Authors: Guy Salama Linda Baker Robert Wolk Jacques Barhanin Barry London
Publish Date: 2009/01/16
Volume: 24, Issue: 2, Pages: 77-87
Abstract
Enhanced dispersion of repolarization DR was proposed as a unifying mechanism central to arrhythmia genesis in the long QT LQT syndrome In mammalian hearts K+ channels are heterogeneously expressed across the ventricles resulting in ‘intrinsic’ DR that may worsen in long QT DR was shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse K+ currents Here we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 mouse homolog of human ERG proteins resulting in loss of function of IKs and IKr respectively Both currents are important human K+ currents associated with LQT5 and LQT2 Loss of minK a protein subunit that interacts with KvLQT1 results in a marked reduction of IKs giving rise to the Jervell and Lange–Nielsen syndrome and the reduced KCNH2 gene reduces MERG and IKrHearts were perfused stained with di4ANEPPS and optically mapped to compare action potential durations APDs and arrhythmia phenotype in homozygous minK minK−/− and heterozygous Merg1 Merg+/− deletions and littermate control mice MinK−/− mice has similar APDs and no arrhythmias n = 4 Merg+/− mice had prolonged APDs from 20 ± 6 to 32 ± 9 ms at the base p 001 from 18 ± 5 to 25 ± 9 ms at the apex p 001 n = 8 longer refractory periods RP 36 ± 14 to 63 ± 27 at the base p 001 and 34 ± 5 to 53 ± 21 ms at the apex p 003 n = 8 higher DR 104 ± 41 vs 14 ± 23 ms p 002 and similar conduction velocities n = 8 Programmed stimulation exposed a higher propensity to VT in Merg+/− mice 60 vs 10 A comparison of mouse models of LQT based on K+ channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability
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