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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.)

MRI with hyperpolarized (HP) 13 C agents, also known as HP 13 C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of HP agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1- 13 C]pyruvate-by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13 C-pyruvate preparation; (2) MRI system setup and calibrations; (3) data acquisition and image reconstruction; and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the "HP 13 C MRI Consensus Group" as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods and Equipment study groups. It further aims to provide a comprehensive reference for future consensus, building as the field continues to advance human studies with this metabolic imaging modality., (© 2024 International Society for Magnetic Resonance in Medicine.)

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 investigate high-resolution hyperpolarized (HP) 13 C pyruvate MRI for measuring cerebral perfusion in the human brain., Methods: HP [1- 13 C]pyruvate MRI was acquired in five healthy volunteers with a multi-resolution EPI sequence with 7.5 × 7.5 mm 2 resolution for pyruvate. Perfusion parameters were calculated from pyruvate MRI using block-circulant singular value decomposition and compared to relative cerebral blood flow calculated from arterial spin labeling (ASL). To examine regional perfusion patterns, correlations between pyruvate and ASL perfusion were performed for whole brain, gray matter, and white matter voxels., Results: High resolution 7.5 × 7.5 mm 2 pyruvate images were used to obtain relative cerebral blood flow (rCBF) values that were significantly positively correlated with ASL rCBF values (r = 0.48, 0.20, 0.28 for whole brain, gray matter, and white matter voxels respectively). Whole brain voxels exhibited the highest correlation between pyruvate and ASL perfusion, and there were distinct regional patterns of relatively high ASL and low pyruvate normalized rCBF found across subjects., Conclusion: Acquiring HP 13 C pyruvate metabolic images at higher resolution allows for finer spatial delineation of brain structures and can be used to obtain cerebral perfusion parameters. Pyruvate perfusion parameters were positively correlated to proton ASL perfusion values, indicating a relationship between the two perfusion measures. This HP 13 C study demonstrated that hyperpolarized pyruvate MRI can assess cerebral metabolism and perfusion within the same study., (© 2023 International Society for Magnetic Resonance in Medicine.)

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.)

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: To develop a coil-based method to obtain accurate sensitivity profiles in 13 C MRI at 3T from the endogenous 23 Na. An eight-channel array is designed for 13 C MR acquisitions. As application examples, the array is used for two-fold accelerated acquisitions of both hyperpolarized 13 C metabolic imaging of pig kidneys and the human brain., Methods: A flexible coil array was tuned optimally for 13 C at 3T (32.1 MHz), with the coil coupling coefficients matched to be nearly identical at the resonance frequency of 23 Na (33.8 MHz). This is done by enforcing a high decoupling (obtained through highly mismatched preamplifiers) and adjusting the coupling frequency response. The SNR performance is compared to reference coils., Results: The measured sensitivity profiles on a phantom showed high spatial similarity for 13 C and 23 Na resonances, with average noise correlation of 9 and 11%, respectively. For acceleration factors 2, 3, and 4, the obtained maximum g-factors were 1.0, 1.1, and 2.6, respectively. The 23 Na profiles obtained in vivo could be used successfully to perform two-fold acceleration of hyperpolarized 13 C 3D acquisitions of both pig kidneys and a healthy human brain., Conclusion: A receive array has been developed in such a way that the 13 C sensitivity profiles could be accurately obtained from measurements at the 23 Na frequency. This technique facilitates accelerated acquisitions for hyperpolarized 13 C imaging. The SNR performance obtained at the 13 C frequency, compares well to other state-of-the-art coils for the same purpose, showing slightly better superficial and central SNR., (© 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.)

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.)

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.)

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.)

