Cardiometabolic biomarker patterns associated with cardiac MRI defined fibrosis and microvascular dysfunction in patients with heart failure with preserved ejection fraction.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a complex disease process influenced by metabolic disorders, systemic inflammation, myocardial fibrosis, and microvascular dysfunction. The goal of our study is to identify potential relationships between plasma biomarkers and cardiac magnetic resonance (CMR) imaging markers in patients with HFpEF. Methods: Nineteen subjects with HFpEF and 15 age-matched healthy controls were enrolled and underwent multiparametric CMR and plasma biomarker analysis using the Olink® Cardiometabolic Panel (Olink Proteomics, Uppsala, Sweden). Partial least squares discriminant analysis (PLS-DA) was used to characterize CMR and biomarker variables that differentiate the subject groups into two principal components. Orthogonal projection to latent structures by partial least squares (OPLS) analysis was used to identify biomarker patterns that correlate with myocardial perfusion reserve (MPR) and extracellular volume (ECV) mapping. Results: A PLS-DA could differentiate between HFpEF and normal controls with two significant components explaining 79% (Q2 = 0.47) of the differences. For OPLS, there were 7 biomarkers that significantly correlated with ECV (R2 = 0.85, Q = 0.53) and 6 biomarkers that significantly correlated with MPR (R2 = 0.92, Q2 = 0.32). Only 1 biomarker significantly correlated with both ECV and MPR. Discussion: Patients with HFpEF have unique imaging and biomarker patterns that suggest mechanisms associated with metabolic disease, inflammation, fibrosis and microvascular dysfunction.

Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating "avatars" (herein defined as an extension of "digital twins") of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

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.

Cardiac Magnetic Resonance, Electromechanical Activation, Kidney Function, and Natriuretic Peptides in Cardiac Resynchronization Therapy Upgrades.

As the mechanism for worse prognosis after cardiac resynchronization therapy (CRT) upgrades in heart failure patients with RVP dependence (RVP-HF) has clinical implications for patient selection and CRT implementation approaches, this study's objective was to evaluate prognostic implications of cardiac magnetic resonance (CMR) findings and clinical factors in 102 HF patients (23.5% female, median age 66.5 years old, median follow-up 4.8 years) with and without RVP dependence undergoing upgrade and de novo CRT implants. Compared with other CRT groups, RVP-HF patients had decreased survival (p = 0.02), more anterior late-activated LV pacing sites (p = 0.002) by CMR, more atrial fibrillation (p = 0.0006), and higher creatinine (0.002). CMR activation timing at the LV pacing site predicted post-CRT LV functional improvement (p < 0.05), and mechanical activation onset < 34 ms by CMR at the LVP site was associated with decreased post-CRT survival in a model with higher pre-CRT creatinine and B-type natriuretic peptide (AUC 0.89; p < 0.0001); however, only the higher pre-CRT creatinine partially mediated (37%) the decreased survival in RVP-HF patients. In conclusion, RVP-HF had a distinct CMR phenotype, which has important implications for the selection of LV pacing sites in CRT upgrades, and only chronic kidney disease mediated the decreased survival after CRT in RVP-HF.

BME 2.0: Engineering the Future of Medicine.

If the 20th century was the age of mapping and controlling the external world, the 21st century is the biomedical age of mapping and controlling the biological internal world. The biomedical age is bringing new technological breakthroughs for sensing and controlling human biomolecules, cells, tissues, and organs, which underpin new frontiers in the biomedical discovery, data, biomanufacturing, and translational sciences. This article reviews what we believe will be the next wave of biomedical engineering (BME) education in support of the biomedical age, what we have termed BME 2.0. BME 2.0 was announced on October 12 2017 at BMES 49 (https://www.bme.jhu.edu/news-events/news/miller-opens-2017-bmes-annual-meeting-with-vision-for-new-bme-era/). We present several principles upon which we believe the BME 2.0 curriculum should be constructed, and from these principles, we describe what view as the foundations that form the next generations of curricula in support of the BME enterprise. The core principles of BME 2.0 education are (a) educate students bilingually, from day 1, in the languages of modern molecular biology and the analytical modeling of complex biological systems; (b) prepare every student to be a biomedical data scientist; (c) build a unique BME community for discovery and innovation via a vertically integrated and convergent learning environment spanning the university and hospital systems; (d) champion an educational culture of inclusive excellence; and (e) codify in the curriculum ongoing discoveries at the frontiers of the discipline, thus ensuring BME 2.0 as a launchpad for training the future leaders of the biotechnology marketplaces. We envision that the BME 2.0 education is the path for providing every student with the training to lead in this new era of engineering the future of medicine in the 21st century.

Erratum to "BME 2.0: Engineering the Future of Medicine".

[This corrects the article DOI: 10.34133/bmef.0001.].

Noninvasive Electrical Mapping Compared with the Paced QRS Complex for Optimizing CRT Programmed Settings and Predicting Multidimensional Response.

