Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

被引:343
作者
Nakahira, Kiichi [1 ,2 ]
Kyung, Sun-Young [1 ,3 ]
Rogers, Angela J. [1 ,4 ,5 ]
Gazourian, Lee [1 ]
Youn, Sojung [1 ]
Massaro, Anthony F. [1 ]
Quintana, Carolina [1 ]
Osorio, Juan C. [1 ]
Wang, Zhaoxi [6 ]
Zhao, Yang [6 ]
Lawler, Laurie A. [1 ]
Christie, Jason D. [7 ]
Meyer, Nuala J. [7 ]
Mc Causland, Finnian R. [8 ]
Waikar, Sushrut S. [8 ]
Waxman, Aaron B. [1 ]
Chung, Raymond T. [9 ]
Bueno, Raphael [10 ]
Rosas, Ivan O. [1 ]
Fredenburgh, Laura E. [1 ]
Baron, Rebecca M. [1 ]
Christiani, David C. [6 ,11 ]
Hunninghake, Gary M. [1 ]
Choi, Augustine M. K. [1 ,2 ,12 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med,Dept Med, Boston, MA 02115 USA
[2] Weill Cornell Med Coll, Dept Med, New York, NY USA
[3] Gachon Univ, Gil Hosp, Dept Internal Med, Inchon, South Korea
[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA
[5] Stanford Univ, Dept Med, Div Pulm & Crit Care Med, Stanford, CA 94305 USA
[6] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA
[7] Univ Penn, Dept Med, Div Pulm Allergy & Crit Care Med, Philadelphia, PA 19104 USA
[8] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA
[9] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02115 USA
[10] Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02115 USA
[11] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA 02115 USA
[12] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea
关键词
INFLAMMATORY RESPONSE SYNDROME; C-REACTIVE PROTEIN; SEVERE SEPSIS; PLASMA NUCLEAR; RISK; OUTCOMES; DISEASE; DAMAGE; PROCALCITONIN; DEFINITIONS;
D O I
10.1371/journal.pmed.1001577
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (>= 3,200 copies/mu l plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p= 1 x 10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p= 9 x 10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1 x 10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
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页码:1 / 12
页数:12
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