Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome
BACKGROUND—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown....
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| creator | Itoh, Hideki Sakaguchi, Tomoko Ding, Wei-Guang Watanabe, Eiichi Watanabe, Ichiro Nishio, Yukiko Makiyama, Takeru Ohno, Seiko Akao, Masaharu Higashi, Yukei Zenda, Naoko Kubota, Tomoki Mori, Chikara Okajima, Katsunori Haruna, Tetsuya Miyamoto, Akashi Kawamura, Mihoko Ishida, Katsuya Nagaoka, Iori Oka, Yuko Nakazawa, Yuko Yao, Takenori Jo, Hikari Sugimoto, Yoshihisa Ashihara, Takashi Hayashi, Hideki Ito, Makoto Imoto, Keiji Matsuura, Hiroshi Horie, Minoru |
| description | BACKGROUND—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.
METHODS AND RESULTS—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P |
| doi_str_mv | 10.1161/CIRCEP.109.862649 |
| format | Article |
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METHODS AND RESULTS—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.
CONCLUSIONS—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.</description><identifier>ISSN: 1941-3149</identifier><identifier>EISSN: 1941-3084</identifier><identifier>DOI: 10.1161/CIRCEP.109.862649</identifier><identifier>PMID: 19843919</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Adult ; Aged ; Animals ; Antiarythmic agents ; Biological and medical sciences ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cardiovascular system ; Computer Simulation ; Cricetinae ; DNA Mutational Analysis ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels - genetics ; Female ; General aspects. Genetic counseling ; Genotype ; Heart ; Humans ; Incidence ; Japan - epidemiology ; KCNQ1 Potassium Channel - genetics ; Long QT Syndrome - chemically induced ; Long QT Syndrome - epidemiology ; Long QT Syndrome - genetics ; Long QT Syndrome - physiopathology ; Male ; Medical genetics ; Medical sciences ; Middle Aged ; Muscle Proteins - genetics ; Mutation, Missense ; NAV1.5 Voltage-Gated Sodium Channel ; Pharmacology. Drug treatments ; Risk Factors ; Sodium Channels - genetics ; Transfection</subject><ispartof>Circulation. Arrhythmia and electrophysiology, 2009-10, Vol.2 (5), p.511-523</ispartof><rights>2009 American Heart Association, Inc.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5157-1365c187bdb23899851b019e1af44542fdfbff34797dcb7629375ad4e930b3673</citedby><cites>FETCH-LOGICAL-c5157-1365c187bdb23899851b019e1af44542fdfbff34797dcb7629375ad4e930b3673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22283764$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19843919$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Itoh, Hideki</creatorcontrib><creatorcontrib>Sakaguchi, Tomoko</creatorcontrib><creatorcontrib>Ding, Wei-Guang</creatorcontrib><creatorcontrib>Watanabe, Eiichi</creatorcontrib><creatorcontrib>Watanabe, Ichiro</creatorcontrib><creatorcontrib>Nishio, Yukiko</creatorcontrib><creatorcontrib>Makiyama, Takeru</creatorcontrib><creatorcontrib>Ohno, Seiko</creatorcontrib><creatorcontrib>Akao, Masaharu</creatorcontrib><creatorcontrib>Higashi, Yukei</creatorcontrib><creatorcontrib>Zenda, Naoko</creatorcontrib><creatorcontrib>Kubota, Tomoki</creatorcontrib><creatorcontrib>Mori, Chikara</creatorcontrib><creatorcontrib>Okajima, Katsunori</creatorcontrib><creatorcontrib>Haruna, Tetsuya</creatorcontrib><creatorcontrib>Miyamoto, Akashi</creatorcontrib><creatorcontrib>Kawamura, Mihoko</creatorcontrib><creatorcontrib>Ishida, Katsuya</creatorcontrib><creatorcontrib>Nagaoka, Iori</creatorcontrib><creatorcontrib>Oka, Yuko</creatorcontrib><creatorcontrib>Nakazawa, Yuko</creatorcontrib><creatorcontrib>Yao, Takenori</creatorcontrib><creatorcontrib>Jo, Hikari</creatorcontrib><creatorcontrib>Sugimoto, Yoshihisa</creatorcontrib><creatorcontrib>Ashihara, Takashi</creatorcontrib><creatorcontrib>Hayashi, Hideki</creatorcontrib><creatorcontrib>Ito, Makoto</creatorcontrib><creatorcontrib>Imoto, Keiji</creatorcontrib><creatorcontrib>Matsuura, Hiroshi</creatorcontrib><creatorcontrib>Horie, Minoru</creatorcontrib><title>Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome</title><title>Circulation. Arrhythmia and electrophysiology</title><addtitle>Circ Arrhythm Electrophysiol</addtitle><description>BACKGROUND—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.
METHODS AND RESULTS—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.
