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Purpose: Tensor-valued diffusion encoding can probe more specific features of tissue microstructure than what is available by conventional diffusion weighting. In this work, we investigate the technical feasibility of tensor-valued diffusion encoding at high b-values with q-space trajectory imaging (QTI) analysis, in the human heart in vivo. Methods: Ten healthy volunteers were scanned on a 3T scanner. We designed time-optimal gradient waveforms for tensor-valued diffusion encoding (linear and planar) with second-order motion compensation. Data were analyzed with QTI. Normal values and repeatability were investigated for the mean diffusivity (MD), fractional anisotropy (FA), microscopic FA (μFA), isotropic, anisotropic and total mean kurtosis (MKi, MKa, and MKt), and orientation coherence (Cc). A phantom, consisting of two fiber blocks at adjustable angles, was used to evaluate sensitivity of parameters to orientation dispersion and diffusion time. Results: QTI data in the left ventricular myocardium were MD = 1.62 ± 0.07 μm2/ms, FA = 0.31 ± 0.03, μFA = 0.43 ± 0.07, MKa = 0.20 ± 0.07, MKi = 0.13 ± 0.03, MKt = 0.33 ± 0.09, and Cc = 0.56 ± 0.22 (mean ± SD across subjects). Phantom experiments showed that FA depends on orientation dispersion, whereas μFA was insensitive to this effect. Conclusion: We demonstrated the first tensor-valued diffusion encoding and QTI analysis in the heart in vivo, along with first measurements of myocardial μFA, MKi, MKa, and Cc. The methodology is technically feasible and provides promising novel biomarkers for myocardial tissue characterization.

Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9–/– mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9–/– mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9–/– mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9–/– mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9–/– mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9–/– mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

Background: Intramyocardial hemorrhage (IMH) following ST-elevation myocardial infarction (STEMI) is associated with poor prognosis. In cardiac magnetic resonance (MR), T2* mapping is the reference standard for detecting IMH while cardiac diffusion tensor imaging (cDTI) can characterize myocardial architecture via fractional anisotropy (FA) and mean diffusivity (MD) of water molecules. The value of cDTI in the detection of IMH is not currently known. Hypothesis: cDTI can detect IMH post-STEMI. Study Type: Prospective. Subjects: A total of 50 patients (20% female) scanned at 1-week (V1) and 3-month (V2) post-STEMI. Field Strength/Sequence: A 3.0 T; inversion-recovery T1-weighted-imaging, multigradient-echo T2* mapping, spin-echo cDTI. Assessment: T2* maps were analyzed to detect IMH (defined as areas with T2* < 20 msec within areas of infarction). cDTI images were co-registered to produce averaged diffusion-weighted-images (DWIs), MD, and FA maps; hypointense areas were manually planimetered for IMH quantification. Statistics: On averaged DWI, the presence of hypointense signal in areas matching IMH on T2* maps constituted to true-positive detection of iron. Independent samples t-tests were used to compare regional cDTI values. Results were considered statistically significant at P, Journal of Magnetic Resonance Imaging, 56 (4), ISSN:1053-1807, ISSN:1522-2586

Biophysical models are a promising means for interpreting diffusion weighted magnetic resonance imaging (DW-MRI) data, as they can provide estimates of physiologically relevant parameters of microstructure including cell size, volume fraction, or dispersion. However, their application in cardiac microstructure mapping (CMM) has been limited. This study proposes seven new two-compartment models with combination of restricted cylinder models and a diffusion tensor to represent intra- and extracellular spaces, respectively. Three extended versions of the cylinder model are studied here: cylinder with elliptical cross section (ECS), cylinder with Gamma distributed radii (GDR), and cylinder with Bingham distributed axes (BDA). The proposed models were applied to data in two fixed mouse hearts, acquired with multiple diffusion times, q-shells and diffusion encoding directions. The cylinderGDR-pancake model provided the best performance in terms of root mean squared error (RMSE) reducing it by 25% compared to diffusion tensor imaging (DTI). The cylinderBDA-pancake model represented anatomical findings closest as it also allows for modelling dispersion. High-resolution 3D synchrotron X-ray imaging (SRI) data from the same specimen was utilized to evaluate the biophysical models. A novel tensor-based registration method is proposed to align SRI structure tensors to the MR diffusion tensors. The consistency between SRI and DW-MRI parameters demonstrates the potential of compartment models in assessing physiologically relevant parameters.

