Basic/Translational Science -> Cell Physiology, Pharmacology, and Signaling D-SP05 - Young Investigator Awards Competition (ID 34) Special Session

D-SP05-02 - Increased Neurotransmission In Sympathetic Neurons Derived From Long QT Syndrome Type 1 Patient Induced Pluripotent Stem Cells (ID 1399)

 A. Winbo: Nothing relevant to disclose.


Background: Sympathetic hyperactivity contributes to cardiac arrhythmia in several disease states. The long QT syndrome type 1 (LQT1) is a sympathetically triggered cardiac arrhythmia with unknown cellular neuronal phenotype.
Objective: To study the functional phenotype of LQT1 sympathetic neurons (SNs) derived from human induced pluripotent stem cells (hiPSCs) in mono- and coculture with hiPSC-cardiomyocytes (CMs).
Methods: We generated iPSC-lines from adult males with compound heterozygous LQT1 (S349W/R518X) or control (WT) genotype. Lines were differentiated into hiPSC-SNs (>5 repeats/line) and hiPSC-CMs. Phenotypes were studied using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell electrophysiology.
Results: LQT1 and WT hiPSC-SNs were tyrosine hydroxylase positive, showed typical neuronal morphology, fired action potentials and exhibited synaptic currents. Significant hyperactivity in LQT1 hiPSC-SNs (Fig1, error bars represent mean ± SEM) was evident via increased noradrenaline release upon stimulation with 50 mM KCl (A), increased action potential firing frequency upon current injection (B), and increased synaptic current amplitude (C), as compared to WT hiPSC-SNs. In coculture, the action potential duration of LQT1 hiPSC-CMs was significantly increased upon nicotinic activation of hiPSC-SNs (D), with frequent triggered activity noted (E).
Conclusion: This is the first phenotypic description of hiPSC-derived LQTS sympathetic neurons. We report consistent increased neurotransmission in hiPSC-SNs from LQT1 patient cells, that could contribute to the increased arrhythmogenicity seen in vitro and in vivo in LQTS.