Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation

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.

Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients

“…After the cardiac differentiation, these differentiated cardiomyocytes (FC-iPSC-CMs) all exhibited CM-like phenotypes ( Figure 2 A) and the expression of cardiac-specific markers, including α-actinin and MYL2, at post-induction 30 days ( Figure 2 B). Comparing with Ctrl-iPSC-CMs, the microscopic examination of all FC-iPSC-CMs revealed remarkable cellular hypertrophy, as described previously [ 31 , 32 ]. Moreover, during differentiation, the mRNA and protein expression levels of GLA ( Figure 2 C,D), as well as the enzyme activity of GLA ( Figure 2 E), were all declined and reached the maximal decrease at day 60 post-induction.…”

“…In Taiwan Fabry cohorts with high incidence of IVS4+919 G>A mutation and later-onset cardiac phenotype, the mechanisms that contribute to development of FC in such cardiac variant remained poorly understood. We previously demonstrated that neutralization of interleukin-18 effectively ameliorated the cardiomyocyte hypertrophy in FC-iPSC-CMs from Fabry patients with IVS4+919 G>A mutation [ 32 ]. Chou et al further reported that conventional ERT did not modify the impaired energy utilization in FC-iPSC-CMs carrying IVS4+919 G>A mutation [ 31 ].…”

A Novel α-Galactosidase A Splicing Mutation Predisposes to Fabry Disease

“…Many GLA splicing mutations have also been described in case reports, but only the deep intronic mutation c.639 + 919 G > A was well studied (Ishii et al, 2002; Chien et al, 2016; Palhais et al, 2016; Chang et al, 2017; Chiang et al, 2017). In the present study, we identified a novel splicing mutation in a FD patient in which the first nucleotide of GLA intron 5 is changed from G to A.…”

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy

“…All patients with FD in our study were patients with a known intronic mutation, IVS4 + 919G > A. This mutation is documented to have a high frequency in Taiwan and mainland Chinese populations and has been linked to late-onset FD [38][39][40][41]. Up to 80% of FD incidence in Taiwan can be accounted for by this specific mutation.…”