Fast, precise, and accurate myocardial T1 mapping using a radial MOLLI sequence with FLASH readout.

PURPOSE: Quantitative cardiac MRI, and more particularly T1 mapping, has become a most important modality to characterize myocardial tissue. In this work, the value of a radial variant of the conventional modified Look-Locker inversion recovery sequence (raMOLLI) is demonstrated. METHODS: The raMOLLI acquisition scheme consisted of five radial echo trains of 80 spokes acquired using either a fast low-angle shot (FLASH) or a true fast imaging with steady-state-precession (TrueFISP) readout at different time points after a single magnetization inversion. View sharing combined with a compressed sensing algorithm allowed the reconstruction of 50 images along the T1 relaxation recovery curve, to which a dictionary-fitting approach was applied to estimate T1 . The sequence was validated on a nine-vial phantom, on 19 healthy subjects, and one patient suffering from dilated cardiomyopathy. RESULTS: The raMOLLI sequence allowed a significant decrease of myocardial T1 map acquisition time down to five heartbeats, while exhibiting a higher degree of accuracy and a comparable precision on T1 value estimation than the conventional modified Look-Locker inversion recovery sequence. The FLASH readout demonstrated a better robustness to B0 inhomogeneities than TrueFISP, and was therefore preferred for in vivo acquisitions. CONCLUSIONS: This sequence represents a good candidate for ultrafast acquisition of myocardial T1 maps. Magn Reson Med 79:1387-1398, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Quantitative ultrashort TE imaging of the short-T2 components in skeletal muscle using an extended echo-subtraction method.

PURPOSE: To introduce an ultrashort echo time (UTE) based method for quantitative mapping of short-T2 signals in skeletal muscle (SKM) in the presence of fat, with the aim of monitoring SKM fibrosis. METHODS: From a set of at least five UTE images of the same slice, a long- T2* map, a fat-fraction map, and a map of short-T2 -signal fraction are extracted. The method was validated by numerical simulations and in vitro studies on collagen solutions. Finaly, the method was applied to image the short-T2 signals in the leg of eight healthy volunteers. RESULTS: The imaged short-T2 -signal fractions in the collagen solutions correlated with their respective collagen concentrations ( R=0.999,  P=0.009). Short-T2 tissues such as cortical bone and fasciae were highlighted in the resulting short-T2 fraction maps. A significant fraction of short-T2 signal was systematically observed in the skeletal muscle of all of the subjects (4.5±1.2%). CONCLUSION: The proposed method allows the quantitative imaging of short-T2 components in tissues containing fat. By also having the fat-fraction and T2* maps as outcomes, long-T2 suppression is accomplished without requiring modifications to the basic UTE sequence. Although the hypersignal observed in the fasciae suggests that the short-T2 signal observed in SKM might arise from interstitial connective tissue, further investigation is necessary to confirm this statement. Magn Reson Med 78:997-1008, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Impact of salbutamol on muscle metabolism assessed by ³¹P NMR spectroscopy.

The potential ergogenic effects of oral salbutamol intake were demonstrated for decades but the underlying mechanisms remain to elucidate. We hypothesized that improved exercise performance after acute oral salbutamol administration is associated with changes in muscle metabolism. Twelve healthy, nonasthmatic, moderately trained, male subjects were recruited to compare in a double-blind crossover randomized study, an oral dose of salbutamol (4 mg) and a placebo. After treatment administration, subjects performed repetitive plantar flexions to exhaustion in a 3T magnet. Continuous (31) P nuclear magnetic resonance spectroscopy assessment of the calf muscles was performed at rest, during exercise, and during recovery. No significant difference between treatments was detected in metabolite concentration at rest (P > 0.05). Creatine phosphate and inorganic phosphate changes during and immediately after exercise were similar between treatments (P > 0.05). Intramuscular pH (pHi) was significantly higher at rest, at submaximal exercise but not at exhaustion with salbutamol (pHi at 50% of exercise duration, 6.8 ± 0.1/6.9 ± 0.1 for placebo and salbutamol, respectively, P < 0.05). The maximal power (28 ± 7 W/23 ± 7 W; P = 0.001) and total work (1702 ± 442 J/1381 ± 432 J; P = 0.003) performed during plantar flexions were significantly increased with salbutamol. Salbutamol induced significant improvement in calf muscle endurance with similar metabolic responses during exercise, except slight differences in pHi. Other mechanisms than changes in muscle metabolism may be responsible for the ergogenic effect of salbutamol administration.

