Wolfgang M. Schaefer

Cardiac resynchronization therapyhomogenizes myocardial glucosemetabolism and perfusion in dilatedcardiomyopathy and left bundle branch block

Abstract Objectives We investigated whether cardiac resynchronization therapy (CRT) affects myocardial glucose metabolism and perfusion in dilated cardiomyopathy (DCM) and left bundle branch block (LBBB). Background Patients with DCM and LBBB present with asynchronous left ventricular (LV) activation, leading to reduced septal glucose metabolism. Cardiac resynchronization therapy recoordinates LV activation, but its effects on myocardial glucose metabolism and perfusion remain unknown. Methods In 15 patients (10 females; 61 ± 13 years) with DCM and LBBB (QRS width 165 ± 15 ms), gated 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and technetium-99m ( 99m Tc)-sestamibi single-photon emission computed tomography were performed before and after two weeks of CRT. Uptake of FDG and 99m Tc-sestamibi was determined in four LV wall areas. Ejection fraction and volumes were calculated from gated PET. Results Baseline FDG uptake was heterogeneous (p 99m Tc-sestamibi uptake was modest (lowest septal 65 ± 10%; maximum lateral 84 ± 5%) and also reduced with CRT, although some heterogeneity (p 99m Tc-sestamibi uptake (0.77 ± 0.13 to 0.85 ± 0.16, p Conclusions Glucose metabolism is reduced more than perfusion in the septal compared with LV lateral wall in patients with DCM and LBBB. Cardiac resynchronization therapy restores homogeneous myocardial glucose metabolism with less influence on perfusion.

EANM/ESC guidelines for radionuclide imaging of cardiac function

Radionuclide imaging of cardiac function represents a number of well-validated techniques for accurate determination of right (RV) and left ventricular (LV) ejection fraction (EF) and LV volumes. These first European guidelines give recommendations for how and when to use first-pass and equilibrium radionuclide ventriculography, gated myocardial perfusion scintigraphy, gated PET, and studies with non-imaging devices for the evaluation of cardiac function. The items covered are presented in 11 sections: clinical indications, radiopharmaceuticals and dosimetry, study acquisition, RV EF, LV EF, LV volumes, LV regional function, LV diastolic function, reports and image display and reference values from the literature of RVEF, LVEF and LV volumes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to “prevailing or general consensus”. The guidelines are designed to assist in the practice of referral to, performance, interpretation and reporting of nuclear cardiology studies for the evaluation of cardiac performance.

Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

OBJECTIVE Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. METHOD Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. RESULTS Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). CONCLUSIONS Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Myocardial viability assessment by endocardial electroanatomic mapping: comparison with metabolic imaging and functional recovery after coronary revascularization

OBJECTIVES The objective of this study was to compare electroanatomic mapping for the assessment of myocardial viability with nuclear metabolic imaging using positron emission computed tomography (PET) and with data on functional recovery after successful myocardial revascularization. BACKGROUND Animal experiments and first clinical studies suggested that electroanatomic endocardial mapping identifies the presence and absence of myocardial viability. METHODS Forty-six patients with prior (> or =2 weeks) myocardial infarction underwent fluorine-18 fluorodeoxyglucose (FDG) PET and Tc-99m sestamibi single-photon emission computed tomography (SPECT) before mapping and percutaneous coronary revascularization. The left ventricular endocardium was mapped and divided into 12 regions, which were assigned to corresponding nuclear regions. Functional recovery using the centerline method was assessed in 25 patients with a follow-up angiography. RESULTS Regional unipolar electrogram amplitude was 11.0 mV +/- 3.6 mV in regions with normal perfusion, 9.0 mV +/- 2.8 mV in regions with reduced perfusion and preserved FDG-uptake and 6.5 mV +/- 2.6 mV in scar regions (p < 0.001 for all comparisons). At a threshold amplitude of 7.5 mV, the sensitivity and specificity for detecting viable (by PET/SPECT) myocardium were 77% and 75%, respectively. In infarct areas with electrogram amplitudes >7.5 mV, improvement of regional wall motion (RWM) from -2.4 SD/chord +/- 1.0 SD/chord to -1.5 SD/chord +/- 1.1 SD/chord (p < 0.01) was observed, whereas, in infarct areas with amplitudes <7.5 mV, RWM remained unchanged at follow-up (-2.3 SD/chord +/- 0.7 SD/chord to -2.4 SD/chord +/- 0.7 SD/chord). CONCLUSIONS These data suggest that the regional unipolar electrogram amplitude is a marker for myocardial viability and that electroanatomic mapping can be used for viability assessment in the catheterization laboratory.

