Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.

Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation / Frustaci, A.; Scarpa, M.; Maria da Riol, R.; Agrati, C.; Finato, N.; Verardo, R.; Grande, C.; Chimenti, C.; Nora, C.; Russo, M. A.; Livi, U.. - In: ESC HEART FAILURE. - ISSN 2055-5822. - 7:3(2020), pp. 1331-1337. [10.1002/ehf2.12723]

Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation

Frustaci A.;Verardo R.;Grande C.;Chimenti C.;Russo M. A.;
2020

Abstract

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.
2020
cardiomiopathy; Fabry Disease; inflammation
01 Pubblicazione su rivista::01a Articolo in rivista
Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation / Frustaci, A.; Scarpa, M.; Maria da Riol, R.; Agrati, C.; Finato, N.; Verardo, R.; Grande, C.; Chimenti, C.; Nora, C.; Russo, M. A.; Livi, U.. - In: ESC HEART FAILURE. - ISSN 2055-5822. - 7:3(2020), pp. 1331-1337. [10.1002/ehf2.12723]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1412954
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