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J Am Coll Cardiol. 2015 Feb 3;65(4):339-351. doi: 10.1016/j.jacc.2014.10.065.

Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling.

Author information

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.

KEYWORDS:

Ca(2+)/calmodulin (CaM)-dependent protein kinase II; biomarker; calcium cycling/excitation-contraction coupling; ventricular arrhythmias

Comment in

PMID:
25634832
DOI:
10.1016/j.jacc.2014.10.065
[Indexed for MEDLINE]
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