title: Glycosylated Chromogranin A in Heart Failure: Implications for Processing and Cardiomyocyte Calcium Homeostasis.
abstract: BACKGROUND
  Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function.
  
  
  RESULTS
  CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca2+spark and wave frequency, reduced Ca2+spark dimensions, increased sarcoplasmic reticulum Ca2+content, and augmented the magnitude and kinetics of cardiomyocyte Ca2+transients and contractions.
  
  
  CONCLUSIONS
  CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca2+handling because of reduced CaMKIIδ inhibition.
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Anett Hellebø
authors.initials: AH
authors.lastname: Ottesen
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Mai Britt
authors.initials: MB
authors.lastname: Dahl
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Sandbu
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Rune Forstrøm
authors.initials: RF
authors.lastname: Johansen
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Hilde
authors.initials: H
authors.lastname: Jarstadmarken
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Arne Didrik
authors.initials: AD
authors.lastname: Høiseth
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Jon
authors.initials: J
authors.lastname: Brynildsen
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Omland
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.). helge.rosjo@medisin.uio.no.
authors.forename: Helge
authors.initials: H
authors.lastname: Røsjø
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation; D006333:Heart Failure / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053379:Chromogranin A; D010446:Peptide Fragments; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban; C506150:CHGA protein, human; C109084:chromogranin A (344-364); C506155:chromogranin A, mouse; C000592748:ryanodine receptor 2. mouse; C517660:CAMK2D protein, human; C517673:Camk2d protein, mouse
keywords: Ca2+/calmodulin–dependent protein kinase II; biomarker; catestatin; chromogranin A