title: Myocardial alterations in the murine model of fabry disease can be reversed by enzyme replacement therapy.
abstract: BACKGROUND
  Fabry disease results from deficiency of alpha-galactosidase A (AGA), causing lysosomal storage of globotriaosylceramide in heart and other tissues. Since 2003, enzymatic replacement therapy with recombinant AGA agalsidase alfa (R-AGA) was approved for clinical use.
  
  
  METHODS
  We evaluated whether, in mice knocked out for AGA (FM, n = 31), the myocardium was altered with respect to the wild-type mice (WT, n = 25) and whether alterations were reversed in FM treated with intravenous R-AGA, 0.5 mg/kg every other week during 2 months (FM-AGA, n = 12).
  
  
  RESULTS
  Left ventricular (LV) contractility was depressed in FM, evaluated by LV ΔP/Δt (FM = 2832 ± 85 mm Hg/s, WT = 3179 ± 119 mm Hg/s; P < 0.05), papillary muscle contraction (FM = 39.8 ± 17.3 mg, WT = 67.5 ± 15.7 mg; P < 0.05), or shortening fraction measured by M-mode echocardiography (FM = 30% ± 6%, WT = 47% ± 2%; P < 0.05). LV stiffness (arrested hearts) decreased in FM (FM = 35.57 ± 3.5 mm Hg/20 μl; WT = 68.86 ± 6.12 mm Hg/20 μl; P < 0.05). FM myocytes showed augmented size, disorganized architecture, and intracytoplasmic vacuolization. Alterations reverted in FM-AGA: LV ΔP/Δt = 3281 ± 456 mm Hg/s and LV stiffness = 58.83 ± 2.15 mm Hg/20 μl, with normalization of myocyte architecture. No reversion was detected with AGA solvent.
  
  
  CONCLUSIONS
  The FM represent a mild, early stage of the disease, since myocardial alterations are not prominent and appear in nonhypertrophic hearts. Reversion of alterations in the FM-AGA suggests that enzymatic replacement therapy can be useful when administered in early stages of this disease.
authors.affiliation: Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, Universidad Nacional de La Plata, La Plata, Argentina. paurozen@biol.unlp.edu.ar
authors.forename: Paula A
authors.initials: PA
authors.lastname: Rozenfeld
authors.forename: Mariana
authors.initials: M
authors.lastname: Fritz
authors.forename: Paula
authors.initials: P
authors.lastname: Blanco
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Rinaldi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D056947:Enzyme Replacement Therapy / Q000379:methods*; D000795:Fabry Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000473:pathology*; D010210:Papillary Muscles / Q000187:drug effects / Q000201:enzymology*; D011897:Random Allocation; D012016:Reference Values; D000519:alpha-Galactosidase / Q000494:pharmacology*
chemical_list: D000519:alpha-Galactosidase