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Modeling Long-QT Syndromes with iPS Cells

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Abstract

The generation of induced pluripotent stem cells (iPSC) from human somatic cells bears the possibility to generate patient-specific stem cell lines which can serve as a theoretically unlimited source of somatic cells carrying the genotype of the patients. Different types of the long-QT syndrome have been studied by analyzing the phenotype of cardiomyocytes generated from patient-specific iPSC lines. Major aspects of the pathophysiology of long-QT syndrome, like prolonged action potentials, arrhythmia, and the effects of pro- and antiarrhythmic drugs could be recapitulated in these cells. In the future, patient-specific iPSC-derived cardiomyocytes might be used to screen for new drugs, to avoid unwanted drug side effects, and to deepen our understanding on the pathophysiology of long-QT syndromes.

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References

  1. Ackerman, M. J., & Clapham, D. E. (2004). Excitability and Conduction. In K. R. Chen (Ed.), Molecular basis of cardiovascular disease: a companion to Braunwald’s heart disease (2nd ed.). Philadelphia, USA: Saunders an Imprint of Elsevier.

    Google Scholar 

  2. Casimiro, M. C., Knollmann, B. C., Ebert, S. N., Vary, J. C., Jr., Greene, A. E., Franz, M. R., Grinberg, A., Huang, S. P., & Pfeifer, K. (2001). Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange–Nielsen syndrome. Proc. Natl. Acad. Sci. USA, 98(5), 2526–2531.

    Article  PubMed  CAS  Google Scholar 

  3. Dessertenne F. (1966) La tachycardie ventriculaire à deux foyers opposés variables. Arch Mal Coeur, 59, 263–72.

    Google Scholar 

  4. Ebert, A. D., Yu, J., Rose, F. F., Jr., Mattis, V. B., Lorson, C. L., Thomson, J. A., & Svendsen, C. N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457, 277–280.

    Article  PubMed  CAS  Google Scholar 

  5. Egashira, T., Yuasa, S., Suzuki, T., Aizawa, Y., Yamakawa, H., Matsuhashi, T., Ohno, Y., Tohyama, S., Okata, S., Seki, T., Kuroda, Y., Yae, K., Hashimoto, H., Tanaka, T., Hattori, F., Sato, T., Miyoshi, S., Takatsuki, S., Murata, M., Kurokawa, J., Furukawa, T., Makita, N., Aiba, T., Shimizu, W., Horie, M., Kamiya, K., Kodama, I., Ogawa, S., & Fukuda, K. (2012). Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovascular Research. doi:10.1039/cvr/cvs206.

  6. Fujiwara, M., Yan, P., Otsuji, T. G., Narazaki, G., Uosaki, H., Fukushima, H., Kuwahara, K., Harada, M., Matsuda, H., Matsuoka, S., Okita, K., Takahashi, K., Nakagawa, M., Ikeda, T., Sakata, R., Mummery, C. L., Nakatsuji, N., Yamanaka, S., Nakao, K., & Yamashita, J. K. (2011). Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS One, 6(2), e16734.

    Article  PubMed  CAS  Google Scholar 

  7. Giorgi, M. A., Bolanos, R., Gonzalez, C. D., & Di Girolamo, G. (2010). QT interval prolongation: preclinical and clinical testing arrhythmogenesis in drugs and regulatory implications. Curr. Drug Safety, 5, 54–57.

    Article  Google Scholar 

  8. Hattori, F., Chen, H., Yamashita, H., Tohyama, S., Satoh, Y. S., Yuasa, S., Li, W., Yamakawa, H., Tanaka, T., Onitsuka, T., Shimoji, K., Ohno, Y., Egashira, T., Kaneda, R., Murata, M., Hidaka, K., Morisaki, T., Sasaki, E., Susuki, T., Sano, M., Makino, S., Oikawa, S., & Fukuda, K. (2010). Nongenetic method for purifying stem cell-derived cardiomyocytes. Nature Methods, 7, 61–66.

