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Purpose: γ-H2AX and 53BP1 are fundamental for cellular DNA damage response (DDR) after radiation exposure and are linked to cell repair, arrest, or apoptosis. We aimed to evaluate whether DDR-markers in peripheral blood lymphocytes (PBLs) may have predictive potential for outcome in metastatic castration-resistant prostate cancer (mCRPC) patients receiving [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT)., Methods: We prospectively enrolled 20 men with advanced mCRPC scheduled for PSMA-targeted RLT. Prior to the first cycle of [ 177 Lu]Lu-PSMA RLT, all patients underwent [ 18 F]F-PSMA-1007 positron emission tomography (PET)/computed tomography (CT) for assessment of tumor PSMA expression (assessing maximum standardized uptake value (SUV max ) of all tumor lesions). Blood samples were collected prior to, + 1 h after, and + 24 h after administration of [ 177 Lu]Lu-PSMA, and DDR-markers γ-H2AX and 53BP1 were determined in PBLs through immunocytofluorescence. We then tested the predictive performance of DDR-markers relative to clinical and PET-based parameters for progressive disease (PSA-PD) after 2 cycles. In addition, the predictive value for progression-free survival (PSA-PFS, provided as median and 95% confidence interval [CI]) was explored., Results: Low baseline 53BP1 and γ-H2AX foci (P = 0.17) tended to predict early PSA-PD, whereas low SUV max was significantly associated with higher risk for PSA-PD (P = 0.04). In Kaplan-Meier analysis, there was a trend towards prolonged PSA-PFS in patients with higher baseline 53BP1 of 6 months (mo; 95%CI, 4-9 mo) compared to 3 mo in patients with low 53BP1 (95% CI, 2-3 mo; P = 0.12). Comparable results were recorded for higher γ-H2AX expression (6 mo [95% CI, 3-9 mo] relative to 3 mo [95% CI, 2-4 mo] in patients with low γ-H2AX; P = 0.12). SUV max , however, did not demonstrate predictive value (P = 0.29). Consistently, in univariate Cox-regression analysis, baseline 53BP1 foci demonstrated borderline significance for predicting PSA-PFS under [ 177 Lu]Lu-PSMA RLT (P = 0.05)., Conclusion: In this prospective study investigating mCRPC patients undergoing [ 177 Lu]Lu-PSMA RLT, low baseline DDR-markers in PBLs tended to predict poor outcome. Although the study group was small and results need further confirmation, these preliminary findings lay the foundation for exploring additive radiosensitizing or treatment intensification in future studies with high-risk individuals scheduled for RLT., (© 2022. The Author(s).)

Purpose: Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18 F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression., Methods: PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (V T ) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance., Results: In controls, V T was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean V T corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect., Conclusion: Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity., (© 2021. The Author(s).)

Purpose: Hematotoxicity is a potentially dose-limiting adverse event in patients with metastasized castration-resistant prostate cancer (mCRPC) undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT). We aimed to identify clinical or PSMA-targeted imaging-derived parameters to predict hematological adverse events at early and late stages in the treatment course., Methods: In 67 patients with mCRPC scheduled for 177 Lu-PSMA-617 RLT, pretherapeutic osseous tumor volume (TV) from 68 Ga-PSMA-11 PET/CT and laboratory values were assessed. We then tested the predictive capability of these parameters for early and late hematotoxicity (according to CTCAE vers. 5.0) after one cycle of RLT and in a subgroup of 32/67 (47.8%) patients after four cycles of RLT., Results: After one cycle, 10/67 (14.9%) patients developed leukocytopenia (lymphocytopenia, 39/67 [58.2%]; thrombocytopenia, 17/67 [25.4%]). A cut-off of 5.6 × 10 3 /mm 3 for baseline leukocytes was defined by receiver operating characteristics (ROC) and separated between patients with and without leukocytopenia (P < 0.001). Baseline leukocyte count emerged as a stronger predictive factor in multivariate analysis (hazard ratio [HR], 33.94, P = 0.001) relative to osseous TV (HR, 14.24, P = 0.01). After four cycles, 4/32 (12.5%) developed leukocytopenia and the pretherapeutic leukocyte cut-off (HR, 9.97, P = 0.082) tended to predict leukocytopenia better than TV (HR, 8.37, P = 0.109). In addition, a cut-off of 1.33 × 10 3 /mm 3 for baseline lymphocytes separated between patients with and without lymphocytopenia (P < 0.001), which was corroborated in multivariate analysis (HR, 21.39, P < 0.001 vs. TV, HR, 4.57, P = 0.03). After four cycles, 19/32 (59.4%) developed lymphocytopenia and the pretherapeutic cut-off for lymphocytes (HR, 46.76, P = 0.007) also demonstrated superior predictive performance for late lymphocytopenia (TV, HR, 5.15, P = 0.167). Moreover, a cut-off of 206 × 10 3 /mm 3 for baseline platelets separated between patients with and without thrombocytopenia (P < 0.001) and also demonstrated superior predictive capability in multivariate analysis (HR, 115.02, P < 0.001 vs.TV, HR, 12.75, P = 0.025). After four cycles, 9/32 (28.1%) developed thrombocytopenia and the pretherapeutic cut-off for platelets (HR, 5.44, P = 0.048) was also superior for the occurrence of late thrombocytopenia (TV, HR, 1.44, P = 0.7)., Conclusions: Pretherapeutic leukocyte, lymphocyte, and platelet levels themselves are strong predictors for early and late hematotoxicity under PSMA-directed RLT, and are better suited than PET-based osseous TV for this purpose., (© 2021. The Author(s).)

Purpose: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18 F-GE-180. This study tested simplified methods for quantification of 18 F-GE-180 PET., Methods: Dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18 F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18 F-GE-180 distribution volume (V T ) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed., Results: Correlation with the reference V T (with individually measured input function) was very high for V T with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for V T with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference V T , population-based V T with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based V T with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect., Conclusion: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18 F-GE-180 PET.

Purpose: Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI., Methods: C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology., Results: Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation., Conclusions: Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

Purpose: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4 + cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [ 68 Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT., Methods: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [ 68 Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared., Results: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68 + inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUV max 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUV max 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUV max 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability., Conclusion: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque.

