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Purpose: This study aims to show the viability of conducting three-dimensional (3D) myocardial perfusion quantification covering the entire heart using both GRE and bSSFP sequences with hyperpolarized HP001., Methods: A GRE sequence and a bSSFP sequence, both with a stack-of-spirals readout, were designed and applied to three pigs. The images were reconstructed using   13 $$ {}^{13} $$ C coil sensitivity maps measured in a phantom experiment. Perfusion was quantified using a constrained decomposition method, and the estimated rest/stress perfusion values from   13 $$ {}^{13} $$ C GRE/bSSFP and Dynamic contrast-enhanced MRI (DCE-MRI) were individually analyzed through histograms and the mean perfusion values were compared with reference values obtained from PET(   15 $$ {}^{15} $$ O-water). The Myocardial Perfusion Reserve Index (MPRI) was estimated for   13 $$ {}^{13} $$ C GRE/bSSFP and DCE-MRI and compared with the reference values., Results: Perfusion values, estimated by both DCE and   13 $$ {}^{13} $$ C MRI, were found to be lower than reference values. However, DCE-MRI's estimated perfusion values were closer to the reference values than those obtained from   13 $$ {}^{13} $$ C MRI. In the case of MPRI estimation, the   13 $$ {}^{13} $$ C estimated MPRI values (GRE/bSSFP: 2.3/2.0) more closely align with the literature value (around 3) than the DCE estimated MPRI value (1.6)., Conclusion: This study demonstrated the feasibility of 3D whole-heart myocardial perfusion quantification using hyperpolarized HP001 with both GRE and bSSFP sequences. The   13 $$ {}^{13} $$ C perfusion measurements underestimated perfusion values compared to the   15 $$ {}^{15} $$ O PET literature value, while the   13 $$ {}^{13} $$ C estimated MPRI value aligned better with the literature. This preliminary result indicates   13 $$ {}^{13} $$ C imaging may more accurately estimate MPRI values compared to DCE-MRI., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Hyperpolarized [1- 13 C]pyruvate magnetic resonance imaging (HP MRI) visualizes key steps in myocardial metabolism. The present study aimed to examine patients with heart (HF) using HP MRI., Methods: A cross-sectional study of patients with HF and healthy controls using HP MRI. Metabolic imaging was obtained using a cardiac-gated spectral-spatial excitation with spiral read-out acquisition. The metabolite signal was analyzed for lactate, bicarbonate, and the alanine signal. Metabolite signal was normalized to the total carbon signal (TC). At the one-year follow-up, echocardiography was performed in all patients and HP MRI in two patients., Results: We included six patients with ischemic heart disease (IHD), six with dilated cardiomyopathy and six healthy controls. In patients, left ventricular ejection fraction (LVEF) correlated with lactate/bicarbonate (r = -0.6, p = 0.03) and lactate/TC (r = -0.7, p = 0.01). In patients with LVEF < 30%, lactate/TC was increased (p = 0.01) and bicarbonate/TC reduced (p = 0.03). Circumferential strain correlated with metabolite ratios: lactate/bicarbonate, r = 0.87 (p = 0.0002); lactate/TC, r = 0.85 (p = 0.0005); bicarbonate/TC, r = -0.82 (p = 0.001). In patients with IHD, a strong correlation was found between baseline metabolite ratios and the change in LVEF at follow-up: lactate/bicarbonate (p = 0.001); lactate/TC (p = 0.011); and bicarbonate/TC (p = 0.012)., Conclusions: This study highlighted the ability of HP MRI to detect changes in metabolism in HF. HP MRI has potential for metabolic phenotyping of patients with HF and for predicting treatment response., Trial Registration: EUDRACT, 2018-003533-15. Registered 4 December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15., Competing Interests: Competing interests The are no competing interests to declare. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

As hyperpolarized (HP) carbon-13 ( 13 C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13 C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13 C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium ( 23 Na) sensitivity maps for SENSE reconstructed 13 C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23 Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique's ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data., (© 2024. The Author(s).)

Purpose: Water freely diffuses across cell membranes, making it suitable for measuring absolute tissue perfusion. In this study, we introduce an imaging method for conducting coronary artery angiography and quantifying myocardial perfusion across the entire heart using hyperpolarized water. Methods: 1 H was hyperpolarized using dissolution dynamic nuclear polarization (dDNP) with UV-generated radicals. Submillimeter resolution coronary artery images were acquired as 2D projections using a spoiled GRE (SPGRE) sequence gated on diastole. Dynamic perfusion images were obtained with a multi-slice SPGRE with diastole gating, covering the entire heart. Perfusion values were analyzed through histograms, and the most frequent estimated perfusion value (the mode of the distribution), was compared with the average values for 15 O water PET from the literature. Results: A liquid state polarization of 10% at the time of the injection and a 30 s T 1 in D 2 O TRIS buffer were measured. Both coronary artery and dynamic perfusion images exhibited good quality. The main and small coronary artery branches were well resolved. The most frequent estimated perfusion value is around 0.6 mL/g/min, which is lower than the average values obtained from the literature for 15 O-water PET (around 1.1 and 1.5 mL/g/min). Conclusions: The study successfully demonstrated the feasibility of achieving high-resolution, motion-free coronary artery angiography and 3D whole-heart quantitative myocardial perfusion using hyperpolarized water.

Objective . Pressure-volume loop analysis, traditionally performed by invasive pressure and volume measurements, is the optimal method for assessing ventricular function, while cardiac magnetic resonance (CMR) imaging is the gold standard for ventricular volume estimation. The aim of this study was to investigate the agreement between the assessment of end-systolic elastance (Ees) assessed with combined CMR and simultaneous pressure catheter measurements compared with admittance catheters in a porcine model. Approach . Seven healthy pigs underwent admittance-based pressure-volume loop evaluation followed by a second assessment with CMR during simultaneous pressure measurements. Main results . Admittance overestimated end-diastolic volume for both the left ventricle (LV) and the right ventricle (RV) compared with CMR. Further, there was an underestimation of RV end-systolic volume with admittance. For the RV, however, Ees was systematically higher when assessed with CMR plus simultaneous pressure measurements compared with admittance whereas there was no systematic difference in Ees but large differences between admittance and CMR-based methods for the LV. Significance . LV and RV Ees can be obtained from both admittance and CMR based techniques. There were discrepancies in volume estimates between admittance and CMR based methods, especially for the RV. RV Ees was higher when estimated by CMR with simultaneous pressure measurements compared with admittance., (Creative Commons Attribution license.)

