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D Fagret

Publications and source records attributed to D Fagret.

At least 19 recordsLinked to original sources

Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p.

PURPOSE: VCAM-1 plays a major role in the chronic inflammatory processes present in vulnerable atherosclerotic plaques. The residues 75-84 (B2702-p) and 84-75/75-84 (B2702-rp) of the major histocompatibility complex-1 (MHC-1) molecule B2702 were previously shown to bind specifically to VCAM-1. We hypothesised that radiolabelled B2702-p and B2702-rp might have potential for the molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic plaques. METHODS: Preliminary biodistribution studies indicated that 125I-B2702-rp was unsuitable for in vivo imaging owing to extremely high lung uptake. 123I- or 99mTc-labelled B2702-p was injected intravenously to Watanabe heritable hyperlipidaemic rabbits (WHHL, n=6) and control animals (n=6). After 180 min, aortas were harvested for ex vivo autoradiographic imaging, gamma-well counting, VCAM-1 immunohistology and Sudan IV lipid staining. RESULTS: Robust VCAM-1 immunostaining was observed in Sudan IV-positive and to a lesser extent in Sudan IV-negative areas of WHHL animals, whereas no expression was detected in control animals. Significant 2.9-fold and 1.9-fold increases in 123I-B2702-p and 99mTc-B2702-p aortic-to-blood ratios, respectively, were observed between WHHL and control animals (p<0.05). Tracer uptake on ex vivo images co-localised with atherosclerotic plaques. Image quantification indicated a graded increase in 123I-B2702-p and 99mTc-B2702-p activities from control to Sudan IV-negative and to Sudan IV-positive areas, consistent with the observed pattern of VCAM-1 expression. Sudan IV-positive to control area tracer activity ratios were 17.0+/-9.0 and 5.9+/-1.8 for 123I-B2702-p and 99mTc-B2702-p, respectively. CONCLUSION: Radiolabelled B2702-p is a potentially useful radiotracer for the molecular imaging of VCAM-1 in atherosclerosis.

Adjuvants, Immunologic↗

Assessment of non-reperfused and reperfused myocardial infarction using diffusible or deposited radiolabelled perfusion imaging agents.

PURPOSE: Incomplete microvascular reperfusion is often observed in patients undergoing thrombolytic therapy or angioplasty for acute myocardial infarction and has important prognostic implications. We compared the myocardial uptake of diffusible ((201)Tl) and deposited ((99m)TcN-NOET) perfusion imaging agents in the setting of experimental infarction. METHODS: Rats were subjected to permanent coronary occlusion (OCC, n=10) or to 45-min occlusion and reperfusion (REP, n=17). Seven days later, the tracers were co-injected and the animals were euthanised 15 min (all ten rats in the OCC group and 12 rats in the REP group) or 120 min (five rats from the REP group, euthanised at this time point to evaluate any redistribution of the tracers: REP-RED group) afterwards. Infarct size determination and (99m)TcN-NOET/(201)Tl ex vivo imaging were performed. Regional flow and tissue oedema were quantified using radioactive microspheres and (99m)Tc-DTPA, respectively. RESULTS: (99m)TcN-NOET and (201)Tl defect magnitudes were similar in OCC animals (0.11+/-0.01 vs 0.13+/-0.01). In REP animals, (201)Tl defect magnitude (0.25+/-0.02) was significantly lower than the magnitude of (99m)TcN-NOET and flow defects (0.14+/-0.03 and 0.17+/-0.01, respectively; p<0.05), despite the lack of (201)Tl redistribution (REP-RED animals). (99m)Tc-DTPA indicated the presence of oedema in the reperfused area. Blood distribution studies showed that, unlike (99m)TcN-NOET, (201)Tl plasma activity was mostly unbound to plasma proteins. CONCLUSION: (99m)TcN-NOET and (201)Tl delineated the non-viable area in chronic non-reperfused and reperfused myocardial infarction. The significantly decreased (201)Tl defect in reperfused infarction was likely due to partial diffusion of the tracer from the plasma into the oedema present in the infarcted area. Deposited perfusion tracers might be better suited than diffusible agents for the assessment of regional flow following reperfusion of myocardial infarction.

Animals↗

[Strategy of investigation of coronary artery disease in diabetes: from screening to suspicion of acute coronary syndromes].

