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Targeted activation of hERG channels rescues electrical instability induced by the hERG R56Q+/- Long QT Syndrome variant

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Long QT Syndrome Type 2 (LQTS2) is associated with inherited variants in the cardiac hERG K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant, and its phenotypic rescue by the type 1 hERG activator, RPR260243.

Methods and Results
These approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean APD90. However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of action potential duration (APD90) during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness.

Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.
Due to the embargo period of the journal Cardiovascular Research and its publisher Oxford University Press, the accepted manuscript of this article will not be available in Summit until September 2024. If you require immediate access to this paper please contact
Accepted date
21 September 2023
Available date
23 September 2024
DOI: 10.1093/cvr/cvad155
Publication title
Cardiovascular Research
Document title
Targeted activation of hERG channels rescues electrical instability induced by the hERG R56Q+/- Long QT Syndrome variant
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Copyright is held by the author(s).
Scholarly level
Peer reviewed?

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