Abstract 19370: Myocardial Extracellular Volume is Elevated in Human Duchenne Muscular Dystrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jonathan H Soslow ◽  
Stephen M Damon ◽  
Bruce M Damon ◽  
David A Parra ◽  
W B Burnette ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Age Of Onset ◽  
Extracellular Volume ◽  
Lv Function ◽  
Therapeutic Approaches ◽  
Matrix Expansion ◽  
The Mean ◽  
Normal Lvef ◽  
Extracellular Matrix Expansion

Introduction: Duchenne muscular dystrophy (DMD) leads to cardiomyopathy (CM) with variable severity and age of onset. Predicting early CM would alter therapeutic approaches and improve morbidity and mortality. Extracellular volume (ECV) calculated with cardiac MRI (CMR) quantifies extracellular matrix expansion, including myocardial fibrosis, and has never been reported in human DMD. We hypothesized that subjects with DMD would have abnormal ECV and that these values would correlate with other markers of LV function. Methods: 27 DMD subjects were prospectively studied. CMR included LVEF, late gadolinium enhancement (LGE), circumferential strain (ε cc ), and modified Look-Locker (MOLLI) sequences to calculate ECV maps (in-house software using Matlab). ECV calculated for each segment in the short axis at mid-ventricle and compared with LVEF and ε cc using linear regression. Normal values taken from unmatched cohort of healthy male adults with mean ECV of 0.25 ± 0.015 (range 0.23-0.28). Results: Imaging was adequate to calculate ECV maps in 20 DMD subjects. Mean age in years was 14. Mean LVEF was 52% and mean global ε cc was -14.6%; 11 subjects had LVEF < 55% and 6 had negative LGE. Mean ECV was 0.33 ± 0.05 (0.25-0.45); there was significant intersubject and intersegment variability (Figure 1). When compared with highest mean control ECV (0.28), only one subject had a normal ECV in every segment. In subjects with LVEF ≥ 55%, the mean ECV was 0.32 ± 0.07 (0.25-0.45). In subjects with negative LGE, the mean ECV was 0.28 ± 0.04 (0.25-0.36). The ECV of the inferolateral and anterolateral segments correlated with LVEF (p=0.025 and p<0.001) and the inferolateral ECV correlated with mean ε cc (p=0.025). Conclusions: In this cohort, 19/20 DMD subjects have elevated segmental ECV, even with normal LVEF and negative LGE. Segmental ECV correlates with both LVEF and mean ε cc . ECV may be a more subtle biomarker of early myocardial disease than standard measures such as LVEF and LGE in human DMD.

scholarly journals T1-Mapping and extracellular volume estimates in pediatric subjects with Duchenne muscular dystrophy and healthy controls at 3T

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Nyasha G. Maforo ◽  
Patrick Magrath ◽  
Kévin Moulin ◽  
Jiaxin Shao ◽  
Grace Hyun Kim ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Genetic Disorder ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Lv Function ◽  
Healthy Controls ◽  
Characteristic Analysis ◽  
Post Contrast ◽  
Classification Tasks

