A modular motion compensation pipeline for prospective respiratory motion correction of multi-nuclear MR spectroscopy.

Magnetic resonance (MR) acquisitions of the torso are frequently affected by respiratory motion with detrimental effects on signal quality. The motion of organs inside the body is typically decoupled from surface motion and is best captured using rapid MR imaging (MRI). We propose a pipeline for prospective motion correction of the target organ using MR image navigators providing absolute motion estimates in millimeters. Our method is designed to feature multi-nuclear interleaving for non-proton MR acquisitions and to tolerate local transmit coils with inhomogeneous field and sensitivity distributions. OpenCV object tracking was introduced for rapid estimation of in-plane displacements in 2D MR images. A full three-dimensional translation vector was derived by combining displacements from slices of multiple and arbitrary orientations. The pipeline was implemented on 3 T and 7 T MR scanners and tested in phantoms and volunteers. Fast motion handling was achieved with low-resolution 2D MR image navigators and direct implementation of OpenCV into the MR scanner's reconstruction pipeline. Motion-phantom measurements demonstrate high tracking precision and accuracy with minor processing latency. The feasibility of the pipeline for reliable in-vivo motion extraction was shown on heart and kidney data. Organ motion was manually assessed by independent operators to quantify tracking performance. Object tracking performed convincingly on 7774 navigator images from phantom scans and different organs in volunteers. In particular the kernelized correlation filter (KCF) achieved similar accuracy (74%) as scored from inter-operator comparison (82%) while processing at a rate of over 100 frames per second. We conclude that fast 2D MR navigator images and computer vision object tracking can be used for accurate and rapid prospective motion correction. This and the modular structure of the pipeline allows for the proposed method to be used in imaging of moving organs and in challenging applications like cardiac magnetic resonance spectroscopy (MRS) or magnetic resonance imaging (MRI) guided radiotherapy.

Magnetic resonance elastography resolving all gross anatomical segments of the kidney during controlled hydration.

Introduction: Magnetic resonance elastography (MRE) is a non-invasive method to quantify biomechanical properties of human tissues. It has potential in diagnosis and monitoring of kidney disease, if established in clinical practice. The interplay of flow and volume changes in renal vessels, tubule, urinary collection system and interstitium is complex, but physiological ranges of in vivo viscoelastic properties during fasting and hydration have never been investigated in all gross anatomical segments simultaneously. Method: Ten healthy volunteers underwent two imaging sessions, one following a 12-hour fasting period and the second after a drinking challenge of >10 mL per kg body weight (60-75 min before the second examination). High-resolution renal MRE was performed using a novel driver with rotating eccentric mass placed at the posterior-lateral wall to couple waves (50 Hz) to the kidney. The biomechanical parameters, shear wave speed (cs in m/s), storage modulus (Gd in kPa), loss modulus (Gl in kPa), phase angle (Υ=2πatanGlGd) and attenuation (α in 1/mm) were derived. Accurate separation of gross anatomical segments was applied in post-processing (whole kidney, cortex, medulla, sinus, vessel). Results: High-quality shear waves coupled into all gross anatomical segments of the kidney (mean shear wave displacement: 163 ± 47 µm, mean contamination of second upper harmonics <23%, curl/divergence: 4.3 ± 0.8). Regardless of the hydration state, median Gd of the cortex and medulla (0.68 ± 0.11 kPa) was significantly higher than that of the sinus and vessels (0.48 ± 0.06 kPa), and consistently, significant differences were found in cs, Υ, and Gl (all p < 0.001). The viscoelastic parameters of cortex and medulla were not significantly different. After hydration sinus exhibited a small but significant reduction in median Gd by -0.02 ± 0.04 kPa (p = 0.01), and, consequently, the cortico-sinusoidal-difference in Gd increased by 0.04 ± 0.07 kPa (p = 0.05). Only upon hydration, the attenuation in vessels became lower (0.084 ± 0.013 1/mm) and differed significantly from the whole kidney (0.095 ± 0.007 1/mm, p = 0.01). Conclusion: High-resolution renal MRE with an innovative driver and well-defined 3D segmentation can resolve all renal segments, especially when including the sinus in the analysis. Even after a prolonged hydration period the approach is sensitive to small hydration-related changes in the sinus and in the cortico-sinusoidal-difference.

Increased cardiac Pi/PCr in the diabetic heart observed using phosphorus magnetic resonance spectroscopy at 7T.