CONCLUSIONS—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Antiarythmic agents</subject><subject>Biological and medical sciences</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cardiovascular system</subject><subject>Computer Simulation</subject><subject>Cricetinae</subject><subject>DNA Mutational Analysis</subject><subject>ERG1 Potassium Channel</subject><subject>Ether-A-Go-Go Potassium Channels - genetics</subject><subject>Female</subject><subject>General aspects. Genetic counseling</subject><subject>Genotype</subject><subject>Heart</subject><subject>Humans</subject><subject>Incidence</subject><subject>Japan - epidemiology</subject><subject>KCNQ1 Potassium Channel - genetics</subject><subject>Long QT Syndrome - chemically induced</subject><subject>Long QT Syndrome - epidemiology</subject><subject>Long QT Syndrome - genetics</subject><subject>Long QT Syndrome - physiopathology</subject><subject>Male</subject><subject>Medical genetics</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Muscle Proteins - genetics</subject><subject>Mutation, Missense</subject><subject>NAV1.5 Voltage-Gated Sodium Channel</subject><subject>Pharmacology. Drug treatments</subject><subject>Risk Factors</subject><subject>Sodium Channels - genetics</subject><subject>Transfection</subject><issn>1941-3149</issn><issn>1941-3084</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMFOwzAMhiMEgjF4AC4oF44dcZMmzRHGgElDDBhcqzRJt7IunZJWaG9PUQf4YCfS99vSh9AFkBEAh-vx9HU8mY-AyFHKY87kARqAZBBRkrLD3zcweYJOQ_gkhEMK_BidgEwZlSAH6GOmGusa_GCdbUqNb5VeL33dOhOwcgY_1ZXVbaU8nqtmVS87LJQBlw7f-XYZTZ1ptTV4Vrtl9LLAbztnfL2xZ-ioUFWw5_s5RO_3k8X4MZo9P0zHN7NIJ5CICChPNKQiN3lMUynTBHIC0oIqGEtYXJgiLwrKhBRG54LHkopEGWYlJTnlgg4R9Hu1r0Pwtsi2vtwov8uAZD-Ost5R95VZ76jLXPaZbZtvrPlP7KV0wNUeUEGrqvDK6TL8cXEcp1Rw1nGs577qqrE-rKv2y_psZVXVrDIClIruXBQTIoF0Ff00Qb8Bp2p-Kg</recordid><startdate>200910</startdate><enddate>200910</enddate><creator>Itoh, Hideki</creator><creator>Sakaguchi, Tomoko</creator><creator>Ding, Wei-Guang</creator><creator>Watanabe, Eiichi</creator><creator>Watanabe, Ichiro</creator><creator>Nishio, Yukiko</creator><creator>Makiyama, Takeru</creator><creator>Ohno, Seiko</creator><creator>Akao, Masaharu</creator><creator>Higashi, Yukei</creator><creator>Zenda, Naoko</creator><creator>Kubota, Tomoki</creator><creator>Mori, Chikara</creator><creator>Okajima, Katsunori</creator><creator>Haruna, Tetsuya</creator><creator>Miyamoto, Akashi</creator><creator>Kawamura, Mihoko</creator><creator>Ishida, Katsuya</creator><creator>Nagaoka, Iori</creator><creator>Oka, Yuko</creator><creator>Nakazawa, Yuko</creator><creator>Yao, Takenori</creator><creator>Jo, Hikari</creator><creator>Sugimoto, Yoshihisa</creator><creator>Ashihara, Takashi</creator><creator>Hayashi, Hideki</creator><creator>Ito, Makoto</creator><creator>Imoto, Keiji</creator><creator>Matsuura, Hiroshi</creator><creator>Horie, Minoru</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>200910</creationdate><title>Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome</title><author>Itoh, Hideki ; Sakaguchi, Tomoko ; Ding, Wei-Guang ; Watanabe, Eiichi ; Watanabe, Ichiro ; Nishio, Yukiko ; Makiyama, Takeru ; Ohno, Seiko ; Akao, Masaharu ; Higashi, Yukei ; Zenda, Naoko ; Kubota, Tomoki ; Mori, Chikara ; Okajima, Katsunori ; Haruna, Tetsuya ; Miyamoto, Akashi ; Kawamura, Mihoko ; Ishida, Katsuya ; Nagaoka, Iori ; Oka, Yuko ; Nakazawa, Yuko ; Yao, Takenori ; Jo, Hikari ; Sugimoto, Yoshihisa ; Ashihara, Takashi ; Hayashi, Hideki ; Ito, Makoto ; Imoto, Keiji ; Matsuura, Hiroshi ; Horie, Minoru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5157-1365c187bdb23899851b019e1af44542fdfbff34797dcb7629375ad4e930b3673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Antiarythmic agents</topic><topic>Biological and medical sciences</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cardiovascular system</topic><topic>Computer Simulation</topic><topic>Cricetinae</topic><topic>DNA Mutational Analysis</topic><topic>ERG1 Potassium Channel</topic><topic>Ether-A-Go-Go Potassium Channels - genetics</topic><topic>Female</topic><topic>General aspects. Genetic counseling</topic><topic>Genotype</topic><topic>Heart</topic><topic>Humans</topic><topic>Incidence</topic><topic>Japan - epidemiology</topic><topic>KCNQ1 Potassium Channel - genetics</topic><topic>Long QT Syndrome - chemically induced</topic><topic>Long QT Syndrome - epidemiology</topic><topic>Long QT Syndrome - genetics</topic><topic>Long QT Syndrome - physiopathology</topic><topic>Male</topic><topic>Medical genetics</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Muscle Proteins - genetics</topic><topic>Mutation, Missense</topic><topic>NAV1.5 Voltage-Gated Sodium Channel</topic><topic>Pharmacology. Drug treatments</topic><topic>Risk Factors</topic><topic>Sodium Channels - genetics</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Itoh, Hideki</creatorcontrib><creatorcontrib>Sakaguchi, Tomoko</creatorcontrib><creatorcontrib>Ding, Wei-Guang</creatorcontrib><creatorcontrib>Watanabe, Eiichi</creatorcontrib><creatorcontrib>Watanabe, Ichiro</creatorcontrib><creatorcontrib>Nishio, Yukiko</creatorcontrib><creatorcontrib>Makiyama, Takeru</creatorcontrib><creatorcontrib>Ohno, Seiko</creatorcontrib><creatorcontrib>Akao, Masaharu</creatorcontrib><creatorcontrib>Higashi, Yukei</creatorcontrib><creatorcontrib>Zenda, Naoko</creatorcontrib><creatorcontrib>Kubota, Tomoki</creatorcontrib><creatorcontrib>Mori, Chikara</creatorcontrib><creatorcontrib>Okajima, Katsunori</creatorcontrib><creatorcontrib>Haruna, Tetsuya</creatorcontrib><creatorcontrib>Miyamoto, Akashi</creatorcontrib><creatorcontrib>Kawamura, Mihoko</creatorcontrib><creatorcontrib>Ishida, Katsuya</creatorcontrib><creatorcontrib>Nagaoka, Iori</creatorcontrib><creatorcontrib>Oka, Yuko</creatorcontrib><creatorcontrib>Nakazawa, Yuko</creatorcontrib><creatorcontrib>Yao, Takenori</creatorcontrib><creatorcontrib>Jo, Hikari</creatorcontrib><creatorcontrib>Sugimoto, Yoshihisa</creatorcontrib><creatorcontrib>Ashihara, Takashi</creatorcontrib><creatorcontrib>Hayashi, Hideki</creatorcontrib><creatorcontrib>Ito, Makoto</creatorcontrib><creatorcontrib>Imoto, Keiji</creatorcontrib><creatorcontrib>Matsuura, Hiroshi</creatorcontrib><creatorcontrib>Horie, Minoru</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Circulation. Arrhythmia and electrophysiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Itoh, Hideki</au><au>Sakaguchi, Tomoko</au><au>Ding, Wei-Guang</au><au>Watanabe, Eiichi</au><au>Watanabe, Ichiro</au><au>Nishio, Yukiko</au><au>Makiyama, Takeru</au><au>Ohno, Seiko</au><au>Akao, Masaharu</au><au>Higashi, Yukei</au><au>Zenda, Naoko</au><au>Kubota, Tomoki</au><au>Mori, Chikara</au><au>Okajima, Katsunori</au><au>Haruna, Tetsuya</au><au>Miyamoto, Akashi</au><au>Kawamura, Mihoko</au><au>Ishida, Katsuya</au><au>Nagaoka, Iori</au><au>Oka, Yuko</au><au>Nakazawa, Yuko</au><au>Yao, Takenori</au><au>Jo, Hikari</au><au>Sugimoto, Yoshihisa</au><au>Ashihara, Takashi</au><au>Hayashi, Hideki</au><au>Ito, Makoto</au><au>Imoto, Keiji</au><au>Matsuura, Hiroshi</au><au>Horie, Minoru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome</atitle><jtitle>Circulation. Arrhythmia and electrophysiology</jtitle><addtitle>Circ Arrhythm Electrophysiol</addtitle><date>2009-10</date><risdate>2009</risdate><volume>2</volume><issue>5</issue><spage>511</spage><epage>523</epage><pages>511-523</pages><issn>1941-3149</issn><eissn>1941-3084</eissn><abstract>BACKGROUND—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.
METHODS AND RESULTS—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.
CONCLUSIONS—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>19843919</pmid><doi>10.1161/CIRCEP.109.862649</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Circulation. Arrhythmia and electrophysiology, 2009-10, Vol.2 (5), p.511-523 |
| issn | 1941-3149 1941-3084 |
| language | eng |
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| source | MEDLINE; EZB Electronic Journals Library; American Heart Association |
| subjects | Adult Aged Animals Antiarythmic agents Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system Cardiovascular system Computer Simulation Cricetinae DNA Mutational Analysis ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels - genetics Female General aspects. Genetic counseling Genotype Heart Humans Incidence Japan - epidemiology KCNQ1 Potassium Channel - genetics Long QT Syndrome - chemically induced Long QT Syndrome - epidemiology Long QT Syndrome - genetics Long QT Syndrome - physiopathology Male Medical genetics Medical sciences Middle Aged Muscle Proteins - genetics Mutation, Missense NAV1.5 Voltage-Gated Sodium Channel Pharmacology. Drug treatments Risk Factors Sodium Channels - genetics Transfection |
| title | Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome |
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