RATIONALE:

Short QT syndrome (SQT) is a rare but arrhythmogenic disorder featured by shortened ventricular repolarization and a propensity toward life-threatening ventricular arrhythmias and sudden cardiac death.

OBJECTIVE:

This study aimed to investigate the single-cell mechanism of SQT using patient-specific and gene-corrected (GC) inducedpluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

METHODS AND RESULTS:

One SQT patient carrying missense mutation T618I in potassium voltage-gated channel subfamily H member 2 ( KCNH2) was recruited as well as two healthy control subjects in this study. Control and SQT patient-specific iPSCs were generated from skin fibroblasts using non-integrated Sendai virus. The KCNH2 T618I mutation was corrected by genome editing in SQT iPSC lines to generate isogenic controls. All iPSCs were differentiated into iPSC-CMs using monolayer-based differentiation protocol. SQT iPSC-CMs exhibited abnormal action potential (AP) phenotype featured by shortened AP duration (APD) and increased beat-beat interval variability, when compared to control and GC iPSC-CMs. Furthermore, SQT iPSC-CMs showed KCNH2 gain of function with increased rapid delayed rectifying potassium current (IKr) density and enhanced membrane expression. Gene expression profiling of iPSC-CMs exhibited a differential cardiac ion-channel gene expression profile of SQT. Moreover, QTc of SQT patient and APDs of SQT iPSC-CMs were both normalized by quinidine, indicating that quinidine is beneficial to KCNH2 T618I of SQT. Importantly, shortened APD phenotype observed in SQT iPSC-CMs was effectively rescued by a short-peptide scorpion toxin BmKKx2 with a mechanism of targeting KCNH2.

CONCLUSIONS:

We demonstrate that patient-specific and gene-corrected iPSC-CMs are able to recapitulate single-cell phenotype of SQT, which is caused by the gain-of-function mutation KCNH2 T618I. These findings will help elucidate the mechanisms underlying SQT and discover therapeutic drugs for treating the disease by using peptide toxins as lead compounds