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Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR). Optimal conditions for the preclinical quantification of MPE using 201Tl SPECT MPI were determined in rats with a T2D-like condition induced by a high-fat diet and streptozotocin injection (feasibility study, n = 43). Using such conditions, echocardiography and post-mortem LV capillary density evaluation were then used in order to assess the effect of LIR and the ability of MPE to assess CMVD (therapeutic study, n = 39). The feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P

Myocardial insulin resistance (IR) could be a predictive factor of cardiovascular events. This study aimed to introduce a new method using 123I-6-deoxy-6-iodo-d-glucose (6DIG), a pure tracer of glucose transport, for the assessment of IR using cardiac dynamic nuclear imaging. The protocol evaluated first in rat-models consisted in two 6DIG injections and one of insulin associated with planar imaging and blood sampling. Compartmental modeling was used to analyze 6DIG kinetics in basal and insulin conditions and to obtain an index of IR. As a part of a translational approach, a clinical study was then performed in 5 healthy and 6 diabetic volunteers. In rodent models, the method revealed reproducible when performed twice at 7 days apart in the same animal. Rosiglitazone, an insulin-sensitizing drug, induced a significant increase of myocardial IR index in obese Zucker rats from 0.96 ± 0.18 to 2.26 ± 0.44 (P

Risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. We hypothesized that myocardial perfusion entropy (MPE) quantified from SPECT myocardial perfusion images may provide incremental prognostic value in T2D patients independently from myocardial ischemia. T2D patients with very high and high cardiovascular risk were prospectively included (n = 166, 65 ± 12 years). Stress perfusion defect was quantified by visual evaluation of SPECT MPI. SPECT MPI was also used for the quantification of rest and stress MPE. The primary end point was major adverse cardiac events (MACEs) defined as cardiac death, myocardial infarction (MI), and myocardial revascularization > 3 months after SPECT. Forty-four MACEs were observed during a 4.6-year median follow-up. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.40; P ≤ .01). By Kaplan-Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ 01). Stress MPE and stress perfusion defect (SSS ≥ 4) were significantly associated with the risk of MACEs (hazard ratio 2.77 and 2.06, respectively, P

International audience; PURPOSE:Insulin resistance is a key feature of the metabolic syndrome and type 2 diabetes, in which noninvasive assessment is not currently allowed by any methodology. We previously validated an iodinated tracer of glucose transport (6DIG) and a new methodology for the in vivo quantification of cardiac insulin resistance in rodents. The aim of this study was to investigate the safety, biodistribution, and radiation dosimetry of this method using I-6DIG in 5 healthy and 6 diabetic volunteers.METHODS:The collection of adverse effects (AEs) and medical supervision of vital parameters and biological variables allowed the safety evaluation. Biodistribution was studied by sequentially acquiring whole-body images at 1, 2, 4, 8, and 24 hours postinjection. The total number of disintegrations in each organ normalized to the injected activity was calculated as the area under the time-activity curves. Dosimetry calculations were performed using OLINDA/EXM.RESULTS:No major adverse events were observed. The average dose corresponding to the 2 injections of I-6DIG used in the protocol was 182.1 ± 7.5 MBq. A fast blood clearance of I-6DIG was observed. The main route of elimination was urinary, with greater than 50% of urine activity over 24 hours. No blood or urine metabolite was detected. I-6DIG accumulation mostly occurred in elimination organs such as kidneys and liver. Mean radiation dosimetry calculations indicated an effective whole-body absorbed dose of 3.35 ± 0.57 mSv for the whole procedure.CONCLUSIONS:I-6DIG was well tolerated in human with a dosimetry profile comparable to that of other commonly used iodinated tracers, thereby allowing further clinical development of the tracer.

International audience; Coronary microvascular dysfunction has recently emerged as a major independent prognostic factor and can be invasively assessed by coronary flow reserve (CFR) and the index of microvascular resistance (IMR). The incremental prognostic value of myocardial ischemia from SPECT myocardial perfusion imaging (MPI) over clinical characteristics, cardiac risk factors, and stress test data for the prediction of hard cardiac events (myocardial infarction and cardiac death) has been well demonstrated over the last two decades regardless of the absence or presence of epicardial CAD. Recently developed semi-conductor, cardiac-dedicated cameras allow for decreased acquisition times and systematic procubitus and decubitus acquisitions thereby limiting the occurrence of false positives historically attributable to artefactual motion, attenuation, and digestive artifacts. It is therefore likely that pathophysiological causes rather than acquisition artifacts might underlie SPECT perfusion abnormalities. Here, we report four representative examples of patients presenting with ischemia in the setting of no obstructive CAD and normal fractional flow reserve together with elevated IMR and low CFR. The results indicate that ischemia from SPECT MPI could result from microvascular dysfunction in patients without obstructive CAD and should be considered as a prognostic factor for hard cardiac events.

The objective of this study was to determine the accuracy of right ventricular function (RVF) assessed by Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography (CZT-ERNA). Twenty-one consecutive patients with cardiomyopathy (aged 54 ± 19 years; 62% male) were included. RV ejection fraction (EF) and volumes were analyzed by CZT-ERNA and compared with values obtained by cardiac magnetic resonance imaging (CMR). Mean values were not different between CZT-ERNA and MRI for RVEF (48.1 ± 10.4% vs 50.8 ± 10.0%; P = .23). Significant correlations (P

Introduction Myocardial perfusion reserve (MPR) is a validated diagnostic and prognostic value by Positron Emission Tomography (PET) scans. However, PET availability stays limited in certain countries as France. Gamma cameras with cadmium-zinc telluride detector (CZT-SPECT) are more available and allow the evaluation of this MPR. However, there is no comparison of its results with the interventional diagnostic procedure. Method Twenty-seven patients with suspected of epicardial or microcirculatory coronary involvement were prospectively included. All patients benefited from an evaluation of the MPR by CZT SPECT as well as an interventional diagnostic procedure with measure of the Fractionnal Flow Reserve (FFR), coronary flow reserve (CRF) and index of microcirculation resistance (IMR). Correlation between MPR and CFR was measured and sensitivity and specificity to detect severe coronary microcirculation disease (CMVD) defined by FFR > 0.8, CFR 25. Results Coronary angiography was performed in 27 patients, with a complete functional evaluation (FFR, CFR, IMR) on 33 vessels. Two patients had significant stenosis (50-90% stenosis and FFR Conclusion MPR was correlated with CRF and presented satisfactory diagnostic performance to discriminate, in the absence of significant stenosis, patients free from patients with severe CMVD.

