Photo Credit: Nutjaree Yomjun
The following is a summary of “Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/− long QT syndrome variant,” published in the November 2023 issue of Cardiology by Venkateshappa et al.
Researchers started a retrospective study to elucidate the pathogenic mechanism of the Long QT syndrome type 2 (LQTS2) associated human ether-à-go-go-related gene (hERG) R56Q variant and its potential rescue using the Type 1 hERG activator, RPR260243, by employing CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs).
They utilized various methods to characterize the unclear causative mechanism of arrhythmia in the R56Q variant (a mutation in the N-terminal PAS domain that mainly speeds up channel deactivation) and investigated the potential for targeted pharmacologic manipulation of hERG deactivation through translationally.
The results showed, utilizing perforated patch clamp electrophysiology of single hiPSC-CMs, that the hERG R56Q variant did not significantly alter the mean action potential duration (APD90). However, it increased beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhanced variance of APD90 during rate transitions, and raised the incidence of 2:1 block. Paired S1–S2 stimulations measuring electrical restitution properties also increased variability in rise time and duration of the response to premature stimulations. The hERG channel activator, RPR260243, decreased APD variance, response variability to premature stimulations, and increased post-repolarization refractoriness in hERG R56Q hiPSC-CMs.
Investigators concluded that the hERG R56Q variant was linked to uneven repolarization, suggesting targeted hERG modulation as a potential antiarrhythmic strategy.
Source: academic.oup.com/cardiovascres/article/119/15/2522/7280101