Dispersion-corrected extracorporeal arterial input functions in PET studies of mice: a comparison to intracorporeal microprobe measurements.

BACKGROUND: Kinetic modelling of dynamic PET typically requires knowledge of the arterial radiotracer concentration (arterial input function, AIF). Its accurate determination is very difficult in mice. AIF measurements in an extracorporeal shunt can be performed; however, this introduces catheter dispersion. We propose a framework for extracorporeal dispersion correction and validated it by comparison to invasively determined intracorporeal AIFs using implanted microprobes. RESULTS: The response of an extracorporeal radiation detector to radioactivity boxcar functions, characterised by a convolution-based dispersion model, gave best fits using double-gamma variate and single-gamma variate kernels compared to mono-exponential kernels for the investigated range of flow rates. Parametric deconvolution with the optimal kernels was performed on 9 mice that were injected with a bolus of 39 ± 25 MBq [18F]F-PSMA-1007 after application of an extracorporeal circulation for three different flow rates in order to correct for dispersion. Comparison with synchronous implantation of microprobes for invasive aortic AIF recordings showed favourable correspondence, with no significant difference in terms of area-under-curve after 300 s and 5000 s. One-tissue and two-tissue compartment model simulations were performed to investigate differences in kinetic parameters between intra- and extracorporeally measured AIFs. Results of the modelling study revealed kinetic parameters close to the chosen simulated values in all compartment models. CONCLUSION: The high correspondence of simultaneously intra- and extracorporeally determined AIFs and resulting model parameters establishes a feasible framework for extracorporeal dispersion correction. This should allow more precise and accurate kinetic modelling in small animal experiments.

Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells.

Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation resulted in decreased JNK activation, leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.

[Policy paper nuclear cardiology - update 2018 - Current status of clinical practice]. / Positionspapier Nuklearkardiologie ­ Update 2018.

The joint position paper of the working community "Cardiovascular Nuclear Medicine" of the German Society of Nuclear Medicine (DGN) and the working group "Nuclear Cardiology Diagnostics" of the German Cardiac Society (DKG) updates the former 2009 paper. It is the purpose of this paper to provide an overview about the application fields, the state-of-the-art and the current value of nuclear cardiology imaging. The topics covered are chronic coronary artery disease, including viability imaging, furthermore cardiomyopathies, infective endocarditis, cardiac sarcoidosis and amyloidosis.

[Myokard-Perfusions-SPECT. Myocardial perfusion SPECT - Update S1 guideline]. / Myokard-Perfusions-SPECT. Update S1-Leitlinie1.

The S1 guideline for myocardial perfusion SPECT has been published by the Association of the Scientific Medical Societies in Germany (AWMF) and is valid until 2/2022. This paper is a short summary with comments on all chapters and subchapters wich were modified and amended.

Statistical Permutation-based Artery Mapping (SPAM): a novel approach to evaluate imaging signals in the vessel wall.

BACKGROUND: Cardiovascular diseases are the leading cause of death worldwide. A prominent cause of cardiovascular events is atherosclerosis, a chronic inflammation of the arterial wall that leads to the formation of so called atherosclerotic plaques. There is a strong clinical need to develop new, non-invasive vascular imaging techniques in order to identify high-risk plaques, which might escape detection using conventional methods based on the assessment of the luminal narrowing. In this context, molecular imaging strategies based on fluorescent tracers and fluorescence reflectance imaging (FRI) seem well suited to assess molecular and cellular activity. However, such an analysis demands a precise and standardized analysis method, which is orientated on reproducible anatomical landmarks, ensuring to compare equivalent regions across different subjects. METHODS: We propose a novel method, Statistical Permutation-based Artery Mapping (SPAM). Our approach is especially useful for the understanding of complex and heterogeneous regional processes during the course of atherosclerosis. Our method involves three steps, which are (I) standardisation with an additional intensity normalization, (II) permutation testing, and (III) cluster-enhancement. Although permutation testing and cluster enhancement are already well-established in functional magnetic resonance imaging, to the best of our knowledge these strategies have so far not been applied in cardiovascular molecular imaging. RESULTS: We tested our method using FRI images of murine aortic vessels in order to find recurring patterns in atherosclerotic plaques across multiple subjects. We demonstrate that our pixel-wise and cluster-enhanced testing approach is feasible and useful to analyse tracer distributions in FRI data sets of aortic vessels. CONCLUSIONS: We expect our method to be a useful tool within the field of molecular imaging of atherosclerotic plaques since cluster-enhanced permutation testing is a powerful approach for finding significant differences of tracer distributions in inflamed atherosclerotic vessels.

Sex differences in absolute myocardial perfusion. Non-invasive H2(15)O-PET in young healthy adults.