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13 C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13 C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13 C studies, [1- 13 C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13 C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Hyperpolarized carbon-13 labeled compounds are increasingly being used in medical MR imaging (MRI) and MR imaging (MRI) and spectroscopy (MRS) research, due to its ability to monitor tissue and cell metabolism in real-time. Although radiological biomarkers are increasingly being considered as clinical indicators, biopsies are still considered the gold standard for a large variety of indications. Bioreactor systems can play an important role in biopsy examinations because of their ability to provide a physiochemical environment that is conducive for therapeutic response monitoring ex vivo. We demonstrate here a proof-of-concept bioreactor and microcoil receive array setup that allows for ex vivo preservation and metabolic NMR spectroscopy on up to three biopsy samples simultaneously, creating an easy-to-use and robust way to simultaneously run multisample carbon-13 hyperpolarization experiments. Experiments using hyperpolarized [1- 13 C]pyruvate on ML-1 leukemic cells in the bioreactor setup were performed and the kinetic pyruvate-to-lactate rate constants ( k PL ) extracted. The coefficient of variation of the experimentally found k PL s for five repeated experiments was C V = 35 % . With this statistical power, treatment effects of 30%-40% change in lactate production could be easily differentiable with only a few hyperpolarization dissolutions on this setup. Furthermore, longitudinal experiments showed preservation of ML-1 cells in the bioreactor setup for at least 6 h. Rat brain tissue slices were also seen to be preserved within the bioreactor for at least 1 h. This validation serves as the basis for further optimization and upscaling of the setup, which undoubtedly has huge potential in high-throughput studies with various biomarkers and tissue types., (© 2024 John Wiley & Sons Ltd.)

The sortilin-related receptor 1 ( SORL1 ) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene for Alzheimer's disease. As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1 variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with Alzheimer's disease and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1 mutations, we applied two metabolic MRI technologies, sodium ( 23 Na) MRI and MRI with hyperpolarized [1- 13 C]pyruvate, in minipigs and mice with compromised expression of SORL1 . At the age analysed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1- 13 C]pyruvate to [1- 13 C]lactate and 13 C-bicarbonate was decreased by 32 and 23%, respectively, in the cerebrum of SORL1 -haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with 23 Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of Alzheimer's disease and Alzheimer's disease-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1 mutations and their potential role in neurodegeneration., Competing Interests: O.M.A. has commercial interests in Retromer Therapeutics, but the company was not involved in any aspects of the study. Ellegaard Göttingen Minipigs A/S owns the commercial rights to the SORL1 minipigs. N.B., O.M.A., C.B.S. and C.L. have filed a patent describing the use of sodium MRI for measuring in vivo SORL1 activity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Magnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI., Methods: A repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6'- 2 H 2 ]glucose. The delivery of 2 H-glucose to the brain and its conversion to 2 H-glutamine + glutamate, 2 H-lactate, and 2 H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a 1 H/ 2 H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated., Results: Six male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%., Conclusions: DMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system., Trial Registration: ClinicalTrials.gov, NCT05402566 , registered the 25th of May 2022., Relevance Statement: Brain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response., Key Points: • Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability.  • The repeatability of deuterium metabolic imaging is on par with FDG-PET.  • The study of deuterium metabolic imaging in clinical populations is feasible., (© 2024. The Author(s).)

Purpose: X-nuclei (also called non-proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of x-nuclei examination warrants the need of a robust and versatile tool improving image quality for diagnostic use. In this work, we compare a novel denoising method with fewer inputs to the current state-of-the-art denoising method., Methods: Denoising approaches were compared on human acquisitions of sodium ( 23 Na) brain, deuterium ( 2 H) brain, carbon ( 13 C) heart and brain, and simulated dynamic hyperpolarized 13 C brain scans, with and without additional noise. The current state-of-the-art denoising method Global-local higher order singular value decomposition (GL-HOSVD) was compared to the few-input method tensor Marchenko-Pastur principal component analysis (tMPPCA). Noise-removal was quantified by residual distributions, and statistical analyses evaluated the differences in mean-square-error and Bland-Altman analysis to quantify agreement between original and denoised results of noise-added data., Results: GL-HOSVD and tMPPCA showed similar performance for the variety of x-nuclei data analyzed in this work, with tMPPCA removing ˜5% more noise on average over GL-HOSVD. The mean ratio between noise-added and denoising reproducibility coefficients of the Bland-Altman analysis when compared to the original are also similar for the two methods with 3.09 ± 1.03 and 2.83 ± 0.79 for GL-HOSVD and tMPPCA, respectively., Conclusion: The strength of tMPPCA lies in the few-input approach, which generalizes well to different data sources. This makes the use of tMPPCA denoising a robust and versatile tool in x-nuclei imaging improvements and the preferred denoising method., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To evaluate the effect of methylene blue administered as a bolus on return of spontaneous circulation (ROSC), lactate levels, vasopressor requirements, and markers of neurological injury in a clinically relevant pig model of cardiac arrest., Materials and Methods: 40 anesthetized pigs were subjected to acute myocardial infarction and 7 min of untreated cardiac arrest. Animals were randomized into three groups: one group received saline only (controls), one group received 2 mg/kg methylene blue and saline (MB + saline), and one group received two doses of 2 mg/kg methylene blue (MB + MB). The first intervention was given after the 3rd rhythm analysis, while the second dose was administered one hour after achieving ROSC. Animals underwent intensive care and observation for six hours, followed by cerebral magnetic resonance imaging (MRI). The primary outcome for this study was development in lactate levels after cardiac arrest. Categorical data were compared using Fisher's exact test and pointwise data were analyzed using one-way analysis of variance (ANOVA) or equivalent non-parametric test. Continuous data collected over time were analyzed using a linear mixed effects model. A value of p < .05 was considered statistically significant., Results: Lactate levels increased in all groups after cardiac arrest and resuscitation, however lactate levels in the MB + MB group decreased significantly faster compared with the control group (p = .007) and the MB + saline group (p = .02). The proportion of animals achieving initial ROSC was similar across groups: 11/13 (85%) in the control group, 10/13 (77%) in the MB + saline group, and 12/14 (86%) in the MB + MB group (p = .81). Time to ROSC did not differ between groups (p = .67). There was no significant difference in accumulated norepinephrine dose between groups (p = .15). Cerebral glycerol levels were significantly lower in the MB + MB group after resuscitation compared with control group (p = .03). However, MRI data revealed no difference in apparent diffusion coefficient, cerebral blood flow, or dynamic contrast enhanced MR perfusion between groups., Conclusion: Treatment with a bolus of methylene blue during cardiac arrest and after resuscitation did not significantly improve hemodynamic function. A bolus of methylene blue did not yield the neuroprotective effects that have previously been described in animals receiving methylene blue as an infusion., Competing Interests: Declaration of Competing Interest None to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Commercial human MR scanners are optimised for proton imaging, containing sophisticated prescan algorithms with setting parameters such as RF transmit gain and power. These are not optimal for X-nuclear application and are challenging to apply to hyperpolarised experiments, where the non-renewable magnetisation signal changes during the experiment. We hypothesised that, despite the complex and inherently nonlinear electrodynamic physics underlying coil loading and spatial variation, simple linear regression would be sufficient to accurately predict X-nuclear transmit gain based on concomitantly acquired data from the proton body coil. We collected data across 156 scan visits at two sites as part of ongoing studies investigating sodium, hyperpolarised carbon, and hyperpolarised xenon. We demonstrate that simple linear regression is able to accurately predict sodium, carbon, or xenon transmit gain as a function of position and proton gain, with variation that is less than the intrasubject variability. In conclusion, sites running multinuclear studies may be able to remove the time-consuming need to separately acquire X-nuclear reference power calibration, inferring it from the proton instead.

