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

被引：0

作者：

Usuda, Keisuke ^{[1
]}

Hayashi, Kenshi ^{[1
]}

Nakajima, Tadashi ^{[2
]}

Kurata, Yasutaka ^{[3
]}

Cui, Shihe ^{[1
]}

Kusayama, Takashi ^{[1
]}

Tsuda, Toyonobu ^{[1
]}

Tada, Hayato ^{[1
]}

Kato, Takeshi ^{[1
]}

Sakata, Kenji ^{[1
]}

Usui, Soichiro ^{[1
]}

Fujino, Noboru ^{[1
]}

Tanaka, Yoshihiro ^{[1
,4
]}

Kaneko, Yoshiaki ^{[2
]}

Kurabayashi, Masahiko ^{[2
]}

Tange, Shoichi ^{[5
]}

Saito, Takekatsu ^{[6
]}

Ohta, Kunio ^{[6
]}

Yamagishi, Masakazu ^{[7
]}

Takamura, Masayuki ^{[1
]}

机构：

[1] Kanazawa Univ, Grad Sch Med Sci, Dept Cardiovasc Med, 13-1 Takara Machi, Kanazawa, Ishikawa 9208641, Japan

[2] Gunma Univ, Grad Sch Med, Dept Cardiovasc Med, Maebashi, Japan

[3] Kanazawa Med Univ, Dept Physiol, Uchinada, Japan

[4] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA

[5] Maebashi Red Cross Hosp, Dept Cardiovasc Med, Maebashi, Japan

[6] Kanazawa Univ, Dept Pediat, Kanazawa, Japan

[7] Osaka Univ Human Sci, Osaka, Japan

来源：

EUROPACE | 2023年 / 25卷 / 06期

基金：

日本学术振兴会;

关键词：

Long QT syndrome; KCNH2; Fever; Steady-state inactivation; Computer simulation; IONIC MECHANISMS; TEMPERATURE; DEPENDENCE; PHENOTYPE; HELIX;

D O I：

10.1093/europace/euad161

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 & DEG;C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35 & DEG;C to 40 & DEG;C than those for WT, M124T, and R269W. The ratios of the TCDs at 40 & DEG;C to 35 & DEG;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 & DEG;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.

引用

页数：11

共 22 条

[21] Not All hERG Pore Domain Mutations Have a Severe Phenotype: G584S Has an Inactivation Gating Defect with Mild Phenotype Compared to G572S, Which Has a Dominant Negative Trafficking Defect and a Severe Phenotype [J].