Phosphorus magnetic resonance spectroscopy (31P-MRS) has previously demonstrated decreased energy reserves in the form of phosphocreatine to adenosine-tri-phosphate ratio (PCr/ATP) in the hearts of patients with type 2 diabetes (T2DM). Recent 31P-MRS techniques using 7T systems, e.g. long mixing time stimulated echo acquisition mode (STEAM), allow deeper insight into cardiac metabolism through assessment of inorganic phosphate (Pi) content and myocardial pH, which play pivotal roles in energy production in the heart. Therefore, we aimed to further explore the cardiac metabolic phenotype in T2DM using STEAM at 7T. Seventeen patients with T2DM and twenty-three healthy controls were recruited and their cardiac PCr/ATP, Pi/PCr and pH were assessed at 7T. Diastolic function of all patients with T2DM was assessed using echocardiography to investigate the relationship between diastolic dysfunction and cardiac metabolism. Mirroring the decreased PCr/ATP (1.70±0.31 vs. 2.07±0.39; p<0.01), the cardiac Pi/PCr was increased (0.13±0.07 vs. 0.10±0.03; p = 0.02) in T2DM patients in comparison to healthy controls. Myocardial pH was not significantly different between the groups (7.14±0.12 vs. 7.10±0.12; p = 0.31). There was a negative correlation between PCr/ATP and diastolic function (R2 = 0.33; p = 0.02) in T2DM. No correlation was observed between diastolic function and Pi/PCr and (R2 = 0.16; p = 0.21). In addition, we did not observe any correlation between cardiac PCr/ATP and Pi/PCr (p = 0.19). Using STEAM 31P-MRS at 7T we have for the first time explored Pi/PCr in the diabetic human heart and found it increased when compared to healthy controls. The lack of correlation between measured PCr/ATP and Pi/PCr suggests that independent mechanisms might contribute to these perturbations.

Evaluation of Acute Supplementation With the Ketone Ester (R)-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle 31P Magnetic Resonance Spectroscopy.

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac 31P-MRS, and 16 aged 60-75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p ≪ 0.001; -28.2%, p = 0.02; and -49.1%, p ≪ 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function.

Investigating the effect of trigger delay on cardiac 31P MRS signals.

The heart's geometry and its metabolic activity vary over the cardiac cycle. The effect of these fluctuations on phosphorus (31P) magnetic resonance spectroscopy (MRS) data quality and metabolite ratios was investigated. 12 healthy volunteers were measured using a 7 T MR scanner and a cardiac 31P-1H loop coil. 31P chemical shift imaging data were acquired untriggered and at four different times during the cardiac cycle using acoustic triggering. Signals of adenosine-triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi) and 2,3-diphosphoglycerate (2,3-DPG) and their fit quality as Cramér-Rao lower bounds (CRLB) were quantified including corrections for contamination by 31P signals from blood, flip angle, saturation and total acquisition time. The myocardial filling factor was estimated from cine short axis views. The corrected signals of PCr and [Formula: see text]-ATP were higher during end-systole and lower during diastasis than in untriggered acquisitions ([Formula: see text]). Signal intensities of untriggered scans were between those with triggering to end-systole and diastasis. Fit quality of PCr and [Formula: see text]-ATP peaks was best during end-systole when blood contamination of ATP and Pi signals was lowest. While metabolite ratios and pH remained stable over the cardiac cycle, signal amplitudes correlated strongly with myocardial voxel filling. Triggering of cardiac 31P MRS acquisitions improves signal amplitudes and fit quality if the trigger delay is set to end-systole. We conclude that triggering to end-systole is superior to triggering to diastasis.

Simultaneous Multiple Resonance Frequency imaging (SMURF): Fat-water imaging using multi-band principles.

