EN-452411-5 THE ELECTROPHYSIOLOGIC EFFECTS OF EXTEND BEYOND EXPRESSION OF : EVIDENCE FROM GENETIC AND PHARMACOLOGIC BLOCK

Co-expression of KCNQ1 and KCNE1 generates the repolarizing current IKs. While mutations in are commonest cause congenital long QT syndrome, we others find only a small IKs normal cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or ventricular myocytes. A role for expression as modulator other major delayed rectifier heart, IKr, has previously been suggested. We used pharmacologic genetic approaches to probe cardiac repolarization. studied population control iPSC-CMs patient with Jervell Lange-Nielsen (JLN) syndrome due compound heterozygous loss function variants. compared effects block HMR-1556 those ablation, using JLN cells, homozygous allele G643S, siRNAs reducing expression. also two IKr blockers setting ablation KCNQ1: moxifloxacin, associated very low risk drug-induced QT, dofetilide, high-risk drug. In was readily recorded but (by high-dose HMR-1556) produced no change action potential duration at 90% repolarization (APD). By contrast, expression, APD prolonged 77%. displayed increased sensitivity acute block: concentration moxifloxacin required prolong 100 msec (μM) 237.4 (median, IQR 100.6-391.6, n=7) versus 22.4 (16.2-27.9, n=8) cells. chronic exposure (300μM) mildly (10%), unexpectedly IKs, while dofetilide (5 nM) greater prolongation (58%) increase suppression did not markedly APD. Our data strongly suggest that modulates baseline repolarization, response block, through mechanisms beyond simply generating