Daniel Labar

Myocardial Blood Flow, Glucose Uptake, and Recruitment of Inotropic Reserve in Chronic Left Ventricular Ischemic Dysfunction Implications for the Pathophysiology of Chronic Myocardial Hibernation

BACKGROUND Previous work has documented that dysfunctional noninfarcted collateral-dependent myocardium, a condition typical of myocardial hibernation, exhibited almost normal resting perfusion. The present study was designed to test whether these observations could be extended to unselected patients with chronic dysfunction and a previous infarction. METHODS AND RESULTS Dynamic positron emission tomographic imaging with [13N]ammonia and [18F]fluorodeoxyglucose (FDG) to assess myocardial perfusion and glucose uptake was performed in 39 patients with chronic anterior wall dysfunction undergoing coronary revascularization. Left ventricular function was evaluated by echocardiography before (at rest and during low-dose dobutamine infusion) and 5 months after revascularization. At follow-up, wall motion was improved in 24 patients and unchanged in 15 patients. Before revascularization, absolute myocardial blood flow was higher (84 +/- 27 versus 60 +/- 26 mL.min-1 x 100 g-1, P = .007) in reversibly compared with persistently dysfunctional segments. In segments with reversible dysfunction, values of myocardial blood flow were similar to those in the remote segments of the same patients or in anterior segments of normal volunteers. During glucose clamp, FDG uptake was higher (69 +/- 17% versus 49 +/- 18%, P < .01) but myocardial glucose uptake was not different (38 +/- 20 versus 29 +/- 19 mumol.min-1.100 g-1, P = NS) in reversibly compared with persistently dysfunctional segments. A flow-metabolism mismatch was present in 18 of 24 reversibly injured but absent in 10 of 15 persistently dysfunctional segments. With dobutamine, wall motion improved in 17 of 24 reversibly dysfunctional segments and did not change in 13 of 15 segments with persistent dysfunction. CONCLUSIONS This study indicates that chronic but reversible ischemic dysfunction is associated with almost normal resting myocardial perfusion, with maintained FDG uptake, and with recruitable inotropic reserve. These data support the contention that chronic hibernation is not the consequence of a permanent reduction of transmural myocardial perfusion at rest.

Direct comparison of [13N]ammonia and [15O]water estimates of perfusion with quantification of regional myocardial blood flow by microspheres.

BackgroundBoth [13N ammonia and [15Olwater have been used to quantify myocardial blood flow with positron emission tomography using appropriate tracer kinetic models. A direct comparison of the two tracers with radioactive microspheres has not been performed in the same experimental preparation. Methods and ResultsThe two tracers have been tested for myocardial blood flow quantification in closed-chest dogs with circumflex coronary stenosis or permanent occlusion at rest and during adenosine-induced hyperemia. [13N]ammonia- and [15Olwater-derived myocardial blood flow values have been compared with radiolabeled microspheres. Validation studies consisted of simultaneous measurements of blood flow with positron emission tomography and microspheres over a wide range of flow values. Blood pool and regional tissue activity curves were fitted with a three-compartment model for [13Nlammonia with and without arterial metabolite correction and with a single-tissue-compartment model for [11Ojwater. A correction for finite-resolution effect before the fit was also applied. In large regions of interest (5 cm3), a good correlation between the microsphere method and [13NJ ammonia (with metabolite correction) was obtained (y=3+0.78x, r=0.94). The correlation with microspheres was slightly better with [15O1water (y=-3+0.89x, r=0.97). Similar correlations were achieved in smaller regions of interest (1 cm3) as well as in akinetic segments and in central infarct regions.Conclsions. Positron emission tomography with appropriate tracer kinetic models using [13NIammonia and [15Ojwater provides an accurate quantitative method for measuring regional myocardial blood flow over a wide range of flow values in normally contracting or akinetic canine myocardium in the absence and in the presence of infarction.

89Zr-labeled anti-endoglin antibody-targeted gold nanoparticles for imaging cancer: implications for future cancer therapy

AIMS Antibody-labeled gold nanoparticles represent an attractive tool for cancer imaging and therapy. In this study, the anti-CD105 antibody was conjugated with gold nanoparticles (AuNPs) for the first time. The antibody biodistribution in mice before and after conjugation to AuNPs was studied, with a focus on tumor targeting. MATERIALS & METHODS Antibodies were radiolabeled with 89Zr before conjugation to AuNPs (5 nm). Immunonanoconjugates were characterized in vitro in terms of size, stability in plasma and binding to the target. Quantitative PET imaging and ICP-MS analysis assessed in vivo distribution and specific tumor targeting of tracers. RESULTS The tumor uptake of immunoconjugates was preserved up to 24 h after injection, with high tumor contrast and selective tumor targeting. No major tracer accumulation was observed over time in nonspecific organs. ICP-MS analysis confirmed the antibody specificity after nanoparticle conjugation. CONCLUSION The anti-CD105 antibody conjugation to AuNPs did not greatly affect CD105-dependent tumor uptake and the efficacy of tumor targeting for cancer detection.

Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging

The regional cerebral blood flow (rCBF) and metabolic rate for glucose (rCMRGlc) are associated with functional activity of the neural cells. The present work reports a comparison study between rCBF and rCMRGlc in a normal population as a function of age. 10 young (25.9+/-5.6 years) and 10 old (65.4+/-6.1 years) volunteers were similarly studied at rest. In each subject, rCBF and rCMRGlc were measured in sequence, during the same session. Both rCBF and rCMRGlc values were found to decrease from young (mean rCBF=43.7 ml/100 g per min; mean rCMRGlc=40.6 micromol/100 g per min) to old age (mean rCBF=37.3 ml/100 g per min; mean rCMRGlc=35.2 micromol/100 g per min), resulting in a drop over 40 years of 14.8% (0.37%/year) and 13.3% (0.34%/year), respectively. On a regional basis, the frontal and the visual cortices were observed to have, respectively, the highest and the lowest reduction in rCBF, while, for rCMRGlc, these extremes were observed in striatum and cerebellum. Despite these differences, the ratio of rCBF to rCMRGlc was found to have a similar behavior in all brain regions for young and old subjects as shown by a correlation coefficient of 88%. This comparative study indicates a decline in rCBF and rCMRGlc values and a coupling between CBF and CMRGlc as a function of age.

Changes in occipital cortex activity in early blind humans using a sensory substitution device

The purpose of this study was to investigate the neural networks involved when using an ultrasonic echolocation device, which is a substitution prosthesis for blindness through audition. Using positron emission tomography with fluorodeoxyglucose, regional brain glucose metabolism was measured in the occipital cortex of early blind subjects and blindfolded controls who were trained to use this prosthesis. All subjects were studied under two different activation conditions: (i) during an auditory control task, (ii) using the ultrasonic echolocation device in a spatial distance and direction evaluation task. Results showed that the abnormally high metabolism already observed in early blind occipital cortex at rest [C. Veraart, A.G. De Volder, M.C. Wanet-Defalque, A. Bol, C. Michel, A.M. Goffinet, Glucose utilization in human visual cortex is, respectively elevated and decreased in early versus late blindness, Brain Res. 510 (1990) 115-121.] was also present during the control task and showed a trend to further increase during the use of the ultrasonic echolocation device. This specific difference in occipital cortex activity between the two tasks was not observed in control subjects. The metabolic recruitment of the occipital cortex in early blind subjects using a substitution prosthesis could reflect a concurrent stimulation of functional cross-modal sensory connections. Given the unfamiliarity of the task, it could be interpreted as a prolonged plasticity in the occipital cortex early deprived of visual afferences.

Quantitation in PET using isotopes emitting prompt single gammas: application to yttrium-86

Several yttrium-90 labelled somatostatin analogues are now available for cancer radiotherapy. After injection, a large amount of the compound is excreted via the urinary tract, while a variable part is trapped in the tumour(s), allowing the curative effect. Unfortunately, the compound may also be trapped in critical tissues such as kidney or bone marrow. As a consequence, a method for assessment of individual biodistribution and pharmacokinetics is required to predict the maximum dose that can be safely injected into patients. However, 90Y, a pure β–particle emitter, cannot be used for quantitative imaging. Yttrium-86 is a positron emitter that allows imaging of tissue uptake using a PET camera. In addition to the positron, 86Y also emits a multitude of prompt single γ-rays, leading to significant overestimation of uptake when using classical reconstruction methods. We propose a patient-dependent correction method based on sinogram tail fitting using an 86Y point spread function library. When applied to abdominal phantom acquisition data, the proposed correction method significantly improved the accuracy of the quantification: the initial overestimation of background activity by 117% was reduced to 9%, while the initial error in respect of kidney uptake by 84% was reduced to 5%. In patient studies, the mean discrepancy between PET total body activity and the activity expected from urinary collections was reduced from 92% to 7%, showing the benefit of the proposed correction method.

Regional oxidative metabolism in patients after recovery from reperfused anterior myocardial infarction. Relation to regional blood flow and glucose uptake.

