Myocardial inflammation in Duchenne Muscular Dystrophy as a precipitating factor for heart failure: a prospective study

Mavrogeni, Sophie; Papavasiliou, Antigoni; Spargias, Kostas; Constandoulakis, Pantelis; Papadopoulos, George; Karanasios, Evangelos; Georgakopoulos, Dimitrios G.; Kolovou, Genovefa; Demerouti, Eftychia; Polymeros, Spyridon; Kaklamanis, Loukas; Magoutas, Anastasios; Papadopoulou, Evangelia; Markussis, Vyron; Cokkinos, Dennis V.

doi:10.1186/1471-2377-10-33

Cited by 73 publications

(48 citation statements)

References 29 publications

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“…Patients with DMD typically exhibit symptoms at 3-5 y of age, with evidence of focal necrotic skeletal myofibers, muscle hypertrophy, and high levels of serum creatine kinase (4). Loss of dystrophin in cardiac tissues of patients with DMD leads to an influx of extracellular calcium, which triggers a pathological cascade of protease activation, myocyte death, necrosis, and inflammation, resulting in increased fibrosis (5,6). Although electrocardiography can detect cardiac dysfunction in more than half of patients with DMD aged 6-10 y, early symptoms of cardiomyopathy may go undetected because of limited exercise tolerance.…”

mentioning

confidence: 99%

Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

Chang

Ong

LaGory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx 4cv /mTR G2 mouse model with "humanized" telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions.Duchenne muscular dystrophy | telomere | mitochondrial dysfunction | metabolic compromise | dilated cardiomyopathy

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mentioning

confidence: 99%

Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

Chang

Ong

LaGory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Enteroviral protease 2A cleaves the viral polyprotein and a small number of host cell proteins such as the cytoskeletal protein dystrophin (1) and the eukaryotic translation initiation factors eIF4G1 and eIF4G2 (2)(3)(4). Genetic deficiency of dystrophin causes cardiomyopathy in Duchenne muscular dystrophy and increases susceptibility to myocarditis (5,6). However, the importance of protease 2A-mediated cleavage of dystrophin is not known.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy

Lim¹,

Peter²,

Xiong³

et al. 2013

J. Clin. Invest.

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Heart failure in children and adults is often the consequence of myocarditis associated with Coxsackievirus (CV) infection. Upon CV infection, enteroviral protease 2A cleaves a small number of host proteins including dystrophin, which links actin filaments to the plasma membrane of muscle fiber cells (sarcolemma). It is unknown whether protease 2A-mediated cleavage of dystrophin and subsequent disruption of the sarcolemma play a role in CV-mediated myocarditis. We generated knockin mice harboring a mutation at the protease 2A cleavage site of the dystrophin gene, which prevents dystrophin cleavage following CV infection. Compared with wild-type mice, we found that mice expressing cleavage-resistant dystrophin had a decrease in sarcolemmal disruption and cardiac virus titer following CV infection. In addition, cleavage-resistant dystrophin inhibited the cardiomyopathy induced by cardiomyocyte-restricted expression of the CV protease 2A transgene. These findings indicate that protease 2A-mediated cleavage of dystrophin is critical for viral propagation, enteroviral-mediated cytopathic effects, and the development of cardiomyopathy. IntroductionCoxsackievirus (CV) is a member of the enteroviral genus of the picornavirus family and is known to be an important cause of myocarditis and heart failure in children and adults. Enteroviral protease 2A cleaves the viral polyprotein and a small number of host cell proteins such as the cytoskeletal protein dystrophin (1) and the eukaryotic translation initiation factors eIF4G1 and eIF4G2 (2-4). Genetic deficiency of dystrophin causes cardiomyopathy in Duchenne muscular dystrophy and increases susceptibility to myocarditis (5, 6). However, the importance of protease 2A-mediated cleavage of dystrophin is not known. We hypothesized that cleavage of dystrophin by protease 2A is important in sarcolemmal membrane disruption, viral propagation, enteroviral-mediated cytopathic effects, and the development of viral myocarditis. In order to address this hypothesis, we knocked in a mutation at the protease 2A cleavage site of the dystrophin gene, thus inhibiting only the cleavage of dystrophin following CVB3 infection. When mice expressing cleavage-resistant dystrophin were infected with CVB3, there was a decrease in the sarcolemmal disruption, cardiac virus titer, and severity of myocarditis compared with control mice expressing cleavable wild-type dystrophin. In addition, the prevention of dystrophin cleavage in protease 2A-expressing transgenic mice (7) markedly inhibited the protease 2A-induced myocytopathic effect and cardiomyopathy. These findings indicate that disruption of the sarcolemma by protease 2A-mediated cleavage of dystrophin can have a critical role in the pathogenesis of viral myocarditis via alterations in viral propagation and enteroviral-mediated cytopathic effects in the intact wild-type heart.

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“…98 Jedna studija povezuje prisutnost varijanti u receptorima nalik na Toll (Toll-like receptors) koji igraju važnu ulogu u urođenim imunološkim reakcijama s lošijom kardiološkom funkcijom kod 158 pacijenata.…”

Section: -89unclassified

“…98 In another study, the presence of variants in Toll-like receptors which play a key role in the innate immune response were associated with poorer cardiac function in 158 patients. 99 Finally, Meder et al 100 present data associating the locus containing major histocompatibility genes (MHC I and II) with DCM.…”

Section: -93mentioning

confidence: 99%

Almanac 2014: Cardiomyopathies.

Guttmann¹,

Mohiddin²,

Elliott³

2015

Cardiol Croat.

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SAŽETAK: Kardiomiopatije su bolesti miokarda koje se ne mogu objasniti abnormalnim uvjetima punjenja niti promjenama koronarnih arterija. One se klasifi ciraju u više morfoloških i funkcionalnih fenotipova čiji uzrok mogu biti genetički i negenetički mehanizmi. Dominantne teme u radovima objavljenima u razdoblju 2012.-2013. slične su onima navedenima u Almanahu 2011.: uporaba (i interpretacija) genetskog testiranja, razvoj i primjena novih neinvazivnih tehnika slikovne dijagnostike te uporaba serumskih biomarkera u procesu dijagnoze i za prognozu. Važna inovacija od posljednjeg Almanaha jest razvoj sofi sticiranijih modela za predviđanje neželjenih kliničkih događaja. SUMMARY:Cardiomyopathies are myocardial disorders that are not explained by abnormal loading conditions and coronary artery disease. They are classifi ed into a number of morphological and functional phenotypes that can be caused by genetic and non-genetic mechanisms. The dominant themes in papers published in 2012-2013 are similar to those reported in Almanac 2011, namely, the use (and interpretation) of genetic testing, development and application of novel non-invasive imaging techniques and use of serum biomarkers for diagnosis and prognosis. An important innovation since the last Almanac is the development of more sophisticated models for predicting adverse clinical events.CITATION: Cardiol Croat. 2014;9(11-12):543-557. | DOI: http://dx

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Myocardial inflammation in Duchenne Muscular Dystrophy as a precipitating factor for heart failure: a prospective study

Cited by 73 publications

References 29 publications

Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy

Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy

Almanac 2014: Cardiomyopathies.

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