Positron Emission Tomography Study of Regional Cerebral Metabolism during General Anesthesia with Xenon in Humans

Background:The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory &ggr;-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans. Methods:The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using 18F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 &mgr;g/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping. Results:Xenon reduced whole-brain metabolic rate of glucose by 26 ± 7% (from 43 ± 5 &mgr;mol · 100 g−1 · min−1 to 31 ± 3 &mgr;mol · 100 g−1 · min−1; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia. Conclusions:Xenon induces metabolic depression in the human brain, suggesting that the inhibition of the glutamatergic system is likely to be of minor significance for the anesthetic action of xenon in vivo.

Indium-111 oxine labelling affects the cellular integrity of haematopoietic progenitor cells.

PurposeCell-based therapy by transplantation of progenitor cells has emerged as a promising development for organ repair, but non-invasive imaging approaches are required to monitor the fate of transplanted cells. Radioactive labelling with 111In-oxine has been used in preclinical trials. This study aimed to validate 111In-oxine labelling and subsequent in vivo and ex vivo detection of haematopoietic progenitor cells.MethodsMurine haematopoietic progenitor cells (106, FDCPmix) were labelled with 0.1 MBq (low dose) or 1.0 MBq (high dose) 111In-oxine and compared with unlabelled controls. Cellular retention of 111In, viability and proliferation were determined up to 48 h after labelling. Labelled cells were injected into the cavity of the left or right cardiac ventricle in mice. Scintigraphic images were acquired 24 h later. Organ samples were harvested to determine the tissue-specific activity.ResultsLabelling efficiency was 75±14%. Cellular retention of incorporated 111In after 48 h was 18±4%. Percentage viability after 48 h was 90±1% (control), 58±7% (low dose) and 48±8% (high dose) (p<0.0001). Numbers of viable cells after 48 h (normalised to 0 h) were 249±51% (control), 42±8% (low dose) and 32±5% (high dose) (p<0.0001). Cells accumulated in the spleen (86.6±27.0% ID/g), bone marrow (59.1±16.1% ID/g) and liver (30.3±9.5% ID/g) after left ventricular injection, whereas most of the cells were detected in the lungs (42.4±21.8% ID/g) after right ventricular injection.ConclusionRadiolabelling of haematopoietic progenitor cells with 111In-oxine is feasible, with high labelling efficiency but restricted stability. The integrity of labelled cells is significantly affected, with substantially reduced viability and proliferation and limited migration after systemic transfusion.

Effect of catheter-based transendocardial delivery of stromal cell-derived factor 1α on left ventricular function and perfusion in a porcine model of myocardial infarction

BackgroundMyocardial regeneration after myocardial infarction can occur via stem cell recruitment. Stromal cell-derived factor 1α (SDF-1α) has been shown to be critical for stem cell homing to injured tissue.MethodsMyocardial infarction was induced in pigs via microembolization of the distal left anterior descending artery. Two weeks after myocardial infarction animals underwent catheter-based transendocardial injection of SDF-1α into the periinfarct myocardium (18 injections, 5 ìg per injection) (n = 12) or sham-intervention (n = 8). Tc99m sestamibi single-photon emission computed tomography (SPECT) and electromechanical mapping (EMM) of the left ventricle were performed two and seven weeks after myocardial infarction.ResultsInfarct size by tetrazolium staining was similar in both groups (8.9 ±1.2% of left ventricle vs. 8.9 ± 2.6%). Vessel density in the periinfarct area was significantly higher in SDF-1α treated animals than in controls (349 ± 17/mm2 vs. 276 ± 21/mm2, p < 0.05). Myocardial perfusion (SPECT) did not change in either group. Ejection fraction and stroke volume (EMM) decreased in SDF-1α animals and increased in controls (difference between groups p = 0.05 for ejection fraction and p < 0.05 for stroke volume). Linear local shortening (EMM) did not change in controls (11.4 ± 1.3% to 11.5 ± 0.5%) but decreased significantly in SDF-1α treated animals (12.1 ± 0.9% to 8.4 ± 0.9%, p < 0.05, p < 0.05 for difference between groups). SDF-1 delivery was associated with a substantial loss of collagen in the periinfarct area (32±5% vs. 61±6% in control animals, p < 0.005).ConclusionA strategy to augment stem cell homing by catheter-based transendocardial delivery of SDF-1α in experimental myocardial infarction increases periinfarct vessel density, fails to improve myocardial perfusion, is associated with loss of collagen in the periinfarct area and impairs left ventricular function.