PURPOSE: To develop a fat-water imaging method that allows reliable separation of the two tissues, uses established robust reconstruction methods, and requires only one single-echo acquisition. THEORY AND METHODS: The proposed method uses spectrally selective dual-band excitation in combination with CAIPIRINHA to generate separate images of fat and water simultaneously. Spatially selective excitation without cross-contamination is made possible by the use of spatial-spectral pulses. Fat and water images can either be visualized separately, or the fat images can be corrected for chemical shift displacement and, in gradient echo imaging, for chemical shift-related phase discrepancy, and recombined with water images, generating fat-water images free of chemical shift effects. Gradient echo and turbo spin echo sequences were developed based on this Simultaneous Multiple Resonance Frequency imaging (SMURF) approach and their performance was assessed at 3Tesla in imaging of the knee, breasts, and abdomen. RESULTS: The proposed method generated well-separated fat and water images with minimal unaliasing artefacts or cross-excitation, evidenced by the near absence of water signal attributed to the fat image and vice versa. The separation achieved was similar to or better than that using separate acquisitions with water- and fat-saturation or Dixon methods. The recombined fat-water images provided similar image contrast to conventional images, but the chemical shift effects were eliminated. CONCLUSION: Simultaneous Multiple Resonance Frequency imaging is a robust fat-water imaging technique that offers a solution to imaging of body regions with significant amounts of fat.

Quantifying the effect of dobutamine stress on myocardial Pi and pH in healthy volunteers: A 31 P MRS study at 7T.

PURPOSE: Phosphorus spectroscopy (31 P-MRS) is a proven method to probe cardiac energetics. Studies typically report the phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio. We focus on another 31 P signal: inorganic phosphate (Pi), whose chemical shift allows computation of myocardial pH, with Pi/PCr providing additional insight into cardiac energetics. Pi is often obscured by signals from blood 2,3-diphosphoglycerate (2,3-DPG). We introduce a method to quantify Pi in 14 min without hindrance from 2,3-DPG. METHODS: Using a 31 P stimulated echo acquisition mode (STEAM) sequence at 7 Tesla that inherently suppresses signal from 2,3-DPG, the Pi peak was cleanly resolved. Resting state UTE-chemical shift imaging (PCr/ATP) and STEAM 31 P-MRS (Pi/PCr, pH) were undertaken in 23 healthy controls; pH and Pi/PCr were subsequently recorded during dobutamine infusion. RESULTS: We achieved a clean Pi signal both at rest and stress with good 2,3-DPG suppression. Repeatability coefficient (8 subjects) for Pi/PCr was 0.036 and 0.12 for pH. We report myocardial Pi/PCr and pH at rest and during catecholamine stress in healthy controls. Pi/PCr was maintained during stress (0.098 ± 0.031 [rest] vs. 0.098 ± 0.031 [stress] P = .95); similarly, pH did not change (7.09 ± 0.07 [rest] vs. 7.08 ± 0.11 [stress] P = .81). Feasibility for patient studies was subsequently successfully demonstrated in a patient with cardiomyopathy. CONCLUSION: We introduced a method that can resolve Pi using 7 Tesla STEAM 31 P-MRS. We demonstrate the stability of Pi/PCr and myocardial pH in volunteers at rest and during catecholamine stress. This protocol is feasible in patients and potentially of use for studying pathological myocardial energetics.

Interleaved 31 P MRS/1 H ASL for analysis of metabolic and functional heterogeneity along human lower leg muscles at 7T.

PURPOSE: MR offers the unique possibility to noninvasively investigate cellular energy metabolism via 31P MRS, while blood perfusion, which provides oxygen and substrates to the tissue, is accessible by arterial spin labeling (ASL) 1H MRI. Because metabolic and hemodynamic parameters are linked, it would be desirable to study them simultaneously. A 3D-resolved method is presented that allows such measurements with high spatiotemporal resolution and has the potential to discern differences along an exercising muscle. METHODS: Multi-voxel localized 31 P MRS was temporally interleaved with multi-slice pASL 1H MRI. Phosphorus spectra were collected from two adjacent positions in gastrocnemius medialis (GM) during rest, submaximal plantar flexion exercise and recovery, while perfusion and T2* -weighted axial images were acquired at the same time. Seventeen healthy volunteers (9 f / 8 m) were studied at 7 T. RESULTS: An increase of postexercise perfusion and T2* -weighted signal in GM positively correlated with end-exercise PCr depletion and pH drop. At proximal positions functional and metabolic activity was higher than distally, that is, perfusion increase and peak T2* -weighted signal, end-exercise PCr depletion, end-exercise pH, and PCr recovery time constant were significantly different. An NOE-induced SNR increase of approximately 20 % (P < .001), at rest, was found in interleaved 31 P spectra, when comparing to 31 P-only acquisitions. CONCLUSIONS: A technique for fast, simultaneous imaging of muscle functional heterogeneity in ASL, T2* and acquisition of time-resolved 31 P  MRS data is presented. These single exercise recovery experiments can be used to investigate local variations during disease progression in patients suffering from vascular or muscular diseases.