Coronary artery disease is a common and serious condition in diabetes and the prognosis of the diabetic without a history of cardiovascular disease is either the same or nearly as serious as that of a non-diabetic patient with a history of coronary disease. This is particularly true in women. The prognosis is even worse in the presence of silent myocardial ischaemia. Conversely, anti-ischaemic and anti-thrombotic therapy and myocardial revascularisation of most severely affected patients are effective. This justifies the recent recommendations (as those of the working group of the French Society of Cardiology and the ALFEDIAM) for the diagnosis of coronary artery disease in diabetes, even in asymptomatic patients. This is a two stage process: --First, the identification of patients who should be screened for ischaemia, diabetics with a priori an intermediate or high risk of the presence of CAD, with respect to the presence of markers easily identified on initial examination, like the presence of clinical macroangiopathy (femoral, carotid), of renal disease or ECG changes or the presence of several classical risk factors; --The second stage is the demonstration of myocardial ischaemia in patients identified to be at risk. This article reviews the advantages and limits of the tests available: ECG stress test, myocardial perfusion imaging on effort or under dipyridamole, stress echocardiography. Coronary angiography in asymptomatic patients is only recommended in the presence of significant ischaemia or with a poor prognosis (affecting over 20% of the myocardium or several myocardial territories). This should precede a myocardial revascularisation procedure. The prescription of coronary angiography may be more direct in some symptomatic patients.

Acute Disease↗

Effects of amlodipine on baroreflex and sympathetic nervous system activity in mild-to-moderate hypertension.

To investigate the effect of amlodipine on baroreflex sensitivity and sympathetic system activity, 36 patients with essential hypertension were randomized to once-daily, double-blind treatment with amlodipine 5 mg or placebo 5 mg for 60 days. Measurements with a Finapres device allowed calculation of baroreflex sensitivity and blood pressure (BP) variability. Adrenergic activity was assessed via measurements of lymphocyte beta2-adrenoceptors and plasma catecholamine concentrations. Compared with placebo, amlodipine significantly decreased BP, but did not significantly alter baroreflex sensitivity. Spectral analysis of Finapres data showed that, compared with placebo, amlodipine decreased the variability of systolic blood pressure, diastolic blood pressure, and RR interval in the low frequency band. There were no simultaneous changes in adrenergic function, however, suggesting that these effects of amlodipine were not mediated via sympathetic nervous system activation.

Adolescent↗

Biodistribution, dosimetry, and safety of myocardial perfusion imaging agent 99mTcN-NOET in healthy volunteers.

UNLABELLED: 99mTcN-NOET (bis[N-ethoxy,N-ethyl]dithiocarbamato nitrido technetium (V)) has been proposed for myocardial perfusion imaging. Biodistribution, safety, and dosimetry were studied in 10 healthy volunteers (5 at rest and 5 during exercise). METHODS: Biodistribution was studied by acquiring dynamic images up to 60 min after injection and whole-body images up to 24 h after injection. The MIRDOSE3 analysis program was used for radiation dosimetry calculations. RESULTS: Safety parameters measured to 48 h after injection revealed no clinically significant changes. Cardiac uptake of 99mTcN-NOET was high (2.9%-3%), with biologic half-life of 210-257 min on average. Lung uptake of 99mTcN-NOET was higher (10%-20%) but, on average, biologic half-life was shorter (1-77 min). Clearance from the blood was rapid (5% by 5 min). Radiation dosimetry calculations indicated an effective absorbed dose of 5.11 x 10(-3) mSv/MBq at rest and 5.38 x 10(-3) mSv/MBq after exercise. CONCLUSION: 99mTcN-NOET exhibits high cardiac uptake and an estimated effective absorbed dose comparable with that of the other 99mTc-labeled compounds used in myocardial perfusion imaging.

Adult↗

[Which coronary tests to use in asymptomatic diabetics?].

Coronary artery disease is a common, serious and insidious complication of diabetes. Myocardial ischaemia is often silent. All diabetics do not have the same coronary risk and, therefore, it is important to determine which investigations to perform and which patients. This strategy is justified because it allows identification of these cases which require a medical or an invasive (angioplasty, surgical revascularisation) approach, as these interventions may improve the prognosis. The first stage is clinical (investigation of cardiovascular risk factors). When more than two risk factors are found, further investigations are justified. Exercise stress testing provide reassuring diagnostic and prognostic data when maximal and negative. When sub-maximal, impossible or significantly ischaemic, a second investigation is useful. Holter ECG recording with analysis of ST variation lacks sensitivity and, above all, specificity. The diagnostic value of perfusion myocardial scintigraphy in the diabetic is not as good as that observed in the general population, but its prognostic value remains good. Ischaemia involving over 20% of the myocardium justifies therapeutic investigation. Stress echocardiography has been validated in the diagnosis and prognosis of coronary artery disease and its sensitivity and specificity are probably the same as those of scintigraphy. The authors conclude that the asymptomatic diabetic requires clinical and staged paraclinical investigation to assess prognosis and, depending on the results, the adoption of a beneficial therapeutic strategy.