International audience; no abstract

Objective In Genetic Absence Epilepsy Rats From Strasbourg (GAERSs), epileptogenesis takes place during brain maturation and correlates with increased mRNA expression of D3 dopamine receptors (D3R). Whether these alterations are the consequence of seizure repetition or contribute to the development of epilepsy remains to be clarified. Here, we addressed the involvement of the dopaminergic system in epilepsy onset in GAERSs. Methods Experiments were performed using rats at different stages of brain maturation from three strains according to their increasing propensity to develop absence seizures: nonepileptic control rats (NECs), Wistar Hannover rats, and GAERSs. Changes in dopaminergic neurotransmission were investigated using different behavioral and neurochemical approaches: autoradiography of D3R and dopamine transporter, single photon emission computed tomographic imaging, acute and chronic drug effects on seizure recordings (dopaminergic agonists and antagonists), quinpirole-induced yawns and dopamine synaptosomal uptake, microdialysis, brain tissue monoamines, and brain-derived neurotrophic factor quantification. Results Autoradiography revealed an increased expression of D3R in 14-day-old GAERSs, before absence seizure onset, that persists in adulthood, as compared to age-matched NECs. This was confirmed by increased yawns, a marker of D3R activity, and increased seizures when animals were injected with quinpirole at low doses to activate D3R. We also observed a concomitant increase in the expression and activity of the dopamine transporter in GAERSs before seizure onset, consistent with both lowered dopamine basal level and increased phasic responses. Significance Our data show that the dopaminergic system is persistently altered in GAERSs, which may contribute not only to behavioral comorbidities but also as an etiopathogenic factor in the development of epilepsy. The data suggest that an imbalanced dopaminergic tone may contribute to absence epilepsy development and seizure onset, as its reversion by a chronic treatment with a dopamine stabilizer significantly suppressed epileptogenesis. Our data suggest a potential new target for antiepileptic therapies and/or improvement of quality of life of epileptic patients.

International audience; PURPOSE:To determine whether the assessment of regional wall thickening (WT) in addition to myocardial perfusion from stress supine acquisitions could compensate for the lack of prone acquisition and the corresponding decrease in the diagnostic performance of SPECT myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease (CAD).METHODS:The study group comprised 41 patients (123 vessels) with known or suspected CAD prospectively recruited for systematic prone and supine 201Tl stress SPECT MPI. The diagnostic performance of SPECT MPI was determined for various image sets including nongated supine images (supine NG), nongated combined prone and supine images (prone and supine NG) and gated supine images, allowing WT evaluation from NG images in addition to perfusion (supine NG + WT) using invasive coronary angiography and fractional flow reserve as the gold standards.RESULTS:The rate of false positives was significantly higher among the supine NG images (20.8%) than among either the prone and supine NG or the supine NG + WT images (3.3% and 2.7%, respectively, P

International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.

Introduction Atherosclerosis is associated with a worse prognosis in many diseases, but its impact in non-ischemic dilated cardiomyopathy (NIDCM) is not known. Purpose This study investigated the prognostic value of coronary atherosclerotic burden, as measured by Gensini score, in a cohort of NIDCM patients. Methods In total, 139 patients with left ventricular (LV) dysfunction due to NIDCM were classified according to both invasive coronary angiography (ICA) and cardiovascular magnetic resonance (CMR) imaging data in 3 subtypes of NIDCM: true NIDCM, NIDCM with bystander coronary artery disease (CAD) and NIDCM with bystander myocardial infarction (MI). Percentage, extent, location of fibrosis was assessed with CMR and coronary atherosclerotic burden by calculating Gensini score. Primary endpoint was a composite of cardiovascular mortality, non-fatal MI and revascularisation by percutaneous coronary intervention (PCI). Results Out of 139 patients (mean age 59.4 ± 14.7 years old, 74% male), there were 101 patients (73%) with true NIDCM, 30 patients (22%) with NIDCM and bystander MI and 8 patients (5%) with NIDCM and bystander MI. 6 patients (4.3%) died and 6 (4.3%) underwent PCI during a median follow-up of 34.2 ± 18 months ( Table 1 ). Gensini score predicted primary composite endpoint, in univariate and multivariate analysis, hazard ratio = 1.08, confidence interval 95% (1.034–1.13) P = 0.001, as well as a history of CAD, LV ejection fraction (LVEF) and age (P Conclusion Coronary atherosclerotic burden, as measured by Gensini score, is a new prognostic factor in NIDCM. Assessing this parameter improves risk stratification and could be used to help personalise treatment in this population ( Fig. 1 ).

Background Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) provides valuable prognostic value. However, the risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. Objectives We hypothesised that myocardial perfusion entropy (MPE) quantified from SPECT myocardial perfusion images may provide an incremental prognostic value in T2D patients independently from the routinely performed assessment of myocardial ischemia. Methods T2D patients with very high and high cardiovascular risk were studied (n = 166, 65 ± 12 years). Ischemia (> 10% of left ventricular area) was assessed by SPECT MPI. In addition, SPECT MPI was used for the quantification of rest and stress MPE. The primary endpoint was major adverse cardiac events (MACEs) defined as cardiac death, Q-wave myocardial infarction (MI) and myocardial revascularisation > 3 months after SPECT. Results Forty-six patients underwent MACEs over a median follow-up of 4.6 years. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.39; P ≤ .01). By Kaplan–Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ .01). Stress MPE and ischemia were significantly associated with the risk of MACEs (hazard ratio: 2.30 and 1.12, respectively, P ≤ .01 for both) after adjustment for clinical and imaging risk factors as identified from preliminary, univariate analysis and including age, hypertension, stress test and ischemia. The incremental prognostic value of MPE over clinical risk factors was quantified using nested models showing improved AIC, reclassification (global continuous Net Reclassification Improvement [NRI]: 54, global Integrated Discrimination Improvement [IDI]: 4.6%), discrimination (change in c-statistic: 0.69 vs. 0.74). Conclusions Stress MPE provided independent and incremental prognostic information for the prediction of MACEs in diabetic patients.

