Atrioventricular block-induced Torsades de Pointes with clinical and molecular backgrounds similar to congenital long QT syndrome.
BACKGROUND
Atrioventricular block (AVB) sometimes complicates QT prolongation and torsades de pointes (TdP).


RESULTS
The clinical and genetic background of 14 AVB patients (57±21 years, 13 females) who developed QT prolongation and TdP was analyzed. Electrophysiological characteristics of mutations were analyzed using heterologous expression in Chinese hamster ovary cells, together with computer simulation models. Every patient received a pacemaker or implantable cardioverter defibrillator; 3 patients had recurrence of TdP during follow-up because of pacing failure. Among the ECG parameters, QTc interval was prolonged to 561±76ms in the presence of AVB, but shortened to 495±42ms in the absence of AVB. Genetic screening for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 revealed four heterozygous missense mutations of KCNQ1 or KCNH2 in 4 patients (28.6%). Functional analyses showed that all mutations had loss of functions and various gating dysfunctions of I(Ks) or I(Kr). Finally, action potential simulation based on the Luo-Rudy model demonstrated that most mutant channels induced bradycardia-related early afterdepolarizations.


CONCLUSIONS
Incidental AVB, as a trigger of TdP, can manifest as clinical phenotypes of long QT syndrome (LQTS), and that some patients with AVB-induced TdP share a genetic background with those with congenital LQTS.
Oka
Yuko
Y
Department of Respiratory and Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
Itoh
Hideki
H
Ding
Wei-Guang
WG
Shimizu
Wataru
W
Makiyama
Takeru
T
Ohno
Seiko
S
Nishio
Yukiko
Y
Sakaguchi
Tomoko
T
Miyamoto
Akashi
A
Kawamura
Mihoko
M
Matsuura
Hiroshi
H
Horie
Minoru
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054537:Atrioventricular Block / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D016466:CHO Cells; D015331:Cohort Studies; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016171:Torsades de Pointes / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human