Cardiovascular Agents↗

Long-term additive prognostic value of thallium-201 myocardial perfusion imaging over clinical and exercise stress test in low to intermediate risk patients : study in 1137 patients with 6-year follow-up.

BACKGROUND: The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. METHODS AND RESULTS: One thousand one hundred thirty-seven patients (857 men, age 55+/-9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72+/-18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload </=75 W) (2. 36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and >/=3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. CONCLUSIONS: The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

Adult↗

Can tumour marker assays be a guide in the prescription of bone scan for breast and lung cancers?

Considering the current need to improve cost-effectiveness in cancer patient management, a prospective study was undertaken in order to define the optimal combination of bone scan and tumour marker assays in breast and lung cancer strategies, as has been done in the case of prostate cancer. All patients with breast or lung cancer referred to the Nuclear Medicine Department of the Grenoble Teaching Hospital between December 1995 and April 1997 were included. A blood sample was drawn in each case for marker assay (CA15-3 or CEA and CYFRA 21-1) on the same day as the bone scan. Two hundred and seventy-five patients were included: 118 with lung cancer and 157 with breast cancer. With regard to lung cancer, no information useful for guiding bone scan prescription was obtained through CEA and CYFRA 21-1 assays. For breast cancer, the results suggest that in asymptomatic patients, a CA15-3 level of less than 25 U/ml (upper normal value chosen as the threshold) is strongly predictive of a negative bone scan; by contrast, high tumour marker levels are predictive of neoplastic bone involvement. When a doubtful bone scan is obtained in a patient with breast cancer, a normal marker level makes it highly probable that bone scan abnormalities are not related to malignancy.

Aged↗

The kinetics of beta-methyl-substituted labelled fatty acids in ischaemic myocardium: an analysis in man and with a blood-perfused isolated heart model.

beta-Methyl-substituted free fatty acids (FFAs) have been developed for myocardial single-photon emission tomography (SPET) imaging, but little is known about their kinetics in ischaemic conditions. The aim of this study was to determine the changes in the myocardial kinetics of a beta-methyl-branched FFA, [123I]16-iodo-3-methyl-hexadecanoic acid (MIHA), under ischaemic conditions. The kinetics of MIHA were analysed: (a) using a blood-perfused isolated heart model subjected to moderate ischaemia (50% flow reduction) and (b) in patients who had an exercise thallium-201 SPET defect corresponding to either necrotic (n = 13) or chronically ischaemic and viable (n = 15) myocardium, and who underwent two consecutive SPET studies after MIHA injection. In animals, the myocardial early retention fraction of MIHA, but not its clearance rate, was dependent on coronary flow, the early retention fraction being higher in ischaemic than in normoxic conditions (0.24 +/- 0.10 vs 0.14 +/- 0.04, P = 0.004). In the patient SPET studies, the uptake of MIHA calculated in ischaemic and viable areas (G1: 74% +/- 9% of maximal left ventricular value) was different from that calculated in necrotic (G2: 59% +/- 7%, P < 0.001) or normal (G3: 88 +/- 6%, P < 0.001) areas. By contrast, MIHA-clearance calculated between the two consecutive SPET studies was not different in G1, G2 and G3. Unlike in the case of other FFAs, the myocardial clearance of MIHA is not decreased by ischaemia. However, the early retention of MIHA is increased in the case of a moderate reduction in coronary flow, a property which might help in the detection of viability in chronically ischaemic myocardium.

Animals↗

Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography.

