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A detailed pathologic examination of heart tissue from three older patients with Anderson-Fabry disease on enzyme
Mary N Sheppard1, Paul Cane, Richard Florio
1Department of Histopathology, Royal Brompton and Harefield NHS Trust, London, UK. m.sheppard@rbht.nhs.uk
Insights
Enzyme replacement therapy (ERT) for Anderson-Fabry disease (AFD) shows limited effectiveness in preventing cardiac substrate accumulation and damage. Hearts from patients on ERT still exhibit globotriaosylceramide (Gb3) buildup, hypertrophy, fibrosis, and cell death.
Area of Science:
- Cardiovascular Pathology
- Lysosomal Storage Diseases
- Pharmacology
Background:
- Anderson-Fabry disease (AFD) is an X-linked metabolic disorder causing cardiac complications due to α-galactosidase A deficiency.
- Globotriaosylceramide (Gb3) accumulates in various tissues, leading to significant morbidity and mortality.
- Enzyme replacement therapy (ERT) using recombinant α-galactosidase A aims to reduce Gb3 levels and disease burden.
Observation:
- Analysis of three male AFD patients (55-73 years) who received ERT for 1.5-4 years.
- Detailed pathological examination of whole hearts, including myocytes, vasculature, and valves.
Findings:
- Despite ERT, significant Gb3 accumulation persisted in cardiac myocytes, endothelial cells, smooth muscle cells, and vasculature.
- Myocytes showed marked hypertrophy, vacuolization, apoptosis, and necrosis.
- Extensive replacement fibrosis (15%) and myocyte disarray were observed in all hearts.
Implications:
- This study reveals the pancardiac impact of AFD and the limited efficacy of current ERT in preventing cardiac pathology.
- Findings underscore the need for earlier and potentially more effective therapeutic strategies for AFD.
- The presence of myocyte necrosis, apoptosis, and disarray has critical implications for understanding AFD's cardiac progression and ERT's timing.
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.
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