Abstract Background Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD)—a fatal X-linked genetic disorder. Late gadolinium enhancement (LGE) imaging is the current gold standard for detecting myocardial tissue remodeling, but it is often a late finding. Current research aims to investigate cardiovascular magnetic resonance (CMR) biomarkers, including native (pre-contrast) T1 and extracellular volume (ECV) to evaluate the early on-set of microstructural remodeling and to grade disease severity. To date, native T1 measurements in DMD have been reported predominantly at 1.5T. This study uses 3T CMR: (1) to characterize global and regional myocardial pre-contrast T1 differences between healthy controls and LGE + and LGE− boys with DMD; and (2) to report global and regional myocardial post-contrast T1 values and myocardial ECV estimates in boys with DMD, and (3) to identify left ventricular (LV) T1-mapping biomarkers capable of distinguishing between healthy controls and boys with DMD and detecting LGE status in DMD. Methods Boys with DMD (N = 28, 13.2 ± 3.1 years) and healthy age-matched boys (N = 20, 13.4 ± 3.1 years) were prospectively enrolled and underwent a 3T CMR exam including standard functional imaging and T1 mapping using a modified Look-Locker inversion recovery (MOLLI) sequence. Pre-contrast T1 mapping was performed on all boys, but contrast was administered only to boys with DMD for post-contrast T1 and ECV mapping. Global and segmental myocardial regions of interest were contoured on mid LV T1 and ECV maps. ROI measurements were compared for pre-contrast myocardial T1 between boys with DMD and healthy controls, and for post-contrast myocardial T1 and ECV between LGE + and LGE− boys with DMD using a Wilcoxon rank-sum test. Results are reported as median and interquartile range (IQR). p-Values < 0.05 were considered significant. Receiver Operating Characteristic analysis was used to evaluate a binomial logistic classifier incorporating T1 mapping and LV function parameters in the tasks of distinguishing between healthy controls and boys with DMD, and detecting LGE status in DMD. The area under the curve is reported. Results Boys with DMD had significantly increased global native T1 [1332 (60) ms vs. 1289 (56) ms; p = 0.004] and increased within-slice standard deviation (SD) [100 (57) ms vs. 74 (27) ms; p = 0.001] compared to healthy controls. LGE− boys with DMD also demonstrated significantly increased lateral wall native T1 [1322 (68) ms vs. 1277 (58) ms; p = 0.001] compared to healthy controls. LGE + boys with DMD had decreased global myocardial post-contrast T1 [565 (113) ms vs 635 (126) ms; p = 0.04] and increased global myocardial ECV [32 (8) % vs. 28 (4) %; p = 0.02] compared to LGE− boys. In all classification tasks, T1-mapping biomarkers outperformed a conventional biomarker, LV ejection fraction. ECV was the best performing biomarker in the task of predicting LGE status (AUC = 0.95). Conclusions Boys with DMD exhibit elevated native T1 compared to healthy, sex- and age-matched controls, even in the absence of LGE. Post-contrast T1 and ECV estimates from 3T CMR are also reported here for pediatric patients with DMD for the first time and can distinguish between LGE + from LGE− boys. In all classification tasks, T1-mapping biomarkers outperform a conventional biomarker, LVEF.

scholarly journals Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shu Zhang ◽  
◽  
Dongdong Qin ◽  
Liwen Wu ◽  
Man Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Hazard Ratio ◽  
Large Cohort ◽  
Muscle Disease ◽  
Clinical Progression ◽  
Large Deletions ◽  
The Mean ◽  
Lower Hazard

Abstract Background Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials. Results A total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The “deletion amenable to skipping exon 44” subgroup and the nonsense-mutation subgroup had older ages at LOA than the “other deletions” subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group. Conclusion Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

scholarly journals Respiratory Telerehabilitation of Boys and Young Men with Duchenne Muscular Dystrophy in the COVID-19 Pandemic

2021 ◽  
Vol 18 (12) ◽  
pp. 6179
Author(s):  
Agnieszka Sobierajska-Rek ◽  
Łukasz Mański ◽  
Joanna Jabłońska-Brudło ◽  
Karolina Śledzińska ◽  
Eliza Wasilewska ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Physical Therapy ◽  
Muscular Dystrophy ◽  
Healthcare System ◽  
Online Survey ◽  
Young Men ◽  
The Mean ◽  
Respiratory Exercises

