Abstract 13897: Native T1-mapping by Cardiac MRI as a Biomarker of Remodeling in Boys With Duchenne Muscular Dystrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Seraina A Dual ◽  
Nyasha G Maforo ◽  
Doff B McElhinney ◽  
Ashley Prosper ◽  
Holden Wu ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
T1 Mapping ◽  
Lateral Wall ◽  
Inferior Wall ◽  
Thin Wall ◽  
Native T1 ◽  
The Difference ◽  
Average Size ◽  
The Right

Cardiac magnetic resonance (CMR) is an important tool to assess cardiac disease progression in boys with Duchenne muscular dystrophy (DMD), with native (pre-contrast) myocardial T1-mapping considered a possible biomarker of fibrosis. Due to its thin wall and highly trabeculated structure, the right ventricle (RV) remains understudied in DMD despite pre-clinical evidence of RV involvement. After determining the most robust method of obtaining RV-T1, we assessed the hypothesis that RV-T1 distinguishes healthy controls from boys with DMD. Boys with DMD (N=27) and age-matched healthy control boys (N=17) were prospectively enrolled for a 3T CMR exam (Skyra, Siemens). The CMR exam included standard functional imaging, LGE imaging, and native T1 maps acquired at diastasis. Native RV-T1 was evaluated in four regions of interest (ROIs): 1 pixel (px) along the RV centerline, 3px dilated RV centerline, a segment within the RV lateral wall, and the RV inferior wall (Figure 1). Robustness was assessed in controls only and was defined as an acceptable number of pixels, coefficient of variation (COV) per ROI, percentage of readable images, and lowest inter-observer variability across three observers. Subsequently, a t-test assessed the difference between boys with DMD and controls using the most robust RV ROI. Comparing the four ROIs, we found an average size of the ROI of 65, 196, 23, 25 px; a COV of 13.4%, 16.6%, 6.0%, 9.9%; and 75%, 75%, 93%, 81% of readable images. Intra-class correlation (0.75) was highest and both mean bias (20ms) and limits of agreement (100ms) were lowest for the RV 1px ROI. Using the 1px ROI, the RV-T1 was higher and more variable in boys with DMD compared to controls (1526 [1457,1650] ms vs. 1432 [1390,1486] ms; p<0.0001). Native RV-T1 is elevated in boys with DMD, if measured along a 1px centerline ROI. The methods described herein may enable using native RV-T1 as a biomarker of fibrosis in DMD and other pathologies. Correlation with functional indices is pending.

scholarly journals Global, segmental and layer specific analysis of myocardial involvement in Duchenne muscular dystrophy by cardiovascular magnetic resonance native T1 mapping

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ke Xu ◽  
Hua-yan Xu ◽  
Rong Xu ◽  
Lin-jun Xie ◽  
Zhi-gang Yang ◽  
...  
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Duchenne Muscular Dystrophy ◽  
Magnetic Resonance ◽  
Muscular Dystrophy ◽  
T1 Mapping ◽  
Healthy Controls ◽  
Native T1 ◽  
Specific Analysis ◽  
Epicardial Layer ◽  
Myocardial Involvement

Abstract Background Progressive cardiomyopathy accounts for almost all mortality among Duchenne muscular dystrophy (DMD) patients.‍ Thus, our aim was to comprehensively characterize myocardial involvement by investigating the heterogeneity of native T1 mapping in DMD patients using global and regional (including segmental and layer-specific) analysis across a large cohort. Methods We prospectively enrolled 99 DMD patients (8.8 ± 2.5 years) and 25 matched male healthy controls (9.5 ± 2.5 years). All subjects underwent cardiovascular magnetic resonance (CMR) with cine, T1 mapping and late gadolinium enhancement (LGE) sequences. Native T1 values based on the global and regional myocardium were measured, and LGE was defined. Results LGE was present in 49 (49%) DMD patients. Global native T1 values were significantly longer in LGE-positive (LGE +) patients than in healthy controls, both in basal slices (1304 ± 55 vs. 1246 ± 27 ms, p < 0.001) and in mid-level slices (1305 ± 57 vs. 1245 ± 37 ms, p < 0.001). No significant difference in global native T1 was found between healthy controls and LGE-negative (LGE−) patients. In segmental analysis, LGE + patients had significantly increased native T1 in all analyzed segments compared to the healthy control group. Meanwhile, the comparison between LGE− patients and healthy controls showed significantly elevated values only in the basal anterolateral segment (1273 ± 62 vs. 1234 ± 40 ms, p = 0.034). Interestingly, the epicardial layer had a significantly higher native T1 in LGE− patients than in healthy controls (p < 0.05), whereas no such pattern was noticed in the global myocardium. Epicardial layer native T1 resulted in the highest diagnostic performance for distinguishing between healthy controls and DMD patients in receiver operating curve analyses (area under the curve [AUC] 0.84 for basal level and 0.85 for middle level) when compared to global native T1 and endocardial layer native T1. Conclusions Myocardial regional native T1, particularly epicardial native T1, seems to have potential as a novel robust marker of very early cardiac involvement in DMD patients. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) ChiCTR1800018340, 09/12/2018, Retrospectively registered.

