Hypoxia imaging of patients with acute myocardial infarction by using dual isotopes of 201Tl and 99mTc-HL91

OBJECTIVE: To evaluate the myocardial ischaemia/viability in patients with acute myocardial infarction (AMI) using the ischaemia-avid agent (99m)Tc-HL91. METHODS: Thirty-three AMI patients received 740 MBq (20 mCi) (99m)Tc-HL91, i.v., first and then 148-185 MBq (4-5 mCi) (201)Tl around 3 h later. The patient underwent initial imaging and 24 h late imaging, 10-15 min and 24 h later, respectively, after intravenous injection of (201)Tl. Myocardial segmental radioactive counts of (99m)Tc-HL91 were quantified by the region of interest technique. The segmental radioactive counts/pixel divided by those of the corresponding left ventricular cavities were ratios, which were compared among normal, ischemic/viable and fixed defect myocardium. The correlation analysis between the segmental scores from (201)Tl imaging and the ratios was performed. RESULTS: The cross-talk of (99m)Tc into (201)Tl could be neglected in the present study. Out of the 33 AMI patients, the (99m)Tc-HL91 image quality analysis classified seven cases into excellent, accounting for 21%, eight cases into good, for 24%, eight cases into fair, for 24%, and 10 cases into poor, for 31%. The ratios were 1.16 (1.01, 1.35) ((median (25th to 75th percentile)), 1.15, 0.20 and 1.01 (0.86, 1.30), respectively, in normal, ischaemic/viable and fixed defect myocardium. Significant differences (chi2=17.2069, P=0.0002) were found in the ratios. The ratios of the ischaemic/viable myocardial segments were significantly higher than those of the fixed defect segments. Unexpectedly, the normal myocardial segments took up (99m)Tc-HL91, too, even slightly higher than the ischaemic/viable myocardial segments. CONCLUSIONS: Myocardial uptake of (99m)Tc-HL91 is perfusion-dependent as well as ischaemia dependent. (99m)Tc-HL91 hypoxia imaging alone is not sufficient to identify ischaemic/viable myocardium. Dual-isotope imaging with (201)Tl and (99m)Tc-HL91 can characterize the myocardium into normal, ischaemic/viable and necrotic (scarred) myocardium.     

用201Tl与99Tcm-HL91双核素显像评价心脏病患者心肌灌注与乏氧

目的用201Tl与99Tcm-4,9-二氮-3,3,10,10-四甲基十二烷-2,11-二酮肟(HL91)同时评价心脏病患者心肌灌注与乏氧.方法22例心脏病患者及9例临床诊断正常者行10 min、3和24 h延迟201Tl与99Tcm-HL91双核素心肌显像,用5分法评价图像质量,用17节段法分析201Tl显像缺损与乏氧显影心肌节段.结果双核素显像中99Tcm-HL91显像图质量不如201Tl(P＜0.01);80.85%(38/47个节段)的急性心肌梗死患者201Tl灌注缺损心肌节段在99Tcm-HL91显像中显影,乏氧显影心肌节段数明显多于201Tl灌注缺损节段数;陈旧性心肌梗死201Tl、99Tcm-HL91均不显影的符合率为85.71%.结论201Tl与99Tcm-HL91双核素心肌显像能同时提供判断心肌血流灌注与乏氧的信息.     

Applicability of 99mTc-HL91, a putative hypoxic tracer, to detection of tumor hypoxia.