Efficacy and safety of hydrokinesitherapy in patients with dystrophinopathy.

Duchenne muscular dystrophy (DMD) is one of the most common forms of hereditary muscular dystrophies in childhood and is characterized by steady progression and early disability. It is known that physical therapy can slow down the rate of progression of the disease. According to global recommendations, pool exercises, along with stretching, are preferable for children with DMD, as these types of activities have a balanced effect on skeletal muscles and allow simultaneous breathing exercises. The present study aimed to evaluate the effectiveness of regular pool exercises in patients with Duchenne muscular dystrophy who are capable of independent movement during 4 months of training. 28 patients with genetically confirmed Duchenne muscular dystrophy, who were aged 6.9 ± 0.2 years, were examined. A 6-min distance walking test and timed tests, namely, rising from the floor, 10-meter running, and stair climbing and descending, muscle strength of the upper and lower extremities were assessed on the baseline and during dynamic observation at 2 and 4 months. Hydrorehabilitation course lasted 4 months and was divided into two stages: preparatory and training (depend on individual functional heart reserve (IFHR)). Set of exercises included pool dynamic aerobic exercises. Quantitative muscle MRI of the pelvic girdle and thigh was performed six times: before training (further BT) and after training (further AT) during all course. According to the results of the study, a statistically significant improvement was identified in a 6-min walking test, with 462.7 ± 6.2 m on the baseline and 492.0 ± 6.4 m after 4 months (p < 0.001). The results from the timed functional tests were as follows: rising from the floor test, 4.5 ± 0.3 s on the baseline and 3.8 ± 0.2 s after 4 months (p < 0.001); 10 meter distance running test, 4.9 ± 0.1 s on the baseline and 4.3 ± 0.1 s after 4 months (p < 0.001); 4-stair climbing test, 3.7 ± 0.2 s on the baseline and 3.2 ± 0.2 s after 4 months (p < 0.001); and 4-stair descent test, 3.9 ± 0.1 s on the baseline and 3.2 ± 0.1 s after 4 months (p < 0.001). Skeletal muscle quantitative MRI was performed in the pelvis and the thighs in order to assess the impact of the procedures on the muscle structure. Muscle water T2, a biomarker of disease activity, did not show any change during the training period, suggesting the absence of deleterious effects and negative impact on disease activity. Thus, a set of dynamic aerobic exercises in water can be regarded as effective and safe for patients with DMD.

Measuring perfusion and bioenergetics simultaneously in mouse skeletal muscle: a multiparametric functional-NMR approach.

A totally noninvasive set-up was developed for comprehensive NMR evaluation of mouse skeletal muscle function in vivo. Dynamic pulsed arterial spin labeling-NMRI perfusion and blood oxygenation level-dependent (BOLD) signal measurements were interleaved with (31)P NMRS to measure both vascular response and oxidative capacities during stimulated exercise and subsequent recovery. Force output was recorded with a dedicated ergometer. Twelve exercise bouts were performed. The perfusion, BOLD signal, pH and force-time integral were obtained from mouse legs for each exercise. All reached a steady state after the second exercise, justifying the pointwise summation of the last 10 exercises to compensate for the limited (31)P signal. In this way, a high temporal resolution of 2.5 s was achieved to provide a time constant for phosphocreatine (PCr) recovery (τ(PCr)). The higher signal-to-noise ratio improved the precision of τ(PCr) measurement [coefficient of variation (CV) = 16.5% vs CV = 49.2% for a single exercise at a resolution of 30 s]. Inter-animal summation confirmed that τ(PCr) was stable at steady state, but shorter (89.3 ± 8.6 s) than after the first exercise (148 s, p < 0.05). This novel experimental approach provides an assessment of muscle vascular response simultaneously to energetic function in vivo. Its pertinence was illustrated by observing the establishment of a metabolic steady state. This comprehensive tool offers new perspectives for the study of muscle pathology in mice models.