OBJECTIVE: We evaluated the prognostic value of an exercise stress test and thallium-201 scintigraphy for the prediction of cardiac events in selected high-risk NIDDM patients. RESEARCH DESIGN AND METHODS: NIDDM patients (n = 158, 105 men, aged 63 +/- 9 years) with two or more of the following criteria were prospectively included: age > or = 65 years, active smoking, hypertension > 160/95 mmHg, hypercholesterolemia (cholesterol > 5.70 mmol/l or LDL > 3.10 mmol/l), peripheral artery disease, abnormal rest electrocardiogram, or microalbuminuria (20-200 micrograms/min). An exercise-stress scintigraphy was performed in 77 patients able to exercise, while a dipyridamole scintigraphy was performed in 80 patients unable to exercise. Follow-up was 23 +/- 17 months. Major end points were cardiac deaths or nonfatal myocardial infarction. RESULTS: The annual event rate was 7.31% (deaths: 8, myocardial infarction: 14). Independent predictors of events were as follows: an age > 60 (P = 0.02), an abnormal rest electrocardiogram (P = 0.02), microalbuminuria (P = 0.001), the inability to exercise (P = 0.009), and the presence of more than two defects on scintigraphy (P = 0.001). A cardiac death occurred in 1.3% of patients able to exercise versus 8.8% of patients unable to exercise (odds ratio = 6.8, P = 0.001). Among patients unable to exercise, large perfusion defects corresponded to an annual mortality rate of 22.3%. Conversely, the negative predictive value of a normal scintigraphy for the occurrence of death was 97%. CONCLUSIONS: Inability to exercise and large perfusion defects on thallium-201 scan are major predictors of future death and myocardial infarction in high-risk NIDDM patients.

Activities of Daily Living↗

[Evaluation of a clinical and scintigraphic management strategy for cardiac risk before abdominal aorta surgery. Apropos of 982 surgical patients].

The incidence of major cardiac events (death, infarction) is over 5% after programmed aortic vascular surgery. The aim of this study was to evaluate a management strategy of this risk based on the clinical status and targeted indication of myocardial scintigraphy, coronary angiography and myocardial revascularisation. A first phase (1991-1993, 451 patients) confirmed the prognostic value of clinical (age, previous cardiac history, diabetes, hypertension, electrocardiogrammes) and scintigraphic features: the cardiac mortality was 1.25% in patients with a low clinical risk (70.3% of cases) and 4.5% in patients with a high clinical risk (2 factors, 29.3% of cases) (p < 0.01). In the latter group, the mortality was zero after normal myocardial scintigraphy and 7.2% after abnormal myocardial scintigraphy (p < 0.01) and 12.5% in cases with reversible defects (p < 0.01). During the second phase of the study (1994-1997, 531 patients) coronary angiography was performed in patients with a high clinical risk and abnormal scintigraphy (10.9% of cases). This led to a myocardial revascularisation in 3.6% of patients. The cardiac mortality was then the same in the low and high a priori clinical risk: 2.3 and 2.8% (NS). The use of simple clinical criteria enables surgery in the majority of candidates for aortic vascular surgery, scintigraphy being reserved for about one patient in ten with myocardial revascularisation in less than 4% of cases. The operative cardiac mortality then decreases to under 2.5%.

Aged↗

Cellular uptake mechanisms of 99mTcN-NOET in cardiomyocytes from newborn rats: calcium channel interaction.

BACKGROUND: Bis[N-ethoxy,N-ethyl(dithiocarbamato)]nitrido Tc (V) (TcN-NOET) is a new technetium complex proposed as a tracer of myocardial perfusion. However, its cellular uptake mechanisms are unknown, although membrane localization on rat heart preparations and preferential binding to polymorphonuclear neutrophils (PMNs) have been reported. Because of the central role of calcium in PMN actions, a relationship was hypothesized between this ion flux and TcN-NOET cellular uptake. METHODS AND RESULTS: The mechanisms of cellular uptake of TcN-NOET were investigated in newborn rat cardiomyocytes by study of the effect of calcium channel modulators on tracer binding. Nifedipine had no effect on tracer uptake at 1 minute. However, verapamil 0.1 micromol/L and diltiazem 0.5 micromol/L induced a 40% decrease in uptake. Conversely, Bay K 8644 0.25 micromol/L increased TcN-NOET uptake by 73%. Alterations in other membrane ion transports failed to modify tracer uptake, indicating the specificity of the relationship between TcN-NOET uptake and calcium channels. Kinetic studies indicated that cellular net accumulation of the tracer was slow (t1/2=28.5 minutes) and retention was prolonged (84% of initial activity retained after 120 minutes of washout). The energy dependence of TcN-NOET uptake was investigated after 60 minutes of metabolic inhibition by iodoacetic acid plus rotenone. The ATP decrease was not associated with reduction in tracer uptake at 1 minute (114.9+/-21.9% of control, P=NS). CONCLUSIONS: The decrease in uptake observed with verapamil and diltiazem, the increase with Bay K 8644, and the lack of effect with nifedipine suggest that TcN-NOET binds to L-type calcium channels in the open configuration, without entering cardiomyocytes. The kinetics of TcN-NOET accumulation and retention are slow, and the mechanism for cellular uptake is not energy-dependent. From a clinical point of view, the effect of concurrent treatment by calcium inhibitors on myocardial binding of TcN-NOET should be taken into account.

