Cardiomyocytes Derived from Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel Disease
Background—Pluripotent stem cells (PSCs) offer a new paradigm for modelling genetic cardiac diseases but it is unclear whether mouse and human PSCs can truly model both gain and loss of function genetic disorders affecting the Na+ current (INa) due to the immaturity of the PSC-derived cardiomyocytes. To address this issue, we generated multiple PSC lines containing a Na+ channel mutation causing a cardiac Na+ channel overlap syndrome.
Methods and Results—Induced PSC (iPSC) lines were generated from mice carrying the Scn5a1798insD/+ (Scn5a-het) mutation. These mouse (m)iPSCs, along with wild-type miPSCs, were compared to the targeted mouse embryonic stem cell (mESC) line used to generate the mutant mice and to the wild-type mESC line. Patch-clamp experiments showed that the Scn5a-het cardiomyocytes had a significant decrease in INa density and a larger persistent INa when compared to Scn5a-wt cardiomyocytes. Action potential (AP) measurements showed a reduced upstroke velocity and longer AP duration in Scn5a-het myocytes. These characteristics recapitulated findings from primary cardiomyocytes isolated directly from adult Scn5a-het mice. Finally, iPSCs were generated from a patient with the equivalent SCN5A1795insD/+ mutation. Patch-clamp measurements on the derivative cardiomyocytes revealed similar changes to those in the mPSC-derived cardiomyocytes.
Conclusions—Here we demonstrate that both ESC- and iPSC-derived cardiomyocytes can recapitulate the characteristics of a combined gain and loss of function Na+ channel mutation and that the electrophysiological immaturity of PSC-derived cardiomyocytes does not preclude their use as an accurate model for cardiac Na+ channel disease.
- Received September 9, 2011.
- Accepted April 24, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited