Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome
Ahmad S. Amin, … , Craig T. January, Arthur A.M. Wilde
Ahmad S. Amin, … , Craig T. January, Arthur A.M. Wilde
Published June 12, 2008
Citation Information: J Clin Invest. 2008;118(7):2552-2561. https://doi.org/10.1172/JCI35337.
View: Text | PDF
Research Article Cardiology

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Abstract

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.

Authors

Ahmad S. Amin, Lucas J. Herfst, Brian P. Delisle, Christine A. Klemens, Martin B. Rook, Connie R. Bezzina, Heather A.S. Underkofler, Katherine M. Holzem, Jan M. Ruijter, Hanno L. Tan, Craig T. January, Arthur A.M. Wilde

×

Figure 3

Trafficking-deficient phenotype of the A558P HERG mutation and attempts to correct the deficient trafficking.

Options: View larger image (or click on image) Download as PowerPoint
Trafficking-deficient phenotype of the A558P HERG mutation and attempts ...
(A) Representative western blot of cells expressing WT and A558P HERG protein (n = 3). WT shows both mature complexly glycosylated (155 kDa) and immature core-glycosylated (135 kDa) protein bands. A558P displays only the immature band, representative for trafficking-deficient mutant HERG proteins. Cells were cultured at 37°C. (B) Representative whole-cell Itail traces of WT or A558P-expressing cells. WT channels display typical Itail, while only small amplitude Itail could be recorded from cells expressing A558P. Cells were cultured at 37°C. Scale bars: 1 nA, 50 ms. (C and D) Representative western blot (n = 3) and corresponding Itail of WT and A558P following culture at 27°C or incubation for 24 hours with 10-μmol/l E-4031 (culture at 37°C). Only incubation with E-4031 could minimally correct the deficient trafficking. Scale is as in B. (E) Average Itail densities. All Itail were measured at 23°C. n, number of cells. *P < 0.05 compared with WT Itail; #P < 0.05 compared with A558P Itail.