Background Cardiac diffusion tensor imaging (cDTI) allows for in vivo characterization of myocardial microstructure. In cDTI, mean diffusivity and fractional anisotropy (FA)-markers of magnitude and anisotropy of diffusion of water molecules-are known to change after myocardial infarction. However, little is known about regional changes in helix angle (HA) and secondary eigenvector angle (E2A), which reflects orientations of laminar sheetlets, and their association with long-term recovery of left ventricular ejection fraction (LVEF). Purpose To assess serial changes in cDTI biomarkers in participants following ST-segment elevation myocardial infarction (STEMI) and to determine their associations with long-term left ventricular remodeling. Materials and Methods In this prospective study, 30 participants underwent cardiac MRI (3 T) after STEMI at 5 days and 3 months after reperfusion (National Institute of Health Research study no. 33963 and Research Ethics no. REC17/YH/0062). Spin-echo cDTI with second-order motion-compensation (approximate duration, 13 minutes; three sections; 18 noncollinear diffusion-weighted scans with b values of 100 sec/mm2 [three acquisitions], 200 sec/mm2 [three acquisitions], and 500 sec/mm2 [12 acquisitions]), functional images, and late gadolinium enhancement images were obtained. Multiple regression analysis was used to assess associations between acute cDTI parameters and 3-month LVEF. Results Acutely infarcted myocardium had reduced FA, E2A, and myocytes with right-handed orientation (RHM) on HA maps compared with remote myocardium (mean remote FA = 0.36 ± 0.02 [standard deviation], mean infarcted FA = 0.25 ± 0.03, P < .001; mean remote E2A = 55° ± 9, mean infarcted E2A = 49° ± 10, P < .001; mean remote RHM = 16% ± 6, mean infarcted RHM = 9% ± 5, P < .001). All three parameters (FA, E2A, and RHM) correlated with 3-month LVEF (r = 0.68, r = 0.59, and r = 0.53, respectively), with acute FA being independently predictive of 3-month LVEF (standardized β = 0.56, P = .008) after multivariable analysis adjusting for factors, including acute LVEF and infarct size. Conclusion After ST-segment elevation myocardial infarction, diffusion becomes more isotropic in acutely infarcted myocardium as reflected by decreased fractional anisotropy. Reductions in secondary eigenvector angle suggest that the myocardial sheetlets are unable to adopt their usual steep orientations in systole, whereas reductions in myocytes with right-handed orientation on helix angle maps are likely reflective of a loss of organization among subendocardial myocytes. Correlations between these parameters and 3-month left ventricular ejection fraction highlight the potential clinical use of cardiac diffusion tensor imaging after myocardial infarction in predicting long-term remodeling. © RSNA, 2021 Online supplemental material is available for this article.

Prospective cardiac gating during MRI is hampered by electromagnetic induction from the rapidly switched imaging gradients into the ECG detection circuit. This is particularly challenging in small animal MRI, as higher heart rates combined with a smaller myocardial mass render routine ECG detection challenging. We have developed an open-hardware system that enables continuously running MRI scans to be performed in conjunction with cardio-respiratory gating such that the relaxation-weighted steady state magnetisation is maintained throughout the scan. This requires that the R-wave must be detected reliably even in the presence of rapidly switching gradients, and that data previously acquired that were corrupted by respiratory motion re-acquired. The accurately maintained steady-state magnetisation leads to an improvement in image quality and removes alterations in intensity that may otherwise occur throughout the cardiac cycle and impact upon automated image analysis. We describe the hardware required to enable this and demonstrate its application and robust performance using prospectively cardio-respiratory gated CINE imaging that is operated at a single, constant TR. Schematics, technical drawings, component listing and assembly instructions are made publicly available.

International audience; Cardiac diffusion tensor imaging (DTI) is an emerging technique for the in vivo characterisation of myocardial microstructure, and there is a growing need for its validation and standardisation. We sought to establish the accuracy, precision, repeatability and reproducibility of state-of-the-art pulse sequences for cardiac DTI among 10 centres internationally. Phantoms comprising 0%-20% polyvinylpyrrolidone (PVP) were scanned with DTI using a product pulsed gradient spin echo (PGSE; N = 10 sites) sequence, and a custom motion-compensated spin echo (SE; N = 5) or stimulated echo acquisition mode (STEAM; N = 5) sequence suitable for cardiac DTI in vivo. A second identical scan was performed 1-9 days later, and the data were analysed centrally. The average mean diffusivities (MDs) in 0% PVP were (1.124, 1.130, 1.113) x 10-3 mm2 /s for PGSE, SE and STEAM, respectively, and accurate to within 1.5% of reference data from the literature. The coefficients of variation in MDs across sites were 2.6%, 3.1% and 2.1% for PGSE, SE and STEAM, respectively, and were similar to previous studies using only PGSE. Reproducibility in MD was excellent, with mean differences in PGSE, SE and STEAM of (0.3 ± 2.3, 0.24 ± 0.95, 0.52 ± 0.58) x 10-5 mm2 /s (mean ± 1.96 SD). We show that custom sequences for cardiac DTI provide accurate, precise, repeatable and reproducible measurements. Further work in anisotropic and/or deforming phantoms is warranted.

