Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome with Life-Threatening Arrhythmias in Japanese Patients

Wataru Shimizu, Hisaki Makimoto, Kenichiro Yamagata, Tsukasa Kamakura, Mitsuru Wada, Koji Miyamoto, Yuko Inoue-Yamada, Hideo Okamura, Kohei Ishibashi, Takashi Noda, Satoshi Nagase, Aya Miyazaki, Heima Sakaguchi, Isao Shiraishi, Takeru Makiyama, Seiko Ohno, Hideki Itoh, Hiroshi Watanabe, Kenshi Hayashi, Masakazu YamagishiHiroshi Morita, Masao Yoshinaga, Yoshiyasu Aizawa, Kengo Kusano, Yoshihiro Miyamoto, Shiro Kamakura, Satoshi Yasuda, Hisao Ogawa, Toshihiro Tanaka, Naotaka Sumitomo, Nobuhisa Hagiwara, Keiichi Fukuda, Satoshi Ogawa, Yoshifusa Aizawa, Naomasa Makita, Tohru Ohe, Minoru Horie, Takeshi Aiba

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures: Sex difference in the genotype-specific risk of congenital LQTS. Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P =.002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P <.001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P <.001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P <.001), but no sex difference was seen. Conclusions and Relevance: In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.

Original languageEnglish
Pages (from-to)246-254
Number of pages9
JournalJAMA Cardiology
Volume4
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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Long QT Syndrome
Cardiac Arrhythmias
Sex Characteristics
Genotype
S 6
Romano-Ward Syndrome
Genes
Incidence
Puberty
Ion Channels
Observational Studies
Retrospective Studies

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome with Life-Threatening Arrhythmias in Japanese Patients. / Shimizu, Wataru; Makimoto, Hisaki; Yamagata, Kenichiro; Kamakura, Tsukasa; Wada, Mitsuru; Miyamoto, Koji; Inoue-Yamada, Yuko; Okamura, Hideo; Ishibashi, Kohei; Noda, Takashi; Nagase, Satoshi; Miyazaki, Aya; Sakaguchi, Heima; Shiraishi, Isao; Makiyama, Takeru; Ohno, Seiko; Itoh, Hideki; Watanabe, Hiroshi; Hayashi, Kenshi; Yamagishi, Masakazu; Morita, Hiroshi; Yoshinaga, Masao; Aizawa, Yoshiyasu; Kusano, Kengo; Miyamoto, Yoshihiro; Kamakura, Shiro; Yasuda, Satoshi; Ogawa, Hisao; Tanaka, Toshihiro; Sumitomo, Naotaka; Hagiwara, Nobuhisa; Fukuda, Keiichi; Ogawa, Satoshi; Aizawa, Yoshifusa; Makita, Naomasa; Ohe, Tohru; Horie, Minoru; Aiba, Takeshi.

In: JAMA Cardiology, Vol. 4, No. 3, 01.03.2019, p. 246-254.

