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. 2019 Oct 1;8(10):1568.
doi: 10.3390/jcm8101568.

Increased Citrullinated Histone H3 Levels in the Early Post-Resuscitative Period Are Associated with Poor Neurologic Function in Cardiac Arrest Survivors-A Prospective Observational Study

Lisa-Marie Mauracher  1 , Nina Buchtele  2   3 , Christian Schörgenhofer  4 , Christoph Weiser  5 , Harald Herkner  6 , Anne Merrelaar  7 , Alexander O Spiel  8 , Lena Hell  9 , Cihan Ay  10   11 , Ingrid Pabinger  12 , Bernd Jilma  13 , Michael Schwameis  14
Affiliations

Increased Citrullinated Histone H3 Levels in the Early Post-Resuscitative Period Are Associated with Poor Neurologic Function in Cardiac Arrest Survivors-A Prospective Observational Study

Lisa-Marie Mauracher et al. J Clin Med. .

Abstract

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1-2) or poor (CPC 3-5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2-2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0-2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1-2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1-2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1-2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1-56, p = 0.039) and fifth (9.0, 95% CI: 1.3-63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future.

Keywords: cardiac arrest; citrullinated histone H3; neurologic function; neutrophil extracellular traps.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Plasma levels of neutrophil extracellular trap (NET) components (y-axis) on admission (0 h) and at 12 h (x-axis) in patients with good (left) and poor (right) 30 day neurologic function. Median levels of cfDNA and nucleosomes decreased in both groups from 0 to 12 h, while median H3Cit levels increased only in patients with poor 30 day neurologic function. Grey lines indicate individual data points, black lines represent median levels of NET-related biomarkers. * indicates significant difference. Individual and median d-dimer levels at 0 h and 12 h in the poor outcome group are available in the Supplementary Materials (Figure S2).
Figure 2
Figure 2
The crude odds of poor 30 day neurologic function (x-axis; crude odds ratio, log scale) according to plasma level quintiles of NET components (y-axis) on admission (left) and at 12 h (right). Confidence bands represent 95% confidence intervals. MoM, multiple-of-the-mean.
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