Background Pressure overload left ventricular (LV) hypertrophy is characterized by increased cardiomyocyte width and ventricle wall thickness, however the regional variation of this remodeling is unclear. Cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) may provide a non-invasive, comprehensive, and geometrically accurate method to detect regional differences in structural remodeling in hypertrophy. We hypothesized that DTI parameters, such as fractional and planar anisotropy, would reflect myocyte remodeling due to pressure overload in a regionally-dependent manner. Methods We investigated the regional distributions of myocyte remodeling in rats with or without transverse aortic constriction (TAC) via direct measurement of myocyte dimensions with confocal imaging of thick tissue sections, and correlated myocyte cross-sectional area and other geometric features with parameters of diffusivity from ex-vivo DTI in the same regions of the same hearts. Results We observed regional differences in several parameters from DTI between TAC hearts and SHAM controls. Consistent with previous studies, helix angles from DTI correlated strongly with those measured directly from histological sections (p 2 = 0.71). There was a transmural gradient in myocyte cross-sectional area in SHAM hearts that was diminished in the TAC group. We also found several regions of significantly altered DTI parameters in TAC LV compared to SHAM, especially in myocyte sheet angle dispersion and planar anisotropy. Among others, these parameters correlated significantly with directly measured myocyte aspect ratios. Conclusions These results show that structural remodeling in pressure overload LV hypertrophy is regionally heterogeneous, especially transmurally, with a greater degree of remodeling in the sub-endocardium compared to the sub-epicardium. Additionally, several parameters derived from DTI correlated significantly with measurements of myocyte geometry from direct measurement in histological sections. We suggest that DTI may provide a non-invasive, comprehensive method to detect regional structural myocyte LV remodeling during disease.

Purpose Structure-guided total variation is a recently introduced prior that allows reconstruction of images using knowledge of the location and orientation of edges in a reference image. In this work, we demonstrate the advantages of a variant of structure-guided total variation known as directional total variation (DTV), over traditional total variation (TV), in the context of compressed-sensing reconstruction and super-resolution. Methods We compared TV and DTV in retrospectively undersampled ex vivo diffusion tensor imaging and diffusion spectrum imaging data from healthy, sham, and hypertrophic rat hearts. Results In compressed sensing at an undersampling factor of 8, the RMS error of mean diffusivity and fractional anisotropy relative to the fully sampled ground truth were 44% and 20% lower in DTV compared with TV. In super-resolution, these values were 29% and 14%, respectively. Similarly, we observed improvements in helix angle, transverse angle, sheetlet elevation, and sheetlet azimuth. The RMS error of the diffusion kurtosis in the undersampled data relative to the ground truth was uniformly lower (22% on average) with DTV compared to TV. Conclusion Acquiring one fully sampled non-diffusion-weighted image and 10 diffusion-weighted images at 8× undersampling would result in an 80% net reduction in data needed. We demonstrate efficacy of the DTV algorithm over TV in reducing data sampling requirements, which can be translated into higher apparent resolution and potentially shorter scan times. This method would be equally applicable in diffusion MRI applications outside the heart.

