(Ⅴ) a new myocardial perfusion imaging agent: comparison with 201 thallium redistribution [Abstract]. Circulation.1996;94:Ⅰ-302.
10. Fagret D, Marie PY, Brunotte F, et al. Myocardial perfusion imaging with technetium-99m-Tc NOET: comparison with thallium-201 and coronary angiography. J Nucl Med 1995;36: 936-943.
11. Li SJ, Hu G, Liu JZ, et al. The clinical use of Tc-99m-NOET: comparing with Tc-99m-MIBI. J Nucl Cardiol 2001,8(1):s1.
12. Li S J, Hu G, Tian M, et al. Gated myocardial SPECT imaging with ~(99m)TcN-NOET: comparing with Tc-99m-MIBI. J Nucl Cardiol 2001,8(1):s1.
13. Boucher CA, Zir LM, Belier GA, et al. Increased lung uptake of thallium-201 during exercise myocardial imaging: clinical, hemodynamic and angiographic implications in patients with coronary artery disease. Am J Cardiol 1980 Aug;46(2): 189-196.
14. Gibson RS, Watson DD, Carabello BA, et al. Clinical implications of increased lung uptake of thallium-201 during exercise scintigraphy 2 weeks after myocardial infarction. Am J Cardiol 1982 May;49(7): 1586-1593.
15. Homma S, Kaul S, Boucher CA. Correlates of lung/heart ratio of thallium-201 in coronary artery disease. J Nucl Med 1987 Oct;28(10): 1531-1535.
16．方平，万卫星，吴春英等．心肌显像剂~(99m)TcN(NOET)_2的临床前药理研究．中华核医学杂志1997；17：230-232．
17．方平，周翔，陈正平．心肌显像剂~(99m)TcN(NOET))_2药盒的研制及质量控制．中华核医学杂志1998；18：120-121．
18. Fagret D, Ghezzi C, Arvieux C, et al. The relation between ~(99m)TcN-NOET retention and myocardial blood flow [Abstract]. Eur J Nucl Med 1992;19:670.
19. Ucceli L, Giganti M, Duatti A, et al. Subcellular distribution of technetium-99m-N-NOEt in rat myocardium. J Nucl Med 1995,Nov;36(11):2075-2079.
20. Johnson G, Allton IL, Nguyen KN, et al. Clearance of technetium 99m N-NOET in normal, ischemic-reperfused, and membrane-disrupted myocardium. J Nucl Cardiol 1996;3(1):42-54.
21. Riou L, Ghezzi C, Mouton O, et al. Cellular uptake mechanism of ~(99m)TcN-NOET in cardiomyocytes from newborn rats: calcium channel interaction. Circulation
1998,Dec 8; 98(23):2591-2597.
22. Zhang Z, Maublant J, Oilier M, et al. Cellular uptake of Tc-99m-NOET, a potent myocardial blood flow imaging agent: comparison with Tl-201, Tc-99m-Sestamibi and Tc-99m-Teboroxime [Abstract]. Circulation 1992;86:Ⅰ-708.
23. Vanzetto G, Fagret D, Pasqualini R, et al. Biodistribution, dosimetry, and safety of myocardial perfusion imaging agent ~(99m)TcN-NOET in healthy volunteers. J Nucl Med 2000; 41:141-148.
24. Giganti M, Cittanti C, Colamussi P, et al. Biodistribution in man of bis(N-ethyl, N-ethoxy) dithiocarbamato] nitrido technetium(Ⅴ), a promising new tracer for myocardial perfusion imaging [Abstract]. J Nucl Med 1994;35:155p.
25. David K, Glover V, Dennis A, et al. Kinetics of bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido 99m-Tc(NOET) in a canine model of transient coronary artery occlusion: comparison with Tl-201 [Abstract]. Circulation 1996;94:Ⅰ-302.
26. Vanzetto G, Calnon DA, Ruiz M, et al. Myocardial uptake and redistribution of 99m-Tc-N-NOET in dogs with either sustained coronary low flow or transient coronary occlusion: comparison with 201Tl and myocardial blood flow.Circulation. 1997,Oct 7;96(7):2325-2331.
27. Brunken RC, Kottov S, Niemaber CA, et al. PET detection of viable tissue inmyocardial segments with persistent defects at ~(201)Tl-SPECT. Radiology 1989;172:65-73.
28. Dilsizian V, Rocco TP, Freedman NMT, et al. Enhanced detection of ischemic but viable myocardium by the rejection of thallium after stress-redistribution imaging. N Engl J Med 1990;323:141-146.
29. Vanzetto G, Glover DK, Ruiz M, et al. 99mTc-N-NOET myocardial uptake reflects myocardial blood flow and not viability in dogs with reperfusion acute myocardial infarction. Circulation 2000; 101:2424-2430.
30. Liu P, Kiess M, Okada RD, et al. Increased thallium lung uptake after exercise in isolated left anterior descending coronary artery disease. Am J Cardiol 1985;55:1469.