scholarly journals Non-contrast cardiovascular magnetic resonance detection of myocardial fibrosis in Duchenne muscular dystrophy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Frank J. Raucci ◽  
Meng Xu ◽  
Kristen George-Durrett ◽  
Kimberly Crum ◽  
James C. Slaughter ◽  
...  
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Duchenne Muscular Dystrophy ◽  
Magnetic Resonance ◽  
Muscular Dystrophy ◽  
Myocardial Fibrosis ◽  
Severity Score ◽  
T1 Mapping ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Native T1

Abstract Background Duchenne muscular dystrophy (DMD) leads to progressive cardiomyopathy. Detection of myocardial fibrosis with late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is critical for clinical management. Due to concerns of brain deposition of gadolinium, non-contrast methods for detecting and monitoring myocardial fibrosis would be beneficial. Objectives We hypothesized that native T1 mapping and/or circumferential (εcc) and longitudinal (εls) strain can detect myocardial fibrosis. Methods 156 CMRs with gadolinium were performed in 66 DMD boys and included: (1) left ventricular ejection fraction (LVEF), (2) LGE, (3) native T1 mapping and myocardial tagging (εcc-tag measured using harmonic phase analysis). LGE was graded as: (1) presence/absence by segment, slice, and globally; (2) global severity from 0 (no LGE) to 4 (severe); (3) percent LGE using full width half maximum (FWHM). εls and εcc measured using feature tracking. Regression models to predict LGE included native T1 and either εcc-tag or εls and εcc measured at each segment, slice, and globally. Results Mean age and LVEF at first CMR were 14 years and 54%, respectively. Global εls and εcc strongly predicted presence or absence of LGE (OR 2.6 [1.1, 6.0], p = 0.029, and OR 2.3 [1.0, 5.1], p = 0.049, respectively) while global native T1 did not. Global εcc, εls, and native T1 predicted global severity score (OR 2.6 [1.4, 4.8], p = 0.002, OR 2.6 [1.4, 6.0], p = 0.002, and OR 1.8 [1.1, 3.1], p = 0.025, respectively). εls correlated with change in LGE by severity score (n = 33, 3.8 [1.0, 14.2], p = 0.048) and εcc-tag correlated with change in percent LGE by FWHM (n = 34, OR 0.2 [0.1, 0.9], p = 0.01). Conclusions Pre-contrast sequences predict presence and severity of LGE, with εls and εcc being more predictive in most models, but there was not an observable advantage over using LVEF as a predictor. Change in LGE was predicted by εls (global severity score) and εcc-tag (FWHM). While statistically significant, our results suggest these sequences are currently not a replacement for LGE and may only have utility in a very limited subset of DMD patients.

Right Ventricular Function and T1 ‐Mapping in Boys With Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Seraina A. Dual ◽  
Nyasha G. Maforo ◽  
Doff B. McElhinney ◽  
Ashley Prosper ◽  
Holden H. Wu ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Right Ventricular Function ◽  
T1 Mapping

scholarly journals T1 mapping is abnormal before decline in EF in patients with Becker and Duchenne muscular dystrophy

2013 ◽  
Vol 15 (S1) ◽  
Author(s):  
Jonathan H Soslow ◽  
Bruce M Damon ◽  
William B Burnette ◽  
David Parra ◽  
Larry W Markham
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
T1 Mapping

scholarly journals Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls

2021 ◽  
pp. 1-11
Author(s):  
Jerry R. Mendell ◽  
Navid Khan ◽  
Nanshi Sha ◽  
Helen Eliopoulos ◽  
Craig M. McDonald ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Term Treatment ◽  
Long Term Treatment ◽  
The Difference ◽  
Dmd Gene ◽  
6 Minute Walk Test

Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51 ®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

Quantitative Muscle Ultrasound versus Magnetic Resonance Imaging in Duchenne Muscular Dystrophy

2020 ◽  
Author(s):  
Jun Hu ◽  
Li Jiang ◽  
Siqi Hong ◽  
Li Cheng ◽  
Qiao Wang ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Duchenne Muscular Dystrophy ◽  
Magnetic Resonance ◽  
Muscular Dystrophy ◽  
Low Cost ◽  
Muscle Thickness ◽  
Resonance Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
The Right ◽  
Muscle Ultrasound

