The Establishment Of Atrioventricular Block Model Mice

Background Atrioventricular block (AVB) is a common clinical manifestation in somepatients with atrial fibrillation (AF). However, its molecular mechanism is still unknown. Threeyears ago chen reported that an S140G mutation in human KCNQ1, an alpha subunit ofpotassium channels, was involved in the pathogenesis of familial AF. At the same time chen alsofound that the AF patients in this family most had distinct AVB by 24-hour ambulatoryelectrocardiography monitoring and the KCNQ1 S140G mutation was shown to co-segregatewith AVB in the family. So we speculated that the family AVB may share the same molecularvariation basis with AF.Objective To establish transgenic mice model of hKCNQ1 S140G, and so confirm the pathophysiologic function of KCNQ1 S140G causing AF and/or AVB.Methods We reverse transcribed RNA from normal human cardio-tissue into cDNA, subclonedit into cardiomyocyte-specific expression vector under the control ofα-cardiac myosin heavychain promoter, and then induced the KCNQ1 S140G mutation by site-directed mutation. Themutation was confirmed as correct by sequencing before the linearized transgene constructwas microinjected into oosperms of male mice and transplanted into oviducts of female mice.After transgenic mice lines were established with propagation, we examined thegenotype,expression and phynotype in the transgenic mice.Results We successfully established transgenic mice model of hKCNQ1 S140G. Four lines oftransgenic mice were established with a high level of human KCNQ1 S140G expression in theheart while the control mice were absent of human KCNQ1 S140G expression in the heart.Frequent episodes of first-, second-, advanced-, or third-degree AVB occurred in at least 65％oftransgenic mice in the 4 lines but AF absent. No AVB or AF episodes occurred in the controlmice without the hKCNQ1 S140G mutation.Conclusions (1) KCNQ1 S140G overexpression in cardiomyocyte can cause AVB but cannot reproduce AF phynotype in mice; (2) the KCNQ1 molecular defect is associated with AF in thisfamily, but also associated with AVB in the family and mice; (3) the transgenic mice may be auseful tool for the study of mechanisms and intervention strategies of atrioventricular blocks.