Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy.

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 alpha-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 alpha-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 alpha-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 alpha-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.

Differential muscular glycogen clearance after enzyme replacement therapy in a mouse model of Pompe disease.

Glycogen storage disease in the alpha-glucosidase knockout(6neo(-)/6neo(-)) (GAA KO) mouse, a model of Pompe disease, results in the pathologic accumulation of glycogen primarily within skeletal myocytes and cardiomyocytes. Intravenous administration of recombinant human alpha-glucosidase (rhGAA, Myozyme, aglucosidase alfa) can result in significant glycogen clearance from both cardiomyocytes and skeletal myocytes, however, the degree of clearance varies from one skeletal muscle type to another. We sought to determine what role muscle fiber type predominance played in this variability. To examine this question in the GAA KO mouse model we delivered intravenous doses of 100 mg/kg rhGAA on Day 1, and Day 14, and harvested a variety of fast and slow twitch muscles on Day 28. We measured glycogen clearance, muscle fiber type content and capillary density by light microscopy with computer morphometry. Recombinant human-GAA administration resulted in differential clearance of glycogen in the various muscles examined. Slow twitch-predominant muscles cleared glycogen significantly more efficiently than fast twitch-predominant muscles. There was a strong correlation between capillary density and glycogen clearance (r=0.55), suggesting that at the high doses used in this study the differential glycogen clearance observed between muscles is largely due to differential bioavailability of rhGAA regulated by blood flow.