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These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na<jats:sup>+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub>), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with <jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub> inhibition. Inducing LQT by elevating <jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub> (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na<jats:sup>+<\/jats:sup>\u2013Ca<jats:sup>2+<\/jats:sup>\u2013CaMKII\u2013ROS\u2013<jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub> arrhythmogenic vicious cycle may exhibit important <jats:italic>on<\/jats:italic>-target and also <jats:italic>trans<\/jats:italic>-target effects (e.g., <jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub> and RyR inhibition can alter <jats:italic>I<\/jats:italic><jats:sub>NaL<\/jats:sub>-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.<\/jats:p>","DOI":"10.1007\/s00395-021-00900-9","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T15:03:20Z","timestamp":1634223800000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors"],"prefix":"10.1007","volume":"116","author":[{"given":"Bence","family":"Hegyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risto-Pekka","family":"P\u00f6l\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim T.","family":"Hellgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher Y.","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Ginsburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mercola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":false,"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"900_CR1","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1161\/01.RES.0000194329.41863.89","volume":"97","author":"X Ai","year":"2005","unstructured":"Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM (2005) Ca2+\/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. 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