Abstract 17041: Cardiomyocytes Derived From Patient-Specific Ipscs Recapitulate Typical Cellular Biophysics of Type 3 Long Qt Syndrome
Aims: 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.
Methods and Results: Dermal fibroblasts obtained from a patient with LQT3 harbouring 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.
- © 2013 by American Heart Association, Inc.