This study evaluated the potential associations between DT-CMR performed soon after STEMI and long-term adverse left ventricular (LV) remodeling following STEMI.Adverse LV remodeling post-ST-segment elevation myocardial infarction (STEMI) is associated with a poor prognosis, but the underlying mechanisms are not fully understood. Diffusion tensor (DT)-cardiac magnetic resonance (CMR) allows in vivo characterization of myocardial architecture and provides unique mechanistic insight into pathophysiologic changes following myocardial infarction.A total of 100 patients with STEMI underwent CMR at 5 days and 12 months post-reperfusion. The protocol included DT-CMR for assessing fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA), cine imaging for assessing LV volumes, and late gadolinium enhancement for calculating infarct and microvascular obstruction size. Adverse remodeling was defined as a 20% increase in LV end-diastolic volume at 12 months.A total of 32 patients experienced adverse remodeling at 12 months. Compared with patients without adverse remodeling, they had lower FA (0.23 ± 0.03 vs 0.27 ± 0.04; P 0.001), lower E2A (37 ± 6° vs 51 ± 7°; P 0.001), and, on HA maps, a lower proportion of myocytes with right-handed orientation (RHM) (8% ± 5% vs 17% ± 9%; P 0.001) in their acutely infarcted myocardium. On multivariable logistic regression analysis, infarct FA (odds ratio [OR]: 0.01; P = 0.014) and E2A (OR: 0.77; P = 0.001) were independent predictors of adverse LV remodeling after adjusting for LV ejection fraction and infarct size. There were no significant changes in infarct FA, E2A, or RHM between the 2 scans.Extensive cardiomyocyte disorganization (evidenced by low FA), acute loss of sheetlet angularity (evidenced by low E2A), and a greater loss of organization among cardiomyocytes with RHM, corresponding to the subendocardium, can be detected within 5 days post-STEMI. These changes persist post-injury, and low FA and E2A are independently associated with long-term adverse remodeling.

Sarcomeres, the basic contractile units of striated muscle, produce the forces driving muscular contraction through cross-bridge interactions between actin-containing thin filaments and myosin II-based thick filaments. Until now, direct visualization of the molecular architecture underlying sarcomere contractility has remained elusive. Here, we use in situ cryo-electron tomography to unveil sarcomere contraction in frozen-hydrated neonatal rat cardiomyocytes. We show that the hexagonal lattice of the thick filaments is already established at the neonatal stage, with an excess of thin filaments outside the trigonal positions. Structural assessment of actin polarity by subtomogram averaging reveals that thin filaments in the fully activated state form overlapping arrays of opposite polarity in the center of the sarcomere. Our approach provides direct evidence for thin filament sliding during muscle contraction and may serve as a basis for structural understanding of thin filament activation and actomyosin interactions inside unperturbed cellular environments., Sarcomeres, the building blocks of striated muscles, comprise ordered actomyosin arrays involved in force production. Here, the authors visualize sarcomere organization in neonatal cardiomyocytes with in situ cryo-electron tomography, revealing a reduced order of the thin filaments, their sliding and functional states enabling contraction.

