Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia.

BACKGROUND: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) 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 CaMKIIδ 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 patch-clamp 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 pro-B-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 CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ 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.

Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death.

BACKGROUND: A systemic inflammatory response is observed after cardiopulmonary resuscitation. We investigated two novel inflammatory markers, pentraxin 3 (PTX3) and soluble suppression of tumorigenicity 2 (sST2), in comparison with the classic high-sensitivity C-reactive protein (hsCRP), for prediction of early multiple organ dysfunction syndrome (MODS), early death, and long-term outcome after out-of-hospital cardiac arrest. METHODS: PTX3, sST2, and hsCRP were assayed at ICU admission and 48 h later in 278 patients. MODS was defined as the 24 h non-neurological Sequential Organ Failure Assessment (SOFA) score ≥ 12. Intensive care unit (ICU) death and 12-month Cerebral Performance Category (CPC) were evaluated. RESULTS: In total, 82% of patients survived to ICU discharge and 48% had favorable neurological outcome at 1 year (CPC 1 or 2). At ICU admission, median plasma levels of hsCRP (2.8 mg/L) were normal, while levels of PTX3 (19.1 ng/mL) and sST2 (117 ng/mL) were markedly elevated. PTX3 and sST2 were higher in patients who developed MODS (p<0.0001). Admission levels of PTX3 and sST2 were also higher in patients who died in ICU and in those with an unfavorable 12-month neurological outcome (p<0.01). Admission levels of PTX3 and sST2 were independently associated with subsequent MODS [OR: 1.717 (1.221-2.414) and 1.340, (1.001-1.792), respectively] and with ICU death [OR: 1.536 (1.078-2.187) and 1.452 (1.064-1.981), respectively]. At 48 h, only sST2 and hsCRP were independently associated with ICU death. CONCLUSIONS: Higher plasma levels of PTX3 and sST2, but not of hsCRP, at ICU admission were associated with higher risk of MODS and early death.

Arterial blood gas tensions after resuscitation from out-of-hospital cardiac arrest: associations with long-term neurologic outcome.

OBJECTIVES: Optimal oxygen and carbon dioxide levels during postcardiac arrest care are currently undefined and observational studies have suggested harm from hyperoxia exposure. We aimed to assess whether mean and time-weighted oxygen and carbon dioxide levels during the first 24 hours of postcardiac arrest care correlate with 12-month neurologic outcome. DESIGN: Prospective observational cohort study. SETTING: Twenty-one ICUs in Finland. PATIENTS: Out-of-hospital cardiac arrest patients treated in ICUs in Finland between March 2010 and February 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood PaO2 and PaCO2 during the first 24 hours from admission were divided into predefined categories from the lowest to the highest. Proportions of time spent in different categories and the mean PaO2 and PaCO2 values during the first 24 hours were included in separate multivariable regression models along with resuscitation factors. The cerebral performance category at 12 months was used as primary endpoint. A total of 409 patients with arterial blood gases analyzed at least once and with a complete set of resuscitation data were included. The average amount of PaO2 and PaCO2 measurements was eight per patient. The mean 24 hours PaCO2 level was an independent predictor of good outcome (odds ratio, 1.054; 95% CI, 1.006-1.104; p = 0.027) but the mean PaO2 value was not (odds ratio, 1.006; 95% CI, 0.998-1.014; p = 0.149). With multivariate regression analysis, time spent in the PaCO2 band higher than 45 mm Hg was associated with good outcome (odds ratio, 1.015; 95% CI, 1.002-1.029; p = 0.024, for each percentage point increase in time) but time spent in different oxygen categories were not. CONCLUSIONS: In this multicenter study, hypercapnia was associated with good 12-month outcome in patients resuscitated from out-of-hospital cardiac arrest. We were unable to verify any harm from hyperoxia exposure. Further trials should focus on whether moderate hypercapnia during postcardiac arrest care improves outcome.

Comparison of spectral entropy and BIS VISTA™ monitor during general anesthesia for cardiac surgery.

OBJECTIVES: We compared the primary metrics of the Spectral entropy M-ENTROPY™ module and BIS VISTA™ monitor-i.e., bispectral index (BIS), state entropy (SE), and response entropy (RE) in terms of agreement and correlation during general anesthesia for cardiac surgery. We also evaluated responsiveness of electroencephalogram (EEG)-based and hemodynamic parameters to surgical noxious stimulation, skin incision, and sternotomy, hypothesizing that RE would be a better responsiveness predictor. METHODS: BIS and entropy sensors were applied before anesthesia induction in 32 patients having elective cardiac surgery. Total intravenous anesthesia was standardized and guided by the BIS index with neuromuscular blockade tested with train-of-four monitoring. Parameters included SE, RE, BIS, forehead electromyography (EMG), and hemodynamic variables. Time points for analyzing BIS, entropy, and hemodynamic values were 1 min before and after: anesthesia induction, intubation, skin incision, sternotomy, cannulation of the aorta, cardiopulmonary bypass (CPB), cross-clamping the aorta, de-clamping the aorta, and end of CPB; also after starting the re-warming phase and at 10, 20, 30, and 40 min following. RESULTS: The mean difference between BIS and SE (Bland-Altman) was 2.14 (+16/- 11; 95% CI 1.59-2.67), and between BIS and RE it was 0.02 (+14/- 14; 95% CI 0.01-0.06). BIS and SE (r(2) = 0.66; P = 0.001) and BIS and RE (r(2) = 0.7; P = 0.001) were closely correlated (Pearson's). EEG parameters, EMG values, and systolic blood pressure significantly increased after skin incision, and sternotomy. The effect of surgical stimulation (Cohen's d) was highest for RE after skin incision (-0.71; P = 0.0001) and sternotomy (-0.94; P = 0.0001). CONCLUSION: Agreement was poor between the BIS index measured by BIS VISTA™ and SE values at critical anesthesia time points in patients undergoing cardiac surgery. RE was a good predictor of arousal after surgical stimulation regardless of the surgical level of muscle relaxation. Index differences most likely resulted from different algorithms for calculating consciousness level.

Is external jugular vein cannulation feasible in emergency care? A randomised study in open heart surgery patients.

UNLABELLED: The optimal intravenous catheterisation site for emergencies is unknown. The external jugular vein might be preferable route compared to cubital veins in emergencies due to more rapid circulation time to heart and faster cardiac responses. However, the feasibility of the different venous catheterisation sites has not been compared in relation to catheterisation time and success rate. METHODS: We examined the time differences and success rates of external jugular compared to antecubital vein catheterisations. 32 paramedics and 28 emergency department residents performed external jugular and antecubital venous catheterisations on anesthetized patients scheduled for elective cardiac surgery. The primary outcome was catheterisation time and the secondary outcomes the failure rate and catheterisation times needed to succeed. RESULTS: Antecubital venous catheterisation was faster (113+/-89s) compared to external jugular vein catheterisation (156+/-112s), p=0.008 and the success rate was higher (93% compared to 68%, respectively, p=0.001). Less attempts were needed for antecubital vein catheterisations compared to external jugular vein catheterisations (p=0.002). For the antecubital vein, subjects needed two attempts in 6 patients and three attempts in 6 patients. For the external jugular vein, subjects needed two attempts in 13 patients and three attempts in 20 patients. Two (6%) paramedics and two (7%) residents failed to catheterise the antecubital vein. Nine (28%) paramedics and 10 (36%) residents failed to catheterise the external jugular vein. CONCLUSIONS: Antecubital vein catheterisation was faster and had a superior success rate compared to external jugular vein catheterisation.