BACKGROUND: Cardiac disease causes considerable morbidity and mortality in men and women with Anderson-Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant. METHODS: A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed. RESULTS: In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts. CONCLUSIONS: This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD. Copyright 2010 Elsevier Inc. All rights reserved.
BACKGROUND:Cardiac disease causes considerable morbidity and mortality in men and women with Anderson-Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant. METHODS: A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed. RESULTS: In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts. CONCLUSIONS: This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD. Copyright 2010 Elsevier Inc. All rights reserved.
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