{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:55:09Z","timestamp":1787018109482,"version":"build-2736575974"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,2,18]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The clinical impact of enzyme replacement therapy on advanced Fabry disease cardiomyopathy appears to be limited. The pathologic mechanisms involved are still unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Ten male patients with advanced Fabry disease cardiomyopathy on enzyme replacement therapy, whose disease progressed from maximal wall thickness of 15.4\u00b12.2 to 19.3\u00b12.1\u2009mm in 8.6\u00b11.4\u2009years of follow\u2010up, underwent left ventricular endomyocardial biopsy before and 4\u2009hours after \u03b2\u2010agalsidase infusion (1\u2009mg\/kg). Comparative studies between pre\u2010 and postinfusion samples included the following: histology, electron microscopy and assessment of myocardial \u03b1\u2010galactosidase A activity; immunohistochemistry for \u03b1\u2010galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; and ultrastructural immunogold analysis with anti\u2010\u03b1\u2010galactosidase A ab; and Western blot quantification of mannose\u20106\u2010phosphate receptors. Controls were surgical biopsies from patients with mitral stenosis. Histologic and ultrastructural evaluation showed myocarditis in 7 of 10 patients, There was no removal of storage material while myocardial fibrosis was 9.8%\u00b16.8% versus 3.8%\u00b12.0% of controls. At ultrastructural immunogold analysis, myocardial \u03b1\u2010galactosidase A activity increased in postinfusion samples by overall 1.89\u2010fold. Alpha\u2010galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in postinfusion samples. Immunogold particles increased by 1.33\u2010fold (17.6\u00b13.6 preinfusion versus 21.5\u00b15.9 postinfusion), remaining far from normal controls (86.9\u00b16.6). Protein analysis showed mannose\u20106\u2010phosphate receptors to be 81% lower than in a normal heart.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">In spite of enzyme delivery to cardiac tissue, our study shows a low accessibility to enzyme replacement therapy of cardiomyocytes affected by advanced Fabry disease cardiomyopathy. It is sustained by myocardial fibrosis, inflammation, and severe down\u2010regulation of mannose\u20106\u2010phosphate receptors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.036815","type":"journal-article","created":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T05:31:31Z","timestamp":1738992691000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Fabry Cardiomyopathy: Myocardial Fibrosis, Inflammation, and Down\u2010Regulation of Mannose\u20106\u2010Phosphate Receptors Cause Low Accessibility to Enzyme Replacement Therapy"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5748-0725","authenticated-orcid":false,"given":"Andrea","family":"Frustaci","sequence":"first","affiliation":[{"name":"Cellular and Molecular Cardiology Lab IRCCS L. Spallanzani Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-567X","authenticated-orcid":false,"given":"Romina","family":"Verardo","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Cardiology Lab IRCCS L. Spallanzani Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9883-0114","authenticated-orcid":false,"given":"Michele","family":"Magnocavallo","sequence":"additional","affiliation":[{"name":"Arrhythmology Unit Ospedale Fatebenefratelli Isola Tiberina\u2010Gemelli Isola Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5250-1362","authenticated-orcid":false,"given":"Emanuela","family":"Frustaci","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome Italy"},{"name":"Technoscience, Parco Scientifico e Tecnologico Pontino Latina Italy"},{"name":"MEBIC Consortium and IRCCS San Raffaele Roma Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-6015","authenticated-orcid":false,"given":"Matteo Antonio","family":"Russo","sequence":"additional","affiliation":[{"name":"MEBIC Consortium and IRCCS San Raffaele Roma Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5954-3796","authenticated-orcid":false,"given":"Cristina","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Respiratory, Nephrologic Anesthesiologic and Geriatric Sciences Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","first-page":"157","article-title":"Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. 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