Secretoneurin Is a Novel Prognostic Cardiovascular Biomarker Associated With Cardiomyocyte Calcium Handling

Ottesen, Anett Hellebø; Louch, William E.; Carlson, Cathrine R.; Landsverk, Ole J. B.; Kurola, Jouni; Johansen, Rune; Moe, Morten K.; Aronsen, Jan Magnus; Høiseth, Arne; Jarstadmarken, Hilde; Nygård, Ståle; Bjørås, Magnar; Sjaastad, Ivar; Pettilä, Ville; Stridsberg, Mats; Omland, Torbjørn; Christensen, Geir; Røsjø, Helge

doi:10.1016/j.jacc.2014.10.065

Cited by 49 publications

(71 citation statements)

References 26 publications

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“…1) (13). Four hundred seventy patients were included, and blood samples were available from 232 patients at ICU admission (median, 9 [Q1-Q3, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] hr from study inclusion to sampling) and from 201 patients after 72 hours.…”

Section: Methodsmentioning

confidence: 99%

“…Other groups have also found secretoneurin to predict outcome after cardiac arrest (10). In contrast, admission secretoneurin levels were not associated with outcome in patients with acute exacerbations of chronic obstructive pulmonary disease (9), although these patients had comparable severity of dyspnea and mortality rates as the acute heart failure patients. Hence, secretoneurin seems to provide incremental prognostic information to established risk indices in patients with CVD, although not being an unspecific biomarker of disease severity per se.…”

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confidence: 91%

“…Circulating secretoneurin levels increase during profound systemic and myocardial stress (7,8), and secretoneurin levels are also increased by renal failure (9). The potential of secretoneurin to integrate information from the cardiovascular, renal, and neuroendocrine system may explain the potent prognostic information recently demonstrated for secretoneurin in patients with cardiovascular disease (CVD) (9). In patients with acute heart failure and after ventricular arrhythmia-induced cardiac arrest, secretoneurin provided additional prognostic information to clinical variables and norepinephrine, NT-proBNP, and hs-TnT levels.…”

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confidence: 99%

“…Hence, secretoneurin seems to provide incremental prognostic information to established risk indices in patients with CVD, although not being an unspecific biomarker of disease severity per se. This model is supported by the direct inhibitory effect by secretoneurin on diastolic Ca 2+ leak via Ca 2+ /calmodulin-dependent protein kinase II δ inhibition (9) and reduced cardiomyocyte apoptosis and myocardial ischemia/reperfusion injury by secretoneurin in experimental models (11,12). Accordingly, as cardiovascular, renal, and neuroendocrine system dysfunctions influence outcome in patients with severe infections (1), we hypothesized that secretoneurin would provide important prognostic information in critically ill patients with infections.…”

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confidence: 99%

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Prognostic Value of Secretoneurin in Critically Ill Patients With Infections

Røsjø

Stridsberg

Ottesen

et al. 2016

Critical Care Medicine

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1Objectives : Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. Design: Two prospective, observational studies. Setting: Twenty-four and twenty-five ICUs in Finland. Patients: A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). Interventions: None. Measurements and Main Results: We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro-B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro-B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was ≈ 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Conclusions: Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections. (Crit Care Med 2016; XX:00-00)

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Section: Methodsmentioning

confidence: 99%

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confidence: 91%

mentioning

confidence: 99%

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confidence: 99%

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Prognostic Value of Secretoneurin in Critically Ill Patients With Infections

Røsjø

Stridsberg

Ottesen

et al. 2016

Critical Care Medicine

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“…In addition, it is not established whether CgA fragments like CST may directly influence cardiomyocyte function. Although previous studies have reported that CST modulates cardiomyocyte Ca 2+ handling only via indirect mechanisms, 14 this finding is surprising given the direct effect of CST on Ca 2+ handling in noncardiac cells, 13 the influence by other chromogranin-secretogranin proteins on cardiomyocyte Ca 2+ handling, 15 and the ability of CST to directly interact with CaM. 13 CaM is an upstream activator of CaMKIIδ (Ca 2+ /CaM-dependent protein kinase IIδ), which is an established regulator of cardiomyocyte Ca 2+ handling.…”

Section: Ottesen Et Al Chromogranin a Processing And Calcium Regulationmentioning

confidence: 98%

Glycosylated Chromogranin A in Heart Failure

Ottesen

Carlson

Louch

et al. 2017

Circ: Heart Failure

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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. Methods and 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 (Ca 2+ /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 Ca 2+ spark and wave frequency, reduced Ca 2+ spark dimensions, increased sarcoplasmic reticulum Ca 2+ content, and augmented the magnitude and kinetics of cardiomyocyte Ca 2+ 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 Ca 2+ handling because of reduced CaMKIIδ inhibition.

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