Purpose: Ischemic injury in the kidney is a common pathophysiological event associated with both acute kidney injury and chronic kidney disease; however, regional ischemia-reperfusion as seen in thromboembolic renal disease is often undetectable and thus subclinical. Here, we assessed the metabolic alterations following subclinical focal ischemia-reperfusion injury with hyperpolarized [1- 13 C]pyruvate MRI in a porcine model., Methods: Five pigs were subjected to 60 min of focal kidney ischemia. After 90 min of reperfusion, a multiparametric proton MRI protocol was performed on a clinical 3T scanner system. Metabolism was evaluated using 13 C MRI following infusion of hyperpolarized [1- 13 C]pyruvate. Ratios of pyruvate to its detectable metabolites (lactate, bicarbonate, and alanine) were used to quantify metabolism., Results: The focal ischemia-reperfusion injury resulted in injured areas with a mean size of 0.971 cm 3 (±1.019). Compared with the contralateral kidney, the injured areas demonstrated restricted diffusion (1269 ± 83.59 × 10 -6  mm 2 /s vs. 1530 ± 52.73 × 10 -6  mm 2 /s; p = 0.006) and decreased perfusion (158.8 ± 29.4 mL/100 mL/min vs. 274 ± 63.1 mL/100 mL/min; p = 0.014). In the metabolic assessment, the injured areas displayed increased lactate/pyruvate ratios compared with the entire ipsilateral and the contralateral kidney (0.35 ± 0.13 vs. 0.27 ± 0.1 vs. 0.25 ± 0.1; p = 0.0086). Alanine/pyruvate ratio was unaltered, and we were unable to quantify bicarbonate due to low signal., Conclusion: MRI with hyperpolarized [1- 13 C]pyruvate in a clinical setup is capable of detecting the acute, subtle, focal metabolic changes following ischemia. This may prove to be a valuable future addition to the renal MRI suite., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Hyperpolarized [1- 13 C]pyruvate MRI is an emerging clinical tool for metabolic imaging. It has the potential for absolute quantitative metabolic imaging. However, the method itself is not quantitative, limiting comparison of images across both time and between individuals. Here, we propose a simple signal normalization to the whole-body oxidative metabolism to overcome this limitation., Theory and Methods: A simple extension of the model-free ratiometric analysis of hyperpolarized [1- 13 C]pyruvate MRI is presented, using the expired 13 CO 2 in breath for normalization. The proposed framework was investigated in two porcine cohorts (N = 11) subjected to local renal hypoperfusion defects and subsequent [1- 13 C]pyruvate MRI. A breath sample was taken before the [1- 13 C]pyruvate injection and 5 min after. The raw MR signal from both the healthy and intervened kidney in the two cohorts was normalized using the 13 CO 2 in the expired air., Results: 13 CO 2 content in the expired air was significantly different between the two cohorts. Normalization to this reduced the coefficients of variance in the aerobic metabolic sensitive pathways by 25% for the alanine/pyruvate ratio, and numerical changes were observed in the bicarbonate/pyruvate ratio. The lactate/pyruvate ratio was largely unaltered (<2%)., Conclusion: Our results indicate that normalizing the hyperpolarized 13 C-signal ratios by the 13 CO 2 content in expired air can reduce variation as well as improve specificity of the method by normalizing the metabolic readout to the overall metabolic status of the individual. The method is a simple and cheap extension to the hyperpolarized 13 C exam., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: This article presents a novel 14-channel receive-only array for 13 C human head imaging at 3 T that explores the SNR gain by operating at cryogenic temperature cooled by liquid nitrogen., Methods: Cryostats are developed to evaluate single-coil bench SNR performance and cool the 14-channel array with liquid nitrogen while having enough thermal insulation between the coils and the sample. The temperature distribution for the coil array is measured. Circuits are adapted to the -189°C environment and implemented in the 14-channel array. 13 C images are acquired with the array at cryogenic and room temperature in a 3T scanner., Results: Compared with room temperature, the array at cryogenic temperature provides 27%-168% SNR improvement over all voxels and 47% SNR improvement near the image center. The measurements show a decrease of the element noise correlation at cryogenic temperature., Conclusion: It is demonstrated that higher SNR can be achieved by cryogenically cooling the 14-channel array. A cryogenic array suitable for clinical imaging can be further developed on the array proposed. The cryogenic coil array is most likely suited for scenarios in which high SNR deep in a head and decent SNR on the periphery are required., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: Intrarenal backflow (IRB) is known to occur at increased intrarenal pressure (IRP). Irrigation during ureteroscopy increases IRP. Complications such as sepsis is more frequent after prolonged high-pressure ureteroscopy. We evaluated a new method to document and visualize intrarenal backflow as a function of IRP and time in a pig model., Methods: Studies were performed on five female pigs. A ureteral catheter was placed in the renal pelvis and connected to a Gadolinium/ saline solution 3 ml/L for irrigation. An occlusion balloon-catheter was left inflated at the uretero-pelvic junction and connected to a pressure monitor. Irrigation was successively regulated to maintain steady IRP levels at 10, 20, 30, 40 and 50 mmHg. MRI of the kidneys was performed at 5-minute intervals. PCR and immunoassay analyses were executed on the harvested kidneys to detect potential changes in inflammatory markers., Results: MRI showed backflow of Gadolinium into the kidney cortex in all cases. The mean time to first visual damage was 15 minutes and the mean registered pressure at first visual damage was 21 mmHg. On the final MRI the mean percentage of IRB affected kidney was 66% after irrigation with a mean maximum pressure of 43 mmHg for a mean duration of 70 minutes. Immunoassay analyses showed increased MCP-1 mRNA expression in the treated kidneys compared to contralateral control kidneys., Conclusions: Gadolinium enhanced MRI provided detailed information about IRB that has not previously been documented. IRB occurs at even very low pressures, and these findings are in conflict with the general consensus that keeping IRP below 30-35 mmHg eliminates the risk of post-operative infection and sepsis. Moreover, the level of IRB was documented to be a function of both IRP and time. The results of this study emphasize the importance of keeping IRP and OR time low during ureteroscopy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lildal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic kidney disease (CKD) is common and has