title: Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.
abstract: Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.
authors.affiliation: Innere Medizin III-Kardiologie und Angiologie, Universitätsklinikum Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
authors.forename: Xuwen
authors.initials: X
authors.lastname: Peng
authors.forename: Gong Xin
authors.initials: GX
authors.lastname: Liu
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Ren
authors.forename: Ohad
authors.initials: O
authors.lastname: Ziv
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mathur
authors.forename: Mohammed
authors.initials: M
authors.lastname: Hajjiri
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
authors.forename: Eric
authors.initials: E
authors.lastname: Steinberg
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.forename: Ekatherini
authors.initials: E
authors.lastname: Pringa
authors.forename: Jason
authors.initials: J
authors.lastname: Centracchio
authors.forename: Roland R
authors.initials: RR
authors.lastname: Macharzina
authors.forename: Tammy
authors.initials: T
authors.lastname: Donahay
authors.forename: Lorraine
authors.initials: L
authors.lastname: Schofield
authors.forename: Naveed
authors.initials: N
authors.lastname: Rana
authors.forename: Malcolm
authors.initials: M
authors.lastname: Kirk
authors.forename: Gary F
authors.initials: GF
authors.lastname: Mitchell
authors.forename: Athena
authors.initials: A
authors.lastname: Poppas
authors.forename: Manfred
authors.initials: M
authors.lastname: Zehender
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000200:Action Potentials; D000818:Animals; D030801:Animals, Genetically Modified; D003645:Death, Sudden; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D004452:Echocardiography; D004594:Electrophysiology / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels; D005838:Genotype; D006352:Heart Ventricles / Q000473:pathology; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology*; D032342:Muscle Cells / Q000473:pathology; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011817:Rabbits
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C000606915:Kcnh2 protein, mouse; D024642:Potassium Channels, Voltage-Gated