scholarly journals A scalable, clinically severe pig model for Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Michael Stirm ◽  
Lina Marie Fonteyne ◽  
Bachuki Shashikadze ◽  
Magdalena Lindner ◽  
Maila Chirivi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Connexin 43 ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Large Animal ◽  
Ventricular Ejection Fraction ◽  
Disease Mechanisms

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for evaluation of diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding. Therefore, we generated female DMD+/- carriers. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. With intensive neonatal management, the majority survived for 3-4 months, providing statistically relevant cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive myocardial fibrosis and increased expression of connexin-43, associated with significantly reduced left ventricular ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies.

scholarly journals A scalable, clinically severe pig model for Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Michael Stirm ◽  
Lina Marie Fonteyne ◽  
Bachuki Shashikadze ◽  
Magdalena Lindner ◽  
Maila Chirivi ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Connexin 43 ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Diagnostic Procedures ◽  
Left Ventricular ◽  
Large Animal ◽  
Large Animal Models ◽  
Disease Mechanisms

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for preclinical evaluation of novel diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but cannot be propagated by breeding due to death before sexual maturity. Therefore, female DMD+/- carriers were generated. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type (WT) offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. The majority of them survived for 3-4 months, providing large cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive fibrosis of myocardium and increased expression of connexin-43, associated with significantly reduced left ventricular fractional shortening and ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability of DMDY/- pigs. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories from DMDY/- pigs, DMD+/- carriers, and WT littermate controls provide important resources for studying DMD disease mechanisms and for testing novel diagnostic procedures and treatment strategies.

scholarly journals Real-world outcomes of long-term prednisone and deflazacort use in patients with Duchenne muscular dystrophy: experience at a single, large care center

2020 ◽  
Vol 9 (3) ◽  
pp. 177-189
Author(s):  
Jessica R Marden ◽  
Jonathan Freimark ◽  
Zhiwen Yao ◽  
James Signorovitch ◽  
Cuixia Tian ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Real World ◽  
Medical Center ◽  
Care Center ◽  
Left Ventricular ◽  
Whole Body ◽  
Left Ventricular Ejection ◽  
Mineral Density ◽  
Ventricular Ejection Fraction

Aim: To assess outcomes among patients with Duchenne muscular dystrophy receiving deflazacort or prednisone in real-world practice. Methods: Clinical data for 435 boys with Duchenne muscular dystrophy from Cincinnati Children’s Hospital Medical Center were studied retrospectively using time-to-event and regression analyses. Results: Median ages at loss of ambulation were 15.6 and 13.5 years among deflazacort- and prednisone-initiated patients, respectively. Deflazacort was also associated with a lower risk of scoliosis and better ambulatory function, greater % lean body mass, shorter stature and lower weight, after adjusting for age and steroid duration. No differences were observed in whole body bone mineral density or left ventricular ejection fraction. Conclusion: This single center study adds to the real-world evidence associating deflazacort with improved clinical outcomes.

scholarly journals Cardiac Dysfunction in Duchenne Muscular Dystrophy Is Less Frequent in Patients With Mutations in the Dystrophin Dp116 Coding Region Than in Other Regions

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Tetsushi Yamamoto ◽  
Hiroyuki Awano ◽  
Zhujun Zhang ◽  
Mio Sakuma ◽  
Shoko Kitaaki ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Left Ventricular Ejection Fraction ◽  
Muscular Dystrophy ◽  
Ejection Fraction ◽  
Cardiac Dysfunction ◽  
Cardiac Involvement ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Coding Region ◽  
Ventricular Ejection Fraction

Background Duchenne muscular dystrophy (DMD), the most common inherited muscular disease in childhood, is caused by dystrophin deficiency because of mutations in the DMD gene. Although DMD is characterized by fatal progressive muscle wasting, cardiomyopathy is the most important nonmuscle symptom threatening the life of patients with DMD. The relationship between cardiac involvement and dystrophin isoforms has not been analyzed. Methods and Results The results of 1109 echocardiograms obtained from 181 Japanese DMD patients with confirmed mutations in the DMD gene were retrospectively analyzed. Patients showed an age-related decline in left ventricular ejection fraction. Patients were divided by patterns of dystrophin isoform deficiency into 5 groups. The cardiac dysfunction-free survival was significantly higher in the group with mutations in the Dp116 coding region than the others, whereas no significant differences in the other 3 groups. At age 25 years, the cardiac dysfunction-free rate was 0.6 in the Dp116 group, but only 0.1 in others. PCR amplification of Dp116 transcript in human cardiac muscle indicated promoter activation. Conclusions Left ventricular ejection fraction in DMD declined stepwise with age. Cardiac dysfunction was less frequent in Dp116-deficient than other patients with DMD. Dp116 transcript was identified in human cardiac muscle for the first time. These results indicate that Dp116 is associated with cardiac involvement in DMD.

scholarly journals A practical approach to cardiac imaging in adults with Duchenne muscular dystrophy - echocardiography or cardiac MRI?