To elucidate the applicability of 99mTc-HL91 (HL91) a putative hypoxic tracer, to the imaging of hypoxia in tumors, a biodistribution study of the tracer was performed. The intratumoral distribution of HL91 was compared with that of 14C-deoxyglucose (DG) and the expression of glucose transporter 1 (GLUT1) in an implanted tumor. METHODS: Biodistribution of HL91 after intravenous injection into Wistar rats with rat mammary tumor (Walker-256) was studied by determining blood and tissue levels of radioactivity from 15 min to 6 h after injection. Dual ex vivo autoradiography was performed on sections of the tumor using HL91 (74 MBq) and DG (185 kBq). The same sections were immunohistologically analyzed with anti-GLUT1 antibody. Tumor tissue was histologically divided into areas of viable cancer cells, necrosis and granulation tissue. The viable cancer cell area was further divided into normoxic and hypoxic areas. Uptake of both tracers in each area was measured quantitatively. The intensity of GLUT1 staining (relative optical density [ROD]) in each area was evaluated by densitometry. RESULTS: The uptake of HL91 in the tumor reached a maximal value (0.897 +/- 0.118% ID [injected dose], mean +/- SD, n = 5) at 120 min after intravenous injection of HL91, then gradually decreased. The tumor-to-muscle ratio continued to increase until 360 min (4.34 at 120 min, 7.01 at 240 min and 10.4 at 360 min). HL91 accumulated to significantly higher levels in the hypoxic area than those in the other tissues (P < 0.0001). Uptake of DG and expression of GLUT1 were significantly higher in the hypoxic area than in the normoxic area (P < 0.0001). In the viable cancer cell area, uptake of HL91 and expression of GLUT1 were strongly correlated (r = 0.624-0.868, mean r = 0.743, P < 0.0001), and DG uptake was moderately correlated with GLUT1 expression (r = 0.328-0.669, mean r = 0.505, P < 0.0001). CONCLUSION: These results indicate that HL91 can be used to detect tumor hypoxia.     

Increased uptake of99mTc-HL91 in tumor cells exposed to X-ray radiation

99mTc-HL91, a hypoxic marker, may be a predictor of tumor response to radiotherapy and an indicator of tumor oxygenation in the course of treatment. In this study, serial changes in 99mTc-HL91 uptake were observed in the normoxic condition in a human bladder cancer cell line exposed to a single dose or a fractionated dose of 10 Gy with an x-ray beam. The uptake per cell increased during cell growth retardation induced by the irradiation. This finding indicates that 99mTc-HL91 uptake is affected by injury to cells due to radiation; it may therefore be difficult to correctly assess the tissue oxygenation status during radiotherapy with 99mTc-HL91.     

Low-flow ischaemia has no deleterious effect on the steady-state kinetics of 201Tl and 99mTc sestamibi within myocardial tissue

OBJECTIVES: This study aimed to specifically analyse the impact of low-flow ischaemia on the ability of myocytes to trap and accumulate Tl and sestamibi (MIBI) within myocardial tissue. METHODS: In order to reach steady-state conditions for the interstitial/cellular concentration ratios (Ci/Cc) of the tracers and thereby simulate the conditions of cell cultures studies, Tl and MIBI were injected continuously during an 80 min period within the coronary circulation of isolated hearts submitted to normoxia (n=7) or low-flow ischaemia (n=7; >50% reduction in coronary flow). Ci was determined by using interstitial microdialysis and Cc was determined from Ci and myocardial retention values of the tracers. RESULTS: At the end of the experiments, under steady-state conditions, Ci/Cc was equivalent between low-flow ischaemia and normoxia for both Tl (ischaemia, 0.60 +/- 0.25% vs normoxia, 0.63 +/-0.34%; NS) and MIBI (ischaemia, 1.00 +/- 0.68% vs normoxia, 0.76 +/- 0.32%, NS), whereas tissue concentrations of ATP were more than 4-fold lower in ischaemia than in normoxia (5.1 +/- 3.5 nmol.g vs 22.5 +/- 4.8 nmol.g; P< 0.001). CONCLUSIONS: In contrast to the published results concerning the effects of anoxia on cell cultures, low-flow ischaemia within myocardial tissue has no deleterious effects on the ability of the cells to accumulate Tl and MIBI under steady-state conditions. This gives definitive evidence of the negligible impact of cellular metabolic disorders in the decrease in Tl or MIBI uptake, which is documented by stress-SPECT within low-flow ischaemic myocardium.     

Comparison of the myocardial distributions of 201Tl and 99Tcm-MIBI on SPECT images

The distributions of 201Tl and 99Tcm-MIBI on stress images were quantitatively measured in a series of 15 patients presenting with documented coronary artery disease. Following two sequential, one-week apart, peak-exercise injections of either 74 MBq of 201Tl or 370 MBq of 99Tcm-MIBI, tomographic views of the myocardium were reconstructed and two thick, central short-axis sections were divided into nine sectors. A sector was considered as showing a defect if its relative activity was lower than 30, 40, 50 or 60% of the highest level of activity in the 18 sectors. Results demonstrate that there were more defects with 201Tl than with 99Tcm-MIBI. However, the difference disappeared if the inferior wall was not included. These results suggest that depth attenuation could be, at least partly, responsible for the higher rate of positive results observed in single photon emission computed tomography with 201Tl than with 99Tcm-MIBI.     