Purpose: Renal tubulointerstitial fibrosis is strongly linked to the progressive decline of renal function seen in chronic kidney disease. State-of-the-art noninvasive diagnostic modalities are currently unable to detect the earliest changes associated with the onset of fibrosis. This study was undertaken to evaluate the potential for detecting the earliest alterations in fibrogenesis using a biofluid-based method and metabolic hyperpolarized [1- 13 C]pyruvate imaging., Methods: We evaluated renal fibrosis in a combined ischemia reperfusion-induced and streptozotocin-induced diabetic nephropathy rodent model by hyperpolarized [1- 13 C]pyruvate MRI and correlated the metabolic MRI parameters with biomarkers of fibrosis measured on renal tissue and plasma/urine., Results: The hyperglycemic rats experienced maladaptive injury repair after the ischemic insults, as shown by the elevation in the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Renal function was significantly impaired in the ischemic hyperglycemic kidney, as seen in the reduced perfusion and single-kidney glomerular filtration rate. A deranged energy metabolism was detected in the ischemic hyperglycemic kidney, as seen in the reduced fractional perfusion of lactate. Renal fibrosis biomarkers correlated significantly with the alanine production., Conclusion: Hyperpolarized carbon-13 MRI provides a promising approach to assess renal fibrosis in an animal model of fibrotic chronic kidney disease. In particular, the metabolic supply of amino acids for fibrogenesis (alanine production) correlates well with biomarkers of fibrosis. Thus, [1- 13 C]pyruvate-to-[1- 13 C]alanine conversion might be a candidate for noninvasive assessment of renal fibrogenesis., (© 2020 International Society for Magnetic Resonance in Medicine.)

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 assess the utility of Laplacian fitting to describe the differences in hyperpolarized [ 13 C, 15 N]urea T 2 relaxation in ischemic and healthy rodent kidneys., Methods: Six rats with unilateral renal ischemia were investigated. [ 13 C, 15 N]Urea T 2 mapping was undertaken with a radial fast spin echo method, with subsequent postprocessing performed with regularized Laplacian fitting., Results: Simulations showed that Laplacian fitting was stable down to a signal-to-noise ratio of 20. In vivo results showed a significant increase in the mono- and decrease in biexponential pools in ischemia reperfusion injury kidneys, in comparison to healthy (14 ± 10% versus 4 ± 2%, 85 ± 10% versus 95 ± 3%; P < .05)., Conclusion: We demonstrate, for the first time, the differences in multiexponential behavior of [ 13 C, 15 N]urea between the healthy and ischemic rodent kidney. The distribution of relaxation pools were found to be both visually and numerically significantly different. The ability to improve the information level in hyperpolarized MR, by using the relaxation contrast mechanisms is an appealing option, that can easily be adopted in large animals and even in clinical studies in the near future., (© 2019 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.)

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.)

Purpose: Owing to its noninvasive nature, hyperpolarized MRI may improve delineation of myocardial metabolic derangement in heart disease. However, consistency may depend on the changeable nature of cardiac metabolism in relation to whole-body metabolic state. This study investigates the impact of feeding status on cardiac hyperpolarized MRI in a large animal model resembling human physiology., Methods: Thirteen 30-kg pigs were subjected to an overnight fast, and 5 pigs were fed a carbohydrate-rich meal on the morning of the experiments. Vital parameters and blood samples were registered. All pigs were then scanned by hyperpolarized [1- 13 C]pyruvate cardiac MRI, and results were compared between the 2 groups and correlated with circulating substrates and hormones., Results: The fed group had higher blood glucose concentration and mean arterial pressure than the fasted group. Plasma concentrations of free fatty acids (FFAs) were decreased in the fed group, whereas plasma insulin concentrations were similar between groups. Hyperpolarized MRI showed that fed animals had increased lactate/pyruvate, alanine/pyruvate, and bicarbonate/pyruvate ratios. Metabolic ratios correlated negatively with FFA levels., Conclusion: Hyperpolarized MR can identify the effects of different metabolic states on cardiac metabolism in a large animal model. Unlike previous rodent studies, all metabolic derivatives of pyruvate increased in the myocardium of fed pigs. Carbohydrate-rich feeding seems to be a feasible model for standardized, large animal hyperpolarized MRI studies of myocardial carbohydrate metabolism., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Anesthesia is necessary for most animal studies requiring invasive procedures. It is well documented that various types of anesthesia modulate a wide variety of important metabolic and functional processes in the body, and as such, represent a potential limitation in the study design. In the present study, we aimed to investigate the renal functional and metabolic consequences of 3 typical rodent anesthetics used in preclinical MRI: sevoflurane, inaction, and a mixture of fentanyl, fluanisone, and midazolam (FFM)., Methods: The renal effects of 3 different classes of anesthetics (inactin, servoflurane, and FFM) were investigated using functional and metabolic MRI. The renal glucose metabolism and hemodynamics was characterized with hyperpolarized [1- 13 C]pyruvate MRI and by DCE imaging., Results: Rats receiving sevoflurane or FFM had blood glucose levels that were 1.3-fold to 1.4-fold higher than rats receiving inactin. A 2.9-fold and 4.8-fold increased 13 C-lactate/ 13 C-pyruvate ratio was found in the FFM mixture anesthetized group compared with the sevoflurane and the inactin anesthetized groups. The FFM anesthesia resulted in a 50% lower renal plasma flow compared with the sevoflurane and the inactin anesthetized groups., Conclusion: This study demonstrates different renal metabolic and hemodynamic changes under 3 different anesthetics, using hyperpolarized MR in rats. Inactin and sevoflurane were found to affect the renal hemodynamic and metabolic status to a lesser degree than FFM. Sevoflurane anesthesia is particularly easy to induce and maintain during the whole anesthesia procedure, and as such, represents a good alternative to inaction, although it alters the blood glucose level., (© 2018 International Society for Magnetic Resonance in Medicine.)

