The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients

Abstract

Long QT syndromes (LQTS) are heritable diseases characterized by prolongation of the QT interval on an electrocardiogram, which often leads to syncope and sudden cardiac death. Here we report the generation of induced pluripotent stems (iPS) cells from two patients with LQTS type 3 carrying a different point mutation in a sodium channel Nav1.5 (p.V240M and p.R535Q) and functional characterization of cardiomyocytes (CM) derived from them. The iPS cells exhibited all characteristic properties of pluripotent stem cells, maintained the disease-specific mutation and readily differentiated to CM. The duration of action potentials at 50% and 90% repolarization was longer in LQTS-3 CM as compared to control CM but this difference did not reach statistical significance due to high variations among cells. Sodium current recordings demonstrated longer time to peak and longer time to 90% of inactivation of the Na+ channel in the LQTS-3 CM. This hints at a defective Na+ channel caused by deficiency in open-state inactivation of the Na+ channel that is characteristic of LQTS-3. These analyses suggest that the effect of channel mutation in the diseased CM is demonstrated in vitro and that the iPS cell-derived CM can serve as a model system for studying the pathophysiology of LQTS-3, toxicity testing and design of novel therapeutics. However, further improvements in the model are still required to reduce cell-to-cell and cell line-to-cell line variability.

Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes

“…The group also found prolonged AP duration in SCN5A mutant cells. Similar observations were made using iPSC-CMs from LQTS-3 patients, however with different mutations in the SCN5A gene [78]. Using patch clamp to study Na + and Ca 2+ currents, as well as whole-cell current clamp to measure AP, they found that LQTS cells have tendencies toward prolonged AP duration, smaller Na+ current density, slower time to inactivation, and increased time to peak.…”

A Universal and Robust Integrated Platform for the Scalable Production of Human Cardiomyocytes From Pluripotent Stem Cells

“…4A), AP parameters (Vm ,10 V/s and AP duration at 90% [APD 90 ] of # 150) [36,37] and mean beating rate .100 (supplemental online Fig. 4B, 4C).…”

Induced pluripotent stem cells: at the heart of cardiovascular precision medicine

“…66 Fatima et al likewise had difficulty showing increased ADP in LQT3 hiPSC-CMs derived from patients carrying different SCN5A mutations (p.V240M and p.R535Q) because of variations in the EP parameters among individual hiPSC-CMs. 68 These findings underscored the current limitations of hiPSC models, including the inability to accurately recapitulate all clinical disease thus far.…”