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

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.