Abstract 15515: Mechanism of Fever-Induced QT Prolongation in Patients With KCNH2 Mutations in the S5-Pore Region: Evidence From Genotypic and Functional Analyses
Introduction: Previous studies demonstrated that patients with type-2 long QT syndrome (LQT2) caused by a mutation in the Kv11.1 S5-pore region have an increased risk of arrhythmia during fever. However, few data exist regarding molecular basis of this phenotype.
Methods and Results: In patients with marked QT prolongation and torsades de pointes during fever, we found KCNH2 mutations G584S and D609G in the S5-pore region. Under these conditions, we characterized the temperature-dependent changes of electrophysiological properties of channels by patch clamp recording. We also evaluated KCNH2 M124T which was identified from patients with drug induced LQTS as controls. At 25 °C, G584S and M124T generated functional channels, whereas D609G did not. The tail current densities (TCDs) for three mutants were significantly smaller than that for wild-type (WT). To mimic physiological and febrile states, we next measured currents at 35°C and 40°C. While average TCDs for WT and M124T significantly increased with rising temperature, there was no statistical difference of TCDs for G584S alone and D609G/WT between at 35°C and 40°C. When we evaluated steady-state inactivation, the potentials of half-maximum inactivation (V1/2) for WT, G584S, and WT + D609G channels were comparable at 35°C; however, those for the G584S and WT + D609G channels at 40°C were significantly shifted towards the negative direction compared to that for the WT channel. In contrast, those for the M124T channel at 35°C and 40°C were significantly shifted to the positive direction compared with those for the WT channel. Computer simulation demonstrated that smaller increases of G584S and WT + D609G channel currents (via the negative shift of inactivation) at higher temperatures cause prolonged action potential durations and EAD formation during high fever.
Conclusion: These results demonstrate that KCNH2 G584S and D609G reduce temperature-dependent increase in TCD through an enhanced inactivation, which may account for the development of QT prolongation and life-threatening arrhythmias at febrile state in this LQT2 patient. The other KCNH2 M124T rather increases the TCD with rising temperature, and may increase the availability of channel opening at higher temperatures.
Author Disclosures: K. Hayashi: None. T. Nakajima: None. Y. Kurata: None. S. Tange: None. N. Fujino: None. K. Sakata: None. T. Konno: None. T. Tsuda: None. Y. Nagata: None. R. Teramoto: None. Y. Tanaka: None. T. Saito: None. M. Kawashiri: None. Y. Kaneko: None. K. Ohta: None. M. Kurabayashi: None. M. Yamagishi: None.
- © 2016 by American Heart Association, Inc.