Clinical paper| Volume 151, P26-32, June 2020

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Imbalance between plasma double-stranded DNA and deoxyribonuclease activity predicts mortality after out-of-hospital cardiac arrest



      Despite an increased rate of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) patients, almost half of patients do not survive up to hospital discharge. Understanding pathophysiological mechanisms of post-cardiac arrest syndrome is essential for developing novel therapeutic strategies. During systemic inflammatory responses and concomitant cell death, double-stranded (ds) DNA is released into circulation, exerting pro-inflammatory effects. Deoxyribonuclease (DNase) degrades dsDNA. The role of DNase activity in OHCA survivors and impact on clinical outcome has not been analyzed yet.


      In a prospective, single-center study, dsDNA and DNase activity were determined at hospital admission (acute phase) and 24 h (subacute phase) after ROSC. The ratio between dsDNA levels and DNase activity was calculated to determine the extent of dsDNA release in relation to the patients’ capacity of degradation. Thirty-day mortality was defined as study end point.


      We enrolled 64 OHCA survivors, of whom 26.6% (n = 17) died within 30 days. A peak of circulating dsDNA was observed at admission which decreased within 24 h. DNase activity did not differ between acute and subacute phase, while dsDNA load per DNase activity significantly decreased. The ratio between dsDNA levels and DNase activity in the subacute phase was the strongest predictor of 30-day mortality with an adjusted HR per 1 SD of 3.59 (95% CI, 1.80–7.18, p < 0.001).


      Disproportionally increased dsDNA levels uncompensated by DNase activity are a strong predictor of mortality in OHCA survivors. This pilot study points to a potentially protective effect of DNase activity in patients undergoing cardiac arrest.