Background The risk assessment for ventricular arrhythmia in patients with ischemic cardiomyopathy is, at the present time, unspecific. Left ventricular (LV) entropy is a measure of myocardial heterogeneity derived from single photon emission computed tomography (SPECT). Purpose This study assesses the utility of LV entropy for predicting cardiovascular events in patients with ischemic cardiomyopathy. Methods Patients with ischemic cardiomyopathy referred for implantable cardioverter-defibrillator (ICD) implantation were included retrospectively. Their LV entropy was measured on SPECT. Patients were followed from implantable cardioverter-defibrillator placement to detect arrhythmic events (appropriate implantable cardioverter-defibrillator therapy and sustained ventricular arrhythmia), end-stage heart failure events (congestive heart failure, transplantation, or ventricular assist device placement), and cardiac death. Results Forty patients (mean age 68.1 ± 9.4 years, 75% men, LV ejection fraction 29.7 ± 4.6%) were followed for 22.8 ± 12.9 months. Of the forty patients, three (7.5%) experienced arrhythmic events, one died of advanced heart failure after receiving the appropriate shock, and three others (7.5%) experienced end-stage heart failure events. On univariate analysis, age (HR: 1.02 [0.99; 1.04]; P = 0.176); diabetes (HR: 0.30 [0.05; 1.68]; P = 0.17), CRT-D (HR: 0.06 [0.007; 0.53]; P = 0.01), NYHA class (HR: 7.6 [2.00; 29.5]; P = 0.003) and ischemia (HR: 1.07 [0.96; 1.18]; P = 0.19) were significant predictors of cardiac events. On multivariate analysis, CRT-D (HR: 0.06 [0.04; 0.89]; P = 0.04) remained a significant predictor of cardiac events. LV entropy was not a predictor of cardiac events. Conclusion In patients with ischemic cardiomyopathy, LV entropy measurement is not a predictor of life-threatening ventricular arrhythmia. However, CRT-D is a strong protector of ventricular arrhythmia in ischemic cardiomyopathy.

a Department of Cardiology, General Hospital Center, Chambery, France b Department of Radiology, University Hospital, Grenoble, France c Department of Nuclear Medicine, General Hospital Center, Chambery, France d INSERM U1039, Bioclinic Radiopharmaceutics Laboratory, Joseph Fourier University, Grenoble, France e Department of Nuclear Medicine, University Hospital, Grenoble, France f Department of Cardiology, University Hospital, Grenoble, France

Introduction Coronary microvascular dysfunction (CMD) is associated with a higher rate of major adverse cardiovascular events (MACEs) in diabetic patients. Liraglutide, a glucagon-like peptide-1 analog, decreases MACEs and all-cause mortality in this population. Purpose The present paper aims to study the effects of liraglutide on heart function and myocardial perfusion entropy (MPE) as a surrogate marker of coronary microvascular dysfunction (CMVD) in a rat model of type-2 diabetes. Methods Thirty-nine rats were divided into three groups, control (CTL), diabetic (T2D) and liraglutide (DT2-LIR). T2D and T2D-LIR rats were fed a high-fat diet and injected with 35 mg/kg streptozotocin intra-peritoneally (IP) to induce diabetes. T2D-LIR rats were injected with a subcutaneous liraglutide solution for four weeks. Heart structure and function were assessed with trans-thoracic-doppler echocardiography and CMVD was assessed with a novel 201 Thallium SPECT-technique, measuring MPE, under stress conditions. Histological analysis was later performed. Results T2D rats had a significantly lower left ventricular (LV) ejection fraction (LVEF) versus CTL (64.5 ± 4.3% vs. 74.4 ± 9.2% P Conclusion Liraglutide is associated with an improvement in heart systolic function and reduced LV hypertrophy in type 2 diabetic rats but only has a small specific effect on CMVD.

Background The routine acquisition of combined prone and supine SPECT myocardial perfusion images remains limited despite the associated improvement in diagnostic and prognostic accuracies. Our aim was to determine whether the assessment of regional wall thickening (WT) in addition to myocardial perfusion from stress supine acquisitions could overcome the lack of prone acquisition and the corresponding decrease in the diagnostic performances of SPECT myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease (CAD). Methods Forty-one (41) patients (123 vessels) with known or suspected CAD were prospectively recruited for systematic prone and supine thallium-201 stress SPECT myocardial perfusion imaging using a semi-conductor, cardiac dedicated SPECT camera. The diagnostic performances of SPECT MPI were determined for various image sets including non-gated, supine images (supine NG), non-gated, combined prone and supine acquisitions (prone & supine NG), and gated supine acquisition allowing the evaluation of WT in addition to that of perfusion from NG images (supine NG + WT) using invasive coronary angiography (ICA) and fractional flow reserve (FFR) as the gold standard. Myocardial perfusion was scored using a 5-point scale (0 = normal, 1 = equivocal, 2 = moderate, 3 = severely reduced radiotracer uptake, 4 = no detectable uptake) and a 17-segment model of the left ventricle leading to summed stress score values (SSS), with patients being classified as positive for the presence of ischemia if SSS ≥ 2. Additional WT analysis was used to classify myocardial perfusion as pathological when a myocardial segment with a SSS ≥ 2 also presented with a WT abnormality. Significant CAD was defined by the presence of ≥ 90% stenosis/occlusion or fractional flow reserve ≤ 0.80 in the presence of a ≥ 50% coronary stenosis. Results Upon per patient analysis, the occurrence of false positives was significantly higher in supine NG images (36.6%) than in both prone & supine NG and supine NG + WT image sets (9.8% and 7.8%, respectively, P Conclusions The diagnostic performances of supine stress SPECT MPI are restored compared with combined prone & supine acquisitions when WT assessment in the ischemic segments is used as an additional diagnostic criterion.

Background Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for the assessment of myocardial ischemia provides valuable prognostic value. However, the risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. Recent studies have highlighted the role of coronary microvascular disease in the occurrence of coronary symptoms in this population. Objectives We hypothesized that enhanced signal analysis from SPECT myocardial perfusion images may allow insights into the status of the coronary microvasculature. More specifically, we hypothesized that myocardial perfusion entropy (MPE) as a surrogate marker of microvascular disease quantified from SPECT myocardial perfusion images may provide an incremental prognostic value in T2D patients independently from the routinely performed assessment of myocardial ischemia. Methods T2D patients with very high cardiovascular risk were studied (n = 166, 65 ± 12 years). Ischemia was assessed by SPECT myocardial perfusion imaging (MPI). In addition, SPECT MPI was used for the quantification of rest and stress MPE using an original algorithm providing a global value of MPE from reconstructed rest and stress SPECT images. The primary end point was major adverse cardiac events (MACEs) defined as cardiac death, Q-wave myocardial infarction (MI) and myocardial revascularization > 3 months after SPECT. Results Forty-six patients underwent MACEs over a median follow-up of 4.6 years. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.39; P ≤ 0.01). By Kaplan-Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ 0.01). Stress MPE was significantly associated with the risk of MACEs (hazard ratio: 2.80, P ≤ 0.01) after adjustment for clinical and imaging risk factors as identified from preliminary, univariate analysis and including age, hypertension and ischemia. The risk of overfitting was controlled by internal validation procedures such as LASSO, stepwise and random forests selections on time-to-MACEs Cox models. A competing risk event (“other deaths”) slightly overestimated Cox estimates. However, the impact of informative censorship was assessed by Fine-Gray subdistribution hazard estimates and proved to be marginal. The incremental prognostic value of MPE over clinical risk factors was quantified using nested models showing improved AIC, reclassification (global continuous Net Reclassification Improvement [NRI]: 70.1, global Integrated Discrimination Improvement [IDI]: 6.6%), discrimination (change in c-statistic: 0.69 vs. 0.74), and time-dependent AUC (0.71 vs. 0.77 at 4 years of follow-up). Conclusions Stress MPE provided independent and incremental prognostic information for the prediction of MACEs in diabetic patients.

