Improving the efficiency and accuracy of CMR with AI - review of evidence and proposition of a roadmap to clinical translation.

Cardiovascular magnetic resonance (CMR) is an important imaging modality for the assessment of heart disease; however, limitations of CMR include long exam times and high complexity compared to other cardiac imaging modalities. Recently advancements in artificial intelligence (AI) technology have shown great potential to address many CMR limitations. While the developments are remarkable, translation of AI-based methods into real-world CMR clinical practice remains at a nascent stage and much work lies ahead to realize the full potential of AI for CMR. Herein we review recent cutting-edge and representative examples demonstrating how AI can advance CMR in areas such as exam planning, accelerated image reconstruction, post-processing, quality control, classification and diagnosis. These advances can be applied to speed up and simplify essentially every application including cine, strain, late gadolinium enhancement, parametric mapping, 3D whole heart, flow, perfusion and others. AI is a unique technology based on training models using data. Beyond reviewing the literature, this paper discusses important AI-specific issues in the context of CMR, including (1) properties and characteristics of datasets for training and validation, (2) previously published guidelines for reporting CMR AI research, (3) considerations around clinical deployment, (4) responsibilities of clinicians and the need for multi-disciplinary teams in the development and deployment of AI in CMR, (5) industry considerations, and (6) regulatory perspectives. Understanding and consideration of all these factors will contribute to the effective and ethical deployment of AI to improve clinical CMR.

Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555.

Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.

Compensation for respiratory motion-induced signal loss and phase corruption in free-breathing self-navigated cine DENSE using deep learning.

PURPOSE: To introduce a model that describes the effects of rigid translation due to respiratory motion in displacement encoding with stimulated echoes (DENSE) and to use the model to develop a deep convolutional neural network to aid in first-order respiratory motion compensation for self-navigated free-breathing cine DENSE of the heart. METHODS: The motion model includes conventional position shifts of magnetization and further describes the phase shift of the stimulated echo due to breathing. These image-domain effects correspond to linear and constant phase errors, respectively, in k-space. The model was validated using phantom experiments and Bloch-equation simulations and was used along with the simulation of respiratory motion to generate synthetic images with phase-shift artifacts to train a U-Net, DENSE-RESP-NET, to perform motion correction. DENSE-RESP-NET-corrected self-navigated free-breathing DENSE was evaluated in human subjects through comparisons with signal averaging, uncorrected self-navigated free-breathing DENSE, and breath-hold DENSE. RESULTS: Phantom experiments and Bloch-equation simulations showed that breathing-induced constant phase errors in segmented DENSE leads to signal loss in magnitude images and phase corruption in phase images of the stimulated echo, and that these artifacts can be corrected using the known respiratory motion and the model. For self-navigated free-breathing DENSE where the respiratory motion is not known, DENSE-RESP-NET corrected the signal loss and phase-corruption artifacts and provided reliable strain measurements for systolic and diastolic parameters. CONCLUSION: DENSE-RESP-NET is an effective method to correct for breathing-associated constant phase errors. DENSE-RESP-NET used in concert with self-navigation methods provides reliable free-breathing DENSE myocardial strain measurement.

Accelerated fatty acid composition MRI of epicardial adipose tissue: Development and application to eplerenone treatment in a mouse model of obesity-induced coronary microvascular disease.

PURPOSE: To develop an accelerated MRI method to quantify the epicardial adipose tissue (EAT) fatty acid composition (FAC) and test the hypothesis that eplerenone (EPL) shifts the EAT FAC toward unsaturation in obese mice. METHODS: Undersampled multi-echo gradient echo imaging employing a dictionary-based compressed-sensing reconstruction and iterative decomposition with echo asymmetry and least-squares-based mapping (IDEAL) was developed, validated, and used to study EAT in obese mice scanned at 7T. Fully sampled and rate 2, 2.5, 3, and 3.5 undersampled image data were acquired, reconstructed, and assessed using RMSE and structural similarity (SSIM). Two groups of mice were studied: untreated (control, n = 10) and EPL-treated (n = 10) mice fed a high-fat high-sucrose diet. MRI included imaging of EAT FAC, EAT volume, and myocardial perfusion reserve. RESULTS: Rate 3 acceleration provided RMSE <5% and structural similarity >0.85 for FAC MRI. After 6 weeks of diet, EPL-treated compared to untreated mice had a reduced EAT saturated fatty acid fraction (0.27 ± 0.09 vs. 0.39 ± 0.07, P < 0.05) and increased EAT unsaturation degree (4.37 ± 0.32 vs. 3.69 ± 0.58, P < 0.05). Also, EAT volume in EPL-treated compared to untreated mice was reduced (8.1 ± 0.6 mg vs. 11.4 ± 0.7 mg, P < 0.01), and myocardial perfusion reserve was improved (1.83 ± 0.15 vs. 1.61 ± 0.17, P < 0.05). CONCLUSION: Rate 3 accelerated FAC MRI enabled accurate quantification of EAT FAC in mice. EPL treatment shifted the EAT FAC toward increased unsaturation and was associated with improvement of coronary microvascular function.

A Slice-Low-Rank Plus Sparse (slice-L + S) Reconstruction Method for k-t Undersampled Multiband First-Pass Myocardial Perfusion MRI.

PURPOSE: The synergistic use of k-t undersampling and multiband (MB) imaging has the potential to provide extended slice coverage and high spatial resolution for first-pass perfusion MRI. The low-rank plus sparse (L + S) model has shown excellent performance for accelerating single-band (SB) perfusion MRI. METHODS: A MB data consistency method employing ESPIRiT maps and through-plane coil information was developed. This data consistency method was combined with the temporal L + S constraint to form the slice-L + S method. Slice-L + S was compared to SB L + S and the sequential operations of split slice-GRAPPA and SB L + S (seq-SG-L + S) using synthetic data formed from multislice SB images. Prospectively k-t undersampled MB data were also acquired and reconstructed using seq-SG-L + S and slice-L + S. RESULTS: Using synthetic data with total acceleration rates of 6-12, slice-L + S outperformed SB L + S and seq-SG-L + S (N = 7 subjects) with respect to normalized RMSE and the structural similarity index (P < 0.05 for both). For the specific case with MB factor = 3 and rate 3 undersampling, or for SB imaging with rate 9 undersampling (N = 7 subjects), the normalized RMSE values were 0.037 ± 0.007, 0.042 ± 0.005, and 0.031 ± 0.004; and the structural similarity index values were 0.88 ± 0.03, 0.85 ± 0.03, and 0.89 ± 0.02 for SB L + S, seq-SG-L + S, and slice-L + S, respectively (P < 0.05 for both). For prospectively undersampled MB data, slice-L + S provided better image quality than seq-SG-L + S for rate 6 (N = 7) and rate 9 acceleration (N = 7) as scored by blinded experts. CONCLUSION: Slice-L + S outperformed SB-L + S and seq-SG-L + S and provides 9 slice coverage of the left ventricle with a spatial resolution of 1.5 mm × 1.5 mm with good image quality.

Reproducibility of global and segmental myocardial strain using cine DENSE at 3 T: a multicenter cardiovascular magnetic resonance study in healthy subjects and patients with heart disease.

BACKGROUND: While multiple cardiovascular magnetic resonance (CMR) methods provide excellent reproducibility of global circumferential and global longitudinal strain, achieving highly reproducible segmental strain is more challenging. Previous single-center studies have demonstrated excellent reproducibility of displacement encoding with stimulated echoes (DENSE) segmental circumferential strain. The present study evaluated the reproducibility of DENSE for measurement of whole-slice or global circumferential (Ecc), longitudinal (Ell) and radial (Err) strain, torsion, and segmental Ecc at multiple centers. METHODS: Six centers participated and a total of 81 subjects were studied, including 60 healthy subjects and 21 patients with various types of heart disease. CMR utilized 3 T scanners, and cine DENSE images were acquired in three short-axis planes and in the four-chamber long-axis view. During one imaging session, each subject underwent two separate DENSE scans to assess inter-scan reproducibility. Each subject was taken out of the scanner and repositioned between the scans. Intra-user, inter-user-same-site, inter-user-different-site, and inter-user-Human-Deep-Learning (DL) comparisons assessed the reproducibility of different users analyzing the same data. Inter-scan comparisons assessed the reproducibility of DENSE from scan to scan. The reproducibility of whole-slice or global Ecc, Ell and Err, torsion, and segmental Ecc were quantified using Bland-Altman analysis, the coefficient of variation (CV), and the intraclass correlation coefficient (ICC). CV was considered excellent for CV ≤ 10%, good for 10% < CV ≤ 20%, fair for 20% < CV ≤ 40%, and poor for CV > 40. ICC values were considered excellent for ICC > 0.74, good for ICC 0.6 < ICC ≤ 0.74, fair for ICC 0.4 < ICC ≤ 0.59, poor for ICC < 0.4. RESULTS: Based on CV and ICC, segmental Ecc provided excellent intra-user, inter-user-same-site, inter-user-different-site, inter-user-Human-DL reproducibility and good-excellent inter-scan reproducibility. Whole-slice Ecc and global Ell provided excellent intra-user, inter-user-same-site, inter-user-different-site, inter-user-Human-DL and inter-scan reproducibility. The reproducibility of torsion was good-excellent for all comparisons. For whole-slice Err, CV was in the fair-good range, and ICC was in the good-excellent range. CONCLUSIONS: Multicenter data show that 3 T CMR DENSE provides highly reproducible whole-slice and segmental Ecc, global Ell, and torsion measurements in healthy subjects and heart disease patients.

