{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:52:31Z","timestamp":1773809551175,"version":"3.50.1"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"content-version":"vor","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Ministry of Health, Labor, and Welfare of Japan"},{"DOI":"10.13039\/501100011746","name":"NOVARTIS Foundation (Japan) for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011746","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>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).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>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\u00b0C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35\u00b0C to 40\u00b0C than those for WT, M124T, and R269W. The ratios of the TCDs at 40\u00b0C to 35\u00b0C 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\u00b0C.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euad161","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T04:55:39Z","timestamp":1688100939000},"source":"Crossref","is-referenced-by-count":3,"title":["Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with <i>KCNH2<\/i> mutation"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6599-629X","authenticated-orcid":false,"given":"Keisuke","family":"Usuda","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8219-7729","authenticated-orcid":false,"given":"Kenshi","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9635-2769","authenticated-orcid":false,"given":"Tadashi","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine , Maebashi , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasutaka","family":"Kurata","sequence":"additional","affiliation":[{"name":"Department of Physiology, Kanazawa Medical University , Uchinada , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihe","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0836-1196","authenticated-orcid":false,"given":"Takashi","family":"Kusayama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toyonobu","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-1809","authenticated-orcid":false,"given":"Hayato","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4108-5525","authenticated-orcid":false,"given":"Takeshi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1752-8082","authenticated-orcid":false,"given":"Soichiro","family":"Usui","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-5748","authenticated-orcid":false,"given":"Noboru","family":"Fujino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6150-1592","authenticated-orcid":false,"given":"Yoshihiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1, Takara-machi, Kanazawa Ishikawa 920-8641 , Japan"},{"name":"Department of Preventive Medicine Northwestern University, Feinberg School of Medicine , Chicago, IL , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine , Maebashi , 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