Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.
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.
Brunner
Michael
M
Innere Medizin III-Kardiologie und Angiologie, Universitätsklinikum Freiburg, Freiburg, Germany.
Peng
Xuwen
X
Liu
Gong Xin
GX
Ren
Xiao-Qin
XQ
Ziv
Ohad
O
Choi
Bum-Rak
BR
Mathur
Rajesh
R
Hajjiri
Mohammed
M
Odening
Katja E
KE
Steinberg
Eric
E
Folco
Eduardo J
EJ
Pringa
Ekatherini
E
Centracchio
Jason
J
Macharzina
Roland R
RR
Donahay
Tammy
T
Schofield
Lorraine
L
Rana
Naveed
N
Kirk
Malcolm
M
Mitchell
Gary F
GF
Poppas
Athena
A
Zehender
Manfred
M
Koren
Gideon
G
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
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