Related Experiment Video
Updated: Jun 29, 2025
Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix
Published on: June 14, 2016
Long-Term Clinical-Pathologic Results of Enzyme Replacement Therapy in Prehypertrophic Fabry Disease Cardiomyopathy
Andrea Frustaci1, Romina Verardo1, Nicola Galea2
1Cellular and Molecular Cardiology Lab IRCCS L. Spallanzani Rome Italy.
Insights
Enzyme replacement therapy (ERT) stabilizes prehypertrophic Fabry disease cardiomyopathy (FDCM) in most patients, but globotriaosylceramide is not fully cleared. Immune-mediated inflammation can limit ERT effectiveness in FDCM.
Area of Science:
- Cardiology
- Genetics
- Biochemistry
Background:
- Enzyme replacement therapy (ERT) has limited efficacy in clearing globotriaosylceramide in advanced Fabry disease cardiomyopathy (FDCM).
- Prehypertrophic FDCM is thought to be stabilized by ERT, but pathological evidence is lacking.
- This study investigates the long-term clinical and pathological effects of ERT on prehypertrophic FDCM.
Purpose of the Study:
- To evaluate the long-term clinical-pathologic impact of ERT on prehypertrophic Fabry disease cardiomyopathy (FDCM).
- To assess the efficacy of ERT in preventing disease progression and globotriaosylceramide accumulation in cardiomyocytes.
Main Methods:
- Fifteen patients with Fabry disease and mild left ventricular hypertrophy underwent endomyocardial biopsy.
- Patients received either α-agalsidase or β-agalsidase ERT for 4 to 20 years.
- Cardiac magnetic resonance and repeat biopsies were performed to assess treatment effects.
Main Results:
- ERT stabilized left ventricular dimensions and cardiomyocyte size in 13 of 15 patients with prehypertrophic FDCM.
- Globotriaosylceramide storage persisted in cardiomyocytes despite long-term ERT.
- Two symptomatic patients showed disease progression, associated with myocardial inflammation.
Conclusions:
- ERT stabilizes prehypertrophic FDCM in 87% of patients by maintaining myocyte dimensions and storage deposits.
- Complete removal of globotriaosylceramide is not achieved with long-term ERT.
- Immune-mediated myocardial inflammation can impede ERT efficacy in FDCM.
Background:
The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM.
Methods And Results:
Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and β-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with β-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation.
Conclusions:
ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.
