| 1. |
- Myhre, Peder L, et al.
(author)
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Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome : Comparison with an Established Secretoneurin Radioimmunoassay
- 2021
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In: Cardiology. - : S. Karger. - 0008-6312 .- 1421-9751. ; 146:5, s. 566-574
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Journal article (peer-reviewed)abstract
- Background: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS).Methods: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years.Results: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10–250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61–0.71) for ELISA and 0.59 (0.54–0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65–0.79) for ELISA versus 0.64 (0.56–0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03–2.84), p = 0.038.Conclusions: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients.
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| 2. |
- Brynildsen, Jon, et al.
(author)
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Circulating Secretoneurin Concentrations After Cardiac Surgery : Data From the FINNish Acute Kidney Injury Heart Study
- 2019
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In: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 47:5, s. E412-E419
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Journal article (peer-reviewed)abstract
- Objectives:Secretoneurin is associated with cardiomyocyte Ca2+ handling and improves risk prediction in patients with acute myocardial dysfunction. Whether secretoneurin improves risk assessment on top of established cardiac biomarkers and European System for Cardiac Operative Risk Evaluation II in patients undergoing cardiac surgery is not known.Design:Prospective, observational, single-center sub-study of a multicenter study.Setting:Prospective observational study of survival in patients undergoing cardiac surgery.Patients:A total of 619 patients undergoing cardiac surgery.Interventions:Patients underwent either isolated coronary artery bypass graft surgery, single noncoronary artery bypass graft surgery, two procedures, or three or more procedures. Procedures other than coronary artery bypass graft were valve surgery, surgery on thoracic aorta, and other cardiac surgery.Measurements and Main Results:We measured preoperative and postoperative secretoneurin concentrations and adjusted for European System for Cardiac Operative Risk Evaluation II, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T concentrations in multivariate analyses. During 961 days of follow- up, 59 patients died (9.5%). Secretoneurin concentrations were higher among nonsurvivors compared with survivors, both before (168 pmol/L [quartile 1-3, 147-206 pmol/L] vs 160 pmol/L [131-193 pmol/L]; p = 0.039) and after cardiac surgery (173 pmol/L [129-217 pmol/L] vs 143 pmol/L [111-173 pmol/L]; p < 0.001). Secretoneurin concentrations decreased from preoperative to postoperative measurements in survivors, whereas we observed no significant decrease in secretoneurin concentrations among nonsurvivors. Secretoneurin concentrations were weakly correlated with established risk indices. Patients with the highest postoperative secretoneurin concentrations had worse outcome compared with patients with lower secretoneurin concentrations (p < 0.001 by the log-rank test) and postoperative secretoneurin concentrations were associated with time to death in multivariate Cox regression analysis: hazard ratio ln secretoneurin 2.96 (95% CI, 1.46-5.99; p = 0.003). Adding postoperative secretoneurin concentrations to European System for Cardiac Operative Risk Evaluation II improved patient risk stratification, as assessed by the integrated discrimination index: 0.023 (95% CI, 0.0043-0.041; p = 0.016).Conclusions:Circulating postoperative secretoneurin concentrations provide incremental prognostic information to established risk indices in patients undergoing cardiac surgery.
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| 3. |
- Myhre, Peder L., et al.
(author)
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Prognostic Value of Secretoneurin in Patients with Acute Respiratory Failure : Data from the FINNALI Study
- 2016
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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:10, s. 1380-1389
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Journal article (peer-reviewed)abstract
- BACKGROUND: We examined whether secretoneurin (SN), a biomarker associated with cardiomyocyte Ca2+ handling, provides prognostic information in patients with acute respiratory failure (ARF).METHODS: We included 490 patients with ARF, defined as ventilatory support >6 h, with blood samples available on admission to the intensive care unit (ICU). SN concentrations were measured by RIA.RESULTS: A total of 209 patients (43%) were hospitalized with cardiovascular (CV)-related ARF, and 90-day mortality rates were comparable between CV- and non CV-related ARF (n = 281): 31% vs 24%, P = 0.11. Admission SN concentrations were higher in nonsurvivors than in survivors in both CV -related (median 148 [quartile 1-3, 117-203] vs 108 [87-143] pmol/L, P < 0.001) and non CV-related ARF (139 [115-184] vs 113 [91-139] pmol/L, P < 0.001). In patients with CV -related ARF, SN concentrations on ICU admission were associated with 90-day mortality [odds ratio (OR) 1.97 (95% CI, 1.04-3.73, P = 0.04)] after adjusting for established risk indices, including N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations. SN also improved patient classification in CV -related ARF as assessed by the net reclassification index: 0.32 (95% CI, 0.04-0.59), P = 0.03. The area under the curve (AUC) of SN to predict mortality in patients with CV -related ARF was 0.72 (95% CI, 0.65-0.79), and the AUC of NT-proBNP was 0.64 (0.56-0.73). In contrast, SN concentrations on ICU admission did not provide incremental prognostic value to established risk indices in patients with non CV-related ARF, and the AUC was 0.67 (0.60-0.75).CONCLUSIONS: SN concentrations measured on ICU admission provided incremental prognostic information to established risk indices in patients with CV -related ARF, but not in patients with non CV-related ARF.
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| 5. |
- Ottesen, Anett H., et al.
(author)
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Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia
- 2019
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In: Circulation. - : Lippincott Williams & Wilkins. - 1941-3149 .- 1941-3084. ; 12:4
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Journal article (peer-reviewed)abstract
- BACKGROUND: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKII delta (Ca2+/calmodulin-dependent protein kinase II delta) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. METHODS: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia-induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9-induced overexpression. Interactions between SN and CaMKII delta were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patchclamp recordings in isolated cardiomyocytes. RESULTS: SN levels were elevated in patients with CPVT and following ventricular arrhythmia-induced cardiac arrest. In contrast to NT-proBNP (N-terminal proB- type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9-induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKII delta. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKII delta in Langendorff hearts and inhibited CaMKII delta-dependent RyR phosphorylation. In line with CaMKII delta and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. CONCLUSIONS: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.
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| 6. |
- Røsjø, Helge, et al.
(author)
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Prognostic Value of Secretoneurin in Critically III Patients With Infections
- 2016
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In: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 44:10, s. 1882-1890
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Journal article (peer-reviewed)abstract
- Objectives : 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 approximate to 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.
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