Skeletal muscle perfusion and oxygenation assessed by dynamic NMR imaging and spectroscopy.

Muscle perfusion, and capillary and intramyocytic oxygenation can be probed non-invasively in vivo by functional NMR techniques, arterial spin labelling combined with imaging, BOLD imaging and deoxymyoglobin (1)H spectroscopy, respectively. After adequate adaptation of equipment, these measurements can be performed in parallel, together with (31)P spectroscopy and provide a comprehensive analysis of various facets of oxygen metabolism in dynamic protocols, in humans as well as in animal models.

Functional assessment of skeletal muscle in intact mice lacking myostatin by concurrent NMR imaging and spectroscopy.

Inhibiting myostatin (mstn) causes spectacular increase in muscle mass, spurring research for therapeutic approaches against neuromuscular disorders. Yet, possible functional deterioration and compromised force production have been reported in isolated muscle of null mstn(-/-) mice. We analyzed vascular and metabolic response to repeated electro-stimulated exercise in vivo in mstn(-/-) mice compared with FVB wild-type controls (WT), using interleaved multi-parametric functional nuclear magnetic resonance (NMR) imaging and spectroscopy. At steady-state exercise, specific force of plantar flexion, phosphocreatine consumption measured by phosphorus spectroscopy and maximum perfusion measured by arterial spin-labeled (ASL) NMR imaging were identical in both groups. After exercise, phosphorus spectroscopy revealed reduced oxidative mitochondrial capacity in mstn(-/-), whereas early recovery perfusion was identical and oxygen extraction, estimated from the blood oxygen level-dependent (BOLD) contrast, was decreased when compared with WT. Hyperemia was prolonged, indicating specific regulation of the perfusional response in mstn(-/-) mice. Histology showed an increased proportion of type IIb fibers in hypertrophied muscles, but the distribution of capillary contacts per fiber between oxidative and glycolytic fibers was unaltered in mstn(-/-) compared with WT. These integrated results formed coherent evidence of a congruous, non-pathologic shift toward a more glycolytic metabolism in this model of mstn(-/-).

Discrepancies between the fate of myoblast xenograft in mouse leg muscle and NMR label persistency after loading with Gd-DTPA or SPIOs.

1H-NMR (nuclear magnetic resonance) imaging is regularly proposed to non-invasively monitor cell therapy protocols. Prior to transplantation, cells must be loaded with an NMR contrast agent (CA). Most studies performed so far make use of superparamagnetic iron oxide particles (SPIOs), mainly for favorable detection sensitivity. However, in the case of labeled cell death, SPIO recapture by inflammatory cells might introduce severe bias. We investigated whether NMR signal changes induced by preloading with SPIOs or the low molecular weight gadolinium (Gd)-DTPA accurately monitored the outcome of transplanted cells in a murine model of acute immunologic rejection. CA-loaded human myoblasts were grafted in the tibialis anterior of C57BL/6 mice. NMR imaging was repeated regularly until 3 months post-transplantation. Label outcome was evaluated by the size of the labeled area and its relative contrast to surrounding tissue. In parallel, immunohistochemistry assessed the presence of human cells. Data analysis revealed that CA-induced signal changes did not strictly reflect the graft status. Gd-DTPA label disappeared rapidly yet with a 2-week delay compared with immunohistochemical evaluation. More problematically, SPIO label was still visible after 3 months, grossly overestimating cell survival (<1 week). SPIOs should be used with extreme caution to evaluate the presence of grafted cells in vivo and could hardly be recommended for the long-term monitoring of cell transplantation protocols.

Characterization of dystrophic muscle in golden retriever muscular dystrophy dogs by nuclear magnetic resonance imaging.