99Tcm-HL91在心肌活性检测中的应用

目的探讨乏氧显像剂99Tcm-4,9-二氮-3,3,10,10-四甲基十二烷-2,11-二酮肟(HL91)检测心肌活性的可能性.方法急性心肌梗死患者25例(病史≤6周)和陈旧性心肌梗死患者5例(病史＞6周)分别行硝酸甘油介入和静息99Tcm-甲氧基异丁基异腈(MIBI)显像、99Tcm-HL91显像,根据99Tcm-MIBI显像结果将心肌分为正常心肌组、缺血心肌组(硝酸甘油介入后99Tcm-MIBI聚集量上升＞20%)和梗死心肌组(硝酸甘油介入后99Tcm-MIBI聚集量上升≤20%),比较三组间99Tcm-HL91聚集量有无差别.结果①急性心肌梗死患者正常心肌组99Tcm-HL91聚集量为95%,缺血心肌组为157%,梗死心肌组为93%,99Tcm-HL91在缺血心肌组聚集量明显高于正常心肌组和梗死心肌组.②陈旧性心肌梗死患者三组间99Tcm-HL91聚集量无差别.结论Tcm-HL91可用于探测缺血但存活的心肌.     

Early scintigraphic detection of experimental myocardial infarction in dogs with technetium-99m-glucaric acid

Recent data have generated some interest in technetium-99m-(99mTc) glucaric acid as an in vivo viability marker. We studied 99mTc-glucaric acid retention in canine models of myocardial ischemia (20-min occlusion of the LAD/40-min reperfusion), acute myocardial infarction (MI) (90-min LAD occlusion/3-hr reperfusion), and chronic MI (90-min occlusion and either 48-hr or 10-day reperfusion). Regional myocardial blood flow was measured by radiolabeled microspheres. No preferential uptake of glucaric acid was observed in ischemic but viable myocardium. The compound showed high affinity for necrotic myocardial tissue for several days following injury. The preferential uptake in infarcted tissue disappeared by 10 days following injury. This study shows that 99mTc-glucaric acid acts exclusively as a marker of necrosis in canine models of MI. Technetium-99m-glucaric acid may have clinical utility in early cardiac imaging of myocardial infarction and in differentiating recent from old injuries.     

Anti-angiogenic therapy and chemotherapy affect 99mTc sestamibi and 99mTc-HL91 accumulation differently in tumour xenografts

BACKGROUND: Favourable effects of cytotoxic chemotherapy for tumours are characterized by the reduced accumulation of radiotracers such as 99mTc sestamibi (MIBI). Anti-angiogenic therapy is primarily cytostatic; consequently, its influence on tracer accumulation may differ from that of cytotoxic treatments. METHODS: Anti-angiogenic therapy employing 2-methoxyestradiol was administered in mice bearing subcutaneous xenografts of LS180 colon cancer cells. The effects of chemotherapy with 5-fluorouracil were examined as a cytotoxic counterpart. Treatments were conducted for 4 days from day 8. Distribution of 99mTc-MIBI and Tc-HL91, a hypoxic marker, was observed on days 8 and 12. Oxygen tension (PO2) in tumours was measured by a microelectrode. Cellular uptake of tracers was examined in vitro in normoxic and hypoxic conditions. RESULTS: 99mTc-MIBI accumulation decreased with increasing tumour weight when no treatment was conducted. Tumour growth was suppressed by anti-angiogenic therapy and chemotherapy. 99mTc-MIBI accumulation in tumours decreased after chemotherapy as compared to pre-therapeutic values, whereas accumulation of 99mTc-HL91 increased. In contrast, accumulation of tracers did not significantly change after anti-angiogenic therapy as compared to that observed pre-therapeutically. Tumour PO2 decreased with increasing tumour volume when no treatment was conducted. Chemotherapy reduced PO2 in tumours. PO2 in tumours treated with anti-angiogenic therapy was as high as that observed before treatment. 2-Methoxyestradiol or 5-fluorouracil did not significantly affect tracer accumulation in cells under both normoxic and hypoxic conditions in vitro. CONCLUSION: These findings indicate that scintigraphic assessment of therapeutic efficacy of anti-angiogenic therapy should be performed from a perspective distinct from that of cytotoxic treatment.     