Suppression of artifact-generating echoes in cine DENSE using deep learning.

PURPOSE: To use deep learning for suppression of the artifact-generating T1 -relaxation echo in cine displacement encoding with stimulated echoes (DENSE) for the purpose of reducing the scan time. METHODS: A U-Net was trained to suppress the artifact-generating T1 -relaxation echo using complementary phase-cycled data as the ground truth. A data-augmentation method was developed that generates synthetic DENSE images with arbitrary displacement-encoding frequencies to suppress the T1 -relaxation echo modulated for a range of frequencies. The resulting U-Net (DAS-Net) was compared with k-space zero-filling as an alternative method. Non-phase-cycled DENSE images acquired in shorter breath-holds were processed by DAS-Net and compared with DENSE images acquired with phase cycling for the quantification of myocardial strain. RESULTS: The DAS-Net method effectively suppressed the T1 -relaxation echo and its artifacts, and achieved root Mean Square(RMS) error = 5.5 ± 0.8 and structural similarity index = 0.85 ± 0.02 for DENSE images acquired with a displacement encoding frequency of 0.10 cycles/mm. The DAS-Net method outperformed zero-filling (root Mean Square error = 5.8 ± 1.5 vs 13.5 ± 1.5, DAS-Net vs zero-filling, P < .01; and structural similarity index = 0.83 ± 0.04 vs 0.66 ± 0.03, DAS-Net vs zero-filling, P < .01). Strain data for non-phase-cycled DENSE images with DAS-Net showed close agreement with strain from phase-cycled DENSE. CONCLUSION: The DAS-Net method provides an effective alternative approach for suppression of the artifact-generating T1 -relaxation echo in DENSE MRI, enabling a 42% reduction in scan time compared to DENSE with phase-cycling.

High spatial resolution spiral first-pass myocardial perfusion imaging with whole-heart coverage at 3 T.

PURPOSE: To develop and evaluate a high spatial resolution (1.25 × 1.25 mm2 ) spiral first-pass myocardial perfusion imaging technique with whole-heart coverage at 3T, to better assess transmural differences in perfusion between the endocardium and epicardium, to quantify the myocardial ischemic burden, and to improve the detection of obstructive coronary artery disease. METHODS: Whole-heart high-resolution spiral perfusion pulse sequences and corresponding motion-compensated reconstruction techniques for both interleaved single-slice (SS) and simultaneous multi-slice (SMS) acquisition with or without outer-volume suppression (OVS) were developed. The proposed techniques were evaluated in 34 healthy volunteers and 8 patients (55 data sets). SS and SMS images were reconstructed using motion-compensated L1-SPIRiT and SMS-Slice-L1-SPIRiT, respectively. Images were blindly graded by 2 experienced cardiologists on a 5-point scale (5, excellent; 1, poor). RESULTS: High-quality perfusion imaging was achieved for both SS and SMS acquisitions with or without OVS. The SS technique without OVS had the highest scores (4.5 [4, 5]), which were greater than scores for SS with OVS (3.5 [3.25, 3.75], P < .05), MB = 2 without OVS (3.75 [3.25, 4], P < .05), and MB = 2 with OVS (3.75 [2.75, 4], P < .05), but significantly higher than those for MB = 3 without OVS (4 [4, 4], P = .95). SMS image quality was improved using SMS-Slice-L1-SPIRiT as compared to SMS-L1-SPIRiT (P < .05 for both reviewers). CONCLUSION: We demonstrated the successful implementation of whole-heart spiral perfusion imaging with high resolution at 3T. Good image quality was achieved, and the SS without OVS showed the best image quality. Evaluation in patients with expected ischemic heart disease is warranted.