The Golden Retriever Muscular Dystrophy dog lacks dystrophin. Disease progression in this model shares many similarities with the Duchenne muscular dystrophy, both from anatomico pathological and clinical standpoints. The model is increasingly used in pre-clinical trials but needs to be further investigated, particularly with reference to the evaluation of therapies. The aim of this study was to identify quantitative indices that would help characterize the dystrophic dog non-invasively using NMR imaging. Two-month-old dystrophic dogs and healthy control animals were scanned at 4T. Standard T2- and T1-weighted images, fat-saturated T1-weighted images pre- and post-gadolinium chelate injection were acquired and kinetics of muscle enhancement were studied over a 2-h period. Several indices were found to be abnormally high in dystrophic dogs: the T2-weighted/T1-weighted signal ratio, T2-weighted image heterogeneity and maximal signal enhancement post-gadolinium. These may be proposed to evaluate muscle structural alterations non-invasively in this disease.

Anatomical and mesoscopic characterization of the dystrophic diaphragm: An in vivo nuclear magnetic resonance imaging study in the Golden retriever muscular dystrophy dog.

Because respiratory failure remains a major issue in Duchenne Muscular Dystrophy patients, respiratory muscles are a key target of systemic therapies. In the Golden Retriever Muscular Dystrophy (GRMD) dogs, the disease shows strong clinical and histological similarities with the human pathology, making it a valuable model for preclinical therapeutic trials. We report here the first nuclear magnetic resonance (NMR) imaging anatomical study of the diaphragm in GRMD dogs and healthy controls. Both T1- and T2-weighted images of the diaphragm of seven healthy and thirteen GRMD dogs, from 3 to 36 months of age, were acquired on a 3 tesla NMR scanner. Abnormalities of texture and shape were revealed and consisted of increases in signal intensity on T2-weighted images and in signal heterogeneity on both T1- and T2-weighted images of the dystrophic diaphragm. These abnormalities were associated with a significant thickening of the muscle and we identified a clear 8-mm-threshold distinguishing clinically preserved GRMD dogs from those more severely affected. In this study, we demonstrated the feasibility of NMR imaging of the diaphragm and depicted several anatomical and mesoscopic anomalies in the dystrophic diaphragm. NMR imaging of the diaphragm shows a promise as an outcome measure in preclinical trials using GRMD dogs.

Myocardial protection during ischemia by prior feeding with the creatine analog: cyclocreatine.

The ability of 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine), a synthetic creatine analog, to protect myocardium during global ischemia was assessed in isovolumic rat hearts using phosphorus-31 nuclear magnetic resonance spectroscopy. Wistar rats were fed a 1% cyclocreatine diet. After 2 weeks, cyclocreatine-fed (n = 8) and control (n = 7) rats were anesthetized, the heart was excised and retrograde perfusion was begun at 10 ml/min per g with 37 degrees C, phosphate-free buffer containing glucose and oxygen. Hemodynamic and spectroscopic data were obtained during baseline, ischemia and recovery periods (each 24 min). During ischemia, the heart of control rats developed a rigor-like increase in tonic pressure (ischemic contracture) not seen in the heart of cyclocreatine-fed rats (22 versus 1 mm Hg, p less than 0.01). This change was associated with significantly more adenosine triphosphate (ATP) at end-ischemia in the cyclocreatine group (1.6 versus 0.6 mumol/g, p less than 0.01) and delayed development of acidosis (p less than 0.001). With reperfusion, the heart of cyclocreatine-fed rats spontaneously defibrillated sooner than did the heart in control rats (178 versus 346 s, p less than 0.03). Diastolic pressure remained significantly elevated throughout recovery in control hearts compared with treated hearts (p less than 0.001). Prior feeding with cyclocreatine preserves myocardial adenosine triphosphate during ischemia, delays the development of acidosis and ischemic contracture and improves recovery of mechanical function on reperfusion.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

The effect of technical conditions and storage medium composition on the phosphomonoesters to inorganic phosphate ratio determined by 31P nuclear magnetic resonance spectroscopy in rabbit kidney.

