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Despite the well\u2010known proarrhythmic effect of methadone, the underlying mechanisms remain less well understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">Computer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The major findings are (1) blocking I\n              <jats:sub>K1<\/jats:sub>\n              potentiates QT prolongation\u2010related arrhythmogenesis by enhancing a tissue\u2010scale dynamical instability for the spontaneous genesis of ectopic excitations; blocking I\n              <jats:sub>K1<\/jats:sub>\n              and the rapid component of the delayed rectifier potassium current together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; (2) blocking I\n              <jats:sub>K1<\/jats:sub>\n              in combination with lowering L\u2010type calcium current potentiates phase 2 reentry caused by spike\u2010and\u2010dome action potential morphology, an arrhythmia mechanism of early repolarization or Brugada syndrome, whereas blocking the rapid component of the delayed rectifier potassium current exhibits little effect for this mechanism of arrhythmias; and (3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation\u2010related arrhythmias at high sympathetic activity and phase 2 reentry at low sympathetic activity, mainly via its effect on the L\u2010type calcium current.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Methadone promotes both early and delayed repolarization arrhythmias. Early repolarization may be responsible for methadone\u2010related deaths occurring mainly during sleep and occurring more often in men. Blocking I\n              <jats:sub>K1<\/jats:sub>\n              can work synergistically with other channel blockers to disproportionately increase arrhythmia propensity, greatly increasing methadone's risk when it is combined with other proarrhythmic drugs or under disease conditions.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.125.042201","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T12:15:05Z","timestamp":1758802505000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Methadone Blockade of Inward Rectifier Potassium Current Promotes Both Early and Delayed Repolarization Arrhythmias: Mechanistic Insights From Computational Modeling"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0656-366X","authenticated-orcid":false,"given":"Zhaoyang","family":"Zhang","sequence":"first","affiliation":[{"name":"Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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