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.


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.
Department of Pathology, Genzyme Corporation, Cambridge, MA, USA. Beth.Thurberg@genzyme.com
Beth L
BL
Thurberg
John T
JT
Fallon
Richard
R
Mitchell
Thomas
T
Aretz
Ronald E
RE
Gordon
Michael W
MW
O'Callaghan
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002196:Capillaries / Q000737:chemistry / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D003324:Coronary Artery Disease / Q000517:prevention & control; D003327:Coronary Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004311:Double-Blind Method; D004699:Endocardium / Q000473:pathology* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000737:chemistry / Q000473:pathology; D000795:Fabry Disease / Q000150:complications*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000648:ultrastructure; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D008833:Microcirculation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D014281:Trihexosylceramides / Q000032:analysis / Q000378:metabolism*; D055815:Young Adult; D000519:alpha-Galactosidase / Q000627:therapeutic use*
D011994:Recombinant Proteins; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase