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

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 2

Fever-associated QTc prolongation and TdP.

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Fever-associated QTc prolongation and TdP. (A) Lead II of the ECG of pat...
(A) Lead II of the ECG of patient I-1 on admission, showing an abnormal repolarization profile and prolonged QTc duration of 540 ms (body temperature, 39.7°C; standard calibration, 25 mm/sec and 10 mm/mV). (B) Two episodes of TdP in patient I-1 during fever. Both episodes are pause-dependent, as is typical for LQT-2 (13). The middle trace shows the pause-dependent onset of multiform ectopic beats (lead II). (C) The left panel shows QTc durations in LQT-2 patients I-1 and II-4 in relation to body temperature. Numbers next to the circles indicate serum K+ levels (mmol/l). Solid lines represent linear fits. In both patients, QTc durations increased with rising body temperature. The slopes of the fits in patient I-1 (14 ms/°C) and patient II-4 (16 ms/°C) are not significantly different. The right panel shows QTc durations in LQT-2 patients compared with control patients in relation to body temperature. Solid lines represent the regression line through both groups based on the common slopes. The common slope of the fit through the LQT-2 patients (15 ms/°C) differs significantly from that of control patients (–6 ms/°C).