Multi-turn multi-gap transmission line resonators - Concept, design and first implementation at 4.7T and 7T.

A novel design scheme for monolithic transmission line resonators (TLRs) is presented - the multi-turn multi-gap TLR (MTMG-TLR) design. The MTMG-TLR design enables the construction of TLRs with multiple turns and multiple gaps. This presents an additional degree of freedom in tuning self-resonant TLRs, as their resonance frequency is fully determined by the coil geometry (e.g. diameter, number of turns, conductor width, etc.). The novel design is evaluated at 4.7T and 7T by simulations and experiments, where it is demonstrated that MTMG-TLRs can be used for MRI, and that the B1 distribution of MTMG-TLRs strongly depends on the number and distribution of turns. A comparison to conventional loop coils revealed that the B1 performance of MTMG-TLRs is comparable to a loop coil with the same mean diameter; however, lower 10g SAR values were found for MTMG-TLRs. The MTMG-TLR design is expected to bring most benefits at high static field, where it allows for independent size and frequency selection, which cannot be achieved with standard TLR design. However, it also enables more accurate geometric optimization at low static field. Thereby, the MTMG-TLR design preserves the intrinsic advantages of TLRs, i.e. mechanical flexibility, high SAR efficiency, mass production, and coil miniaturization.

Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner.

PURPOSE: Modification of a clinical MRI scanner to enable simultaneous or rapid interleaved acquisition of signals from two different nuclei. METHODS: A device was developed to modify the local oscillator signal fed to the receive channel(s) of an MRI console. This enables external modification of the frequency at which the receiver is sensitive and rapid switching between different frequencies. Use of the device was demonstrated with interleaved and simultaneous 31 P and 1 H spectroscopic acquisitions, and with interleaved 31 P and 1 H imaging. RESULTS: Signal amplitudes and signal-to-noise ratios were found to be unchanged for the modified system, compared with data acquired with the MRI system in the standard configuration. CONCLUSION: Interleaved and simultaneous 1 H and 31 P signal acquisition was successfully demonstrated with a clinical MRI scanner, with only minor modification of the RF architecture. While demonstrated with 31 P, the modification is applicable to any detectable nucleus without further modification, enabling a wide range of simultaneous and interleaved experiments to be performed within a clinical setting. Magn Reson Med 76:1636-1641, 2016. © 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 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Dynamic PCr and pH imaging of human calf muscles during exercise and recovery using (31) P gradient-Echo MRI at 7 Tesla.

PURPOSE: Simultaneous acquisition of spatially resolved (31) P-MRI data for evaluation of muscle specific energy metabolism, i.e., PCr and pH kinetics. METHODS: A three-dimensional (3D) gradient-echo sequence for multiple frequency-selective excitations of the PCr and Pi signals in an interleaved sampling scheme was developed and tested at 7 Tesla (T). The pH values were derived from the chemical shift-induced phase difference between the resonances. The achieved spatial resolution was ∼2 mL with image acquisition time below 6 s. Ten healthy volunteers were studied performing plantar flexions during the delay between (31) P-MRI acquisitions, yielding a temporal resolution of 9-10 s. RESULTS: Signal from anatomically matched regions of interest had sufficient signal-to-noise ratio to allow single-acquisition PCr and pH quantification. The Pi signal was clearly detected in voxels of actively exercising muscles. The PCr depletions were in gastrocnemius 42 ± 14% (medialis), 48 ± 17% (lateralis) and in soleus 20 ± 11%. The end exercise pH values were 6.74 ± 0.18 and 6.65 ± 0.27 for gastrocnemius medialis and lateralis, respectively, and 6.96 ± 0.12 for soleus muscle. CONCLUSION: Simultaneous acquisition of PCr and Pi images with high temporal resolution, suitable for measuring PCr and pH kinetics in exercise-recovery experiments, was demonstrated at 7T. This study presents a fast alternative to MRS for quantifying energy metabolism of posterior muscle groups of the lower leg. Magn Reson Med 75:2324-2331, 2016. © 2015 Wiley Periodicals, Inc.

Dynamic ASL and T2-weighted MRI in exercising calf muscle at 7 T: a feasibility study.

