The electrophysiologic effects of KCNQ1 extend beyond expression of I_Ks: evidence from genetic and pharmacologic block

While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small I_Ks in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes.

We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic I_Ks block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of I_Kr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small I_Ks was readily recorded but the pharmacologic I_Ks block produced no change in action potential duration at 90% repolarization (APD₉₀). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD₉₀ was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute I_Kr block: the concentration (μM) of moxifloxacin required to prolong APD₉₀ 100 msec was 237.4 [median, interquartile range (IQR) 100.6–391.6, n = 7] in population cells vs. 23.7 (17.3–28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 μM) mildly prolonged APD₉₀ (10%) and increased I_Ks, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in I_Ks. However, in the siRNA-treated cells, moxifloxacin did not increase I_Ks and markedly prolonged APD₉₀.

Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to I_Kr block, through mechanisms beyond simply generating I_Ks.