Treatment of Patients with Long-QT Syndrome: Differentiation of Patient-Derived Induced Pluripotent Stem Cells into Functional Cardiac Myocytes

  • Daniel Sinnecker
  • Tatjana Dorn
  • Ralf J. Dirschinger
  • Alexander Goedel
  • Alessandra Moretti
  • Karl-Ludwig Laugwitz
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 9)


The long-QT syndrome, which can be inherited (e.g. due to mutations in genes encoding cardiac ion channels) or acquired (e.g. due to the application of certain drugs), is characterized by a prolonged QT interval in the ECG which is caused by prolonged action potentials of single cardiomyocytes. Affected patients are susceptible to ventricular arrhythmias like torsades de pointes, which lead to palpitations, syncopes, or even sudden cardiac death. Induced pluripotent stem cell lines generated from skin fibroblasts of patients affected by congenital long-QT syndromes can be ­differentiated to cardiomyocytes, in which the pathophysiology of the disease can be studied in vitro. These patient-specific cardiomyocytes recapitulate typical features of the disease like a prolonged action potential duration, a defect of the physiological shortening of the action potential duration under conditions of increased heart rate, and a susceptibility to arrhythmogenic early afterdepolarizations. Moreover, the therapeutic effect of beta receptor antagonists can be recapitulated in vitro in these cells. Such patient-specific induced pluripotent stem cell models of the long-QT syndrome might be used in the future to screen for new drugs, to avoid unwanted drug side effects, and to individualize drug therapy.