huge implications for health and mortality. It is aggravated by intrarenal fibrosis, but the assessment of fibrosis is limited to kidney biopsies, which carry a risk of complications and sampling errors. This calls for a noninvasive modality for diagnosing and staging intrarenal fibrosis. The current, exploratory study evaluates a multiparametric MRI protocol including sodium imaging ( 23 Na-MRI) to determine the opportunities within this modality to assess kidney injury as a surrogate endpoint of fibrosis. The study includes 43 pigs exposed to ischemia-reperfusion injury (IRI) or unilateral ureteral obstruction (UUO), or serving as healthy controls. Fibrosis was determined using gene expression analysis of collagen. The medulla/cortex ratio of 23 Na-MRI decreased in the injured kidney in the IRI pigs, but not in the UUO pigs (p = 0.0180, p = 0.0754). To assess the combination of MRI parameters in estimating fibrosis, we created a linear regression model consisting of the cortical apparent diffusion coefficient, ΔR2*, ΔT1, the 23 Na medulla/cortex ratio, and plasma creatinine (R 2  = 0.8009, p = 0.0117). The 23 Na medulla/cortex ratio only slightly improved the fibrosis prediction model, leaving 23 Na-MRI in an ambiguous place for evaluation of intrarenal fibrosis. Use of multiparametric MRI in combination with plasma creatinine shows potential for the estimation of fibrosis in human kidney disease, but more translational and clinical work is warranted before MRI can contribute to earlier diagnosis and evaluation of treatment for acute kidney injury and CKD., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD., Competing Interests: Declaration of interests L.B. and M.D. are employees of AbbVie and own AbbVie stock. AbbVie participated in the design and study conduct for this research as well as in the interpretation of data, review, and approval of the publication. Ellegaard Göttingen Minipigs A/S has the commercialization rights to the genetically altered Göttingen minipig SORL1 model. S.A.S. is a co-founder of Retromer Therapeutics, has equity in the company, and is a paid consultant to the company. O.M.A. also has commercial interests in Retromer Therapeutics, but the company was not involved in any aspects of the study., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the potential effects of [1- 13 C]lactate RF saturation pulses on [ 13 C]bicarbonate detection in hyperpolarized [1- 13 C]pyruvate MRI of the brain., Methods: Thirteen healthy rats underwent MRI with hyperpolarized [1- 13 C]pyruvate of either the brain (n = 8) or the kidneys, heart, and liver (n = 5). Dynamic, metabolite-selective imaging was used in a cross-over experiment in which [1- 13 C]lactate was excited with either 0° or 90° flip angles. The [ 13 C]bicarbonate SNR and apparent [1- 13 C]pyruvate-to-[ 13 C]bicarbonate conversion (k PB ) were determined. Furthermore, simulations were performed to identify the SNR optimal flip-angle scheme for detection of [1- 13 C]lactate and [ 13 C]bicarbonate., Results: In the brain, the [ 13 C]bicarbonate SNR was 64% higher when [1- 13 C]lactate was not excited (5.8 ± 1.5 vs 3.6 ± 1.3; 1.2 to 3.3-point increase; p = 0.0027). The apparent k PB decreased 25% with [1- 13 C]lactate saturation (0.0047 ± 0.0008 s -1 vs 0.0034 ± 0.0006 s -1 ; 95% confidence interval, 0.0006-0.0019 s -1 increase; p = 0.0049). These effects were not present in the kidneys, heart, or liver. Simulations suggest that the optimal [ 13 C]bicarbonate SNR with a TR of 1 s in the brain is obtained with [ 13 C]bicarbonate, [1- 13 C]lactate, and [1- 13 C]pyruvate flip angles of 60°, 15°, and 10°, respectively., Conclusions: Radiofrequency saturation pulses on [1- 13 C]lactate limit [ 13 C]bicarbonate detection in the brain specifically, which could be due to shuttling of lactate from astrocytes to neurons. Our results have important implications for experimental design in studies in which [ 13 C]bicarbonate detection is warranted., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Hyperpolarized 13 C MRI is a powerful technique to study dynamic metabolic processes in vivo; but it has predominantly been used in mammals, mostly humans, pigs, and rodents., Methods: In the present study, we use this technique to characterize the metabolic fate of hyperpolarized [1- 13 C]pyruvate in Burmese pythons (Python bivittatus), a large species of constricting snake that exhibits a four- to tenfold rise in metabolism and large growth of the visceral organs within 24-48 h of ingestion of their large meals., Results: We demonstrate a fivefold elevation of the whole-body lactate-to-pyruvate ratio in digesting snakes, pointing to a large rise in lactate production from pyruvate. Consistent with the well-known metabolic stimulation of digestion, measurements of mitochondrial respiration in hepatocytes in vitro indicate a marked postprandial upregulation of mitochondrial respiration. We observed that a low SNR of the hyperpolarized 13 C produced metabolites in the python, and this lack of signal was possibly due to the low metabolism of reptiles compared with mammals, preventing quantification of alanine and bicarbonate production with the experimental setup used in this study. Spatial quantification of the [1- 13 C]lactate was only possible in postprandial snakes (with high metabolism), where a statistically significant difference between the heart and liver was observed., Conclusion: We confirm the large postprandial rise in the wet mass of most visceral organs, except for the heart, and demonstrated that it is possible to image the [1- 13 C]pyruvate uptake and intracellular conversion to [1- 13 C]lactate in ectothermic animals., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Hyperpolarized (HP) [1- 13 C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1- 13 C]pyruvate to either [1- 13 C]lactate or 13 C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1- 13 C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress., Methods: A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1- 13 C]pyruvate CMR at rest and during adenosine stress. HP [1- 13 C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1- 13 C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress., Results: Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1- 13 C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (k PL ) for lactate increased from 11 ± 9 *10 -3 to 20 ± 10 * 10 -3  s -1 , p = 0.04. The pyruvate oxidation rate (k PB ) increased from 4 ± 4 *10 -3 to 12 ± 7 *10 -3  s -1 , p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R 2  = 0.44, p = 0.02)., Conclusions: Adenosine stress testing combined with HP [1- 13 C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1- 13 C]pyruvate CMR into clinical cardiac imaging. Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15., (© 2022. The Author(s).)

