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- W4377015730 abstract "Co-expression of KCNQ1 and KCNE1 generates the repolarizing current IKs. While mutations in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in normal cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. A role for IKs expression as a modulator of the other major delayed rectifier in the heart, IKr, has previously been suggested. We used pharmacologic and genetic approaches to probe the role of IKs in human cardiac repolarization. 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 with HMR-1556 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 IKr blockers in the setting of pharmacologic and genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In population cells, a small IKs was readily recorded but pharmacologic IKs block (by high-dose HMR-1556) produced no change in action potential duration at 90% repolarization (APD). By contrast, in cells with genetic ablation of KCNQ1 expression, APD was prolonged 77%. JLN cells displayed increased sensitivity to acute IKr block: the concentration of moxifloxacin required to prolong APD 100 msec (μM) was 237.4 (median, IQR 100.6-391.6, n=7) in population cells versus 22.4 (16.2-27.9, n=8) in JLN cells. In population control cells, chronic moxifloxacin exposure (300μM) mildly prolonged APD (10%), and unexpectedly increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (58%) and no increase in IKs. In cells with genetic suppression of KCNQ1 expression, moxifloxacin did not increase IKs, and markedly prolonged APD. Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs." @default.
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- W4377015730 date "2023-05-01" @default.
- W4377015730 modified "2023-10-01" @default.
- W4377015730 title "EN-452411-5 THE ELECTROPHYSIOLOGIC EFFECTS OF EXTEND BEYOND EXPRESSION OF : EVIDENCE FROM GENETIC AND PHARMACOLOGIC BLOCK" @default.
- W4377015730 doi "https://doi.org/10.1016/j.hrthm.2023.03.411" @default.
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