Purpose: [ 68 Ga]Tris(hydroxypyridinone)(THP)-PSMA is a novel radiopharmaceutical for one-step kit-based radiolabelling, based on direct chelation of 68 Ga 3+ at low concentration, room temperature and over a wide pH range, using direct elution from a 68 Ge/ 68 Ga-generator. We evaluated the clinical detection rates of [ 68 Ga]THP-PSMA PET/CT in patients with biochemically recurrent prostate cancer after prostatectomy., Methods: Consecutive patients (n=99) referred for evaluation of biochemical relapse of prostate cancer by [ 68 Ga]THP-PSMA PET/CT were analyzed retrospectively. Patients underwent a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified cohorts of positive PET/CT results, standardized uptake values (SUVs) and target-to-background ratios (TBRs) were analyzed, and compared between standard and delayed imaging., Results: At least one lesion suggestive of recurrent or metastatic prostate cancer was identified on PET images in 52 patients (52.5%). Detection rates of [ 68 Ga]THP-PSMA PET/CT increased with increasing PSA level: 94.1% for a PSA value of ≥10 ng/mL, 77.3% for a PSA value of 2 to <10 ng/mL, 54.5% for a PSA value of 1 to <2 ng/mL, 14.3% for a PSA value of 0.5 to <1 ng/mL, 20.0% for a PSA value of >0.2 to <0.5, and 22.2% for a PSA value of 0.01 to 0.2 ng/mL. [ 68 Ga]THP-PSMA uptake (SUVs) in metastases decreased over time, whereas TBRs improved. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 2% of [ 68 Ga]THP-PSMA PET/CT scans. Detection rate was higher in patients with a Gleason score ≥8 (P=0.02) and in patients receiving androgen deprivation therapy (P=0.003)., Conclusions: In this study, [ 68 Ga]THP-PSMA PET/CT showed suitable detection rates in patients with biochemical recurrence of prostate cancer and PSA levels ≥ 2 ng /mL. Detections rates were lower than in previous studies evaluating other PSMA ligands, though prospective direct radiotracer comparison studies are mandatory particularly in patients with low PSA levels to evaluate the relative performance of different PSMA ligands.

Purpose: The aim of this study was to assess the value of dual-time point imaging in PET/CT for detection of biochemically recurrent or persistent prostate cancer, using the prostate-specific membrane antigen (PSMA) ligand [ 68 Ga]PSMA I&T., Methods: 240 patients who underwent a [ 68 Ga]PSMA I&T PET/CT in the context of biochemical relapse of prostate cancer were included in this retrospective analysis. Imaging consisted of a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified proportions of positive PET/CT results, standardized uptake values and target-to-background ratios were analyzed, and compared between standard and delayed imaging., Results: The overall detection rates of [ 68 Ga]PSMA I&T PET/CT were 94.2, 71.8, 58.6, 55.9 and 38.9% for PSA levels of ≥2, 1 to <2, 0.5 to <1, >0.2 to <0.5, and 0.01 to 0.2 ng/mL, respectively. Although the target-to-background ratio improved significantly over time (P < 0.0001), the majority (96.6%) of all lesions suggestive of recurrent disease could already be detected in standard imaging. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 5.4% (10/184) of abnormal [ 68 Ga]PSMA I&T PET/CT scans, and exclusively detected 3.4% (38/1134) of all lesions suggestive of recurrent disease., Conclusions: [ 68 Ga]PSMA I&T PET/CT shows high detection rates in patients with prostate-specific antigen persistence or biochemical recurrence of prostate cancer. Delayed imaging can detect lesions with improved contrast compared to standard imaging. However, the impact on detection rates was limited in this study.

Purpose: Continuous bed motion has recently been introduced for whole-body PET/CT, and represents a paradigm shift towards individualized and flexible acquisition without the limitations of bed position-based planning. Increased patient comfort due to lack of abrupt table position changes may be another albeit still unproven advantage. For robust clinical implementation, image quality and quantitative accuracy should at least be equal to the prior standard of bed position-based step-and-shoot imaging., Methods: The study included 68 consecutive patients referred for whole-body PET/CT for various malignancies. The patients underwent traditional step-and-shoot and novel continuous bed motion acquisition in the same session in a randomized crossover design. The patients and two independent observers were blinded to the sequence of scan techniques. Patient comfort/satisfaction was examined using a standardized questionnaire. SUVs were compared for reference tissue (liver, muscle) and tumour lesions. PET image quality and misalignment with CT images were evaluated on a scale of 1 - 4., Results: Patients preferred continuous bed motion over step-and-shoot (P = 0.0001). It was considered to be more relaxing (38 % vs. 8 %), quieter (34 % vs. 8 %), and more fluid (64 % vs. 8 %). Image quality, SUV and CT misalignment did not differ between the techniques. Continuous bed motion resulted in better end-plane image quality (P < 0.0001). Regardless of the technique, second examinations had significantly higher tumour lesion SUVmax values (P = 0.0002), and a higher CT misalignment score (P = 0.0017)., Conclusion: Oncological PET/CT with continuous bed motion enhances patient comfort and is associated with image quality at least comparable to that with traditional bed position-based step-and-shoot acquisition.qq.

Purpose: IQ-SPECT, an add-on to general purpose cameras based on multifocal collimation, can reduce myocardial perfusion imaging (MPI) acquisition times to one-fourth that of standard procedures (to 12 s/view). In a phantom study, a reduction of the acquisition time to one-eighth of the standard time (to 6 s/view) was demonstrated as feasible. It remains unclear whether such a reduction could be extended to clinical practice., Methods: Fifty patients with suspected or diagnosed CAD underwent a 2-day stress-rest (99m)Tc-sestamibi MPI protocol. Two consecutive SPECT acquisitions (6 and 12 s/view) were performed. Electrocardiogram-gated images were reconstructed with and without attenuation correction (AC). Polar maps were generated and visually scored by two blinded observers for image quality and perfusion in 17 segments. Global and regional summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) were determined. Left ventricular volumes and ejection fraction were calculated based on automated contour detection., Results: Image quality was scored higher with the 12 s/view acquisition, both with and without AC. Summed scores were statistically comparable between the 6 s/view and the 12 s/view acquisition, both globally and in individual coronary territories (e.g. in images with AC, SSS were 6.6 ± 8.3 and 6.2 ± 8.2 with 6 s and 12 s/view, respectively, p = 0.10; SRS were 3.9 ± 5.6 and 3.5 ± 5.3, respectively, p = 0.19; and SDS were 2.8 ± 5.7 and 2.6 ± 5.7, respectively, p = 0.59). Both acquisitions allowed MPI-based diagnosis of CAD in 25 of the 50 patients (with AC). Calculated end-diastolic volume (EDV) and end-systolic volume (ESV) were modestly higher with the 6 s/view acquisition than with the 12 s/view acquisition (EDV +4.8 ml at rest and +3.7 ml after stress, p = 0.003; ESV +4.1 ml at rest and +2.6 ml after stress, p = 0.01), whereas the ejection fraction did not differ (-1.2 % at rest, p = 0.20, and -0.9 % after stress, p = 0.27)., Conclusion: Image quality and LV functional parameters obtained with a one-eighth acquisition time were statistically comparable to the previously validated one-fourth time protocol using IQ-SPECT. Shorter acquisition times without loss of diagnostic accuracy provide improved patient comfort and streamlined departmental efficiency.

