Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
June-Wha Rhee,
Hyoju Yi,
Dilip Thomas,
Chi Keung Lam,
Nadjet Belbachir,
Lei Tian,
Xulei Qin,
Jessica Malisa,
Edward Lau,
David T. Paik,
Youngkyun Kim,
Beatrice SeungHye Choi,
Nazish Sayed,
Karim Sallam,
Ronglih Liao,
Joseph C. Wu
Affiliations
June-Wha Rhee
Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA
Hyoju Yi
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Dilip Thomas
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Chi Keung Lam
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Nadjet Belbachir
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Lei Tian
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Xulei Qin
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Jessica Malisa
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Edward Lau
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
David T. Paik
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Youngkyun Kim
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Beatrice SeungHye Choi
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Nazish Sayed
Stanford Cardiovascular Institute, Stanford, CA 94305, USA
Karim Sallam
Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA
Ronglih Liao
Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA
Joseph C. Wu
Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA 94305, USA; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA; Corresponding author
Summary: 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.
