Modeling Long-QT Syndromes with iPS Cells

  • Daniel SinneckerEmail author
  • Alexander Goedel
  • Tatjana Dorn
  • Ralf J. Dirschinger
  • Alessandra Moretti
  • Karl-Ludwig Laugwitz


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.


LQT Long-QT syndrome Disease modeling iPS cells Reprogramming 



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).


  1. 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. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Dessertenne F. (1966) La tachycardie ventriculaire à deux foyers opposés variables. Arch Mal Coeur, 59, 263–72.Google Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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. 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.PubMedCrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Keller, G. M. (1995). In vitro differentiation of embryonic stem cells. Current Opinion in Cell Biology, 7(6), 862–869.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Mummery, C. (2010). Sorting cardiomyocytes: a simple solution after all? Nat. Meth., 7, 40–42.CrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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. 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. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Daniel Sinnecker
    • 1
    Email author
  • Alexander Goedel
    • 1
  • Tatjana Dorn
    • 1
  • Ralf J. Dirschinger
    • 1
  • Alessandra Moretti
    • 1
  • Karl-Ludwig Laugwitz
    • 1
  1. 1.I. Medizinische Klinik Kardiologie, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

Personalised recommendations