Since the publication of the European Association of Nuclear Medicine (EANM) procedural guidelines for radionuclide myocardial perfusion imaging (MPI) in 2005, many small and some larger steps of progress have been made, improving MPI procedures. In this paper, the major changes from the updated 2015 procedural guidelines are highlighted, focusing on the important changes related to new instrumentation with improved image information and the possibility to reduce radiation exposure, which is further discussed in relation to the recent developments of new International Commission on Radiological Protection (ICRP) models. Introduction of the selective coronary vasodilator regadenoson and the use of coronary CT-contrast agents for hybrid imaging with SPECT/CT angiography are other important areas for nuclear cardiology that were not included in the previous guidelines. A large number of minor changes have been described in more detail in the fully revised version available at the EANM home page: http://eanm.org/publications/guidelines/2015&#95;07&#95;EANM&#95;FINAL&#95;myocardial&#95;perfusion&#95;guideline.pdf .

Purpose: Myelofibrosis is a haematopoietic stem cell neoplasm characterized by bone marrow inflammation, reactive marrow fibrosis and extramedullary haematopoiesis. The aim of this study was to determine if (18)F-FDG PET/CT can be used to noninvasively visualize and quantify the extent and activity of bone marrow involvement., Methods: In 30 patients, the biodistribution of (18)F-FDG was analysed by measuring the standardized uptake value in the bone marrow compartment and spleen. Imaging findings were compared with laboratory, cytogenetic and histopathological data., Results: Retention of (18)F-FDG was observed in bone marrow and spleen. Bone marrow involvement varied, ranging from mildly increased uptake in the central skeleton to extensive uptake in most parts of the skeleton. The extent of bone marrow involvement decreased over time from initial diagnosis (r s  = -0.43, p = 0.019). Metabolic activity of the bone marrow decreased as the histopathological grade of fibrosis increased (r s  = -0.37, p = 0.04). There was a significant positive correlation between the metabolic activity of the bone marrow and that of the spleen (p = 0.04)., Conclusion: (18)F-FDG PET/CT is as a promising technique for the quantitation of bone marrow inflammation in myelofibrosis. Our data indicate that the intensity of bone marrow (18)F-FDG uptake decreases as bone marrow fibrosis increases. Further evaluation in prospective studies is required to determine the potential clinical impact and prognostic significance of PET.

Purpose: Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been employed, but requires an approach for suppression of cardiomyocyte uptake. We tested clinically viable strategies for their suitability in mouse models in order to optimize preclinical imaging protocols., Methods: C57BL/6 mice (n = 56) underwent FDG PET under various conditions. In healthy animals, the effect of low-dose (5 units/kg) or high-dose (500 units/kg, 15 min prior) intravenous heparin, extended fasting (18 h) and the impact of conscious injection with limited, late application of isoflurane anaesthesia after 40 min of conscious uptake were examined in comparison to ketamine/xylazine anaesthesia. Conscious injection/uptake strategies were further evaluated at 3 days after permanent coronary artery occlusion., Results: Under continuous isoflurane anaesthesia, neither heparin administration nor extended fasting significantly impacted myocardial (18)F-FDG accumulation. Injection with 40 min uptake in awake mice resulted in a marked reduction of global myocardial (18)F-FDG uptake compared to standard isoflurane anaesthesia (5.7 ± 1.1 %ID/g vs 30.2 ± 7.9 %ID/g, p < 0.01). Addition of heparin and fasting further reduced uptake compared to conscious injection alone (3.8 ± 1.5 %ID/g, p < 0.01) similar to ketamine/xylazine (2.4 ± 2.2 %ID/g, p < 0.001). In the inflammatory phase, 3 days after myocardial infarction, conscious injection/uptake with and without heparin/fasting identified a marked increase in myocardial (18)F-FDG accumulation that was similar to that observed under ketamine/xylazine., Conclusion: Continuous isoflurane anaesthesia obscures any suppressive effect of heparin or fasting on cardiomyocyte glucose utilization. Conscious injection of FDG in rodents significantly reduces cardiomyocyte uptake and enables further suppression by heparin and fasting, similar to clinical observations. In contrast to ketamine/xylazine, this represents a more physiological, translatable strategy for suppression of cardiomyocyte (18)F-FDG uptake when targeting myocardial inflammation.

Unlabelled: Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. (18)F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by (68)Ga-citrate and somatostatin receptor binding by (68)Ga-DOTATATE., Methods: C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 - 7 days after MI using (68)Ga-citrate, (68)Ga-DOTATATE, or (18)F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by (13)N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT., Results: Mice exhibited a perfusion defect of 30 - 40% (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. (18)F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). (68)Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). (68)Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03)., Conclusion: Neither (68)Ga nor (68)Ga-DOTATATE is a useful alternative to (18)F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, (18)F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.