    Article  PubMed  CAS  Google Scholar 

  9. Itzhaki, I., Maizels, L., Huber, I., Zwi-Dantsis, L., Caspi, O., Winterstern, A., Feldman, O., Gepstein, A., Arbel, G., Hammerman, H., Boulos, M., & Gepstein, L. (2011). Modelling the long-QT syndrome with induced pluripotent stem cells. Nature, 471(7337), 225–229.

    Article  PubMed  CAS  Google Scholar 

  10. Jung, C. B., Moretti, A., Mederos, Y., Schnitzler, M., Iop, L., Storch, U., Bellin, M., Dorn, T., Ruppenthal, S., Pfeiffer, S., Goedel, A., Dirschinger, R. J., Seyfarth, M., Lam, J. T., Sinnecker, D., Gudermann, T., Lipp, P., & Laugwitz, K.-L. (2011). Dantrolene rescues arrhythmogenic RYR defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Molecular Medicine, 4, 180–191.

    Article  Google Scholar 

  11. Kannankeril, P. J., Roden, D. M., Norris, K. J., Whalen, S. P., George, A. L., Jr., & Murray, K. T. (2005). Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart Rhythm, 2(2), 134–140.

    Article  PubMed  Google Scholar 

  12. Keller, G. M. (1995). In vitro differentiation of embryonic stem cells. Current Opinion in Cell Biology, 7(6), 862–869.

    Article  PubMed  CAS  Google Scholar 

  13. Kong, C. W., Akar, F. G., & Li, R. A. (2010). Translational potential of human embryonic and induced pluripotent stem cells for myocardial repair: insights from experimental models. Thrombosis and Haemostasis, 104, 30–38.

    Article  PubMed  CAS  Google Scholar 

  14. Lahti, A. L., Kujala, V. J., Chapman, H., Koivisto, A.-P., Pekkanen-Mattila, M., Kerkelä, E., Hyttinen, J., Kontula, K., Swan, H., Conklin, B. R., Yamanaka, S., Silvennoinen, O., & Aalto-Setälä, K. (2012). Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Disease Models & Mechanisms, 5, 220–230.

    Article  CAS  Google Scholar 

  15. Lasser, K. E., Allen, P. D., Woolhandler, S. J., Himmelstein, D. U., Wolfe, S. M., & Bor, D. H. (2002). Timing of new black box warnings and withdrawals for prescription medications. JAMA, 287, 2215–2220.

    Article  PubMed  Google Scholar 

  16. Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., & Studer, L. (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature, 461, 402–406.

    Article  PubMed  CAS  Google Scholar 

  17. Lee, M. P., Ravenel, J. D., Hu, R.-J., Lustig, L. R., Tomaselli, G., Berger, R. D., Brandenburg, S. A., Litzi, T. J., Bunton, T. E., Limb, C., Francis, H., Gorelikow, M., Gu, H., Washington, K., Argani, P., Goldenring, J. R., Coffey, R. J., & Feinberg, A. P. (2000). Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. The Journal of Clinical Investigation, 106, 1447–1455.

    Article  PubMed  CAS  Google Scholar 

  18. Lehnart, S. E., Ackerman, M. J., Benson, W., Brugada, R., Clancy, C. E., Donahue, J. K., George, A. L., Jr., Grant, A. O., Groft, S. C., January, C. T., Lathrop, D. A., Lederer, J., Makielski, J. C., Mohler, P. J., Moss, A., Nerbonne, J. M., Olson, T. M., Przywara, D. A., Towbin, J. A., Wang, L.-H., & Marks, A. R. (2007). Inherited arrhythmias. A national heart, lung, and blood institute and office of rare diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation, 116, 2325–2345.

    Article  PubMed  CAS  Google Scholar 

  19. Malan, D., Friedrichs, S., Fleischmann, B. K., & Sasse, P. (2011). Cardiomyocytes obtained from induced pluripotent stem cells with long-QT syndrome 3 recapitulate typical disease-specific features in vitro. Circulation Research, 109, 841–847.

    Article  PubMed  CAS  Google Scholar 

  20. Matsa, E., Rajamohan, D., Dick, E., Young, L., Mellor, I., Stainforth, A., & Denning, C. (2011). Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long-QT syndrome type 2 mutation. European Heart Journal, 32(8), 952–962.

