Background—In classic Fabry patients, accelerated coronary atherosclerosis and left ventricular hypertrophy manifest in the fourth decade; however, signs of cardiovascular disease also are observed later in life in "cardiac variant" patients and symptomatic female heterozygotes. These disturbances are caused by globotriaosylceramide (GL-3) accumulation in the heart resulting from lysosomal -galactosidase A deficiency.

Methods and Results—We analyzed pretreatment and posttreatment endomyocardial biopsies from 58 Fabry patients enrolled in a 5-month, phase 3, double-blind, randomized, placebo-controlled trial, followed by a 54-month open-label extension study of recombinant human -galactosidase A. Baseline evaluations revealed GL-3 deposits in interstitial capillary endothelial cells and large, laminated inclusions within cardiomyocytes. In this study, we evaluated microvascular GL-3 clearance; no clearance of GL-3 was observed in the cardiomyocytes during this trial. Five months of recombinant human -galactosidase A treatment in the phase 3 trial resulted in complete microvascular clearance of GL-3 from 72% of treated patients compared with only 3% of placebo patients (P<0.001). The placebo group achieved similar results after 6 months of treatment in the open-label trial. In addition, the capillary endothelium remained free of GL-3 for up to 60 months in 6 of 8 patients who consented to an end-of-study biopsy.

Conclusions—The findings suggest that long-term treatment with recombinant human -galactosidase A may halt the progression of vascular pathology and prevent the clinical manifestations of atherosclerotic disease. This histopathological study should be a useful guide for clinicians and pathologists who diagnose and follow Fabry patients.