Purpose: In clinical cardiac (82)Rb PET, globally impaired coronary flow reserve (CFR) is a relevant marker for predicting short-term cardiovascular events. However, there are limited data on the impact of different software and methods for estimation of myocardial blood flow (MBF) and CFR. Our objective was to compare quantitative results obtained from previously validated software tools., Methods: We retrospectively analyzed cardiac (82)Rb PET/CT data from 25 subjects (group 1, 62 ± 11 years) with low-to-intermediate probability of coronary artery disease (CAD) and 26 patients (group 2, 57 ± 10 years; P=0.07) with known CAD. Resting and vasodilator-stress MBF and CFR were derived using three software applications: (1) Corridor4DM (4DM) based on factor analysis (FA) and kinetic modeling, (2) 4DM based on region-of-interest (ROI) and kinetic modeling, (3) MunichHeart (MH), which uses a simplified ROI-based retention model approach, and (4) FlowQuant (FQ) based on ROI and compartmental modeling with constant distribution volume., Results: Resting and stress MBF values (in milliliters per minute per gram) derived using the different methods were significantly different: using 4DM-FA, 4DM-ROI, FQ, and MH resting MBF values were 1.47 ± 0.59, 1.16 ± 0.51, 0.91 ± 0.39, and 0.90 ± 0.44, respectively (P<0.001), and stress MBF values were 3.05 ± 1.66, 2.26 ± 1.01, 1.90 ± 0.82, and 1.83 ± 0.81, respectively (P<0.001). However, there were no statistically significant differences among the CFR values (2.15 ± 1.08, 2.05 ± 0.83, 2.23 ± 0.89, and 2.21 ± 0.90, respectively; P=0.17). Regional MBF and CFR according to vascular territories showed similar results. Linear correlation coefficient for global CFR varied between 0.71 (MH vs. 4DM-ROI) and 0.90 (FQ vs. 4DM-ROI). Using a cut-off value of 2.0 for abnormal CFR, the agreement among the software programs ranged between 76 % (MH vs. FQ) and 90 % (FQ vs. 4DM-ROI). Interobserver agreement was in general excellent with all software packages., Conclusion: Quantitative assessment of resting and stress MBF with (82)Rb PET is dependent on the software and methods used, whereas CFR appears to be more comparable. Follow-up and treatment assessment should be done with the same software and method.

Purpose: (11)C-Hydroxyephedrine (HED) and radioiodinated metaiodobenzylguanidine ((123)I/(131)I-MIBG) are catecholamine analogue tracers for sympathetic nerve positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging. In contrast to humans, rat hearts demonstrate high nonneural catecholamine uptake-2 in addition to neural uptake-1, the contributions of which to tracer accumulation are not fully elucidated., Methods: Wistar rats were studied using the following pretreatments: uptake-1 blockade with desipramine 2 mg/kg IV, both uptake-1 and -2 blockade with phenoxybenzamine 50 mg/kg IV, or control with saline IV. HED or (123)I-MIBG was injected 10 min after pretreatment, and rats were sacrificed 10 min later. Heart to blood tissue count ratio (H/B ratio) was obtained using a gamma counter. To determine regional tracer uptake, dual-tracer autoradiography was performed with HED and (131)I-MIBG in Wistar rats with chronic infarction by transient coronary occlusion and reperfusion and in healthy control rats. Local tracer distributions were analyzed, and the infarcted rats' local tracer distributions were compared with histology., Results: The H/B ratios in control hearts were 34.4 ± 1.7 and 25.5 ± 2.1 for HED and (123)I-MIBG, respectively. Desipramine led to a significant decrease in HED (3.2 ± 0.5, p < 0.0001), while there was no change in (123)I-MIBG (25.5 ± 6.4, p = n.s.). Phenoxybenzamine led to a significant decrease in both HED and (123)I-MIBG (3.5 ± 0.02, 4.3 ± 0.7, p < 0.0001). Only HED showed a subepicardium-subendocardium gradient in healthy control hearts which is consistent with physiological innervation, while (131)I-MIBG was evenly distributed throughout the myocardium. (131)I-MIBG uptake defect closely matched the scar area determined by histology [3.8 ± 2.3% ((131)I-MIBG defect) vs 4.0 ± 2.4% (scar)]. However, the scar area was clearly exceeded by the HED uptake defect (9.1 ± 2.2%, p < 0.001)., Conclusion: HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.

Purpose: We compared the quality, interpretive confidence and interreader agreement between SPECT and PET myocardial perfusion imaging (MPI) in the same group of patients., Methods: The study group comprised 27 patients (age 55 ± 8.5 years, 12 men) with known or suspected coronary artery disease (CAD) who had undergone gated rest/stress MPI with (99m)Tc-labelled agent SPECT (with and without attenuation correction, AC), and subsequent clinical confirmation with (82)Rb PET. Three experienced readers blinded to the clinical information interpreted all MPI studies., Results: Interreader agreement was significantly superior for PET studies than for SPECT studies. Following consensus interpretation, the quality of 22 % of the non-AC SPECT studies, 33 % of the AC SPECT studies and 63 % of the PET studies was assessed as excellent or good (p = 0.016). Interpretations were definitely normal or abnormal in 7 % of non-AC SPECT studies, 30 % of AC SPECT studies and 85 % of PET studies (p = 0.046). In 13 patients who had received either invasive coronary angiography or CT angiography with no significant CAD, the true-positive rate for significant CAD was higher for PET, and the true-negative rate was equal for PET and AC SPECT, and lower for non-AC SPECT., Conclusion: (82)Rb PET MPI, used as a confirmatory test after SPECT, offers improved image quality, interpretive confidence and interreader agreement.

Background: Regadenoson is a novel selective A2A adenosine receptor agonist, which is administered as an intravenous bolus at a fixed dose. It is currently not clear if the absolute flow increase in response to this fixed dose is a function of distribution volume in individual patients or if it is generally comparable to the previous standard agents dipyridamole or adenosine, which are dosed based on weight. We used quantitative analysis of clinical 82Rb PET/CT studies to obtain further insights., Methods: A total of 104 subjects with normal clinical rest/stress 82Rb perfusion PET/CT were included in a retrospective analysis. To rule out confounding factors, none had evidence of prior cardiac disease, ischaemia or infarction, cardiomyopathy, diabetes with insulin use, calcium score>400, renal disease or other significant systemic disease. A group of 52 patients stressed with regadenoson were compared with a group of 52 patients stressed with dipyridamole before regadenoson became available. The groups were matched for clinical characteristics, risk factors and baseline haemodynamics. Myocardial blood flow (MBF) and myocardial flow reserve (MFR) were quantified using a previously validated retention model, after resampling of dynamic studies from list-mode 82Rb datasets., Results: At rest, heart rate, blood pressure and MBF were comparable between the groups. Regadenoson resulted in a significantly higher heart rate (34±14 vs. 23±10 beats per minute increase from baseline; p<0.01) and rate-pressure product. Patients in the regadenoson group reported less severe symptoms and required less aminophylline. Stress MBF and MFR were not different between the groups (2.2±0.6 vs. 2.1±0.6 ml/min/g, p=0.39, and 2.9±0.8 vs. 2.8±0.7, p=0.31, respectively). In the regadenoson group, there was no correlation between stress flow or MFR and body weight or BMI., Conclusion: Despite its administration at a fixed dose, regadenoson results in an absolute increase in MBF which is comparable to that following dipyridamole administration and is independent of patient distribution volume. This further supports its usefulness as a clinical stress agent.

