Myocardial Alterations in the Murine Model of Fabry Disease Can Be Reversed by Enzyme Replacement Therapy

ROZENFELD PA; FRITZ M; BLANCO P; GONZALEZ P; RINALDI GJ

CANADIAN JOURNAL OF CARDIOLOGY

PULSUS GROUP INC

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 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 P/t (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 (FM35.57 3.5 mm Hg/20 l; WT 68.86 6.12 mm Hg/20 l; P 0.05). FM myocytes showed augmented size, disorganized architecture, and intracytoplasmic vacuolization. Alterations reverted in FM-AGA: LV P/t 3281 456 mm Hg/s and LV stiffness 58.83 2.15 mm Hg/20 l, 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.