Background: The COVID-19 pandemic forced reorganization of the multidisciplinary healthcare system for Duchenne muscular dystrophy. Digital solutions seem to be optimal for providing rehabilitation at this time. The aim of this study was to investigate whether it is possible to conduct respiratory physical therapy with the use of telerehabilitation in Duchenne muscular dystrophy. Methods: The study was conducted during an online conference for families with DMD. During the physical therapy panel we showed the video with the instructions of respiratory exercises. All participants (n = 152) were asked to fill in the online survey evaluating the quality, acceptance, and understanding of the instructions. Results: The survey was filled in by 45 (29.6%) participants. The mean rating of satisfaction was 4.70/5, and for intelligibility was 4.78/5. Thirty-seven (82.2%) patients declared that they had performed the exercises, all caregivers declared that it was possible to perform the proposed exercises a few times a week or daily, and only two respondents replied to invitations to individual online sessions. Conclusions: Findings from the study show that respiratory telerehabilitation may be implemented for DMD patients; however, the interest in digital rehabilitation among caregivers of DMD boys in Poland is low. The reasons for this situation require further research.

Genetic Therapeutic Approaches for Duchenne Muscular Dystrophy

2012 ◽  
Vol 23 (7) ◽  
pp. 676-687 ◽  
Author(s):  
Helen Foster ◽  
Linda Popplewell ◽  
George Dickson
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Therapeutic Approaches

scholarly journals Twenty-Four Hour Noninvasive Ventilation in Duchenne Muscular Dystrophy: A Safe Alternative to Tracheostomy

2013 ◽  
Vol 20 (1) ◽  
pp. e5-e9 ◽  
Author(s):  
Douglas A McKim ◽  
Nadia Griller ◽  
Carole LeBlanc ◽  
Andrew Woolnough ◽  
Judy King
Keyword(s):  
Respiratory Failure ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Noninvasive Ventilation ◽  
Gas Analysis ◽  
Blood Gas ◽  
Safe Alternative ◽  
Arterial Blood Gas ◽  
Arterial Blood ◽  
The Mean

BACKGROUND: Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative.METHODS: The authors’ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported.RESULTS: The mean (± SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8±3.5 years and 0.90±0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8±3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2and, predominantly, by end-tidal CO2. While the results suggested improved CO2levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years).CONCLUSIONS: Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone.

scholarly journals Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches

2019 ◽  
Vol 9 (1) ◽  
pp. 1 ◽  
Author(s):  
Yuko Shimizu-Motohashi ◽  
Hirofumi Komaki ◽  
Norio Motohashi ◽  
Shin’ichi Takeda ◽  
Toshifumi Yokota ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Stop Codon ◽  
Genetic Disorder ◽  
Premature Stop Codon ◽  
Exon Skipping ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Dystrophin Expression

Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by progressive muscle weakness, is caused by the absence or a decreased amount of the muscle cytoskeletal protein dystrophin. Currently, several therapeutic approaches to cure DMD are being investigated, which can be categorized into two groups: therapies that aim to restore dystrophin expression, and those that aim to compensate for the lack of dystrophin. Therapies that restore dystrophin expression include read-through therapy, exon skipping, vector-mediated gene therapy, and cell therapy. Of these approaches, the most advanced are the read-through and exon skipping therapies. In 2014, ataluren, a drug that can promote ribosomal read-through of mRNA containing a premature stop codon, was conditionally approved in Europe. In 2016, eteplirsen, a morpholino-based chemical capable of skipping exon 51 in premature mRNA, received conditional approval in the USA. Clinical trials on vector-mediated gene therapy carrying micro- and mini- dystrophin are underway. More innovative therapeutic approaches include CRISPR/Cas9-based genome editing and stem cell-based cell therapies. Here we review the current status of therapeutic approaches for DMD, focusing on therapeutic approaches that can restore dystrophin.

