Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model

Ashish Mehta, Chrishan J.A. Ramachandra, Pritpal Singh, Anuja Chitre, Chong Hui Lua, Manuela Mura, Lia Crotti, Philip Wong, Peter J. Schwartz, Massimiliano Gnecchi, Winston Shim

Research output: Contribution to journalArticlepeer-review


Aims Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced I Kr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. Methods and results From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2 S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Conclusion Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.

Original languageEnglish
Pages (from-to)1446-1455
Number of pages10
JournalEuropean Heart Journal
Issue number16
Publication statusPublished - Apr 21 2018


  • Antiarrhythmic therapy
  • Arrhythmia
  • Calcium regulation
  • Long QT Syndrome 2
  • Lumacaftor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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