Using 31P nuclear magnetic resonance spectroscopy, we compared the state of the high-energy phosphates in rabbit kidneys stored at 4 degrees C for 24 hr with 3 different solutions: Ringer (Rg), University of Wisconsin (UW), and Euro-Collins (EC) solutions. We found the highest phosphomonoester/inorganic phosphate (MP:Pi) ratio in the group of kidneys stored in the Rg solution (Rg, 0.93 +/- 0.04; UW, 0.36 +/- 0.02; EC, 0.28 +/- 0.02). This medium has been demonstrated in previous physiological studies to give poor results in terms of organ preservation compared to the solutions that mimic the "intracellular" fluid, such as the EC and UW solutions. Because the commonly used cold storage solutions contain phosphates, which superimpose on the intracellular Pi and, thus, can distort the results, we attempted to eliminate the contaminating solution around the kidney and in the vasculature by flushing the kidney with a phosphate-free solution (Rg). The MP:Pi ratio increased in the UW and EC groups (UW, 0.82 +/- 0.04; EC, 0.64 +/- 0.04) in identical proportion in the 2 groups. It remained highest in the Rg group (1.02 +/- 0.03). Comparisons of data before and after flush showed that external phosphate contamination was not predominant. There was no equilibrium in phosphate distribution between intra- and extracellular spaces at 24 hr of storage. We conclude that the validity of the MP:Pi ratio, as a viability index of renal transplant, might have to be restricted to comparisons of kidneys preserved in the same storage conditions. Therefore, it would be necessary to establish normal and pathological values of this ratio for each cold storage solution.

Interrelationship of hypertension, plasma lipids and atherosclerosis.

The relationship between hypertension and atherosclerosis has been illustrated by epidemiological, clinical and experimental observations. Typical atherosclerotic lesions develop in arterial wall when hypercholesterolaemia is present. Hypertension aggravates these lesions by causing vascular structural changes. In clinical studies, however, the correction of high blood pressure does not decrease the incidence of coronary heart disease. Several hypotheses have been formulated to account for this observation: one is that reversibility of the structural vascular changes induced by hypertension is not complete when the blood pressure is lowered; another is that antihypertensive drugs have a deleterious effect on the vascular wall.

A comparison of voluntary and electrically induced contractions by interleaved 1H- and 31P-NMRS in humans.

Skeletal muscle voluntary contractions (VC) and electrical stimulations (ES) were compared in eight healthy men. High-energy phosphates and myoglobin oxygenation were simultaneously monitored in the quadriceps by interleaved (1)H- and (31)P-NMR spectroscopy. For the VC protocol, subjects performed five or six bouts of 5 min with a workload increment of 10% of maximal voluntary torque (MVT) at each step. The ES protocol consisted of a 13-min exercise with a load corresponding to 10% MVT. For both protocols, exercise consisted of 6-s isometric contractions and 6-s rest cycles. For an identical mechanical level (10% MVT), ES induced larger changes than VC in the P(i)-to-phosphocreatine ratio [1.38 +/- 1.14 (ES) vs. 0.13 +/- 0.04 (VC)], pH [6.69 +/- 0.11 (ES) vs. 7.04 +/- 0.07 (VC)] and myoglobin desaturation [43 +/- 15.9 (ES) vs. 6.1 +/- 4.6% (VC)]. ES activated the muscle facing the NMR coil to a greater extent than did VCs when evaluated under identical technical conditions. This metabolic pattern can be interpreted in terms of specific temporal and spatial muscle cell recruitment. Furthermore, at identical levels of energy charge, the muscle was more acidotic and cytoplasm appeared more oxygenated during ES than during VC. These results are in accordance with a preferential recruitment of type II fibers and a relative muscle hyperperfusion during ES.

C13 NMR spectroscopy of lipids: a simple method for absolute quantitation.

