Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Comparison of distortion correction preprocessing pipelines for DTI in the upper limb.

PURPOSE: DTI characterizes tissue microstructure and provides proxy measures of nerve health. Echo-planar imaging is a popular method of acquiring DTI but is susceptible to various artifacts (e.g., susceptibility, motion, and eddy currents), which may be ameliorated via preprocessing. There are many pipelines available but limited data comparing their performance, which provides the rationale for this study. METHODS: DTI was acquired from the upper limb of heathy volunteers at 3T in blip-up and blip-down directions. Data were independently corrected using (i) FSL's TOPUP & eddy, (ii) FSL's TOPUP, (iii) DSI Studio, and (iv) TORTOISE. DTI metrics were extracted from the median, radial, and ulnar nerves and compared (between pipelines) using mixed-effects linear regression. The geometric similarity of corrected b = 0 images and the slice matched T1-weighted (T1w) images were computed using the Sörenson-Dice coefficient. RESULTS: Without preprocessing, the similarity coefficient of the blip-up and blip-down datasets to the T1w was 0·80 and 0·79, respectively. Preprocessing improved the geometric similarity by 1% with no difference between pipelines. Compared to TOPUP & eddy, DSI Studio and TORTOISE generated 2% and 6% lower estimates of fractional anisotropy, and 6% and 13% higher estimates of radial diffusivity, respectively. Estimates of anisotropy from TOPUP & eddy versus TOPUP were not different but TOPUP reduced radial diffusivity by 3%. The agreement of DTI metrics between pipelines was poor. CONCLUSIONS: Preprocessing DTI from the upper limb improves geometric similarity but the choice of the pipeline introduces clinically important variability in diffusion parameter estimates from peripheral nerves.

In vivo diffusion MRI of the human heart using a 300 mT/m gradient system.

PURPOSE: This work reports for the first time on the implementation and application of cardiac diffusion-weighted MRI on a Connectom MR scanner with a maximum gradient strength of 300 mT/m. It evaluates the benefits of the increased gradient performance for the investigation of the myocardial microstructure. METHODS: Cardiac diffusion-weighted imaging (DWI) experiments were performed on 10 healthy volunteers using a spin-echo sequence with up to second- and third-order motion compensation ( M 2 $$ {M}_2 $$ and M 3 $$ {M}_3 $$ ) and b = 100 , 450 $$ b=100,450 $$ , and 1000 s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ (twice the b max $$ {b}_{\mathrm{max}} $$ commonly used on clinical scanners). Mean diffusivity (MD), fractional anisotropy (FA), helix angle (HA), and secondary eigenvector angle (E2A) were calculated for b = [100, 450] s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ and b = [100, 1000] s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ for both M 2 $$ {M}_2 $$ and M 3 $$ {M}_3 $$ . RESULTS: The MD values with M 3 $$ {M}_3 $$ are slightly higher than with M 2 $$ {M}_2 $$ with Δ MD = 0 . 05 ± 0 . 05 [ × 1 0 - 3 mm 2 / s ] ( p = 4 e - 5 ) $$ \Delta \mathrm{MD}=0.05\pm 0.05\kern0.3em \left[\times 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=4e-5\right) $$ for b max = 450 s / mm 2 $$ {b}_{\mathrm{max}}=450\kern0.3em \mathrm{s}/{\mathrm{mm}}^2 $$ and Δ MD = 0 . 03 ± 0 . 03 [ × 1 0 - 3 mm 2 / s ] ( p = 4 e - 4 ) $$ \Delta \mathrm{MD}=0.03\pm 0.03\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=4e-4\right) $$ for b max = 1000 s / mm 2 $$ {b}_{\mathrm{max}}=1000\kern0.3em \mathrm{s}/{\mathrm{mm}}^2 $$ . A reduction in MD is observed by increasing the b max $$ {b}_{\mathrm{max}} $$ from 450 to 1000 s / mm 2 $$ \mathrm{s}/{\mathrm{mm}}^2 $$ ( Δ MD = 0 . 06 ± 0 . 04 [ × 1 0 - 3 mm 2 / s ] ( p = 1 . 6 e - 9 ) $$ \Delta \mathrm{MD}=0.06\pm 0.04\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=1.6e-9\right) $$ for M 2 $$ {M}_2 $$ and Δ MD = 0 . 08 ± 0 . 05 [ × 1 0 - 3 mm 2 / s ] ( p = 1 e - 9 ) $$ \Delta \mathrm{MD}=0.08\pm 0.05\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=1e-9\right) $$ for M 3 $$ {M}_3 $$ ). The difference between FA, E2A, and HA was not significant in different schemes ( p > 0 . 05 $$ p>0.05 $$ ). CONCLUSION: This work demonstrates cardiac DWI in vivo with higher b-value and higher order of motion compensated diffusion gradient waveforms than is commonly used. Increasing the motion compensation order from M 2 $$ {M}_2 $$ to M 3 $$ {M}_3 $$ and the maximum b-value from 450 to 1000 s / mm 2 $$ \mathrm{s}/{\mathrm{mm}}^2 $$ affected the MD values but FA and the angular metrics (HA and E2A) remained unchanged. Our work paves the way for cardiac DWI on the next-generation MR scanners with high-performance gradient systems.

