{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:58:17Z","timestamp":1790117897632,"version":"4.0.1"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,6,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K\n                      <jats:sup>+<\/jats:sup>\n                      current (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Kr<\/jats:sub>\n                      )\n                      <jats:sub>,<\/jats:sub>\n                      the principal mechanism of drug\u2010associated arrhythmia. Congenital defects of inward rectifier K\n                      <jats:sup>+<\/jats:sup>\n                      current (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      ) have been linked to increased U\u2010wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      , contributing to delayed repolarization and manifesting on surface ECGs as augmented U\u2010wave integrals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Using a whole\u2010cell voltage clamp, methadone inhibited both recombinant and native\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      with a half\u2010maximal inhibitory concentration IC50) of 1.5\u00a0\u03bcmol\/L, similar to that observed for\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Kr<\/jats:sub>\n                      block (half\u2010maximal inhibitory concentration of 2.9\u00a0\u03bcmol\/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U\u2010wave integral compared with premethadone (lead V3; mean +38%\u00b115%,\n                      <jats:italic>P<\/jats:italic>\n                      =0.016), along with increased QT and T\n                      <jats:sub>Peak<\/jats:sub>\n                      to T\n                      <jats:sub>End<\/jats:sub>\n                      intervals, likely reflective of\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Kr<\/jats:sub>\n                      block.\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 is a potent\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      block may better explain methadone\u2019s arrhythmia risk beyond\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Kr<\/jats:sub>\n                      inhibition alone. Drug\u2010induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>K1<\/jats:sub>\n                      may be warranted.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.121.023482","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T06:00:09Z","timestamp":1654495209000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Methadone Blockade of Cardiac Inward Rectifier K\n                    <sup>+<\/sup>\n                    Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1521-6915","authenticated-orcid":false,"given":"Michael G.","family":"Klein","sequence":"first","affiliation":[{"name":"Cardiology Division Department of Medicine Uniformed Services University Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4115-4092","authenticated-orcid":false,"given":"Mori J.","family":"Krantz","sequence":"additional","affiliation":[{"name":"Denver Health Medical Center Cardiology Division Denver CO"},{"name":"Department of Medicine University of Colorado School of Medicine Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naheed","family":"Fatima","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology &amp; Genetics Uniformed Services University Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7587-8948","authenticated-orcid":false,"given":"Ashlie","family":"Watters","sequence":"additional","affiliation":[{"name":"ACUTE at Denver Health Denver CO"},{"name":"Department of Medicine University of Colorado School of Medicine Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayan","family":"Colon\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Psychiatry Division Outpatient Behavioral Health Services, Denver Health, &amp; University of Colorado School of Medicine Denver CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology &amp; Genetics Uniformed Services University Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Cardiology Division Department of Medicine Uniformed Services University Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-2479","authenticated-orcid":false,"given":"Soroosh","family":"Solhjoo","sequence":"additional","affiliation":[{"name":"Cardiology Division Department of Medicine Uniformed Services University Bethesda MD"},{"name":"Military Cardiovascular Outcomes Research (MiCOR) Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Mehler","sequence":"additional","affiliation":[{"name":"ACUTE at Denver Health Denver CO"},{"name":"Department of Medicine University of Colorado School of Medicine Aurora CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3147-4060","authenticated-orcid":false,"given":"Thomas P.","family":"Flagg","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology &amp; Genetics Uniformed Services University Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Haigney","sequence":"additional","affiliation":[{"name":"Cardiology Division Department of Medicine Uniformed Services University Bethesda MD"},{"name":"Military Cardiovascular Outcomes Research (MiCOR) Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","unstructured":"Opioid Data Analysis and Resources | CDC\u2019s Response to the Opioid Overdose Epidemic | CDC . n.d. 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