title: 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: BACKGROUND
  A 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.
  
  
  OBJECTIVE
  Using 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
  The 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Chian-Shiu
authors.initials: CS
authors.lastname: Chien
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Huai-Chih
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Anatomy and Cell Biology, Taipei, Taiwan.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Huang
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Shih-Jie
authors.initials: SJ
authors.lastname: Chou
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University and Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Pharmacology, Taipei, Taiwan.
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Taipei, Taiwan.
authors.forename: Hsin-Bang
authors.initials: HB
authors.lastname: Leu
authors.affiliation: Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Taipei, Taiwan.
authors.forename: Kuan-Hsuan
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Taipei, Taiwan.
authors.forename: Kang-Ling
authors.initials: KL
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medicine, Taipei, Taiwan.
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Lai
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, Taipei, Taiwan.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Medical Research, Cheng-Hsin Hospital, Taipei, Taiwan.
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Anatomy and Cell Biology, Taipei, Taiwan.
authors.forename: Hsin-Yang
authors.initials: HY
authors.lastname: Li
authors.affiliation: Institute of Anatomy and Cell Biology, Taipei, Taiwan.
authors.forename: Yen-Jen
authors.initials: YJ
authors.lastname: Sung
authors.affiliation: College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan.
authors.forename: Yann-Jang
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Yu
mesh_terms: D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: C000589760:IL18 protein, human; D020382:Interleukin-18; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: IL-18; enzyme replacement therapy; fabry cardiomyopathy; iPSC