Measuring cardiomyocyte cellular characteristics in cardiac hypertrophy using diffusion-weighted MRI.

PURPOSE: This paper presents a hierarchical modeling approach for estimating cardiomyocyte major and minor diameters and intracellular volume fraction (ICV) using diffusion-weighted MRI (DWI) data in ex vivo mouse hearts. METHODS: DWI data were acquired on two healthy controls and two hearts 3 weeks post transverse aortic constriction (TAC) using a bespoke diffusion scheme with multiple diffusion times ( Δ $$ \Delta $$ ), q-shells and diffusion encoding directions. Firstly, a bi-exponential tensor model was fitted separately at each diffusion time to disentangle the dependence on diffusion times from diffusion weightings, that is, b-values. The slow-diffusing component was attributed to the restricted diffusion inside cardiomyocytes. ICV was then extrapolated at Δ = 0 $$ \Delta =0 $$ using linear regression. Secondly, given the secondary and the tertiary diffusion eigenvalue measurements for the slow-diffusing component obtained at different diffusion times, major and minor diameters were estimated assuming a cylinder model with an elliptical cross-section (ECS). High-resolution three-dimensional synchrotron X-ray imaging (SRI) data from the same specimen was utilized to evaluate the biophysical parameters. RESULTS: Estimated parameters using DWI data were (control 1/control 2 vs. TAC 1/TAC 2): major diameter-17.4 µ $$ \mu $$ m/18.0 µ $$ \mu $$ m versus 19.2 µ $$ \mu $$ m/19.0 µ $$ \mu $$ m; minor diameter-10.2 µ $$ \mu $$ m/9.4 µ $$ \mu $$ m versus 12.8 µ $$ \mu $$ m/13.4 µ $$ \mu $$ m; and ICV-62%/62% versus 68%/47%. These findings were consistent with SRI measurements. CONCLUSION: The proposed method allowed for accurate estimation of biophysical parameters suggesting cardiomyocyte diameters as sensitive biomarkers of hypertrophy in the heart.

Cardiac q-space trajectory imaging by motion-compensated tensor-valued diffusion encoding in human heart in vivo.

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.

Endothelial IGF-1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

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.

Validation of cardiac diffusion tensor imaging sequences: A multicentre test-retest phantom study.

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.

Detection of Intramyocardial Iron in Patients Following ST-Elevation Myocardial Infarction Using Cardiac Diffusion Tensor Imaging.

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 ≤ 0.05. RESULTS: At V1, 24 patients had IMH on T2*. On averaged DWI, all 24 patients had hypointense signal in matching areas. IMH size derived using averaged-DWI was nonsignificantly greater than from T2* (2.0 ± 1.0 cm2 vs 1.89 ± 0.96 cm2 , P = 0.69). Compared to surrounding infarcted myocardium, MD was significantly reduced (1.29 ± 0.20 × 10-3  mm2 /sec vs 1.75 ± 0.16 × 10-3  mm2 /sec) and FA was significantly increased (0.40 ± 0.07 vs 0.23 ± 0.03) within areas of IMH. By V2, all 24 patients with acute IMH continued to have hypointense signals on averaged-DWI in the affected area. T2* detected IMH in 96% of these patients. Overall, averaged-DWI had 100% sensitivity and 96% specificity for the detection of IMH. DATA CONCLUSION: This study demonstrates that the parameters MD and FA are susceptible to the paramagnetic properties of iron, enabling cDTI to detect IMH. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Acute Microstructural Changes after ST-Segment Elevation Myocardial Infarction Assessed with Diffusion Tensor Imaging.

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 ß = 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.

Motion-compensated gradient waveforms for tensor-valued diffusion encoding by constrained numerical optimization.

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.