Characteristics of Disease Progression and Genetic Correlation in Ambulatory Iranian Boys With Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Gholamreza Zamani ◽  
Sareh Hosseinpour ◽  
Mahmoud Reza Ashrafi ◽  
Mahmoud Mohammadi ◽  
Reza Shervin Badv ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Motor Function ◽  
Pediatric Population ◽  
Disease Onset ◽  
Clinical History ◽  
Disease Diagnosis ◽  
The Mean ◽  
Mutation Type

Abstract Introduction: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations are progressive muscle weakness, impairment in walking and motor function leading to loss of ambulation by age of 13 years. Molecular studies are standard tests for diagnosis. This article describes the status of disease progression and genetic pattern in the Iranian affected boys and furthermore, concerns to find a correlation between the genotype and motor function phenotype of them. Methods This study was performed on 152 DMD patients. Clinical history including disease phenotype, steroid therapy data and the NorthStar Ambulatory Assessment (NSAA) score were all collected. Molecular diagnoses were confirmed by multiplex ligation dependent probe amplification and Next Generation Sequencing tests. Results We studied a total of 152 Iranian DMD patients. The mean age at disease onset was 4.04 ± 2.00 year and the mean age at diagnosis was 5.05 ± 2.08 year. The mean age of loss of ambulatory was 10.9 year. Contracture was seen in 38.9 %. The overall mean of NSAA total score versus age of the patients peaked at 4 year with mean NSAA score of 24. We assessed the yearly changes in the NSAA linear score for all cases based on mutation type and exon site. We found deletion mutation in 79.1%, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon was deletion exon 44 in our patients (5.3%) and the most common multiexon deletion was 45–50 and 45–52 exon equally with 4.6%. This study did not show any correlation between age at disease onset, loss of ambulation age and wheelchair dependency with mutation type but a correlation between contracture with mutation type was found. A significant deference in NSAA score were seen between deletion and nonsense groups at the age of 3 year (P = 0.036) and 3.5 years (p = 0.04). We couldn’t find any correlation among phenotype and Exon site. 91.1% had a history of corticosteroid taking and 54.1% of patient had compliance with rehabilitation. Conclusion This study has demonstrated the phenotype and mutational features of DMD boys and provide information of the disease natural motor history, disease progression and disease diagnosis with the management status of DMD in Iran. Achieved data will encourage the development of clinical trials and advance future molecular therapies in Iran.

scholarly journals Alterations of Membrane Phosphorylation in Erythrocyte Membranes from Patients with Duchenne Muscular Dystrophy

1978 ◽  
Vol 5 (4) ◽  
pp. 437-442 ◽  
Author(s):  
J.D. Vickers ◽  
A.J. McComas ◽  
M.P. Rathbone
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Temperature Response ◽  
Band 3 ◽  
Erythrocyte Membranes ◽  
Band 3 Protein ◽  
Membrane Phosphorylation ◽  
The Mean ◽  
Lipid Environment ◽  
Age And Sex

SUMMARY:The phosphorylation of spectrin, hand 3 protein, and the phospholipids of erythrocyte membranes (ghosts) was examined in 10 patients with Duchenne muscular dystrophy (DMD) and in healthy age- and sex-matched controls. The rales of phosphorylation of spectrin and band 3 protein were significantly higher in ghosts prepared from patient blood than from control blood at both 30° C and 37° C. However, the mean increases in the rate of phosphorylation of both spectrin and band 3 protein in response to a temperature change from 30° C to 37° C were identical in gliosis from patient and controls. Phosphorylation of phospholipid and its temperature response did not differ between patients and controls. These results complement previous observations of differences in erythrocytes from patients with DMD. The similarity of the changes in phosphorylation of both spectrin and band 3 protein indicates a common cause, possibly their lipid environment.

Elevated Myocardial Extracellular Volume Fraction in Duchenne Muscular Dystrophy

2017 ◽  
Vol 38 (7) ◽  
pp. 1485-1492 ◽  
Author(s):  
James J. Starc ◽  
Ryan A. Moore ◽  
Mantosh S. Rattan ◽  
Chet R. Villa ◽  
Zhiqian Gao ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Volume Fraction ◽  
Extracellular Volume ◽  
Extracellular Volume Fraction
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