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        • Roger V.L.
        • Go A.S.
        • Lloyd-Jones D.M.
        • et al.
        Heart disease and stroke statistics – 2012 update: a report from the American Heart Association.
        Circulation. 2012; 125: e2-e220
        • Nolan J.P.
        • Neumar R.W.
        • Adrie C.
        • et al.
        Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication: a scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
        Resuscitation. 2008; 79: 350-379
        • Adrie C.
        • Adib-Conquy M.
        • Laurent I.
        • et al.
        Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome.
        Circulation. 2002; 106: 562-568
        • Sekhon M.S.
        • Ainslie P.N.
        • Griesdale D.E.
        Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model.
        Crit Care. 2017; 21: 90
        • Gornik I.
        • Wagner J.
        • Gasparovic V.
        • et al.
        Prognostic value of cell-free DNA in plasma of out-of-hospital cardiac arrest survivors at ICU admission and 24 h post-admission.
        Resuscitation. 2014; 85: 233-237
        • Patel S.J.
        • Jindal R.
        • King K.R.
        • Tilles A.W.
        • Yarmush M.L.
        The inflammatory response to double stranded DNA in endothelial cells is mediated by NFkappaB and TNFalpha.
        PloS One. 2011; 6: e19910
        • Weber C.
        • Jenke A.
        • Chobanova V.
        • et al.
        Targeting of cell-free DNA by DNase I diminishes endothelial dysfunction and inflammation in a rat model of cardiopulmonary bypass.
        Sci Rep. 2019; 9: 19249
        • Gando S.
        • Nanzaki S.
        • Morimoto Y.
        • Kobayashi S.
        • Kemmotsu O.
        Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury.
        Intensive Care Med. 2000; 26: 38-44
        • Luo L.
        • Zhang S.
        • Wang Y.
        • et al.
        Proinflammatory role of neutrophil extracellular traps in abdominal sepsis.
        Am J Physiol Lung Cell Mol Physiol. 2014; 307: L586-L596
        • Fuchs T.A.
        • Brill A.
        • Duerschmied D.
        • et al.
        Extracellular DNA traps promote thrombosis.
        Proc Natl Acad Sci U S A. 2010; 107: 15880-15885
        • Mangold A.
        • Alias S.
        • Scherz T.
        • et al.
        Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size.
        Circ Res. 2015; 116: 1182-1192
        • Laridan E.
        • Denorme F.
        • Desender L.
        • et al.
        Neutrophil extracellular traps in ischemic stroke thrombi.
        Ann Neurol. 2017; 82: 223-232
        • Kawane K.
        • Motani K.
        • Nagata S.
        DNA degradation and its defects.
        Cold Spring Harbor Perspect Biol. 2014; 6
        • Distelmaier K.
        • Muqaku B.
        • Wurm R.
        • et al.
        A Proteomics-enriched prediction model for poor neurological outcome in cardiac arrest survivors.
        Crit Care Med. 2020; 48: 167-175
        • Teasdale G.
        • Jennett B.
        Assessment of coma and impaired consciousness. A practical scale.
        Lancet (London, England). 1974; 2: 81-84
        • Callaway C.W.
        • Donnino M.W.
        • Fink E.L.
        • et al.
        Part 8: post-cardiac arrest care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
        Circulation. 2015; 132: S465-S482
        • Jacobs I.
        • Nadkarni V.
        • Bahr J.
        • et al.
        Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa).
        Circulation. 2004; 110: 3385-3397
        • Jennett B.
        • Bond M.
        Assessment of outcome after severe brain damage.
        Lancet (London, England). 1975; 1: 480-484
        • Zellner T.
        • Gartner R.
        • Schopohl J.
        • Angstwurm M.
        NSE and S-100B are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest.
        Resuscitation. 2013; 84: 1382-1386
        • Jimenez-Alcazar M.
        • Limacher A.
        • Panda R.
        • et al.
        Circulating extracellular DNA is an independent predictor of mortality in elderly patients with venous thromboembolism.
        PloS One. 2018; 13: e0191150
        • Hofbauer T.M.
        • Mangold A.
        • Scherz T.
        • et al.
        Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction.
        Basic Res Cardiol. 2019; 114: 33
        • Jimenez-Alcazar M.
        • Rangaswamy C.
        • Panda R.
        • et al.
        Host DNases prevent vascular occlusion by neutrophil extracellular traps.
        Science (New York, NY). 2017; 358: 1202-1206
        • Aschauer S.
        • Dorffner G.
        • Sterz F.
        • Erdogmus A.
        • Laggner A.
        A prediction tool for initial out-of-hospital cardiac arrest survivors.
        Resuscitation. 2014; 85: 1225-1231
        • Tong Y.K.
        • Lo Y.M.
        Diagnostic developments involving cell-free (circulating) nucleic acids.
        Clin Chim Acta. 2006; 363: 187-196
        • Arnalich F.
        • Menendez M.
        • Lagos V.
        • et al.
        Prognostic value of cell-free plasma DNA in patients with cardiac arrest outside the hospital: an observational cohort study.
        Crit Care. 2010; 14: R47
        • Huang C.H.
        • Tsai M.S.
        • Hsu C.Y.
        • et al.
        Circulating cell-free DNA levels correlate with postresuscitation survival rates in out-of-hospital cardiac arrest patients.
        Resuscitation. 2012; 83: 213-218
        • Mauracher L.M.
        • Buchtele N.
        • Schorgenhofer C.
        • et al.
        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.
        J Clin Med. 2019; 8
        • Gaitzsch E.
        • Czermak T.
        • Ribeiro A.
        • et al.
        Double-stranded DNA induces a prothrombotic phenotype in the vascular endothelium.
        Sci Rep. 2017; 7: 1112
        • Napirei M.
        • Ricken A.
        • Eulitz D.
        • Knoop H.
        • Mannherz H.G.
        Expression pattern of the deoxyribonuclease 1 gene: lessons from the Dnase1 knockout mouse.
        Biochem J. 2004; 380: 929-937
        • Fuchs T.A.
        • Brill A.
        • Wagner D.D.
        Neutrophil extracellular trap (NET) impact on deep vein thrombosis.
        Arterioscler Thromb Vasc Biol. 2012; 32: 1777-1783
        • Jimenez-Alcazar M.
        • Napirei M.
        • Panda R.
        • et al.
        Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies.
        J Thromb Haemost. 2015; 13: 732-742
        • Kumamoto T.
        • Kawai Y.
        • Arakawa K.
        • et al.
        Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients.
        Eur Heart J. 2006; 27: 2081-2087
        • Nadano D.
        • Yasuda T.
        • Kishi K.
        Measurement of deoxyribonuclease I activity in human tissues and body fluids by a single radial enzyme-diffusion method.
        Clin Chem. 1993; 39: 448-452
        • Saffarzadeh M.
        • Juenemann C.
        • Queisser M.A.
        • et al.
        Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones.
        PloS One. 2012; 7: e32366
        • Pena-Martinez C.
        • Duran-Laforet V.
        • Garcia-Culebras A.
        • et al.
        Pharmacological modulation of neutrophil extracellular traps reverses thrombotic stroke tPA (tissue-type plasminogen activator) resistance.
        Stroke. 2019;
        • Vogel B.
        • Shinagawa H.
        • Hofmann U.
        • Ertl G.
        • Frantz S.
        Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin.
        Basic Res Cardiol. 2015; 110: 15
        • Ge L.
        • Zhou X.
        • Ji W.J.
        • et al.
        Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy.
        Am J Physiol Heart Circ Physiol. 2015; 308: H500-H509
        • Boettcher M.
        • Meier D.
        • Jimenez-Alcazar M.
        • et al.
        Degradation of extracellular DNA by DNase1 significantly reduces testicular damage after testicular torsion in rats.
        Urology. 2017; 109: 223.e1-223.e7