International audience; Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.

Comment inRole of I-123 MIBG in sepsis-induced cardiomyopathy. [J Nucl Cardiol. 2018]; International audience; BACKGROUND:Sympathetic system abnormalities have been reported in sepsis-related cardiac dysfunction. The present study aimed at evaluating the potential of the norepinephrine radiolabeled analogue [123I]-meta-iodobenzylguanidine (123I-MIBG) for the noninvasive assessment of modifications in cardiac sympathetic activity occurring in lipopolysaccharide (LPS)-induced experimental acute sepsis by single-photon emission computed tomographic imaging (SPECT).METHODS AND RESULTS:Sepsis was induced in male Wistar rats by intraperitoneal injection of 10 mg·kg-1 lipopolysaccharide (n = 16), whereas control animals (n = 7) were injected with vehicle (NaCl 0.9%). Echocardiography in LPS-injected animals (n = 8) demonstrated systolic and diastolic cardiac dysfunction. 123I-MIBG was injected 1 hour after LPS or vehicle administration (n = 8 and 7, respectively), and in vivo SPECT imaging was performed early and late (20 and 180 minutes) after tracer injection prior to animal euthanasia and ex vivo assessment of 123I-MIBG biodistribution. Global and 17-segment SPECT image analysis indicated that early 123I-MIBG activity was not affected by LPS treatment, whereas late cardiac tracer activity was significantly decreased in LPS-treated animals. Consequently, the cardiac washout of 123I-MIBG was significantly higher in LPS-treated (63.3% ± 4.0%) than that in control animals (56.7% ± 5.8%) (P < .05).CONCLUSION:Sepsis-induced modifications in cardiac sympathetic nervous system activity were evidenced by noninvasive in vivo 123I-MIBG SPECT imaging.

International audience; Cardiac computed tomography (CT) provides additional information with ultrasound in the transcatheter heart valve (THV) size selection. However, the influence of these incremental data on outcomes has not been evaluated in a randomized study. A single-center prospective, randomized, and open study was performed. Patients referred for transfemoral transcatheter aortic valve implantation with a balloon-expandable endoprothesis were included. THV size selection was performed using either transthoracic and transesophageal echocardiography data (control group) or ultrasound and CT results (CT group). The primary composite end point included the occurrence of stroke, major vascular complications, and moderate or severe paravalvular aortic regurgitation (PAR) at 1 year. Fifty patients (n = 25 in the control and CT groups) were enrolled. The primary composite end point occurred in 40% and 8% of patients from the control and CT groups, respectively (p = 0.008). The Kaplan-Meier analysis revealed a pejorative association with not performing the CT (p = 0.007). A decrease in the occurrence of PAR was observed in the CT group compared with the control group (PAR 28% vs 4%, p = 0.04; major vascular complications 12% vs 4%, p = 0.6; all-cause death 16% vs. 4%, p = 0.34; no stroke). In conclusion, the use of cardiac CT in addition to ultrasound data in THV size selection reduced the long-term occurrence of cardiovascular events.

International audience; BACKGROUND:The aim of this study was to determine the diagnostic accuracy of stress thallium-201/rest technetium-99m-sestamibi sequential dual-isotope high-speed myocardial perfusion imaging (DI-HS-MPI) against invasively determined fractional flow reserve (FFR).METHODS:Fifty-four consecutive patients prospectively underwent DI-HS-MPI before invasive coronary angiography. Perfusion was scored visually by summed stress score on a patient and coronary territory basis. Significant coronary artery disease (CAD) was defined by the presence of ≥ 90% stenosis/occlusion or fractional flow reserve ≤ 0.80 for coronary stenosis ≥ 50%.RESULTS:FFR was measured in 69 of 162 coronary vessels, with 1.28 ± 0.56 vessels assessed/patient. Sensitivity, specificity, and diagnostic accuracy of MPI for the detection of significant CAD were 92.8%, 69.2%, and 81.4%, on a patient basis, and 83.7%, 90.4%, and 88.8% by coronary territory.CONCLUSIONS:DI-HS-MPI accurately detects functionally significant CAD as defined by using FFR.

International audience; Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic apoE(-/-) mice, in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero-stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE(-/-) mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans.

Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (p < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.

Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the (99m)Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that (99m)Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis.A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE(-/-)) mice was used (n = 82). (99m)Tc-B2702p and (99m)Tc-B2702p1-(99m)Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE(-/-) mice was also performed with (99m)Tc-B2702p1. The animals were then euthanized, and the biodistribution of (99m)Tc-labeled peptides was evaluated by γ-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology.Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, (99m)Tc-B2702p1 exhibited the most favorable properties. By γ-well counting, there was a significant 2.0-fold increase in the (99m)Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 ± 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 ± 0.4) in comparison to (99m)Tc-B2702p (1.3 ± 0.2 and 0.4 ± 0.1, respectively, P0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in (99m)Tc-B2702p1- than in (99m)Tc-B2702p-injected mice (1.2 ± 0.1 vs. 1.0 ± 0.0, respectively, P0.05). Finally, a significantly higher (99m)Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 ± 0.4 vs. 1.4 ± 0.3 cpm/mm(2)/injected dose, respectively, P0.05).(99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.

International audience; Unmixing is often a necessary step to analyze 2D SPECT image sequence. However, factor analysis of dynamic sequences (FADS), the commonly used method for unmixing SPECT sequences, suffers from non-uniqueness issue. Optimization-based methods were developed to overcome this issue. These methods are effective but need improvement when the mixing is important or with very low SNR. In this paper, a new objective function using soft spatial prior knowledge is developed. Comparison with previous methods, efficiency and robustness to the choice of priors are illustrated with tests on synthetic dataset. Results on 2D SPECT sequences with high level of noise are also presented and compared.

