Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.
Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.
Amin
Ahmad S
AS
Heart Failure Research Center, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Herfst
Lucas J
LJ
Delisle
Brian P
BP
Klemens
Christine A
CA
Rook
Martin B
MB
Bezzina
Connie R
CR
Underkofler
Heather A S
HA
Holzem
Katherine M
KM
Ruijter
Jan M
JM
Tan
Hanno L
HL
January
Craig T
CT
Wilde
Arthur A M
AA
D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D001831:Body Temperature; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005334:Fever / Q000150:complications*; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D020125:Mutation, Missense; D021381:Protein Transport; D029597:Romano-Ward Syndrome / Q000175:diagnosis / Q000503:physiopathology; D013696:Temperature; D014162:Transfection
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human