99mTc-HL91乏氧显像探测肿瘤乏氧状态的研究进展

乏氧显像剂99mTc-HL91能选择性地浓集于肿瘤的乏氧组织或细胞中,通过核医学显像探测肿瘤组织的乏氧,能直接提供肿瘤组织乏氧及其乏氧程度和分布的证据,不仅能用于恶性肿瘤的早期诊断,还能动态监测肿瘤组织乏氧状态,为临床诊断和治疗决策提供重要信息。     

A comparative study of myocardial scintigraphy with 99mTc-SQ-30,217 and 201Tl in cases with myocardial infarction

A comparative study of myocardial scintigraphy with 99mTc-SQ-30217 (SQ) and 201Tl was performed in 6 patients having ischemic heart diseases which were confirmed by the coronary angiography. The SQ study was done 1 week after the 201Tl study. Both studies were performed in exercise and resting state. Degree of perfusion defect was compared between SQ and 201Tl SPECT by means of scoring 0-2 (0: no defect, 1: equivocal, 2: definite defect) by five doctors (two physicians and three radiologists). Ability of this agent to detect the ischemic lesions was similar to that of 201Tl except for two regions. Effect of the liver image on the evaluation of the inferior wall of the left ventricle was small on this study, although the hepatic accumulation of the tracer was prominent. This agent is a promising tracer for the evaluation of myocardial perfusion in the cases with myocardial infarction.     

Incremental prognostic value of myocardial SPET with dual-isotope rest 201Tl/stress 99mTc-tetrofosmin

The incremental prognostic value of dual-isotope myocardial perfusion scintigraphy using technetium-99m tetrofosmin for the stress images was evaluated in 597 consecutive patients with known or suspected coronary artery disease. We used semi-quantitative visual analysis with a five-point scoring system and calculated the summed stress score, the summed rest score and the summed difference score. During the 2-year follow-up period, 46 "hard" cardiac events occurred: 16 cardiac deaths and 30 non-fatal myocardial infarctions. Kaplan-Meier analysis demonstrated a favourable prognosis for patients with normal scans as compared with patients with mildly to moderately or severely abnormal scans ( P<0.001). Multivariate analysis demonstrated incremental prognostic information for nuclear variables. A very low rate of hard cardiac events was observed in patients with a low summed stress score. Thus, nuclear variables provide incremental prognostic information and could be used to guide the management process with respect to whether or not to proceed with further invasive procedures.     

Feasibility of simultaneous stress 99mTc-sestamibi/rest 201Tl dual-isotope myocardial perfusion SPECT in the detection of coronary artery disease.

This study assesses feasibility and diagnostic accuracy of simultaneous stress 99mTc-sestamibi/rest 201 TI dual-isotope myocardial perfusion SPECT with Moore's correction method, in which contamination originating from lead x-rays produced in a collimator was subtracted in the 201TI windows. METHODS: Eighty-one patients with suspected coronary artery disease received exercise 99mTc-sestamibi injection, followed by rest 201TI injection 50 min later, and dual-isotope SPECT was performed (group 1). These results were compared with coronary angiographic findings. Furthermore, to estimate the accuracy of Moore's correction method, 201TI crosstalk into the 99mTc acquisition window (group 2A, n = 20) and 99mTc crosstalk into the 201TI acquisition windows (group 2B, n = 20) were studied. For group 2A, stress 99mTc-sestamibi SPECT (single 99mTc-sestamibi SPECT) was performed, followed by 201TI injection at rest and dual-isotope SPECT acquisition 50 min later. For group 2B, rest 201TI SPECT (single 201TI SPECT) was performed, followed by 99mTc-sestamibi injection at rest and dual-isotope SPECT acquisition 30 min later. RESULTS: Sensitivity and specificity in group 1 were 83% and 99%, respectively, when > or =75% coronary artery narrowing was considered significant. In groups 2A and 2B, SPECT images were divided into 24 segments, and relative regional uptake in each segment was obtained. In group 2A, relative regional uptake of single 99mTc-sestamibi SPECT correlated well with that of dual-isotope SPECT (r = 0.942). In group 2B, relative regional uptake of single 201TI SPECT correlated well with that of dual-isotope SPECT (r = 0.935). Furthermore, in low 201TI uptake segments with relative regional uptake in both single- and dual-isotope SPECT of < or =70%, the degree of concordance between single- and dual-rest 201TI was considered to be high with Bland-Altman analysis and the kappa statistic. Comparison of perfusion defect type demonstrated that, of 22 stress defects within infarct zones, 95% were irreversible and 5% were reversible. In contrast, of 28 stress defects within stenosed vessel zones in noninfarct zones, 89% were reversible and 11% were irreversible (P < 0.0001 versus infarct zones). CONCLUSION: Simultaneous dual-isotope imaging with Moore's correction method is feasible, with acceptable accuracy for detection of coronary artery disease and a small amount of crosstalk into each window.     