Purpose: Since 2006, the working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine, in cooperation with the working group Nuclear Cardiology of the German Cardiac Society, has been surveying the utilization and technical realization of myocardial perfusion scintigraphy (MPS) in Germany. This paper presents the results of the reporting year 2009., Methods: A total of 291 centres participated in the inquiry, including 179 private practices (PP), 86 hospitals (HO) and 26 university hospitals (UH)., Results: MPS of 98,103 patients were reported. The MPS numbers per million population (pmp) were estimated at 2,360; 76% of the MPS were performed in PP, 17% in HO and 7% in UH. The ratio of MPS to coronary angiography to revascularization was 0.5 to 2.3 to 1. Data from 134 centres which participated in the surveys from 2005 to 2009 showed a decrease in MPS utilization of 2.2%. Nearly half of the MPS were requested by ambulatory care cardiologists. Of all MPS studies, 89% were conducted with (99m)Tc perfusion tracers. Ergometry was the preferred stress test (69%). Adenosine was used in 16%, adenosine + exercise in 7%, dipyridamole in 3%, dipyridamole + exercise in 5% and dobutamine in <1%. Gated single proton emission computed tomography (SPECT) acquisition was performed in 56% of all rest MPS and in 56% of all stress MPS. Both rest and stress MPS were ECG gated in 41%. Only 33% of the centres always performed a quantification of the perfusion studies, whereas 51% did not apply any quantification; 4% of the MPS studies were corrected for attenuation, and 17 centres used transmission sources of 12 CT-based systems., Conclusion: A scan activity of 2,380 MPS pmp is in the upper third of the European range. The ratios to coronary angiography and to revascularization suggest that angiography dominates diagnosis and management of coronary artery disease (CAD). The clinical and technical realizations reveal that the predominant goals of further trainings to optimize MPS are in the field of gated SPECT and quantitative perfusion SPECT.

Purpose: Myocardial washout of the potassium analogue (82)Rb may indicate tissue impairment. Few studies have evaluated its usefulness for viability assessment, and controversial results were reported. We revisited this topic using list-mode positron emission tomography (PET)/CT., Methods: A total of 22 patients with chronic ischemic cardiomyopathy (ICM) and 11 control subjects with normal CT coronary angiogram were studied. Rest (82)Rb PET/CT studies were acquired in list mode and resampled to static, gated, and dynamic images. Using a 17-segment model, (82)Rb washout was determined by monoexponential fitting of myocardial time-activity curves. In ICM patients, (18)F-fluorodeoxyglucose (FDG) studies were obtained in the same session and segments were classified as normally perfused, mismatch, or matched defect., Results: (82)Rb washout was minimal and homogeneous in control subjects. Normally perfused segments of ICM did not differ (p = 0.33). ICM patients had a left ventricular ejection fraction (LVEF) of 25 ± 12%, 25/353 mismatched, and 46/353 matched defect segments. (82)Rb washout was higher in hypoperfused vs normal segments (p < 0.05), but not different between mismatch and matched defect (p = 0.18). Intraindividual analysis in nine patients showing both FDG mismatch and matched defect confirmed absence of differences. Overall, segmental (82)Rb washout correlated inversely with (82)Rb uptake (r = -0.70; p < 0.05) and less well with FDG uptake (r = -0.31; p < 0.05)., Conclusion: Using state-of-the-art PET/CT technology for myocardial viability assessment, (82)Rb washout does not distinguish between perfusion/metabolism patterns of hibernating myocardium and scar. Tissue integrity may be at least partially impaired in hibernation.

Purpose: PET perfusion imaging with (82)Rb is a powerful tool for evaluating coronary artery disease (CAD). Little is known about normal patterns or significance of (82)Rb lung distribution in the setting of heart disease. Herein, PET/CT hybrid imaging was used to obtain insights into the frequency and potential radiomorphologic correlates of altered (82)Rb distribution., Methods: Myocardial perfusion PET/CT studies of 58 patients referred for workup of CAD were analyzed [28 normal and 30 patients with low left ventricular ejection fraction (LVEF)]. Organ regions of interest were placed on PET images, and (82)Rb uptake was measured and compared under resting and stress conditions., Results: Qualitatively increased lung uptake was observed in 13 patients-5 with normal LVEF(R) and 8 with reduced LVEF(R); 12 of 13 had lung infiltrates/atelectasis on CT. Lung to heart ratios in the normal and low EF groups were (mean ± SD) 0.168 ± 0.047 and 0.171 ± 0.075 at rest, and 0.128 ± 0.035 and 0.147 ± 0.067 during stress (p = 0.87 and 0.18, respectively). Lung to liver ratios were not significantly different between the two groups under stress or rest conditions., Conclusion: Increased lung uptake of (82)Rb occurs in a subset of patients referred for workup of CAD by PET/CT and may be influenced by primary parenchymal abnormalities and LV dysfunction. Thus, the relevance of pulmonary (82)Rb uptake as a marker of cardiac outcome may be limited. Larger studies are needed to determine how non-cardiac (82)Rb uptake and CT findings may be integrated to increase the diagnostic and prognostic value of cardiac PET/CT.