A kinematic model-based analysis framework for 3D Cine-DENSE-validation with an axially compressed gel phantom and application in sheep before and after antero-apical myocardial infarction.

PURPOSE: Myocardial strain is increasingly used to assess left ventricular (LV) function. Incorporation of LV deformation into finite element (FE) modeling environment with subsequent strain calculation will allow analysis to reach its full potential. We describe a new kinematic model-based analysis framework (KMAF) to calculate strain from 3D cine-DENSE (displacement encoding with stimulated echoes) MRI. METHODS: Cine-DENSE allows measurement of 3D myocardial displacement with high spatial accuracy. The KMAF framework uses cine cardiovascular magnetic resonance (CMR) to facilitate cine-DENSE segmentation, interpolates cine-DENSE displacement, and kinematically deforms an FE model to calculate strain. This framework was validated in an axially compressed gel phantom and applied in 10 healthy sheep and 5 sheep after myocardial infarction (MI). RESULTS: Excellent Bland-Altman agreement of peak circumferential (Ecc ) and longitudinal (Ell ) strain (mean difference = 0.021 ± 0.04 and -0.006 ± 0.03, respectively), was found between KMAF estimates and idealized FE simulation. Err had a mean difference of -0.014 but larger variation (±0.12). Cine-DENSE estimated end-systolic (ES) Ecc , Ell and Err exhibited significant spatial variation for healthy sheep. Displacement magnitude was reduced on average by 27%, 42%, and 56% after MI in the remote, adjacent and MI regions, respectively. CONCLUSIONS: The KMAF framework allows accurate calculation of 3D LV Ecc and Ell from cine-DENSE.

Fully-automated global and segmental strain analysis of DENSE cardiovascular magnetic resonance using deep learning for segmentation and phase unwrapping.

BACKGROUND: Cardiovascular magnetic resonance (CMR) cine displacement encoding with stimulated echoes (DENSE) measures heart motion by encoding myocardial displacement into the signal phase, facilitating high accuracy and reproducibility of global and segmental myocardial strain and providing benefits in clinical performance. While conventional methods for strain analysis of DENSE images are faster than those for myocardial tagging, they still require manual user assistance. The present study developed and evaluated deep learning methods for fully-automatic DENSE strain analysis. METHODS: Convolutional neural networks (CNNs) were developed and trained to (a) identify the left-ventricular (LV) epicardial and endocardial borders, (b) identify the anterior right-ventricular (RV)-LV insertion point, and (c) perform phase unwrapping. Subsequent conventional automatic steps were employed to compute strain. The networks were trained using 12,415 short-axis DENSE images from 45 healthy subjects and 19 heart disease patients and were tested using 10,510 images from 25 healthy subjects and 19 patients. Each individual CNN was evaluated, and the end-to-end fully-automatic deep learning pipeline was compared to conventional user-assisted DENSE analysis using linear correlation and Bland Altman analysis of circumferential strain. RESULTS: LV myocardial segmentation U-Nets achieved a DICE similarity coefficient of 0.87 ± 0.04, a Hausdorff distance of 2.7 ± 1.0 pixels, and a mean surface distance of 0.41 ± 0.29 pixels in comparison with manual LV myocardial segmentation by an expert. The anterior RV-LV insertion point was detected within 1.38 ± 0.9 pixels compared to manually annotated data. The phase-unwrapping U-Net had similar or lower mean squared error vs. ground-truth data compared to the conventional path-following method for images with typical signal-to-noise ratio (SNR) or low SNR (p < 0.05), respectively. Bland-Altman analyses showed biases of 0.00 ± 0.03 and limits of agreement of - 0.04 to 0.05 or better for deep learning-based fully-automatic global and segmental end-systolic circumferential strain vs. conventional user-assisted methods. CONCLUSIONS: Deep learning enables fully-automatic global and segmental circumferential strain analysis of DENSE CMR providing excellent agreement with conventional user-assisted methods. Deep learning-based automatic strain analysis may facilitate greater clinical use of DENSE for the quantification of global and segmental strain in patients with cardiac disease.