201Tl in the scintigraphic evaluation of the "cold" thyroid areas

201Tl-chloride, which has a metabolic behaviour similar to that of potassium and cesium, has been used in 68 patients for the evaluation of thyroid nodules previously recognized as "cold" on 131I or 99mTc scans. All patients were re-examined with gamma-camera and/or sequential scintigraphic recordings during 60 min after i.v. administration of thallium. In some cases, simultaneous imaging and integral digital plot with 131I or 99mTc and 201Tl were performed. In all 12 malignant nodules, 201 Tl has showed a high uptake, while it did not concentrate in 47 benign nodules (cystic or macrofollicular adenomas); thallium uptake was nevertheless found in 10 solid neoformations in which histological pictures were negative for malignancy or atypical lesions. The computerized study of the 201Tl intranodular concentration, with the analysis of its dynamic function curves, seems to offer further possibility in differentiating and in a more objective evaluation of the "cold" areas on the thyroid scan.     

99mTc-HL91显像在缺血性脑血管病中脑乏氧组织的应用研究

目的 探讨99mTc-4,9-二氮.3,3,10,10-四甲基十二烷-2,11-二酮肟(99mTc-HL91)在缺血性脑血管病中脑乏氧组织的临床应用价值.方法 对9例对照组和17例急性脑梗死患者于起病7 d内进行脑乏氧显像,同时进行了CT或MRI检查.其中2例分别于第一次显像阳性后9 d和12 d进行第二次乏氧显像.结果 对照组未见脑实质有明显核素浓聚,左侧,右侧比值为0.98±0.04.17例急性脑梗死患者中,乏氧显像阳性11例,阳性率64.7%,其患侧/健侧比值为1.54±0.55,与对照组比较有显著性差异(t=3.081,P＜0.05).结论 99mTc-HL91显像可以区分乏氧与坏死的脑组织,对指导治疗、评价疗效有一定的临床意义.     

99mTc-MIBI and 201Tl SPET in the detection of recurrent brain tumours after radiation therapy

The purpose of this study was to evaluate whether Tc-hexakis-2-methoxyisobutylisonitrile ( Tc-MIBI) or Tl single photon emission tomography (SPET) could detect recurrent tumours in patients with previous radiation therapy for brain tumours. Dual SPET with Tc-MIBI and Tl was performed in 21 patients suspected of having recurrent brain tumours. SPET images were acquired 15 min (early) and 2 h (delayed) after injection. The ratio of the average counts for the region of interest in the lesion area and its mirror image in normal brain tissue was obtained. Early and delayed ratios were calculated. On the basis of histological and/or clinical findings, the final diagnosis was considered as recurrent tumours in 15 patients and radiation necrosis in six. Both ratios using Tc-MIBI and Tl were significantly higher in recurrent tumours than in radiation necrosis. Based on a cut-off of 5.89 of the early ratio using Tc-MIBI to distinguish between recurrent tumours and radiation necrosis, the accuracy was 90%. Based on a cut-off of 6.77 of the delayed ratio using Tc-MIBI, the accuracy was 86%. The corresponding values using cut-offs of 2.40 and 1.85 with Tl were 90% and 86%, respectively. However, within recurrent tumours, both ratios for Tc-MIBI were significantly higher than those for Tl. Early Tc-MIBI SPET may be especially useful for the detection of recurrent tumours in patients who have previously undergone radiation therapy for brain tumours.     