BackgroundEnhanced uptake of the glucose analogue 18F-fluorodeoxyglucose (FDG) in relation to flow has been proposed as an accurate method of identifying viable myocardium. The evaluation of myocardial oxidative metabolism could be an alternate way to identify reversible injury. The aim of the present study was to investigate in patients with reperfused anterior infarction whether differences in regional oxidative metabolism exist among regions with and without flow-metabolism mismatch. Methods and Resuts.Fifteen patients with reperfused anterior myocardial infarction were studied between 2 weeks and 3 months after the acute event. Regional myocardial blood flow (13N-ammonia; three-compartment model), oxidative metabolism (11C-acetate; monoexponential clearance), and glucose uptake (FDG, linear graphic analysis) were evaluated with dynamic positron emission tomography. Flow-metabolism patterns were used to differentiate reversibly (FDG/flow >1.2) from irreversibly injured myocardium (FDG/flow < 1.2) using circumferential profile technique. Relative 13N-ammonia uptake was reduced in 71 of 90 anterior and/or septal segments, including 24 with (seven patients) and 38 without (eight patients) flow-metabolism mismatch. Acetate clearance (k), reflecting oxidative metabolism, was reduced by 51% in the center of the infarct area versus remote segments (27±12 versus 55±13 min−1. 10−3, p < 0.001). Compared with infarct segments without flow-metabolism mismatch, segments exhibiting increased glucose uptake relative to flow had faster acetate clearance (35±14 versus 23±9 min−1.10−3, p < 0.01). Similarly, myocardial blood flow was better preserved in segments with flow-metabolism mismatch (54±13 versus 45±8 ml/min/100 g, p < 0.0l) compared with segments without mismatch. However, at similar levels of hypoperfusion, there was no significant difference in acetate clearance among segments with and those without flow-metabolism mismatch: 37±14 versus 41±15 min−1.10−3, respectively. A positive correlation (r = 0.89, p < 0.001) was found between absolute myocardial blood flow and acetate clearance, regardless of the flow-metabolism pattern. ConclusionsIn patients with reperfused myocardial infarction studied between 2 weeks and 3 months after the acute event, regional oxidative metabolism is reduced in proportion to residual myocardial blood flow and does not differ significantly among similarly hypoperfused segments with and without flow-metabolism mismatch.

Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: A comparison with Oxylite, EPR Oximetry and 19F-MRI Relaxometry

BACKGROUND AND PURPOSE (18)F-FAZA is a nitroimidazole PET tracer that can provide images of tumor hypoxia. However, it cannot provide absolute pO(2) values. To qualify (18)F-FAZA PET, we compared PET images to pO(2) measured by OxyLite, EPR oximetry and (19)F-MRI. MATERIALS AND METHODS Male WAG/Rij rats grafted with rhabdomyosarcoma were used. Tumor oxygenation was modified by gas breathing (air or carbogen). The same day of PET acquisition, the pO(2) was measured in the same tumor either by OxyLite probes (measurement at 10 different sites), EPR oximetry using low frequency EPR or (19)F-relaxometry using 15C5 on an 11.7T MR system. RESULTS There was a good correlation between the results obtained by PET and EPR (R = 0.93). In the case of OxyLite, although a weaker correlation was observed (R = 0.55), the trend for two values to agree was still related to the inverse function theoretically predicted. For the comparison of (18)F-FAZA PET and (19)F-MRI, no change in T(1) was observed. CONCLUSIONS A clear correlation between (18)F-FAZA PET image intensities and tumor oxygenation was demonstrated, suggesting that (18)F-FAZA PET is a promising imaging technique to guide cancer therapy.

A Direct Measurement of the F-18(p,Alpha)o-15 Reaction

The cross section for the F-18(p,alpha) O-15 reaction has been obtained in reverse kinematics (F-18 beam on CH2 target) between 550 and 740 keV above threshold, i.e. in a region of astrophysical interest. The reaction yield is dominated by a wide resonant state whose spin, parity, total width and partial widths were deduced from the analysis of the alpha-particle and elastic proton data.

Synthesis of [18F]-labeled EF3 [2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide], a marker for PET detection of hypoxia.

[18F]-2-(2-Nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide ([18F]-EF3) has been prepared, in 65% chemical yield and 5% radiochemical yield, by coupling 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate 1 with [18F]-3,3,3-trifluoropropylamine 7. This original radiolabelled key-synthon was obtained in 40% overall chemical yield by oxidative [18F]-fluorodesulfurization of ethyl N-phthalimido-3-aminopropane dithioate 4, followed by deprotection with hydrazine of the resulting [18F]-N-phthalimido-3,3,3-trifluoropropylamine 5. All the process was performed within 90 min, from the [18F]-HF production in the cyclotron to the purification of the final target.