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.