Aims Microvascular dysfunction in hypertrophic cardiomyopathy (HCM) is predictive of clinical decline, however underlying mechanisms remain unclear. Cardiac diffusion tensor imaging (cDTI) allows in vivo characterization of myocardial microstructure by quantifying mean diffusivity (MD), fractional anisotropy (FA) of diffusion, and secondary eigenvector angle (E2A). In this cardiac magnetic resonance (CMR) study, we examine associations between perfusion and cDTI parameters to understand the sequence of pathophysiology and the interrelation between vascular function and underlying microstructure. Methods and results Twenty HCM patients underwent 3.0T CMR which included: spin-echo cDTI, adenosine stress and rest perfusion mapping, cine-imaging, and late gadolinium enhancement (LGE). Ten controls underwent cDTI. Myocardial perfusion reserve (MPR), MD, FA, E2A, and wall thickness were calculated per segment and further divided into subendocardial (inner 50%) and subepicardial (outer 50%) regions. Segments with wall thickness ≤11 mm, MPR ≥2.2, and no visual LGE were classified as ‘normal’. Compared to controls, ‘normal’ HCM segments had increased MD (1.61 ± 0.09 vs. 1.46 ± 0.07 × 10−3 mm2/s, P = 0.02), increased E2A (60 ± 9° vs. 38 ± 12°, P Conclusion In HCM patients, even in segments with normal wall thickness, normal perfusion, and no scar, diffusion is more isotropic than in controls, suggesting the presence of underlying cardiomyocyte disarray. Increased E2A suggests the myocardial sheetlets adopt hypercontracted angulation in systole. Increased MD, most notably in the subendocardium, is suggestive of regional remodelling which may explain the reduced subendocardial blood flow.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Cardiac diffusion tensor imaging (cDTI) is a novel technique for the non-invasive assessment of myocardial microstructure. It allows in-vivo characterisation of microstructural changes post myocardial infarction (MI). Previously published evidence shows significant loss of sheetlet orientation as derived by cDTI secondary eigenvector (E2A), and loss of subendocardial cardiomyocytes derived by reductions in the proportions of myocytes with right-handed orientation (RHM) on helix angle (HA) maps. The assessment of myocardial strain by feature tracking (FT) allows the measurement of radial strain (RS), thought to be driven by the dynamic reorientation of laminar sheetlets, and longitudinal strain (LS), which is thought to relate to subendocardial function. We sought to explore the relationship between the strain and cDTI parameters in patients at 3 months following ST-elevation MI (STEMI). Methods Twenty five STEMI patients (M:F = 18:7, mean age 58 ± 9) underwent 3T CMR scan (mean interval 106 ± 17 days) with the following protocol: second order motion compensated (M2), free-breathing spin echo DTI (3 slices, 18 diffusion directions at b-values 100s/mm2, 200s/mm2 and 500s/mm2, acquired resolution was 2.20*2.27*8mm3; cine gradient echo and Late Gadolinium Enhancement (LGE) imaging. HA maps were described by dividing values into left-handed HA (LHM, -90< HA < -30), circumferential HA (CM, -30° < HA < 30°), and right-handed HA (RHM, 30° < HA < 90°) and reported as relative proportions. Segmental analysis were undertaken to derive: HA proportions, E2A, longitudinal strain and LGE%. Segments positive for LGE were classed as infarct segments. Results cDTI acquisition was successful in all patients (acquisition time 13 ± 5mins). Mean ejection fraction was 47 ± 8% with mean LGE in the infarcted segment of 57 ± 27%. Mean radial strain was 21 (95% confidence interval, 15-26). The mean E2A was 44 (95% confidence interval 41-47). There was a significant correlation between segmental radial strain and segmental E2A in infarcted segments (p Conclusion Through the combined use of cDTI and FT in patients with chronic infarcts, our results show that the loss of sheetlet orientation assessed using E2A, correlates with worsening radial strain. Segments with less subendocardial cardiomyocytes, evidenced by a lower proportion of myocytes with right-handed orientation on HA maps, correlated with worse longitudinal strain. While this could potentially elucidate the complex association between myocardial microstructure and regional function, further studies are needed to define the incremental clinical value of cDTI.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background The microstructural changes following myocardial infarction (MI) can be characterised in-vivo with cardiac diffusion tensor imaging (cDTI) imaging, using mean diffusivity (MD), fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA) maps. In this study, we use cDTI to explore the microstructural differences between subendocardial and transmural chronic infarct segments. Method Twenty STEMI patients (15 men, 5 women, mean age 59) underwent 3T CMR scan at 3 months following presentation (mean interval 107 ± 18 days). Scan protocol included: second order motion compensated (M012) free-breathing spin echo DTI (3 slices, 18 diffusion directions at b-values 100s/mm2[3], 200s/mm2[3] and 500s/mm2[12], acquired resolution was 2.20x2.27x8mm3; cine gradient echo and LGE imaging. Average MD, FA, E2A and HA parameters were calculated on a 16-AHA-segmental level. HA maps were described by dividing values into left-handed HA (LHM, -90° < HA < -30°), circumferential HA (CM, -30° < HA < 30°), and right-handed HA (RHM, 30° < HA < 90°) and reported as relative proportions. Infarct segments were identified using LGE; patients were categorised according to the maximal transmurality of their infarct segments, into subendocardial (50% LGE) MI. Results DTI acquisition was successful in all patients (acquisition time 13 ± 5mins). Ten patients had transmural MI. The results are shown in table 1. Transmurally infarcted segments had significantly lower FA (FA subendocardial MI = 0.27 ± 0.04, FA transmural MI = 0.23 ± 0.02, p Conclusion Compared to subendocardial MI segments, the diffusion of water molecules is more isotropic in transmurally infarcted myocardium as evidenced by lower FA values, signifying increased structural disarray. The significantly lower E2A values suggest that laminar sheetlets of transmural infarct segments remain fixed at shallower angles during systole and are unable to reach their usual contractile configuration. The lower proportions of RHM on HA maps highlight the significantly greater loss of subendocardial cardiomyocytes in transmural infarct segments. Further studies are required to assess if these segmental changes can be predictive of long-term LV remodelling.

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk., Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.

