Abstract 16547: Human Induced Pluripotent Stem Cells Validate a Novel Iks Activator as a Potential Therapeutic for Long QT Syndrome
Introduction: Long QT syndrome (LQTS) affects 1 in 3,000 individuals and causes 4,000 US deaths annually. Despite our understanding of the genetic defects in LQTS, there is no therapy that addresses the underlying problem of prolonged repolarization. A novel compound, 2MMB, was recently found to rescue a zebrafish long QT model, although its activity in higher organisms remained unknown. As induced pluripotent stem (iPS) cell derived cardiomyocytes from subjects with LQTS have been shown to recapitulate disease phenotypes and drug responses, we sought to study 2MMB activity in this model.
Methods: iPS cell lines were generated from probands with genetically confirmed LQT2 (KCNH2 A422T) and LQT3 (SCN5a N406K), as well as a wild type control. Cardiomyocytes differentiated from these iPS cells were subjected to whole cell current and voltage clamp recordings. Antisense morpholino knockdown of zebrafish KCNQ1 gene (encoding the alpha subunit of the channel mediating IKs) was performed in the LQTS zebrafish model and knockdown embryos were analyzed for the ability of 2MMB to rescue the LQT phenotype.
Results: Application of 2MMB to human iPS derived LQT2 and LQT3 cardiomyocytes resulted in significant action potential duration (APD) shortening within minutes (Fig 1A,B). Reverse use dependence was noted with greater APD shortening at lower beating frequencies (Fig 1C,D). 2MMB had no significant effect on the magnitude of the late sodium current or on the rapid component of the delayed rectifier current, IKr, but did activate the slow component, IKs. Knockdown of KCNQ1 abrogated the ability of 2MMB to rescue the zebrafish LQT model, confirming that IKs activation underlies the 2MMB effect.
Conclusion: These data demonstrate that 2MMB shortens both zebrafish and human LQTS cardiomyocyte APDs by activation of IKs. The reverse rate dependence observed may prove to be clinically protective as the malignant arrhythmia torsade de pointes is a bradycardia or pause dependent rhythm.
- © 2012 by American Heart Association, Inc.