Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy. Thurberg, B. L, Fallon, J. T, Mitchell, R., Aretz, T., Gordon, R. E, & O'Callaghan, M. W Circulation, 119(19):2561–2567, May, 2009.
Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy [link]Paper  doi  abstract   bibtex   
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\textless0.001). 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.
@article{thurberg_cardiac_2009,
	title = {Cardiac microvascular pathology in {Fabry} disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy},
	volume = {119},
	issn = {1524-4539},
	shorttitle = {Cardiac microvascular pathology in {Fabry} disease},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/19414635},
	doi = {10.1161/CIRCULATIONAHA.108.841494},
	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{\textless}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.},
	number = {19},
	urldate = {2010-10-18},
	journal = {Circulation},
	author = {Thurberg, Beth L and Fallon, John T and Mitchell, Richard and Aretz, Thomas and Gordon, Ronald E and O'Callaghan, Michael W},
	month = may,
	year = {2009},
	pmid = {19414635},
	keywords = {Adolescent, Adult, Biopsy, Capillaries, Clinical Trials, Phase III as Topic, Coronary Artery Disease, Coronary Disease, Double-Blind Method, Endocardium, Endothelium, Vascular, Fabry Disease, Female, Humans, Inclusion Bodies, Lysosomes, Male, Microcirculation, Myocytes, Cardiac, Randomized Controlled Trials as Topic, Recombinant Proteins, Trihexosylceramides, Young Adult, alpha-Galactosidase},
	pages = {2561--2567},
}

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