Non-Cartesian slice-GRAPPA and slice-SPIRiT reconstruction methods for multiband spiral cardiac MRI.

PURPOSE: Spiral MRI has advantages for cardiac imaging, and multiband (MB) spiral MRI of the heart shows promise. However, current reconstruction methods for MB spiral imaging have limitations. We sought to develop improved reconstruction methods for MB spiral cardiac MRI. METHODS: Two reconstruction methods were developed. The first is non-Cartesian slice-GRAPPA (NCSG), which uses phase demodulation and gridding operations before application of a Cartesian slice-separating kernel. The second method, slice-SPIRiT, formulates the reconstruction as a minimization problem that enforces in-plane coil consistency and consistency with the acquired MB data, and uses through-plane coil sensitivity information in the iterative solution. These methods were compared with conjugate-gradient SENSE in phantoms and volunteers. Temporal alternation of CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration) phase and the use of a temporal filter were also investigated. RESULTS: Phantom experiments with 3 simultaneous slices (MB = 3) showed that mean artifact power was highest for conjugate-gradient SENSE, lower for NCSG, and lowest for slice-SPIRiT. For volunteer cine imaging (MB = 3, N = 5), the artifact power was 0.182 ± 0.037, 0.148 ± 0.036, and 0.139 ± 0.034 for conjugate-gradient SENSE, NCSG, and slice-SPIRiT, respectively (P < .05, analysis of variance). Temporal alternation of CAIPIRINHA reduced artifacts for both NCSG and slice-SPIRiT. CONCLUSION: The NCSG and slice-SPIRiT methods provide more accurate reconstructions for MB spiral cine imaging compared with conjugate-gradient SENSE. These methods hold promise for non-Cartesian MB imaging.

Cardiac MRI Myocardial Functional and Tissue Characterization Detects Early Cardiac Dysfunction in a Mouse Model of Chemotherapy-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin and doxorubicin-trastuzumab combination chemotherapy have been associated with cardiotoxicity that eventually leads to heart failure and may limit dose-effective cancer treatment. Current diagnostic strategies rely on decreased ejection fraction (EF) to diagnose cardiotoxicity. PURPOSE: The aim of this study is to explore the potential of cardiac MR (CMR) imaging to identify imaging biomarkers in a mouse model of chemotherapy-induced cardiotoxicity. METHODS: A cumulative dose of 25 mg/kg doxorubicin was administered over three weeks using subcutaneous pellets (n = 9, Dox). Another group (n = 9) received same dose of Dox and a total of 10 mg/kg trastuzumab (DT). Mice were imaged at baseline, 5/6 weeks and 10 weeks post-treatment on a 7T MRI system. The protocol included short-axis cine MRI covering the left ventricle (LV) and mid-ventricular short-axis tissue phase mapping (TPM), pre- and post-contrast T1 mapping, T2 mapping and Displacement Encoding with Stimulated Echoes (DENSE) strain encoded MRI. EF, peak myocardial velocities, native T1, T2, extracellular volume (ECV), and myocardial strain were quantified. N = 7 mice were sacrificed for histopathologic assessment of apoptosis at 5/6 weeks. RESULTS: Global peak systolic longitudinal velocity was reduced at 5/6 weeks in Dox (0.6 ± 0.3 vs 0.9 ± 0.3, p = 0.02). In the Dox group, native T1 was reduced at 5/6 weeks (1.3 ± 0.2 ms vs 1.6 ± 0.2 ms, p = 0.02), and relatively normalized at week 10 (1.4 ± 0.1 ms vs 1.6 ± 0.2 ms, p > 0.99). There was no change in EF and other MRI parameters and histopathologic results demonstrated minimal apoptosis in all mice (~1-2 apoptotic cell/high power field), suggesting early-stage cardiotoxicity. CONCLUSIONS: In a mouse model of chemotherapy-induced cardiotoxicity using doxorubicin and trastuzumab, advanced CMR shows promise in identifying treatment-related decrease in myocardial velocity and native T1 prior to the onset of cardiomyocyte apoptosis and reduction of EF.

Nitroxide-enhanced MRI of cardiovascular oxidative stress.