Insight Into Myocardial Microstructure of Athletes and Hypertrophic Cardiomyopathy Patients Using Diffusion Tensor Imaging.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) remains the commonest cause of sudden cardiac death among young athletes. Differentiating between physiologically adaptive left ventricular (LV) hypertrophy observed in athletes' hearts and pathological HCM remains challenging. By quantifying the diffusion of water molecules, diffusion tensor imaging (DTI) MRI allows voxelwise characterization of myocardial microstructure. PURPOSE: To explore microstructural differences between healthy volunteers, athletes, and HCM patients using DTI. STUDY TYPE: Prospective cohort. POPULATION: Twenty healthy volunteers, 20 athletes, and 20 HCM patients. FIELD STRENGTH/SEQUENCE: 3T/DTI spin echo. ASSESSMENT: In-house MatLab software was used to derive mean diffusivity (MD) and fractional anisotropy (FA) as markers of amplitude and anisotropy of the diffusion of water molecules, and secondary eigenvector angles (E2A)-reflecting the orientations of laminar sheetlets. STATISTICAL TESTS: Independent samples t-tests were used to detect statistical significance between any two cohorts. Analysis of variance was utilized for detecting the statistical difference between the three cohorts. Statistical tests were two-tailed. A result was considered statistically significant at P ≤ 0.05. RESULTS: DTI markers were significantly different between HCM, athletes, and volunteers. HCM patients had significantly higher global MD and E2A, and significantly lower FA than athletes and volunteers. (MDHCM = 1.52 ± 0.06 × 10-3 mm2 /s, MDAthletes = 1.49 ± 0.03 × 10-3 mm2 /s, MDvolunteers = 1.47 ± 0.02 × 10-3 mm2 /s, P < 0.05; E2AHCM = 58.8 ± 4°, E2Aathletes = 47 ± 5°, E2Avolunteers = 38.5 ± 7°, P < 0.05; FAHCM = 0.30 ± 0.02, FAAthletes = 0.35 ± 0.02, FAvolunteers = 0.36 ± 0.03, P < 0.05). HCM patients had significantly higher E2A in their thickest segments compared to the remote (E2Athickest = 66.8 ± 7, E2Aremote = 51.2 ± 9, P < 0.05). DATA CONCLUSION: DTI depicts an increase in amplitude and isotropy of diffusion in the myocardium of HCM compared to athletes and volunteers as reflected by increased MD and decreased FA values. While significantly higher E2A values in HCM and athletes reflect steeper configurations of the myocardial sheetlets than in volunteers, HCM patients demonstrated an eccentric rise in E2A in their thickest segments, while athletes demonstrated a concentric rise. Further studies are required to determine the diagnostic capabilities of DTI. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.

Improved compressed sensing and super-resolution of cardiac diffusion MRI with structure-guided total variation.

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.

The Geometry of the roots of the Brachial Plexus.

Diffusion tensor magnetic resonance imaging (DTI) can be used to reconstruct the brachial plexus in 3D via tracts connecting contiguous diffusion tensors with similar primary eigenvector orientations. When creating DTI tractograms, the turning angle of connecting lines (step angle) must be prescribed by the user; however, the literature is lacking detailed geometry of brachial plexus to inform such decisions. Therefore, the spinal cord and brachial plexus of 10 embalmed adult cadavers were exposed bilaterally by posterior dissection. Photographs were taken under standardised conditions and spatially calibrated in MATLAB. The roots of the brachial plexus were traced from the dorsal root entry zone for 5 cm laterally using a 2.5-mm2 Cartesian grid overlay. The trace was composed of points connected by lines, and the turning angle between line segments (the step angle) was resolved. Our data show that the geometry of the roots increased in tortuosity from C5 to T1, with no significant differences between sides. The 1st thoracic root had the most tortuous course, turning through a maximum angle of 56° per 2.5 mm (99% CI 44° to 70°). Significantly higher step angles and greater variability were observed in the medial 2 cm of the roots of the brachial plexus, where the dorsal and ventral rootlets coalesce to form the spinal root. Throughout the brachial plexus, the majority of step angles (>50%) were smaller than 20° and <1% of step angles exceeded 70°. The geometry of the brachial plexus increases in tortuosity from C5 to T1. To reconstruct 99% of tracts representing the roots of the brachial plexus by DTI tractography, users can either customise the step angle per root based on our findings or select a universal threshold of 70°.

Motion-compensated b-tensor encoding for in vivo cardiac diffusion-weighted imaging.