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.)

Purpose: To investigate the correlation between renal ischemia and 13 C-urea T 2 relaxation rate in an acute kidney injury (AKI) rat model., Methods: Six rats subjected to unilateral renal ischemia were investigated. Creatinine clearance, urine output, plasma creatinine as well as blood-urea nitrogen (BUN) values were acquired before and after the procedure. 1 H T2* mapping was acquired using blood oxygenation level dependent (BOLD) MRI and hyperpolarized 13 C-urea T 2 mapping was acquired using a 2D golden-angle radial approach. Kidney perfusion was estimated using noncontrast flow alternating inversion recovery arterial spin labeling., Results: All rats showed clinical signs of AKI with increased plasma creatinine and increased BUN. Whole kidney 13 C-urea T 2 significantly decreased 26% (P = 0.001) 24 h after reperfusion. A significantly different (3.7 times steeper; P = 0.008) osmolality gradient was observed in the contralateral kidney (P = 0.008; R 2  = 0.86) compared with the postischemic kidney (P = 0.0004, R 2 =0.97). Whole kidney T2* signal (P = 0.14) and T2* gradient (P = 0.26) was similar between the two kidneys. Oxygen availability dependency on 13 C-urea T 2 was investigated by means of the correlation between the BOLD and T 2 signals; a statistically significant difference (P = 0.03) was found in the contralateral kidney (P = 0.0001; R 2  = 0.95), but not in the postischemic kidney (P = 0.31; R 2  = 0.25)., Conclusion: We demonstrate that hyperpolarized [ 13 C, 15 N 2 ]urea T 2 relaxation correlates with renal oxygen tension ( T2*) in the healthy contralateral kidney, but not in the postischemic kidney. The whole kidney T 2 relaxation difference between the postischemic and contralateral kidney may originate from altered blood volume in the postischemic kidney. Magn Reson Med 80:696-702, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: To study hyperpolarized water as an angiography and perfusion tracer in a large animal model., Methods: Protons dissolved in deuterium oxide (D 2 O) were hyperpolarized in a SPINlab dissolution dynamic nuclear polarization (dDNP) polarizer and subsequently investigated in vivo in a pig model at 3 Tesla (T). Approximately 15 mL of hyperpolarized water was injected in the renal artery by hand over 4-5 s., Results: A liquid state polarization of 5.3 ± 0.9% of 3.8 M protons in 15 mL of deuterium oxide was achieved with a T 1 of 24 ± 1 s. This allowed injection through an arterial catheter into the renal artery and subsequently high-contrast imaging of the entire kidney parenchyma over several seconds. The dynamic images allow quantification of tissue perfusion, with a mean cortical perfusion of 504 ± 123 mL/100 mL/min., Conclusion: Hyperpolarized water MR imaging was successfully demonstrated as a renal angiography and perfusion method. Quantitative perfusion maps of the kidney were obtained in agreement with literature and control experiments with gadolinium contrast. Magn Reson Med 78:1131-1135, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: It has been demonstrated that hyperpolarized 13 C MR is a useful tool to study cultured cells. However, cells in culture can alter phenotype, which raises concerns regarding the in vivo significance of such findings. Here we investigate if metabolic phenotyping using hyperpolarized 13 C MR is suitable for cells isolated from kidney tissue, without prior cell culture., Methods: Isolation of tubular cells from freshly excised kidney tissue and treatment with either ouabain or antimycin A was investigated with hyperpolarized MR spectroscopy on a 9.4 Tesla preclinical imaging system., Results: Isolation of tubular cells from less than 2 g of kidney tissue generally resulted in more than 10 million live tubular cells. This amount of cells was enough to yield robust signals from the conversion of 13 C-pyruvate to lactate, bicarbonate and alanine, demonstrating that metabolic flux by means of both anaerobic and aerobic pathways can be quantified using this technique., Conclusion: Ex vivo metabolic phenotyping using hyperpolarized 13 C MR in a preclinical system is a useful technique to study energy metabolism in freshly isolated renal tubular cells. This technique has