Experimental regional myocardial ischaemia and myocardial uptake of potassium analogues; Intercomparison of 42K, 86Rb and 201Tl

The uptake of ⁴²K, ⁸⁶Rb and ²⁰¹Tl by non-ischaemic and ischaemic myocardium was determined in rats with coronary artery ligature lasting 10, 30, 60 and 120 min, and in control rats without ischaemia. Whereas the myocardial concentration of ²⁰¹Tl and ⁴²K in control rats was similar and higher than that of ⁸⁶Rb, ²⁰¹Tl was superior to the other two radionuclides due to its significantly higher accumulation in non-ischaemic myocardium and the higher ratio of non-ischaemic to ischaemic radioactivity.The ⁸⁶Rb accumulation in non-ischaemic myocardium and non-ischaemic/ischaemic ratio began to decrease from its maximum at 10 min. ²⁰¹Tl, ⁴²K and ⁸⁶Rb blood levels in intact animals decreased rapidly after intravenous injection to low and nearly stabilized values at 5 min.Na⁺K⁺-ATPase activity in the ischeamic myocardium was high in the acutely ischaemic myocardium and decreased to below control levels after 4 h of ischaemia; changes in activity could not influence the low uptake of potassium analogues in fresh ischaemic myocardium.     

Segmental analysis of SPECT99mTc-methoxy isobutyl isonitrile and201Tl myocardial imaging in ischaemic heart disease

To study the potential usefulness of^99mTc-methoxy isobutyl isonitrile (^99mTc-MIBI) as a substitute for²⁰¹Tl in assessing patients with ischaemic heart disease, 24 patients underwent 1 day rest and exercise^99mTc-MIBI single photon emission computerised topography (SPECT) 1 week after SPECT exercise²⁰¹Tl. All patients were catheterized within 1 month after myocardial imaging. In 17 patients, resting first pass radionuclide angiography (FPRNA) was performed with^99mTc-MIBI. The heart to lung ratio for^99mTc-MIBI and²⁰¹Tl was calculated both at rest and exercise. The segmental analysis for myocardial perfusion reveals that 87/96 segments (91 %) were correctly classified by SPECT²⁰¹Tl and 84/96 segments (88%) were correctly classified by^99mTc-MIBI. A significant correlation was present between LVEF measured by^99mTc-MIBI FPRNA and contrast ventriculography (r = 0.85,P < 0.0001). The heart to lung ratio both at rest and exercise for^99mTc-MIBI is significantly higher than²⁰¹Tl (P < 0.01 and <0.001 respectively). We conclude that^99mTc-MIBI is a promising agent for simultaneous evaluation of myocardial perfusion and cardiac function.     

Segmental analysis of SPECT 99mTc-methoxy isobutyl isonitrile and 201Tl myocardial imaging in ischaemic heart disease

To study the potential usefulness of 99mTc-methoxy isobutyl isonitrile (99mTc-MIBI) as a substitute for 201Tl in assessing patients with ischaemic heart disease, 24 patients underwent 1 day rest and exercise 99mTc-MIBI single photon emission computerised tomography (SPECT) 1 week after SPECT exercise 201Tl. All patients were catheterized within 1 month after myocardial imaging. In 17 patients, resting first pass radionuclide angiography (FPRNA) was performed with 99mTc-MIBI. The heart to lung ratio for 99mTc-MIBI and 201Tl was calculated both at rest and exercise. The segmental analysis for myocardial perfusion reveals that 87/96 segments (91%) were correctly classified by SPECT 201Tl and 84/96 segments (88%) were correctly classified by 99mTc-MIBI. A significant correlation was present between LVEF measured by 99mTc-MIBI FPRNA and contrast ventriculography (r = 0.85, P less than 0.0001). The heart to lung ratio both at rest and exercise for 99mTc-MIBI is significantly higher than 201Tl (P less than 0.01 and less than 0.001 respectively). We conclude that 99mTc-MIBI is a promising agent for simultaneous evaluation of myocardial perfusion and cardiac function.