In vivo evidence of deep brain stimulation-induced dopaminergic modulation in Tourette's syndrome

To the Editor: D ue to its large effect size, deep brain stimulation (DBS) is progressively considered in the treatment of medicationresistant Tourette’s syndrome (TS) (1). Nevertheless, the underlying beneficial mechanisms of DBS in TS are still a matter of debate (2,3). Treatment strategies (D2-receptor antagonists) as well as previous research results point to a dysfunction of basal gangliarelated circuits and hyperactive dopaminergic innervations (4 – 8). It might thus be hypothesized that DBS acts via modulation of dopamine transmission; however, corresponding in vivo evidence is lacking, except for one positive single-patient [F]fallypride-positron emission tomography (FP) investigation (9). In fact, FP allows for quantification of D2/3-receptor availability in striatal and extrasriatal regions within a single positron emission tomography (PET) can but requires more than 3 hours of acquisition time. Because TS atients suffer from heavy motor tics, a long-term anesthesia was ecessary during the PET scan. Encouraged by the observation of elevant FP-binding changes within the pilot-investigation, we proeeded to enlarge the number of such investigations. This investigation was approved by the local ethics committee nd the German drug safety and radiation safety authorities. Three atients (two men, one woman) (Table 1) suffering from medicaion-resistant TS were investigated. The two male patients underent prior bilateral thalamic DBS in the pallidal and nigral input egions of the thalamus (Th). The female patient (Patient 3) underent a left-sided unilateral thalamic stimulation, because the leftided intraoperative test-stimulation revealed already-complete tic uppression (detailed electrode positions) (Table 2). They all responded with substantial improvements in the Yale Global Tic Severity Scale (YGTSS) (reductions of 30%– 80%) (Table 1). The PET scans were scheduled 6 months after the surgery. For an orientating comparison with stimulation-free conditions we used FP-PET results of eight age-matched healthy subjects (seven men/ one woman; age: 19 –29 years; mean SD: 23.6 3.8). The FP-radiosynthesis has been described previously (10). Each patient experienced two PET scans (first: “stimulator-on”; second: “stimulator-off”) under general propofol/remifentanil anesthesia of 4 –5 hours in duration (3 hours: FP-scan; 1 hour: anesthesia preparation; 1 hour: latency between stimulation deactivation and ligand injection [second scan]). Control subjects were scanned without

The quantification of dynamic FET PET imaging and correlation with the clinical outcome in patients with glioblastoma

The PET tracer O-(2-[18F]Fluoroethyl)-l-tyrosine (FET) has been shown to be valuable for different roles in the management of brain tumours. The aim of this study was to evaluate several quantitative measures of dynamic FET PET imaging in patients with resected glioblastoma. We evaluated dynamic FET PET in nine patients with histologically confirmed glioblastoma. Following FET PET, all subjects had radiation and chemotherapy. Tumour ROIs were defined by a threshold-based region-growing algorithm. We compared several standard measures of tumour uptake and uptake kinetics: SUV, SUV/background, distribution volume ratio (DVR), weighted frame differences and compartment model parameters. These measures were correlated with disease-free and overall survival, and analysed for statistical significance. We found that several measures allowed robust quantification. SUV and distribution volume did not correlate with clinical outcome. Measures that are based on a background region (SUV/BG, Logan-DVR) highly correlated with disease-free survival (r = -0.95, p < 0.0001), but not overall survival. Some advanced measures also showed a prognostic value but no improvement over the simpler methods. We conclude that FET PET probably has a prognostic value in patients with resected glioblastoma. The ratio of SUV to background may provide a simple and valuable predictive measure of the clinical outcome. Further studies are needed to confirm these explorative results.

Quantification of left ventricular volumes and ejection fraction from gated 99mTc-MIBI SPECT: validation of an elastic surface model approach in comparison to cardiac magnetic resonance imaging, 4D-MSPECT and QGS

PurposeThe segmentation algorithm ESM based on an elastic surface model was validated for the assessment of left ventricular volumes and ejection fraction from ECG-gated myocardial perfusion SPECT. Additionally, it was compared with the commercially available quantification packages 4D-MSPECT and QGS. Cardiac MRI was used as the reference method.MethodsSPECT and MRI were performed on 70 consecutive patients with suspected or proven coronary artery disease. End-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were derived from SPECT studies by using the segmentation algorithms ESM, 4D-MSPECT and QGS and from cardiac MRI.ResultsESM-derived values for EDV and ESV correlated well with those from cardiac MRI (correlation coeffients R = 0.90 and R = 0.95, respectively), as did the measurements for LVEF (R = 0.86). Both EDV and ESV were slightly overestimated for larger ventricles but not for smaller ventricles; LVEF was slightly overestimated irrespective of ventricle size. The above correlation coefficients are comparable to those for the 4D-MSPECT and QGS segmentation algorithms. However, results obtained with the three segmentation algorithms are not interchangeable.ConclusionThe ESM algorithm can be used to assess EDV, ESV and LVEF from gated perfusion SPECT images. Overall, the performance was similar to that of 4D-MSPECT and QGS when compared with cardiac MRI. Results obtained with the three tested segmentation methods are not interchangeable, so that the same algorithm should be used for follow-up studies and control subjects.