Cause of Cardiac Disease in a Female Carrier of Duchenne Muscular Dystrophy

Florian, Anca; Ludwig, Anna; Ong, Peter; Klingel, Karin; Kandolf, Reinhard; Bornemann, Antje; Sechtem, Udo; Yılmaz, Ali

doi:10.1161/circulationaha.113.006891

Cited by 12 publications

(8 citation statements)

References 5 publications

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“…Immunofluorescence staining confirmed a mosaic pattern of dystrophin expression in the hearts of female mdx carriers (Fig. 2E) consistent with random X-inactivation in the cardiomyocytes (37,116). This mosaic dystrophin expression resulted in a net reduction in dystrophin protein levels in the hearts of female mdx carriers compared with WT (Fig.…”

Section: H585 Ddah Attenuates Exercise-induced Fatigue In Dmd Carrier Micesupporting

confidence: 66%

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice

Garbincius

Merz

Cuttitta

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates post-exercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically-necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac β-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers, or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in DMD patients.

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Section: H585 Ddah Attenuates Exercise-induced Fatigue In Dmd Carrier Micesupporting

confidence: 66%

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice

Garbincius

Merz

Cuttitta

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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“…In recent years, CMR imaging has gained wide acceptance for non-invasive evaluation of ischaemic as well as non-ischaemic cardiomyopathies since multi-parametric CMR does not only allow the assessment of functional parameters (such as systolic function) but also enables a non-invasive assessment of myocardial scarring based on LGE-imaging or T1-mapping [ 22 ]. Within the last years, the distribution pattern of myocardial scarring in MD patients (as well as female MD carriers) was assessed based on such comprehensive CMR studies and it could be consistently shown that the posterolateral LV wall segments represent the first and most extensive sites of myocardial fibrosis in MD patients – as well as their female MD carrier relatives [ 17 , 23 – 25 ] (Fig. 1 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of cardiomyopathy associated circulating miRNA biomarkers in patients with muscular dystrophy using a complementary cardiovascular magnetic resonance and plasma profiling approach

Becker

Florian

Patrascu

et al. 2016

Journal of Cardiovascular Magnetic Resonance

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BackgroundDuchenne and Becker muscular dystrophy (DMD and BMD) are X-chromosomal recessive neuromuscular disorders that are caused by mutations in the dystrophin gene and characterized by cardiac involvement. Circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases. However, circulating miRNAs reflecting the presence and/or disease severity of cardiac involvement in DMD/BMD patients have not been described so far.MethodsSixty-three male patients with known MD and 26 age-matched healthy male controls were prospectively enrolled. All MD patients and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day.ResultsAn impaired left ventricular (LV) systolic function (defined as LV-EF <55 %) was detected in 29 (46 %) and presence of late gadolinium enhancement (LGE) indicative of myocardial fibrosis in 48 (76 %) MD patients with an exclusively non-ischemic pattern. Whereas no significant differences were observed for the 27 selected circulating miRNAs in MD patients with abnormal CMR findings (comprising structural and/or functional impairments) compared to those with completely normal CMR studies, a significant up-regulation of three miRNAs was observed in LGE-positive MD patients compared to LGE-negative ones: miR-222 (1.8-fold, p = 0.035), miR-26a (2.1-fold, p = 0.03) and miR-378a-5p (2.4-fold, p = 0.026). A signature of these three miRNAs (miR-26a, miR-222 and miR-378a-5p) resulted in an area under the curve (AUC) value of 0.74 for the diagnosis of LGE-positive MD patients. In a multivariable model, three independent predictors for LGE presence were identified comprising not only clinical and laboratory markers (LV-EF: OR 0.47, 95 % CI 0.24-0.89, p = 0.021 and elevated hs-Trop: OR 2559, 95 % CI 2.97-22.04*105, p = 0.023) but also the circulating miR-222 (OR 938, 95 % CI 938.46, 3.56-24.73*104, p = 0.016).ConclusionsUp-regulation of circulating miRNAs miR-222, miR-26a and miR-378a-5p indicates the presence of myocardial scars in MD patients. Plasma miR-222 appears to be a promising novel biomarker reflecting structural – but not functional – cardiac alterations in MD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-016-0244-3) contains supplementary material, which is available to authorized users.

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“…In the last years, cardiovascular magnetic resonance (CMR) has been increasingly used for diagnosis as well as for follow-up of cardiac involvement in DMD/BMD patients [11–14]. CMR does not only offer an accurate and reproducible tool for LV systolic function assessment, but also the possibility of non-invasive myocardial tissue characterization and early fibrosis detection based on late gadolinium enhancement (LGE) imaging.…”

Section: Introductionmentioning

confidence: 99%

Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients

Florian

Ludwig

Engelen

et al. 2014

Journal of Cardiovascular Magnetic Resonance

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BackgroundCardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients.MethodsEighty-eight male DMD/BMD patients (age 29 ± 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT).ResultsDuring a mean follow-up time of 47 ± 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF (HR, 95% CI: 0.94, 0.89-0.97, p = 0.001) and the presence of “transmural” LGE (HR, 95% CI: 2.89, 1.09-7.68, p = 0.033) were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio (HR, 95% CI: 11.50, 4.49-29.43, p < 0.0001) in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing “transmural” LGE had a significantly lower event-free-survival (HR, 95% CI: 13.48, 1.89-96.12, p = 0.009) compared to those without.ConclusionsAn impaired LV systolic function (LV-EF ≤45%) and a “transmural” pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter “transmural LGE” is of additive prognostic value.

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Cause of Cardiac Disease in a Female Carrier of Duchenne Muscular Dystrophy

Abstract: The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl

Cited by 12 publications

References 5 publications

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice

Identification of cardiomyopathy associated circulating miRNA biomarkers in patients with muscular dystrophy using a complementary cardiovascular magnetic resonance and plasma profiling approach

Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients

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