PURPOSE Diffusion-weighted MRI is sensitive to incoherent tissue motion, which may confound the measured signal and subsequent analysis. We propose a "motion-compensated" gradient waveform design for tensor-valued diffusion encoding that negates the effects bulk motion and incoherent motion in the ballistic regime. METHODS Motion compensation was achieved by constraining the magnitude of gradient waveform moment vectors. The constraint was incorporated into a numerical optimization framework, along with existing constraints that account for b-tensor shape, hardware restrictions, and concomitant field gradients. We evaluated the efficacy of encoding and motion compensation in simulations, and we demonstrated the approach by linear and planar b-tensor encoding in a healthy heart in vivo. RESULTS The optimization framework produced asymmetric motion-compensated waveforms that yielded b-tensors of arbitrary shape with improved efficiency compared with previous designs for tensor-valued encoding, and equivalent efficiency to previous designs for linear (conventional) encoding. Technical feasibility was demonstrated in the heart in vivo, showing vastly improved data quality when using motion compensation. The optimization framework is available online in open source. CONCLUSION Our gradient waveform design is both more flexible and efficient than previous methods, facilitating tensor-valued diffusion encoding in tissues in which motion would otherwise confound the signal. The proposed design exploits asymmetric encoding times, a single refocusing pulse or multiple refocusing pulses, and integrates compensation for concomitant gradient effects throughout the imaging volume.

Diffusion MRI studies include tests on standardised phantoms and measurements on the output images to assess and benchmark the imaging system. These tests are an essential methodological step to guarantee the reproducibility of measurement outcomes. However, in longitudinal and multi-centre studies, analysis tasks become more complex with the increase in the sources and volume of data, as well as the parameters of interest. To manage this complexity, Visual Analytics (VA) allows researchers to explore large amounts of data easily and quickly by providing key information in a readily interpretable format and reducing the cognitive load of information. This paper presents CMRDiffMonitor, a VA tool for monitoring and benchmarking Diffusion Tensor Imaging (DTI) databases developed in the context of a multi-centre MRI project. Through an interactive dashboard, CMRDiffMonitor enables users to capture a snapshot of the study which includes: a temporal overview of the data sets (monitoring of the system stability across sites) and statistical measurements in Regions of Interest on Diffusion Anisotropy Indices (benchmarking of the different imaging sequences and systems).

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Heart Research UK Background Diffusion tensor cardiac magnetic resonance (DT-CMR) imaging allows for characterising myocardial microstructure in-vivo using mean diffusivity (MD), fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA) maps. Following myocardial infarction (MI), alterations in MD, FA and HA proportions have previously been reported. E2A depicts the contractile state of myocardial sheetlets, however the behaviour of E2A in infarct segments, and all DTI markers in areas of microvascular obstruction (MVO) is also not fully understood. Purpose We performed spin echo DTI in patients following ST-elevation MI (STEMI) in order to investigate acute changes in DTI parameters in remote and infarct segments both with and without MVO. Method Twenty STEMI patients (16 men, 4 women, mean age 59) had acute (5 ± 2d) 3T CMR scans. CMR protocol included: second order motion compensated (M012) free-breathing spin echo DTI (3 slices, 18 diffusion directions at b-values 100s/mm2[3], 200s/mm2[3] and 500s/mm2[12], reconstructed resolution was 1.66x1.66x8mm); cine and late gadolinium enhancement (LGE) imaging. Average MD, FA, E2A HA parameters were calculated on a 16 AHA segmental level. HA maps were described by dividing values into left-handed HA (LHM, -90° < HA < -30°), circumferential HA (CM, -30° < HA < 30°), and right-handed HA (RHM, 30° < HA < 90°) and reported as relative proportions. Segments were defined as infarct (positive for LGE) and remote (opposite to the infarct). Results DTI acquisition was successful in all patients (acquisition time 13 ± 5mins). Ten patients had evidence of MVO on LGE images. MD was significantly higher in infarct regions in comparison to remote; MVO-ve infarct segments had significantly higher MD than MVO + ve infarct segments (MD remote= 1.46 ± 0.12x10-3mm2/s, MD MVO + ve = 1.59 ± 0.12x10-3mm2/s, MD MVO-ve = 1.75 ± 0.12x10-3mm2/s, ANOVA p E2A values were significantly lower in infarct segments compared to remote; MVO + ve infarct segments had significantly lower values than MVO-ve. (E2A remote= 57.4 ± 5.2°, E2A MVO-ve = 46.8 ± 2.5°, E2A MVO + ve = 36.8 ± 3.1°, ANOVA p Conclusion The presence of MVO results in a decrease in MD and increase in FA in comparison to surrounding infarct segments. However, the reduction in E2A and right-handed myocytes on HA in infarct segments is further exacerbated by the presence of MVO. Further study is required to investigate the underlying mechanisms for such alterations in signal intensity. Abstract Figure. A case of transmural septal MI with MVO