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Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy.
Circulation. 2009 May 19; 119(19):2561-7.Circ

Abstract

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.

Authors+Show Affiliations

Department of Pathology, Genzyme Corporation, Cambridge, MA, USA. Beth.Thurberg@genzyme.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19414635

Citation

Thurberg, Beth L., et al. "Cardiac Microvascular Pathology in Fabry Disease: Evaluation of Endomyocardial Biopsies Before and After Enzyme Replacement Therapy." Circulation, vol. 119, no. 19, 2009, pp. 2561-7.
Thurberg BL, Fallon JT, Mitchell R, et al. Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy. Circulation. 2009;119(19):2561-7.
Thurberg, B. L., Fallon, J. T., Mitchell, R., Aretz, T., Gordon, R. E., & O'Callaghan, M. W. (2009). Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy. Circulation, 119(19), 2561-7. https://doi.org/10.1161/CIRCULATIONAHA.108.841494
Thurberg BL, et al. Cardiac Microvascular Pathology in Fabry Disease: Evaluation of Endomyocardial Biopsies Before and After Enzyme Replacement Therapy. Circulation. 2009 May 19;119(19):2561-7. PubMed PMID: 19414635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy. AU - Thurberg,Beth L, AU - Fallon,John T, AU - Mitchell,Richard, AU - Aretz,Thomas, AU - Gordon,Ronald E, AU - O'Callaghan,Michael W, Y1 - 2009/05/04/ PY - 2009/5/6/entrez PY - 2009/5/6/pubmed PY - 2009/6/9/medline SP - 2561 EP - 7 JF - Circulation JO - Circulation VL - 119 IS - 19 N2 - 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/19414635/Cardiac_microvascular_pathology_in_Fabry_disease:_evaluation_of_endomyocardial_biopsies_before_and_after_enzyme_replacement_therapy_ DB - PRIME DP - Unbound Medicine ER -