PURPOSE: The aim of this study was to develop a measurement protocol for noninvasive simultaneous perfusion quantification and T2 *-weighted MRI acquisition in the exercising calf muscle at 7 Tesla. METHODS: Using a nonmagnetic ergometer and a dedicated in-house built calf coil array, dynamic pulsed arterial spin labeling (PASL) measurements with a temporal resolution of 12 s were performed before, during, and after plantar flexion exercise in 16 healthy volunteers. RESULTS: Postexercise peak perfusion in gastrocnemius muscle (GAS) was 27 ± 16 ml/100g/min, whereas in soleus (SOL) and tibialis anterior (TA) muscles it remained at baseline levels. T2 *-weighted and ASL time courses in GAS showed comparable times to peak of 161 ± 72 s and 167 ± 115 s, respectively. The T2 *-weighted signal in the GAS showed a minimum during exercise (88 ± 6 % of the baseline signal) and a peak during the recovery (122 ± 9%), whereas in all other muscles only a signal decrease was observed (minimum 91 ± 6% in SOL; 87 ± 8% in TA). CONCLUSION: We demonstrate the feasibility of dynamic perfusion quantification in skeletal muscle at 7 Tesla using PASL. This may help to better investigate the physiological processes in the skeletal muscle and also in diseases such as diabetes mellitus and peripheral arterial disease.

Exercising calf muscle T2∗ changes correlate with pH, PCr recovery and maximum oxidative phosphorylation.

Skeletal muscle metabolism is impaired in disorders like diabetes mellitus or peripheral vascular disease. The skeletal muscle echo planar imaging (EPI) signal (S(EPI) ) and its relation to energy metabolism are still debated. Localised ³¹P MRS and S(EPI) data from gastrocnemius medialis of 19 healthy subjects were combined in one scanning session to study direct relationships between phosphocreatine (PCr), pH kinetics and parameters of T2∗ time courses. Dynamic spectroscopy (semi-LASER) and EPI were performed immediately before, during and after 5 min of plantar flexions. Data were acquired in a 7 T MR scanner equipped with a custom-built ergometer and a dedicated ³¹P/¹H radio frequency (RF) coil array. Using a form-fitted multi-channel ³¹P/¹H coil array resulted in high signal-to-noise ratio (SNR). PCr and pH in the gastrocnemius medialis muscle were quantified from each ³¹P spectrum, acquired every 6 s. During exercise, SEPI (t) was found to be a linear function of tissue pH(t) (cross-correlation r = -0.85 ± 0.07). Strong Pearson's correlations were observed between post exercise time-to-peak (TTP) of SEPI and (a) the time constant of PCr recovery τPCr recovery (r = 0.89, p < 10⁻6), (b) maximum oxidative phosphorylation using the linear model, Q(max, lin) (r = 0.65, p = 0.002), the adenosine-diphosphate-driven model, Q(max,ADP) (r = 0.73, p = 0.0002) and (c) end exercise pH (r = 0.60, p = 0.005). Based on combined accurately localised ³¹P MRS and T2∗ weighted MRI, both with high temporal resolution, strong correlations of the skeletal muscle SEPI during exercise and tissue pH time courses and of post exercise SEPI and parameters of energy metabolism were observed. In conclusion, a tight coupling between skeletal muscle metabolic activity and tissue T2∗ signal weighting, probably induced by osmotically driven water shift, exists and can be measured non-invasively, using NMR at 7 T.

Lower fasting muscle mitochondrial activity relates to hepatic steatosis in humans.

OBJECTIVE: Muscle insulin resistance has been implicated in the development of steatosis and dyslipidemia by changing the partitioning of postprandial substrate fluxes. Also, insulin resistance may be due to reduced mitochondrial function. We examined the association between mitochondrial activity, insulin sensitivity, and steatosis in a larger human population. RESEARCH DESIGN AND METHODS: We analyzed muscle mitochondrial activity from ATP synthase flux (fATP) and ectopic lipids by multinuclei magnetic resonance spectroscopy from 113 volunteers with and without diabetes. Insulin sensitivity was assessed from M values using euglycemic-hyperinsulinemic clamps and/or from oral glucose insulin sensitivity (OGIS) using oral glucose tolerance tests. RESULTS: Muscle fATP correlated negatively with hepatic lipid content and HbA1c. After model adjustment for study effects and other confounders, fATP showed a strong negative correlation with hepatic lipid content and a positive correlation with insulin sensitivity and fasting C-peptide. The negative correlation of muscle fATP with age, HbA1c, and plasma free fatty acids was weakened after adjustment. Body mass, muscle lipid contents, plasma lipoproteins, and triglycerides did not associate with fATP. CONCLUSIONS: The association of impaired muscle mitochondrial activity with hepatic steatosis supports the concept of a close link between altered muscle and liver energy metabolism as early abnormalities promoting insulin resistance.