Motion is a major confound in diffusion-weighted imaging (DWI) in the body, and it is a common cause of image artefacts. The effects are particularly severe in cardiac applications, due to the nonrigid cyclical deformation of the myocardium. Spin echo-based DWI commonly employs gradient moment-nulling techniques to desensitise the acquisition to velocity and acceleration, ie, nulling gradient moments up to the 2nd order (M2-nulled). However, current M2-nulled DWI scans are limited to encode diffusion along a single direction at a time. We propose a method for designing b-tensors of arbitrary shapes, including planar, spherical, prolate and oblate tensors, while nulling gradient moments up to the 2nd order and beyond. The design strategy comprises initialising the diffusion encoding gradients in two encoding blocks about the refocusing pulse, followed by appropriate scaling and rotation, which further enables nulling undesired effects of concomitant gradients. Proof-of-concept assessment of in vivo mean diffusivity (MD) was performed using linear and spherical tensor encoding (LTE and STE, respectively) in the hearts of five healthy volunteers. The results of the M2-nulled STE showed that (a) the sequence was robust to cardiac motion, and (b) MD was higher than that acquired using standard M2-nulled LTE, where diffusion-weighting was applied in three orthogonal directions, which may be attributed to the presence of restricted diffusion and microscopic diffusion anisotropy. Provided adequate signal-to-noise ratio, STE could significantly shorten estimation of MD compared with the conventional LTE approach. Importantly, our theoretical analysis and the proposed gradient waveform design may be useful in microstructure imaging beyond diffusion tensor imaging where the effects of motion must be suppressed.

Motion-Induced Signal Loss in In Vivo Cardiac Diffusion-Weighted Imaging.

LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:319-320.

Regional variations in ex-vivo diffusion tensor anisotropy are associated with cardiomyocyte remodeling in rats after left ventricular pressure overload.

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 < 0.001, R2 = 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.

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.

BACKGROUND: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). METHODS: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. DISCUSSION: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03716401 ).

Investigation of the Role of Myocyte Orientations in Cardiac Arrhythmia Using Image-Based Models.

Cardiac electrical excitation-propagation is influenced by myocyte orientations (cellular organization). Quantitatively understanding this relationship presents a significant research challenge, especially during arrhythmias in which excitation patterns become complex. Tissue-scale simulations of cardiac electrophysiology, incorporating both dynamic action potential behavior and image-based myocardial architecture, provide an approach to investigate three-dimensional (3D) propagation of excitation waves in the heart. In this study, we aimed to assess the importance of natural variation in myocyte orientations on cardiac arrhythmogenesis using 3D tissue electrophysiology simulations. Three anatomical models (i.e., describing myocyte orientations) of healthy rat ventricles-obtained using diffusion tensor imaging at 100 µm resolution-were registered to a single biventricular geometry (i.e., a single cardiac shape), in which the myocyte orientations could be represented by each of the diffusion tensor imaging data sets or by an idealized rule-based description. The Fenton-Karma cellular excitation model was modified to reproduce rat ventricular action potential duration restitution to create reaction-diffusion cardiac electrophysiology models. Over 250 3D simulations were performed to investigate the effects of myocyte orientations on the following: 1) ventricular activation, 2) location-dependent arrhythmia induction via rapid pacing, and 3) dynamics of re-entry averaged over multiple episodes. It was shown that 1) myocyte orientation differences manifested themselves in local activation times, but the influence on total activation time was small; 2) differences in myocyte orientations could critically affect the inducibility and persistence of arrhythmias for specific stimulus-location/cycle-length combinations; and 3) myocyte orientations alone could be an important determinant of scroll wave break, although no significant differences were observed in averaged arrhythmia dynamics between the four myocyte orientation scenarios considered. Our results show that myocyte orientations are an important determinant of arrhythmia inducibility, persistence, and scroll wave break. These findings suggest that where specificity is desired (for example, when predicting location-dependent, patient-specific arrhythmia inducibility), subject-specific myocyte orientations may be important.

Efficient gradient calibration based on diffusion MRI.

PURPOSE: To propose a method for calibrating gradient systems and correcting gradient nonlinearities based on diffusion MRI measurements. METHODS: The gradient scaling in x, y, and z were first offset by up to 5% from precalibrated values to simulate a poorly calibrated system. Diffusion MRI data were acquired in a phantom filled with cyclooctane, and corrections for gradient scaling errors and nonlinearity were determined. The calibration was assessed with diffusion tensor imaging and independently validated with high resolution anatomical MRI of a second structured phantom. RESULTS: The errors in apparent diffusion coefficients along orthogonal axes ranged from -9.2% ± 0.4% to + 8.8% ± 0.7% before calibration and -0.5% ± 0.4% to + 0.8% ± 0.3% after calibration. Concurrently, fractional anisotropy decreased from 0.14 ± 0.03 to 0.03 ± 0.01. Errors in geometric measurements in x, y and z ranged from -5.5% to + 4.5% precalibration and were likewise reduced to -0.97% to + 0.23% postcalibration. Image distortions from gradient nonlinearity were markedly reduced. CONCLUSION: Periodic gradient calibration is an integral part of quality assurance in MRI. The proposed approach is both accurate and efficient, can be setup with readily available materials, and improves accuracy in both anatomical and diffusion MRI to within ±1%. Magn Reson Med 77:170-179, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.