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Modelling the long QT syndrome with induced pluripotent stem cells

Abstract

The ability to generate patient-specific human induced pluripotent stem cells (iPSCs)1,2,3 offers a new paradigm for modelling human disease and for individualizing drug testing4. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death5,6,7. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current IKr. Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, KATP-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.

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Figure 1: Establishment and characterization of type-2 LQTS human iPSCs (clone 1).
Figure 2: Phenotypic characterization of LQTS human iPSC-derived cardiac-tissue.
Figure 3: Whole-cell patch-clamp recording from human iPSC-CMs.
Figure 4: Drug screening using LQTS human iPSC-CMs.

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Acknowledgements

This study was supported in part by the Israel Science Foundation and Legacy Heritage Foundation (no. 1225/09), by the Yad Hanadiv Foundation Bruno Award, by the Lorry Lokey research fund, and by the Nancy and Stephen Grand Philanthropic Fund. We thank E. Suss-Toby and O. Shenker (from the multidisciplinary laboratory unit) and M. Tzukerman for their valuable help, A. Zamir for writing the MEA analysis software and I. Laevsky and T. Falik-Zaccai for the karyotype analysis.

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Authors

Contributions

I.I., L.M., I.H. and L.G. designed the experiments; I.I., L.M., I.H., L.Z.-D., O.C., A.W., O.F., A.G. and G.A performed the experiments; I.I. and L.M. analysed and interpreted the electrophysiological data; M.B. and H.H. performed the clinical assessment; L.G wrote the manuscript; all authors read and approved the manuscript; and L.G. supervised this research work.

Corresponding author

Correspondence to Lior Gepstein.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Tables 1-3 and Supplementary Figures 1-14 with legends. (PDF 7906 kb)

Supplementary Movie 1

This movie shows the spontaneous contraction of the healthy-control and LQTS human iPSC-derived cardiac tissues. Note the prolonged contraction time of the human iPSC-derived cardiac tissue. (MOV 5000 kb)

Supplementary Movie 2

This movie shows arrhythmogenic activity in the LQTS human iPSC-derived cardiac tissue. Note the appearance of a premature triggered contraction after the third beat. (MOV 1348 kb)

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Itzhaki, I., Maizels, L., Huber, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011). https://doi.org/10.1038/nature09747

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