Personalized medicine or individualized therapy promises a paradigm shift in healthcare. This is particularly true in complex and multifactorial diseases such as diabetes and the multitude of related pathophysiological complications. Diabetic cardiomyopathy represents an emerging condition that could be effectively treated if better diagnostic and, in particular, better therapeutic monitoring tools were available. In this study, we investigate the ability to differentiate low and high doses of metabolically targeted therapy in an obese type 2 diabetic rat model. Low-dose dichloroacetate (DCA) treatment was associated with increased lactate production, while no or little change was seen in bicarbonate production. High-dose DCA treatment was associated with a significant metabolic switch towards increased bicarbonate production. These findings support further studies using hyperpolarized [1- 13 C]-pyruvate magnetic resonance imaging to differentiate treatment effects and thus allow for personalized titration of therapeutics., (© 2021 John Wiley & Sons, Ltd.)

Aims: Persistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection., Methods and Results: 22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal., Conclusion: Among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wood, Kirkevang, Agergaard, Leth, Hansen, Laustsen, Larsen, Jensen, Østergaard, Bøtker, Poulsen and Kim.)

Background: Magnetic resonance imaging (MRI) with hyperpolarized [1- 13 C]pyruvate allows real-time and pathway specific clinical detection of otherwise unimageable in vivo metabolism. However, the comparability between sites and protocols is unknown. Here, we provide initial experiences on the agreement of hyperpolarized MRI between sites and protocols by repeated imaging of same healthy volunteers in Europe and the US., Methods: Three healthy volunteers traveled for repeated multicenter brain MRI exams with hyperpolarized [1- 13 C]pyruvate within one year. First, multisite agreement was assessed with the same echo-planar imaging protocol at both sites. Then, this was compared to a variable resolution echo-planar imaging protocol. In total, 12 examinations were performed. Common metrics of 13 C-pyruvate to 13 C-lactate conversion were calculated, including the k PL , a model-based kinetic rate constant, and its model-free equivalents. Repeatability was evaluated with intraclass correlation coefficients (ICC) for absolute agreement computed using two-way random effects models., Results: The mean k PL across all examinations in the multisite comparison was 0.024 ± 0.0016 s -1 . The ICC of the k PL was 0.83 ( p = 0.14) between sites and 0.7 ( p = 0.09) between examinations of the same volunteer at any of the two sites. For the model-free metrics, the lactate Z-score had similar site-to-site ICC, while it was considerably lower for the lactate-to-pyruvate ratio., Conclusions: Estimation of metabolic conversion from hyperpolarized [1- 13 C]pyruvate to lactate using model-based metrics such as k PL suggests close agreement between sites and examinations in volunteers. Our initial results support harmonization of protocols, support multicenter studies, and inform their design.

Purpose: The number of glomeruli is different in men and women, as they also present different prevalence and progression of chronic kidney disease. A recent study has demonstrated a potential difference in renal metabolism between sexes, and a potential explanation could be the differences in glomeruli number. This study investigates the potential correlation between glomerular number and pyruvate metabolism in healthy kidneys., Methods: This study is an experimental study with rats (N = 12). We used cationized-ferritin MRI to visualize and count glomeruli and hyperpolarized [1- 13 C]pyruvate to map the metabolism. Dynamic contrast-enhanced MRI was used to analyze kidney hemodynamics using gadolinium tracer., Results: Data showed no or subtle correlation between the number of glomeruli and the pyruvate metabolism. Minor differences were observed in the number of glomeruli (female = 24,509 vs. male = 26 350; p = .16), renal plasma flow (female = 606.6 vs. male= 455.7 ml/min/100 g; p = .18), and volume of distribution (female = 87.44 vs. male = 76.61 ml/100 ml; p = .54) between sexes. Mean transit time was significantly prolonged in males compared with females (female = 8.868 s vs. male = 10.63 s; p = .04)., Conclusion: No strong statistically significant correlation between the number of glomeruli and the pyruvate metabolism was found in healthy rat kidneys., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: Hyperpolarized [1- 13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1- 13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment., Methods: Thirty-five rats were scanned with hyperpolarized [1- 13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with β-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point., Results: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1- 13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO 2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO 2 /pyruvate ratio, as measured by hyperpolarized MRS., Conclusion: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1- 13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism., (© 2021 International Society for Magnetic Resonance in Medicine.)

New Findings: What is the central question of this study? Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model? What is the main finding and its importance? The logistical set-up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1- 13 C]lactate to [1- 13 C]pyruvate, [1- 13 C]alanine to [1- 13 C]pyruvate, and 13 C-bicarbonate to [1- 13 C]pyruvate, implying that the hyperpolarization technique might not be optimal for detecting effects of insulin in skeletal muscle of anaesthetized animals, which is of significance for future studies., Abstract: In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1- 13 C]pyruvate injection and hMR at baseline and after intervention. The glucose infusion rate per kilogram increased by a statistically significant amount in the HE and HH groups (P < 0.001). Hyperpolarized magnetic resonance showed no statistically significant changes in metabolite ratios: [1- 13 C]lactate to [1- 13 C]pyruvate in the HH group versus control group (P = 0.19); and 13 C-bicarbonate to [1- 13 C]pyruvate ratio in the HE group versus the control group (P = 0.12). We found evidence of profound increments in glucose infusion rates representing skeletal muscle glucose uptake, but interestingly, no signs of significant changes in aerobic and anaerobic metabolism using hMR. These results imply that hyperpolarized [1- 13 C]pyruvate might not be optimally suited to detect effects of insulin in anaesthetized resting skeletal muscle, which is of significance for future studies., (© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The purpose of the current study was to investigate if hyperpolarized [1- 13 C]pyruvate can inform us on the metabolic consequences for the kidney glucose metabolism upon treatment with the pyruvate kinase M2 (PKM2) activator TEPP-46, which has shown promise as a novel therapeutic target for diabetic nephropathy. A healthy male Wistar rat model was employed to study the conversion of [1- 13 C]pyruvate to [1- 13 C]lactate in the kidney 2 and 4 h after treatment with TEPP-46. All rats were scanned with hyperpolarized [1- 13 C]pyruvate kidney MR and vital parameters and blood samples were taken after scanning. The PKM2 activator TEPP-46 increases the glycolytic activity in the kidneys, leading to an increased lactate production, as seen by hyperpolarized pyruvate-to-lactate conversion. The results are supported by an increase in blood lactate, a decreased blood glucose level and an increased pyruvate kinase (PK) activity. The metabolic changes observed in both kidneys following treatment with TEPP-46 are largely independent of renal function and could as such represent a new and extremely sensitive metabolic readout for future drugs targeting PKM2. These results warrant further studies in disease models to evaluate if [1- 13 C]pyruvate-to-[1- 13 C]lactate conversion can predict treatment outcome., (© 2021 John Wiley & Sons, Ltd.)

Purpose: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1- 13 C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts., Methods: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1- 13 C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts., Results: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1- 13 C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values., Conclusion: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information-in combination with already established MR methods for cardiac investigation-provides a powerful tool to aid the progress of donor heart preservation., (© 2020 International Society for Magnetic Resonance in Medicine.)

Mechanical unloading of the left ventricle reduces infarct size after acute myocardial infarction by reducing cardiac work. Left ventricular veno-occlusive unloading reduces cardiac work and may reduce ischemia and reperfusion injury. In a porcine model of myocardial ischemia-reperfusion injury we randomized 18 pigs to either control or veno-occlusive unloading using a balloon engaged from the femoral vein into the inferior caval vein and inflated at onset of ischemia. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to determine the myocardial area at risk and infarct size, respectively. Pressure-volume loops were recorded to calculate cardiac work, left ventricular (LV) volumes and ejection fraction. Veno-occlusive unloading reduced infarct size compared with controls (Unloading 13.9 ± 8.2% versus Control 22.4 ± 6.6%; p = 0.04). Unloading increased myocardial salvage (54.8 ± 23.4% vs 28.5 ± 14.0%; p = 0.02), while the area at risk was similar (28.4 ± 6.7% vs 27.4 ± 5.8%; p = 0.74). LV ejection fraction was preserved in the unloaded group, while the control group showed a reduced LV ejection fraction. Veno-occlusive unloading reduced myocardial infarct size and preserved LV ejection fraction in an experimental acute ischemia-reperfusion model. This proof-of-concept study demonstrated the potential of veno-occlusive unloading as an adjunctive cardioprotective therapy in patients undergoing revascularization for acute myocardial infarction.