the potential to advance our understanding of both normal cell physiology as well as pathological processes contributing to kidney disease. Magn Reson Med 78:457-461, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: In the current study, we investigated hyperpolarized urea as a possible imaging biomarker of the renal function by means of the intrarenal osmolality gradient., Methods: Hyperpolarized three-dimensional balanced steady state 13 C MRI experiments alongside kidney function parameters and quantitative polymerase chain reaction measurements was performed on two groups of rats, a streptozotocin type 1 diabetic group and a healthy control group., Results: A significant decline in intrarenal steepness of the urea gradient was found after 4 weeks of untreated insulinopenic diabetes in agreement with an increased urea transport transcription., Conclusion: MRI and hyperpolarized [ 13 C, 15 N]urea can monitor the changes in the corticomedullary urea concentration gradients in diabetic and healthy control rats. Magn Reson Med 77:1650-1655, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: A decline in cortico-medullary osmolality gradient of the kidney may serve as an early indicator of pathological disruption of the tubular reabsorption process. The purpose of this study was to investigate the feasibility of hyperpolarized 13 C, 15 N 2 -urea MRI as a biomarker of renal function in healthy porcine kidneys resembling the human physiology., Methods: Five healthy female Danish domestic pigs (weight 30 kg) were scanned at 3 Tesla (T) using a 13 C 3D balanced steady-state MR pulse sequence following injection of hyperpolarized 13 C, 15 N 2 -urea via a femoral vein catheter. Images were acquired at different time points after urea injection, and following treatment with furosemide., Results: A gradient in cortico-medullary urea was observed with an intramedullary accumulation 75 s after injection of hyperpolarized 13 C, 15 N 2 -urea, whereas images acquired at earlier time points postinjection were dominated by cortical perfusion. Furosemide treatment resulted in an increased urea accumulation in the cortical space, leading to a reduction of the medullary-to-cortical signal ratio of 49%., Conclusion: This study demonstrates that hyperpolarized 13 C, 15 N 2 -urea MRI is capable of identifying the intrarenal accumulation of urea and can differentiate acute renal functional states in multipapillary kidneys, highlighting the potential for human translation. Magn Reson Med 76:1895-1899, 2016. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: The aim of this work was to investigate whether hyperpolarized 13 C, 15 N 2 -urea can be used as an imaging marker of renal injury in renal unilateral ischemic reperfusion injury (IRI), given that urea is correlated with the renal osmotic gradient, which describes the renal function., Methods: Hyperpolarized three-dimensional balanced steady-state 13 C magnetic resonance imaging (MRI) experiments alongside kidney function parameters and quantitative polymerase chain reaction measurements were performed in rats subjected to unilateral renal ischemia for 60-minute and 24-hour reperfusion., Results: We revealed a significant reduction in the intrarenal gradient in the ischemic kidney in agreement with cortical injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, as well as functional kidney parameters., Conclusion: Hyperpolarized functional 13 C, 15 N 2 urea MRI can be used to successfully detect changes in the intrarenal urea gradient post-IRI, thereby enabling in vivo monitoring of the intrarenal functional status in the rat kidney. Magn Reson Med 76:1524-1530, 2016. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: Our aim was to assess a novel (13) C radial fast spin echo golden ratio single shot method for interrogating early renal changes in the diabetic kidney, using hyperpolarized (HP) [(13) C,(15) N2 ]urea as a T2 relaxation based contrast bio-probe., Methods: A novel HP (13) C MR contrast experiment was conducted in a group of streptozotocin type-1 diabetic rat model and age matched controls., Results: A significantly different relaxation time (P = 0.004) was found in the diabetic kidney (0.49 ± 0.03 s) compared with the controls (0.64 ± 0.02 s) and secondly, a strong correlation between the blood oxygen saturation level and the relaxation times were observed in the healthy controls., Conclusion: HP [(13) C,(15) N2 ]urea apparent T2 mapping may be a useful for interrogating local renal pO2 status and renal tissue alterations. Magn Reson Med, 2015. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., (© 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Our aim was to determine the quantitative reproducibility of metabolic breakdown products in the kidney following intravenous injection of hyperpolarized [1-(13)C]pyruvate and secondly to investigate the metabolic effect on the pyruvate metabolism of oral sucrose load using dissolution dynamic nuclear polarization. By this technique, metabolic alterations in several different metabolic related diseases and their metabolic treatment responses can be accessed., Methods: In four healthy pigs the lactate-to-pyruvate, alanine-to-pyruvate and bicarbonate-to-pyruvate ratio was measured following administration of regular cola and consecutive injections of hyperpolarized [1-(13)C]pyruvate four times within an hour., Results: The overall lactate-to-pyruvate metabolic profile changed significantly over one hour following an acute sucrose load leading to a significant rise in blood glucose., Conclusion: The reproducibility of hyperpolarized magnetic resonance spectroscopy in the healthy pig kidney demonstrated a repeatability of more than 94% for all metabolites and, furthermore, that the pyruvate to lactate conversion and the blood glucose level is elevated following endogastric sucrose administration., (© 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: The use of hyperpolarization to enhance the sensitivity of MRI has so far been limited by the decay of the polarization through T1 relaxation. Recently, methods have been proposed that extend the lifetime of the hyperpolarization by storing the spin order in slowly relaxing singlet states., Methods: With this aim, optimal control theory was applied to create pulses that for near-equivalent spins accomplish transfers in and out of the singlet state with maximum efficiency while ensuring robustness toward variations in the nuclear spin system Hamiltonian (chemical shift, J-couplings, B1 and B0 magnetic field inhomogeneity)., Results: The pulses are designed to accomplish efficient transfer with low B1 amplitude, essential for applications on preclinical and clinical MR scanners., Conclusion: It is demonstrated that significantly improved efficiency and robustness can be obtained within the limitations of typical MR scanner performance., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to demonstrate that dissolution- dynamic nuclear polarization is capable of hyperpolarizing water protons and that the signal from the hyperpolarized bolus injection can be exploited in angiographic applications., Methods: We hyperpolarized water/glycerol using dynamic nuclear polarization followed by dissolution in D2 O., Results: A water (1) H signal enhancement of 77 times compared with 4.7 Tesla was obtained. This corresponds to a polarization of 3.5% for the 3.9 mol/L (1) H in D2 O . Moreover, a T1 in excess of 20 s was achieved., Conclusion: The use of hyperpolarized water as a contrast agent presents a new opportunity to obtain MRA images with high contrast-to-noise in a fraction of a second., (Copyright © 2013 Wiley Periodicals, Inc.)

Nuclear spin hyperpolarization makes a significant advance toward overcoming the sensitivity limitations of in vivo magnetic resonance imaging, particularly in the case of low-gamma nuclei. The sensitivity may be improved further by storing the hyperpolarization in slowly relaxing singlet populations of spin-1/2 pairs. Here, we report hyperpolarized (13) C spin order transferred into and retrieved from singlet spin order using a small animal magnetic resonance imaging scanner. For spins in sites with very similar chemical shifts, singlet spin order is sustained in high magnetic field without requiring strong radiofrequency irradiation. The demonstration of robust singlet-to-magnetization conversion, and vice versa, on a small animal scanner, is promising for future in vivo and clinical deployments., (Copyright © 2012 Wiley Periodicals, Inc.)