Improvements in software and hardware have enabled the integration of dual imaging modalities into hybrid systems, which allow combined acquisition of the different data sets. Integration of positron emission tomography (PET) and computed tomography (CT) scanners into PET/CT systems has shown improvement in the management of patients with cancer over stand-alone acquired CT and PET images. Hybrid cardiac imaging either with single photon emission computed tomography (SPECT) or PET combined with CT depicts cardiac and vascular anatomical abnormalities and their physiologic consequences in a single setting and appears to offer superior information compared with either stand-alone or side-by-side interpretation of the data sets in patients with known or suspected coronary artery disease (CAD). Hybrid systems are also advantageous for the patient because of the single short dual data acquisition. However, hybrid cardiac imaging has also generated controversy with regard to which patients should undergo such integrated examination for clinical effectiveness and minimization of costs and radiation dose, and if software-based fusion of images obtained separately would be a useful alternative. The European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC) in this paper want to present a position statement of the institutions on the current roles of SPECT/CT and PET/CT hybrid cardiac imaging in patients with known or suspected CAD.

Purpose: Absolute quantification of myocardial blood flow expands the diagnostic potential of PET for assessment of coronary artery disease. (82)Rb has significantly contributed to increasing utilization of PET; however, clinical studies are still mostly analysed qualitatively. The aim of this study was to reevaluate the feasibility of (82)Rb for flow quantification, using hybrid PET-CT in an animal model of coronary stenosis., Methods: Nine dogs were prepared with experimental coronary artery stenosis. Dynamic PET was performed for 8 min after (82)Rb(1480-1850 MBq) injection during adenosine-induced vasodilation. Microspheres were injected simultaneously for reference flow measurements. CT angiography was used to determine the myocardial regions related to the stenotic vessel. Two methods for flow calculation were employed: a two-compartment model including a spill-over term, and a simplified retention index., Results: The two-compartment model data were in good agreement with microsphere flow (y = 0.84x + 0.20; r = 0.92, p<0.0001), although there was variability in the physiological flow range <3 ml/g per minute (y = 0.54x + 0.53; r = 0.53, p = 0.042). Results from the retention index also correlated well with microsphere flow (y = 0.47x + 0.52; r = 0.75, p = 0.0004). Error increased with higher flow, but the correlation was good in the physiological range (y = 0.62x + 0.29; r = 0.84, p = 0.0001)., Conclusion: Using current state-of-the-art PET-CT systems, quantification of myocardial blood flow is feasible with (82)Rb. A simplified approach based on tracer retention is practicable in the physiological flow range. These results encourage further testing of the robustness and usefulness in the clinical context of cardiac hybrid imaging.

Purpose: Myocardial perfusion imaging with (82)Rb PET allows for ECG-gated studies to be obtained early after radiotracer injection, capturing ventricular function close to peak pharmacologic action of dipyridamole. This is different from gated SPECT and may potentially provide additional diagnostic information. We sought to identify potential correlates of the PET-derived ejection fraction response to vasodilator stress., Methods: One hundred ten consecutive patients undergoing (82)Rb PET myocardial perfusion imaging during evaluation for coronary artery disease were included. Using a GE Discovery STRx PET-CT scanner, ECG-gated images (eight bins) were obtained at rest and 4 min after dipyridamole infusion, 90 s after infusion of 1,480-2,220 MBq of (82)Rb. Summed rest, stress, and difference scores (SRS, SSS, and SDS) were determined using a five-point scoring system and 20-segment model. Ejection fraction was calculated using automated QGS software., Results: Significant reversibility (SDS > or = 4) was found in 23 patients (21%). Mean LVEF in all patients was 47 +/- 13% at rest and 53 +/- 13% during dipyridamole. LVEF increased in 89 patients, and decreased in 17 patients during vasodilation. The change in LVEF was inversely correlated with SDS (r = -0.26; p = 0.007). Additionally, it was inversely correlated with resting LVEF (r = -0.20; p = 0.03) and SSS (r = -0.25; p = 0.009). No significant correlations were observed with SRS, heart rate, blood pressure, age, hypertension, hypercholesterolemia, or pretest likelihood of disease. At multivariate regression analysis, SDS was an independent predictor of the change in LVEF., Conclusions: Gated (82)Rb PET during pharmacologic stress allows for assessment of the functional response to vasodilation. The magnitude of LVEF increase is determined by stress perfusion/reversible perfusion defects. Functional response to hyperemia may thus be incorporated in future evaluations of diagnostic and prognostic algorithms based on (82)Rb PET.

Purpose: Misalignment of low-dose-CT used for attenuation correction (AC) may cause artifacts in cardiac-PET-CT. The aim was to evaluate incidence and severity of misalignment and its quantitative effects on regional myocardial (82)Rb-distribution., Methods: Rest/dipyridamole (82)Rb-perfusion-PET-CT studies of 92 consecutive patients were analyzed for misalignment. Two different scanning protocols were employed: the first 57 patients had separate CTs for rest and stress PET. The following 35 patients had one CT at rest, used for AC of rest and stress PET. Misalignment was visually scored on a five-point scale (0 = no, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe). In five representative patients with normal perfusion and low probability of disease, 95 polarmaps were created by shifting CT vs PET prior to reconstruction of attenuation-corrected data sets using dedicated software (three dimensions of space; magnitude of shifts, 5, 10, 14 mm)., Results: PET/CT -misalignment was detected in 60% of rest and 67% of stress studies. Alignment for rest was better than that for stress (0.7 +/- 0.7 vs 1.0 +/- 0.9, P = 0.03). Comparison of the two protocols revealed no effect on the alignment of the stress study (1.0 +/- 0.9 vs 1.0 +/- 0.9, P = 0.9). Quantitatively, the largest individual effect of any artificial misalignment was a 25% reduction of relative (82)Rb uptake. With a shift of 1 cm, the largest effect in an individual was a 19% decrease. Anterior wall was most frequently influenced by misalignment, but changes of uptake also occurred in all other segments., Conclusions: Misalignment between CT and PET in cardiac-PET-CT influences regional tracer distribution in multiple segments. Repeated CT imaging after dipyridamole does not improve alignment. These results emphasize the need for strategies to improve coregistration in clinical imaging protocols.

