Cardiomyocyte Globotriaosylceramide Accumulation in Adult Male Patients with Fabry Disease and IVS4 + 919G>A GLA Mutation is Progressive with Age and Correlates with Left Ventricular Hypertrophy and Reduced Left Ventricular Ejection Fraction

BackgroundWhile cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully elucidated. MethodsWe developed unbiased stereology protocols to quantify the ultrastrcture of Fabry cardiomyopathy. Endomyocardial biopsies from 10 adult male enzyme replacement therapy naive Fabry patients with IVS4 + 919G>A GLA mutation were studied. The findings were correlated with cardiac MRI and clinical data. ResultsUltrastructural parameters showed significant relationships with key imaging and clinical and functional variables. Average cardiomyocyte volume and GL-3 volume per cardiomyocyte were progressively increased with age. Eighty-four percent of left ventricular mass index (LVMI) variability was explained by cardiomyocyte nuclear volume, age and plasma globotriaosylsphingosine with cardiomyocyte nuclear volume being the only independent predictor of LVMI. Septal thickness was directly and left ventricular ejection fraction (LVEF) was inversely correlated with cardiomyocyte GL-3 accumulation. Sixty-five percent of left ventricular ejection fraction (LVEF) variability was explained by cardiomyocyte GL3 volume, serum -galactosidase-A activity and age with cardiomyocyte GL3 volume being the only independent predictor of LVEF. Residual -galactosidase-A activity was directly correlated with myocardial microvasculature density. ConclusionsThe unbiased stereological methods introduced in this study unraveled novel relationships between cardiomyocyte structure and important imaging and clinical parameters. These novel tools can help better understand Fabry cardiomyopathy pathophysiology. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIWe developed a novel unbiased quantitative approach to study cardiac biopsies by electron microscopy. C_LIO_LIUltrastructural parameters showed significant relationships with key clinical, imaging, cardiac functional variables in cardiac biopsies from patients with Fabry disease. C_LI What are the clinical implications?O_LIThese quantitative approaches are powerful tools to better understand pathophysiology of Fabry disease and potentially in other cardiomyopathies. C_LI