Complement and cardiac MRI biomarkers in Fabry disease cardiomyopathy

Abstract

Introduction: Fabry disease (FD) is a lysosomal storage disorder caused by alpha-galactosidase A deficiency, leading to globotriaosylceramide (Gb3) accumulation. Cardiomyopathy is the leading cause of FD-related mortality, yet its pathophysiology remains unclear. Current treatments have limited efficacy once left ventricular hypertrophy (LVH) develops, suggesting additional mechanisms such as inflammation. Complement-mediated inflammation, implicated in other lysosomal storage disorders (e.g., Gaucher disease),(1) may also contribute to FD cardiomyopathy. Purpose(s): This study investigated inflammatory biomarkers associated with FD cardiomyopathy and their relationship with cardiac magnetic resonance (CMR) markers of disease severity to improve early diagnosis and intervention. Method(s): A total of 147 Fabry patients (58% female, 45 +/-14 years, 43% LVH-positive; 42% ERT), 41 apical hypertrophic cardiomyopathy (aHCM) patients (75% male, 55 +/-13 years), and 82 healthy controls (46% female, 51 +/-18 years) with paired plasma and CMR were included. Prior targeted proteomic studies guided mass spectrometry-based biomarker profiling.(2) A validated AI tool assessed Left ventricular volumetrics and wall thickness.(3) A subset of Fabry patients (n=72) underwent comprehensive CMR analysis (GLS, T1/T2, LGE). Biomarkers were compared across cohorts using ANOVA with Dunnett's post hoc testing. Correlations with myocardial parameters were assessed using Pearson's coefficient and regression modelling. Sex differences in statistically significant complement biomarkers were analysed within the FD group using t-tests. Result(s): Of 146 biomarkers, 53 were statistically significant. Fabry LVH showed complement activation via classical (C3, C4b, C4d) and alternative: complement factor D (CFD) pathways, amplified by immune complexes (IGHA1, IGHG2, IGHG3), distinct from aHCM, which exhibited predominantly extracellular matrix remodelling (Talin, NGAL, Versican, ECM1), fig 1. Complement activation was also present in Fabry patients without LVH, suggesting a pre-hypertrophy inflammatory phase. C3 and C4d were the only biomarkers differing between sexes in the LVH group (p<0.05), with higher complement levels in females, fig 2. GLS correlated with CFD (r= 0.40, p<0.05) and IGHG3 (-0.31, p<0.05), indicating a role for innate immunity in early myocardial dysfunction. While T1 mapping showed no significant correlations, T2 correlated with inflammatory markers (A2M, AGT). C3 was the only biomarker differing between LGE-positive and negative groups (p<0.05). Conclusion(s): CMR detects early myocardial dysfunction in FD before hypertrophy, correlating with complement activation. These findings suggest revising the current staging model (4) to include a subclinical inflammatory phase. Complement-targeted therapies may enable early intervention, while CMR and biomarker analysis could facilitate early detection, risk stratification, and LVH prevention.