There is both epidemiological and experimental evidence of the effect of fatty acid molecular structure, particularly the degree of saturation in fatty acyl chains, on the growth and regulation of certain tumours. In vivo carbon nuclear magnetic resonance spectroscopy has previously been shown to offer a non invasive technique for the evaluation of proportions of monounsaturated, polyunsaturated and saturated fatty acids in human adipose tissue. We present a simple method, which uses both endogenous water and fat as reference, to quantify in molar terms these lipid sub-categories for tissues other than pure fat. This could provide additional information in the debate on the protective effect in cancer of high polyunsaturated fatty acid (PUFA) diet. The method was validated by characterization of a lipid emulsion of known composition in various experimental set-ups and was applied to measure the lipid composition of the calves of two volunteers. Limitations and perspectives of the method are discussed.

Simultaneous measurement of perfusion and oxygenation changes using a multiple gradient-echo sequence: application to human muscle study.

We have developed a magnetic resonance imaging (MRI) technique based on a multiple gradient-echo sequence designed to probe perfusion and oxygenation simultaneously within skeletal muscle. Processing of the images acquired at successive echo times (TEs) generates two functional maps: one of the signal intensity (SI) extrapolated to zero echo time, which is sensitive to perfusion; and a second one of R2*, which reflects oxygenation. An advantage of the processing procedure lies in the selection of tissue of interest through the profile of T2* decay, leading to automatic rejection of pixels containing small vessels. This allows a more specific assessment of tissue perfusion and oxygenation. This technique was demonstrated successfully during post-ischemic reactive hyperemia in human calf. A perfusion peak of 123 mL x 100 g(-)1 x min(-1) was measured immediately after ischemia, whereas R2* value showed an 11.5% decrease at the same time, essentially reflecting blood oxygenation changes. Differences in the time courses of reperfusion and re-oxygenation were observed, oxygenation presenting a slower recovery. The mechanisms responsible for such a differential dynamic response are discussed.

1H NMR spectroscopy study of the dynamic properties of glycogen in solution by steady-state magnetisation measurement with off-resonance irradiation.

The dynamics of size-selected fractions of glycogen in solution have been investigated by proton NMR spectroscopy, using a recently described relaxation study method which relies on strong offresonance irradiation. The dependence of the steady-state magnetisation on angle and intensity of the effective radio-frequency field was measured and compared to theoretical curves derived from different models of motion. Absence or presence of contributions to relaxation from molecular motions on the microsecond time scale can be tested with this method, without having to resort to models. We found that glycogen dipolar relaxation did not result from isotropic Brownian rotation, and despite some contribution from slow motion (> 1 microsecond) to relaxation in glycogen alpha-particles extracted from rat liver, bulk movement of the molecules did not appear to participate in averaging the dipolar term to zero. Whereas hepatic glycogen rat beta-particles and commercial oyster glycogen displayed very similar relaxation properties, alpha-particles showed significantly different behaviour. However, all results were compatible with a diversity of movements within the molecule, ranging from freely rotating pyranoside rings through collective chain motion and possibly to bulk movement of the beta sub-units within the alpha-particle.

Vasopressin as a putative mediator in SHR hypoalgesia.

The purpose of this note is to show that vasopressin might be involved in the hypoalgesia of the spontaneously hypertensive rat. This proposal rests upon published data.

[Does ambulatory blood pressure measurement allow a better definition of arterial hypertension?]. / La mesure ambulatoire de la pression artérielle permet d'améliorer la définition de l'hypertension artérielle.

The lack of effect of treatment of mild hypertension on the coronary heart disease has motivated researches for a better diagnosis of hypertension. One of the approaches presently under study uses the recording of ambulatory blood pressure using semi-automatic devices. The usefulness of these apparatus is however restricted by the lack of reference values recorded in normotensive control patients. We have recorded ambulatory blood pressure (PAA) in 24 normotensives, 22 untreated hypertensives and 45 treated hypertensive patients, and compared the data obtained to the blood pressure recorded during medical examination (PAC). If a good correlation is usually observed between PAA and PAC, very large and unpredictable discordances are frequently observed. No correlation is found between the difference PAA-PAC and the variability of PAA. This variability does not fully explain the difference observed between PAA and PAC. This variability expressed in mmHg increases with age and the level of BP. Ambulatory BP appears to be a very reproducible value which may allow to improve the definition of hypertension and there-fore the cardiovascular risk.