Objective: Magnetic resonance imaging with hyperpolarized contrast agents can provide unprecedented in vivo measurements of metabolism, but yields images that are lower resolution than that achieved with proton anatomical imaging. In order to spatially localize the metabolic activity, the metabolic image must be interpolated to the size of the proton image. The most common methods for choosing the unknown values rely exclusively on values of the original uninterpolated image., Methods: In this work, we present an alternative method that uses the higher-resolution proton image to provide additional spatial structure. The interpolated image is the result of a convex optimization algorithm which is solved with the fast iterative shrinkage threshold algorithm (FISTA)., Results: Results are shown with images of hyperpolarized pyruvate, lactate, and bicarbonate using data of the heart and brain from healthy human volunteers, a healthy porcine heart, and a human with prostate cancer.

The signal acquired in sodium ( 23 Na) MR imaging is proportional to the concentration of sodium in a voxel, and it is possible to convert between the two using external calibration phantoms. Postprocessing, and subsequent analysis, of sodium renal images is a simple task that can be performed with readily available software. Here we describe the process of conversion between sodium signal and concentration, estimation of the corticomedullary sodium gradient and the procedure used for quadrupolar relaxation analysis.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Regardless of the importance of acid-base disturbances in cardiac disease, there are currently no methods for clinical detection of pH in the heart. Several magnetic resonance imaging techniques hold translational promise and may enable in-vivo mapping of pH. We provide a brief overview of these emerging techniques. A particular focus is on the promising advance of magnetic resonance spectroscopy and imaging with hyperpolarized 13 C-subtrates as biomarkers of myocardial pH. Hyperpolarization allows quantification of key metabolic substrates and their metabolites. Hereby, pH-sensitive reactions can be probed to provide a measure of acid-base alterations. To date, the most used substrates are [1- 13 C]pyruvate and 13 C-labeled bicarbonate; however, others have been suggested. In cardiovascular medicine, hyperpolarized magnetic resonance spectroscopy has been used to probe acid-base disturbances following pharmacological stress, ischemia and heart failure in animals. In addition to pH-estimation, the technique can quantify fluxes such as the pivotal conversion of pyruvate to lactate via lactate dehydrogenase. This capability, a good safety profile and the fact that the technique is employable in clinical scanners have led to recent translation in early clinical trials. Thus, magnetic resonance spectroscopy and imaging may provide clinical pH-imaging in the near future., (Copyright © 2020 Bøgh, Hansen, Mariager, Bertelsen, Ringgaard and Laustsen.)

Purpose: Normothermic perfusion is an emerging strategy for donor organ preservation and therapy, incited by the high worldwide demand for organs for transplantation. Hyperpolarized MRI and MRS using [1- 13 C]pyruvate and other 13 C-labeled molecules pose a novel way to acquire highly detailed information about metabolism and function in a noninvasive manner. This study investigates the use of this methodology as a means to study and monitor the state of ex vivo perfused porcine kidneys, in the context of kidney graft preservation research., Methods: Kidneys from four 40-kg Danish domestic pigs were perfused ex vivo with whole blood under normothermic conditions, using an MR-compatible perfusion system. Kidneys were investigated using 1 H MRI as well as hyperpolarized [1- 13 C]pyruvate MRI and MRS. Using the acquired anatomical, functional and metabolic data, the state of the ex vivo perfused porcine kidney could be quantified., Results: Four kidneys were successfully perfused for 120 minutes and verified using a DCE perfusion experiment. Renal metabolism was examined using hyperpolarized [1- 13 C]pyruvate MRI and MRS, and displayed an apparent reduction in pyruvate turnover compared with the usual case in vivo. Perfusion and blood gas parameters were in the normal ex vivo range., Conclusion: This study demonstrates the ability to monitor ex vivo graft metabolism and function in a large animal model, resembling human renal physiology. The ability of hyperpolarized MRI and MRS to directly compare the metabolic state of an organ in vivo and ex vivo, in combination with the simple MR implementation of normothermic perfusion, renders this methodology a powerful future tool for graft preservation research., (© 2020 International Society for Magnetic Resonance in Medicine.)