BACKGROUND: In vivo imaging of oxidative stress can facilitate the understanding and treatment of cardiovascular diseases. We evaluated nitroxide-enhanced MRI with 3-carbamoyl-proxyl (3CP) for the detection of myocardial oxidative stress. METHODS: Three mouse models of cardiac oxidative stress were imaged, namely angiotensin II (Ang II) infusion, myocardial infarction (MI), and high-fat high-sucrose (HFHS) diet-induced obesity (DIO). For the Ang II model, mice underwent MRI at baseline and after 7 days of Ang II (n = 8) or saline infusion (n = 8). For the MI model, mice underwent MRI at baseline (n = 10) and at 1 (n = 8), 4 (n = 9), and 21 (n = 8) days after MI. For the HFHS-DIO model, mice underwent MRI at baseline (n = 20) and 18 weeks (n = 13) after diet initiation. The 3CP reduction rate, Kred , computed using a tracer kinetic model, was used as a metric of oxidative stress. Dihydroethidium (DHE) staining of tissue sections was performed on Day 1 after MI. RESULTS: For the Ang II model, Kred was higher after 7 days of Ang II versus other groups (p < 0.05). For the MI model, Kred , in the infarct region was significantly elevated on Days 1 and 4 after MI (p < 0.05), whereas Kred in the noninfarcted region did not change after MI. DHE confirmed elevated oxidative stress in the infarct zone on Day 1 after MI. After 18 weeks of HFHS diet, Kred was higher in mice after diet versus baseline (p < 0.05). CONCLUSIONS: Nitroxide-enhanced MRI noninvasively quantifies tissue oxidative stress as one component of a multiparametric preclinical MRI examination. These methods may facilitate investigations of oxidative stress in cardiovascular disease and related therapies.

Displacement Encoding With Stimulated Echoes Enables the Identification of Infarct Transmurality Early Postmyocardial Infarction.

BACKGROUND: Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post-ST-segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery. HYPOTHESIS: We hypothesized that segmental circumferential strain with displacement encoding with stimulated echoes (DENSE) would be a stronger predictor of infarct transmurality than feature-tracking strain, and noninferior to extracellular volume fraction (ECV). STUDY TYPE: Prospective. POPULATION: Fifty participants (mean ± SD, 59 ± 9 years, 40 [80%] male) underwent cardiac MRI on day 1 post-STEMI. FIELD-STRENGTH/SEQUENCES: 1.5T/cine, DENSE, T1 mapping, ECV, LGE. ASSESSMENT: Two observers assessed segmental percentage LGE extent, presence of microvascular obstruction (MVO), circumferential and radial strain with DENSE and feature-tracking, T1 relaxation times, and ECV. STATISTICAL TESTS: Normality was tested using the Shapiro-Wilk test. Skewed distributions were analyzed utilizing Mann-Whitney or Kruskal-Wallis tests and normal distributed data using independent t-tests. Diagnostic cutoff values were identified using the Youden index. The difference in area under the curve was compared using the z-statistic. RESULTS: Segmental circumferential strain with DENSE was associated with the extent of infarction ≥50% (AUC [95% CI], cutoff value = 0.9 [0.8, 0.9], -10%) similar to ECV (AUC = 0.8 [0.8, 0.9], 37%) (P = 0.117) and superior to feature-tracking circumferential strain (AUC = 0.7[0.7, 0.8], -19%) (P < 0.05). For the detection of segmental infarction ≥75%, circumferential strain with DENSE (AUC = 0.9 [0.8, 0.9], -10%) was noninferior to ECV (AUC = 0.8 [0.7, 0.9], 42%) (P = 0.132) and superior to feature-tracking (AUC = 0.7 [0.7, 0.8], -13%) (P < 0.05). For MVO detection, circumferential strain with DENSE (AUC = 0.8 [0.8, 0.9], -12%) was superior to ECV (AUC = 0.8 [0.7, 0.8] 34%) (P < 0.05) and feature-tracking (AUC = 0.7 [0.6, 0.7] -21%) (P < 0.05). DATA CONCLUSION: Circumferential strain with DENSE is a functional measure of infarct severity and may remove the need for gadolinium contrast agents in some circumstances. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 5 J. MAGN. RESON. IMAGING 2020;52:1722-1731.

Circumferential Strain Predicts Major Adverse Cardiovascular Events Following an Acute ST-Segment-Elevation Myocardial Infarction.

