@article{NordbeckBoenhofHilleretal.2013, author = {Nordbeck, Peter and B{\"o}nhof, Leoni and Hiller, Karl-Heinz and Voll, Sabine and Arias-Loza, Paula and Seidlmaier, Lea and Williams, Tatjana and Ye, Yu-Xiang and Gensler, Daniel and Pelzer, Theo and Ertl, Georg and Jakob, Peter M. and Bauer, Wolfgang R. and Ritter, Oliver}, title = {Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0068275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130064}, pages = {e68275}, year = {2013}, abstract = {Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. Conclusion Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients.}, language = {en} } @article{LapaAriasLozaHayakawaetal.2017, author = {Lapa, Constantin and Arias-Loza, Paula and Hayakawa, Nobuyuki and Wakabayashi, Hiroshi and Werner, Rudolf A. and Chen, Xinyu and Shinaji, Tetsuya and Herrmann, Ken and Pelzer, Theo and Higuchi, Takahiro}, title = {Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-17148-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159066}, pages = {16795}, year = {2017}, abstract = {Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.}, language = {en} } @article{WernerEisslerHayakawaetal.2018, author = {Werner, Rudolf A. and Eissler, Christoph and Hayakawa, Nobuyuki and Arias-Loza, Paula and Wakabayashi, Hiroshi and Javadi, Mehrbod S. and Chen, Xinyu and Shinaji, Tetsuya and Lapa, Constantin and Pelzer, Theo and Higuchi, Takahiro}, title = {Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {17631}, doi = {10.1038/s41598-018-35986-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171765}, year = {2018}, abstract = {In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5\%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.}, language = {en} } @article{EisslerWernerAriasLozaetal.2021, author = {Eissler, Cristoph and Werner, Rudolf A. and Arias-Loza, Paula and Nose, Naoko and Chen, Xinyu and Pomper, Martin G. and Rowe, Steven P. and Lapa, Constantin and Buck, Andreas K. and Higuchi, Takahiro}, title = {The number of frames on ECG-gated \(^{18}\)F-FDG small animal PET has a significant impact on LV systolic and diastolic functional parameters}, series = {Molecular Imaging}, volume = {2021}, journal = {Molecular Imaging}, doi = {10.1155/2021/4629459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265778}, year = {2021}, abstract = {Objectives. This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods. \(^{18}\)F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results. Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 \& PLUSMN; 57.7 mu l*, 380.8 \& PLUSMN; 57.2 mu l*, 398.0 \& PLUSMN; 63.1 mu l*, and 444.8 \& PLUSMN; 75.3 mu l at 4, 8, 12, and 16 frames, respectively; *P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames. Conclusions. Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.}, language = {en} } @article{MatsusakaChenAriasLozaetal.2022, author = {Matsusaka, Yohji and Chen, Xinyu and Arias-Loza, Paula and Werner, Rudolf A. and Nose, Naoko and Sasaki, Takanori and Rowe, Steven P. and Pomper, Martin G. and Lapa, Constantin and Higuchi, Takahiro}, title = {In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [\(^{18}\)F]Me4FDG PET in Rats}, series = {Molecular Imaging}, volume = {2022}, journal = {Molecular Imaging}, doi = {10.1155/2022/4635171}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300708}, year = {2022}, abstract = {Background. Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[\(^{18}\)F]fluoro-D-glucopyranoside ([\(^{18}\)F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods. We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose ([\(^{18}\)F]FDG), or the SGLT-targeting agent, [\(^{18}\)F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results. Serving as reference, intestinal administration of [\(^{18}\)F]FDG led to slow absorption with retention of \% of administered radioactivity at 15 min. [\(^{18}\)F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of \% (). Intraintestinal phlorizin led to marked increase of [\(^{18}\)F]Me4FDG uptake (15 min, \%; vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [\(^{18}\)F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (\%ID/g at 60 min, vs. untreated controls, ; ). Conclusion. As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [\(^{18}\)F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [\(^{18}\)F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.}, language = {en} } @article{TolstikAliGuoetal.2022, author = {Tolstik, Elen and Ali, Nairveen and Guo, Shuxia and Ebersbach, Paul and M{\"o}llmann, Dorothe and Arias-Loza, Paula and Dierks, Johann and Schuler, Irina and Freier, Erik and Debus, J{\"o}rg and Baba, Hideo A. and Nordbeck, Peter and Bocklitz, Thomas and Lorenz, Kristina}, title = {CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms23105345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284427}, year = {2022}, abstract = {Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient's prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90-96\%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.}, language = {en} } @article{MatsusakaWernerAriasLozaetal.2022, author = {Matsusaka, Yohji and Werner, Rudolf A. and Arias-Loza, Paula and Nose, Naoko and Sasaki, Takanori and Chen, Xinyu and Lapa, Constantin and Higuchi, Takahiro}, title = {Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals}, series = {Molecular Imaging}, volume = {2022}, journal = {Molecular Imaging}, doi = {10.1155/2022/9810097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300713}, year = {2022}, abstract = {Background. Equipped with two stationary detectors, a large bore collimator for medium-sized animals has been recently introduced for dedicated preclinical single-photon emission computed tomography (SPECT) imaging. We aimed to evaluate the basic performance of the system using phantoms and healthy rabbits. Methods. A general-purpose medium-sized animal (GP-MSA) collimator with 135 mm bore diameter and thirty-three holes of 2.5 mm diameter was installed on an ultrahigh-resolution scanner equipped with two large stationary detectors (U-SPECT5-E/CT). The sensitivity and uniformity were investigated using a point source and a cylinder phantom containing 99mTc-pertechnetate, respectively. Uniformity (in \%) was derived using volumes of interest (VOIs) on images of the cylinder phantom and calculated as , with lower values of \% indicating superior performance. The spatial resolution and contrast-to-noise ratios (CNRs) were evaluated with images of a hot-rod Derenzo phantom using different activity concentrations. Feasibility of in vivo SPECT imaging was finally confirmed by rabbit imaging with the most commonly used clinical myocardial perfusion SPECT agent [99mTc]Tc-sestamibi (dynamic acquisition with a scan time of 5 min). Results. In the performance evaluation, a sensitivity of 790 cps/MBq, a spatial resolution with the hot-rod phantom of 2.5 mm, and a uniformity of 39.2\% were achieved. The CNRs of the rod size 2.5 mm were 1.37, 1.24, 1.20, and 0.85 for activity concentration of 29.2, 1.0, 0.5, and 0.1 MBq/mL, respectively. Dynamic SPECT imaging in rabbits allowed to visualize most of the thorax and to generate time-activity curves of the left myocardial wall and ventricular cavity. Conclusion. Preclinical U-SPECT5-E/CT equipped with a large bore collimator demonstrated adequate sensitivity and resolution for in vivo rabbit imaging. Along with its unique features of SPECT molecular functional imaging is a superior collimator technology that is applicable to medium-sized animal models and thus may promote translational research for diagnostic purposes and development of novel therapeutics.}, language = {en} }