title: Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients.
abstract: OBJECTIVE
  Despite underlying pathologies leading to ICU admittance are heterogeneous, many patients develop a systemic inflammatory response syndrome often in the absence of microbial pathogens. Mitochondrial DNA that shows similarities to bacterial DNA may be released after tissue damage and activates the innate immune system by binding to toll-like receptor-9 on immune cells. The aim of this study was to analyze whether levels of mitochondrial DNA are associated with 30-day survival and whether this predictive value is modified by the expression of its receptor toll-like receptor-9.
  
  
  METHODS
  Single-center, prospective, observational study.
  
  
  METHODS
  A tertiary ICU in a university hospital.
  
  
  METHODS
  Two hundred twenty-eight consecutive patients admitted to a medical ICU between August 2012 and August 2013.
  
  
  METHODS
  None.
  
  
  RESULTS
  Blood was taken within 24 hours after ICU admission, and the levels of circulating mitochondrial DNA were quantified by real-time polymerase chain reaction. Toll-like receptor-9 expression in monocytes was measured by flow cytometry. Median acute physiology and chronic health evaluation II score was 20, and 30-day mortality was 25%. Median mitochondrial DNA levels at admission were significantly higher in nonsurvivors when compared with survivors (26.9, interquartile range = 11.2-60.6 ng/mL vs 19.7, interquartile range = 9.5-34.8 ng/mL; p < 0.05). Patients with plasma levels of mitochondrial DNA in the highest quartile (mitochondrial DNA > 38.2 ng/mL) had a 2.6-fold higher risk (p < 0.001) of dying, independently of age, gender, diagnosis, and acute physiology and chronic health evaluation II score. Mitochondrial DNA improved the c-statistic of acute physiology and chronic health evaluation II score (p < 0.05) and showed enhancement in individual risk prediction indicated by a net reclassification improvement of 32.3% (p < 0.05). Stratification of patients according to toll-like receptor-9 expression above/below median demonstrated that only patients with high expression of toll-like receptor-9 showed an increased risk associated with increased mitochondrial DNA levels (odds ratio, 2.7; p < 0.01), whereas circulating mitochondrial DNA was not associated with mortality in patients with low toll-like receptor-9 expression (odds ratio, 1.1; p = 0.98).
  
  
  CONCLUSIONS
  Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.
authors.affiliation: 1Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. 2Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria. 33rd Medical Department, Wilhelminen Hospital, Vienna, Austria. 4Core Facilities, Medical University of Vienna, Vienna, Austria.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Krychtiuk
authors.forename: Sarah
authors.initials: S
authors.lastname: Ruhittel
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Hohensinner
authors.forename: Lorenz
authors.initials: L
authors.lastname: Koller
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaun
authors.forename: Max
authors.initials: M
authors.lastname: Lenz
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bauer
authors.forename: Lisa
authors.initials: L
authors.lastname: Wutzlhofer
authors.forename: Dominik F
authors.initials: DF
authors.lastname: Draxler
authors.forename: Gerald
authors.initials: G
authors.lastname: Maurer
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
authors.forename: Gottfried
authors.initials: G
authors.lastname: Heinz
authors.forename: Alexander
authors.initials: A
authors.lastname: Niessner
authors.forename: Walter S
authors.initials: WS
authors.lastname: Speidl
mesh_terms: D018806:APACHE; D000367:Age Factors; D000368:Aged; D016638:Critical Illness / Q000401:mortality*; D004272:DNA, Mitochondrial / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry; D017052:Hospital Mortality; D006785:Hospitals, University; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index; D012737:Sex Factors; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis*
chemical_list: D004272:DNA, Mitochondrial; D051217:Toll-Like Receptor 9