AIMS: Positron emission tomography-computed tomography (PET-CT) is a highly sensitive clinical molecular imaging modality to study atherosclerotic plaque biology. Therefore, we sought to develop a new PET tracer, targeting vascular cell adhesion molecule (VCAM)-1 and validate it in a murine atherosclerotic model as a potential agent to detect atherosclerotic plaque inflammation. METHODS AND RESULTS: The anti-VCAM-1 nanobody (Nb) (cAbVCAM-1-5) was radiolabelled with Fluorine-18 ((18)F), with a radiochemical purity of >98%. In vitro cell-binding studies showed specific binding of the tracer to VCAM-1 expressing cells. In vivo PET/CT imaging of ApoE(-/-) mice fed a Western diet or control mice was performed at 2h30 post-injection of [(18)F]-FB-cAbVCAM-1-5 or (18)F-control Nb. Additionally, plaque uptake in different aorta segments was evaluated ex vivo based on extent of atherosclerosis. Atherosclerotic lesions in the aortic arch of ApoE(-/-) mice, injected with [(18)F]-FB-anti-VCAM-1 Nb, were successfully identified using PET/CT imaging, while background signal was observed in the control groups. These results were confirmed by ex vivo analyses where uptake of [(18)F]-FB-cAbVCAM-1-5 in atherosclerotic lesions was significantly higher compared with control groups. Moreover, uptake increased with the increasing extent of atherosclerosis (Score 0: 0.68 ± 0.10, Score 1: 1.18 ± 0.36, Score 2: 1.49 ± 0.37, Score 3: 1.48 ± 0.38%ID/g, Spearman's r(2) = 0.675, P < 0.0001). High lesion-to-heart, lesion-to-blood, and lesion-to-control vessel ratios were obtained (12.4 ± 0.4, 3.3 ± 0.4, and 3.1 ± 0.6, respectively). CONCLUSION: The [(18)F]-FB-anti-VCAM-1 Nb, cross-reactive for both mouse and human VCAM-1, allows non-invasive PET/CT imaging of VCAM-1 expression in atherosclerotic plaques in a murine model and may represent an attractive tool for imaging vulnerable atherosclerotic plaques in patients.

This paper presents a level set segmentation of the myocardium, endocardium and epicardium surfaces of the heart from 2D SPECT rest and stress perfusion images of the same patient to compute a heterogeneity index. Cardiac SPECT images have low resolution, low signal to noise ratio and lack of anatomical information. So accurate segmentation is difficult. The proposed method adds joint constraints of shape, parallelism and intensity in a level-set framework to simultaneously extract myocardium from rest and stress images. Results are compared to classical level-set segmentation.

This paper presents a segmentation process of the myocardium, endocardium and epicardium surfaces of the heart from 3D SPECT images to compute a heterogeneity index. This index represents the distribution of the activity in the myocardium. Because of the low resolution of SPECT images, the thickness of the myocardium is 1 to 4 voxels and a sub-voxel accuracy is therefore needed. The segmentation process is based on the minimization of an energy by dynamic programming after a coarse segmentation to define the center surface of the myocardium. A Gaussian mixture is fitted on the data to ensure subvoxel accuracy. The heterogeneity index is compared to the reference index on 58 SPECT images and the segmentation is visually validated on 300 SPECT images by a clinician.

Recent advances in nuclear myocardial perfusion imaging (MPI) have made it possible to develop a dual-isotope protocol for high-speed acquisition with image quality and radiation delivery comparable to that obtained with conventional single isotope protocols. So far, no study has compared dual-isotope high-speed MPI to invasive coronary angiography (ICA) in a large cohort using a Cadmium-zinc-telluride SPECT system. Over a 1-year period (May 2011 to April 2012), 1366 patients underwent dual-isotope high-speed MPI. Patients with ICA within 3 months after dual-isotope high-speed MPI were included together with patients with a low likelihood of coronary artery disease (CAD) in order to assess normalcy rate. Global summed stress score (SSS) and summed rest score (SRS) were calculated, and ICA results were analyzed independently. The main end point was a patient-based assessment of the diagnostic performance of dual-isotope high-speed MPI in detecting or ruling out significant CAD (>70% reduction in lumen diameter). Inclusion criteria were fulfilled for 214 patients (143 men; age 60 ± 14 years; ICA, n = 104; low likelihood for CAD, n = 110). An exercise stress test was performed in 62% of patients and a pharmacological stress test was performed with either dipyridamole (32%) or dobutamine (6%). Average examination duration was 22.4 ± 4.5 minutes. Mean SSS, SRS, and SDS were 8.0 ± 4.9, 3.1 ± 4.3, and 5.0 ± 3.2, respectively. Prevalence of angiographic CAD was 75%. ICA detected stenosis in the left main trunk, left anterior descending artery, left circumflex artery, and right coronary artery in 4, 33, 31, and 42 patients, respectively. Sensitivity of dual-isotope high-speed MPI was 94%, normalcy rate was 92%, and accuracy was 83% for detecting CAD. Dual-isotope high-speed MPI is reliable at detecting or ruling out CAD. NCT01785589

Background: Intestinal cholesterol absorption inhibitor ezetimibe (EZE) added to a statin therapy has demonstrated benefits in the IMPROVE-IT trial by further reducing LDL-cholesterol levels than statin therapy alone. We investigated the mechanisms by which EZE could contribute to cardiovascular events reduction in apolipoprotein E knock-out (apoE ko) mice. Methods: ApoE ko mice were fed a Paigen diet without (control) or with EZE (7mg/kg/day) for 6 weeks. To evaluate the effects of EZE on LDL-cholesterol metabolism and excretion, a first set of mice was injected intravenously with 3 H-cholesteryl oleate labeled human LDL. A second set of mice was used for in vivo SPECT/CT imaging of 99m Tc-cAbVCAM1-5, a single domain antibody directed against the Vascular Cell Adhesion Molecule-1 (VCAM-1), which was used as a marker of inflamed atherosclerotic plaques. The same mice were sacrificed for autoradiography and histology of aortic atherosclerotic plaques. Results: Compared with control, EZE treatment for 6 weeks induced a significant 41% and 65% reduction in plasma total cholesterol levels and atherosclerotic plaque area, respectively. After injection of 3 H-cholesteryl oleate labeled human LDL, mice treated with EZE showed a 173% higher LDL-cholesteryl ester catabolism (p3 H-tracer hepatic recovery was reduced by 61% with EZE (p3 H-tracer excretion in the feces was increased by 107% in the fecal cholesterol fraction (p After intravenous injection of 99m Tc-cAbVCAM1-5, mice treated with EZE also showed a significant 52% reduction in aortic uptake, which was confirmed by significant reduction in tracer uptake in ex vivo biodistribution and autoradiography analysis. Conclusion: EZE promotes anti-atherosclerotic effects through increased LDL-cholesterol catabolism and LDL-derived cholesterol fecal excretion, and reduced inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding EZE to a statin therapy.

