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

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Figure 5

Effect of temperature on current density.

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Effect of temperature on current density. (A) Representative Itail for W...
(A) Representative Itail for WT and WT+A558P mutant channels first measured at 23°C, repeated at 35°C, and then at 40°C for each cell. Scale bars for representative Itail: 1 nA, 1 s; scale bars for enlarged WT Itail: 2 nA, 0.25 s; scale bars for enlarged WT+A558P Itail: 0.5 nA, 0.25 s. Itail increased for both channels with rising temperature. (B) Average Itail densities at 23°C, 35°C, and 40°C. Compared with WT, the temperature-dependent increase of Itail density was significantly smaller for WT+A558P and WT+F640V channels. Cells were cultured at 37°C. (C) Average differences between WT and WT+A558P or WT+F640V Itail densities at 23°C, 35°C, and 40°C. Differences in Itail densities increased with rising temperature. *P < 0.001 compared with 23°C; #P < 0.001 compared with 35°C.