Research output: Contribution to journalArticle

Shimizu, W, Makimoto, H, Yamagata, K, Kamakura, T, Wada, M, Miyamoto, K, Inoue-Yamada, Y, Okamura, H, Ishibashi, K, Noda, T, Nagase, S, Miyazaki, A, Sakaguchi, H, Shiraishi, I, Makiyama, T, Ohno, S, Itoh, H, Watanabe, H, Hayashi, K, Yamagishi, M, Morita, H, Yoshinaga, M, Aizawa, Y, Kusano, K, Miyamoto, Y, Kamakura, S, Yasuda, S, Ogawa, H, Tanaka, T, Sumitomo, N, Hagiwara, N, Fukuda, K, Ogawa, S, Aizawa, Y, Makita, N, Ohe, T, Horie, M & Aiba, T 2019, 'Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome with Life-Threatening Arrhythmias in Japanese Patients', JAMA Cardiology, vol. 4, no. 3, pp. 246-254. https://doi.org/10.1001/jamacardio.2018.4925
Shimizu, Wataru ; Makimoto, Hisaki ; Yamagata, Kenichiro ; Kamakura, Tsukasa ; Wada, Mitsuru ; Miyamoto, Koji ; Inoue-Yamada, Yuko ; Okamura, Hideo ; Ishibashi, Kohei ; Noda, Takashi ; Nagase, Satoshi ; Miyazaki, Aya ; Sakaguchi, Heima ; Shiraishi, Isao ; Makiyama, Takeru ; Ohno, Seiko ; Itoh, Hideki ; Watanabe, Hiroshi ; Hayashi, Kenshi ; Yamagishi, Masakazu ; Morita, Hiroshi ; Yoshinaga, Masao ; Aizawa, Yoshiyasu ; Kusano, Kengo ; Miyamoto, Yoshihiro ; Kamakura, Shiro ; Yasuda, Satoshi ; Ogawa, Hisao ; Tanaka, Toshihiro ; Sumitomo, Naotaka ; Hagiwara, Nobuhisa ; Fukuda, Keiichi ; Ogawa, Satoshi ; Aizawa, Yoshifusa ; Makita, Naomasa ; Ohe, Tohru ; Horie, Minoru ; Aiba, Takeshi. / Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome with Life-Threatening Arrhythmias in Japanese Patients. In: JAMA Cardiology. 2019 ; Vol. 4, No. 3. pp. 246-254.
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abstract = "Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures: Sex difference in the genotype-specific risk of congenital LQTS. Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95{\%} CI, 1.19-2.17; P =.002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95{\%} CI, 1.44-2.44; P <.001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2{\%}] vs 19 of 94 [20.2{\%}]; P <.001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95{\%} CI, 2.09-8.36; P <.001), but no sex difference was seen. Conclusions and Relevance: In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.",
author = "Wataru Shimizu and Hisaki Makimoto and Kenichiro Yamagata and Tsukasa Kamakura and Mitsuru Wada and Koji Miyamoto and Yuko Inoue-Yamada and Hideo Okamura and Kohei Ishibashi and Takashi Noda and Satoshi Nagase and Aya Miyazaki and Heima Sakaguchi and Isao Shiraishi and Takeru Makiyama and Seiko Ohno and Hideki Itoh and Hiroshi Watanabe and Kenshi Hayashi and Masakazu Yamagishi and Hiroshi Morita and Masao Yoshinaga and Yoshiyasu Aizawa and Kengo Kusano and Yoshihiro Miyamoto and Shiro Kamakura and Satoshi Yasuda and Hisao Ogawa and Toshihiro Tanaka and Naotaka Sumitomo and Nobuhisa Hagiwara and Keiichi Fukuda and Satoshi Ogawa and Yoshifusa Aizawa and Naomasa Makita and Tohru Ohe and Minoru Horie and Takeshi Aiba",
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T1 - Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome with Life-Threatening Arrhythmias in Japanese Patients

AU - Shimizu, Wataru

AU - Makimoto, Hisaki

AU - Yamagata, Kenichiro

AU - Kamakura, Tsukasa

AU - Wada, Mitsuru

AU - Miyamoto, Koji

AU - Inoue-Yamada, Yuko

AU - Okamura, Hideo

AU - Ishibashi, Kohei

AU - Noda, Takashi

AU - Nagase, Satoshi

AU - Miyazaki, Aya

AU - Sakaguchi, Heima

AU - Shiraishi, Isao

AU - Makiyama, Takeru

AU - Ohno, Seiko

AU - Itoh, Hideki

AU - Watanabe, Hiroshi

AU - Hayashi, Kenshi

AU - Yamagishi, Masakazu

AU - Morita, Hiroshi

AU - Yoshinaga, Masao

AU - Aizawa, Yoshiyasu

AU - Kusano, Kengo

AU - Miyamoto, Yoshihiro

AU - Kamakura, Shiro

AU - Yasuda, Satoshi

AU - Ogawa, Hisao

AU - Tanaka, Toshihiro

AU - Sumitomo, Naotaka

AU - Hagiwara, Nobuhisa

AU - Fukuda, Keiichi

AU - Ogawa, Satoshi

AU - Aizawa, Yoshifusa

AU - Makita, Naomasa

AU - Ohe, Tohru

AU - Horie, Minoru

AU - Aiba, Takeshi

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures: Sex difference in the genotype-specific risk of congenital LQTS. Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P =.002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P <.001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P <.001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P <.001), but no sex difference was seen. Conclusions and Relevance: In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.

AB - Importance: Long QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear. Objective: To examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias. Design, Setting, and Participants: This retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018. Main Outcomes and Measures: Sex difference in the genotype-specific risk of congenital LQTS. Results: Among the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P =.002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P <.001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P <.001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P <.001), but no sex difference was seen. Conclusions and Relevance: In this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.

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