Abstract
RationaleA high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown.ObjectiveUsing FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC.Results and methodsThe iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients’ sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs.ConclusionOur data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.
Highlights
Fabry disease, resulting from deficiency of α-galactosidase A (α-Gal A) enzyme activity, is an lysosomal storage disorder of glycosphingolipids metabolism and leads to accumulation of glycosphingolipids, globotriaosylceramide in many tissues and cell types [1]
The induced pluripotent stem cell (iPSC)-differentiated cardiomyocytes derived from Fabry cardiomyopathy (FC)-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation
Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs
Summary
Fabry disease, resulting from deficiency of α-galactosidase A (α-Gal A) enzyme activity, is an lysosomal storage disorder of glycosphingolipids metabolism and leads to accumulation of glycosphingolipids, globotriaosylceramide in many tissues and cell types [1]. Enzyme replacement therapy (ERT) is currently the only effective therapy to reduce Gb3 accumulations in Fabry disease. It improves cardiac function and left ventricular mass, in patients with late phase Fabry cardiomyopathy (FC), ERT introduced a minor reduction in LVH and have not been able to improve myocardial performance [2]. Gb3 and globotriaosylsphingosine (lysoGb3) have high sensitivity and correlate with the severity of LVH in FC [3], recent reports have suggested that Gb3 and/or lyoGb3 might not be suitable biomarkers for monitoring the long-term therapeutic outcome of ERT and the progression of FC [4, 5], including that in Fabry patients carrying IVS4+919 G>A mutation [6]. The identification of pathogenic biomarkers for monitoring patient outcomes in FC, especially in FC patients with myocardial fibrosis, is an urgent need
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