Purpose To investigate the prognostic value of circumferential left ventricular (LV) strain measured by using cardiac MRI for prediction of major adverse cardiac events (MACE) following an acute ST-segment-elevation myocardial infarction (STEMI). Materials and Methods Participants with acute STEMI were prospectively enrolled from May 11, 2011, to November 22, 2012. Cardiac MRI was performed at 1.5 T during the index hospitalization. Displacement encoding with stimulated echoes (DENSE) and feature tracking of cine cardiac MRI was used to assess circumferential LV strain. MACE that occurred after discharge were independently assessed by cardiologists blinded to the baseline observations. Results A total of 259 participants (mean age, 58 years ± 11 [standard deviation]; 198 men [mean age, 58 years ± 11] and 61 women [mean age, 58 years ± 12]) underwent cardiac MRI 2.2 days ± 1.9 after STEMI. Average infarct size was 18% ± 13 of LV mass and circumferential strain was -13% ± 3 (DENSE method) and -24% ± 7 (feature- tracking method). Fifty-one percent (131 of 259 participants) had presence of microvascular obstruction. During a median follow-up period of 4 years, 8% (21 of 259) experienced MACE. Area under the curve (AUC) for DENSE was different from that of feature tracking (AUC, 0.76 vs 0.62; P = .03). AUC for DENSE was similar to that of initial infarct size (P = .06) and extent of microvascular obstruction (P = .08). DENSE-derived strain provided incremental prognostic benefit over infarct size for prediction of MACE (hazard ratio, 1.3; P < .01). Conclusion Circumferential strain has independent prognostic importance in study participants with acute ST-segment-elevation myocardial infarction. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Kramer in this issue.

Whole-heart spiral simultaneous multi-slice first-pass myocardial perfusion imaging.

PURPOSE: To develop and evaluate a simultaneous multislice (SMS) spiral perfusion pulse sequence with whole-heart coverage. METHODS: An orthogonal set of phase cycling angles following a Hadamard pattern was incorporated into a golden-angle (GA) variable density spiral perfusion sequence to perform SMS imaging at different multiband (MB) factors. Images were reconstructed using an SMS extension of L1-SPIRiT that we have termed SMS-L1-SPIRiT. The proposed sequence was evaluated in 40 subjects (10 each for MB factors of 1, 2, 3, and 4). Images were blindly graded by 2 cardiologists on a 5-point scale (5, excellent). To quantitatively evaluate the reconstruction performance against images acquired without SMS, the MB =1 data were used to retrospectively simulate data acquired at MB factors of 2 to 4. RESULTS: Analysis of the SMS point-spread function for the desired slice showed that the proposed sampling strategy significantly canceled the main-lobe energy of the other slices and has low side-lobe energy resulting in an incoherent temporal aliasing pattern when rotated by the GA. Retrospective experiments demonstrated the SMS-L1-SPIRiT method removed aliasing from the interfering slices and showed excellent agreement with the ground-truth MB =1 images. Clinical evaluation demonstrated high-quality perfusion images with average image-quality scores of 4.3 ± 0.5 (MB =2), 4.2 ± 0.5 (MB =3), and 4.4 ± 0.4 (MB =4) with no significant quality difference in image quality between MB factors (P = 0.38). CONCLUSION: SMS spiral perfusion at MB factors 2, 3, and 4 produces high-quality perfusion images with whole-heart coverage in a clinical setting with high sampling efficiency.

Free-breathing cine DENSE MRI using phase cycling with matchmaking and stimulated-echo image-based navigators.

PURPOSE: This study aimed to develop a self-navigated method for free-breathing spiral cine displacement encoding with stimulated echoes (DENSE), a myocardial strain imaging technique that uses phase-cycling for artifact suppression. The method needed to address 2 consequences of motion for DENSE: striping artifacts from incomplete suppression of the T1 -relaxation echo and blurring. METHODS: The method identifies phase-cycled spiral interleaves at matched respiratory phases by minimizing the residual signal due to T1 relaxation after phase-cycling subtraction. Next, the method reconstructs image-based navigators from matched phase-cycled interleaves that are comprised of the stimulated echo (ste-iNAVs). Ste-iNAVs are used for motion estimation and compensation of k-space data. The method was demonstrated in phantoms and compared to diaphragm-based navigator (dNAV) and conventional iNAV (c-iNAV) methods for the reconstruction of free-breathing volunteer data sets (N = 10). RESULTS: Phantom experiments demonstrated that the proposed method removes striping artifacts and blurring due to motion. Volunteer results showed that respiratory motion measured by ste-iNAVs was better correlated than c-iNAVs to dNAV data (R2 = 0.82 ± 0.03 vs. 0.70 ± 0.05, P < 0.05). Match-making reconstructions of free-breathing data sets achieved lower residual T1 -relaxation echo energy (1.04 ± 0.01 vs. 1.18 ± 0.04 for dNAV and 1.18 ± 0.03 for c-iNAV, P < 0.05), higher apparent SNR (11.93 ± 1.05 vs. 10.68 ± 1.06 for dNAV and 10.66 ± 0.99 for c-iNAV, P < 0.05), and better phase quality (0.147 ± 0.012 vs. 0.166 ± 0.017 for dNAV, P = 0.06, and 0.168 ± 0.015 for c-iNAV, P < 0.05) than dNAV and c-iNAV methods. CONCLUSION: For free-breathing cine DENSE, the proposed method addresses both types of breathing-induced artifacts and provides better quality images than conventional dNAV and iNAV methods.