Interrelation of 31P-MRS metabolism measurements in resting and exercised quadriceps muscle of overweight-to-obese sedentary individuals.

Phosphorus magnetic resonance spectroscopy ((31)P-MRS) enables the non-invasive evaluation of muscle metabolism. Resting Pi-to-ATP flux can be assessed through magnetization transfer (MT) techniques, and maximal oxidative flux (Q(max)) can be calculated by monitoring of phosphocreatine (PCr) recovery after exercise. In this study, the muscle metabolism parameters of 13 overweight-to-obese sedentary individuals were measured with both MT and dynamic PCr recovery measurements, and the interrelation between these measurements was investigated. In the dynamic experiments, knee extensions were performed at a workload of 30% of maximal voluntary capacity, and the consecutive PCr recovery was measured in a quadriceps muscle with a time resolution of 2 s with non-localized (31)P-MRS at 3 T. Resting skeletal muscle metabolism was assessed through MT measurements of the same muscle group at 7 T. Significant linear correlations between the Q(max) and the MT parameters k(ATP) (r = 0.77, P = 0.002) and F(ATP) (r = 0.62, P = 0.023) were found in the study population. This would imply that the MT technique can possibly be used as an alternative method to assess muscle metabolism when necessary (e.g. in individuals after stroke or in uncooperative patients).

Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

BACKGROUND: Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles. METHODS: A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. RESULTS: Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after heme arginate compared to placebo (106.2 ± 0.6% at 175 ± 16s vs. 104.5 ± 0.6% at 221 ± 19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). CONCLUSIONS: A single high dose of heme arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle.

A single nucleotide polymorphism associates with the response of muscle ATP synthesis to long-term exercise training in relatives of type 2 diabetic humans.

OBJECTIVE: Myocellular ATP synthesis (fATP) associates with insulin sensitivity in first-degree relatives of subjects with type 2 diabetes. Short-term endurance training can modify their fATP and insulin sensitivity. This study examines the effects of moderate long-term exercise using endurance or resistance training in this cohort. RESEARCH DESIGN AND METHODS: A randomized, parallel-group trial tested 16 glucose-tolerant nonobese relatives (8 subjects in the endurance training group and 8 subjects in the resistance training group) before and after 26 weeks of endurance or resistance training. Exercise performance was assessed from power output and oxygen uptake (VO(2)) during incremental tests and from maximal torque of knee flexors (MaxT(flex)) and extensors (MaxT(ext)) using isokinetic dynamometry. fATP and ectopic lipids were measured with (1)H/(31)P magnetic resonance spectroscopy. RESULTS: Endurance training increased power output and VO(2) by 44 and 30%, respectively (both P < 0.001), whereas resistance training increased MaxT(ext) and MaxT(flex) by 23 and 40%, respectively (both P < 0.001). Across all groups, insulin sensitivity (382 ± 90 vs. 389 ± 40 mL · min(-1) · m(-2)) and ectopic lipid contents were comparable after exercise training. However, 8 of 16 relatives had 26% greater fATP, increasing from 9.5 ± 2.3 to 11.9 ± 2.4 µmol · mL(-1) · m(-1) (P < 0.05). Six of eight responders were carriers of the G/G single nucleotide polymorphism rs540467 of the NDUFB6 gene (P = 0.019), which encodes a subunit of mitochondrial complex I. CONCLUSIONS: Moderate exercise training for 6 months does not necessarily improve insulin sensitivity but may increase ATP synthase flux. Genetic predisposition can modify the individual response of the ATP synthase flux independently of insulin sensitivity.

Skeletal muscle phosphodiester content relates to body mass and glycemic control.