The aim was to test the hypothesis that left ventricular (LV) and right ventricular (RV) activation from body surface electrical mapping (CardioInsight 252-electrode vest, Medtronic) identifies optimal cardiac resynchronization therapy (CRT) pacing strategies and outcomes in 30 patients. The LV80, RV80, and BIV80 were defined as the times to 80% LV, RV, or biventricular electrical activation. Smaller differences in the LV80 and RV80 (|LV80-RV80|) with synchronized LV pacing predicted better LV function post-CRT (p = 0.0004) than the LV-paced QRS duration (p = 0.32). Likewise, a lower RV80 was associated with a better pre-CRT RV ejection fraction by CMR (r = - 0.40, p = 0.04) and predicted post-CRT improvements in myocardial oxygen uptake (p = 0.01) better than the biventricular-paced QRS (p = 0.38), while a lower LV80 with BIV pacing predicted lower post-CRT B-type natriuretic peptide (BNP) (p = 0.02). RV pacing improved LV function with smaller |LV80-RV80| (p = 0.009). In conclusion, 3-D electrical mapping predicted favorable post-CRT outcomes and informed effective pacing strategies.

StrainNet: Improved Myocardial Strain Analysis of Cine MRI by Deep Learning from DENSE.

Purpose: To develop a three-dimensional (two dimensions + time) convolutional neural network trained with displacement encoding with stimulated echoes (DENSE) data for displacement and strain analysis of cine MRI. Materials and Methods: In this retrospective multicenter study, a deep learning model (StrainNet) was developed to predict intramyocardial displacement from contour motion. Patients with various heart diseases and healthy controls underwent cardiac MRI examinations with DENSE between August 2008 and January 2022. Network training inputs were a time series of myocardial contours from DENSE magnitude images, and ground truth data were DENSE displacement measurements. Model performance was evaluated using pixelwise end-point error (EPE). For testing, StrainNet was applied to contour motion from cine MRI. Global and segmental circumferential strain (Ecc) derived from commercial feature tracking (FT), StrainNet, and DENSE (reference) were compared using intraclass correlation coefficients (ICCs), Pearson correlations, Bland-Altman analyses, paired t tests, and linear mixed-effects models. Results: The study included 161 patients (110 men; mean age, 61 years ± 14 [SD]), 99 healthy adults (44 men; mean age, 35 years ± 15), and 45 healthy children and adolescents (21 males; mean age, 12 years ± 3). StrainNet showed good agreement with DENSE for intramyocardial displacement, with an average EPE of 0.75 mm ± 0.35. The ICCs between StrainNet and DENSE and FT and DENSE were 0.87 and 0.72, respectively, for global Ecc and 0.75 and 0.48, respectively, for segmental Ecc. Bland-Altman analysis showed that StrainNet had better agreement than FT with DENSE for global and segmental Ecc. Conclusion: StrainNet outperformed FT for global and segmental Ecc analysis of cine MRI.Keywords: Image Postprocessing, MR Imaging, Cardiac, Heart, Pediatrics, Technical Aspects, Technology Assessment, Strain, Deep Learning, DENSE Supplemental material is available for this article. © RSNA, 2023.

Obesity-Induced Coronary Microvascular Disease Is Prevented by iNOS Deletion and Reversed by iNOS Inhibition.

Coronary microvascular disease (CMD) caused by obesity and diabetes is major contributor to heart failure with preserved ejection fraction; however, the mechanisms underlying CMD are not well understood. Using cardiac magnetic resonance applied to mice fed a high-fat, high-sucrose diet as a model of CMD, we elucidated the role of inducible nitric oxide synthase (iNOS) and 1400W, an iNOS antagonist, in CMD. Global iNOS deletion prevented CMD along with the associated oxidative stress and diastolic and subclinical systolic dysfunction. The 1400W treatment reversed established CMD and oxidative stress and preserved systolic/diastolic function in mice fed a high-fat, high-sucrose diet. Thus, iNOS may represent a therapeutic target for CMD.

Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[18F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[18F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Improved computation of Lagrangian tissue displacement and strain for cine DENSE MRI using a regularized spatiotemporal least squares method.

Introduction: In displacement encoding with stimulated echoes (DENSE), tissue displacement is encoded in the signal phase such that the phase of each pixel in space and time provides an independent measurement of absolute tissue displacement. Previously for DENSE, estimation of Lagrangian displacement used two steps: first a spatial interpolation and, second, least squares fitting through time to a Fourier or polynomial model. However, there is no strong rationale for such a through-time model. Methods: To compute the Lagrangian displacement field from DENSE phase data, a minimization problem is introduced to enforce fidelity with the acquired Eulerian displacement data while simultaneously providing model-independent regularization in space and time, enforcing only spatiotemporal smoothness. A regularized spatiotemporal least squares (RSTLS) method is used to solve the minimization problem, and RSTLS was tested using two-dimensional DENSE data from 71 healthy volunteers. Results: The mean absolute percent error (MAPE) between the Lagrangian displacements and the corresponding Eulerian displacements was significantly lower for the RSTLS method vs. the two-step method for both x- and y-directions (0.73±0.59 vs 0.83 ±0.1, p < 0.05) and (0.75±0.66 vs 0.82 ±0.1, p < 0.05), respectively. Also, peak early diastolic strain rate (PEDSR) was higher (1.81±0.58 (s-1) vs. 1.56±0. 63 (s-1), p<0.05) and the strain rate during diastasis was lower (0.14±0.18 (s-1) vs 0.35±0.2 (s-1), p < 0.05) for the RSTLS vs. the two-step method, with the former suggesting that the two-step method was over-regularized. Discussion: The proposed RSTLS method provides more realistic measurements of Lagrangian displacement and strain from DENSE images without imposing arbitrary motion models.

