title: Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside.
abstract: Genetic defects of the dystrophin-glycoprotein complex (DGC) cause hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated cardiomyopathy: The enteroviral protease 2A directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. During infection of mice with coxsackievirus B3, the DGC in the heart is disrupted and the sarcolemmal integrity is lost in virus-infected cardiomyocytes. Additionally, dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy in vivo, suggesting a pathogenetic role of the dystrophin cleavage in enterovirus-induced cardiomyopathy. Here, we extend these experimental findings to a patient with dilated cardiomyopathy due to a coxsackievirus B2 myocarditis. Endomyocardial biopsy specimens showed an inflammatory infiltrate and myocytolysis. Immunostaining for the enteroviral capsid antigen VP1 revealed virus-infected cardiomyocytes. Focal areas of cardiomyocytes displayed a loss of the sarcolemmal staining pattern for dystrophin and beta-sarcoglycan identical to previous findings in virus-infected mouse hearts. In vitro, coxsackievirus B2 protease 2A cleaved human dystrophin. These findings demonstrate that in human coxsackievirus B myocarditis a focal disruption of the DGC can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy.
authors.affiliation: Department of Medicine, University of California, San Diego, USA. badorff@em.uni-frankfurt.de
authors.forename: Cornel
authors.initials: C
authors.lastname: Badorff
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000328:Adult; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000473:pathology* / Q000821:virology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D049030:Dystroglycans; D016189:Dystrophin / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009205:Myocarditis / Q000473:pathology* / Q000821:virology; D009206:Myocardium / Q000166:cytology; D011817:Rabbits; D012508:Sarcolemma / Q000473:pathology; D014764:Viral Proteins
chemical_list: D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016189:Dystrophin; D008562:Membrane Glycoproteins; D014764:Viral Proteins; D049030:Dystroglycans; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus