Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation

• Published in: Europace (London, England) Vol. 25; no. 6
• Main Authors: Usuda, Keisuke, Hayashi, Kenshi, Nakajima, Tadashi, Kurata, Yasutaka, Cui, Shihe, Kusayama, Takashi, Tsuda, Toyonobu, Tada, Hayato, Kato, Takeshi, Sakata, Kenji, Usui, Soichiro, Fujino, Noboru, Tanaka, Yoshihiro, Kaneko, Yoshiaki, Kurabayashi, Masahiko, Tange, Shoichi, Saito, Takekatsu, Ohta, Kunio, Yamagishi, Masakazu, Takamura, Masayuki
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 02.06.2023
• Subjects: Basic Science; Computer Simulation; DNA-Binding Proteins; ERG1 Potassium Channel - genetics; Humans; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Mutation; Torsades de Pointes - diagnosis; Torsades de Pointes - genetics; Long QT syndrome; Steady-state inactivation; Computer simulation; Fever; KCNH2
• ISSN: 1099-5129; 1532-2092; 1532-2092
• DOI: 10.1093/europace/euad161

Abstract Aims Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). Methods and results We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. Conclusion These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2. Graphical Abstract Graphical Abstract