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.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.(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; p0.05), 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.(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.

Previous studies demonstrated that the intrinsic myocardial washout of bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium(V) (technetium 99m N-NOET) was affected by changes occurring in the intravascular compartment such as variations in circulating lipid levels. We sought to determine whether the myocardial kinetics of Tc-99m N-NOET were affected by hyperlipidemia in a clinically relevant experimental model.Tc-99m N-NOET (50 MBq/kg) and thallium 201 (12 MBq/kg) were injected intravenously into hyperlipidemic fa/fa Zucker rats (n=6) and their lean, normolipidemic littermates (n=8), and dual-isotope in vivo planar imaging was performed for 60 minutes. In vivo image quantification indicated significantly faster cardiac washout of Tc-99m N-NOET in fa/fa animals versus lean animals (time constant, 411+/-64 minutes vs 1094+/-226 minutes, respectively; P.05), whereas Tl-201 cardiac washout was not affected (356+/-85 minutes vs 337+/-53 minutes, respectively; P=not significant).The cardiac kinetics of Tc-99m N-NOET, but not those of Tl-201, were accelerated after intravenous injection of the tracer in fa/fa Zucker rats with circulating lipid levels similar to those encountered clinically in hyperlipidemic patients. The relationship between lipidemia and the rate of Tc-99m N-NOET myocardial washout warrants further clinical investigation.

Abdominal aortic aneurysms (AAA) usually progress asymp-tomatically and are undetected until rupture occurs. Onceruptured, the mortality rate of AAA is about 80 %. Amongall patients with ruptured AAA, about one-third die withoutreachinghospital,andaboutanotherquarterreachhospitalbutdie prior to surgical intervention. Among the remaining pa-tients (about 40 %) surviving AAA rupture long enough tobenefit from surgical intervention, the perioperative mortalityhas historically reached about 50 % [1], a value that hashowever recently decreased owing to the introduction ofendovascular repair [2]. On the other hand, elective AAArepair has a much lower in-hospital mortality rate, with re-cently reported values of 1.3 % and 4.7 % for endovascularand open surgical repair, respectively [3], thereby stronglyemphasizingtheneedforscreeningandidentificationofthosepatients with prone-to-rupture AAA.The crude estimate of AAA diameter remains the mostwidely used predictive risk factor for AAA rupture and thesole therapeutic management criterion. Indeed, in both the2014EuropeanSocietyofCardiologyandthe2011AmericanCollege of Cardiology/American Heart Association guide-lines, aortic repair is a class I indication if the AAA diameterexceeds55mm[4,5].However,thelimitationsofthisparam-eter are well acknowledged, and it is therefore unanimouslyagreed that a more robust noninvasive predictor of the indi-vidual riskofAAA rupture is required. Althoughbeing muchless documented than atherogenesis, the current knowledgeregarding the pathophysiology of AAA indicates that parietalinflammation, matrix degradation and smooth muscle cellapoptosis are required for AAA pathogenesis [6]. FDG hasbeen suggested as a potentially useful agent for the molecularimaging of vascular inflammation due to the elevated carbo-hydratemetabolismofextravasatedinflammatorycells[7].Assuch, the tracer has been extensively evaluated in both theexperimentalandclinicalsettingsforthenoninvasiveimagingof inflammatory processes in vulnerable atherosclerotic le-sions as well as in AAA.In the multicentre study by Barwick and colleagues pub-lished in this issue of the European Journal of Nuclear Med-icine&MolecularImaging[8],theauthorsusedPETimagingof FDG uptake to retrospectively compare the metabolicactivity in the abdominal aortic wall of 151 patients withAAA (mean aortic diameter, 50±13 mm) with that of 159individuals with no AAA (mean aortic diameter, 21±3 mm)and matched for age, sex, diabetes, smoking status, statin useand indication for PET/CT. This cohort is the largest so farused for the comparison of FDG uptake between AAA andnormal vessels in well-matched patients. FDG uptake wasanalysed by semiquantitative visual scoring as well as quan-titatively using SUVmax and target to background ratiosutilizing mediastinal blood pool or descending thoracic aortaactivities for normalization.Althoughthe retrospective natureand the design of the study limit the conclusions that can bedrawn with respect to the potential of FDG for predictingAAA growth or rupture, the results unequivocally show thatthere was no correlation between AAA size and FDG uptakeand that there was no statistically significant difference inFDG uptake between AAA and normal abdominal aortas.The study by Barwick et al. therefore joins the ranks ofthose suggesting the suboptimal usefulness of FDG for AAAevaluation, which face the ranks of previously publishedstudies that reached opposite conclusions by suggesting the

Objectives The aim of this study was to determine the diagnostic accuracy of stress thallium-201/rest technetium-99m sequential dual-isotope high-speed myocardial perfusion imaging (DI-HS-MPI) against invasively determined fractional flow reserve (FFR) and to establish the correlation between myocardium at risk defined by using the invasive BARI-score and DI-HS-MPI. Background Relatively few studies have compared the diagnostic performance of new Cadmium Zinc Telluride - cameras versus FFR. Methods Fifty-four patients referred for angiography underwent DI-HSMPI. Perfusion was scored visually by summed stress score (SSS) on a patient and coronary territory basis, and ischemic burden was calculated by quantitative segmentation of the extent of ischemia. Significant coronary artery disease (CAD) was defined by the presence of ≥90% stenosis/occlusion or fractional flow reserve ≤0.80 in vessels >2mm. The relation between FFR and perfusion was determined for each vascular zone. The BARI-score was calculated from the coronary angiograms to quantify the myocardium at risk. Results FFR was measured in 70 of 162 coronary vessels; Vessels FFR measured per patient was 1.3±0.57. Sensitivity, specificity, and diagnostic accuracy of MPI for the detection of significant CAD were 92%, 88%, and 90% by coronary territory and 87%, 93%, and 92%, on a patient basis. The area under the summary receiver-operating characteristic at the patient level was 0.94 (95% CI: 0.88 to 1) and 0.90 (95% CI: 0.83 to 0.97) at the artery and territory levels, respectively. The mean ischemic burden for MPI and BARI-score showed a strong correlation between techniques (r=0.71, P Conclusions Stress thallium-201/rest technetium-99m sequential DI-HSMPI accurately detects functionally significant CAD as defined by using FFR and provides an assessment of ischemic burden in agreement with the invasive BARI-score.