Sodium magnetic resonance imaging (MRI) is a powerful, non-invasive technique to assess sodium distribution within the kidney. Here we undertook pre-clinical and clinical studies to quantify the corticomedullary sodium gradient in healthy individuals and in a porcine model of diuresis. The results demonstrated that sodium MRI could detect spatial differences in sodium biodistribution across the kidney. The sodium gradient of the kidney changed significantly after diuresis in the pig model and was independent of blood electrolyte measurements. Thus, rapid sodium MRI can be used to dynamically quantify sodium biodistribution in the porcine and human kidney., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Renal ischemia-reperfusion injury (IRI) is one of the most common types of acute kidney injury. Spironolactone has shown promising kidney protective effects in renal IRI in rats. We investigated the hemodynamic and metabolic effects of spironolactone (100 mg/kg) administered immediately after 40 min unilateral kidney ischemia in rats. Hyperpolarized MRI using co-polarized [1- 13 C]pyruvate and [ 13 C, 15 N 2 ]urea as well as 1 H dynamic contrast-enhanced (DCE) MRI was performed 24 h after induction of ischemia. We found a significant decrease in renal blood flow (RBF) in the ischemic kidney compared with the contralateral one measured using DCE and [ 13 C, 15 N 2 ]urea. The RBF measured using [1- 13 C]pyruvate and [ 13 C, 15 N 2 ]urea was significantly altered by spironolactone. The RBFs in the ischemic kidney compared with the contralateral kidney were decreased similarly as measured using both [ 13 C, 15 N 2 ]urea and [1- 13 C]pyruvate in the spironolactone-treated group. Spironolactone treatment increased the perfusion-corrected pyruvate metabolism by 54% in both the ischemic and contralateral kidney. Furthermore, we showed a correlation between vascular permeability using a histological Evans blue analysis and the ratio of the volumes of distribution (VoDs), ie VoD-[ 13 C, 15 N 2 ]urea/VoD-[1- 13 C]pyruvate. This suggests that [ 13 C, 15 N 2 ]urea/[1- 13 C]pyruvate VoD ratio may be a novel indicator of renal vascular permeability associated with renal damage in rodents., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Calibration of hyperpolarized 13 C-MRI is limited by the low signal from endogenous carbon-containing molecules and consequently requires 13 C-enriched external phantoms. This study investigated the feasibility of using either 23 Na-MRI or 1 H-MRI to calibrate the 13 C excitation., Methods: Commercial 13 C-coils were used to estimate the transmit gain and center frequency for 13 C and 23 Na resonances. Simulations of the transmit B 1 profile of a Helmholtz loop were performed. Noise correlation was measured for both nuclei. A retrospective analysis of human data assessing the use of the 1 H resonance to predict [1- 13 C]pyruvate center frequency was also performed. In vivo experiments were undertaken in the lower limbs of 6 pigs following injection of hyperpolarized 13 C-pyruvate., Results: The difference in center frequencies and transmit gain between tissue 23 Na and [1- 13 C]pyruvate was reproducible, with a mean scale factor of 1.05179 ± 0.00001 and 10.4 ± 0.2 dB, respectively. Utilizing the 1 H water peak, it was possible to retrospectively predict the 13 C-pyruvate center frequency with a standard deviation of only 11 Hz sufficient for spectral-spatial excitation-based studies., Conclusion: We demonstrate the feasibility of using the 23 Na and 1 H resonances to calibrate the 13 C transmit B 1 using commercially available 13 C-coils. The method provides a simple approach for in vivo calibration and could improve clinical workflow., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To test a new parallel imaging strategy for acceleration of hyperpolarized 13 C MR acquisitions based on a 3D blipped stack-of-spirals trajectory and conjugate-gradient SENSE reconstruction with precalibrated sensitivities., Methods: The blipped stack-of-spirals trajectory was developed for an acceleration factor of 4, based on an undersampled stack-of-spirals with gradient blips during spiral readout. The trajectory was developed with volumetric coverage of a large FOV and with high spatial resolution. High temporal resolution was attained through spectral-spatial excitation and 4 excitations per volume. The blipped stack-of-spirals was evaluated in simulations and phantom experiments. Next, the method was evaluated for kidney and cardiac imaging in 2 separate healthy pigs., Results: Simulation and phantom results showed successful acquisition and reconstruction, but also revealed reconstruction challenges for certain locations and for wide signal sources. For the kidney experiment, the accelerated acquisition showed high similarity to 2 separately acquired fully sampled data sets with matched spatial and temporal resolution, respectively. For the cardiac experiment, the accelerated acquisition proved able to map each metabolite in 3 dimensions within a single cardiac cycle., Conclusion: The proposed method demonstrated effective mapping of metabolism in both kidneys and the heart of healthy pigs. Limitations seen in phantom experiments, may be irrelevant for most clinical applications, but should be kept in mind as well as reconstruction challenges related to residual aliasing. All in all, we show that the blipped stack-of-spirals is a relevant parallel imaging method for hyperpolarized human imaging, facilitating better insights into metabolism compared with nonaccelerated acquisition., (© 2020 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop an autonomous, in-bore, MR-compatible cryostat cooled with liquid nitrogen that provides full-day operation, and to demonstrate that the theoretical signal-to-noise benefit can be achieved for 13 C imaging at 3 T (32.13 MHz)., Methods: The cryogenic setup uses a vacuum-insulated fiberglass cryostat, which indirectly cools a cold finger where the RF coil is attached. The cryostat was evacuated before use and had a reservoir of liquid nitrogen for full-day operation. A 30 × 40 mm 2 copper coil was mounted inside the cryostat with a 3-mm distance to the sample. Two examples of in vivo experiments of rat brain metabolism after a hyperpolarized [1- 13 C]pyruvate injection are reported., Results: A coil Q-factor ratio of Q 88K /Q 290K = 550/280 was obtained, and the theoretical SNR enhancement was verified with MR measurements. We achieved a coil temperature of 88 K and a preamplifier temperature of 77 K. A 2-fold overall SNR enhancement was achieved, compared with the best case at room temperature. The thermal performance of the coil was adequate for in vivo experiments, with an autonomy of 5 hours consuming 6 L of LN 2 , extendable to over 12 hours by LN 2 refilling., Conclusion: Cryogenic surface coils can be highly beneficial for 13 C imaging, provided that the coil-to-sample distance remains short. An autonomous, in-bore cryostat was developed that achieved the theoretical improvement in SNR., (© 2019 International Society for Magnetic Resonance in Medicine.)

In heart failure, myocardial overload causes vast metabolic changes that impair cardiac energy production and contribute to deterioration of contractile function. However, metabolic therapy is not used in heart failure care. We aimed to investigate the interplay between cardiac function and myocardial carbohydrate metabolism in a large animal heart failure model. Using magnetic resonance spectroscopy with hyperpolarized pyruvate and magnetic resonance imaging at rest and during pharmacological stress, we investigated the in-vivo cardiac pyruvate metabolism and contractility in a porcine model of chronic pulmonary insufficiency causing right ventricular volume overload. To assess if increasing the carbohydrate metabolic reserve improves the contractile reserve, a group of animals were fed dichloroacetate, an activator of pyruvate oxidation. Volume overload caused heart failure with decreased pyruvate dehydrogenase flux and poor ejection fraction reserve. The animals treated with dichloroacetate had a larger contractile response to dobutamine stress than non-treated animals. Further, dichloroacetate prevented myocardial hypertrophy. The in-vivo metabolic data were validated by mitochondrial respirometry, enzyme activity assays and gene expression analyses. Our results show that pyruvate dehydrogenase kinase inhibition improves the contractile reserve and decreases hypertrophy by augmenting carbohydrate metabolism in porcine heart failure. The approach is promising for metabolic heart failure therapy.

Aims: Early detection of heart failure is important for timely treatment. During the development of heart failure, adaptive intracellular metabolic processes that evolve prior to macro-anatomic remodelling, could provide an early signal of impending failure. We hypothesized that metabolic imaging with hyperpolarized magnetic resonance would detect the early development of heart failure before conventional echocardiography could reveal cardiac dysfunction., Methods and Results: Five 8.5 kg piglets were subjected to pulmonary banding and subsequently examined by [1-13C]pyruvate hyperpolarization, conventional magnetic resonance imaging, echocardiography, and blood testing, every 4 weeks for 16 weeks. They were compared with a weight matched, healthy control group. Conductance catheter examination at the end of the study showed impaired right ventricular systolic function along with compromised left ventricular diastolic function. After 16 weeks, we saw a significant decrease in the conversion ratio of pyruvate/bicarbonate in the left ventricle from 0.13 (0.04) in controls to 0.07 (0.02) in animals with pulmonary banding, along with a significant increase in the lactate/bicarbonate ratio to 3.47 (1.57) compared with 1.34 (0.81) in controls. N-terminal pro-hormone of brain natriuretic peptide was increased by more than 300%, while cardiac index was reduced to 2.8 (0.95) L/min/m2 compared with 3.9 (0.95) in controls. Echocardiography revealed no changes., Conclusion: Hyperpolarization detected a shift towards anaerobic metabolism in early stages of right ventricular dysfunction, as evident by an increased lactate/bicarbonate ratio. Dysfunction was confirmed with conductance catheter assessment, but could not be detected by echocardiography. Hyperpolarization has a promising future in clinical assessment of heart failure in both acquired and congenital heart disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Placenta metabolism is closely linked to pregnancy outcome, and few modalities are currently available for studying the human placenta. Here, we aimed to investigate a novel ex vivo human placenta perfusion system for metabolic imaging using hyperpolarized [1- 13 C]pyruvate. The metabolic effects of 3 different human placentas were investigated using functional and metabolic magnetic resonance imaging. The placenta glucose metabolism and hemodynamics were characterized with hyperpolarized [1- 13 C]pyruvate magnetic resonance imaging and by dynamic contrast-enhanced (DCE) imaging. Hyperpolarized [1- 13 C]pyruvate showed a decrease in the 13 C-lactate/ 13 C-pyruvate ratio from the highest to the lowest metabolic active placenta. The metabolic profile was complemented by a more homogenous distributed hemodynamic response, with a longer mean transit time and higher blood volume. This study shows different placenta metabolic and hemodynamic features associated with the placenta functional status using hyperpolarized magnetic resonance ex vivo. This study supports further studies using ex vivo metabolic imaging of the placenta alterations associated with pregnancy complications., (© 2019 The Authors. Published by Grapho Publications, LLC.)

