title: Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for Fabry disease.
abstract: Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3-4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose.
authors.affiliation: Inserm U872 Team 1, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Vincent
authors.initials: V
authors.lastname: Agrapart
authors.forename: Violaine
authors.initials: V
authors.lastname: Griol-Charhbili
authors.forename: Trenton
authors.initials: T
authors.lastname: Schoeb
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.forename: Edgar
authors.initials: E
authors.lastname: Jaimes
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy*; D055786:Gene Knockout Techniques; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007527:Isoenzymes / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D000519:alpha-Galactosidase / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007527:Isoenzymes; D000519:alpha-Galactosidase; C459420:agalsidase beta