Abstract Background: Nowadays, it needs favorable biomarkers to follow up the disease progression and therapeutic responses of Duchenne muscular dystrophy (DMD). This study evaluates which one of Quantitative muscle ultrasound (QMUS) and magnetic resonance imaging (MRI) is suitable for the disease in China. Methods: Thirty-six boys with DMD engaged in the longitudinal observational cohort study, who used prednisone from baseline to 12th month. Muscle thickness (MT) and echo intensity (EI) of QMUS and T1-weighted MRI grading were measured in the right quadriceps femoris of the boys with DMD. Results: The scores of MT and EI of QMUS and T1-weighted MRI grading showed significant correlations with the clinical ones of muscle strength, timed testing, and quality of life. The scores of MT and EI of QMUS showed good correlations with the ones of T1-weighted MRI grading too (P<0.05). But 15 of 36 boys with DMD did not take MRI examinations for different reasons. Conclusions: QMUS and MRI can use as biomarkers for tracking DMD. Nevertheless, QMUS, because of its practical, low cost, and patient-friendly, applies for DMD widely than MRI in China. Keywords: Ultrasonography, Magnetic resonance imaging, Duchenne muscular dystrophy, Child

scholarly journals Deleterious impacts of inactivity and beneficial impacts of neuromuscular electrical stimulation on muscle structure and function in the zebrafish model of Duchenne Muscular Dystrophy

2020 ◽  
Author(s):  
Elisabeth A. Kilroy ◽  
Kaylee L. Brann ◽  
Claire E. Schaffer ◽  
Devon Varney ◽  
Kodey J. Silknitter ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Longitudinal Design ◽  
Neuromuscular Electrical Stimulation ◽  
Weight Lifting ◽  
Muscle Disease ◽  
Neuromuscular Stimulation ◽  
Zebrafish Model ◽  
Muscle Structure ◽  
The Right

AbstractAlthough it is known that inactivity is deleterious for healthy individuals, less is known about the consequences of inactivity on muscle disease. Reduced activity is frequently encouraged for individuals with congenital muscular dystrophies such as Duchenne Muscular Dystrophy (DMD). We used the zebrafish dmd mutant and a longitudinal design to elucidate the consequences of inactivity versus activity on muscle health. Inactivity worsened muscle structure and survival. We designed four neuromuscular stimulation paradigms loosely based on weight lifting regimens. Each paradigm differentially affected muscle structure, function, and survival. Only endurance neuromuscular stimulation (eNMES) improved all outcome measures. We found that eNMES (1) returns gene expression to wild-type levels, (2) increases muscle adhesion to the extracellular matrix (ECM), and (3) remodels the ECM and supports regeneration. Our data indicate that inactivity is deleterious but neuromuscular stimulation can be beneficial, suggesting that the right type of activity may benefit patients with muscle disease.

Abstract 44: Telomere and Mitochondrial Dysfunction in Duchenne Muscular Dystrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alex C Chang ◽  
Sang-Ging Ong ◽  
Joseph Wu ◽  
Helen M Blau
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Mitochondrial Dysfunction ◽  
Telomere Length ◽  
Dystrophin Gene ◽  
Glycoprotein Complex ◽  
The Difference

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease that is result of mutations in the dystrophin gene and is the most common myopathic disease in humans with a prevalence of one in every 3500 males. Dystrophin is crucial for the formation of a dystrophin-glycoprotein complex (DGC), which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix in both skeletal and cardiac muscles. In the heart, loss of dystrophin leads to increased fibrosis and death in the third decade of life due to dilated cardiomyopathy. A conundrum in studying and developing therapies for DMD has been the lack of a mouse model that fully recapitulates the clinical phenotype, as mice that lack dystrophin (mdx model), unlike patients, exhibit only mild skeletal muscle defects, essentially no cardiac defects and have a relatively normal lifespan. Our lab reasoned that the difference in the manifestation of the disease in mice and humans could be telomere length, as mice have substantially longer telomeres than humans. We created a novel mouse model with shortened telomere lengths (similar to humans) that fully recapitulates the skeletal muscle (Cell. 2010;143:1059-1071; the mdx/mTRKO model) and cardiac muscle phenotype of DMD (Nat Cell Biol. 2013; 15:895-904; dilated cardiomyopathy). Interestingly, we observed a relative 45% reduction in cardiomyocyte telomere length in our mdx/mTRKO animals (3 animals per group, N = 300-400) as well as patient samples (4 DMD patient samples, N = 40-95). Here we present new evidence of mitochondrial dysfunction and telomere dysfunction.

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