AIM: To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET). RESULTS: Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences. CONCLUSION: Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

Serial F-18-FDG PET/CT distinguishes inflamed from stable plaque phenotypes in shear-stress induced murine atherosclerosis.

BACKGROUND: Detection of inflamed atherosclerotic plaques is of crucial importance. The carotid artery cuff-model in ApoE(-/-) mice results in shear-stress induced atherosclerosis with inflamed plaques upstream (US) and 'stable' plaques downstream (DS) of the cuff. We evaluated the potential of F-18-FDG PET/CT to differentiate these plaque phenotypes. METHODS: A predefined cuff was implanted round the left (n = 23) or right (n = 12) common carotid artery (CCA) of 35 ApoE(-/-) mice on a cholesterol-rich diet. Small animal F-18-FDG PET/CT was performed after 4, 6 and 8 weeks. F-18-FDG uptake was quantified US and DS of the cuff and on the contralateral CCA. Subsequently, regional F-18-FDG uptake was normalized by the contralateral CCA uptake to obtain plaque-to-background (P/B)-ratios. Thereafter, CCA were explanted and investigated by immunohistology. RESULTS: P/B-ratio in the US-plaques increased from 1.22 ± 0.23 at 4 weeks over 1.23 ± 0.32 at 6 weeks to 1.37 ± 0.56 (p = ns) at 8 weeks after cuff implantation (left and right side of cuff implantation considered together). Uptake in the DS-plaques remained stable (1.14 ± 0.23, 1.10 ± 0.26 and 1.11 ± 0.25; p = ns). Uptake in the US-plaques was significantly higher than in the DS-plaques (all p < 0.05). P/B-ratios correlated with plaque size, degree of stenosis and macrophage density in the plaques. Moreover, there was a correlation between plaque size and macrophage density in the plaque. CONCLUSIONS: F-18-FDG-PET/CT distinguishes atherosclerotic plaques with an inflamed from those with a 'stable' phenotype in a mouse model of shear-stress induced atherosclerosis in vivo.

Use of gated 13N-NH3 micro-PET to examine left ventricular function in rats.

INTRODUCTION: Myocardial perfusion gating techniques offer the possibility of measurement of left ventricular end-systolic (ESV) and end-diastolic volume (EDV) and left ventricular ejection fraction (LVEF) in clinical and preclinical trials. The aim of this study was to evaluate left ventricular volumes (LVV) and LVEF with 13N-NH3 in comparison with the reference 18F-FDG in different rat models. METHODS: In this study, 18 male Wistar rats, 12 control rats and 6 rats with myocardial infarction (MI) were imaged with micro-PET. The ratswere scanned with gated 13N-NH3 and 18F-FDG sequentially for the assessment of LVV and LVEF. A validated three-dimensional segmentation algorithm was used to calculate LVV and LVEF. RESULTS: Mean LVEF measured with 13N-NH3 was 45.6±8.9 and 75.3±9.4%, mean ESV was 0.40±0.12 and 0.14±0.11 ml, and mean EDVwas 0.53±16 and 0.75±0.18 ml for MI and control rats, respectively. Moderate to good correlations were observed between values of 13N-NH3 and 18F-FDG for calculation of ESV [r=0.80, P<.0001, standard error of estimate (SEE)=0.10], EDV (r=0.63, P=.005, SEE=0.14) and LVEF (r=0.84, P<.0001, SEE=9.5). LVEF measured with 13N-NH3 was significantly lower in MI rats in comparison to measurement with 18F-FDG (45.6±8.9 vs 54.9±9.3 %; P=.04). CONCLUSION: Correlations were moderate to good for the assessment of ESV, EDV and LVEF between gated 13N-NH3 and 18F-FDG. LVEF was underestimated with gated 13N-NH3 in rats with myocardial infarction. In healthy rats, LV volumes and LVEF can be measured reproducibly with either approach.

Myocardial perfusion in nonischemic dilated cardiomyopathy with and without atrial fibrillation.

