{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:20:58Z","timestamp":1785853258866,"version":"3.56.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKII\u03b4 (Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin-dependent protein kinase II\u03b4) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia\u2013induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9\u2013induced overexpression. Interactions between SN and CaMKII\u03b4 were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              SN levels were elevated in patients with CPVT and following ventricular arrhythmia\u2013induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9\u2013induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKII\u03b4. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKII\u03b4 in Langendorff hearts and inhibited CaMKII\u03b4-dependent RyR phosphorylation. In line with CaMKII\u03b4 and RyR inhibition, SN treatment decreased Ca\n              <jats:sup>2+<\/jats:sup>\n              spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca\n              <jats:sup>2+<\/jats:sup>\n              waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca\n              <jats:sup>2+<\/jats:sup>\n              current.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              SN production is upregulated in conditions with cardiomyocyte Ca\n              <jats:sup>2+<\/jats:sup>\n              dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.118.007045","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T09:01:46Z","timestamp":1554368506000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Secretoneurin Is an Endogenous Calcium\/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca\n            <sup>2+<\/sup>\n            -Dependent Arrhythmia"],"prefix":"10.1161","volume":"12","author":[{"given":"Anett H.","family":"Ottesen","sequence":"first","affiliation":[{"name":"Division of Medicine, Akershus University Hospital, L\u00f8renskog, Norway (A.H.O., P.L.M., J.E.H., T.O., H.R.)."},{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine R.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav S\u00f8vik","family":"Eken","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mani","family":"Sadredini","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peder L.","family":"Myhre","sequence":"additional","affiliation":[{"name":"Division of Medicine, Akershus University Hospital, L\u00f8renskog, Norway (A.H.O., P.L.M., J.E.H., T.O., H.R.)."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn","family":"Dalhus","sequence":"additional","affiliation":[{"name":"Department for Microbiology, Clinic for Laboratory Medicine (B.D.), Oslo University Hospital, Norway."},{"name":"Department for Medical Biochemistry, Institute for Clinical Medicine (B.D.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek R.","family":"Laver","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (D.R.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per Kristian","family":"Lunde","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouni","family":"Kurola","sequence":"additional","affiliation":[{"name":"Division of Intensive Care Medicine, Kuopio University Hospital, Finland (J.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Lunde","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon Erik","family":"Hoff","sequence":"additional","affiliation":[{"name":"Division of Medicine, Akershus University Hospital, L\u00f8renskog, Norway (A.H.O., P.L.M., J.E.H., T.O., H.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Godang","sequence":"additional","affiliation":[{"name":"Section of Specialized Endocrinology, Department of Endocrinology (K.G.), Oslo University Hospital, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivar","family":"Sjaastad","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."},{"name":"K.G. Jebsen Center for Cardiac Research (I.S., G.C., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ville","family":"Pettil\u00e4","sequence":"additional","affiliation":[{"name":"Division of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki &amp; Helsinki University Hospital, Finland (V.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Stridsberg","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, Sweden (M. Stridsberg)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan E.","family":"Lehnart","sequence":"additional","affiliation":[{"name":"Heart Research Center Goettingen, University Medicine Center Goettingen, Germany (S.E.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."},{"name":"Simula Research Laboratory, Fornebu, Norway (A.G.E)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida G.","family":"Lunde","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torbj\u00f8rn","family":"Omland","sequence":"additional","affiliation":[{"name":"Division of Medicine, Akershus University Hospital, L\u00f8renskog, Norway (A.H.O., P.L.M., J.E.H., T.O., H.R.)."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathis K.","family":"Stokke","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir","family":"Christensen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."},{"name":"K.G. Jebsen Center for Cardiac Research (I.S., G.C., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helge","family":"R\u00f8sj\u00f8","sequence":"additional","affiliation":[{"name":"Division of Medicine, Akershus University Hospital, L\u00f8renskog, Norway (A.H.O., P.L.M., J.E.H., T.O., H.R.)."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Louch","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research (A.H.O., C.R.C., O.S.E., M. Sadredini, X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., M.K.S., G.C., W.E.L.), Oslo University Hospital, Norway."},{"name":"Center for Heart Failure Research (A.H.O., C.R.C., O.S.E., M. Sadredini, P.L.M., X.S., P.K.L., M.L., I.S., A.G.E., I.G.L., T.O., M.K.S., G.C., H.R., W.E.L.), University of Oslo, Norway."},{"name":"K.G. Jebsen Center for Cardiac Research (I.S., G.C., W.E.L.), University of Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00110"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.243956"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00021"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.10.006"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.108.815654"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.6.H2168"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.10.065"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037401"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000001832"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2016.258764"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003050"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003670"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2009.197"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35346"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw095"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1236921"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.602581"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-013-3043-4"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-014-3423-4"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.369"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.10.001"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7440com"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1996.66031312.x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.85.1.6314"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00144"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.37.26199"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.118.007045","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:03:28Z","timestamp":1715558608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.118.007045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4]]},"references-count":26,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1161\/CIRCEP.118.007045"],"URL":"https:\/\/doi.org\/10.1161\/circep.118.007045","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4]]},"assertion":[{"value":"2017-11-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e007045"}}