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.

Machine learning for multidimensional response and survival after cardiac resynchronization therapy using features from cardiac magnetic resonance.

Background: Cardiac resynchronization therapy (CRT) response is complex, and better approaches are required to predict survival and need for advanced therapies. Objective: The objective was to use machine learning to characterize multidimensional CRT response and its relationship with long-term survival. Methods: Associations of 39 baseline features (including cardiac magnetic resonance [CMR] findings and clinical parameters such as glomerular filtration rate [GFR]) with a multidimensional CRT response vector (consisting of post-CRT left ventricular end-systolic volume index [LVESVI] fractional change, post-CRT B-type natriuretic peptide, and change in peak VO2) were evaluated. Machine learning generated response clusters, and cross-validation assessed associations of clusters with 4-year survival. Results: Among 200 patients (median age 67.4 years, 27.0% women) with CRT and CMR, associations with more than 1 response parameter were noted for the CMR CURE-SVD dyssynchrony parameter (associated with post-CRT brain natriuretic peptide [BNP] and LVESVI fractional change) and GFR (associated with peak VO2 and post-CRT BNP). Machine learning defined 3 response clusters: cluster 1 (n = 123, 90.2% survival [best]), cluster 2 (n = 45, 60.0% survival [intermediate]), and cluster 3 (n = 32, 34.4% survival [worst]). Adding the 6-month response cluster to baseline features improved the area under the receiver operating characteristic curve for 4-year survival from 0.78 to 0.86 (P = .02). A web-based application was developed for cluster determination in future patients. Conclusion: Machine learning characterizes distinct CRT response clusters influenced by CMR features, kidney function, and other factors. These clusters have a strong and additive influence on long-term survival relative to baseline features.

Cardiac magnetic resonance defines mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy.

Background: Mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood. Objective: To use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type. Materials and methods: In a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis. Results: Among 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67). Conclusion: CMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.

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.

Cardiac Magnetic Resonance Assessment of Response to Cardiac Resynchronization Therapy and Programming Strategies.

OBJECTIVES: The objective was to determine the feasibility and effectiveness of cardiac magnetic resonance (CMR) cine and strain imaging before and after cardiac resynchronization therapy (CRT) for assessment of response and the optimal resynchronization pacing strategy. BACKGROUND: CMR with cardiac implantable electronic devices can safely provide high-quality right ventricular/left ventricular (LV) ejection fraction (RVEF/LVEF) assessments and strain. METHODS: CMR with cine imaging, displacement encoding with stimulated echoes for the circumferential uniformity ratio estimate with singular value decomposition (CURE-SVD) dyssynchrony parameter, and scar assessment was performed before and after CRT. Whereas the pre-CRT scan constituted a single "imaging set" with complete volumetric, strain, and scar imaging, multiple imaging sets with complete strain and volumetric data were obtained during the post-CRT scan for biventricular pacing (BIVP), LV pacing (LVP), and asynchronous atrial pacing modes by reprogramming the device outside the scanner between imaging sets. RESULTS: 100 CMRs with a total of 162 imaging sets were performed in 50 patients (median age 70 years [IQR: 50-86 years]; 48% female). Reduction in LV end-diastolic volumes (P = 0.002) independent of CRT pacing were more prominent than corresponding reductions in right ventricular end-diastolic volumes (P = 0.16). A clear dependence of the optimal CRT pacing mode (BIVP vs LVP) on the PR interval (P = 0.0006) was demonstrated. The LVEF and RVEF improved more with BIVP than LVP with PR intervals ≥240 milliseconds (P = 0.025 and P = 0.002, respectively); the optimal mode (BIVP vs LVP) was variable with PR intervals <240 milliseconds. A lower pre-CRT displacement encoding with stimulated echoes (DENSE) CURE-SVD was associated with greater improvements in the post-CRT CURE-SVD (r = -0.69; P < 0.001), LV end-systolic volume (r = -0.58; P < 0.001), and LVEF (r = -0.52; P < 0.001). CONCLUSIONS: CMR evaluation with assessment of multiple pacing modes during a single scan after CRT is feasible and provides useful information for patient care with respect to response and the optimal pacing strategy.

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.

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.