BACKGROUND: Aging and insulin resistance have been related to reduced mitochondrial function and oxidative stress. Muscular phosphodiesters (PDE) are comprised of metabolites of phospholipid breakdown and may reflect membrane damage. We aimed to test the hypothesis that myocellular PDE are increased in patients with type 2 diabetes (T2D) and correlate inversely with mitochondrial ATP turnover. METHODS: A Cross-sectional study in the Clinical Research Facility of an University hospital was performed. 10 nonobese middle-aged patients with T2D, 10 healthy humans matched for sex, age and physical activity index (CONm) and 18 young healthy humans (CONy) were included. Myocellular PDE and unidirectional flux through ATP synthase (fATP) were measured with (31)P magnetic resonance spectroscopy (MRS). Intramyocellular (IMCL) and hepatocellular lipid deposition (HCL) were quantified with (1)H MRS. Insulin sensitivity (Rd) was assessed from hyperinsulinemic-euglycemic clamp tests in 10 T2D, 10 CONm and 11 CONy. RESULTS: During fasting, T2D and CONm had 1.5 fold greater PDE than CONy (2.8±0.2, 2.5±0.2, 1.7±0.1 mmol/l, P = 0.004). Stimulation by insulin did not affect PDE in any group. PDE correlated negatively with Rd (r = -0.552, p<0.005) and fATP (r = -0.396, p<0.05) and positively with age (r = 0.656, p<0.001) and body mass (r = 0.597, p<0.001). PDE also related positively to HbA1c (r = 0.674, p<0.001) and fasting plasma glucose (r = 0.629, p<0.001) within T2D and across all participants. CONCLUSIONS: Muscular PDE concentrations associate with age, lower resting mitochondrial activity and insulin resistance, which is determined mainly by body mass and glycemia.

Semi-LASER localized dynamic 31P magnetic resonance spectroscopy in exercising muscle at ultra-high magnetic field.

Magnetic resonance spectroscopy (MRS) can benefit from increased signal-to-noise ratio (SNR) of high magnetic fields. In this work, the SNR gain of dynamic 31P MRS at 7 T was invested in temporal and spatial resolution. Using conventional slice selective excitation combined with localization by adiabatic selective refocusing (semi-LASER) with short echo time (TE = 23 ms), phosphocreatine quantification in a 38 mL voxel inside a single exercising muscle becomes possible from single acquisitions, with SNR = 42 ± 4 in resting human medial gastrocnemius. The method was used to quantify the phosphocreatine time course during 5 min of plantar flexion exercise and recovery with a temporal resolution of 6 s (the chosen repetition time for moderate T1 saturation). Quantification of inorganic phosphate and pH required accumulation of consecutively acquired spectra when (resting) Pi concentrations were low. The localization performance was excellent while keeping the chemical shift displacement acceptably small. The SNR and spectral line widths with and without localization were compared between 3T and 7 T systems in phantoms and in vivo. The results demonstrate that increased sensitivity of ultra-high field can be used to dynamically acquire metabolic information from a clearly defined region in a single exercising muscle while reaching a temporal resolution previously available with MRS in non-localizing studies only. The method may improve the interpretation of dynamic muscle MRS data.

Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes.

OBJECTIVE: Steatosis associates with insulin resistance and may even predict type 2 diabetes and cardiovascular complications. Because muscular insulin resistance relates to myocellular fat deposition and disturbed energy metabolism, we hypothesized that reduced hepatic ATP turnover (fATP) underlies insulin resistance and elevated hepatocellular lipid (HCL) contents. RESEARCH DESIGN AND METHODS: We measured hepatic fATP using (31)P magnetic resonance spectroscopy in patients with type 2 diabetes and age- and body mass-matched controls. Peripheral (M and M/I) and hepatic (suppression of endogenous glucose production) insulin sensitivity were assessed with euglycemic-hyperinsulinemic clamps. RESULTS: Diabetic individuals had 29% and 28% lower peripheral and hepatic insulin sensitivity as well as 42% reduced fATP than controls. After adjusting for HCL, fATP correlated positively with peripheral and hepatic insulin sensitivity but negatively with waist circumference, BMI, and fasting plasma glucose. Multiple regression analysis identified waist circumference as an independent predictor of fATP and inorganic phosphate (P(I)) concentrations, explaining 65% (P = 0.001) and 56% (P = 0.003) of the variations. Hepatocellular P(I) primarily determined the alterations in fATP. CONCLUSIONS: In patients with type 2 diabetes, insulin resistance relates to perturbed hepatic energy metabolism, which is at least partly accounted for by fat depots.