Challenging the Conventional Treatment Initiation Paradigm: Early Detection of Irreversible Cellular Damage in Cardiac Biopsies of Fabry Disease Before the Formation of Gb3 Inclusion Bodies

Background: Fabry disease (FD) is a lysosomal storage disorder impacting multiple organs, including the heart. We investigated whether early-stage globotriaosylceramide (Gb3) accumulation, before occurrence of inclusion bodies, could cause significant stress and irreversible damages of the cardiomyocytes in FD patients. To assess the cellular stress and irreversible damage of cardiomyocytes in FD during early-stage Gb3 accumulation before the occurrence of typical pathology. Methods: Immunofluorescent (IF) staining or Western blotting were performed on fibroblasts from FD patients and myocardial biopsies from G3Stg/GLAko mice and FD patients. Notably, all biopsies exhibited detectable Gb3 accumulation under IF but lacked typical FD (Gb3 inclusion body) pathology. Staining targeted nuclear factor-κB (NF-κB), interleukin-18 (IL-18), phospho-p42/44 mitogen-activated protein kinase (MAPK), and inducible nitric oxide synthase (iNOS) as inflammatory and oxidative stress markers. Alpha-smooth muscle actin (α-SMA) IF staining was conducted to detect myofibroblasts. Results: Fibroblasts from FD patients, in conjunction with cardiomyocytes from both G3Stg/GLAko mice and FD patients, exhibited significant accumulation of inflammatory markers such as NF-κB IL-18 and phospho-p42/44 MAPK, as well as the oxidative stress marker iNOS. Despite the absence of typical FD pathology, the presence of fibrosis was confirmed in myocardial biopsies from these patients through strong positive staining of α-SMA. Conclusions: Significant cellular stress and even irreversible damage may occur before the onset of typical pathological changes in cardiomyocytes of FD. Based on our findings, treatment should be initiated much earlier than we currently thought to prevent irreversible damage and improve the prognosis of FD patients.