UNLABELLED: Recent studies have shown that idiopathic atrial fibrillation (AF) is associated with diminished myocardial perfusion and perfusion reserve, which are also impaired in various forms of cardiomyopathies. In many cases, AF develops during progression of dilated cardiomyopathy (DCM) and may aggravate heart failure. This study compared myocardial perfusion between patients with nonischemic DCM with and without AF. METHODS: Twelve men (age +/- SD, 55 +/- 12 y) who had DCM and persistent AF were compared with a group of 18 men (mean age, 43 +/- 15 y, P = not statistically significant) who had DCM and sinus rhythm and with 22 healthy controls (mean age, 47 +/- 13 y, P = not statistically significant). Myocardial blood flow (MBF) was noninvasively quantified at rest and during adenosine infusion using PET and radioactive-labeled water (H(2)(15)O PET). RESULTS: Compared with controls, DCM patients without AF showed impaired hyperemic perfusion (2.52 +/- 1.29 vs. 3.57 +/- 0.88 mL/min/mL, P = 0.014) and perfusion reserve (2.10 +/- 1.01 vs. 3.37 +/- 0.97, P = 0.003). However, compared with DCM patients without AF, DCM patients with AF showed an additional impairment in resting perfusion (0.82 +/- 0.31 mL/min/mL, P = 0.010) and hyperemic perfusion (1.32 +/- 0.93 mL/min/mL, P = 0.022), and compared with controls, DCM patients with AF showed a further diminishment of perfusion reserve (1.68 +/- 0.94 vs. 3.37 +/- 0.97, P < 0.001) accompanied by the highest coronary vascular resistance of all groups. CONCLUSION: Compared with patients with sinus rhythm, patients with AF have significantly reduced myocardial perfusion reserve and increased coronary resistance in nonischemic DCM. Further studies on the underlying pathomechanisms are warranted.

Quantification of left ventricular volumes and ejection fraction in mice using PET, compared with MRI.

UNLABELLED: PET has become an important noninvasive imaging technique in cardiovascular research for the characterization of mouse models in vivo. This modality offers unique insight into biochemical changes on a molecular level, with excellent sensitivity. However, morphologic and functional changes may be of equal importance for a thorough assessment of left ventricular (LV) pathophysiology. Although echocardiography and MRI are widely considered the imaging techniques of choice for the assessment of these parameters, their use with PET considerably increases study complexity and decreases cost- and time-efficiency. In this study, a novel method for the additional quantification of LV volumes and ejection fraction (EF) from PET was evaluated using cardiac MRI as the reference method. METHODS: The radiolabeled glucose derivative 18F-FDG was injected into 33 mice (6 mice with previous permanent occlusion of the left anterior descending artery [LAD], 15 mice with a temporary 30-min occlusion of the LAD, and 12 mice without previous surgery). 18F-FDG uptake within the LV myocardium was measured using a dedicated small-animal PET scanner. After we reconstructed the images into 16 electrocardiogram (ECG)-gated frames, we determined the LV cavity volumes in end-diastole (EDV) and end-systole (ESV) and the EF using a semiautomatic segmentation algorithm based on elastic surfaces. A 6.3-T cardiac MRI examination was performed in the same animals using an ECG-triggered and respiratory-gated multislice cine sequence. The MR images were segmented with a semiautomatic algorithm using commercially available software. RESULTS: Overall, measurements from PET agreed well with those obtained by MRI. Mean EDV and ESV were slightly overestimated by PET (86+/-43 microL and 44+/-42 microL), compared with MRI (73+/-44 microL and 41+/-46 microL); mean (+/-SD) EF was similar (PET, 55+/-19 microL; MRI, 54+/-18 microL). Correlation between PET and MRI was excellent for EDV (0.97) and ESV (0.96) and good for EF (0.86). The slope of the regression line was nearly perfect for EDV (0.98) and EF (1.01) and slightly below 1 for ESV (0.90), indicating a good separation of abnormal and normal values with PET. The y-intercept was above zero for EDV (15 microL) and ESV (7 microL) and near to zero for EF (0.2%). CONCLUSION: The quantification of LV volumes and EF in mice with PET is both efficient and accurate. This method allows for combined molecular and functional imaging of the left ventricle within a single scan, obviating additional sophisticated MRI in many cases.

Accurate noninvasive measurement of infarct size in mice with high-resolution PET.

UNLABELLED: Reliable, repeatable, and time-efficient noninvasive measurement of infarct size in mice with PET would benefit studies aimed at the exploration of biochemical and functional changes associated with acute myocardial infarction (MI). PET with the radioactively labeled glucose derivative (18)F-FDG is used in humans to distinguish between viable but dysfunctional and nonviable myocardium. In this study, the feasibility, accuracy, and time efficiency of (18)F-FDG PET for quantification of infarct size in mice using a high-resolution animal PET device was evaluated in comparison with histomorphometry. METHODS: Mice were subjected to surgery with permanent ligation of the left anterior descending artery. PET was performed before and 7 d after surgery. The infarct size was determined from the PET studies using both manual and automated delineation. The second PET scan was followed by histomorphometric analysis. RESULTS: An excellent correlation between PET and histomorphometry was found for both manual (R = 0.98) and automated (R = 0.98) delineation, with linear regression curves close to unity (manual: y = 1.10x - 0.01; automated: y = 1.12x - 0.02). Automated analysis required <1 min per study. CONCLUSION: The measurement of infarct size in mice with (18)F-FDG PET is feasible and highly accurate. This noninvasive methodology permits unique longitudinal studies of biochemical parameters in mice and facilitates studies that aim to assess the effect of surgical and pharmacologic intervention after acute MI.