title: Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling.
abstract: BACKGROUND
  Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown.
  
  
  OBJECTIVE
  This study sought to evaluate the merit of SN as a cardiovascular biomarker and assess effects of SN on cardiomyocyte Ca(2+) handling.
  
  
  METHODS
  We assessed the association between circulating SN levels and mortality in 2 patient cohorts and the functional properties of SN in experimental models.
  
  
  RESULTS
  In 143 patients hospitalized for acute HF, SN levels were closely associated with mortality (n = 66) during follow-up (median 776 days; hazard ratio [lnSN]: 4.63; 95% confidence interval: 1.93 to 11.11; p = 0.001 in multivariate analysis). SN reclassified patients to their correct risk strata on top of other predictors of mortality. In 155 patients with ventricular arrhythmia-induced cardiac arrest, SN levels were also associated with short-term mortality (n = 51; hazard ratio [lnSN]: 3.33; 95% confidence interval: 1.83 to 6.05; p < 0.001 in multivariate analysis). Perfusing hearts with SN yielded markedly increased myocardial levels and SN internalized into cardiomyocytes by endocytosis. Intracellularly, SN reduced Ca(2+)/calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ) activity via direct SN-CaM and SN-CaMKII binding and attenuated CaMKIIδ-dependent phosphorylation of the ryanodine receptor. SN also reduced sarcoplasmic reticulum Ca(2+) leak, augmented sarcoplasmic reticulum Ca(2+) content, increased the magnitude and kinetics of cardiomyocyte Ca(2+) transients and contractions, and attenuated Ca(2+) sparks and waves in HF cardiomyocytes.
  
  
  CONCLUSIONS
  SN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest.
authors: Division of Medicine, Akershus University Hospital, Lørenskog, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Anett Hellebø
authors: AH
authors: Ottesen
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: William E
authors: WE
authors: Louch
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Cathrine R
authors: CR
authors: Carlson
authors: Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
authors: Ole J B
authors: OJB
authors: Landsverk
authors: Division of Intensive Care Medicine, Kuopio University Hospital, Kuopio, Finland.
authors: Jouni
authors: J
authors: Kurola
authors: Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Rune Forstrøm
authors: RF
authors: Johansen
authors: Division for Diagnostics and Technology, Akershus University Hospital, Lørenskog, Norway.
authors: Morten K
authors: MK
authors: Moe
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Jan Magnus
authors: JM
authors: Aronsen
authors: Division of Medicine, Akershus University Hospital, Lørenskog, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Arne Didrik
authors: AD
authors: Høiseth
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Hilde
authors: H
authors: Jarstadmarken
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Ståle
authors: S
authors: Nygård
authors: Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Magnar
authors: M
authors: Bjørås
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Ivar
authors: I
authors: Sjaastad
authors: Department of Surgery, Intensive Care Units, Helsinki University Hospital, Helsinki, Finland.
authors: Ville
authors: V
authors: Pettilä
authors: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Mats
authors: M
authors: Stridsberg
authors: Division of Medicine, Akershus University Hospital, Lørenskog, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Torbjørn
authors: T
authors: Omland
authors: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors: Geir
authors: G
authors: Christensen
authors: Division of Medicine, Akershus University Hospital, Lørenskog, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway. Electronic address: helge.rosjo@medisin.uio.no.
authors: Helge
authors: H
authors: Røsjø
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006323:Heart Arrest / Q000097:blood* / Q000209:etiology; D006333:Heart Failure / Q000097:blood* / Q000401:mortality; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009479:Neuropeptides / Q000097:blood*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D053381:Secretogranin II / Q000097:blood*; D018754:Ventricular Dysfunction / Q000150:complications
chemical_list: D015415:Biomarkers; D009479:Neuropeptides; D053381:Secretogranin II; C081159:secretoneurin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Ca(2+)/calmodulin (CaM)-dependent protein kinase II; biomarker; calcium cycling/excitation-contraction coupling; ventricular arrhythmias