Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

• Published in: Cell reports (Cambridge) 2020-07, Vol.32 (2), p.107886-107886, Article 107886
• Main Authors: Rhee, June-Wha, Yi, Hyoju, Thomas, Dilip, Lam, Chi Keung, Belbachir, Nadjet, Tian, Lei, Qin, Xulei, Malisa, Jessica, Lau, Edward, Paik, David T., Kim, Youngkyun, Choi, Beatrice SeungHye, Sayed, Nazish, Sallam, Karim, Liao, Ronglih, Wu, Joseph C.
• Format: Article
• Language: English
• Subjects: Arrhythmias, Cardiac - complications; Arrhythmias, Cardiac - physiopathology; Azoles - pharmacology; Calcium - metabolism; calcium handling; cardiac spheroids; cardiomyocytes; Cardiomyopathies - etiology; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cell Line; DMT1; ebselen; Electrophysiological Phenomena - drug effects; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; iPSC; Iron - metabolism; Iron Overload - complications; Iron Overload - pathology; iron overload cardiomyopathy; Isoindoles; Kinetics; Mitochondria - drug effects; Mitochondria - pathology; Models, Biological; Myocardial Contraction - drug effects; Myocytes, Cardiac - pathology; Organoselenium Compounds - pharmacology; Oxidative Stress - drug effects; Phenotype; Time Factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Transcriptome - drug effects; Transcriptome - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107886

Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload. [Display omitted] •Human iPSC-CMs recapitulate clinical features of iron overload cardiomyopathy•Iron overload impairs calcium kinetics leading to iPSC-CM contractile dysfunction•Ebselen, a selective DMT1 inhibitor, can prevent iron overload phenotypes Rhee et al. model iron overload cardiomyopathy in a dish using human iPSC-CMs. They find significantly altered calcium kinetics mediating contractile dysfunction and arrhythmia. Ebselen, a selective DMT1 inhibitor and antioxidant, effectively prevents the observed iron overload phenotypes and therefore may provide a promising therapeutic solution for iron overload cardiomyopathy.