Background Impairment of insulin-stimulated glucose transport is a characteristic of type 2 diabetes. A radioactive glucose analogue has been synthesized: [125I]-6-deoxy-6-iodo-D-glucose. Its biological behaviour in vitro is similar to that of 3-O-methyl-D-glucose, the reference tracer of glucose transport. The aim of the present study was to determine the ability of [125I]-6-deoxy-6-iodo-D-glucose to evaluate variations in glucose transport in vivo. Methods Biodistributions of [125I]-6-deoxy-6-iodo-D-glucose were performed with or without exogenous insulin (iv injection of 1.5 IU/kg) in db/+ non-diabetic control mice and in db/db type 2 diabetic mice, exhibiting a severe insulin resistance characterized by a lack of increase in glucose uptake in response to insulin. Results In db/+ mice, insulin increased [125I]-6-deoxy-6-iodo-D-glucose transport by 30% in most insulin-sensitive tissues (heart, diaphragm and skeletal muscle, p < 0.05) and had no effect in other organs. In db/db mice, [125I]-6-deoxy-6-iodo-D-glucose transport in these organs was not modified by insulin. Conclusion [125I]-6-deoxy-6-iodo-D-glucose is able to trace in vivo an increase in glucose transport with insulin in non-diabetic mice and a defect of glucose transport in type 2 diabetic mice. It is the first time that an iodinated analogue of glucose has shown such promising results after in vivo injection. The use of this tracer to assess glucose transport in vivo in humans via nuclear imaging warrants further investigation. Copyright © 2003 John Wiley & Sons, Ltd.

Resume Une nouvelle technique de mesure de l’insulinoresistance, utilisant l’imagerie nucleaire, a ete developpee. Sur un modele d’infarctus experimental chez le rat, les resultats indiquent un phenomene marque d’insulinoresistance cardiaque sept jours apres l’ischemie. Cette etude montre la sensibilite de la technique de mesure de la resistance a l’insuline par imagerie nucleaire.

International audience; Background - The great clinical potential of myocardial β-AR imaging has been shown by recent studies evaluating the β-AR specific, non selective agent [11C]-CGP12177 in the setting of idiopathic dilated cardiomyopathy and myocardial infarction. However, the short half-life of 11C hampers the potential of [11C]-CGP12177 for routine clinical use. AMI9 is an analog of the β-adrenoceptor ligand practolol that can readily be labeled using radioactive isotopes of iodine. The present study was aimed at characterizing the in vitro, ex vivo, and in vivo β-AR binding properties of [125I]-AMI9. Methods and Results – Newborn rat cardiomyocytes were used for saturation and kinetic binding assays as well as for displacement and competition experiments. Isolated perfused rat hearts were used to evaluate the pharmacological activity of AMI9. The in vivo kinetics of [125I]-AMI9 were studied using biodistribution experiments in mice. [125I]-AMI9 displayed high specific affinity for β-AR with no β-AR subtype selectivity (KD, 5.6±0.3 nM; Bmax, 231±7 fmol/mg of protein). AMI9 potently inhibited the inotropic effects of isoproterenol. The early in vivo cardiac and lung activities of [125I]-AMI9 compared favorably with those of the clinically validated tracer CGP12177. Conclusions – Iodine-labeled AMI9 is a promising agent for the molecular imaging of myocardial β-AR density.

UNLABELLED: (99m)Tc-cAbVCAM1-5, a single-domain antibody fragment directed against mouse or human vascular cell adhesion molecule 1 (VCAM-1), recently has been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, (99m)Tc-cAbVCAM1-5 specifically bound to VCAM-1-positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate (99m)Tc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy. METHODS: Thirty apolipoprotein E-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and (99m)Tc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography. Second, longitudinal SPECT/CT imaging was performed on control (n = 9) or atorvastatin-treated mice (0.01% w/w, n = 9). RESULTS: (99m)Tc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P < 0.05).Atorvastatin exerted significant antiatherogenic effects, and (99m)Tc-cAbVCAM1-5 lesion uptake was significantly reduced in 35-wk-old atorvastatin-treated mice, as indicated by ex vivo γ-well counting and autoradiography (P < 0.05). SPECT imaging quantification based on contrast-enhanced CT was reproducible (interexperimenter intraclass correlation coefficient, 0.97; intraexperimenter intraclass correlation coefficient, 0.90), and yielded results that were highly correlated with tracer biodistribution (r = 0.83; P < 0.0001). Therefore, reduced (99m)Tc-cAbVCAM1-5 uptake in atorvastatin-treated mice was successfully monitored noninvasively by SPECT/CT imaging (0.87 ± 0.06 vs. 1.11 ± 0.09 percentage injected dose per cubic centimeter in control group, P < 0.05). CONCLUSION: (99m)Tc-cAbVCAM1-5 imaging allowed the specific, sensitive, and reproducible quantification of VCAM-1 expression in mouse atherosclerotic lesions. (99m)Tc-cAbVCAM1-5 therefore exhibits suitable characteristics for the evaluation of novel antiatherogenic agents.

In vivo imaging of GABAA receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [(123)I]Iomazenil, an antagonist of the GABAA receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained.Five male Sprague-Dawley rats were used for [(123)I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TCc), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data.BPND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BPF values obtained with 2TCc (r=0.954 and 0.945 respectively, p0.0001). Equally significant correlations were found between values obtained with 2TCc and SRTM2 in raw and FA-denoised images (r=0.961 and 0.909 respectively, p0.0001). Scans of at least 100min are required to obtain stable BPND values from raw images while scans of only 70min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TCc and SRTM2 BP values.Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BPND values from rat brain [(123)I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50min after tracer injection or with FA-denoising of images.

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 μmol/L and diltiazem 0.5 μmol/L induced a 40% decrease in uptake. Conversely, Bay K 8644 0.25 μmol/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 (t 1/2 =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.

Objective— Despite the fact that mechanical stresses are well recognized as key determinants for atherosclerotic plaque rupture, very little is known about stress amplitude and distribution in atherosclerotic lesions, even in the standard apolipoprotein E (apoE) −/− mouse model of atherosclerosis. Our objectives were to combine immunohistology, atomic force microscopy measurements, and finite element computational analysis for the accurate quantification of stress amplitude and distribution in apoE −/− mouse aortic atherosclerotic lesions. Methods and Results— Residual stresses and strains were released by radially cutting aortic arch segments from 7- to 30-week-old pathological apoE −/− (n=25) and healthy control mice (n=20). Immunohistology, atomic force microscopy, and biomechanical modeling taking into account regional residual stresses and strains were performed. Maximum stress values were observed in the normal arterial wall (276±71 kPa), whereas low values ( Conclusion— Low mechanical stress amplitude was observed in apoE −/− mouse aortic atherosclerotic lesions. This original study provides a basis for further investigations aimed at determining whether low stress levels are responsible for the apparently higher stability of murine aortic atherosclerotic lesions.

