{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T09:06:18Z","timestamp":1793437578663,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,2,28]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased CaMKII (Ca\/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              We hypothesized that CaMKII-dependent dysregulation of Na current (I\n              <jats:sub>Na<\/jats:sub>\n              ) may contribute to atrial proarrhythmic activity in patients with SDB.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index \u226515\/h) was assessed with a portable SDB monitor the night before surgery. Compared with 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I\n              <jats:sub>Na<\/jats:sub>\n              . There was a significantly enhanced late I\n              <jats:sub>Na<\/jats:sub>\n              , but reduced peak I\n              <jats:sub>Na<\/jats:sub>\n              due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na\n              <jats:sub>V<\/jats:sub>\n              1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP [autocamtide-2 related inhibitory peptide]). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions in atrial trabeculae of patients with SDB, which could be blocked by either AIP or KN93 (N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide). In multivariable linear regression models incorporating age, sex, body mass index, existing atrial fibrillation, existing heart failure, diabetes mellitus, and creatinine levels, apnea-hypopnea index was independently associated with increased CaMKII activity, enhanced late I\n              <jats:sub>Na<\/jats:sub>\n              and correlated with premature atrial contraction severity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              In atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of Na\n              <jats:sub>V<\/jats:sub>\n              1.5 results in dysregulation of I\n              <jats:sub>Na<\/jats:sub>\n              with proarrhythmic activity that was independent from preexisting comorbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">http:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique identifier: NCT02877745.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Visual Overview:<\/jats:title>\n            <jats:p>An online visual overview is available for this article.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.315755","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T10:00:19Z","timestamp":1578304819000},"page":"603-615","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":65,"title":["Enhanced CaMKII-Dependent Late I\n            <sub>Na<\/sub>\n            Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing"],"prefix":"10.1161","volume":"126","clinical-trial-number":[{"clinical-trial-number":"nct02877745","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Simon","family":"Lebek","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. Tafelmeier, J.M., L.S.M., M.A., S.W.), University Hospital Regensburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Pichler","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. Tafelmeier, J.M., L.S.M., M.A., S.W.), University Hospital Regensburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Reuthner","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. Tafelmeier, J.M., L.S.M., M.A., S.W.), University Hospital Regensburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximillian","family":"Trum","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. Tafelmeier, J.M., L.S.M., M.A., S.W.), University Hospital Regensburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tafelmeier","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. Tafelmeier, J.M., L.S.M., M.A., S.W.), University Hospital Regensburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Mustroph","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine II (S.L., K.P., K.R., M. Trum, M. 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