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

AIMS: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. METHODS AND RESULTS: 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 KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 loss of function allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, 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 IKs was readily recorded but pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). By 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 IKr block: the concentration (µM) of moxifloxacin required to prolong APD90 100 msec was 237.4 (median, IQR 100.6-391.6, n = 7) in population cells versus 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300µM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs, and markedly prolonged APD90. CONCLUSION: Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs. TRANSLATIONAL PERSPECTIVE: Mutations in KCNQ1 - whose expression generates IKs - are the major cause of long QT syndrome. We report here that while pharmacologic IKs block in human cardiomyocytes generates minimal change in repolarization, suppressing KCNQ1 expression markedly increases both baseline repolarization duration and sensitivity to some (but not all) specific IKr blockers. Thus, beyond simply generating IKs, KCNQ1 subserves critical additional role(s) in repolarization control at baseline and in response to IKr block. Our findings imply that assessment of arrhythmic risk in individual patients and by drugs requires a framework that extends beyond a simple one gene-one ion current paradigm.