International audience; SCOPE: Post-infarct left ventricular dysfunction and cardiac remodeling are the primary causes of chronic heart failure in industrialized countries. In the present study, we examined the influence of dietary selenium intake on cardiac remodeling after reperfused myocardial infarction and explored one of the possible mechanisms. METHODS AND RESULTS: Rats were fed a diet containing either 0.05 mg/kg (Low-Se, group of rats receiving the low-selenium diet) or 1.50 mg/kg (group of rats receiving the high-selenium diet) selenium. At the end of the 5th week of the diet, rats were subjected to transient (1 h) coronary ligation followed by 8 days of reperfusion. Infarct size and cardiac passive compliance were increased in the Low-Se group compared with group of rats receiving the high-selenium diet. Similarly, indices of cardiac remodeling (thinning index and expansion index) were more altered in Low-Se hearts. These adverse effects of the Low-Se diet on cardiac remodeling were accompanied by an increase in cardiac TNF-α content, a decreased activity of antioxidant seleno-enzymes and an increase in connexin-43 dephosphorylation. CONCLUSION: Dietary selenium intake influences post-infarct cardiac remodeling even when provided within the range of physiological values. Our data suggest that the cardioprotective effect of selenium might be mediated by a reduced oxidative stress, a lower connexin-43 dephosphorylation, and a decreased TNF-α expression.

Myocardial angiogenesis following reperfusion of an infarcted area may impact on patient prognosis and pro-angiogenic treatments are currently evaluated. The non-invasive imaging of angiogenesis would therefore be of potential clinical relevance in these settings. (99m)Tc-RAFT-RGD is a novel (99m)Tc-labeled tracer that targets the alpha(v)beta(3) integrin. Our objective was to determine whether this tracer was suitable for myocardial angiogenesis imaging.A rat model of reperfused myocardial infarction was employed. Fourteen days following reperfusion, the animals were injected with (99m)Tc-RAFT-RGD or with its negative control (99m)Tc-RAFT-RAD. Fourteen animals were dedicated to autoradiographic imaging, infarct staining, and gamma-well counting of myocardial activity. In vivo dual-isotope pinhole SPECT imaging of (201)Tl and (99m)Tc-RAFT-RGD or (99m)Tc-RAFT-RAD was also performed in 11 additional animals. Neovessels were observed by immunostaining in the infarcted and peri-infarct areas. (99m)Tc-RAFT-RGD infarct-to-normal ratios by gamma-well counting and ex vivo imaging (2.5 +/- 0.6 and 4.9 +/- 0.9, respectively) were significantly higher than those of (99m)Tc-RAFT-RAD (1.7 +/- 0.2 and 2.2 +/- 0.4, respectively, P.05). The infarcted area was readily visible in vivo by SPECT with (99m)Tc-RAFT-RGD but not with (99m)Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.5 +/- 0.6 and 1.7 +/- 0.4, respectively, P.05).(99m)Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.

Objectives Vascular Cell Adhesion Molecule-1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. It has been shown that the technetium-labelled HMC-I derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in WHHL rabbits. However, B2702p target-to-background ratio was suboptimal for in vivo imaging of VCAM-1 expression in atherosclerotic lesions. In order to increase the target to background ratio, ten derivatives of B2702p were synthesized (B2702p-1 to 10). We hypothesized that technetium radiolabelled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis. Material and Methods A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in ApoE-/- mice was used. 99mTc-B2702p (n=9) and 99mTc- B2702p-1 – 10 (n=3 for each except B2702p-1, n=5, and B2702p-4, n=5) were injected intravenously to the anesthetized animals 3 weeks following the ligation. Whole-body planar image acquisition was performed for 3 hrs with all radiolabelled peptides and SPECT imaging of 6 additionnal mice was also performed with 99mTc-B2702p-1. The animals were then euthanized and the biodistribution evaluated by gamma-well counting of excised organs. The expression of VCAM-1 in the ligated and contralateral arteries was evaluated by immunohistology. Results A robust VCAM-1 immunostaining was observed in ApoE-/- mice in the atherosclerotic lesions at the level of the left carotid whereas no VCAM-1 expression was detected in the contralateral carotid. Among the ten evaluated peptides, 99mTc-B2702p-1 exhibited the more favourable properties. By gamma-well counting, there was a significant 2.0-fold increase in 99mTc-B2702p-1 left-to-right carotid artery activity ratio (2.61±0.61) and a 3.4-fold increase in left carotid-to-blood activity ratio (1.41±0.36) in comparison to 99mTc-B2702p (1.32±0.23 and 0.41±0.09, respectively, P

Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected 99mTc-HMPAO-labeled hMSC in normal rats ( n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 ± 0.9 × 10−3 % of injected dose (ID)/g] than in the control group (3.6 ± 1.2 × 10−3 %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 ± 2.8 vs. 9.8 ± 1.7 × 10−3 %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.

International audience; Myocardial infarction induces contractile dysfunction and remodeling that can lead to heart failure. Nitric oxide has been proposed as one of the major actors of this pathophysiologic process. We note that N (G)-nitro-L-arginine methyl ester (L-NAME) administration from day 2 to day 7 after myocardial infarction in rats improves stroke volume, preserves cardiac compliance, and reduces infarct expansion. Our observations lead to the hypothesis that the mechanisms by which cytokines contribute to myocardial remodeling and dysfunction in the days after infarction might involve *NO signalling pathways.

IntroductionRecent advances in nuclear myocardial perfusion imaging (MPI) have provided opportunity for improved image information with an important reduction of exam time and radiation. This technology can be used to explore novel protocols (dual isotope high-speed MPI). Today, two devices exist: D-SPECT and Discovery NM 530c (DNM) camera. With D-SPECT, it was showed that rapid stress Tl-201/rest Tc-99m protocol for use with high-speed MPI has offered the superior qualities of Tl-201 for stress imaging and of the Tc-99m agents for rest imaging can be preserved. However, no study has evaluated the same dual-isotope protocol with the other system.MethodsA total of 38 consecutive patients underwent simultaneous dual-radionuclide (stress thallium-201/rest technetium-99m) perfusion imaging with a DNM camera and standard dual dectector camera (S-SPECT) during the month of May 2011.ResultsAll patients successfully underwent stress/rest MPI with both cameras. In 38 patients (50%) pharmacological stress was induced with dipyridamole. DNM SPECT SSS and SRS correlated linearly with conventional S-SPECT respective scores (r=0.84, p

BACKGROUND [18F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE-/-) mouse atherosclerotic lesion imaging with FDG. METHODS ApoE-/- mice (36 ± 2 weeks-old) were injected with FDG (12 ± 2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution. RESULTS Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P