Early Potentially Irreversible Cardiac Damage in Fabry Disease Precedes Gb3 Inclusion Body Formation.

Abstract

Background: Fabry disease (FD) is a lysosomal storage disorder impacting multiple organs, including the heart. In this study we investigated whether early-stage globotriaosylceramide (Gb3) accumulation, occurring before the formation of inclusion bodies, could cause significant stress and potentially irreversible damage of the cardiac tissue in patients with FD.

Methods: Immunofluorescent staining and Western blotting were performed on fibroblasts from FD IVS4 patients and myocardial biopsies from G3Stg/GLAko mice as well as 3 IVS4 patients (aged 44, 37, and 41 years). Notably, all biopsies showed detectable Gb3 accumulation under immunoflourescence (IF) but lacked the typical pathology of FD (Gb3 inclusion bodies). Staining targeted nuclear factor-kappaB (NF-κB), interleukin-18 (IL-18), phospho-p42/44 mitogen-activated protein kinase (MAPK), and inducible nitric oxide synthase (iNOS) as markers of inflammation and oxidative stress. In addition, α-smooth muscle actin (α-SMA) IF staining was conducted to identify myofibroblasts.

Results: Fibroblasts from FD patients, along with cardiac tissues 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 fibrogenesis was confirmed in myocardial biopsies from these patients through strong positive staining of α-SMA.

Conclusions: Significant cellular stress and potential irreversible damage may occur before the onset of typical pathologic changes in the cardiac tissues of FD patients. Our findings raise an intriguing question: Should enzyme replacement therapy be initiated much earlier than currently recommended? To answer this, validation through rigorous randomized controlled trials is needed to draw definitive conclusions.