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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.
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Research Article Cardiology

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

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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 4

Dominant-negative effect of A558P HERG protein.

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Dominant-negative effect of A558P HERG protein.
(A) Representative weste...
(A) Representative western blot of cells transfected with 3-μg WT HERG cDNA, 1.5-μg WT cDNA plus 1.5-μg pCDNA3 vector, or 1.5-μg WT plus 1.5-μg A558P cDNA (n = 3). Cells transfected with 3-μg or 1.5-μg WT cDNA show both immature and mature protein bands. Cells coexpressing WT+A558P show the immature band with minimal or no mature protein band. Cells were cultured at 37°C. (B) Representative whole-cell Itail. Scale bars: 1 nA, 50 ms. (C) Average Itail densities. Cells were cultured at 37°C, and all Itail were measured at 23°C. *P < 0.05 compared with 3-μg WT Itail; #P < 0.05 compared with 1.5-μg WT Itail.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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