Purpose: To investigate auto- and pre-calibration coil profile estimation for parallel imaging reconstruction of hyperpolarized 13 C MRI volumetric data., Methods: Parallel imaging reconstruction was studied with 3 different approaches for coil profile estimation: auto-calibration, phantom calibration, and theoretic calibration. Acquisition was performed with a 3D stack-of-spirals sequence with spectral-spatial excitation and Cartesian undersampling. Parallel imaging reconstructions were done with conjugate gradient SENSE and 3D gridding with inhomogeneity correction. The approaches were compared in simulations with different SNR, through phantom experiments, and in an in vivo pig study focused on the kidneys. All imaging was done with a rigid home-built 12-channel 13 C receive coil at 3T., Results: The phantom calibrated and theoretic approaches resulted in the best structural similarities in simulations and demonstrated higher image quality in the phantom experiments compared to the auto-calibrated approach. In vivo mapping of pyruvate uptake and lactate conversion improved for accelerated acquisitions because of a better temporal resolution. From a practical and image quality point of view, use of theoretic coil profiles led to improved results compared to the other approaches., Conclusion: The success of the theoretic coil profile estimation demonstrates a negligible effect of load on sensitivity profiles at the carbon frequency at 3T. Through theoretic or phantom calibrated parallel imaging, accelerated 3D volumes could be reconstructed with sufficient sensitivity, temporal, and spatial resolution to map the metabolism of kidneys exemplifying abdominal organs. This approach overcomes a critical step in the clinical translation of parallel imaging in hyperpolarized 13 C MR., (© 2019 International Society for Magnetic Resonance in Medicine.)

Aims: Contact force (CF) between radiofrequency (RF) ablation catheter and myocardium and ablation index (AI) correlates with RF lesion depth and width in normal-voltage (>1.5 mV) myocardium (NVM). We investigate the impact of CF on RF lesion depth and width in low (<0.5 mV) (LVM) and intermediate-voltage (0.5-1.5 mV) myocardium (IVM) following myocardial infarction. Correlation between RF lesion depth and width evaluated by native contrast magnetic resonance imaging (ncMRI) and gross anatomical evaluation was investigated., Methods and Results: Twelve weeks after myocardial infarction, 10 pigs underwent electroanatomical mapping and endocardial RF ablations were deployed in NVM, IVM, and LVM myocardium. In vivo ncMRI was performed before the heart was excised and subjected to gross anatomical evaluation. Ninety (82%) RF lesions were evaluated. Radiofrequency lesion depth and width were smaller in IVM and LVM compared with NVM (P < 0.001). Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM (CF and AI P < 0.001) and IVM (CF and AI depths P < 0.001; CF and AI widths P < 0.05). Native contrast magnetic resonance imaging evaluated RF lesion depth and width correlated with gross anatomical depth and width (NVM and IVM P < 0.001; LVM P < 0.05)., Conclusions: Radiofrequency lesions deployed by similar duration, power and CF are smaller in IVM and LVM than in NVM. Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM and IVM but not in LVM. Native contrast magnetic resonance imaging may be useful to assess RF lesion depth and width in NVM, IVM, and LVM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The purpose of the study was to validate by histopathology, contrast enhanced cine steady-state free precession and T2-weighted CMR for the assessment of ischemic myocardial area-at-risk (AAR) in the presence of microvascular obstruction (MVO). Eleven anesthetized pigs underwent CMR 7 to 10 days post infarction. The area-at-risk was measured from T2-weighted fast spin echo (T2-STIR) and contrast-enhanced steady-state free precession magnetic resonance imaging (CE-SSFP) images using semi-automated algorithms based on a priori knowledge of perfusion territory. Also, late gadolinium enhancement (LGE) was performed to measure final infarct size (FIS). Histopathological comparison with Evans blue dye to define AAR and triphenyltetrazolium chloride to define FIS served as the reference. All infarcts demonstrated MVO on LGE images. Bland-Altman analysis showed no significant bias in AAR or myocardial salvage between T2-STIR and CE-SSFP or between CMR and histopathology. The mean differences ± 2SD from Bland-Altman analysis were: AAR: Evans Blue vs. T2-STIR [0.7%; + 13.5%; - 12.1%]; AAR: Evans Blue vs. CE-SSFP [0.1%; + 13.8%; - 13.7%]; AAR: T2-STIR vs. CE-SSFP [0.7%; + 6.2%; - 4.9%]; Salvage: Evans Blue - TTC vs. T2-STIR-LGE [0.8%; + 11.1%; - 9.6%]; Salvage: Evans Blue - TTC vs. CE-SSFP-LGE [0.1%; + 9.9%; - 9.6%]; Salvage: CE-SSFP-LGE vs. T2-STIR-LGE [0.7%; + 6.2%; - 4.9%]. Both T2-STIR and CE-SSFP sequences allow for unbiased quantification of AAR in the presence of ischemia/reperfusion injury when analysed by semi-automated algorithms. These experimental data, which was validated by histopathology, supports the use of CMR for the assessment of myocardial salvage during the subacute phase.

Purpose: Deranged metabolism is now recognized as a key causal factor in a variety of heart diseases, and is being studied extensively. However, invasive methods may alter metabolism, and conventional imaging techniques measure tracer uptake but not downstream metabolism. These challenges may be overcome by hyperpolarized MR, a noninvasive technique currently crossing the threshold into human trials. The aim of this study was to image metabolic changes in the heart in response to endogastric glucose bolus and to acute hypertension., Methods: Five postprandial pigs were scanned with hyperpolarized [1- 13 C]pyruvate cardiac MR at baseline, after oral glucose bolus, and after infusion of angiotensin-II., Results: No effect of glucose bolus was seen using hyperpolarized [1- 13 C]pyruvate MR despite changes in circulating substrates. During angiotensin-II infusion, blood pressure increased 179% (P = 0.008) and ejection fraction decreased from 54 ± 2% to 47 ± 6% (P = 0.03) The hemodynamic changes were accompanied by increases in the hyperpolarized [1- 13 C]pyruvate MR derived ratios of lactate/alanine (from 0.58 ± 0.13 to 0.78 ± 0.06, P = 0.03) and bicarbonate/alanine (from 0.55 ± 0.12 to 0.91 ± 0.14, P = 0.007)., Conclusion: Glucose loading did not alter cardiac metabolism, but during acute hypertensive stress, cardiac aerobic, carbohydrate metabolism, and pyruvate-lactate exchange was altered. Hyperpolarized MR allows noninvasive evaluation of acute changes in cardiac metabolism. However, hemodynamics must be taken into account when interpreting the results., (© 2018 International Society for Magnetic Resonance in Medicine.)