Anett Hellebø Ottesen1, William E Louch2, Cathrine R Carlson2, Ole J B Landsverk3, Jouni Kurola4, Rune Forstrøm Johansen5, Morten K Moe6, Jan Magnus Aronsen2, Arne Didrik Høiseth7, Hilde Jarstadmarken2, Ståle Nygård2, Magnar Bjørås5, Ivar Sjaastad2, Ville Pettilä8, Mats Stridsberg9, Torbjørn Omland7, Geir Christensen2, Helge Røsjø10. 1. 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. 2. 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. 3. Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, Oslo, Norway. 4. Division of Intensive Care Medicine, Kuopio University Hospital, Kuopio, Finland. 5. Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 6. Division for Diagnostics and Technology, Akershus University Hospital, Lørenskog, Norway. 7. 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. 8. Department of Surgery, Intensive Care Units, Helsinki University Hospital, Helsinki, Finland. 9. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 10. 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.
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. OBJECTIVES: 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.
BACKGROUND:Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown. OBJECTIVES: 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: Cathrine R Carlson; Jan Magnus Aronsen; Anna Bergan-Dahl; Marie Christine Moutty; Marianne Lunde; Per Kristian Lunde; Hilde Jarstadmarken; Pimthanya Wanichawan; Laetitia Pereira; Terje R S Kolstad; Bjørn Dalhus; Hariharan Subramanian; Susanne Hille; Geir Christensen; Oliver J Müller; Viacheslav Nikolaev; Donald M Bers; Ivar Sjaastad; Xin Shen; William E Louch; Enno Klussmann; Ole M Sejersted Journal: Circ Res Date: 2021-11-24 Impact factor: 23.213
Authors: Jacob A Winther; Jon Brynildsen; Arne Didrik Høiseth; Heidi Strand; Ivar Følling; Geir Christensen; Ståle Nygård; Helge Røsjø; Torbjørn Omland Journal: Respir Res Date: 2017-11-03