The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Duchenne Muscular Dystrophy Cardiomyopathy

Soslow, Jonathan H.; Xu, Meng; Slaughter, James C.; Crum, Kimberly; Burnette, W. Bryan; Su, Yan; Tomasek, Kelsey; Parra, David; Markham, Larry W.

doi:10.1016/j.cardfail.2019.02.006

Cited by 26 publications

(26 citation statements)

References 43 publications

(44 reference statements)

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“…The presence or absence of LGE was qualitatively assessed by one reader (JS). Global severity score was calculated as described previously, with a range of 0 (no LGE) to 4 (severe LGE) [ 10 , 28 ]. A second reader (FR) performed a blinded analysis of 30 CMRs to evaluate reproducibility of global severity score.…”

Section: Methodsmentioning

confidence: 99%

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

Raucci

George‐Durrett

et al. 2021

Journal of Cardiovascular Magnetic Resonance

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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.

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Section: Methodsmentioning

confidence: 99%

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

Raucci

George‐Durrett

et al. 2021

Journal of Cardiovascular Magnetic Resonance

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“…Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) modulate the turnover of the deposited ECM through their respective actions of promoting and inhibiting the degradation of matrix components like collagen. Interestingly, there is a trend toward an increase in some MMPs in DMD, with levels of MMP7 in particular significantly correlating with increased cardiac and skeletal muscle pathology in dystrophic patients [118,119]. However, the interpretation of this result is complicated, as the relationship between MMP7 and fibrosis could be secondary to its modulation of inflammation rather than through direct effects on the ECM.…”

Section: Pathophysiological Mechanisms Of Dystrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers

Townsend

2019

IJMS

114

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Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.

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“…age, mutations, baseline levels in healthy individuals, etc. [114][115][116]. Besides muscle-specific proteins, other targets are identified as biomarker candidates.…”

Section: Biomarkers For Dmdmentioning

confidence: 99%

Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application

Szigyarto

2020

Expert Review of Proteomics

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Introduction: Early biomarker discovery studies have praised the value of their emerging results, predicting an unprecedented impact on health care. Biomarkers are expected to provide tests with increased specificity and sensitivity compared to existing measures, improve the decision-making process, and accelerate the development of therapies. For rare disorders, like Duchenne Muscular Dystrophy (DMD) such biomarkers can assist the development of therapies, therefore also helping to find a cure for the disease. Area covered: State-of-the-art technologies have been used to identify blood biomarkers for DMD and efforts have been coordinated to develop and promote translation of biomarkers for clinical practice. Biomarker translation to clinical practice is however, adjoined by challenges related to the complexity of the disease, involving numerous biological processes, and the limited sample resources. This review highlights the current progress on the development of biomarkers, describing the proteomics technologies used, the most promising findings and the challenges encountered. Expert opinion: Strategies for effective use of samples combined with orthogonal proteomics methods for protein quantification are essential for translating biomarkers to the patient's bed side. Progress is achieved only if strong evidence is provided that the biomarker constitutes a reliable indicator of the patient's health status for a specific context of use.

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The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Duchenne Muscular Dystrophy Cardiomyopathy

Cited by 26 publications

References 43 publications

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

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

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application

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