    Article  PubMed  CAS  Google Scholar 

  21. Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flügel, L., Dorn, T., Goedel, A., Höhnke, C., Hofmann, F., Seyfarth, M., Sinnecker, D., Schömig, A., & Laugwitz, K.-L. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. The New England Journal of Medicine, 363(15), 1397–1409.

    Article  PubMed  CAS  Google Scholar 

  22. Mummery, C. (2010). Sorting cardiomyocytes: a simple solution after all? Nat. Meth., 7, 40–42.

    Article  CAS  Google Scholar 

  23. Nerbonne, J. M., Nichols, C. G., Schwarz, T. L., & Escande, D. (2001). Genetic manipulation of cardiac K + channel function in mice. What we have learned, and where do we go from here? Circulation Research, 89, 944–956.

    Article  PubMed  CAS  Google Scholar 

  24. Shafa, M., Sjonesen, K., Yamashita, A., Liu, S., Michalak, M., Kallos, M. S., & Rancourt, D. E. (2011). Expansion and long-term maintenance of induced pluripotent stem cells in stirred suspension bioreactors. Journal of Tissue Engineering and Regenerative Medicine. doi:10.1002/term.450.

  25. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. & Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–72.

    Google Scholar 

  26. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.

    Article  PubMed  CAS  Google Scholar 

  27. Wu, G., Ai, T., Kim, J. J., Mohapatra, B., Xi, Y., Li, Z., Abbasi, S., Purevjav, E., Samani, K., Ackerman, M. J., Qi, M., Moss, A. J., Shimizu, W., Towbin, J. A., Cheng, J., & Vatta, M. (2008). α 1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circulation. Arrhythmia and Electrophysiology, 1(3), 193–201.

    Article  PubMed  CAS  Google Scholar 

  28. Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H. B., Ellinor, P. T., Gao, L., Lin, X., Li, L., Wang, L., Xiao, J., Liu, Y., Liu, Y., Zhang, S., Liang, D., Peng, L., Jespersen, T., & Chen, Y.-H. (2010). Identification of a Kir3.4 mutation in congenital long QT syndrome. American Journal of Human Genetics, 86, 872–880.

    Article  PubMed  CAS  Google Scholar 

  29. Yazawa, M., Hsue, B., Jia, X., Pasca, A., Bernstein, J. A., Hallmayer, J., & Dolmetsch, R. E. (2011). Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature, 471(7337), 230–234.

    Article  PubMed  CAS  Google Scholar 

  30. Ye, L., Chang, J. C., Lin, C., Sun, X., Yu, J., & Kan, Y. W. (2009). Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proc Natl Acad Sci USA, 106(24), 9826–9830.

    Article  PubMed  CAS  Google Scholar 

  31. Yu, J., Vodyanìk, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., & Thomson, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang, J., Wilson, G. F., Soerens, A. G., Koonce, C. H., Yu, J., Palecek, S. P., Thomson, J. A., & Kamp, T. J. (2009). Functional cardiomyocytes derived from human induced pluripotent stem cells. Circulation Research, 104, e30–e41.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the European Research Council (ERC 261053-CHD-iPS) and the German Research Foundation (La 1238/3-1/4-1, Si 1747/1-1).

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Authors and Affiliations

  1. I. Medizinische Klinik Kardiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675, Munich, Germany

    Daniel Sinnecker, Alexander Goedel, Tatjana Dorn, Ralf J. Dirschinger, Alessandra Moretti & Karl-Ludwig Laugwitz

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  1. Daniel Sinnecker
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  2. Alexander Goedel
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Correspondence to Daniel Sinnecker.

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Sinnecker, D., Goedel, A., Dorn, T. et al. Modeling Long-QT Syndromes with iPS Cells. J. of Cardiovasc. Trans. Res. 6, 31–36 (2013). https://doi.org/10.1007/s12265-012-9416-1

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  • DOI: https://doi.org/10.1007/s12265-012-9416-1

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