Animals↗

Biological evaluation of two iodine-123-labeled D-glucose acetals prepared as glucose transporter radioligands.

Two iodinated acetals of D-glucose, 4,6-(R)-O-(2'-iodoethylidene)-alpha, beta-D-glucose (1) and 4,6-(R)-O-(4'-iodobenzylidene)-alpha, beta-D-glucose (2), were prepared and their potential as suitable SPECT radioligands for imaging of glucose transporters was studied. Both are analogs of acetal D-glucose derivatives, which are known to bind to the exofacial sites of the glucose transport protein (GluT). To assess whether iodinated acetals 1 and 2 interacted with the glucose transporter, they were tested in vitro in human erythrocytes (GluT1) and neonatal rat cardiomyocytes (GluT4). The results indicated that 1 and 2 had a very low affinity for the glucose transporter and probably accumulated in cells. Study of their tissue distribution was carried out in the mouse in vivo: Both compounds showed fast tissue clearance with preferential renal elimination. It is concluded that iodinated acetals of D-glucose 1 and 2 are not suitable for GluT targeting in vivo.

Acetals↗

Assessment of myocardial viability in patients with previous myocardial infarction by using single-photon emission computed tomography with a new metabolic tracer: [123I]-16-iodo-3-methylhexadecanoic acid (MIHA). Comparison with the rest-reinjection thallium-201 technique.

OBJECTIVES: We compared the ability of rest single-photon emission computed tomography (SPECT) with [123I]-16-iodo-3-methylhexadecanoic acid (MIHA) and the thallium-201 (Tl-201) rest-reinjection technique to detect myocardial viability after infarction. BACKGROUND: After myocardial infarction, MIHA frequently shows increased uptake in the areas with exercise Tl-201 defects (mismatch), even in patients with an irreversible Tl-201 reinjection defect. Whether such increased uptake is indicative of ischemic but viable myocardium is not known. METHODS: We studied 38 patients who 1) underwent exercise SPECT Tl-201 with rest-reinjection and rest SPECT with MIHA before undergoing percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related coronary artery, and 2) were found to have successful revascularization at follow-up angiography. The relation between SPECT results before PTCA and subsequent improvement in left ventricular wall motion was assessed. RESULTS: A mismatch was evident before PTCA in 51 of 76 infarct-related segments and correlated with subsequent improvement in wall motion (overall accuracy 71%), even for the 27 segments whose exercise defects remained irreversible after Tl-201 reinjection (overall accuracy 81%). The finding of a mismatch clearly enhanced the results provided by the finding of > or = 50% Tl-201 uptake as determined at redistribution (p < 0.05), but not as determined at reinjection, although there was a trend toward a better specificity for the findings of a mismatch. CONCLUSIONS: MIHA is an efficient marker of viability inside exercise-underperfused areas after infarction, even in patients with irreversible Tl-201 reinjection defects. Assessment by conventional SPECT of a mismatch between results obtained with a metabolic tracer (MIHA) and a flow tracer analyzed at exercise (Tl-201) as a marker of myocardial viability is a promising area of research.

Adult↗

Metabolic myocardial viability assessment with iodine 123-16-iodo-3-methylhexadecanoic acid in recent myocardial infarction: comparison with thallium-201 and fluorine-18 fluorodeoxyglucose.

The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18 fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methylhexadecanoic acid (MIHA) as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and to evaluate its contribution compared with the 201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection 201Tl imaging, rest MIHA imaging and glucose-loaded FDG imaging were performed in 22 patients with recent myocardial infarction. Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75 of maximum uptake on stress 201Tl imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a) 201Tl activity during exercise, redistribution and reinjection and (b) MIHA uptake, using the two FDG thresholds most commonly considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that 201Tl reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85 and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively; P<0.05 vs other tests). The global predictive values of MIHA and 201Tl reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold (NS). When only the 177 severely hypoperfused segments were considered, 201Tl reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold), while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold, P<0.05 vs 201Tl reinjection). In all circumstances, MIHA was less specific than 201Tl reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA accurately detects the persistence of metabolic viability, but is not superior to 201Tl.

Deoxyglucose↗