MRI assessment of coronary microvascular endothelial nitric oxide synthase function using myocardial T1 mapping.

PURPOSE: Endothelial nitric oxide synthase (eNOS) plays a central role in regulating vascular tone, blood flow, and microvascular permeability. Endothelial dysfunction, including eNOS dysfunction, is an early biomarker of vascular disease. This study aimed to show that myocardial T1 mapping during nitric oxide synthase (NOS) inhibition could assess coronary microvascular eNOS function. METHODS: Wild-type mice, eNOS-/- mice, and wild-type mice fed a high-fat diet underwent T1 mapping at baseline and for 20 min after injection of NG -nitro-L-arginine methyl ester (LNAME), a NOS inhibitor. First-pass perfusion MRI was performed in wild-type mice at baseline and 5 min after LNAME injection. RESULTS: T1 mapping detected an increase in myocardial T1 5 min after an injection of 4 mg/kg LNAME compared with baseline in control mice (T1 = 1515 ± 30 ms with LNAME versus T1 = 1402 ± 30 ms at baseline, P < 0.05). No change in myocardial T1 after LNAME injection was observed in eNOS-/- mice. The change in T1 after LNAME injection was less in high-fat-diet mice (ΔT1 = 31 ± 14 ms at 12 weeks of diet and ΔT1 = 16 ± 17 ms at 18 weeks of diet) compared with mice fed a standard diet (ΔT1 = 113 ± 15 ms), with P < 0.05. First-pass MRI measured similar perfusion at baseline and 5 min after LNAME injection. CONCLUSIONS: NOS inhibition causes an increase in myocardial T1 in healthy mice, and this effect is mediated through eNOS. T1 mapping during NOS inhibition detects coronary microvascular eNOS dysfunction in high-fat-diet mice. T1 mapping during NOS inhibition may be useful in preclinical studies aiming to investigate mechanisms underlying and therapies for coronary microvascular eNOS dysfunction. Magn Reson Med 79:2246-2253, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Reduced field of view single-shot spiral perfusion imaging.

PURPOSE: To develop a single-shot spiral perfusion pulse sequence with outer-volume suppression (OVS) to achieve whole-heart coverage with a short temporal footprint of 10 ms per slice location. METHODS: A highly accelerated single-shot variable density spiral pulse sequence with an integrated OVS module for reduced field of view (rFOV) perfusion imaging with 2 mm spatial resolution was developed and evaluated in simulations, phantom experiments and in clinical patients with (n = 8) or without (n = 8) OVS. Images were reconstructed by block low-rank sparsity with motion guidance (BLOSM) and graded by two cardiologists on a 5-point scale (1, excellent; 5, poor). RESULTS: Simulation and phantom results showed that OVS effectively suppressed the signal outside the desired field of view (FOV). Clinical patient data demonstrated high quality perfusion images with rFOV. The average image quality scores of full FOV cases and rFOV cases were 3.1 ± 0.64 and 2.3 ± 0.46, respectively, (P = 0.02) from cardiologist 1 and 2.5 ± 0.54 and 1.8 ± 0.47, respectively, (P = 0.04) from cardiologist 2, showing superior image quality for the rFOV images compared with the full FOV images. CONCLUSION: A single-shot spiral perfusion sequence that uses OVS and BLOSM performs perfusion imaging with a very short temporal footprint per image supporting whole-heart coverage with good image quality. Magn Reson Med 79:208-216, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction.

Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.