Myocardial alterations in the murine model of Fabry disease can be reversed by enzyme replacement therapy

ROZENFELD P.; FRITZ M.; BLANCO P.; GONZALEZ P.; RINALDI G.

CANADIAN JOURNAL OF CARDIOLOGY

PULSUS GROUP INC

Lugar: Ontario; Año: 2011 vol. 27 p. 339 - 345

0828-282X

Background: Fabry disease results from deficiency of alpha-galactosidase A (AGA), causing lysosomal storage of globotriaosylceramide (Gb3) in heart and other tissues. Since 2003, enzymatic replacement therapy (ERT) with recombinant AGA agalsidase alfa (R-AGA) was approved for clinical use. Objectives: 1) to evaluate if in mice knocked out for AGA (FM, n=31) the myocardium was altered with respect to the wild-type mice (WT, n=25), and 2) if 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 LVDP/Dt (FM= 2832 ± 85 mmHg/sec, WT= 3179 ± 119 mmHg/sec, 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 mmHg/20 ml; WT= 68.86 ± 6.12  mmHg/20 ml, p < 0.05). FM myocytes showed augmented size, disorganized architecture and intracytoplasmic vacuolization; alterations reverted in FM-AGA: LV DP/Dt = 3281 ± 456 mmHg/sec, LV stiffness = 58.83 ± 2.15  mmHg/20 ml, 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  non-hypertrophic hearts. Reversion of alterations in the FM-AGA suggests that ERT can be useful when administered in early stages of this disease.