Abstract 16916: Asymptomatic Patients With Duchenne Muscular Dystrophy Have Elevated Troponin

Introduction: Cardiomyopathy is the leading cause of death in Duchenne Muscular Dystrophy (DMD), but traditional heart failure biomarkers have limited utility. Cardiac Troponin I (cTnI) has been used in DMD research studies as a marker of toxicity, but little is known about cTnI levels in asymptomatic patients. The goal of this study was to longitudinally evaluate cTnI, NTproBNP, and BNP in an asymptomatic DMD cohort. We hypothesized the biomarkers would not correlate with cardiac function, but some asymptomatic patients would exhibit a cTnI leak, reflecting ongoing myocardial inflammation related to disease progression. Methods: Asymptomatic DMD patients (N=69) and controls with normal cardiac evaluations (N=18) were enrolled. In DMD subjects, biomarker levels were obtained at time of cardiac magnetic resonance imaging (CMR), which included assessment of atrial and ventricular volumes, function, and late gadolinium enhancement (LGE). Normal ranges for biomarkers were created based on control values. Spearman correlation was used for analysis. Results: There was no consistent correlation between biomarkers and disease progression by CMR (Table 1). Several DMD subjects had transiently elevated cTnI (Fig 1). Those with elevated cTnI trended towards being more likely to have LGE on baseline CMR, though this did not reach statistical significance (p= 0.08). Conclusions: CTnI, BNP, and NTproBNP do not correlate with CMR assessment of cardiomyopathy progression. There is a subset of the DMD cohort with asymptomatic cTnI leak. While this cTnI leak is of uncertain clinical significance, it is important to recognize if cTnI is used to assess for cardiac toxicity in future drug trials.

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A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210689 ◽

2021 ◽

pp. 1-16

Author(s):

Richard S. Finkel ◽

Craig M. McDonald ◽

H. Lee Sweeney ◽

Erika Finanger ◽

Erin Neil Knierbein ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Statistical Significance ◽

Slow Disease Progression ◽

Phase 3 ◽

Double Blind ◽

The North ◽

Health Related ◽

Group A

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). Objective: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 – < 8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks. Methods: Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI). Results: One hundred thirty one patients received edasalonexent (n = 81) or placebo (n = 38). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea). Conclusions: Edasalonexent was generally well tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882)

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Troponin I Levels Correlate with Cardiac MR LGE and Native T1 Values in Duchenne Muscular Dystrophy Cardiomyopathy and Identify Early Disease Progression

Pediatric Cardiology ◽

10.1007/s00246-020-02372-5 ◽

2020 ◽

Vol 41 (6) ◽

pp. 1173-1179 ◽

Cited By ~ 2

Author(s):

Sonia Voleti ◽

Laura Olivieri ◽

Karin Hamann ◽

Heather Gordish-Dressman ◽

Christopher Spurney

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Troponin I ◽

Early Disease ◽

Cardiac Mr ◽

Native T1 ◽

Duchenne Muscular Dystrophy Cardiomyopathy

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Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy

Annals of Neurology ◽

10.1002/ana.24904 ◽

2017 ◽

Vol 81 (5) ◽

pp. 633-640 ◽

Cited By ~ 24

Author(s):

Craig M. Zaidman ◽

Jim S. Wu ◽

Kush Kapur ◽

Amy Pasternak ◽

Lavanya Madabusi ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Muscle Ultrasound

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802425115 ◽

2018 ◽

Vol 115 (30) ◽

pp. 7741-7746 ◽

Cited By ~ 2

Author(s):

Antonio Filareto ◽

Katie Maguire-Nguyen ◽

Qiang Gan ◽

Garazi Aldanondo ◽

Léo Machado ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Premature Death ◽

Response To Therapy ◽

Luciferase Reporter ◽

Luciferase Expression ◽

Muscle Degeneration ◽

Reporter Strain ◽

Novel Treatments

Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.

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Abstract 17250: Serum vs. Imaging Biomarkers of Myocardial Injury in Duchenne Muscular Dystrophy: Findings from the E-SCAR DMD Trial

Circulation ◽

10.1161/circ.130.suppl_2.17250 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Subha V Raman ◽

Kan N Hor ◽

Wojciech Mazur ◽

Nancy Halnon ◽

Tam Tran ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Myocardial Injury ◽

Troponin I ◽

Left Ventricular ◽

Serum Biomarkers ◽

Left Ventricular Ejection ◽

Imaging Biomarkers ◽

Mineralocorticoid Receptor Antagonist ◽

Lge Cmr

Introduction: Cardiomyopathy has become a leading cause of death in Duchenne muscular dystrophy (DMD). We previously showed that early mineralocorticoid receptor antagonist therapy reduces myocardial damage in a preclinical model of DMD. The Eplerenone for Subclinical Cardiomyopathy in DMD (E-SCAR DMD, NCT01521546) is a multicenter randomized placebo-controlled clinical trial evaluating eplerenone in boys with preserved left ventricular ejection fraction (LVEF) and evident myocardial injury by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Hypothesis: To better define biomarkers of early disease, we hypothesized that LGE has greater sensitivity vs. serum biomarkers for myocardial injury in DMD cardiomyopathy. Methods: Boys with DMD age ≥ 7 years were enrolled across 3 centers. LGE-CMR images were acquired using comparable techniques across 3T scanners, and core laboratory LGE quantification was performed blinded to laboratory findings as a percentage of LV mass using software based on the full-width half-maximum technique. Troponin-I, creatine kinase (CK) and CK isoenzymes were measured from blood samples obtained at the time of CMR examination using standardized clinical assays. Results: 42 boys age 16 ± 7 years had preserved LVEF (57 ± 6%), and LGE-positive regions averaged 5.0 ± 2.6% of LV myocardium. While 100% had evident myocardial injury by LGE, 43% had measurable CK-MB and only 18% had detectable troponin-I in serum (Figure). %LGE was higher (5.4 ± 2.7 vs. 3.3 ± 1.8%, p<0.05) and LVEF was lower (55.4 ± 4.9 vs. 59.0 ± 7.1%, p < 0.01) in boys with detectable vs. those with undetectable troponin-I, whereas detectable CK-MB did not predict higher %LGE or lower LVEF. Conclusion: DMD patients with abnormal myocardium by LGE-CMR may have no detectable abnormalities by serum biomarkers, underscoring the importance of myocardial injury imaging in identifying patients with subclinical cardiomyopathy who may benefit from early treatment.

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