2021 ◽  
Vol 22 (Supplement_2) ◽  
Author(s):  
K Hewitt ◽  
J Carron ◽  
S Quinn ◽  
R Sheahan
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cardiac Imaging ◽  
Imaging Techniques ◽  
Demographic Data ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Lv Function ◽  
Cardiac Device ◽  
Ventricular Ejection Fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background The incidence of cardiomyopathy in Duchenne muscular dystrophy (DMD) increases with age, accounting for up to 20% of mortality in the third decade of life. As patients are frequently asymptomatic until advanced stages of disease, imaging plays an essential role in screening for cardiac involvement and monitoring progression. Guidelines recommend annual transthoracic echocardiography assessment, with periodic use of cardiac magnetic resonance imaging (CMR). However, some studies suggest that CMR should be the gold standard imaging in DMD. This study aimed to review the use echo and CMR in adult patients with DMD, with particular focus on practical utility and real-world limitations. Methods   A retrospective chart review of 24 patients attending our DMD cardiomyopathy clinic was undertaken. Demographic data including age, genotyping and medical therapy were noted. Results of cardiac imaging, as well as discussions regarding referral for CMR were recorded. Results All patients had echocardiography performed in our facility (table 1) and all had a documented discussion regarding referral for CMR in their medical notes. 15 patients (60%) were unsuitable for CMR and were not referred. Reasons were inability to lie flat due to breathing/claustrophobia (n = 12) and difficulty with positioning due to contractures (n = 9). 2 patients (8%) attended for CMR but were unable to proceed due to difficulty with positioning in the scanner. 4 patients (16.5%) had CMR performed, 3 additional patients were referred and awaited CMR. Results outlined in table 1 and image 1 show correlation between measurement of left ventricular ejection fraction (LVEF) on echo and CMR. Wall motion abnormalities and fibrosis were better detected with CMR.  Conclusion   Significant limitations were seen with both imaging techniques. Accessibility of CMR for adults with DMD is poor, related primarily to the severity of underlying musculoskeletal and respiratory disease. Echocardiography is easily accessible, but images are frequently suboptimal. Despite this, strong correlation was seen in assessment of LV function in those who underwent both echocardiography and CMR, with indication that echocardiography can accurately guide intensification of medications and cardiac device therapy. CMR remains the optimal modality for the assessment of myocardial fibrosis. Improving accessibility of CMR for patients with DMD should be prioritised for the future of this modality.

Abstract 15618: Cardiac Magnetic Resonance Evaluation of Diastolic Indices in Boys With Duchenne Muscular Dystrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jeffrey Weiner ◽  
Kristen GeorgeDurrett ◽  
Kimberly Crum ◽  
Joshua Chew ◽  
Christopher Spurney ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
End Diastolic Volume ◽  
Mean Time

Introduction: Cardiomyopathy (CM) is the leading cause of death in boys with Duchenne Muscular Dystrophy (DMD). Diastolic dysfunction precedes systolic dysfunction in DMD, but while CMR is used routinely to assess fibrosis and left ventricular ejection fraction (LVEF), CMR measures of DMD diastolic dysfunction have not been reported. Hypothesis: Boys with DMD have diastolic dysfunction based on CMR indices when compared with healthy controls. Methods: Prospectively enrolled DMD patients (n = 54) and healthy male controls (n = 40) underwent CMR. Standard volumes and function were calculated. LV filling curves were generated by contouring every phase in the short axis. Indices were compared between groups using a Wilcoxon rank sum and within DMD using a Spearman’s rho test. Results: There was no difference in LVEF between DMD and controls, though DMD patients had significantly smaller indexed left ventricular end diastolic volume (LVEDVi) (see data in Table 1). Peak ventricular filling rates (PFR) were significantly slower in DMD vs controls as were peak ventricular emptying rates (PER). Mean time to PFR (tPFR) and mean time to PER (tPER) were significantly shorter in DMD patients vs controls. In a subset analysis excluding patients with LVEF < 55%, observed differences in PFR, PER, tPFR and TPER remain statistically significant. In DMD patients, tPER correlates negatively with LVEF (rho = -0.57, p <0.001). PER corrected to LVEDVi correlated strongly with LVEF (rho = 0.74, p <0.001). PFR corrected to LVEDVi also correlated strongly with LVEF (rho = 0.75, p <0.001). Conclusions: Despite having normal baseline systolic function, boys with DMD have significantly different CMR diastolic indices compared with controls. CMR diastolic indices may help detect subclinical dysfunction in DMD. Future analyses should evaluate for correlation between diastolic dysfunction and clinical outcomes.

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