Purpose: CT-based attenuation correction may influence cardiac PET owing to its higher susceptibility to misalignment compared with conventional (68)Ge transmission scans. The aims of this study were to evaluate whether CT attenuation correction leads to changes in tracer distribution compared with conventional cardiac PET and to determine a suitable CT protocol., Methods: A total of 27 patients underwent PET/CT and subsequently a PET scan. Twenty patients received a low-dose CT (LDCT group; 120 kV, 26 mA, 8-s scan time), seven patients a slow CT (SCT group; 120 kV, 99 mA, 46-s scan time) and ten patients an ultra-low-dose CT (ULDCT group; 80 kV, 13 mA, 5-s scan time) as the transmission scan in PET/CT. Polar maps were divided into 17 segments and regression analysis was computed in every scan pair (CT attenuation corrected-(68)Ge attenuation corrected). Correlation coefficient (r), the slope (s) and the offset (os) of the regression line were determined. Visual assessment of misalignment between the transmission and emission data was performed. The effective dose of the different transmission scans was calculated., Results: Overall, there was a moderate correlation between the mean values measured in all segments on PET/CT and on PET when using LDCT (r=0.78, p<0.0001), SCT (r=0.79, p<0.0001) and ULDCT (r=0.82, p<0.0001). No differences were observed when comparing the scores assigned in the visual misalignment assessment in the three groups (p=0.12). The differences between the results from the regression analysis observed in the respective groups were not statistically significant (Kruskal-Wallis p=0.11 for r, p=0.67 for s and p=0.27 for os). The effective dose was lowest for the ULDCT., Conclusion: Our study shows that CT-based attenuation correction is feasible for cardiac PET imaging. The results indicate that ultra-low-dose CT is the preferable choice for transmission scanning.

Introduction: Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases., Pet as an Imaging Tool: PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resolution of PET enables noninvasive quantification of neurophysiologic processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to determine involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia., Review: This review summarizes the recent findings in neurocardiological PET imaging. Experimental studies with several radioligands and clinical findings in cardiac dysautonomias are discussed.

Advances in medical imaging now make it possible to investigate any patient with cardiovascular disease using multiple methods which vary widely in their technical requirements, benefits, limitations and costs. The appropriate use of alternative tests requires their integration into joint clinical diagnostic services where experts in all methods collaborate. This statement summarises the principles that should guide developments in cardiovascular diagnostic services.

Cell therapy for cardiac repair has emerged as one of the most exciting and promising developments in cardiovascular medicine. Evidence from experimental and clinical studies is increasing that this innovative treatment will influence clinical practice in the future. But open questions and controversies with regard to the basic mechanisms of this therapy continue to exist and emphasise the need for specific techniques to visualise the mechanisms and success of therapy in vivo. Several non-invasive imaging approaches which aim at tracking of transplanted cells in the heart have been introduced. Among these are direct labelling of cells with radionuclides or paramagnetic agents, and the use of reporter genes for imaging of cell transplantation and differentiation. Initial studies have suggested that these molecular imaging techniques have great potential. Integration of cell imaging into studies of cardiac cell therapy holds promise to facilitate further growth of the field towards a broadly clinically useful application.

Purpose: Genes encoding for intracellular enzymes or transmembrane proteins are suitable as reporters, but may differ in terms of applicability for cardiac imaging. The aim of this study was to compare the human sodium iodide symporter gene (hNIS) with the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) as the reporter gene in non-invasive imaging of cardiac transgene expression with positron emission tomography (PET)., Methods: Equal doses of adenoviral vectors encoding for hNIS, wild-type HSV1-tk, mutant HSV1-sr39tk or LacZ as the control gene were directly injected into the myocardium of 34 animals. Two days later, dynamic PET was performed with a clinical scanner, using reporter probes specific for the respective reporter gene. Imaging with (13)N-ammonia was also performed to identify cardiac regions of interest., Results: Kinetics differed significantly: (124)I as the probe for hNIS showed rapid early uptake, remaining stable over time. Maximal myocardial concentration was 3.61+/-1.15%. The nucleoside (18)F-FHBG, as the specific probe for HSV1-sr39tk, showed increasing uptake over time, but maximal accumulation was significantly lower (1.45+/-0.54%, P=0.0009). (124)I-FIAU, as the specific probe for wild-type HSV1-tk, showed early uptake with subsequent washout. Maximal accumulation was lowest (0.63+/-0.23%, P<0.0001). Post-mortem analysis by autoradiography and gamma counting confirmed the in vivo data., Conclusion: Reporter genes encoding for transporter proteins such as hNIS are an attractive alternative to overexpression of intracellular enzymes for cardiac gene product imaging. hNIS yielded higher signal intensity and imaging contrast for PET than did HSV1-tk and HSV1-sr39tk. Therefore, this approach may be preferable for the future monitoring of cardiac gene- or cell-based therapy.

Electron-beam computed tomography (EBCT) allows non-invasive imaging of coronary calcification and has been promoted as a screening tool for coronary artery disease (CAD) in asymptomatic high-risk subjects. This study assessed the relation of coronary calcifications to alterations in coronary vascular reactivity by means of positron emission tomography (PET) in asymptomatic subjects with a familial history of premature CAD. Twenty-one subjects (mean age 51+/-10 years) underwent EBCT imaging for coronary calcifications expressed as the coronary calcium score (CCS according to Agatston) and rest/adenosine-stress nitrogen-13 ammonia PET with quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR). The mean CCS was 237+/-256 (median 146, range 0-915). The CCS was <100 in eight subjects and >100 units in 13. As defined by age-related thresholds, 15 subjects had an increased CCS (>75th percentile). Overall mean resting and stress MBF and CFR were 71+/-16 ml 100 g(-1) min(-1), 218+/-54 ml 100 g(-1) min(-1) and 3.20+/-0.77, respectively. Three subjects with CCS ranging from 114 to 451 units had an abnormal CFR (<2.5). There was no relation between CCS and resting or stress MBF or CFR ( r=0.17, 0.18 and 0.10, respectively). In asymptomatic subjects a pathological CCS was five times more prevalent than an abnormal CFR. The absence of any close relationship between CCS and CFR reflects the fact that quantitative myocardial perfusion imaging with PET characterises the dynamic process of vascular reactivity while EBCT is a measure of more stable calcified lesions in the arterial wall whose presence is closely related to age.

