Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells

Int J Cardiol. 2013 Oct 15;168(6):5277-86. doi: 10.1016/j.ijcard.2013.08.015. Epub 2013 Aug 15.


Background: Type 3 long QT syndrome (LQT3) is the third most common form of LQT syndrome and is characterized by QT-interval prolongation resulting from a gain-of-function mutation in SCN5A. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of LQT3, which could be used for future drug testing and development of novel treatments for this inherited disorder.

Methods and results: Dermal fibroblasts obtained from a patient with LQT3 harboring a SCN5A mutation (c.5287G>A; p.V1763M) were reprogrammed to hiPSCs via repeated transfection of mRNA encoding OCT-4, SOX-2, KLF-4, C-MYC and LIN-28. hiPSC-derived cardiomyocytes (hiPSC-CMs) were obtained via cardiac differentiation. hiPSC-CMs derived from the patient's healthy sister were used as a control. Compared to the control, patient hiPSC-CMs exhibited dominant mutant SCN5A allele gene expression, significantly prolonged action potential duration or APD (paced CMs of control vs. patient: 226.50 ± 17.89 ms vs. 536.59 ± 37.1 ms; mean ± SEM, p < 0.005), an increased tetrodotoxin (TTX)-sensitive late or persistent Na(+) current (control vs. patient: 0.65 ± 0.11 vs. 3.16 ± 0.27 pA/pF; n = 9, p < 0.01), a positive shift of steady state inactivation and a faster recovery from inactivation. Mexiletine, a NaV1.5 blocker, reversed the elevated late Na(+) current and prolonged APD in LQT3 hiPSC-CMs.

Conclusions: We demonstrate that hiPSC-CMs derived from a LQT3 patient recapitulate the biophysical abnormalities that define LQT3. The clinical significance of such an in vitro model is in the development of novel therapeutic strategies and a more personalized approach in testing drugs on patients with LQT3.

Keywords: Cardiomyocytes; Induced pluripotent stem cells; Long QT syndrome; SCN5A; Sodium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 3*
  • Dermis / cytology
  • Electrocardiography
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Genotype
  • Heart Arrest / genetics
  • Heart Arrest / physiopathology
  • Humans
  • Long QT Syndrome / genetics
  • Long QT Syndrome / physiopathology*
  • Membrane Potentials / physiology
  • Mexiletine / pharmacology
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology*
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • Patch-Clamp Techniques
  • Pluripotent Stem Cells / cytology*
  • Voltage-Gated Sodium Channel Blockers / pharmacology


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Voltage-Gated Sodium Channel Blockers
  • Mexiletine

Supplementary concepts

  • Long Qt Syndrome 3