Action Potential Duration iPSC Line Cardiac Action Potential Delay Rectifier Potassium Current Catecholamine Stimulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Antzelevitch C (2005) Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes. Heart Rhythm 2(2 Suppl):S9–S15PubMedCrossRefGoogle Scholar
  2. Brown ME, Rondon E, Rajesh D, Mack A, Lewis R, Feng X, Zitur LJ, Learish RD, Nuwaysir EF (2010) Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes. PLoS One 5(6):e11373PubMedCrossRefGoogle Scholar
  3. Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, 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):2526–2531PubMedCrossRefGoogle Scholar
  4. Demolombe S, Lande G, Charpentier F, van Roon MA, van den Hoff MJB, Toumaniantz G, Baro I, Guihard G, Le Berre N, Corbier A, de Bakker J, Opthof T, Wilde A, Moorman AFM, Escande D (2001) Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: phenotypic characterisation. Cardiovasc Res 50:314–327PubMedCrossRefGoogle Scholar
  5. Dessertenne F (1966) La tachycardie ventriculaire à deux foyers opposés variables. Arch Mal Coeur Vaiss 59:263–272PubMedGoogle Scholar
  6. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280PubMedCrossRefGoogle Scholar
  7. Eckardt L, Haverkamp W, Borggrefe M, Breithardt G (1998) Experimental models of torsade de pointes. Cardiovasc Res 39:178–193PubMedCrossRefGoogle Scholar
  8. 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):225–229PubMedCrossRefGoogle Scholar
  9. Kannankeril PJ, Roden DM, Norris KJ, Whalen SP, George AL Jr, Murray KT (2005) Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart Rhythm 2(2):134–140PubMedCrossRefGoogle Scholar
  10. Keller GM (1995) In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 7(6):862–869PubMedCrossRefGoogle Scholar
  11. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH (2002) Timing of new black box warnings and withdrawals for prescription medications. JAMA 287:2215–2220PubMedCrossRefGoogle Scholar
  12. Lee MP, Ravenel JD, Hu R-J, Lustig LR, Tomaselli G, Berger RD, Brandenburg SA, Litzi TJ, Bunton TE, Limb C, Francis H, Gorelikow M, Gu H, Washington K, Argani P, Goldenring JR, Coffey RJ, Feinberg AP (2000) Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest 106:1447–1455PubMedCrossRefGoogle Scholar
  13. Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, 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 461:402–406PubMedCrossRefGoogle Scholar
  14. Lehnart SE, Ackerman MJ, Benson W, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, January CT, Lathrop DA, Lederer J, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, Wang L-H, Marks AR (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 116:2325–2345PubMedCrossRefGoogle Scholar
  15. London B (2001) Cardiac arrhythmias: from (transgenic) mice to men. J Cardiovasc Electrophysiol 12(9):1089–1091PubMedCrossRefGoogle Scholar
  16. 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. Eur Heart J 32(8):952–962PubMedCrossRefGoogle Scholar
  17. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, 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. N Engl J Med 363(15):1397–1409PubMedCrossRefGoogle Scholar
  18. Nerbonne JM, Nichols CG, Schwarz TL, Escande D (2001) Genetic manipulation of cardiac K  +  channel function in mice. What we have learned, and where do we go from here? Circ Res 89:944–956PubMedCrossRefGoogle Scholar
  19. Novak A, Shtrichman R, Germanguz I, Segev H, Zeevi-Levin N, Fishman B, Mandel YE, Barad L, Domev H, Kotton D, Mostoslavsky G, Binah O, Itskovitz-Eldor J (2010) Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram 12(6):665–678PubMedCrossRefGoogle Scholar
  20. Peal DS, Mills RW, Lynch SN, Mosley JM, Lim E, Ellinor PT, January CT, Peterson RT, Milan DJ (2011) Novel chemical suppressors of long QT syndrome identified by an in vivo functional screen. Circulation. doi: 10.1161/CIRCULATIONAHA.110.003731
  21. Salama G, London B (2007) Mouse models of long-QT syndrome. J Physiol 578(1):43–53PubMedCrossRefGoogle Scholar
  22. Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299–307PubMedCrossRefGoogle Scholar
  23. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AAM, Toivonen L, Zareba W, Robinson J, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R (2001) Genotypephenotype correlation in the long QT syndrome. Gene-specific triggers for life-threatening arrhythmias. Circulation 103:89–95PubMedCrossRefGoogle Scholar
  24. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C (2009) Prevalence of the congenital long-QT syndrome. Circulation 120:1761–1767PubMedCrossRefGoogle Scholar
  25. Sidhu KS (2011) New approaches for the generation of induced pluripotent stem cells. Expert Opin Biol Ther 11(5):569–579PubMedCrossRefGoogle Scholar
  26. Strasser BJ (1999) Molecular medicine: sickle cell anemia, a molecular disease. Science 286:1488–1490PubMedCrossRefGoogle Scholar
  27. Studenik CR, Zhou Z, January CT (2001) Differences in action potentials and early afterdepolarization properties in LQT2 and LQT3 models of long-QT syndrome. Br J Pharmacol 132:85–92PubMedCrossRefGoogle Scholar
  28. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRefGoogle Scholar
  29. Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107:1912–1916PubMedCrossRefGoogle Scholar
  30. 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(5):861–872PubMedCrossRefGoogle Scholar
  31. Tran TH, Wang X, Browne C, Zang Y, Schinke M, Izumo S, Burcin M (2009) Wnt3a-induced mesoderm formation and cardiomyogenesis in human embryonic stem cells. Stem Cells 27:1869–1878PubMedCrossRefGoogle Scholar
  32. Wu G, Ai T, Kim JJ, Mohapatra B, Xi Y, Li Z, Abbasi S, Purevjav E, Samani K, Ackerman MJ, Qi M, Moss AJ, Shimizu W, Towbin JA, Cheng J, Vatta M (2008) α-1-Syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol 1(3):193–201PubMedCrossRefGoogle Scholar
  33. Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, Olesen S-P, Rasmussen HB, Ellinor PT, 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. Am J Hum Genet 86:872–880PubMedCrossRefGoogle Scholar
  34. Yazawa M, Hsue B, Jia X, Pasca A, Bernstein JA, Hallmayer J, Dolmetsch RE (2011) Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471(7337):230–234PubMedCrossRefGoogle Scholar
  35. Ye L, Chang JC, Lin C, Sun X, Yu J, Kan YW (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):9826–9830PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Daniel Sinnecker
    • 1
  • Tatjana Dorn
    • 1
  • Ralf J. Dirschinger
    • 1
  • Alexander Goedel
    • 1
  • Alessandra Moretti
    • 1
  • Karl-Ludwig Laugwitz
    • 1
  1. 1.Cardiology Division, First Department of Medicine and German Heart Center Munich, Kilinikim recht der IsarTechnological University of MunichMunichGermany

Personalised recommendations