Gene therapy is a promising modality for the treatment of various cardiovascular diseases such as ischaemia, heart failure, restenosis after revascularisation, hypertension and hyperlipidaemia. An increasing number of approaches are moving from experimental and preclinical validation to clinical application, and several multi-centre trials are currently underway. Despite the rapid progress in cardiac gene therapy, many basic tools and principles remain under development. Questions with regard to the optimal method for gene delivery in a given situation remain open, as do questions concerning therapeutic efficacy and the time course and magnitude of gene expression in target and remote areas. Nuclear imaging provides valuable tools to address these open issues non-invasively. Functional effects of molecular therapy at the tissue level can be identified using tracers of blood flow, metabolism, innervation or cell death. The use of reporter genes and radiolabelled reporter probes allows for non-invasive assessment of location, magnitude and persistence of transgene expression in the heart and the whole body. Co-expression of a reporter gene will allow for indirect imaging of the expression of a therapeutic gene of choice, and linkage of measures of transgene expression to downstream functional effects will enhance the understanding of basic mechanisms of cardiac gene therapy. Hence, nuclear imaging offers great potential to facilitate and refine the determination of therapeutic effects in preclinical and clinical cardiovascular gene therapy.

In diabetic patients, a number of studies have suggested an impairment of vascular reactivity in response to vasodilatory stimuli. The pattern of dysregulation at the coronary microcirculatory level, however, has not been clearly defined. Thus, it was the aim of this study to characterise coronary microvascular function non-invasively in a homogeneous group of asymptomatic type 2 diabetic patients. In 46 patients with type 2 diabetes, myocardial blood flow (MBF) was quantified at baseline, in response to cold pressor test (CPT) and during adenosine-mediated vasodilation using positron emission tomography and nitrogen-13 ammonia. None of the patients had been treated with insulin, and none had symptoms of cardiac disease. Decreased MBF during CPT, indicating microvascular dysregulation, was observed in 16 patients (CPT-), while 30 patients demonstrated increased MBF during CPT (CPT+). Response to CPT was mildly, but significantly correlated with response to adenosine ( r=0.44, P=0.0035). There was no difference in HbA1c, serum lipid levels or serum endothelial markers between the groups. Microvascular dysregulation in the CPT- group was associated with elevated baseline MBF ( P<0.0001), reduced baseline vascular resistance ( P=0.0026) and an abnormal increase in resistance during CPT ( P=0.0002). In conclusion, coronary microvascular dysregulation is present in approximately one-third of asymptomatic, non-insulin-treated type 2 diabetic patients. Elevated baseline blood flow and reduced microvascular resistance at rest are characteristics of this dysregulation. These data suggest a state of activation of endothelial-dependent vasodilation at baseline which appears to limit the flow response to stress conditions.

Effects of oxygen-derived free radicals are suggested to be a potential pathogenic factor for endothelial dysfunction. In this study we sought to evaluate the effect of hydroxyl radicals on the human coronary vascular bed in type I diabetes mellitus using positron emission tomography (PET). Thirteen patients with type 1 diabetes underwent PET using nitrogen-13 ammonia at rest and during sympathetic stimulation with the cold pressor test (CPT). The rest-stress study protocol was repeated twice (on different days) using pre-stress infusion of either saline as placebo or deferoxamine, an iron chelator which inhibits generation of hydroxyl radicals. At rest, global MBF was higher in diabetics than in normal controls (78.1+/-17.5 vs 63.2+/-14.9 mg 100 g(-1) min(-1), P<0.05) and myocardial vascular resistance (MVR) showed a trend towards lower values (patients, 1.28+/-0.35; controls, 1.55+/-0.32, P=NS). CPT increased MBF in all controls while 7/13 diabetics responded normally. CPT decreased MVR in 10/13 controls but in only 4/13 diabetics. There was no significant difference in the duration of diabetes, HbA1c, daily insulin dose, body mass index, or lipid profiles between patients with and patients without abnormal MBF or MVR responses. Pre-stress infusion of deferoxamine normalized MBF response in all six patients, and MVR response in six of the nine patients. Another group consisting of seven patients underwent a rest-rest protocol after infusion of deferoxamine and saline to investigate the effect of deferoxamine on resting MBF. Deferoxamine did not change the resting MBF (deferoxamine, 81+/-17 ml 100 g(-1) min(-1); saline, 75+/-19 ml 100 g(-1) min(-1), P=NS) or MVR (deferoxamine, 1.0+/-0.5 mmHg ml(-1) 100 g(-1) min(-1); saline, 1.2+/-0.6 mmHg ml(-1) 100 g(-1) min(-1), P=NS). In conclusion, inhibition of hydroxyl radical formation using deferoxamine significantly improved the responses of coronary microvasculature to sympathetic stimulation. Hydroxyl radicals may play a role in the pathogenesis of flow abnormalities in type 1 diabetes.

Little is known about the effects of altered sympathetic innervation on the efficiency of the cardiomyopathic heart. Thus, it was the aim of this study to determine non-invasively the relationship between the metabolic cost of cardiac work and alterations of the sympathetic nervous system. In ten patients with chronic idiopathic dilated cardiomyopathy, left ventricular function and geometry were assessed by tomographic radionuclide angiography. Myocardial oxidative metabolism was quantified by the clearance constant k(mono) for carbon-11 acetate, determined by positron emission tomography (PET). Cardiac efficiency was then estimated by the work-metabolic index [WMI = stroke volume index x heart rate x systolic pressure/k(mono)]. Additionally, myocardial presynaptic sympathetic innervation was investigated in the same PET session using 11C-hydroxyephedrine, and plasma norepinephrine levels were determined by high-performance liquid chromatography. The WMI was 3.0+/-1.3 mmHg x ml x 10(6)/m2 and correlated significantly with left ventricular ejection fraction (19%+/-10%; r=0.66, P<0.04) and peripheral vascular resistance (3,638+/-1,085 dynes x s/cm5; r=-0.75, P<0.01). Cardiac hydroxyephedrine retention, reflecting integrity of presynaptic innervation, was abnormally low in 58%+/-38% of the left ventricle. Cardiac hydroxyephedrine retention (r=0.65, P<0.05) and plasma norepinephrine concentration (r=-0.80, P<0.01) both correlated significantly with the WMI. At multivariate stepwise linear regression, only plasma norepinephrine and peripheral vascular resistance were independent determinants of the WMI. In conclusion, metabolic performance of the cardiomyopathic heart decreases with increasing alterations of the sympathetic nervous system. Increasing afterload and effects of systemic sympathetic activation, however, seem to play a dominant role while direct alterations of cardiac presynaptic sympathetic innervation are not independently associated.