Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:190

Article

Harrell, Daniel Toshio¹  Ashihara, Takashi²  Ishikawa, Taisuke¹  Tominaga, Ichiko¹  Mazzanti, Andrea³  Takahashi, Kazuhiro⁴  Oginosawa, Yasushi⁵  Abe, Haruhiko⁶  Maemura, Koji⁷  Sumitomo, Naokata⁸  Uno, Kikuya⁹  Takano, Makoto¹⁰  Priori, Silvia G.^3,11  Makita, Naomasa¹ 

[1] Nagasaki Univ, Dept Mol Physiol, Grad Sch Biomed Sci, Nagasaki 8528523, Japan

[2] Shiga Univ Med Sci, Heart Rhythm Ctr, Dept Cardiovasc & Resp Med, Otsu, Shiga, Japan

[3] IRCCS Salvatore Maugeri Fdn, Mol Cardiol, Pavia, Italy

[4] Okinawa Childrens Med Ctr, Dept Pediat Cardiol, Shimajiri District, Okinawa, Japan

[5] Univ Occupat & Environm Hlth, Dept Internal Med 2, Kitakyushu, Fukuoka 807, Japan

[6] Univ Occupat & Environm Hlth, Dept Heart Rhythm Management, Kitakyushu, Fukuoka 807, Japan

[7] Nagasaki Univ, Dept Cardiovasc Med, Grad Sch Biomed Sci, Nagasaki 8528523, Japan

[8] Saitama Int Med Ctr, Dept Pediat Cardiol, Hidaka, Japan

[9] Sapporo Heart Ctr, Sapporo, Hokkaido, Japan

[10] Kurume Univ, Sch Med, Dept Physiol, Kurume, Fukuoka 830, Japan

[11] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy

关键词: Short QT syndrome;    Mutation;    Patch clamp;    Meta-analysis;    Computer simulation;   

DOI  :  10.1016/j.ijcard.2015.04.090

来源: Elsevier

【 摘 要 】

Background: Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype specific clinical differences between SQTS patients remain to be elucidated. Methods and results: We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift(+ 14mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3-6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35 +/- 19 years, n = 30; SQT2: 17 +/- 25 years, n = 8, SQT3-6: 19 +/- 15 years, n = 15; p = 0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p < 0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p=0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. Conclusion: We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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