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The mechanisms underlying doxorubicin\u2010induced toxic cardiomyopathy (DICM) involve electrophysiological remodelling with intracellular Na\n                      <jats:sup>+<\/jats:sup>\n                      overload because of increased late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      and hyperactivation of CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      . Increased [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>\n                        <jats:italic>i<\/jats:italic>\n                      <\/jats:sub>\n                      contributes to CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      activation through Na\u2010dependent Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload, and CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      can further amplify late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We tested whether pharmacological inhibition of the late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      by either ranolazine (RAN, 10\u2009\u03bcmol\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) or empagliflozin (EMPA, 1\u2009\u03bcmol\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) is sufficient to attenuate DOX\u2010mediated hyperactivation of CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      in isolated wildtype (WT) ventricular cardiomyocytes. The contribution of reciprocal CaMKII\u2010dependent stimulation of late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      was tested in transgenic S571A cardiomyocytes lacking the CaMKII\u2010specific phosphorylation site S571A on Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5. Functional readouts were obtained using patch\u2010clamp technique, as well as confocal and epifluorescence microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      DOX acutely increased late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      in WT cardiomyocytes by twofold, which was associated with redox\u2010\n                      <jats:italic>and<\/jats:italic>\n                      phospho\u2010dependent activation of CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      . Hyperactivated CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      led to acutely impaired Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling because of diastolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      loss from the sarcoplasmic reticulum (SR) mediated by phosphorylation of the RyR2 at the CaMKII\u2010specific phosphorylation site serine\u20102814. Pharmacological inhibition of late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      by EMPA or RAN, and genetic deletion of the CaMKII\u2010specific phosphorylation\u2010site serine\u2010571 at Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5 prevented DOX\u2010related stimulation of the late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      and subsequent CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      hyperactivation, which functionally preserved intracellular Ca handling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      Inhibition of late\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      protects cardiomyocytes from pathologic CaMKII\n                      <jats:italic>\u03b4<\/jats:italic>\n                      hyperactivation and impaired Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling in the setting of acute DOX cardiotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70561","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:28:08Z","timestamp":1785302888000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of late sodium current prevents pathological hyperactivation of calcium\/calmodulin\u2010dependent protein kinase II\u03b4 in a murine model of acute doxorubicin\u2010related cardiotoxicity"],"prefix":"10.1111","author":[{"given":"Anna\u2010Lena","family":"Feder","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u2010Maria","family":"Pf\u00fctzenreuter","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea Maria","family":"Funke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Johanna","family":"Baier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Tarnowski","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Stengel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Siegfried","family":"Maier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can Martin","family":"Sag","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\/Cardiology University Medical Centre Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"S307","article-title":"The concise guide to PHARMACOLOGY 2025\/26: Enzymes","volume":"182","author":"Alexander S. 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